<![CDATA[Current Molecular Pharmacology (Volume 17 - Issue 1)]]> https://www.benthamscience.com/journal/98 RSS Feed for Journals | BenthamScience EurekaSelect (+https://www.benthamscience.com) 2024-03-28 <![CDATA[Current Molecular Pharmacology (Volume 17 - Issue 1)]]> https://www.benthamscience.com/journal/98 <![CDATA[Peptides for Dual Targeting of ErbB1 and ErbB2: Blocking EGFR Cell Signaling Transduction Pathways for Cancer Chemotherapy]]>https://www.benthamscience.com/article/1297872024-03-28 <![CDATA[Protective Effect of Chrysin against Chlorpyrifos-Induced Metabolic Impairment and Pancreatitis in Male Rats]]>https://www.benthamscience.com/article/1295972024-03-28Background: This study was performed to evaluate the protective effects of chrysin (CH) on metabolic impairment and pancreatic injury caused by sub-chronic chlorpyrifos (CPF) intoxication in male rats.

Methods: Forty male Wistar rats were randomly allocated into five groups (n=8). Intraperitoneal injections of chrysin (12.5, 25 and 50 mg/kg for 45 days) and CPF (10 mg/kg for 45 days) gavage were performed. Present findings indicated that the serum levels of glucose, total cholesterol, and lowdensity lipoprotein-cholesterol, as well as body weight, were increased in the CPF-exposed group.

Results: It was also found that CPF decreased superoxide dismutase activity as well as increased malondialdehyde and nitric oxide levels in the pancreatic tissue of exposed animals. Histopathological examination also confirmed the toxic effects of CPF on pancreatic tissue as mostly evidenced by infiltration of inflammatory cells and necrosis. CH (50 mg/kg) decreased blood glucose concentration (p < 0.05), TG (p < 0.05), and LDL-C in CPF-exposed animals. CH decreased the pancreas levels of MDA in all treated CPF-exposed groups versus the non-treated CPF-exposed group (p < 0.05, p < 0.001, p < 0.001, respectively). A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls. A significant difference was not seen in the NO and MDA levels and SOD activity between CHtreated (50 mg/kg) animals exposed to CPF and controls.

Conclusion: A significant difference was not seen in the NO and MDA levels and SOD activity between CH-treated (50 mg/kg) animals exposed to CPF and controls. In conclusion, CH could prevent initiate and progress of CPF-induced metabolic impairment by modulating oxidative stress in pancreatic tissue as a target organ of organophosphorus pesticides.

]]>
<![CDATA[Fangchinoline, an Extract of the <i>Stephania tetrandra</i> S. Moore Root, Promoted Oxidative Stress-induced DNA Damage and Apoptosis and Inhibited Akt Signaling in Jurkat T Cells]]>https://www.benthamscience.com/article/1294262024-03-28Background: Fangchinoline (Fan) is extracted from traditional Chinese medicine (called Fangji), or the root of Stephania tetrandra Moore. Fangji is well-known in Chinese medical literature for treating rheumatic diseases. Sjogren's syndrome (SS) is a rheumatic disease whose progression can be mediated via CD4+ T cell infiltration.

Objective: This study identifies the potential role of Fan in inducing apoptosis in Jurkat T cells.

Methods: First, we explored the biological process (BP) associated with SS development by performing a gene ontology analysis of SS salivary gland-related mRNA microarray data. The effect of Fan on Jurkat cells was investigated by analyzing the viability, proliferation, apoptosis, reactive oxygen species (ROS) production, and DNA damage.

Results: Biological process analysis showed that T cells played a role in salivary gland lesions in patients with SS, indicating the significance of T cell inhibition in SS treatment. Viability assays revealed that the half-maximal inhibitory concentration of Fan was 2.49 μM in Jurkat T cells, while the proliferation assay revealed that Fan had an inhibitory effect on the proliferation of Jurkat T cells. The results of the apoptotic, ROS, agarose gel electrophoresis, and immunofluorescence assays showed that Fan induced oxidative stress-induced apoptosis and DNA damage in a dosedependent manner.

Conclusion: These results indicate that Fan could significantly induce oxidative stress-induced apoptosis and DNA damage and inhibit the proliferation of Jurkat T cells. Moreover, Fan further enhanced the inhibitory effect on DNA damage and apoptosis by inhibiting the pro-survival Akt signal.

]]>
<![CDATA[Hsa_Circ_0000021 Sponges miR-3940-3p/KPNA2 Expression to Promote Cervical Cancer Progression]]>https://www.benthamscience.com/article/1295902024-03-28Background: Circular RNAs (circRNAs) have a vital role in the occurrence of numerous cancers. However, its function and pattern of expression in cervical cancer (CC) remain unclear. This research aims to investigate the hsa_circ_000002’s regulatory mechanism in CC.

Methods: Hsa_circ_0000021, miR-3940-3p, and KPNA2 expression levels were estimated through qRT-PCR. Nuclear/cytoplasmic separation was conducted to find the subcellular location of hsa_circ_0000021. Western blot was done to estimate the levels of KPNA2 protein. CCK-8, BrdU, wound healing, transwell, and tumor xenograft assays were performed to study how hsa_circ_0000021/miR-3940-3P/KPNA2 function affect CC. Hsa_circ_0000021’s targeting relationships with miR-3940-3p and KPNA2 were ascertained through RIP and luciferase experiments.

Results: Hsa_circ_0000021 and KPNA2 were overexpressed and inversely associated with the levels of miR-3940-3p in CC. Knocking down either hsa_circ_0000021 or KPNA2 repressed the growth of CC tumors as well as the proliferation, invasion, and migration of CC cells. Silencing miR-3940-3p promoted the malignant proliferation of CC cells. Regarding its mechanism, hsa_circ_0000021 affected the malignant CC cell proliferation via the sponging of miR-3940-3p, which targeted KPNA2.

Conclusion: Hsa_circ_0000021 regulates the miR-3940-3p/KPNA2 axis to promote CC occurrence. This potentially is a novel target for CC treatment.

]]>
<![CDATA[A Comprehensive Review of Essential Aspects of Molecular Pathophysiological Mechanisms with Emerging Interventions for Sarcopenia in Older People]]>https://www.benthamscience.com/article/1300602024-03-28Background: As people age, physical impairments may have a deleterious role on skeletal muscles. Sarcopenia Clinical Practice Guidelines 2017 and the European Working Group on Sarcopenia in older people are two organizations that have published essential guidelines on the definition of “Sarcopenia”. Sarcopenia is a geriatric syndrome, characterized by skeletal muscle mass degeneration brought on by ageing, which lowers muscular function and quality. Moreover, Sarcopenia can be classified as primary or age-associated Sarcopenia and secondary Sarcopenia. Also, secondary Sarcopenia occurs when other diseases such as diabetes, obesity, cancer, cirrhosis, myocardial failure, chronic obstructive pulmonary disease, and inflammatory bowel disease also contribute to muscle loss. Furthermore, Sarcopenia is linked with a high risk of negative outcomes, considering a gradual reduction in physical mobility, poor balance, and increased fracture risks which ultimately leads to poor quality of life.

