Islet Cell Cancer

Resiliency of Protein Dictates Human Health

Proteins are functional in their three-dimensional form; any type of modification in the conformation of the protein affects its functions. Thus, the role of the proteins in the body depicts the functional ability and ensures health of an organism. Besides its presence in the body, proteins are consumed by the body in the form of dietary uptake. The free amino group of the protein in the body when interacting with the carbonyl group of the reducing sugar follows the Maillard reaction to produce hazardous by-products which is an advanced glycation end products (AGEs). The process of AGEs formation routes towards the aggregation process. Different studies have shown different aggregation pathways, some restricting the partial unfolding of the protein and the other oligomerization leading to fibril formation depending upon the conditions of the study. It is noteworthy that in in-vivo cases, glycation and aggregation are the two sides of the same coin because it is obvious that we have seen the diseased condition due to AGEs formation that also shows aggregation or vice versa. Hence, the two causative agents depend upon each other.

Modulatory Mechanism of NLRP3 Inflammasome in Heart Diseases: “An Enigma Wrapped in a Riddle”

Despite breakthroughs in therapy over the prior two decades, heart failure is considered the foremost cause of mortality globally. The inflammasome plays a pivotal role in the advancement of heart failure, abdominal aortic aneurysm, atherosclerosis, diabetic cardiomyopathy, hypertension, dilated cardiomyopathy, cardiac remodeling and calcific aortic valve disease. The NLRP3 inflammasome is a crucial multi-protein signaling platform that tightly regulates inflammatory responses. It regulates antimicrobial host defense, which causes pyroptosis through caspase-1 activation by the eventual production of pro-inflammatory cytokines. The investigation of the NLRP3 inflammasome in various cardiovascular diseases may reveal critical disease triggers and endogenous modulators, leading to the development of new therapeutic interventions in the future. The target of this chapter is to summarise the recent literature describing the activation mechanism of the NLRP3 inflammasome by implicating different inflammatory pathways in the pathophysiology of heart failure.

Human Diseases and Recent Biotechnology Breakthroughs in Curbing Diseases

Medical biotechnology represents a field in continuous progress and today has revolutionized how illnesses are diagnosed and treated. A look at the latest medical biotechnological breakthroughs shows how biotechnology innovations are changing medicine. Recently, we saw how biotechnology affected efforts to combat the coronavirus disease 2019 (COVID-19) pandemic on the world's health. The scientific community has been working assiduously to develop effective treatments for the prevention and management of other diseases, such as cancer, human immunodeficiency virus (HIV), cardiovascular disease, diabetes mellitus, and neurodegenerative disorders such as Alzheimer's disease, along with other dementia variants that stand out among the leading causes of mortality worldwide. This effort has recently resulted in the development of RNA vaccines. Some of the most promising biotechnological developments include gene therapy to alter an individual's genetic makeup through diverse techniques, immunotherapeutic methods that bolster the body's natural immune defense mechanisms, and precision medicine strategies in which treatment is personalized to a patient's genetic profile. This chapter provides an overview of the most prevalent and deadly human diseases with a focus on recent biotechnological breakthroughs.

Autoimmune Diseases in Animals

Autoimmune diseases, known as immune-mediated diseases, occur when the immune system targets and attacks its own cells. In the field of medicine, there is a wide range of autoimmune conditions, including insulin-dependent Type 1 Diabetes Mellitus T1DM, Type 2 Diabetes Mellitus T2DM, Rheumatoid Arthritis RA, and Thyroiditis. These diseases can either be primary, with no clearly defined cause, or secondary, triggered by factors such as medications, infections, or malignancies. Animal models have proven invaluable for gaining insights into the underlying pathologies, causes, and specific signaling pathways associated with human autoimmune diseases. This is because these animal models share physiological similarities with humans and have shorter lifespans, allowing researchers to observe the entire disease progression. To replicate the complexity of autoimmune diseases in experimental models, researchers utilize various animal species, including monkeys, rabbits, rats, and mice. These methods can be broadly categorized into three strategies: immunization with autoantigens, transfer of autoimmunity, and induction through environmental factors. Numerous studies have been conducted using animal models to investigate the immunological pathophysiology of RA and assess the effectiveness of anti-rheumatic medications. There are several mouse models designed to mimic RAlike disease, each focusing on specific aspects of the condition. While animal models come with limitations, such as incomplete disease manifestations and limited genetic similarity to humans due to human genetic diversity, they remain an essential tool for understanding the pathogenesis of autoimmune diseases. Among the various animal models used in research, mice and other rodents like rats and hamsters account for over 90% of the total number of animals employed in these studies.

Nanoscience for Nucleotide Delivery in Diabetes

The convergence of nanoscience and nucleotide delivery holds tremendous promise in revolutionizing diabetes treatment. Nucleotide delivery emerged as a promising tool to modulate gene expression and cellular function in diabetes. Integration of nanoscience and nucleotide delivery in diabetes treatment opens avenues for efficient therapies. This approach has the potential to significantly improve glucose regulation and mitigate long-term complications associated with the disease. This chapter discussed DNA and RNA delivery approaches in diabetes treatment and the future and challenges of nucleotide delivery in diabetes.

Nanoscience for Drug Delivery in Diabetes

Current conventional diabetes mellitus (DM) therapies are inadequate and have poor patient compliance. Subsequently, it is necessary to explore nanomedicine in managing diabetes. In recent years, several nanocarrier systems have been proven effective in various aspects of diabetes treatment, increasing drug stability, overcoming different biological barriers, and in enhancing bioavailability. Nanomedicine can potentially improve the therapeutic effect of drug substances to gain the patient’s belief and impart a greater level of acceptability. In the present scientific spectrum, nanomedicines promise to provide sustained and targeted delivery with potential physical stability for a prolonged period, rendering a safe and effective therapy for diabetes. This chapter comprehensively elaborates on trends in the drug delivery system in treating diabetes for improved delivery of different classes of antidiabetic agents compared to contemporary therapies.

Chromosome 21

The significance of human chromosome 21 is that the trisomy of human chromosome 21 causes Down syndrome in children. There are about 235 protein-coding genes on chromosome 21. Mutations like translocation in human chromosome 21 cause different conditions such as partial monosomy 21, core binding factor acute myeloid leukemia, ring chromosome 21, and other types of cancers such as acute lymphoblastic leukemia. Mutation in the DSCAM gene causes mental retardation and facial deformities in down syndrome. The human chromosome 21 also comprises the APP gene, where the expression of the gene causes Alzheimer's disease. The genes that are involved in causing Down syndrome and Alzheimer's diseases are also involved in cancer. This chapter discusses 63 genes of human chromosome 21 that are involved in different types of cancer.

Chromosome 19

Gene is considered discrete coding units that contain the information for individual proteins. These lot of genes were combined and named DNA which is tightly coiled many times over the histone protein to form Chromosomes. Humans have got 23pairs of chromosomes, including the sex chromosome. The current study is about the major genes and their functions that are present in chromosome 19. There are approximately 1500 genes present in this chromosome, and changes in chromosome 19 are identified in many cancers. Dislocation of the chromosome, a mutation in genes that are present in a chromosome (rearrangements, deletions, or duplications) of DNA in the chromosome, epigenetic modification, and lifestyle changes are some of the chromosomal abnormalities that are responsible for cancer-causing. These changes will trigger the growth of normal cells and induce cancer cell proliferation, migration, invasion, angiogenesis, and metastasis. The signaling pathways like PI3K/AKT, JAK/STAT, NF-κB, and TGF-β are responsible for the various cellular functions with the result of autocrine, juxtacrine, intracrine, paracrine, or endocrine. When the dysregulation of these signaling pathways leads to cancer progression and metastasis. Prostate cancer, breast cancer, gastric cancer, pancreatic cancer, colon cancer, gastric cancer, lung cancer, leukemia, and cervical cancer are the major cancers that are caused because of mutation that occurs in chromosome 19.

Chromosome 18

Cancer is an abnormal or unusual growth of cells in the body with invasive and migrating potential. It leads to loss of function, weakens the immune system, and is the second leading cause of death worldwide. This makes it important to eliminate the disease. Genetic predisposition imposes a high relative risk for several kinds of cancer. Inherited genetic mutations are responsible for causing 5 to 10 percent of all cancers. Scientists have investigated mutations in specific genes with more than 50 hereditary cancer syndromes. For this, chromosome 18 was explored for its genes associated with cancer and this study unveiled 30 genes involved in causing cancer. Of these, the genes DCC, EPB41L3, MBD1 PHLPP1, and RBBP8 were the potential tumor suppressors. This chromosome consists of the target genes of the transforming growth factor-beta (TGF-β) signaling pathway. The SMAD family genes (SMAD4, SMAD7, and SMAD2) are encoded by this chromosome, of which SMAD4 acts as a tumor suppressor. SERPINB5 and TCF-4 were the potential oncogenes. The enzyme coded by TYMS was a potential therapeutic target for chemotherapy. Several fusion genes of this chromosome (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) have been identified to cause cancer. Therefore, this chapter provides a summary of the genes in chromosome 18 that are involved in the initiation and proliferation of cancer and provides an insight into the potential biomarkers and therapeutic targets for clinical application to develop a cancer-free world.

Chromosome 15

The genomic alteration at chromosome 15 has been widely recognized as the utmost significant and prevalent alteration in several cancers, including non-small-cell lung cancer, breast cancer, ovarian cancer, prostate cancer, gastrointestinal cancer, acute lymphoblastic leukemia, colorectal carcinoma, hepatocellular carcinoma, myeloma, pituitary adenomas, etc. Emerging reports suggest that the abnormalities of prime genes in chromosome 15 have drastic effects on tumor development and progression, and can be candidate biomarkers of disease prognosis, disease progression, and response to treatment. The translocations involving chromosome 15 and other chromosomes have been found in tumors, including mucoepidermoid carcinomas, mixed-lineage leukemia, colorectal cancer, pancreatic cancer, sarcoma, lung adenocarcinoma, melanoma, brain cancer, cholangiocarcinoma, spitz tumor, congenital mesoblastic nephroma, papillary thyroid cancer, pontine glioma tumors, and acute promyelocytic leukemia. The tumor suppressor genes such as C15orf65, CSK, CRABP1, DAPK2, FES, GREM1, KNSTRN, NEDD4-1, NTRK3, PML, SPRED1, TPM1, and TCF12 under chromosome 15 play a crucial role by enhancing cellular growth, proliferation, migration, invasion, metastasis, cellular differentiation, and development in various cancer, including colorectal cancer, acute promyelocytic leukemia, myeloid leukemia, breast cancer, thyroid carcinoma, glioblastoma, intrahepatic cholangiocarcinoma, chondrosarcoma, cartilaginous cancer, Squamous cell carcinoma, non- small-cell lung carcinomas, mucosal melanoma, and oral squamous cell carcinoma. Chapter 15 discusses the significance of each important gene under chromosome 15 in mediating oncogenesis. The elevated or attenuated expression levels of these cardinal genes can either act as an oncogene or a tumor suppressor. Thus, shedding light on these genes would be a game changer in the field of cancer genetics and theragnostic.

Platelet-Rich Plasma and its Derivatives for Tissue Engineering

Platelet-rich plasma (PRP) is a well-established biological product used in the tissue engineering field to promote wound healing and tissue regeneration. PRP can form platelet gel with the addition of thrombin and/or calcium salts. Nonetheless, PRP is more commonly combined with biomaterial and cells for various tissue engineering applications. Over the years, PRP has been used in the dermatology field for hair follicle regeneration and wound healing, in the orthopaedic field for bone, muscle, tendon, and ligament repair, and in dentistry for many dental procedures, including dental implants. Despite the long historical use of PRP in the clinic, the PRP isolation technique is still continuously changing, evolving, and improving to increase the therapeutic effect of PRP. Nowadays, PRP is not only used as a biomaterial but it also can be used to replace foetal bovine serum and human serum in primary cell culture, especially for cell therapy purposes. PRP derivatives such as platelet lysate, plateletderived growth factors, and platelet-derived extracellular vesicles also are precious functional materials used clinically in the tissue engineering field. In this book chapter, we review the different subclasses of PRP, including its derivatives, its research, and clinical applications, and underline the challenges of PRP in clinical translations.

A Comprehensive Overview of Estrogen: Physiological and Pathological Insights

Estrogens (estrone, estriol, and estradiol) are a class of steroidal hormones produced by developing ovarian follicles. These hormones induce various cyclic events in the uterine endothelium and vaginal epithelium and make the female body competent for conception and ultimately for motherly care. While estrogen is primarily produced by ovaries from cholesterol, the non-reproductive tissues including the brain, liver, and heart also produce a considerable amount of it. Apart from its important role in controlling sexual behavior and reproductive function, estrogen also functions in the regulation of various physiological functions including reproduction, skin physiology, cardiovascular health, skeletal homeostasis, bone integrity, electrolyte balance, cognition, and behavior. These biological functions are regulated by diffusion through the plasma membrane in vitro signaling through specific binding to nuclear receptors such as estrogen receptors (ERα and ERβ) or binding to cell membrane receptors such as GPR30 and ER-X. The signaling mechanism can be genomic (change in gene expression) or non-genomic (activation of various signaling cascades). Disruption in estrogen functioning has a pivotal role in the pathogenesis of many diseases such as osteoporosis, insulin resistance, neurodegenerative disease, obesity, and endometriosis. Also, dysregulation in the levels of estrogen has been linked to the development of many cancers such as breast cancer, etc. This chapter aims to summarize the complete insight of estrogen by providing a clear understanding of its synthesis, receptor binding, signaling, regulation of physiological functions, and role in various diseases.