Objective: In this comprehensive review, we have elaborated on the pathophysiology, and various signaling pathways linked with Sarcopenia. Also, discussed the preclinical models and current interventional therapeutics to treat muscle wasting in older patients.

Conclusion: In a nutshell, a comprehensive description of the pathophysiology, mechanisms, animal models, and interventions of Sarcopenia. We also shed light on pharmacotherapeutics present in clinical trials which are being developed as potential therapeutic options for wasting diseases. Thus, this review could fill in the knowledge gaps regarding Sarcopenia-related muscle loss and muscle quality for both researchers and clinicians.

]]>
<![CDATA[DDR1-Induced Paracrine Factors of Hepatocytes Promote HSC Activation and Fibrosis Development]]>https://www.benthamscience.com/article/1297132024-03-28Background: This study investigated the role and potential mechanisms of Discoidin domain receptors-1 (DDR1) during liver fibrogenesis.

Methods: Blood and livers were collected from mice. In the in vitro experiments, human normal hepatocyte (LO2 cell line) and human hepatoma cells (HepG2 cell line) with overexpressed DDR1 (DDR1-OE) or DDR1 knockdown (DDR1-KD) were constructed by transfecting the corresponding lentivirus. Human hepatic stellate cells (LX2 cell line) were incubated with a conditioned medium (CM) of the above stable transfected cells treated with collagen. The cells and supernatants were collected for molecular and biochemical analyses.

Results: DDR1 expression was increased in hepatocytes from carbon tetrachloride (CCL4)-induced fibrotic livers compared to normal livers in wild-type (WT) mice. Liver fibrosis was relieved, and hepatic stellate cells (HSC) activation was decreased in CCL4-treated DDR1 knockout (DDR1-KO) mice compared with CCL4-treated WT mice. LX2 cells cultured in CM of LO2 DDR1-OE cells revealed increased α-smooth muscle actin (αSMA) and type I collagen (COL1) expressions and cell proliferation. Meanwhile, cell proliferation and the expression levels of αSMA and COL1 in LX2 cells cultured in CM of HepG2 DDR1-KD cells were decreased. Moreover, IL6, TNFα, and TGFβ1 in CM of DDR1-OE cells appeared to promote LX2 cell activation and proliferation, regulated by NF-κB and Akt pathways.

Conclusion: These results indicated that DDR1 in hepatocytes promoted HSC activation and proliferation and that paracrine factors IL6, TNFα, and TGFβ1 induced by DDR1 through activating NF-κB and Akt pathways may be the underlying mechanisms. Our study suggests that collagen-receptor DDR1 may be a potential therapeutic target for hepatic fibrosis.

]]>
<![CDATA[E2F1 Reduces Sorafenib’s Sensitivity of Esophageal Carcinoma Cells via Modulating the miR-29c-3p/COL11A1 Signaling Axis]]>https://www.benthamscience.com/article/1300042024-03-28Objective: Esophageal carcinoma (ESCA) is a common malignancy characterized by high morbidity and mortality. Our work managed to dissect the modulatory mechanism of E2F1/miR-29c-3p/COL11A1 in the malignant progression and sensitivity of ESCA cells to sorafenib.

Methods: Via bioinformatics approaches, we identified the target miRNA. Subsequently, CCK-8, cell cycle analysis, and flow cytometry were used to check the biological influences of miR-29c-3p on ESCA cells. TransmiR, mirDIP, miRPathDB, and miRDB databases were used as tools for the prediction of upstream transcription factors and downstream genes of miR-29c-3p. The targeting relationship of genes was detected via RNA immunoprecipitation and chromatin immunoprecipitation, which was further validated by dual-luciferase assay. Finally, in vitro experiments revealed the way E2F1/miR-29c-3p/COL11A1 affected sorafenib’s sensitivity, and in vivo experiments were used to verify the way E2F1 and sorafenib impacted ESCA tumor growth.

Results: miR-29c-3p, downregulated in ESCA, could suppress ESCA cell viability, arrest the cell cycle in the G0/G1 phase, and impel apoptosis. E2F1 was found to be upregulated in ESCA and it could abate the transcriptional activity of miR-29c-3p. COL11A1 was found to be a downstream target of miR-29c-3p to enhance cell viability, induce cell cycle arrest in S phase, and constrain apoptosis. Cellular and animal experiments together demonstrated that E2F1 abated the sorafenib’s sensitivity of ESCA cells via miR-29c-3p/COL11A1.

Conclusion: E2F1 affected the viability, cell cycle, and apoptosis of ESCA cells by modulating miR-29c-3p/COL11A1, and it attenuated the sensitivity of ESCA cells to sorafenib, shedding new light on the treatment of ESCA.

]]>
<![CDATA[A Detailed Review of Molecular Pathways and Mechanisms Responsible for the Development and Aggravation of Neuropathy and Nephropathy in Diabetes]]>https://www.benthamscience.com/article/1303832024-03-28Background: Diabetic mellitus is responsible for triggering many conditions, such as neuropathy, nephropathy, and retinopathy. Hyperglycemia leads to the development of oxidative stress conditions, activation of pathways, and generation of metabolites, leading to complications like neuropathy and nephropathy.

Objective: This paper aims to discuss the mechanism of actions, pathways, and metabolites triggered due to the development of neuropathy and nephropathy post-long-haul diabetes in patients. The therapeutic targets are also highlighted, proving to be a potential cure for such conditions.

Methods: Research works were searched from international and national databases with keywords like “diabetes,” “diabetic nephropathy,” “NADPH,” “oxidative stress,” “PKC,” “Molecular mechanisms,” “ cellular mechanisms,” “complications of diabetes,” and “factors.” The databases searched were PubMed, Scopus, Directory of open access journals, Semantic Scholar, Core, Europe PMC, EMBASE, Nutrition, FSTA- Food Science and Technology, Merck Index, Google Scholar, PubMed, Science Open, MedlinePlus, Indian citation index, World Wide Science, and Shodhganga.

Results: Pathways causing protein kinase C (PKC) activation, free radical injury, oxidative stress, and aggravating the conditions of neuropathy and nephropathy were discussed. In diabetic neuropathy and nephropathy, neurons and nephrons are affected to the extent that their normal physiology is disturbed, thus leading to further complications and conditions of loss of nerve sensation in diabetic neuropathy and kidney failure in diabetic nephropathy.

Current treatment options available for the management of diabetic neuropathy are anticonvulsants, antidepressants, and topical medications, including capsaicin. According to AAN guidelines, pregabalin is recommended as the first line of therapy, whereas other drugs currently used for treatment are gabapentin, venlafaxine, opioids, amitriptyline, and valproate.

Drug targets for treating diabetic neuropathy must suppress the activated polyol pathways, kinase C, hexosamine, and other pathways, which amplify neuroinflammation. Targeted therapy must focus on the reduction of oxidative stress and proinflammatory cytokines and suppression of neuroinflammation, NF-κB, AP-1, etc.

Conclusion: Potential drug targets must be considered for new research on the treatment of neuropathy and nephropathy conditions.]]> <![CDATA[Mammalian Target of Rapamycin (mTOR) Signalling Pathway-A Potential Target for Cancer Intervention: A Short Overview]]>https://www.benthamscience.com/article/1305712024-03-28Background: The mammalian role of the rapamycin (mTOR) pathway is the practical nutrient-sensitive regulation of animal growth and plays a central role in physiology, metabolism, and common diseases. The mTOR is activated in response to nutrients, growth factors, and cellular energy. The mTOR pathway activates in various cellular processes and human cancer diseases. Dysfunction of mTOR signal transduction is associated with metabolic disorders, cancer for instance.

Objective: In recent years, significant achievements envisaged in developing targeted drugs for cancer. The global impact of cancer continues to grow. However, the focus of disease-modifying therapies remains elusive. The mTOR is a significant target in cancer to be considered for mTOR inhibitors, even though the costs are high. Despite many mTOR inhibitors, potent, selective inhibitors for mTOR are still limited. Therefore, in this review, the mTOR structure and protein-ligand interactions of utmost importance to provide the basis for molecular modelling and structure-based drug design are discussed.

Conclusion: This review introduces the mTOR, its crystal structure, and the latest research on mTOR.Besides, the role of mTOR in cancer, its function, and its regulation are reviewed. In addition, the mechanistic role of mTOR signalling networks in cancer and interaction with drugs that inhibit the development of mTOR and crystal structures of mTOR and its complexes are explored. Finally, the current status and prospects of mTOR-targeted therapy are addressed.

]]>
<![CDATA[A Network Medical Framework based on Inflammatory Genes to Identify Drug Candidates for Abdominal Aortic Aneurysms]]>https://www.benthamscience.com/article/1318552024-03-28Background: Clinically, abdominal aortic aneurysms (AAA) can be treated with surgical intervention, but there is currently no effective drug for the disease.

Methods: This study analyzed the biomedical data of single-cell RNA sequencing (scRNA-seq), RNA-seq and the network medical data of drug-target interaction as well as protein-protein interaction to identify key targets and potential drug compounds of AAA.

Results: Firstly, we identified 10 types of cells from AAA and nonaneurysmal control samples and screened monocyte, mast cell, smooth muscle cell and 327 genes showing significant differences between non-dilated PVATs and dilated PVATs. To further explore the association of three types of cells in AAA, we screened the common DEGs associated with the three types of cells and then identified 10 potential therapeutic targets for AAA. SLC2A3 and IER3 were the key targets that were the most closely related to immune score and significantly related to inflammatory pathways. We then designed a network-based proximity measure to identify potential drugs targeting SLC2A3. Finally, with computer simulation, we found that the compound with the highest affinity to SLC2A3 protein was DB08213, which was embedded into the SLC2A3 protein cavity and formed close contact with various amino acid residues, and was stable during the 100-ns MD simulation.

Conclusion: This study provided a computational framework for drug design and development. It revealed key targets and potential therapeutic drug compounds for AAA, which might contribute to the drug development for AAA.

]]>
<![CDATA[Targeting Cellular Senescence: A Potential Therapeutic approach for Alzheimer’s Disease]]>https://www.benthamscience.com/article/1322082024-03-28 <![CDATA[Pathophysiology, Current Therapeutic Options, Vaccine Candidates, and Drug Targets for Human Brucellosis]]>https://www.benthamscience.com/article/1328682024-03-28 <![CDATA[Perspectives on the Role of P21-Activated Kinase 1 (PAK1) in the Intestinal Anti-inflammatory and Antitumor Potential of Artepillin C]]>https://www.benthamscience.com/article/1312192024-03-28 <![CDATA[CD73 Blockade Alleviated Hepatic Fibrosis via Inhibiting Hepatic Stellate Cells Proliferation and Activation]]>https://www.benthamscience.com/article/1303192024-03-28Background: Liver fibrosis is associated with the activation of hepatic stellate cells (HSCs). Inhibition of HSCs activation is a strategy for alleviating hepatic fibrogenesis. CD73 is involved in liver disease development, while the mechanism remains unclear.

Objective: This study aimed to investigate the effect of CD73 targeting inhibition on liver fibrosis.

Methods: Intraperitoneal injection of CCl4 was used to induce liver fibrosis in mice models. Adenosine 5′-(α, β-methylene) diphosphate sodium salt (APCP) was used for CD73 blockade. The siRNA was used to induce CD73 knockdown in HSCs. LX2 and HSC-T6 were used to investigate the role of CD73 in HSCs activation in vitro.

Results: The results showed that APCP treatment could alleviate hepatic fibrosis. In fibrotic liver tissues, CD73 exhibited a positive correlation with markers of HSCs activation. Furthermore, APCP treatment and CD73 knockdown could inhibit HSCs (LX2 and HSC-T6) activation and proliferation. By using RNA sequencing of liver tissues from control, CCl4-mice, and APCP-treated mice, 851 genes that were significantly changed in CCl4 mice (vs. control) were reversed by APCP treatment. These genes were mainly enriched in cell division-associated biological processes. Moreover, we found that CD73 might be associated with autophagy in HSCs. In fibrotic liver tissues and HSCs, ATG5 and Beclin1 expression could be downregulated by CD73 knockdown and APCP treatment.

Conclusion: This study demonstrated the effects and mechanism of CD73 in HSCs activation and proliferation, which presents the therapeutical potential of CD73 blockage for liver fibrosis.

]]>
<![CDATA[Fenbufen Alleviates Severe Acute Pancreatitis by Suppressing Caspase-1/Caspase-11-mediated Pyroptosis in Mice]]>https://www.benthamscience.com/article/1317002024-03-28Aim: In the present study, we aimed to investigate the effects of Fenbufen treatment on the SAP model induced by caerulein and lipopolysaccharide.

Background: Severe acute pancreatitis (SAP) is an extremely dangerous disease with high mortality, which is associated with inflammatory response and acinar cell death. The caspase family plays an important role in cell death, such as caspase-1 and caspase-11 in pyroptosis. In recent years, caspases have been shown to be a novel pharmacological target of Fenbufen.

Objective: Effects of Fenbufen on pancreatic tissue damage and serum levels of lipase and amylase in SAP in mice; Effect of Fenbufen on caspase-1 pathway in SAP in mice; Effect of Fenbufen on caspase-1/caspase-11-mediated pyroptosis of PACs in SAP in mice; Effect of Fenbufen on isolated PACs and caspase-1/caspase-11-mediated pyroptosis in vitro.

Methods: In vivo, eighteen female C57BL/6 mice were randomly divided into 3 groups: the NC group, the SAP group, and the Fenbufen +SAP group with 6 mice in each group. The SAP model was induced by intraperitoneal injection of caerulein and lipopolysaccharide. The pathological changes in pancreatic and the serum levels of lipase and amylase and the relative gene and protein expressions in each group were compared. In vitro, pancreatic acinar cells were assigned to 5 groups: medium group, SAP group, Fenbufen 100μM group, Fenbufen 200μM group, and Fenbufen 400μM group. The cell damage and the relative gene and protein expressions in each group were evaluated.