Chromosome 11

Over the years, many scientists and doctors have been treating the deadly cancer disease but cannot find a permanent treatment for this disease. Also, sometimes it becomes tough to understand the mechanisms and causes of cancer as it is a very complex disease that involves many biological processes. Due to the redundancy in our biological system, cancer progression becomes very easy, thus making it difficult to cure. To find the root cause of this disease, we should know what genetic alterations are causing cancer progress and who is participating in these alterations, like proteins, signaling pathways, or genes. Cancer is caused due to various reasons; it can be due to genetics but primarily due to carcinogens, causing mutations in the genes, thereby making them an oncogene. The Proto-oncogenes are those genes that usually assist the growth of tumor cells. The alteration, mutation, or increased copy number of a particular gene may turn into a proto-oncogene, which could end up completely activated or turned on. Many Tumor-causing alterations or mutations related to oncogenes are usually acquired and not inherited. These tumor-causing mutations often actuate oncogenes via chromosomal rearrangement or changes in the chromosome, which sequestrates one gene after another, thereby permitting the first gene to prompt the alternative. Search which genes are involved in different cancer types would help scientists proceed with new methods for finding a cure for this disease. This article will depict which genes and their location on which chromosomes, specifically on chromosome 11, are related to different types of cancer.

Antidiabetic Activity Methods

Diabetes mellitus (DM) is a metabolic disease characterized by the destruction of pancreatic β cells or reduced insulin secretion and action, and is one of the most common health problems worldwide. Its incidence is increasing at a high rate, resulting in enormous social costs. Various drugs show their effectiveness by improving insulin sensitivity, and reducing glucose production in the liver or other tissues. Several preclinical studies on diabetes-induced in animals using surgical, pharmacological or genetic methods demonstrated the effectiveness of these drugs. The anti-diabetic activity of plants has been attributed to the occurrence of primary and secondary metabolites characterized by many beneficial effects with advantages over chemical treatments. A number of studies have demonstrated the potential health benefits of phytocomponents in treating DM by acting on multiple molecular targets. Therefore, it is important to test in vitro assays. This review includes methods for the evaluation of preclinical anti-diabetic activities and summarizes the potential of natural resources to prevent and/or treat diabetes. In addition, the database contains information including the plant name, useful plant parts, active compounds, and their mechanisms of action, in which in vitro and in vivo methods were studied.

Antidiabetic Attributes of Mushrooms

Mushrooms are macrofungi, with distinct mycelia structure, and fruiting bodies, divided into stalk and cap that contains spores in most of the species. These mushrooms are edible with diverse therapeutic applications. Old civilizations from India, China, and Korea used these mushrooms to cure diseases, especially diabetes. Diabetes is now a newly emerging pandemic, affecting people worldwide, with special reference to developing countries. There are several medications available for the management of diabetes, but their permanent treatment is still to be explored. Due to synthetic medicines and their adverse effect, people are searching for natural therapeutic agents. Many mushroom species have shown their potential to control diabetes and its related complications, such as weight loss, lipidemia, hypertension, etc. In this chapter, we have discussed five different mushroom species, i.e., Auricularia auricula-judae, Agaricus bisporus, Ophiocordycep sinensis, Ganoderma lucidum, and Pleurotus species with their potential therapeutic application against diabetes and its related complications.

Future Path and Perspectives of Immunomodulators

Immunity is the inherent ability of the body to fight against various infections, and foreign invaders. When the host body comes in contact with a foreign body, a series of chemical mediators are released, which collectively elicit an immune response. The biomolecules capable of stimulating, suppressing and modulating innate or acquired immunity, biological or synthetic in origin, are termed as immunomodulators or immunoaugmentors. Limited clinical use of synthetic immunomodulators has attracted the attention of researchers toward immunomodulatory characteristics of natural therapeutics. Though natural immunomodulators render their efficacy in several chronic illnesses, there are challenges that need to be addressed and resolved to make them viable alternate therapeutics. This chapter highlights the challenges and future perspectives of natural immunomodulators.

Treatment of Cancer

Surgery, the oldest cancer treatment, is a mainstay in the cure and control of most cancers. Indeed, for many patients, surgery, usually in combination with chemotherapy, is the only hope for long-term survival or cure. But surgery can do more than treat cancer; it can also diagnose cancer (diagnostic surgery), investigate cancer further (staging surgery), debulk tumors (debulking surgery), relieve pain (palliative surgery), prevent cancer from occurring in the first place (preventative surgery), restore the appearance or function of the body after cancer surgery (reconstructive surgery) and help medical staff to administer chemotherapy (access surgery). This chapter looks at each of these purposes of cancer surgery in detail.

Biology of Cancer

Loss of genomic stability in the cell due to defects in the checkpoint of DNA damage, mitotic checkpoint, and telomere maintenance led to increased incidences of base pair alterations. Therefore, that genomic instability plays a critical role in tumor initiation and progression. Tumor progression requires a dynamic tumor/normal exchange in their microenvironment to support tumor growth. The histological alteration seen in the tumor at early stages confirms that the surface between the epithelium and the stroma undergoes progressive disturbance. Tumor progression is also affected by the immune system in which chronic inflammations promote the growth of tumor. Tumor cells experience altered metabolic profiling to support their growth. Cancer cells are characterized by uncontrolled cell division. For that, they utilize glucose as a source of energy to help them grow faster than normal cells. Hence, Glycolysis is a key metabolomics pathway consumed at a high rate during carcinogenesis.

Introduction

Cancer is a complex family of diseases that usually begins with carcinogenesis, in which abnormal cells divide or develop wildly by not following the regular path of cell division and likewise can invade nearby tissues. Cancer cells demonstrate transformations in metabolism, which is frequently more anaerobic than normal and probably can tolerate hypoxic surroundings. The remarkable variability of the disease, at all levels, is the major challenge for cancer medicine. Six biological abilities gained during the multi-stage advances of human tumors are the maintenance of proliferative signaling, the prevention of growth suppressors, cell death resistance, replicative immortality allowance, angiogenesis induction, invasion, and metastasis activation. In this chapter, we discuss the features of cancer cells and the epidemiology of cancer for better understanding.

SPR-Based Biosensors in the Diagnostics and Therapeutics

To analyze the physio-chemical measures of the cellular environment and display them in digital units, transducing methods are applied in biosensors. The labelfree biosensors employ biophysical characteristics such as spectroscopic methods, crystallization, and Surface plasmonic resonance (SPR) to determine the availability or concentration of substances. SPR is a method to elucidate interaction among biomolecules exhibiting affinity binding, structural changes, or alteration in pathological conditions. SPR methods are now employed in conjunction with a variety of transducer topologies, including optical fibers, nanoparticle-based SPR, immobilized or localized SPR (LSPR), long-range SPR, image SPR, immune-assay-based SPR, and phase sensing SPR biosensors' versatile configuration allows for the early detection of several illnesses, such as COVID-19, dengue, non-invasive cancer, biomarker-based fetuses identification, therapeutic antibody characterization, drug monitoring, etc. SPR system is leading in diagnostics and therapeutics with various advantages, such as their portable size, cost-effectiveness, quick result, and easy-to-handle method, but at extension, this technique needs development to ensure high sensitivity, averting background effect and evolution of label-free direct detector to quantify real sample. This chapter reviews the model’s instrumentation and bioassay of clinical samples from SPR and its associated biosensor.

Diabetes Type II: Should Aspartame be a Concern?

Blood sugar levels have to be controlled by individuals with type II diabetes (T2D) to preserve health and longevity. For such people, artificial sweeteners (including aspartame) are proposed sugar substitutes. In particular, the protection of aspartame has long been the point of discussion. Although it is such a problematic product, T2D patients are advised by many physicians to use it during a managed diet and as part of a treatment modality. Aspartame is 200 times sweeter than sugar and has a marginal effect on blood glucose levels. It is recommended for use so that T2D can regulate carbohydrate consumption and blood sugar levels. Previous studies, however, indicate that aspartame consumption may increase a person's risk of gaining weight instead of losing weight, resulting in intolerance to blood glucose in T2D. By increasing the levels of cortisol, aspartame can act as a biochemical stressor. It may cause systemic oxidative stress by creating excess free radicals, altering the gut's microbial activity, and interacting with the receptor N-methyl D-aspartate (NMDA), resulting in insulin deficiency or tolerance. Due to the lack of reliable evidence, aspartame and its derivatives are safe for T2D yet are still debatable. In the already stressful physiology of T2D, more research is needed to provide indications and raise concerns that aspartame may worsen the prevalence of pathological physiology.

Current Strategies of New Drugs for Diabetes Management

Several aspects need to be explored in drug therapy for diabetes patients. Some specific glucose-reducing medicines are present, while other medicines are associated with unintentional changes in hyperglycemia. Diabetes is a developing epidemic that has caused significant socioeconomic problems in several countries throughout the world. Despite scientific discoveries, greater healthcare services, and higher literacy rates, the disease continues to plague many industries, particularly developing countries. The current trends show an increase in premature mortality, which threatens world prosperity. Experimental and technical improvements have been made in sulphonylureas, alpha-glucosidase inhibitors, biguanides, and thiazolidinediones, all of which are beneficial in lowering glucose levels. The latest drug research techniques have led to the development of novel therapeutic groups such as amylin analogs, incretin mimetics, GIP analogs, active peroxisome proliferator receptors, and dipeptidyl peptidase-4 inhibitors as targets for future diabetes therapy medications. Furthermore, drug development and detection for diabetes treatment have been revolutionized by identifying and investigating bioactive compounds from herbs. This chapter discusses vital fields of clinical diabetology regarding opportunities for stem cells and nanotechnology as next-generation therapies, with an emphasis on evolving developments and reviews why plant-derived products are reliably common for treating and managing diabetes.

Protein Cancer Biomarkers

Cancer is one of the leading causes of death worldwide and it is becoming increasingly important to be able to efficiently identify and map the progression of cancers. The study of the diagnostic, predictive and prognostic value of protein biomarkers has become one of the main aspects at the forefront of cancer research. The diversity of various biomarkers for different cancers and their varying roles in each disease presents a continual challenge for researchers to understand, with new biomarkers still being discovered today. Understanding the role of protein biomarkers ensures patients are diagnosed with greater confidence and helps clinicians with treatment regimes. This chapter aims to discuss the clinical significance of various protein biomarkers in terms of their diagnostic, prognostic, and predictive value in the treatment of their respective cancers.

Combretastatin Derivatives as Tubulin Inhibitors: A Fascinating Journey from Nature to Drug Discovery Strategies

The combretastatins are a family of stilbene phenolic natural products isolated from the bark of the South African bush willow tree Combretum caffrum. Since their isolation and structural elucidation, these molecules have attracted a lot of interest due to their potent cytotoxic activity against several human cancer cell lines. Combretastatin A-4, a cis-stilbene, is the most potent member of these natural products, has the ability to strongly inhibit tubulin polymerization, resulting in high cytotoxic activity. Indeed, it also displays an additional activity as a potent vascular disrupting agent. This interesting double bioactive profile accounts for the potent antiproliferative and antivascular action in tumors. However, combretastatin A-4, due to the sensitive cis-stilbene moiety, is prone to isomerization giving the less bioactive trans-isomer and exhibits diminished water solubility. Hence, a wide panel of synthetic derivatives were therefore developed with the aim of overcoming these limitations. The development of prodrugs such as fosbretabulin, ombrabulin and Oxi4503 isrepresentative of successful attempts to overcome pharmacokinetic disadvantages, whereas the most recent approaches aim to develop combretastatin prodrugs able to selectively target tumor site, possessing also theranostic properties. Herein, miscellaneous and the most potent synthetic analogues are presented. In addition, a general outlook on combretastatin derivatives and drug delivery approaches based on innovative nanoformulations is also presented.

Potential Applications of Nitric Oxide Donors in Type 2 Diabetes

Nitric oxide (NO) donors are chemical agents that produce NO-related activity in biological systems, mimic endogenous NO-related responses, or compensate for NO deficiency. NO donors have been increasingly studied as promising therapeutic agents for insulin resistance and type 2 diabetes (T2D). Here, we provide evidence, which investigated the effects of the most frequently studied and implemented NOreleasing compounds, including sodium nitroprusside (SNP), S-nitrosothiols [RSNOs, i.e., S-nitrosoglutathione (GSNO), S-nitroso-N-acetyl-penicillamine, (SNAP)], and NDiazeniumdiolates (NONOates, i.e., spermine NONOate, diethylamine NONOate) on glucose and insulin homeostasis. Available evidence could not draw a clear conclusion regarding therapeutic applications of NO donors in T2D due to different methodological approaches (i.e., in vitro vs. in vivo) and different doses and formulations used to assess the potential effects of NO donors on carbohydrate metabolism. Considering key properties and different kinetic behaviors between various classes of NO donors, targeted compound selection, defining optimum doses, and appropriate use of NO-releasing platforms (topical vs. systemic delivery mode) seem to be critical issues that can accelerate the bench-to-beside translation of NO donors in T2D.

Nitrate, Nitrite and Type 2 Diabetes

Recent research punctuates that the nitrate (NO3)-nitrite (NO2)-nitric oxide (NO) pathway may be a potential therapeutic target in type 2 diabetes (T2D), a NOdisrupted metabolic disorder. Nutritional aspects of the NO3-NO2-NO pathway has been highlighted by focusing on the protective effects of some traditional high-NO3 diet, such as Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets and their NO3-rich components, i.e., fruits, vegetables, legumes, and green leafy vegetables, against the development of T2D. Both acute and long-term administration of inorganic NO3 and NO2 in animal experiments display anti-diabetic properties; inorganic NO3 decreases fasting blood glucose, glycosylated hemoglobin, and proinsulin to insulin ratio and improves glucose tolerance. In contrast to animal experiments, NO3/NO2 therapy has failed to show anti-diabetic properties and beneficial effects on glucose and insulin homeostasis in humans. This lost-i- -translation remains an open question, and long-term clinical trials are needed to confirm the salutary effects of inorganic NO3 and NO2 as the natural NO boosters in patients with T2D.