Results: Our results showed that Fenbufen ameliorated the severity of SAP and decreased the serum levels of lipase and amylase. Meanwhile, the in vivo and in vitro data demonstrated that Fenbufen inhibited the activation of caspase-1 and caspase-11, decreasing the levels of IL-1β, IL-18, and GSDMD. In in vitro experiments, we found that by inhibiting the activation of caspase-1 and caspase-11, Fenbufen significantly reduced lactate dehydrogenase (LDH) excretion by acinar cells.

Conclusion: In general, our data showed that Fenbufen could protect the pancreatic acinar cell from injury by inhibiting pyroptosis.

]]>
<![CDATA[Antimicrobial Resistance of Clinical <i>Klebsiella pneumoniae</i> Isolates: Involvement of <i>AcrAB</i> and <i>OqxAB</i> Efflux Pumps]]>https://www.benthamscience.com/article/1305702024-03-28Background: Over the last several decades, the AcrAB and OqxAB efflux pumps have been found to cause multidrug resistance (MDR) in various bacteria, most notably Klebsiella pneumoniae. Antibiotic resistance surges with increased expression of the acrAB and oqxAB efflux pumps.

Methods: In accordance with CLSI guidelines, a disk diffusion test was carried out using 50 K. pneumoniae isolates obtained from various clinical samples. CT was computed in treated samples and compared to a susceptible ciprofloxacin strain (A111). The final finding is presented as the fold change in the target gene's expression in treated samples relative to a control sample (A111), normalized to a reference gene. As ΔΔCT = 0 and 2 to the power of 0 = 1, relative gene expression for reference samples is often set to 1

Results: The highest rates of resistance were recognized with cefotaxime (100%), cefuroxime (100%), cefepime (100%), levofloxacin (98%), trimethoprimsulfamethoxazole (80%), and gentamicin (72%), whereas imipenem (34%) had the lowest rates. Overexpression of acrA and acrB, oqxA and oqxB, regulators marA, soxS, and rarA were greater in ciprofloxacin-resistant isolates compared to the reference strain (strain A111). There was also a moderate connection between ciprofloxacin MIC and acrAB gene expression and a moderate connection between ciprofloxacin MIC and oqxAB gene expression.

Conclusion: This work provides a deeper knowledge of the role of efflux pump genes, particularly acrAB and oqxAB, as well as transcriptional regulators marA, soxS, and rarA, in bacterial resistance to ciprofloxacin.

]]>
<![CDATA[E7386 is not a Specific CBP/β-Catenin Antagonist]]>https://www.benthamscience.com/article/1321282024-03-28Background and Objective: The first clinically evaluated CBP/β-catenin antagonist, PRI-724, displayed an excellent safety profile administered intravenously via continuous infusion. Eisai recently disclosed a third-generation, orally available, reportedly CBP/β-catenin antagonist, E7386. However, several structural features and the reported cytotoxicity of E7386 were unexpected for a specific CBP/β-catenin antagonist. Therefore, we undertook a comparison of E7386 versus the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82, the active agents derived from the prodrug PRI-724.

Introduction: CBP/β-catenin antagonists rebalance the equilibrium between CBP/β-catenin and p300/β-catenin dependent transcription and may be able to treat or prevent many diseases of aging via maintenance of somatic stem cell pool and regulating mitochondrial function and metabolism involved in differentiation and immune cell function. The safety, efficacy, and therapeutic potential of the specific CBP/β-catenin antagonists, ICG-001, and the second-generation compound, C82, the active agent derived from the pro-drug PRI-724, have been studied extensively in a variety of preclinical disease models and in the clinic for oncology and hepatic fibrosis. However, the lack of oral bioavailability has hampered the further development of PRI-724. Thus, Eisai recently proposed a third-generation, orally available, reportedly CBP/β-catenin antagonist E7386. Here, we have performed a comparative analysis of E7386 with the highly specific bona fide CBP/β-catenin antagonists, ICG-001 and C82.

Methods: We utilized a series of previously validated biochemical and transcriptional assays to investigate the selective targeting of the CBP/β-catenin interaction in conjunction with global transcriptional profiling to compare the three small molecules, ICG-001, C82, and E7386.

Result: Our data cast significant doubt that the mechanism of action of E7386 is via specific CBP/β-catenin antagonism.

Conclusion: It can thus be concluded that E7386 is not a specific CBP/β-catenin antagonist.

]]>
<![CDATA[Antiarrhythmic Potential of Epicardial Botulinum Toxin Injection for Suppression of Postoperative Atrial Fibrillation]]>https://www.benthamscience.com/article/1325852024-03-28 <![CDATA[Hepatic Ischemia-reperfusion Injury: Protective Approaches and Treatment]]>https://www.benthamscience.com/article/1333592024-03-28 <![CDATA[Grp94 Inhibitor HCP1 Suppressed the Replication of SVA in BHK-21 Cells and PK-15 Cells]]>https://www.benthamscience.com/article/1327502024-03-28Background: Glucoregulatory protein 94 (Grp94) is necessary for the post-viral life cycle and plays a quality control role in viral proteins, but the role of Grp94 in regulating viral replication in host cells is not well known. Therefore, finding a compound that can regulate Grp94 will help us to study the mechanism of viral replication. Previously, we synthesized a coumarin pyrazoline derivative HCP1 that is an effective inhibitor of Grp94. We suppose that HCP1 may inhibit viral replication.

Objective: This study aimed to investigate the effect of HCP1 on the replication ability of Senecavirus A (SVA), so as to provide a target and a leading compound for revealing the pathogenic mechanism of the virus and developing antiviral drugs.

Methods: Rat cell lines BHK-21 and porcine cell lines PK-15 were infected with SVA, and the infected cells were treated with different concentrations of HCP1. The cell viability (CCK-8), virus titer (TCID50), autophagy level, and Grp94 expression were measured.

Results: The results showed that a low concentration of HCP1 decreased viral titer and viral load in BHK-21 and PK-15 cells, and 5μM HCP1 significantly decreased the expression of SVA VP2 protein. In addition, SVA infection can lead to an increased level of autophagy, and HCP1 can inhibit host cell autophagy caused by SVA infection, thereby inhibiting viral replication and infection.

Conclusion: These findings reveal that Grp94 is a key factor in controlling SVA replication, and its inhibitor HCP1 suppresses SVA replication by inhibiting the increase of Grp94 protein level and autophagy induced by SVA. This study will contribute to the development of a new class of small-molecule antiviral drugs.

]]>
<![CDATA[Physalin B Reduces Tau Phosphorylation and Cell Apoptosis in HEK293 Cells by Activating FoxO1]]>https://www.benthamscience.com/article/1330712024-03-28Background: Physalin B (PB) is one of the main active compounds of Solanaceae plants, with a wide range of biological activities. PB reportedly has the potential to treat Alzheimer’s disease (AD).

Objective: In this study, we investigated the effect of PB on Tau phosphorylation and cell apoptosis using Tau-expressing HEK293 cells (HEK293/Tau) as a cellular model.

Methods: The optimum concentration of PB to treat HEK293/Tau cells was determined using the CCK-8 assay. Additionally, the expression of FoxO1, Tau-5, p-Tau (T231, S262, and S404), ERK, p-ERK, GSK-3β, and p-GSK-3β was detected using western blotting to determine the effect of PB on Tau phosphorylation. The apoptosis rate was detected using flow cytometry, and the expression of Bax and Bcl-2 was detected using western blotting and verified using real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, cells were transfected with FoxO1 siRNA to downregulate FoxO1 expression, and the expression of the above-mentioned proteins was detected to verify the effect of PB on Tau phosphorylation and cell apoptosis.

Results: After 24 h of PB treatment, the phosphorylation levels of Tau at S404, S262, and T231 sites decreased significantly, and the activities of GSK-3β and ERK were inhibited. PB also reduced cell apoptosis by reducing the expression of Bax and increasing the expression of Bcl-2. In addition, PB decreased Tau phosphorylation and cell apoptosis by upregulating FoxO1.

Conclusion: The natural compound PB exhibited a protective effect in the AD cell model by increasing FoxO1 expression and reducing Tau phosphorylation and cell apoptosis.

]]>
<![CDATA[Differential Kat3 Coactivator Usage Regulates Brain Metabolism and Neuronal Differentiation]]>https://www.benthamscience.com/article/1337212024-03-28Introduction: Our previous work has demonstrated significant effects on the oxidative stress response, mitochondrial function, and oxidative phosphorylation in the livers and intestines of p300 S89A knockin (S89AKI) mice. We now show that this mutation is also associated with brain metabolic defects and neuronal differentiation.

Methods: p300 S89A edited P19 cells, and S89AKI mice demonstrated metabolic and neuronal differentiation defects based on proteomic, cell biological and PET imaging studies.

Results: The metabolic and differentiation defects associated with the p300 S89A knockin mutation could be corrected both in vitro and in vivo utilizing the small molecule CBP/beta-catenin antagonist ICG-001.

Conclusion: Rebalancing the equilibrium between CBP/β-catenin versus p300/β-catenin associated transcription, utilizing the small molecule CBP/beta-catenin antagonist ICG-001, enhances mitochondrial oxidative phosphorylation, metabolic function, and neuronal differentiation and may be able to ameliorate the cognitive decline seen in neurodegenerative disorders, including Alzheimer’s Disease.

]]>
<![CDATA[Ketamine Metabolites-waiting in the Wings as Therapeutic Candidate for Depression?]]>https://www.benthamscience.com/article/1334642024-03-28 <![CDATA[Mitochondria-targeted Uncouplers Decrease Inflammatory Reactions in Endothelial Cells by Enhancing Methylation of the ICAM1 Gene Promoter]]>https://www.benthamscience.com/article/1335972024-03-28Introduction: The study aimed to investigate the effects of low concentrations of mitochondrial uncouplers in endothelial cells on the CpG dinucleotide methylation of the ICAM1 gene promoter. The excessive inflammatory response in the endothelium is responsible for the development of many cardiovascular diseases. Mitochondria are important regulators of endothelial cell functions. Mild uncoupling of oxidative phosphorylation and respiration in endothelial mitochondria exerts a long lasting anti-inflammatory effect. However, the detailed mechanism of the anti-inflammatory activity of mitochondrial uncouplers remains unclear.We hypothesized that mild mitochondrial uncoupling leads to epigenetic changes in genomic DNA contributing to the anti-inflammatory response.

Methods: We studied the long-term effects of mitochondria-targeted compounds with the uncoupler’s activities: the antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1), dodecyl-triphenylphosphonium (C12TPP), and 2,4-dinitrophenol (DNP). The mRNA expression of the intercellular adhesion molecule 1 (ICAM1), a marker of inflammatory activation of endothelial cells, was measured by RT-qPCR. Cytosine methylation in the CpG sites of the ICAM1 gene promoter was estimated by bisulfite sequencing of individual clones.

Results: It was found that downregulation of ICAM1 expression caused by DNP and C12TPP was accompanied by an increase in the methylation of CpG sites in the ICAM1 gene promoter. None of the compounds affected intracellular or intramitochondrial ATP levels.

Conclusion: Low concentrations of mitochondrial oxidative phosphorylation uncouplers are able to increase methylation of ICAM1 gene promoter, which corresponds to the observed decrease in the levels of mRNA of this gene. Thus, the change in methylation of the ICAM1 gene promoter may underlie the mechanism of decreased ICAM1 expression caused by mild mitochondrial depolarization. Mitochondrial uncouplers may be exploited as possible therapeutic candidates to treat excessive inflammation in endothelium, by changing the methylation status of genomic DNA.

]]>
<![CDATA[A Deeply Quiescent Subset of CML LSC depend on FAO yet Avoid Deleterious ROS by Suppressing Mitochondrial Complex I]]>https://www.benthamscience.com/article/1343022024-03-28Background and Objective: Disease relapse and therapy resistance remain serious impediments to treating cancer. Leukemia stem cells (LSC) are therapy resistant and the cause of relapse. A state of deep quiescence appears to enable cancer stem cells (CSC) to acquire new somatic mutations essential for disease progression and therapy resistance. Both normal hematopoietic stem cells (HSC) and LSC share many common features, thereby complicating the safe elimination of LSC. A recent study demonstrated that long lived normal oocytes exist without mitochondrial complex I (MC-1), expressing it in a developmentally regulated fashion, thereby mitigating their vulnerability to ROS. Quiescent CSC rely on mitochondrial FAO, without complex I expression, thereby avoiding the generation of damaging ROS, similar to long lived normal human stem cells. A deeper understanding of the biology of therapy resistance is important for the development of optimal strategies to attain complete leukemia cures.

Methods: Here, using scRNA-sequencing and ATAC-seq on primary chronic myelogenous leukemia (CML) patient samples, combined with bioinformatics analyses, we further examine the heterogeneity of a previously characterized in vitro imatinib-selected CD34-CD38- CML LSC population. We utilized a series of functional analyses, including single-cell metabolomic and Seahorse analyses, to validate the existence of the deepest quiescent leukemia initiators (LI) subset.

Results: Current study revealed heterogeneity of therapy resistant LSC in CML patients and their existence of two functionally distinct states. The most deeply quiescent LI suppress the expression of MC-1, yet are highly dependent on fatty acid oxidation (FAO) for their metabolic requirements and ATAC-seq demonstrated increased chromatin accessibility in this population, all consistent with an extremely primitive, quiescent stemness transcriptional signature. Importantly, the specific CREB binding protein (CBP)/β-catenin antagonist ICG-001 initiates the differentiation of LSC, including LI, decreases chromatin accessibility with differentiation and increasing expression of MC-1, CD34, CD38 and BCR-ABL1, thereby resensitizing them to imatinib.