Hyperuricemia, Type 2 Diabetes and Insulin Resistance: Role of Nitric Oxide

Uric acid (UA) is the end product of purine catabolism in humans. Hyperuricemia, defined as elevated plasma concentrations of UA above 7 mg/dL, is a risk factor for developing hypertension, cardiovascular diseases, chronic kidney disease, and type 2 diabetes. Hyperuricemia can induce pancreatic β-cell death and impaired insulin secretion. It can also disrupt insulin-induced glucose disposal and insulin signaling in different insulin-sensitive tissues, including cardiomyocytes, skeletal muscle cells, adipocytes, hepatocytes, and endothelial cells. These events lead to the development of systemic insulin resistance and impaired glucose metabolism. Induction of inflammation, oxidative stress, and impairment of nitric oxide (NO) metabolism mediate hyperuricemia-induced insulin resistance and dysglycemia. This chapter is focused on the potential mediatory role of NO metabolism on hyperuricemia-induced dysglycemia and insulin resistance.

Impaired Nitric Oxide Metabolism in Type 2 Diabetes: At a Glance

Abnormal nitric oxide (NO) metabolism has been associated with the development of insulin resistance and type 2 diabetes (T2D). The concept of NO deficiency is supported by human studies on polymorphisms of endothelial NO synthase (eNOS) gene, animal knockout models for NO synthase isoforms (NOSs), and pharmacological evidence, showing detrimental effects of NOS inhibitors and salutary effects of NO donors on carbohydrate metabolism. On the other hand, T2D and insulin resistance may impair NO homeostasis due to hyperglycemia, oxidative stress, and inflammation. Reduced production of NO [i.e., impaired L-arginine-NOS pathway and function of the nitrate (NO3)-nitrite (NO2)-NO pathway], impaired NO transport within the circulation and delivery to target cells, as well as disrupted NO signaling (e.g., via oxidative-induced NO quenching, and impaired NO-cGMP signaling pathway) can all lead to a reduced NO bioactivity in T2D. This chapter focuses on the role of impaired NO metabolism in T2D.

Green Synthesis Application in Diabetes Therapy

The use of medicinal plants and or medicinal plants-aided nanoparticles (NPs) in the management of diabetes mellitus has progressively received wider acceptance over the years due to the accompanying side effects with conventional therapy. The review explores the application of green-synthesized nanostructures in the control or management of diabetes as well as probable mechanism of NPs formation and possible toxicity. Information sourced from scientific databases including Science Direct, Google Scholar, PubMed, Web of Science, SciFinder, JSTOR revealed 58 medicinal plants explored in the synthesis of four (4) NS such as gold, silver, zinc oxide and platinum with established antidiabetic potential. The NS is characterized by varying microscopic and or spectroscopic instruments such as UV-Vis, SEM, EDS, FTIR and XRD commonly are stable, smaller-sized and mostly crystalline in nature. The functional groups responsible for the reduction and stabilization of the nanoparticles are predominantly C-O, C-H, COOH, N-H found in phenols, flavonoids, alkaloids, proteins and so on. The review identified and revealed 45% studies with less than 5% (mostly from India) conducted on animal models for antidiabetic and toxicity determinations, respectively with none for clinical studies, indicating the need for intensified efforts on research on these identified plants and unidentified species for drug development.

Plant Secondary Metabolites in the Management of Degenerative Diseases

Medicinal plants have been indispensable in the development of lead compounds for the management of human health. However, herbal remedies have not been explored maximally in modern therapeutics for the management of drug-resistant diseases, re-emerging diseases, metabolic syndrome, etc.

Several secondary metabolites with proven efficacious pharmacological effects have been identified from plants, some isolated but unfortunately never developed into a marketable pharmaceutical product.

Thus, this chapter provides resourceful information on the secondary metabolites of herbal plants with great pharmacological potential. Databases such as JSTOR, Science Direct, Google, PubMed, and Medline were explored for relevant information on this concept.

A spectrum of plant secondary metabolites with potent antibactarial, antiviral, antimalarial, anticancer, antidiabetic activities in different plant species were collated, the class of these metabolites and mechanism of action was compiled.

An acquaintance with efficacious secondary metabolites used in the management of various diseases will serve as a basic tool for Ethnomedical Scientists in the integration of folkloric knowledge in contemporary medicine for the formulation of herbal remedies with superior pharmacological relevance than conventional medicine.

Plant Based Bioactive Molecules in Diabetes with Their Therapeutic Mechanism

Plant based bioactive compounds are the secondary metabolites that are produced by them to perform their non-essential functions. They provide an ample source of nutraceuticals and therapeutics for humans. The research on these compounds is on trend these days and most of the research suggests their importance as therapeutic agents and as prophylactic agents against many diseases. Easy accessibility, and better efficacy with lesser adverse effects of bioactive compounds have made their research trending. Diabetes is the oldest known metabolic disease which requires a multimodal treatment approach for its management. The available drugs and treatment options are still unable to control the complications and economic burden faced by the patients. Many plants have been used traditionally for the management of diabetes worldwide. Now it has been well established that the plants provide a rich reservoir of bioactive compounds which have the potential to modulate various pathways involved in the regulation of blood glucose. This chapter discusses the common groups of plant derived bioactive compounds, their sources, and their mechanistic antidiabetic role.

Biomarkers and their Clinical Applications in Pediatrics

Biomarker studies are becoming increasingly interesting for many fields of medicine. The use of biomarkers in medicine is involved in detecting diseases and supporting diagnosis and treatment decisions. New research and new discoveries on the molecular basis of the disease show that there may be a number of promising new biomarkers for use in daily clinical practice. Clinical trials in children lag behind adult research both in quality and quantity. The number of biomarkers validated to optimize pediatric patient management is limited. In the pathogenesis of many diseases, it should not be extrapolated to the pediatric clinical setting, taking into account that biomarkers that are effective in adults are clearly different in children and that ontogeny directly affects disease development and therapeutic response in children. The search for ideal biomarkers or markers that can make an early and definitive diagnosis in neonatal sepsis is still ongoing. The ideal biomarker for pediatric diseases should be costeffective, noninvasive, applicable to pediatric specific diseases, and its results should correspond to age-related physiological changes. Lactate, troponin and B-type natriuretic peptide are valuable biomarkers in the evaluation and management of critically ill children with cardiac disease. Tumor markers in children are biochemical substances used in the clinical treatment of pediatric tumors and to detect the presence of cancer (regression or progression). In this chapter, current and brief information about biomarkers and their clinical applications used in the diagnosis and monitoring of pediatric diseases is presented.

Circulating Biomarkers in Thyroid Cancer

Thyroid cancer is the most important endocrine cancer with increasing incidence. While thyroid cancers, especially papillary thyroid cancers, are known to exhibit generally a favorable outcome with excellent survival rates, some thyroid cancers are more aggressive with a poor prognosis. Several different biomarkers have been introduced for the diagnosis of disease, identification of tumor load, assessment of therapy response, and the detection of recurrence during follow-up of the thyroid cancer patients. This chapter gives a brief overview of the circulating biomarkers used in thyroid cancer patients.

Phytochemistry and Pharmacology of Terminalia chebula: An Update

Various plants and shrubs with enormous medicinal values are easily found in India. These are mostly used in routine home remedies and the treatment of various diseases or ailments. Since the ancient era, medicinal plants are being used in various traditional systems of medicine to treat minor to major diseases or disorders. Considering their valuable contribution at various levels of treatment, these medicinal plants have gained importance and emerged as one of the most cost-effective remedies in the current health care system. Ayurveda, an ancient system of Indian medicine, has mentioned several important medicinal plants; out of all these, Terminalia chebula has owned its importance because of its phytoconstituents and potent action on enormous diseases. It is also an important part of Triphala churna, which is one of the important formulations in the Ayurvedic system of medicine. The current review focuses on the phytochemistry and pharmacological effects of Terminalia chebula. The literature search was performed using various datasets like EBSCO, PubMed, Scopus, ProQuest, and selected websites, such as the World Health Organization (WHO) and the National Institutes of Health (NIH). Terminalia chebula shows the presence of tannins like ellagic acid, gallic acid, ethyl gallate, chebulinic acid, tannic acid, chebulin, arjungenin, arjunglucoside I, terflavin A, punicalagin, and luteolin, which is mainly responsible for showing their pharmacological effects. The various parts of the plant have been reported for the treatment of various ailments. It has laxative, antiseptic, antidiabetic, and hepatoprotective properties. It is also used in the treatment of upper respiratory tract infections and bronchitis. Half ripe fruits are used as purgative and ripe fruit as tonic, astringent, antipyretic, expectorant, dyspepsia, diarrhoea, allergic eruptions, biliousness, cough, and leprosy. The dry powder form of fruit is used for emesis, hoarseness of voice, and worm infestation, as an anthelmintic, asthma, useful in hepatitis, eye diseases, and piles. Kernels of Terminalia chebula have been reported as anodyne.
Kernel oil has been reported for its purgative action. Gum of the bark is a painkiller and laxative. In conclusion, Terminalia chebula contains important phytochemicals like tannins, gallic acid, and ellagic acid. These indicate that the plant and its different parts have a wide range of pharmacological effects. This book chapter provides detailed information on the recent studies for pharmacological activities of T. chebula and its active components.

Role of GSK-3 in the Regulation of Insulin Release and Glucose Metabolism

Protein kinase (PK) has always been an attractive target for the discovery of

new drugs. However, this year is significant for PK therapeutics since it marks the 20th

anniversary of the FDA’s approval of the first PK drug, imatinib, which was approved

in 2001 as the first protein kinase drug. GSK-3 is a serin protease protein kinase that

plays a key role in glucose homeostasis in our body. It also regulates insulin resistance

and the expression of glucose transporter. In type 2 diabetes mellitus (T2DM), glucose

homeostasis in our body becomes jeopardized due to poor glucose utilization by the

liver, muscle, and adipose tissue. GSK-3 is generally overexpressed among obese

diabetics; therefore, the GSK-3 inhibitor might be a better therapeutic target for the

discovery of new antidiabetic treatment. The lithium salt was experimented with as a

GSK-3 inhibitor using different animal models to evaluate its antidiabetic activity and

prove its action on glucose regulation inside cells. However, owing to the significant

toxicity of lithium salt in the development of colorectal cancer, the WNT signalling

pathway is inhibited. Currently, the major pharmaceutical companies are trying to

design and synthesize some GSK-3 inhibitors that are safe and effective for diabetics.

Some of these molecules are in the initial stages of the clinical trial to assess their

effectiveness. In this chapter, the role of GSK3 in the regulation of insulin release and

glucose metabolism was explained with a number of schematic representations in order

to facilitate biomedical scientists in the drug discovery process.

Free Radical Biology of Diabetes Mellitus

Free radicals play a pivotal role in the etiology of different diseases,

including diabetes mellitus (DM). In the past three decades, the understanding of the

fundamental role of free radicals in the etiology and disease progression of DM was

studied broadly. This chapter aimed to enumerate the recent progress in the areas of

free radical biology for the management of DM. Free radicals, as well as reactive

oxygen species (ROS), having extra electrons in their outer orbitals, react with all

biomolecules, including “protein, lipids, and DNA,” causing oxidative stress and

damage. DM is also associated with oxidative stress induced by the elevated production

of free radicals or reduced antioxidant activity. Recently, the importance of an

antioxidant rich diet, yoga, and exercise has been well documented for the management

of DM. Studies confirmed that exercise-induced ROS is an acute effect, while the

chronic effect of exercise produces endogenous antioxidant defences and promotes a

state of endogenous antioxidant defence mechanism. Therefore, regulating oxidative

stress will lead to a significant future area of research for DM disease management.

Infection of Novel Coronavirus in Patients with DiabetesMellitus

According to the preliminary research, coronavirus disease 2019 (COVID19) has been found to be more severe in patients with diabetes mellitus. Furthermore, COVID-19 might also lead to hyperglycaemia. Along with other risk factors, high blood glucose may also affect immune and inflammatory responses, thus inclining patients to severe COVID-19 witha much higher mortality rate. Angiotensin-converting enzyme 2 (ACE2) receptors are the common entry point for SARS-CoV-2. Recent findings suggest that dipeptidyl peptidase 4 (DPP4) can also act as a binding and entry target. Glucose-lowering agents and anti-viral treatments can alter the risk, but there exist limitations to their use, and its possible interactions with COVID-19 treatments should be carefully assessed. TMPRSS2 and Neuropilin-1, the key components that facilitate SARS-CoV-2 infection, are also the potential targets forthe treatment of COVID-19. Finally, severe acute respiratory syndrome coronavirus 2 infections might represent a worsening factor for people with diabetes, as it can precipitate acute metabolic complications through direct negative effects on cell function. Thus, this chapter deals with the treatment options of diabetes and COVID-19. Most of these conclusions are preliminary, and further investigation of the optimal management in patients with diabetes mellitus is warranted.

Epigenetic Alterations and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is one of the most challenging public health issues of the 21st century. T2DM, a complex polygenic metabolic disorder, is characterized by hyperglycemia and hyperinsulinemia resulting from the interplay of genetic/epigenetic and environmental factors. Epigenetic alterations present in T2DM patients and not in normal healthy individuals may give an insight into how environmental factors contribute to T2DM. Epigenetic mechanisms involve DNA methylation, histone modification, and gene expression alterations via micro RNAs (miRNA). These changes lead to glucose intolerance, insulin resistance, β-cell dysfunction, and ultimately T2DM. Extensive studies based on alterations in gene expression associated with DNA methylation/histone modifications are required to elucidate the relationship between vital environmental factors and T2DM progression. Candidate genes responsible for inter-individual differences in antidiabetic responses may also undergo epigenetic alterations. Identification and characterization of such epigenetic biomarkers may help in the prediction of T2DM risk as well as response to antidiabetic treatment and form an essential part of personalized medicine

Microbiota and Diabesity: Relationship and New Perspectives for the Treatment of Obesity

Diabesity refers to the co-occurrence of diabetes and obesity. Obesity and type 2 diabetes have been associated with unfavorable changes in the composition and functionality of the intestinal microbiota (dysbiosis), accompanying glucose and lipids metabolic alterations in the host. Moreover, an interrelationship seems to exist between the chronic low-grade inflammation occurring in obesity/diabetes, with mood disorders and early cognitive impairment, frequently associated with these pathologies. Focus on the intestinal microbiota, as a target for developing/evaluating strategies to fight against diabesity, constitutes a novel point of view in the management of this condition. Apart from calorie restricted diets, with proven low efficacy in the long-term, recent studies are focused on particular dietary components such as fatty acids, polyphenols, probiotics and prebiotics and their effect on diabesity, mediated by the intestinal microbiota. Medical treatments include the use of drugs with different mechanisms of action, most of them showing effects on the gut microbiota. The use of bariatric surgery is increasing in recent years for the treatment of severe obesity and favorable changes in microbiota composition and its metabolites have been evidenced linked to weight loss. Further studies are needed to elucidate whether changes in the microbiota are a cause or consequence of diabesity

Medicinal And Edible Plants And Their Bioactive Phytochemicals For The Prevention Or Reduction Of Diabesity

The change in the lifestyle of the world population towards a westernized style has generated important effects on the metabolism of the population over the years. These metabolic changes trigger negative effects on human health, one of these effects is called Diabesity, a combination of symptoms related to diabetes and obesity. Various ways have been sought to compensate for these negative effects, pharmacologically and in folk medicine, but the focus points are the generation of new habits of foods and/or medicinal plants consumption capable of reversing the negative effects of Diabesity. In this chapter, a series of medicinal and edible plants with reported activity on both weight reduction and consumer glycemic levels are described. The origin of the use of these foods is often based on the ancestral consumption of traditional medicines, which awakened the interest in the scientific community as starting points for the development of new functional foods to reduce the impact of Diabesity worldwide.

New Phytochemical Compounds for Prevention or Reduction of Diabesity

Towards the end of the last century, the researchshowed that several vegetables and medicinal plants have hypoglycemic potential and therefore may exhibit a positive effect in reducing hyperglycemia in the human body. In vitro and in vivo studies support the antidiabetic effects of polyphenols extracted from berries, black currants, raspberries, and strawberries fruits, out of which the most important are the anthocyanins. Among anthocyanins, the most commonly identified in berries are cyanidin, delfinidine, malvidin, pelargonidine, peonidine and petunidine. Within this chapter, we present the importance of phenolic compounds in the diabetic diet, two plants Helianthus tuberosus and Momordica charantia L. with beneficial effects in the prevention of type 2 diabetes and their mechanisms of action. Also, the market of food supplements currently existing in Romania is presented, along with the products and their form of presentation.

Diabesity: Obesity And Type II Diabetes As A Real Health Problem In Developed Countries

is a multifactor disease resulting from the interaction of multiple genetic and environmental factors, such as sedentary lifestyle and the diet of the individual. On the other hand, diabetes mellitus is a complex metabolic disease that involves multiple organ systems, and it is characterized by chronic hyperglycemia due to a defect in the glycemic regulation as a result of insulin secretion, its actions or both. Combined, these diseases provide the concept of diabesity, which is defined as the alloy of type II diabetes and obesity, with or without associated risk factors. Obesity encourages diabetes, and both diseases are considered two global epidemics of the modern age that show no signs of decreasing their prevalence and contribute to cardiovascular diseases, the leading cause of death worldwide. This chapter is aimed to characterize both physiopathology and impact on health to understand their management and treatment.

Swertiamarin for the Treatment of Metabolic Syndrome

Metabolic syndrome, formerly termed ‘Syndrome X’, is a disease of energy

metabolism and storage. Metabolic syndrome is characterized by

hyperglycemia/impaired glucose tolerance, dyslipidemia, hypertension, and obesity.

Swertiamarin is a secoiridoid glycoside extensively found in the Gentianaceae family,

which has been reported to cure many diseases, such as diabetes, hypertension,

atherosclerosis, arthritis, malaria, and abdominal ulcers. The present book chapter aims

to compile up-to-date information on the progress made in the protective role of

swertiamarin in metabolic syndrome to provide a guide for future research on this

bioactive molecule. In preclinical studies, swertiamarin and its metabolites have shown

a wide range of biological activities such as antidiabetic, hypolipidemic, antiatherosclerotic,

anti-inflammatory, and antioxidant activities. These activities were

mainly due to its effect on various signaling pathways associated with swertiamarin,

such as PPAR-gene upregulation, P-407-induction, inhibition of HMG-CoA reductase,

LDL oxidation, lipid peroxidation markers and stimulation of antioxidant enzymes.

This book chapter presents evidence supporting that swertiamarin could be considered

as a potential therapeutic agent for the treatment of metabolic syndrome.

Heme-oxygenase and Autophagy connected as a Cytoprotective Mechanism: Potential Therapeutic Target

Heme-oxygenase (HO) is an enzyme that catalyzes the main step of heme

degradation generating anti-inflammatory end products with protective roles in

physiologic and pathological situations. The relevance of HO in inflammatory

conditions is well reported through pharmacological and/or genetic modulation,

pointing out its importance in several models of stress such as infection, inflammation,

and oxidative disturbance. Under the referred situations, another well-known protective

process triggered is autophagy, in which defective cytosolic components and organelles

are eliminated via lysosomes. Besides its role on organelles and macromolecules

recycling, autophagy also contributes to cellular homeostasis by generating the

functional blocks required for anabolic reactions. Recently, different studies have

demonstrated a link between HO activity and autophagy activation. In this chapter, we

would like to draw the reader's attention to the interconnection between HO and

autophagy regarding stress response mechanisms, highlighting its importance in

homeostasis maintenance that might be useful in the therapy of inflammatory diseases

in the future.

Beta Glucan And Chronic Kidney Disease (CKD)

Chronic kidney disease (CKD) is a global health problem that is associated

with a high risk for cardiovascular morbidity and death. It is a clinical syndrome

characterized by the progressive and irreversible loss of renal function. Dietary

supplementation with grains containing high β-glucan fiber has been shown to

attenuate the progression of CKD and vascular calcification in animal models. In this

mini-review, the therapeutic effect of beta glucan on CKD was investigated. For this

reason, many studies were examined and promising results were obtained for the use of

beta glucan in the treating of CKD

PDX Clinical Trial Design in Anti-Cancer Research

Animal models are useful tools for understanding cancer biology and genetics and serve as an essential platform for the preclinical development of anticancer therapeutics. In this context, cancer-bearing patient-derived xenograft (PDX) models, also called cancer avatars, have successfully replaced the traditional cell linederived models in recent years. PDX-based studies are now widely used for preclinical testing of novel treatments as well as tailoring personalized medicine. For anti-cancer research, however, the use of PDX models propagated from a unique patient does not fully represent the true therapeutic efficacy and toxicity of a drug. That is why many studies in this format later failed to show efficacy and safety in human clinical trials. Hence, the concepts of PDX clinical trials and co-clinical trials have gained importance and prospered in recent years. A PDX clinical trial implies investigation on a set of PDXs originated from multiple patients prior to an early phase human trial, whereas a co-clinical trial refers to drug response assays, in parallel and simultaneously with a human clinical trial, on a set of PDX models established from the same clinical trial participants. A carefully designed PDX- /co- clinical trial requires a meticulous calculation of the sample size, enrollment of pathologically and molecularly diverse patients, and selection of suitable endpoints and outcome measures. With a special focus on PDX clinical trial design in anti-cancer research, this chapter specifically addresses how to develop cancer-bearing PDX models, what to consider in characterizing them, how to track their fidelity to the parental tumor, how to estimate the number of animals included in a PDX trial, how to achieve greater power in the translation of final outcomes, what are the minimum endpoints to be considered, and what measures are preferred for evaluating the response to therapeutic interventions.

Antiviral Activity of Vitamin D and COVID 19: Current Understanding

Innate and adaptive immune responses, which are intimately related to the evolution of many infectious diseases, are influenced by the biologically active form of vitamin D. From a mechanical perspective, there are several rationales to assume that vitamin D positively modifies host responses to SARS-CoV-2, either in the early infection or subsequent hyper-inflammatory stages of COVID-19. It has been long known that vitamin D metabolites induce antiviral effects through indirect and direct mechanisms via antimicrobial peptides, immune modulation, the interaction between major viral and cellular particles, initiation of apoptosis and autophagy, and diversity of hereditary and epigenetic aspects. The remarkable overlap between the deficiency of vitamin D and risk factors for severe COVID-19, including obesity, aging, and Black or Asian ethnicity, has motivated researchers to assume that supplementation of vitamin D can be promising as a preventive or treatment agent for COVID-19. Since the outset of the pandemic, researchers have integrated literature searches and crosssectional statistical studies to appraise the vitamin D level impact of COVID-19, whereby nearly 30 observational studies have confirmed that the incidence, severity, and mortality of COVID-19 are inversely related to the serum 25OHD concentrations. Also, some recently announced clinical trials indicated that vitamin D supplementation has a positive effect on the severity of COVID-19; however, other studies, including clinical trials, have not supported that, especially if we take into account what was revealed in a recent clinical trial, i.e., airway diseases are related to the irregular metabolism of vitamin D increasing the potential of developing vitamin D deficiency due to pulmonary inflammation. Therefore, more dedicated studies are required without critical limitations to ascertain the actual effect of vitamin D in preventing and treating COVID-19, and if its effectiveness is proven, the effective dose must be determined.

MicroRNAs as Targets for the Management of Obesity

Obesity is a global health problem and one of the major causes of chronic disorders, such as metabolic syndrome, insulin resistance, type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Obesity is not only an expansion of adipose tissue but also is accompanied by numerous biochemical changes. For example, several adipokines are secreted from adipose tissue and their levels are altered in obesity. The same is true for many metabolic regulators and epigenetic modifiers, such as microRNAs and inflammatory cytokines. MicroRNAs are short noncoding RNA molecules that generally suppress the expression of various genes by binding to the untranslated regions of their target mRNAs. There is growing evidence that metabolic diseases are associated with dysregulation of microRNAs. These molecules are potentially valuable biomarkers that can assist in accurate diagnostic and/or prognostic procedures as well as drug design. Therefore, this chapter, attempted to review the previous findings regarding the relationship between microRNAs and obesity and its associated metabolic alterations.

Current Treatment of Obesity versus the Next Generation of Anti-Obesogenic Drugs: An Ecologically and Sustainable Approach to Health

Obesity is currently recognized as an epidemic and one of the most important health problems worldwide. World Health Organization data indicates that in developing countries, obesity in adults is more frequent than malnutrition. More than 1.9 billion adults are overweight, with 650 million of these being obese. More than 200 million school-aged children are overweight, making this generation more likely to have a shorter productive life and life expectancy than their parents. This portion of the population has a greatly increased risk of developing cardiovascular disease, diabetes, dyslipidemia, hypertension, hepatic steatosis, certain types of tumor and infertility, negatively impacting their quality of life. Obesity can be prevented and is treatable with the adoption of a healthy and appropriate diet, and with regular physical exercise. However,lifestyle modification therapy for the obese population remains unsatisfactory. In addition, it is important to emphasize that obesity treatment presents better results when accompanied by a multidisciplinary team, using diet therapy, prescribed physical exercise, psychotherapy and drug therapy, according to the needs of each patient. Obesity is a multifactorial, complex, chronic and relapsing disease involving gene-environment interaction and should therefore be treated with a systemic and ecological approach. This is because many roles of intestinal microbiota in human health have recently been discovered, mainly in relation to weight gain or loss. Additionally, recent studies suggest that human gut microbiota may contribute to the regulation of multiple neurochemical and neurometabolic pathways through complex systems that interact and interconnect the gastrointestinal tract, skin, liver, and other organs, such as the central nervous system. The brain and intestine form a complex nervous, endocrine and immune bidirectional communication axis, involving neurotransmitters and neuromodulators. Changes in one organ will affect other organs, and disturbances in the composition and number of intestinal microorganisms can affect the enteric and central nervous systems. Alterations in intestinal microbiota may increase intestinal barrier permeability, raising the risk of developing chronic diseases, like obesity. Furthermore, the imbalance between gut microbiota and its host leads to dysbiosis, which, in turn, contributes to the establishment of an inflammatory and oxidative process, impaired glucose metabolism, insulin resistance, obesity, increased risk of developing of metabolic syndrome, type 2 diabetes, inflammatory bowel, autoimmune diseases, and cancers. Studies have shown that less-industrialized populations, such as those in Africa, present a more diversified gut microbiota that is richer in terms of bacterial genera, which encode enzymes that hydrolyze cellulose and xylan. This finding suggests these individuals have a fiber-rich diet, a different situation from industrialized populations who obtain energy from an ultra-processed diet, rich in fats, salt, sugars and preservatives, and who present a high prevalence of obesity and other chronic diseases. In this sense, it is fundamental to reflect on what type of anti-obesity drug should be developed to treat this pathology, as most of these drugs act on the central nervous system and, therefore, interfere in communication between the brain and intestine. It is important to develop an anti-obesity drug that acts not only on appetite control and on increased satiety, but also engages with and is friendly to intestinal microbiota, via increased diversity of this ecosystem, decreased fat storage and chronic oxidation inflammation, and correct modulation of the immune system. Nonetheless, we must not forget that obesity is a complex and multifactorial disease, and that its drug treatment must be combined with a healthy and adequate diet, physical exercise and cognitive-behavioral therapy. Within this context, this chapter aims to promote reflection around this theme and to provide the theoretical foundation for development of the next generation of anti-obesogenic drugs.

The Effect of Sleep on Weight and Obesity Management

Obesity is a global pandemic with far reaching implications. The overall trend of Americans who are classified as obese and morbidly obese continues to rise. Alongside, the cost of healthcare as it relates to obesity and obesity-related illness continues to rise, in fact, it has doubled over the past 10 years. Obesity-related illnesses include type 2 diabetes, cardiovascular diseases, chronic kidney disease, and chronic liver disease among others. Paralleling the obesity epidemic, sleep loss and dysfunction have emerged as a public health issue. Both obesity and sleep dysfunction share important pathophysiologic pathways, resulting in a persistent low-grade inflammatory state which ultimately contributes to chronic disease as part of the metabolic syndrome. This chapter outlines the role of sleep in the pathogenesis of obesity and reviews the potential therapeutic implications of restoring normal sleep function in patients with obesity and obesity-associated diseases.