Conclusion: We investigated the biological aspects related to LSC heterogeneity in CML patients and demonstrated the ability of specific small molecule CBP/β-catenin antagonists to safely eliminate deeply quiescent therapy resistant CSC. These observations may represent an attractive generalizable therapeutic strategy that could help develop better protocols to eradicate the quiescent LSC population.

]]>
<![CDATA[The Mediating Role of miR-451/ETV4/MMP13 Signaling Axis on Epithelialmesenchymal Transition in Promoting Non-small Cell Lung Cancer Progression]]>https://www.benthamscience.com/article/1330682024-03-28Background: Lung cancer is a leading cause of cancer mortality. It is one of the most abundant cancer types clinically, with 2 million new cases diagnosed yearly.

Aims: Using clinically collected non-small cell lung cancer (NSCLC) samples, we sought to hypothesize an innovative intact signaling cascade for the disorder.

Methods: We dissected snap-frozen NSCLC tissues along with sibling-paired nearby non-tumorous tissues from 108 NSCLC patients. We measured the expression levels of miR-451/ETV4/MMP13 using qRT-PCR and did a thorough investigation of the molecular mechanism for the signaling axis in NSCLC cell line A549. We also studied the epithelial-mesenchymal transition (EMT) process.

Results: The activity of miR-451 was significantly decreased in NSCLC tissues, while the expression levels of ETV4 and MMP13 were remarkably increased. At the same time, miR-451 levels maintained a declining trend across TNM stage I–III. Inversely, ETV4 and MMP13 increased as the TNM stage increased. The miR-451/ETV4/MMP13 signaling axis was closely associated with prognosis in NSCLC patients. Based on in vitro experiments, ETV4 was a direct targeting factor for miRNA-451. Meanwhile, ETV4 promoted the tumor properties of NSCLC cells by directly activating MMP13. Silencing MMP13 blocked the EMT progress of NSCLC cells.

Conclusion: Overall, we hypothesized an impeccable signaling pathway for NSCLC from a new aspect, and this can offer alternative insights for a better understanding of the disorder.

]]>
<![CDATA[Apelin Receptor Dimerization and Oligomerization]]>https://www.benthamscience.com/article/1338102024-03-28 <![CDATA[The Targeted Therapies for Osteosarcoma <i>via</i> Six Major Pathways]]>https://www.benthamscience.com/article/1338852024-03-28 <![CDATA[PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway]]>https://www.benthamscience.com/article/1346132024-03-28Introduction: Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anticolorectal cancer therapeutics are urgently needed.

Methods: In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression.

Results: Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression.

Conclusion: Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

]]>
<![CDATA[Targeting Mutant-p53 for Cancer Treatment: Are We There Yet?]]>https://www.benthamscience.com/article/1345112024-03-28Background: Mutations in the TP53 gene are the most common among genetic alterations in human cancers, resulting in the formation of mutant p53 protein (mutp53). Mutp53 promotes proliferation, migration, invasion, and metastasis in cancer cells. Not only does the initiation of oncogenesis ensue due to mutp53, but resistance towards chemotherapy and radiotherapy in cancer cells also occurs. This review aims to summarise and discuss the oncogenesis of mutant p53 in cancer cells and introduce the various mutant p53 inhibitors currently being evaluated at the pre-clinical and clinical stages. Compounds that induce the wild-type conformation on the targeted p53 missense mutation, restore or enhance the DNA binding of mutant p53, and inhibit cancer cells' growth are highlighted. In addition, the progression and development of the mutant p53 inhibitors in clinical trials are updated.

Conclusion: The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial.

]]>
<![CDATA[Research Progress of the Molecular Mechanism of Antithyroid Cancer Activity of Shikonin]]>https://www.benthamscience.com/article/1342512024-03-28 <![CDATA[Co-treatment of Astragaloside IV with Vitamin D in Diabetic Peripheral Neuropathic Rats: Protective Effects and Potential Mechanisms]]>https://www.benthamscience.com/article/1352222024-03-28Objective: The potential mechanism underlying the protective effect of Astragaloside IV (AS-IV) co-treatment with 1, 25-dihydroxy-vitamin D (Vit-D) on neuropathy in diabetic high-fat rats was investigated.

Methods: The rat diabetic hyperlipidemia (DH) model was established via streptozotocin and a high-fat diet (HFD). After co-treatment (of AS-IV and Vit-D at respective doses of 50 mg/kg via oral gavage and 30000 IU/kg via intramuscular injection), blood glucose levels, markers of inflammation and oxidative stress, as well as apoptosis and histopathology were evaluated with appropriate techniques.

Results: Co-treatment could effectively reduce blood glucose levels substantially (p< 0.01), improve weight loss, and decrease oral glucose tolerance. Reduced respective sensory and motor nerve conduction velocities in rats were substantially improved (p<0.01) after co-treatment. Also, we observed obvious improvement in DH-induced injured nerve fiber myelin structure and other organ pathologies in co-treated rats. Besides, we observed up-regulated expressions of peroxisomal-proliferator activated receptor-alpha (PPAR-α) and Vit-D receptors (VDR) (p< 0.01) through the western blotting technique. Using the same technique, we also discovered reduced levels of interleukin (IL)1 beta, IL-6, and tumor necrosis factor-alpha, coupled with increased IL-10 and superoxide dismutase levels (p< 0.01). Importantly, co-treatment could effectively exert antioxidative and anti-inflammatory effects. Also, co-treatment resulted in the up-regulation of PPAR-α and VDR expressions, inhibition of the renin–angiotensin–aldosterone system, and promotion of β-cell sensitivity to insulin.

Conclusion: The combined application of AS-IV and Vit-D exhibited health effects such as anti-oxidation, regulation of inflammatory factors, and promotion of cell repair, which may be considered as the mechanisms underlying treatment of diabetic peripheral neuropathy and improvement in biochemical indicators.

]]>
<![CDATA[RBM3 Accelerates Wound Healing of Skin in Diabetes through ERK1/2 Signaling]]>https://www.benthamscience.com/article/1352232024-03-28Background: With the increasing risk of infections and other serious complications, the underlying molecular mechanism of wound healing impairment in diabetes deserves attention. Cold shock proteins (CSPs), including CIRP and RBM3 are highly expressed in the skin; however, it is unknown whether CSPs are involved in the wound-healing impairment of diabetic skin.

Objectives: The objective of this study is to investigate the effects of RBM3 on skin wound healing in diabetes.

Methods: In vitro experiments, western blot assay was used to test the levels of proteins in HaCaT cells treated with different concentrations of glucose. RBM3 was over-expressed in HaCaT cells using lentivirus particles. Cell viability was analyzed by Cell-Counting Kit-8 assay and colony formation assay. The migration of HaCaT cells at different concentrations of glucose was evaluated by wound healing assay. In vivo experiments, the mouse model of diabetes was established by intraperitoneal injection of streptozotocin. Four weeks later, the mice were anesthetized by intraperitoneal injection of pentobarbital sodium for skin tissue collection or wound healing experiments. RBM3 knockout mice were established by removing exons 2–6 using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technique and then used in skin wound healing experiments with or without diabetic stress.