Chalcones as Anti-inflammatory, Anti-diabetic, and Anti-depressant Agents

Flavonoids are naturally sourced compounds found in many substances consumed as food and have beneficial effects on human health. Chalcones, essential members of the flavonoid family, have also attracted many researchers' attention due to their wide range of pharmacological effects. In this chapter, the antiinflammatory, antidiabetic, and antidepressant activities of the natural compounds in the structure of chalcones and the compounds synthesized with the help these compounds will be discussed. It has been written after a literature review of the articles published between 2000 and 2020 and aims to be a guide for designing new active drug ingredients.

Curcuma Longa as Dietary Supplement and Diabetes Mellitus: Evidence from Experimental Studies

Curcuma longa, due to its broad scope of remedial possibilities, is still utilized as a diet-based remedy against diabetes mellitus and diabetic intricacies by legitimately connecting with various cellular pathways that incite diabetes mellitus pathogenesis. This chapter investigates the general valuable impacts of Curcuma longa on diabetes mellitus and its related complications based on experimental studies. Alongside clarifying the useful facts of Curcuma longa, it might be helpful to consider those cellular pathways which directly relate to diabetes. The possible mechanism of action of Curcuma longa as anti-hyperglycemic considered inhibition of lipid peroxidation, starch using compounds, transcriptional compounds, and activation of antioxidant enzyme capacity. Subsequently, Curcuma longa shows its antidiabetic restorative impacts by expanding insulin affectability, securing β-cells of pancreatic islets, diminishing fat accumulation, reducing oxidative stress, or enhancing glucose take-up by the tissues. Other than this, Curcuma longa, likewise, shows defensive impacts against a few diabetic-linked complications, prominently diabetic cataracts, and kidney function, along with the antioxidant agents. Taking everything into account, this work recommends that Curcuma longa help in treating diabetes and complications that occur due to diabetes; however, tolerant advising is also necessary as directing power to achieve diet-based treatment if there should be an occurrence of diabetes. In this chapter, we discuss basic and clinical proof of Curcuma longa's potential for diabetes mellitus treatment mainly due to its hypoglycemic, antioxidant, and antiinflammatory qualities.

Urge for Herbal Anti-Diabetic Medicines Towards Clinical and Therapeutic Implications

Diabetes is a deep-seated and persistent ailment that has a comprehensive and long term effect on carbohydrate, fat, and protein metabolism. This malady is usually associated with hyperglycemia over an extended time which may be due to either flaw in the production of pancreatic insulin or implausible insulin target tissue.

Current pharmacological treatment strategies aim to promote pancreatic insulin release, reduce glucose output from the liver, or increase insulin sensitivity of adipocytes. But none of these current strategies have an appreciable curative effect on diabetes. Continuous exercise and workouts accompanied by lifestyle modifications have been found to improve glycemic control in diabetic patients which have not been well adapted with all patients. This emphasizes the role and urges herbal anti-diabetic drugs as they have a remarkably wide array of primary and secondary metabolites that have noted anti-diabetic actions accompanied by anti-oxidant action. But an herbal antidiabetic drug has got some limitations like a difference in constituents due to different geographical locations, scientific misidentification, product contamination, inappropriate time and method of harvesting, adulteration, etc. So, drug standardization is an indispensable tool to ensure the safety and efficacy of herbal anti-diabetic drugs. Regulatory agencies worldwide have set up stringent regulatory frameworks that have led to the development of herbal anti-diabetic drugs positively. When two or more drugs (either herbal or synthetic) are administered together, there may be either chemical or pharmacological interaction that may alter the effect of either both or sometimes one agent which cannot be easily predicted and understandable. These interactions may affect clinical safety and efficacy via additive/synergistic or antagonistic interactions. While antagonistic interactions tend to receive more attention due to safety concerns, additive/synergistic interactions increase the desired pharmacological response which is a boon to us in treatment, for which special attention has to be paid. In this chapter, a detailed and in-depth analysis of herbal antidiabetic drugs and various commonly used anti-diabetic plants are discussed. Also, problems associated with herbal anti-diabetic drugs and methods to overcome along with special emphasis on their clinical and therapeutic implications including reported herb-drug interactions, are examined.

Foods For Diabetics

The chapter deals with diabetes overview, focuses on the relation of diet and diabetes, the conventional and non-conventional raw material for the development of foods for the diabetic. The chapter also discusses natural and synthetic sweeteners’ overview. Dietary approaches to produce food for diabetic consumers also are addressed, with special emphasis on foods with insulin-secreting, insulin-sensitizing, and insulin-mimetic properties. Also, the terms: glycemic index, insulin index, and glycemic load are defined. And finally, some recipes for diabetic consumers are recommended.

Biomaterials for Cardiac Regeneration

Globally, cardiovascular disease is one of the predominant clinical conditions, which accounts for about 50% of human mortality and morbidity. No doubt pharmacological and surgical interventions have dramatically improved the quality of life of patients with cardiovascular diseases. However, the demand for new therapeutic interventions as well as regenerative strategies is currently increasing. Biomaterials, both natural and synthetic, have exhibited great potential in cardiac regenerative therapy. Therefore, the development of biomaterials based extracellular matrix, grafts or stents, etc. would be highly beneficial for supporting the natural function and physiology of heart tissues.

Nanocarriers for Biologicals Delivery to Cardiovascular System

As cardiovascular diseases remain the leading cause of mortality worldwide, a large number of clinical trials are under development, investigating the safety and efficacy of RNA therapeutics in clinical conditions. Nanomedicine based drug delivery systems are currently the new avenue for the treatment of CVDs, providing great advantages to the treatment regime of CVDs. Currently, antisense therapy DNA- and RNA-based and microRNAs are widely applied therapeutic strategies to regulate gene expression and its effect on CVDs. In this review, different biological-based targeting therapies for cardiovascular diseases and their outcomes are discussed.

Recent Developments in Diabetes Evaluation and Management: Implications for the Practicing Clinicians

Diabetes is a major public health problem affecting millions of people around the globe. In the United States alone, over 7.5 million have type 2 diabetes and an alarming 78 million adults have prediabetes and remain largely undiagnosed. This epidemic was ushered in by the ongoing epidemic of obesity and is caused in-part by sedentary life style and aging population. In this chapter we discuss the diabetes epidemic highlighting the major risk factor of diabetes, particularly type 2. We also discuss the complications of diabetes including microvascular complications as well as macrovascular disease including coronary heart disease and stroke, the major cause of morbidity and mortality in the diabetic population. Finally, we present the major therapeutic advances in diabetes including modern pharmacologic agents and their potential effects on cardiovascular risk. We also outline the recent technological advances in diabetes management including closed loop systems, artificial pancreas, stem cell therapy among other ongoing research bound to prevent and/or alleviate the effects of this ongoing epidemic.

Genetically Modified T-cells Affinity to Tumor Cells-Development of Adoptive T-cell Immunotherapy

T-cells play an essential role in the cell-mediated immune response to tumor cells, while tumor cells in tumor sites take many strategies to evade the host immune response, including creating many immune-suppressive factors from tumor microenvironment (TME) or decreasing expression of immunogenicity of target antigens. To resolve the evasion of tumor cells from T-cells attacking, some strategies such as genetically modified T-cells altering the specificity of the T-cell receptor (TCR) or introducing antibody-like recognition of chimeric antigen receptors (CARs) have made significant advances. The modified TCR T-cells or CAR T-cells have been administered to cure B-cell lymphoma or B-lymphocyte leukemia in clinical trials successfully. We have been going to study the specificity and safety of T-cell adoptive immunotherapy for more than 30 years so that our experiences to apply for genetically modified T-cell more focus on the specificity and safety of these therapies. Moreover, the strategies using genetically modified T-cell immunotherapy need face challenges for immunogenicity from different types of tumors. The chapter will introduce T-cell specific affinity between T-cell and tumor cells such as TCR and CAR T-cells, discuss challenges from the selection of antigen targets, and address safety issues to clinical development. All in all, T-cell adoptive immunology regarding TCR and CAR T-cell improves the clinical application.

Gender Differences in Obesity - Related Type 2 Diabetes: Possible Role of Meta-inflammation

Biological and psychosocial differences between men and women affect the epidemiology and pathophysiology of many diseases, including type 2 diabetes mellitus (T2DM). Obesity is a major risk factor for T2DM. Sex hormones, estrogens, and androgens contribute to gender differences in obesity-related T2DM since they regulate not only biological characteristics but also adipose tissue function and metabolism. Obesity, in particular visceral obesity, is characterized by systemic lowgrade inflammation or meta-inflammation. Meta-inflammation that occurs locally in adipose tissue becomes systemic via the release of various active inflammatory cytokines and acute-phase proteins, including TNF- α, interleukins 1β, 6, 17, and Creactive protein (CRP) into the bloodstream and consequently leads to insulin resistance. Understanding the differences between sex and gender is equally important in the prevention of obesity-related T2DM, its diagnosis and therapy. The initial stages of meta-inflammation involve adipocyte hypertrophy, hypoxia and cellular stress. Studies on the role of gender differences in obesity-induced inflammatory response have shown that males have a greater inflammatory response in adipose tissue, increased adipocyte apoptosis and macrophage infiltration, greater accumulation of pro-inflammatory adipose tissue macrophages and increased expression of inflammatory cytokines. These data suggest that adipose tissue in males is more susceptible to inflammation when compared to females and that this might lead to a higher incidence of insulin resistance. It is still debated whether oxidative stress is more pronounced in women than in men with T2DM. However, in female patients with T2DM, serum levels of IL-6, TNF-α and CRP were significantly higher compared to males with T2DM. Gender differences have a major impact on the development and the progression of obesity-related T2DM and its complications. Future studies should contribute to a better understanding of gender differences in obesity-related T2DM and differences in the inflammatory response between men and women to establish prevention and treatment of diabetes by gender-related guidelines.

The Role of Meta-Inflammation in The Adipose Tissue Dysfunction and Obesity

The term “meta-inflammation” refers to chronic metabolic inflammation, which is thought to have an important role in the pathogenesis of numerous metabolic diseases. Majority of authors agree that inflammation, as a component of immune system, may serve as a link between obesity and numerous diseases. Hence, the role of meta-inflammation in the pathogenesis of obesity-related diseases is extensively investigated. Mitochondrial dysfunction in adipocytes is lately regarded as a primary cause of adipose tissue inflammation. This newly proposed hypothesis contradicts currently prevailing concept that “adipose tissue hypoxia” underlies adipose tissue dysfunction in obesity. Infiltration of adipose tissue by immune cells is one of the hallmarks of adipose tissue dysfunction. Based on the current knowledge, adipose tissue (AT) macrophages are considered to have a pivotal role in the development of adipose tissue inflammation and dysfunction. Macrophages that infiltrate the adipose tissue are divided into: pro-inflammatory (M1) and anti-inflammatory (M2) AT macrophages. Studies have shown that M1 AT macrophages contribute to insulin resistance by producing pro-inflammatory cytokines. Conversely, M2 AT macrophages are involved in the repair or remodeling of tissues. In obesity, adipose tissue becomes inflamed and goes through cellular remodeling. Adipocytes increase in number (hyperplasia) and size (hypertrophy), become infiltrated by macrophages and undergo fibrosis. Hypertrophic adipocytes secrete more pro-inflammatory molecules that lead to a shift of M2 to M1 AT macrophages. Adipose tissue dysfunction in obesity is characterized by changes on cellular and molecular level, which include immune cells such as T cells, B cells and dendritic cells. However, their role in meta-inflammation and adipose tissue dysfunction remains to be fully elucidated. Novel findings suggest that dysregulation of autophagy in adipose tissue has an important role in metainflammation. Studies have shown that there is a strong relationship between the prenatal and perinatal environment and obesity-related diseases. Childhood obesity is associated with meta-inflammation that affects not only adipose tissue but other organs as well. Since adipose tissue dysfunction in obesity plays a pivotal role in disturbing homeostatic processes in the human body, it is of essential importance that health care systems at the global level work on implementation of precautionary strategies in order to prevent the development and progression of meta-inflammation and obesity-related metabolic complications starting at early stages of life.

The Endocrine Function of Adipose Tissue

White adipose tissue secretes adipokines that regulate numerous biological processes by autocrine, paracrine, and endocrine mechanisms. Adipokines are essential in the balance between appetite and satiety, regulation of body fat stores and energy expenditure, glucose tolerance, insulin release and sensitivity, cell growth, inflammation, oxidative stress, angiogenesis, and atherosclerosis. Cytokines are secreted directly from adipocytes, but also from other stromal cells in the adipose depot and primarily play a role in immune regulation. Among adipokines, leptin, resistin, and visfatin were described as markers that are positively related to body weight, fat mass, insulin resistance, and exhibit pro-inflammatory properties. Opposite to the proinflammatory cytokines, adipose tissue can secrete a series of anti-inflammatory adipokines, including adiponectin, apelin, vaspin, and omentin, which play crucial protective roles in inflammation states, insulin resistance, and atherosclerosis. In obese person dysregulation of adipokines secretion, in addition to upregulated inflammatory response, contributes to obesity-induced insulin resistance and systemic low-grade inflammation. Brown adipose tissue (BAT) might also have a secretory role, secreting “brownkines” that act in a paracrine or autocrine manner. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced.

Phytochemicals for the Treatment of Human Diseases

Medicinal plants are a major source of remedies for the treatment of human ailments in under-developed and developing countries. Traditional or alternative medicines were practiced in ancient civilizations for the cure of human ailments. In recent years, natural products play a vital role in drug discovery for life-threatening ailments like cancer, malaria, diabetes, and cardiovascular problems. Due to the advancement of scientific techniques, isolated phytochemicals can be developed as a medicine for lifestyle and chronic disorders. Herbal medicinal products are also developed for effective treatment of several diseases like cancer, malaria, diabetes, cardiovascular complications, etc. Recently,drug discovery from plants for the treatment of cancer has become more focused, leading to the discovery of novel anticancer drugs such as paclitaxel, docetaxel, topotecan, irinotecan, vincristine, and vinblastine, etc. In this book chapter, we have discussed important medicinal plants and bioactive natural products for the treatment or management of diabetes mellitus, cancer, obesity, and cardiovascular complications.

Fluorescence Biosensors

This chapter provides an overview of state of the art in fluorescence detection using molecular-sized biosensors. In the past three decades, a number of activatable or tunable fluorescence biosensors have been developed, including FRET sensors, intercalating dyes, electron transfer-based sensors, fluorescein-based sensors, split GFP, biarsenical-tetracysteine sensors, aptamer sensors, H-dimer sensors, lanthanide-based sensors, carbon nanotube sensors, quencher transfer/detachment, FRET binary probes and chameleon NanoCluster Beacons. Researchers have proposed various methods to increase the dynamic range, the specificity, and the sensitivity of the aforementioned sensors. The requirements for using fluorescence sensors in biomedical imaging are reviewed, which provide general guidance for readers to conduct medical diagnosis with these newly-developed biosensing technologies. The chapter concludes with a brief perspective into the future of fluorescence-based biosensing systems.

AMPK as a Postulated Target for Metabolic Syndrome and Obesity

The predominance of obesity is consistently rising worldwide. Development of obesity is intimately related with other chronic diseases such as type 2 diabetes and cardiovascular diseases. Treatment of obesity is achieved by losing weight, but to reach this, beyond strategies based on food deprivation, innovative therapeutic interventions are necessary. AMP-activated protein kinase (AMPK) is considered the master regulator of metabolism. AMPK is activated by a low cellular energy status. Activated AMPK promotes catabolic processes to generate ATP while inhibits the synthesis pathways (anabolism) requiring ATP for maintain the cellular energy homeostasis. Additionaly, AMPK is involved in other cellular processes (i.e. cell cycle regulation). The ability of AMPK to drive metabolism makes it a postulated target for the treatment of obesity, diabetes, inflammation and cancer. We review here recent knowledge about AMPK and its role in an obesity context. Furthermore, we provide an overview of the effect of different drugs on AMPK activity and the association between this effect and the treatment of obesity and its associated comorbidities.

Tamarind (Tamarindus indica L.): A Review of its Use as a Spice, a Culinary Herb and Medicinal Applications

Tamarind (Tamarindus indica) is a highly valued multipurpose fruit tree indigenous to tropical Africa. T. indica is extensively used in traditional medicine and has been widely studied. Different authors have provided reviews on the various aspects of tamarind, with a focus on its traditional uses, ecology, phytochemistry and pharmacology. Limited studies on the preclinical and clinical aspects of tamarind have been explored in most reviews. Even less attention has been given to the use of tamarind as a spice or a culinary herb. This chapter reviews the health benefits of tamarind as a spice and a culinary herb. It also explores the choice of tamarind use over other spices and how it is utilized to improve people’s livelihoods. The ethnomedicinal uses of tamarind are supported with recent scientific evidence from preclinical and clinical studies. The threats to the sustainable use of tamarind, particularly environmental degradation, land conversion and climate change are discussed. We conclude by highlighting the conservation strategies that are currently being implemented to ensure sustainable utilization of tamarind.

Genomic Fingerprint of Molecular Mechanisms of Breast Carcinogenesis

Breast cancer in women is the most frequent cancer with the highest mortality worldwide. The risk factor includes aging, family history, genetic predisposition, and hormone factor. In recent years, many new gene signatures have been identified, which have a profound effect on breast cancer initiation and progression. Extensive research has been done in the past five decades in understanding breast cancer biology through genomics and proteomics. All these comprehensive studies from breast cancer patients elucidate heterogeneity of disease as one of the complex problems in its treatment and management. The outburst of molecular information has led to an understanding of the biological diversity of breast cancer. The involvement of various genes at different steps of cancer progression, such as proliferation, evading apoptosis, migration, immunosuppression, and chemoresistance, have been described in this chapter. With the advent of miRNA and splicing factors, new differential regulators of genes have been identified in breast cancer. The breast cancer therapeutic approach can be accomplished by identifying the oncogene and tumor suppressor genes at an early stage of the disease. Elucidation of novel genes in breast cancer will lead to identifying new molecular pathways that may be targeted for its treatment. For the prognostic and diagnostic treatment of breast cancer it is very important to identify newer genomic fingerprints and to develop novel therapeutic targets against them. Our main goal is to make available inclusive understanding of molecular mechanisms and hallmarks of breast carcinogenesis.

An Overview of Genetic, Proteomic and Metabolomic Biomarkers in Breast Cancer

The molecular techniques play an important role in the diagnosis and treatment of breast cancer. Recent advances in molecular techniques have contributed significantly to understanding tumor biology, tumor heterogeneity, identification of different biomarkers, and discovery of new therapeutic measures and improvement in overall survival, especially in specific subsets of breast cancer. There are other challenging areas in breast cancer research, such as the development of treatments for the highly aggressive triple-negative breast cancer subtype, chemotherapy-resistant cancer stem cell subpopulation, and male breast cancer. New knowledge emerging from researches in genetics, proteomics, and metabolomics offers a promising opportunity for the identification of new biomarkers, and to find novel targets that could facilitate future therapeutic interventions.

Environmental Chemical Obesogens

Understanding the myriad of factors contributing to obesity is essential for curbing its decade-long expansion. Recently, despite the evidence of traditional contributing factors, the role of environmental chemicals with endocrine disrupting activity has also been highlighted. Undeniably, even very small concentrations of these endocrine disrupting chemicals (EDCs) have the capacity to induce severe health damages. The “environmental obesogen” hypothesis associates EDCs to the disruption of energy homeostasis, in particular because of their ability to modulate adipocyte biology. Further studies have revealed numerous potential mechanisms, including modulation of nuclear hormone receptor function and modification of the epigenome. More recently, their involvement in exacerbating metabolic dysfunction in an obesity context reinforces the hypothesis that EDCs have an important “environmental dysmetabolic” effect. Besides adulthood exposure, the perinatal effects are very important since they may allow a change in metabolic programming, encouraging the further development of obesity. Consequently, additional research directed at understanding the nature and action of EDCs will illuminate the connection between health and environment as well as the possible effects triggered by these compounds in respect to public health. Nutrition is being further substantiated as an important modulator of inflammatory and antioxidant pathways, especially associated with environmental insult; nutrition is also emerging as a tool to address exposure toxicity of ECDs as both a sensing and remediation platform. Ultimately, improving EDC exposure measurement, reducing confounding bias, identifying discrete periods of vulnerability and quantifying the effects of EDC mixtures will enhance inferences originated from epidemiological studies.

Obesity and Adipose Tissue Remodeling

Adipose Tissue (AT) is an endocrine organ with a key role in the regulation of the energy homeostasis. White AT accumulates energy in the form of triglycerides within lipid droplets and, therefore, is particularly abundant in obesity. In contrast, brown AT is specialized for energy expenditure playing a pivotal role on thermogenesis control and its mass decreases with obesity. AT secretes a large number of adipokines that regulate the central control of appetite and the metabolism of diverse peripheral tissues. This secretion and also the anatomical features of AT are closely related with the nutritional status and, naturally, strongly differ between normal weight and obese individuals. AT remodeling is indeed an ongoing process, that is pathologically exacerbated in the obese state. This review will discuss and present updated data describing the main changes in AT that correlate with an obese status. In obesity, AT changes in mass, capacity for energy storage, distribution through the organism, cellular composition, endocrine role and signaling. In summary, the chronic excess of nutrient supply leads to adipocyte hyperplasia and hypertrophy, hypoxia, mitochondrial dysfunction, proinflammatory signaling, adipokine secretion and, ultimately, to cell death. The extent of AT remodeling is closely associated with the pathophysiological consequences of obesity, including insulin resistance, cardiovascular disease, hypertension and hepatic steatosis.

Mortality, Salvation, and Remembrance Motifs

This chapter presents the range of motifs found in churchyards and kirkyards based on still-upstanding headstones belonging to Anglican and Presbyterian parish sites. A range of motifs were discovered on what are referred to as ‘motifed’ headstones as those headstones that had a legible date of death and contained motifs. Table seriations were produced to convey these findings. Floral motifs were most popular, followed by urn and cross motifs – the cross motif was commonly introduced between 1800 and 1849 in England and Inverness. Motifs of mortality, such as urn, torch, and hourglass, were present in England on legible headstones, but were not evident on motifed headstones in Scotland.

Research Methods

Details of the east-leaning transect for site sampling in the study spanning England and Scotland are provided in this chapter, detailing the methods deployed in the research. This includes an outline of site and field methods used at the six locations and 13 sites comprised in this study. Outputs for the study are also relayed, entailing digital photographs of each upright headstone and location maps at a scale of 1:500. A database of information has been developed through various site visits since 2006. Inferential statistics are used to define the correlation of headstone dimensions with age at death or year of death.

Transient Receptor Potential Channels: Therapeutic Targets for Cardiometabolic Diseases?

Transient receptor potential (TRP) channels are ubiquitously expressed cellular sensors that respond to changes in the cellular environment. They act in nociception, taste perception, thermosensation, mechanosensing, osmolarity sensing, and signal transduction. Mammalian TRP channels comprise 28 members divided into six subfamilies: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin) and TRPV (vanilloid). TRP mutations that result in either gain or loss of function have been linked to several human diseases, among them hypertension, cardiac hypertrophy, obesity, and diabetes. In the myocardium, TRP channels modulate Ca+2 handling and are differentially expressed in models of cardiac remodeling and dysfunction. TRP channels are also involved in insulin release from pancreatic beta-cells and glucose tolerance in rodent models of type 2 diabetes. Some of these channels promote thermogenesis and thus prevent diet-induced obesity. How TRP channels are modulated in vivo is still unknown since few endogenous ligands were identified so far. However, a wide range of natural products with therapeutic potential activates TRP channels and might serve as models for new drug discovery and development to prevent cardiometabolic morbidity and mortality. Studies with TRP channels show promising results, but the translation to preventive or therapeutic strategies against cardiometabolic diseases is challenging since they are found in multiple tissues and enrolled in several physiological actions, which increases the risk of adverse effects.

Response of Eukaryotes to Stress

Eukaryotic stress response involves changes in transcription, translation, and proteostasis. Some changes are similar across many stress responses. Stressors such as misfolded proteins, oxidative stress, viral RNAs, heme deficiency, heat shock, amino acid shortage, and others activate the integrated stress response (ISR) kinases PERK, PKR, HRI, and GCN2; they phosphorylate eIF2α inducing global inhibition of translation. Some stresses, e.g. oxidative and osmotic can activate several kinases. Transcriptional response to stress involves the suppression of genes functioning in energy-consuming processes such as protein biosynthesis and activation of genes that mitigate damage caused by stress. Many stresses interfere with the synthesis and folding of proteins. When unfolded protein level exceeds folding and clearance capacity of the cell, the unfolded protein response is triggered, which increases that capacity by producing more chaperones and proteases. Autophagy is another common response to stress that helps to cleanse the cell of aggregated proteins and dysfunctional organelles and replenish the supply of biosynthetic precursors and energy. There are also responses specific to heat, cold, osmotic, pH, oxidative, and mitochondrial stress. They involve activation of programs that mediate adjustment to specific stress.

Subject Index

Effects of Dietary Polyphenols on Chronic Diseases: Epidemiological Data and Molecular Mechanisms of Action

Non-communicable diseases (NCDs) such as cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DMM), cancers, and chronic respiratory diseases are usually chronic in nature, and the mortality rate associated with these NCDs is high. However, epidemiological evidence implies a relationship between dietary polyphenols and reduced risk of a number of NCDs, and indicated that dietary polyphenols inhibit NCD-related pathological changes and prophylactically prevent occurrence of NCDs. In this review, I described the role of dietary polyphenols in the prevention of NCDs, and discussed the possible utility of several polyphenols as prophylactic agents for obesity, CVD, T2DMM, and cancer. Polyphenols are classified based on structure; particularly, flavonoids, which is further divided into six major subclasses, are the most common dietary polyphenols, and help in the prevention of NCDs. In addition, consumption of polyphenols was associated with a reduced risk of T2DMM and obesity. The preventive effect on NCD by polyphenols such as epigallocatechin gallate and resveratrol was associated with potent anti-oxidative and anti-inflammatory effects. Furthermore, these polyphenols regulated the signaling pathway, associated with NCDs. Polyphenol contributed to NCD prevention, and the protective effects may have resulted from its anti-oxidative and anti-inflammatory effect. The intake of polyphenolrich diets such as vegetable and fruit is important for prevention of NCDs. In future, the difference in polyphenol preventive effects and novel mechanism for preventing NCDs with polyphenol, need to be clarified.

Herbal Extracts from Carica papaya and Azadirachta indica: What Role for ROS in Cancer Cell Lines?

The use of plant-derived medications in the treatment and prevention of diseases, i.e., phytotherapy, comprises the traditional knowledge of therapeutic advantages deriving from the use of herbal parts to prevent, protect against and cure several pathologic conditions, such as cancerous, metabolic and inflammatory diseases. Herbal medications are prevalent in countries with limited resources, but, recently, increasing attention is devoted to their exploitation in cancer management on the basis of their low cost and side effects absence compared to conventional radiation or chemotherapic cancer approach. Currently, about 114,000 herbal extracts have screened for anticancer activity and 60% of the commercially available and clinically used cancer drugs, such as vinblastine and vincristine, paclitaxel, campothecin and its derivatives, are from natural sources. These compounds are active against a number of cancer types (ovarian, breast, lung, colon, liver, blood, prostate cancer). There are many types of cancer elicited by several factors that still render this disease a major public health problem, almost everywhere in the world.

The human body is constantly exposed to free radicals arising from exogenous and endogenous origins, which cause oxidative stress. Oxidative stress is closely related to various diseases, including cancer. There are many evidences that ROS are pivotal in cancer progression (via damage of DNA leading to genomic instability) and regression (via cell death induction through oxidative stress burst). Antioxidants stabilize free radicals and, in turn, prevent the oxidative stress, playing a key role in protection of the body, In this context, natural plants-derived antioxidants are universally considered very important for the prevention and treatment of oxidative stress and cancer. However, a dual role of plants in ROS generation or scavenging is recognized as plants extracts can also increase ROS production in the cells. Consequently, the role of plant extracts in ROS balancing inside cancer cells is a very fascinating feature in phytotherapy.