Results: In this study, the expression of RBM3, rather than CIRP, was altered in the skin of diabetic specimens, and the RBM3’s overexpression accelerated the cell viability and proliferation of HaCaT cells under high glucose conditions. RBM3 deficiency caused delayed wound healing in RBM3 knockout in diabetic conditions. Moreover. RBM3 enhanced the ERK1/2 signaling pathway, and its inhibitor FR180204 blocked the beneficial effect of RBM3 overexpression on skin wound healing in diabetes.

Conclusion: RBM3 activated the ERK1/2 signal to facilitate skin wound healing in diabetes, offering a novel therapeutic target for its treatment.

]]>
<![CDATA[Targeting FGFR3 is a Useful Therapeutic Strategy for Rheumatoid Arthritis Treatment]]>https://www.benthamscience.com/article/1352242024-03-28Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease in which TNF-α plays an important role. Fibroblast growth factor receptor 3 (FGFR3) is reportedly involved in RA by regulating the expression of inflammatory cytokines.

Objective: This study examined the expression profile of FGFR3 in human synovial biopsy tissues and evaluated its gene-silencing effects on behaviors of synovial cells.

Methods: Immunohistochemical staining was used to measure FGFR3 expression in human RA joint tissues. Cell proliferation, migration, and apoptosis assays were used to monitor behavioral changes in cultured synovial SW-982 cells with siRNA-mediated FGFR3 gene silencing. Immunofluorescent staining and western blotting were used to detect molecular changes in the FGFR3 gene-silenced cells.

Results: FGFR3 up-regulation was noted in both cytoplasms and nuclei of synovial cells in human RA joints. FGFR3 siRNA delivery experiments corroborated that FGFR3 knockdown decreased proliferation and migration, and triggered apoptosis of synovial cells. The FGFR3 gene knockdown enhanced constitutive expression of epithelial marker E-cadherin and conversely suppressed expression of epithelial-mesenchymal transition (EMT) markers, including Snail, fibronectin, and vimentin. In addition, FGFR3 silencing significantly reduced the constitutive expressions of TNF-α, transcription factor NF-κΒ, and downstream COX-2 protein and collagenolytic enzyme MMP-9. MAPK inhibition markedly suppressed constitutive levels of NF-κΒ, COX-2, and MMP-9.

Conclusion: Genetic interference of FGFR3 could modulate the expression of inflammatory mediators and EMT markers in the synovial cells. Targeting the FGFR3/MAPK signal axis may be considered a useful therapeutic strategy to ameliorate the development of RA.

]]>
<![CDATA[Artemisinin Attenuates Isoproterenol-induced Cardiac Hypertrophy via the ERK1/2 and p38 MAPK Signaling Pathways]]>https://www.benthamscience.com/article/1352252024-03-28Background: Artemisinin (ART) is mainly derived from Artemisia annua, a traditional Chinese medicinal plant, and has been found to affect cellular biochemical processes, such as proliferation, angiogenesis, and apoptosis, in addition to its antimalarial properties. However, its effect on cardiac hypertrophy and the underlying mechanisms remain unclear.

Objectives: This study aimed to investigate the effect of ART on cardiac hypertrophy and explore its possible mechanisms.

Materials and Methods: A rat model was established by intraperitoneal injection of isoproterenol (ISO) for 3 days, and the degree of myocardial hypertrophy was compared among 5 groups: a control (CON) group, an ISO group, and groups treated with different doses of ART (7 mg/kg/d, 35 mg/kg/d, and 75 mg/kg/d). Echocardiography was used to evaluate cardiac function and structure. The cross-sectional area of cardiomyocytes was measured by hematoxylin and eosin (H&E) staining. The heart weight (HW), body weight (BW), and tail length were measured, and the HW/tail length ratio and the HW/BW ratio were calculated. H9c2 rat cardiomyocytes were cultured, and different amounts of ART were added 2 hours before ISO stimulation. Phalloidin staining was used to evaluate the degree of cell hypertrophy. The levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were quantified in rat plasma and cell supernatant using enzyme-linked immunosorbent assay (ELISA), while the expression levels of p- ERK1/2, p-JNK, and p-p38 MAPK were assessed in the myocardium and H9c2 cells via western blot analysis.

Results: Intragastric administration of ART at a dosage of 35 mg/kg/d or over mitigated the early-stage cardiac hypertrophy induced by ISO in rats led to a reduction in left ventricular posterior wall diastolic thickness, interventricular septal thickness at diastole, lowered ANP and BNP levels, as well as a decrease in HW/tail length and HW/BW ratio. In vitro studies demonstrated that ART at a concentration of 100 μM inhibited ISO-mediated hypertrophy of H9c2 cells. The ISO group showed a higher p-ERK/GAPDH ratio and p-p38 MAPK/GAPDH ratio than the control group both in vivo and in vitro. Although the p-JNK/GAPDH ratio was increased in the ISO group, there was no statistical difference. The p-ERK/GAPDH and p-p38/GAPDH ratios were significantly lower in the ART group than in the ISO group.

Conclusion: The mechanism of ART against cardiac hypertrophy was related to inhibition of the ERK1/2 and p38 MAPK signaling pathways.]]> <![CDATA[Maprotiline Prompts an Antitumour Effect by Inhibiting PD-L1 Expression in Mice with Melanoma]]>https://www.benthamscience.com/article/1352272024-03-28Background: Research has revealed that the expression of PD-L1 is significantly upregulated in tumour cells and that the binding of programmed cell death protein 1 (PD-1) to programmed cell death 1 ligand 1 (PD-L1) inhibits the response of T cells, thereby suppressing tumour immunity. Therefore, blocking PD-L1/PD-1 signalling has become an important target in clinical immunotherapy. Some old drugs, namely, non-anticancer drugs, have also been found to have antitumour effects, and maprotiline is one of them. Maprotiline is a tetracyclic antidepressant that has been widely used to treat depression. However, it has not yet been reported whether maprotiline can exert an antitumour effect on melanoma.

Objective: This study aimed to investigate the antitumour efficacy of maprotiline in mice with melanoma.

Methods: In this study, female C57BL/6 mice were used to establish a tumour-bearing animal model. After treatment with maprotiline, the survival rate of mice was recorded daily. The expression of relevant proteins was detected by Western blotting, the proportion of immune cells was detected by flow cytometry, and the infiltration of immune cells in tumour tissue was detected by immunofluorescence staining.

Results: Maprotiline was found to inhibit the proliferation and migration of B16 cells while increasing cell apoptosis. Importantly, treatment with maprotiline decreased the expression of PD-L1 and increased the proportion of CD4+ T cells, CD8+ T cells, and NK cells in the spleen. It also increased the infiltration of CD4+ and CD8+ T cells in tumour tissue.

Conclusion: Our research findings suggest that maprotiline enhances the antitumour immune response in mouse melanoma by inhibiting PD-L1 expression. This study may discover a new PD-L1 inhibitor, providing a novel therapeutic option for the clinical treatment of tumours.