Among the plants reported in traditional medicine as a very panacea in active compounds, Carica papaya and Azadiracta indica (also known as Neem) extracts from different parts (leaves, seeds, fruits, etc.) are scientifically validated in the treatment of several diseases, including cancer. In this context, the two plants have different impact on cancer cell lines. In particular hydro-alcoolic extract of Neem leaves shows a pro-oxidant activity in hepatoma HepG2 cells, whereas water extract of C. papaya seeds exerts an anti-oxidant activity in leukemia HL-60 cells. Neem extract is unable to quench oxidative stress induced on HepG2 and synergizes with hydrogen peroxide (H2O2) in inducing cell death. Conversely, C. papaya extract quenches ROS induced by H2O2 in HL-60 cells but at the same time negatively affects cell viability.

These evidences corroborate the idea that the extracts from plants could act in patients with cancer to modulate oxidative homeostasis and obtain benefit during cancer therapy.

Pharmacological Mechanism of PPARγ Ratio in Diabetes and Obesity

The worldwide prevalence of obesity has increased at alarming rates over the last four decades. Overweight and obesity featuring the excess of white adipose tissue are cardiovascular risk conditions consistently associated with the development of complex metabolic disorders, including insulin resistance, type 2 diabetes mellitus ( T2DM) and coronary heart diseases. Many natural and synthetic agonists of peroxisome proliferator-activated receptors (PPARs; nuclear receptors) are used in the treatment of glucose and lipid disorders. PPARs perform different activities, mainly via endogenous ligands produced in the metabolic pathways of fatty acids; and therefore, they are called lipid sensors. PPAR agonists have different properties and specificities for individual PPAR receptor, different absorption/distribution profiles, and distinct gene expression profiles, which ultimately lead to different clinical outcomes. The isoform PPARγ is expressed in white and brown adipose tissue, large intestine and spleen. However, its expression is highest in adipocytes and it plays a key role in the adipogenesis regulation, energy balance and lipid biosynthesis. PPARγ has been the focus of intense research once its ligands have been described to treat T2DM. Some of them are currently prescribed as anti-diabetic drugs, such as thiazolidinedione. PPARγ activation modulates not only insulin sensitization, but also lipid metabolism, vascular tone and inflammation, all processes involved in atherogenesis. Considering the impact of this subject in the public health and the necessity of new approaches for the development of new drugs to treat metabolic diseases and to improve the quality of life, this chapter has the aim of revising important points concerning the involvement of the nuclear receptors in obesity, diabetes and discuss the real possibility of this target to become an effective and safe pharmacological therapy.

Through the Perspective of Histology - The Alzheimer’s Disease Promotion by Obesity and Glucose Metabolism: Type 3 Diabetes

Since the 1990s The World Health Organisation (WHO) has stated that “… obesity should now be regarded as one of the greatest neglected public health problems of our time…” and defined the global epidemic of being overweight and obese as “globesity”. A positive energy balance, which consists of an imbalance between energy intake and calorie expenditure is the main cause of obesity, however, genetic, environmental, socioeconomical, behavioral and psychological factors may also be the inducing factors when it comes to obesity. The excess of adiposity has an enhancing effect on the development of hypertension, cardiovascular diseases and type 2 diabetes mellitus (T2DM) as a result of the resistance to insulin-mediated glucose disposal. T2DM which represents a common disease associated with obesity and often aging is characterized by high blood glucose levels, impaired insulin production and peripheral insulin resistance. Homeostatic degradation of glucose affects the cerebral functions directly or indirectly because glucose is a significant metabolic substrate for all cells and also for the cells of the brain. Insulin has a key effect on the regulation of energy metabolism of neurons and neuronal recovery, which acts as a growth factor on all cells including neurons in the central nervous system. Therefore, simply put, impairment in neuronal homeostasis which occurs as a result of insulin deficiency. These are considered to be a risk factor for Alzheimer’s disease (AD) development. Indeed, many studies have shown that glucose intolerance and impairment of insulin secretion are associated with a higher risk to develop dementia or AD. It is worth remembering that AD is associated with brain insulin resistance and deficiency, whereas T2DM is associated with peripheral insulin resistance. In short, it can be said that T2DM causes AD-type neurodegeneration in the brain. T2DM and AD share several molecular processes that underlie the degenerative developments. Dysregulated glucose metabolism, abnormalities in insulin signaling, the formation of advanced glycation end products, oxidative stress, the activation of inflammatory pathways and abnormal protein processing are the common characteristics of T2DM and AD. The misfolding of proteins plays an important role in both diseases, so as the aggregation of amyloid peptides. AD is characterized by the deposition of amyloid within neurons and amyloid plaques. Also in AD, the formation of amyloid fibers could be the product of ubiquitin-mediated protein degradation defects induced by a dysfunction of the proteasome. According to one study which was conducted on T2DM rats, T2DM-dependent decreases in p62 (a known cargo molecule that transports polyubiquitinated tau to proteosomal and autophagic degradation systems) transcription which is a primary mechanism underlying increased AD-like pathology. In some studies, brain amyloid deposition occurs as a result of increased blood-brain barrier permeability in case of diabetes conditions. In the recent years, according to some members of the diabetes community, AD is seen as a neuroendocrine disorder and the term “Type 3 Diabetes” defines the insulin deficiency and resistance in the brain of those with AD. In the context of these information, in this chapter, we propose a study about “Type 3 Diabetes” with the underlying mechanisms through the perspective of histology.

Recent Advances in Nutrigenomics: Patent Applications

Nutrition and dietary habits are investigated as environmental factors in cancer development and a strong relationship has been found between diet and cancer. Nutrients affect gene expression, gene regulation and eventually individuals’ genome. Genes related to carcinogen metabolism, steroid hormone metabolism and DNA repair are involved in cancer progress. Therefore, it is crucial to understand the factors affecting the change in cancer-related genes. Nutrigenomics is a new multidisciplinary field, investigating the effect of nutrients on genome and its expression through molecular techniques. Nutrigenomics enables to unveil how nutrients regulate cellular metabolism via gene and protein expressions and provide information on the functions of genome. The resulting differences or similarities in gene expressions as response to diets, will enable to understand diet-gene interactions at personalized levels that will implement the concept of personalized nutrition. The genetic variations among individuals will explain the health and disease status of human to be used to determine the cancer risk of individuals. In this chapter, it is aimed to review nutrient-cancer interaction, nutrigenomics approaches and patents related to the implications of nutrigenomics in cancer treatments.

Phytochemicals Content and Health Effects of Cultivated and Underutilized Species of the Cucurbitaceae Family

Cucurbitaceae represents a large plant family with more than 120 genera and 800 species, among which many significant cultivated vegetable species are included, such as watermelon, melon, cucumber and cucurbits (squash, pumpkin and zucchini). These species are usually consumed for their edible fruits, however several other uses have been reported for the various plant parts, including medicinal and therapeutic ones among others. The present chapter will demonstrate the most common vegetable species in terms of their chemical composition and health effects, as well as their edible, medicinal and industrial uses, based on the phytochemical content of the various plant parts. Special focus will be given on cucurbitacins which are an important group of phytochemicals present in the Cucurbitaceae family, since several studies have confirmed its bioactive properties and multiple health effects. Finally, selected less known species of this family (gourds) will be presented, considering their important health effects and their use in vegetable grafting. In conclusion, future perspectives for further valorization of these species will be highlighted, especially for the ones that are less commonly used.

Amyloidogenic Peptide Structure, Aggregation, And Membrane Interaction

It is estimated that 44 millions of people have Alzheimer’s disease (AD) or related dementia around the world. The AD is an irreversible progressive brain disorder that destroys the memory and thinking and causes the loss of cognitive functions. The development of AD is strongly correlated with the development of plaques and tangles in the brain. Beta-amyloid (Aβ) peptides are the main compound in the brain plaques however, their neurotoxic effects remain unclear. These peptides are generated from Amyloid Precursor Protein (APP) and the APP processing may be modulated by many factors, such as lipid rafts. Aβ coexists in different forms in the brain and the exact neurotoxic effect of each one is not understood. The majority of the studies about Aβ neurotoxicity suggests that the fibrillar form is the most neurotoxic and for this reason, much effort has been employed to understand mechanisms that modulate or inhibit the fibrillation process. Other studies suggest that the main neurotoxic form is the oligomer, which forms channels in the lipid membrane and induces cell death. In this chapter, we explore the mechanism of Aβ’s production and fibrillation, and the factors that can modulate it.

Stem Cells in Endocrinology: Facts and Future

The main characteristic of a stem cell is its multipotency that has to be demonstrated experimentally as follows: I) the differentiation pathway can be characterized by specific surface receptor expression; II) it is possible to generate lineage-specific cells in vitro, and III) in a depleted organ the repopulation process can be reached in vivo. In this regard, the scientific activity to propose and improve techniques of stem cell transplant focused on its clinical application in the endocrinological field is being studied extensively. Unfortunately, not a lot is known about stem cell transplantation to cure diseases and we depend a lot on murine studies. The aim of this chapter is to review some of the most important research lines about stem cells that could have a clinical application in endocrinology.

Unravelling Mesenchymal Stem Cell Signature in Regenerative Medicine

Mesenchymal stromal/stem cells (MSCs) represent suitable candidates for regenerative medicine purposes given their ability to differentiate in several cellular lineages, to migrate to site of injury, to secrete soluble factors crucial for cell survival and proliferation, as well as to modulate immune response. Although the exact mechanisms of action are still under investigation, several MSC- based clinical trials developed for various diseases, including organ injuries, systemic diseases, chronic inflammatory and autoimmune pathologies are ongoing. Recently, the possibility of using less immunogenic and more specific MSC by-products (i.e. microvesicles and exosomes) to overcome MSC transplantation criticisms and side effects is currently under consideration.

Tautomycetin, Protein Phosphatase 1 Specific Inhibitor, opened the Door for understanding the Role of PP1 in Minkowski Space

When the structure of tautomycin (TM) was determined, it was pointed out that the molecule must have potent inhibitory effects against protein phosphatases (PPs). The hint was brought from the structure of okadaic acid (OA), which was just disclosed to be a potent inhibitor of PPs. Protein phosphatase type 2A (PP2A) was the primary molecular target of OA, while TM was found to be a dual inhibitor for protein phosphatase type 1 (PP1) and PP2A, with partial selectivity to PP1. The rigid structure of OA, however, exhibited the biological activity as a tumor promoter, whereas the flexible structure of TM did not induce any tumor promotion in vivo. Tautomycetin (TC), having very similar structure to TM, was found to be the only inhibitor specific to PP1 at low concentrations, and the discovery opened the door to therapeutic strategies for immune disorders, cancer or neurological disorders involving PP1 and to understanding the distinguishable roles of PP1 and PP2A, two major Ser/Thr PPs in human cells. Sephin1, a selective inhibitor of PP1 holoenzyme containing growth arrest and DNA damage-inducible protein (GADD34), attenuated expression of stressinducible gene products. The approach was one of the several challenges for developing PP1-targeted therapeutics for neurological disorders to which circadian rhythm would be related. Thus appropriately modulating PP1 activity could lead to new treatments for neurological disorders in Minkowski space, a combination of threedimensional space and one dimension of time.

Complex Exodontia and Guidelines in Management of Medically Compromised Patients in Dental Chair

Many dental practitioners do not differentiate between the complex extraction and the surgical (trans-alveolar) extraction. By definition, the surgical extraction is one of complex extraction procedures, but the complex extraction is not limited to surgical extraction. In this chapter, the complex extraction has been defined. The pre-operative, intra-operative and post-operative factors that may contribute to the complexity of dental extraction have been discussed. This chapter contains a separated part about the management of medically compromised patients, as those patients can be considered under the definition of complex extraction. This chapter also contains a separated part about physics of elevator’s uses.

Immunity against HPV-Related Cancers

The induction of immunotolerance of the host's immune system by the persistent infection of HPV is one of the most important mechanisms for cervical lesions. The immune system modifications induced by HPV infection include tumorassociated macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T-helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and down-regulated DC activation. In this chapter, the effects of HPV and its mechanism of action will be discussed on immune system.

The Pituitary Gland and Etiology of Craniopharyngioma

As histological benign tumor with malignant cellular characteristic, craniophayrngyioma (CP) caused big trouble not only for surgery but also for the postsurgical management. So, it is important to emphase the understanding of the pituitary gland and also it’s connected structures, such as pituitary stalk, hypothalamus, and so on. In this chapter, we described the anatomical and cytological constructors of pituitary gland. As with combined the etiology of CP, we depicted the embryonic development of gland and its accessory structures. On the other hand, several hypotheses about the origin of CP were also analysed and described.

Dental Tissue Engineering and Regeneration; Perspectives on Stem Cells, Bioregulators, and Porous Scaffolds

Dental/orofacial tissue engineering is an emerging field that offers alternative solutions for dental problems resulting from pathologies such as caries, trauma, periodontal disease and others. Various stem cell types such as bone marrow stem cells (BMSCs) and adipose tissue-derived stem cells (ADSCs) can be employed as cell sources for dental tissue repair. In particular, dental tissue-derived stem cells such as dental pulp stem cells (DPSCS) and dental follicle stem cells (DFSCs) can be utilized due to their favorable origin and properties. On the other hand, natural and synthetic polymers are used to fabricate 3D dental tissue scaffolds to support cellular activities. Several bioregulators such as cytokines and growth factors can also be incorporated to induce cells interaction and cell-scaffold integration. The literature on the regeneration of dental tissues via tissue engineering principles presents numerous results that are superior to the traditional methods, which are vital for advancing dental therapy. Herein, the types, properties, and applications of dental stem cells (DSCs) were reviewed, as well as the tissue engineering and regeneration strategies for different types of dental tissues.

Stem Cell-based Modalities: From Basic Biology to Integration and Regeneration

Stem cells have attracted great interest of biomedical scientists and clinicians due to their unique abilities of self-renewal and multipotential differentiation. With the most current technologies, stem cells have been isolated from almost all types of tissue, including embryonic stem cells, somatic stem cells, and induced pluripotent stem cells. The mechanisms of cells behavior have been fully studied. In combination with tissue engineering skills, stem cells have been investigated in a better environment by simulating the three-dimensional environment. However, the long-term safety and efficiency of stem cell-based outcomes should be further evaluated prior to any clinical application.

Endocrine Disruptors: What Do We Know about the Effects and Risk Factors in Humans?

In the last few decades, the theme of endocrine disruption and endocrine disrupting chemicals has become more and more relevant, raising alarm in the scientific community and amongst public health officials, as well as questioning the traditional concepts of toxicology. This chapter is a revision and summary of the latest information and articles concerning this subject. It discusses the terms and definitions of endocrine disruption, the sources and mechanisms of action of these chemicals both naturally and artificially made, reviewing the potential adverse development, reproductive, neurological, and immune effects that they can have on the different systems in the body, and how they can relate to the different epidemics of cancer, diabetes and obesity. It also provides the latest up-to-date information on the tests and methods used to detect and assess these entities, offering ideas and lines of future investigation to attempt to better understand the knowledge in this field and reduce the potential threat of these environmental hazards to mankind.

Vitamin D: from Bone Metabolism to New Applications

Vitamin D is a fat-soluble vitamin, which has been classically associated with rickets and osteomalacia. The main function of Vitamin D is the regulation of calcium and phosphorus homeostasis. Plasma levels of 25-hydroxyvitamin D or calcidiol are considered the status indicator of Vitamin D in the human body, although it is biologically inert. 25-hydroxyvitamin D is transformed by 1α-hydroxylase to produce 1,25-dihydroxyvitamin D or calcitriol, the active metabolite of the vitamin. Vitamin D performs its actions through the Vitamin D receptor (VDR) that is present in more than 40 different tissues, as well as the enzyme 1α-hydroxylase, so it is now thought that Vitamin D may play a role in other physiological mechanisms. In the recent years, great interest has been a roused in Vitamin D and its involvement in different pathologies. However, the results of the studies are unclear, due to the involvement of mixed patients of different races, diagnostic criteria, latitude and season blood draw and the confounding variables such as age, BMI or sex not taken into account. The purpose of this chapter is to review the most recent publications of Vitamin D, in relation to new applications such as: diabetes, cancer, pregnancy and cardiovascular disease.

Alternative Anti-Infective/Anti-Inflammatory Therapeutic Options for Fighting Alzheimer’s Disease

Neurodegenerative diseases (NDs) have a serious impact on global health with no effective treatments yet available. Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder, considered to be the most common cause of dementia. There is increasing evidence for the infectious/inflammatory etiology of AD. Although brain is assumed to be an immunologically isolated organ, many bacteria (Helicobacter pylori), viruses (Herpes simplex virus, influenza, CMV etc.), fungi, toxoplasma, are associated with AD. The presence of immune-related antigens around amyloid plaques, activated complement factors, cytokines and a wide range of related receptors in the brain of AD patients, led to the concept of “neuro-inflammation”. Persistent or acute neuronal and peripheral inflammatory response to infectious agents is gradually gaining more attention, as a risk factor for someone to develop sporadic AD. The human microbiome (HM) has a pivotal role in nutrition, health and disease. About 100 trillion bacteria from up to 1000 bacterial species inhabit the gastrointestinal (GI) tract, contributing, at least in part, to what is known as the “human-biochemical” or “genetic-individuality” and resistance to disease. Several pathologies, including AD and inflammatory bowel disease, are associated with alterations in gut microbiome. Microbes of the gut microbiota or of extracorporeal origin possess the ability of producing functional amyloid proteins. These amyloids, via lymphatic and systemic transport to the Central Nervous System (CNS), seem to have an important role in the expression of neurologic and psychiatric disorders, such as schizophrenia, anxiety and AD. Cross-seeding of the neurodegenerative disorder proteins may be induced by these amyloids. Moreover, chronic inflammatory response to these immune-reactive proteins can also be an important risk factor for CNS well-being. Therapeutic/preventive options for halting CNS disorders’ onset, could include: (a) Anti-inflammatory, anti-amyloid drugs (β-sheet breakers and other inhibitors of amyloid fibrillization), monoclonal antibodies, nanoparticles, which target pathological components of AD, or other medical interventions to remove infectious agents or to ameliorate their biochemical influence on GI-CNS tract, (b) Prebiotics to enhance the growth of desired organisms and reduce oxidative stress - a cause that has been implicated with AD, (c) Probiotics to provide both the desired bacteria, which increase the competitive effects with pathogens, and essential metabolic products, and to modulate the host immune system to resist in infection (d) The consumption of natural products, and the dedication to the Mediterranean (MeDi) and Asian (AsDi) Diets, abundant in bioactive compounds, are capable to prevent AD or reduce danger of AD, and strengthen the host's ability to confront infections. The significance of diet diversity leading to the microbiota diversity is a new clinically important concept. Finally, and (e) preventive medical and/or other therapies to alter the amyloids produced by bacteria, to decrease their production or stimulate their removal. This chapter is addressed to, and urges the excellent cooperation between experts of neurology/psychiatry, microbiology, biochemistry, dietary and nutritional sciences, in order to confront AD.

Pediatric Type 2 Diabetes Mellitus

Pediatric Type 2 Diabetes Mellitus (T2DM) is an increasing medical concern for the pediatric community. It is most commonly diagnosed in adolescents but has also been seen in patients as young as 5 years of age. Presentation of T2DM can range from mild symptoms of polyuria, polydipsia and nocturia to diabetic ketoacidosis. Guidelines by the American Diabetes Association are used to diagnose and treat children with diabetes. Early diagnosis and aggressive treatment is critical in delaying complications of diabetes. Poorly controlled diabetes can lead to significant increase in morbidity and mortality with development of hypertension, nephropathy and retinopathy. In this chapter, a review of the epidemiology of Type 2 diabetes, diagnosis and treatment options will be discussed.

Proteomics in the Characterization of New Target Therapies in Pediatric Obesity Treatment

Adipose tissue (AT) with a central role in body weight homeostasis, inflammation and insulin resistance, is a highly orchestrated tissue involving receptor and second messenger pathways with steps and passes that influence hyperplasia, hypertrophy, adipocyte differentiation, turnover, lipolysis, free-fatty acid (FFA) metabolism, lipogenesis and the secretome profile. Due to the limitations of the classical molecular biological methods only pieces of the puzzle have been studied, with studies failing to consider the global, time-resolved changes that are evident in this highly plastic organ. “Proteomics”, first coined in 1995 is a large-scale characterization of the entire protein profile of a cell line, tissue, or organism not only from the perspective of expression but also post-translational modifications. As such proteomic technologies offer powerful tools for identifying key components of the adipose proteome, which may contribute to the pathogenesis of adipose tissue dysfunction in obesity. In this review, we plan to address the recent advances in the proteomic characterization of pediatric obesity, in particular the newly identified proteins that potentially play relevant roles and offer targets for novel therapies.

Bioactive Compounds and Diabetes

Diabetes mellitus (DM) is the most common endocrine disorder, and with a very high development rate. There are two main groups of DM: type 1 DM (basically due to an insulin deficiency), and type 2 DM (basically due to insulin resistance, i.e.: there is plenty of insulin, but actually the cells are resistant to its action). Both types lead to both abnormal glucose and lipids metabolism, sub-clinical inflammation and higher oxidative stress. We will speak mainly about type 2 DM. Its genesis is multifactorial, but we can ascertain that the diet is the principal modifiable factor. The benefits of a healthy diet are not limited to its nutrient content, must also provide other protective factors against oxidative stress, metabolic syndrome, diabetes and carcinogenesis content especially in plant foods, called compounds bioactive, serving in the body that can promote good health. A diet with high intake of phytochemicals and rich in antioxidant capacity with polyphenolic compounds (as the Mediterranean Diet), is related to a decreased risk of DM.

The Mesendoderm: A Wellspring of Cell Lineages for Regenerative Medicine

Regenerative medicine is centred around the premise that progenitor populations can be engineered to give rise to mature cell lineages forming a complex tissue architecture which in turn produces functional organs. The potency of the starting progenitor population is therefore a critical consideration. The mesendoderm is a rare population of cells present in the embryo only at gastrulation. This bipotent population gives rise to the mesoderm and the definitive endoderm and all mature cell types derived from these germ layers. Mesodermal progenitors generate cardiac, smooth and skeletal muscle, as well as the blood and vascular lineages, bone and connective tissue cells. The endoderm is the source of numerous cell lineages with potential utility for regenerative medicine including hepatocytes, pancreatic lineages and the epithelial cells of the respiratory, gastrointestinal and reproductive tracts. The development of numerous organs is dependent upon mesoderm-derived lineages interacting with endodermal-derived cell types. The kidney, adrenal gland, pancreas and genito-urinary tract development all require interactions between mesodermal and endodermal derivative cell types. Here, we describe the unique genetic programmes that lead to mesendoderm formation, the pathways leading to mesoderm and endoderm specification and examples where mature cell types from both germ layers interact to support their mutual development. We will also show how these programmes are being harnessed to direct the differentiation of pluripotent cells in vitro into mesendodermderived cells and tissues which can be used to improve the quality of human life. Finally, we will discuss considerations for combining stem cell differentiation with tissue engineering through 3D bioprinting modalities.

Humanized Mouse Models as An Experimental Tool to Investigate Disease Immunology

Many studies of human immunology have been limited to ex vivo analysis due to ethical considerations. Detailed study, however, requires in vivo analysis, as ex vivo analysis of human immune cells does not always represent in vivo status. Therefore, small animal models have been used to overcome this limitation and several humanized mouse models that reproduce the human immune system have been developed. This review summarizes humanized mouse model characteristics and progress in their use for research of human diseases immunology.

Tumor Homing Peptides: Promising Futuristic Hope for Cancer Therapy

Tumor homing peptides (THPs) are cyclic or linear peptides of few amino acids having inherent property to recognize the tumor cells, which specifically bind to the receptors present on the tumor cells, tumor blood vessels or tumor lymphatic vessels. These can be utilized as major tool for targeted drug delivery particularly to cancerous cells, hence these are important for efficient cancer treatment. The present chapter summarizes the recent progression in the researches, databases and patents available in the field of cancer therapies utilizing THPs. It elucidates details about THPs; their modes of functioning, the molecules these may translocate; different methods of entry into the cells as well as diverse uses like gene correction and targeting of various tissues. Screening of THPs from phage library, natural occurrence of THPs in bacteria like Salmonella, Pseudomonas and engineered baculovirus have also been explicated. The specificity of THPs can be further enhanced by blending these with amphipathic conjugates, whereas the penetrability may be improved by adding cysteine or maleimidohexanoic acid to their N-terminal. Their half-life can also be increased by adding unnatural amino acids and modifying backbone or cyclization of THPs. For diagnostic and therapeutic purposes, several THPs have already been entered in different stages of clinical trials. THPs could serve as an ideal futuristic approach for targeting tumors based on their higher specificity, improved penetrability and half-life, acting as efficient delivery cargos for anticancer drugs and large therapeutic molecules.

Obesity and Type 2 Diabetes Mellitus: Adipocytokines as Markers of Insulin Resistance

The obesity epidemic has become one of the major challenges for the modern society, first of all because of its clinical and social consequences. In 1998 the World Health Organization (WHO) proclaimed obesity a worldwide epidemic encompassing both adults and children and acknowledged it one of the biggest threats to the human health. The cause of overweight and obesity is body mass increase as a result of fat tissue increment. It has been proven that obesity increases the risk of hypertension, type 2 diabetes (T2DM), as well as leads to cardiovascular complications such as stroke or heart attack. The fat tissue that is superfluous in obesity is the source of many hormonally active compounds influencing bodily homeostasis. The recent research has pointed to the particular importance of abdominal obesity in the pathogenesis of metabolic disturbances linked with the endocrine activity of the visceral fat. This visceral fat tissue produces many adipokines, such as tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL6), leptin, adiponectin, resistin, omentin, visfatin, nesfatin, vaspin, chemerin, ghrelin or apelin. Adipocytokines, released into the bloodstream thanks to specific receptors on the surface of the target cells, act as classic hormones influencing organ and tissue metabolism. Moreover adipokines may decrease tissue sensitivity to insulin and induce inflammatory processes, endothelial dysfunction and atherosclerotic changes. At present much attention is given to determination of adipokines as contemporary markers of insulin resistance. Research authors suggest that changes in adipokine concentrations can be seen at least a few years earlier that first symptoms of improper glucose metabolism. Although there are still many controversies regarding what is the most important causative factor for T2DM, it cannot be denied that the endocrine activity of fat tissue as well as the immunological status both play important roles in the pathogenesis of T2DM. Promising research results point to the necessity of elaborating methods of measuring pro-inflammatory factors, especially adipokines, that would be both diagnostically sensitive and specific and that could be implemented in the laboratory diagnostics as well as primary prevention of diabetes.

β-Cells from Embryonic and Adult Stem Cells and Progenitors

Diabetes is a chronic autoimmune disease, causing the destruction of the insulin-producing β-cells of the pancreatic islet and leading to glycemic dysregulation. Exogenous insulin administration and glucose testing moderately rectifies hyperglycemia, but does not provide adequate fine tuning necessary for complete prevention of hypoglycemia acutely, nor micro- and macro-vascular complications in the long-term. Islet transplants have shown great promise for this dynamic glucose regulation, but a shortage of cadaveric-sourced cells, and lifelong immune suppression requirements vastly restrict this technique from being widely available to patients with the disease. Therefore alternative sources of insulin-producing cells are needed. In this chapter, the role of stem cell biology in the current context of diabetes therapy is discussed, including an assessment of human embryonic and human induced pluripotent stem cells for the restoration of β-cell mass. Additionally, the existence of putative resident stem cells, and possible fluidity in lineage fate determination within endocrine pancreas- related cell types is examined.