]]>
<![CDATA[Dual Role of Pregnane X Receptor in Nonalcoholic Fatty Liver Disease]]>https://www.benthamscience.com/article/1352282024-03-28 <![CDATA[At the Crossroads of TNF α Signaling and Cancer]]>https://www.benthamscience.com/article/1343632024-03-28 <![CDATA[Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model]]>https://www.benthamscience.com/article/1353782024-03-28Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.

Objective: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.

Methods: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.

Results: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.

Conclusion: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.

]]>
<![CDATA[Screening and Identification of ESR1 as a Target of Icaritin in Hepatocellular Carcinoma: Evidence from Bibliometrics and Bioinformatic Analysis]]>https://www.benthamscience.com/article/1352262024-03-28Background: In 2022, icaritin a Traditional Chinese Medicine with estrogen-like activities was recommended by the CSCO guidelines as a systematic treatment for patients with advanced HCC due to its clinical safety and efficacy. However the mechanism and targets of icaritin are unclear. In this study we aimed to reveal the target of icaritin in HCC.

Methods: First literature related to icaritin was downloaded from the Web of Science. The software programs “Rstudio” “VOSviewer” and “Mendeley Desktop” were used to analyze the distribution of icaritin publications and research hotspots. Meanwhile icaritin-related genes were obtained by combining them with the PubChem database. Second transcriptome data of HCC patients were obtained from the TCGA database. The proteinprotein interaction (PPI) analysis of icaritin-related genes was performed using the String data platform and the visualization and network topology analysis were performed using Cytoscape. Cox regression analyses were combined to screen the hub target and verified it through cell experiments.

Results: A total of 239 icaritin-related articles were obtained HCC is a new hotspot in the icaritin field. 292 icaritin-related genes were obtained and a core module containing 34 genes was obtained by module division. Among them ESR1 was an independent prognostic factor. Molecular docking showed that ESR1 and icaritin had a high affinity. Functional studies revealed that ESR1 inhibits HCC cell malignant proliferation and improves the sensitivity of HCC cells to icaritin.

Conclusion: We propose that ESR1 as a target of icaritin may be conducive to improving icaritin therapy.

]]>
<![CDATA[The Effect of Fingolimod on Renal Ischemia/Reperfusion Injury in a Rat Model]]>https://www.benthamscience.com/article/1340582024-03-28Background: Ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI) that induces inflammation and oxidative stress. The main goal of the current study was to assess the impact of fingolimod on kidney IRI in rats.

Methods: For this purpose, 18 male Wistar rats (220–250g) were divided into three groups including (i) Sham, (ii) I/R, and (iii) fingolimod+I/R. The last group was pretreated with a single dose of fingolimod (1mg/kg) (intraperitoneal injection) before induction of the I/R injury. Kidney function, oxidative stress marker (malondialdehyde), and antioxidant markers (catalase, superoxide dismutase, glutathione, glutathione peroxidase, and total antioxidant capacity) were determined in the kidney tissue of the rats. Moreover, kidney samples were taken for histological analysis.

Results: Fingolimod pre-treatment could significantly improve the glutathione peroxidase (p<0.01) and glutathione (p<0.001) activities along with the total antioxidant capacity levels (p<0.001) when compared to the I/R group. Moreover, significant recovery of kidney function and histology was seen in the fingolimod+ I/R group compared to the I/R group (p<0.01).

Conclusion: Fingolimod pretreatment could improve renal function, antioxidant capacity, and histological alterations after I/R injury. Hence, it might protect the kidney against IRI-related kidney damage including AKI and transplantation.

]]>
<![CDATA[Regulating miRNAs Expression by Resveratrol: Novel Insights based on Molecular Mechanism and Strategies for Cancer Therapy]]>https://www.benthamscience.com/article/1354702024-03-28 <![CDATA[SGLT2 Inhibitors and Diabetic Kidney Disease: Targeting Multiple and Interrelated Signaling Pathways for Renal Protection]]>https://www.benthamscience.com/article/1354962024-03-28 <![CDATA[All-trans Retinoic Acid Increased Transglutaminase 2 Expressions in BV-2 Cells and Cultured Astrocytes]]>https://www.benthamscience.com/article/1355062024-03-28Background: Activation of microglia and astrocytes has been observed in Alzheimer’s disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.

Objective: We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.

Methods: After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.

Results: In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.

Conclusion: These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.

]]>
<![CDATA[Deregulated MicroRNAs involved in P53 Signaling Pathway in Breast Cancer with Focus on Triple-negative Breast Cancer]]>https://www.benthamscience.com/article/1355112024-03-28Background: Breast cancer (BC), as a heterogenous disease, is the most common cancer among women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive and malignant subtype with a poor prognosis and a high rate of relapse and metastasis that is closely linked to epithelial–mesenchymal transition (EMT). It is well-documented that miRNAs play oncogenic (oncomiR) or tumor-suppressive (TS-miR) roles in controlling apoptosis (apoptomiR), differentiation, cell proliferation, invasion, migration, etc. Regarding the regulatory roles of miRNAs in the expression levels of various genes, dysfunction or deregulated expression of these molecules can lead to various disorders, including various types of cancers, such as BC. Many miRNAs have been identified with critical contributions in the initiation and development of different types of BCs due to their influence on the p53 signaling network.

Objective: The aim of this review was to discuss several important deregulated miRNAs that are involved in the p53 signaling pathway in BC, especially the TNBC subtype. Finally, miRNAs’ involvement in tumor properties and their applications as diagnostic, prognostic, and therapeutic agents have been elaborated in detail.

Results: The miRNA expression profile of BC is involved in tumor-grade estrogen receptor (ER) and progesterone receptor (PR) expression, and other pathological properties from luminal A to TNBC/basal-like subtypes via p53 signaling pathways.

Conclusion: Developing our knowledge about miRNA expression profile in BC, as well as molecular mechanisms of initiation and progression of BC can help to find new prognostic, diagnostic, and therapeutic biomarkers, which can lead to a suitable treatment for BC patients.

]]>
<![CDATA[Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease]]>https://www.benthamscience.com/article/1355782024-03-28Background: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition.

Aims: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer’s disease.

Methods: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer’s disease through the published article from Pubmed and Scopus.

Description: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by β-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article.

Conclusion: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer’s disease.

]]>
<![CDATA[Review of the Role of Metabolic Factors in Determining the Post-surgical Adhesion and its Therapeutic Implications, with a Focus on Extracellular Matrix and Oxidative Stress]]>https://www.benthamscience.com/article/1356192024-03-28 <![CDATA[Are Purinergic Receptors Overlooked Targets in Hyperinflammatory Responses?]]>https://www.benthamscience.com/article/1368992024-03-28 <![CDATA[Creatine in Cognitive Performance: A Commentary]]>https://www.benthamscience.com/article/1372172024-03-28 <![CDATA[Calpain Inhibitor Calpeptin Improves Pancreatic Fibrosis in Mice with Chronic Pancreatitis by Inhibiting the Activation of Pancreatic Stellate Cells]]>https://www.benthamscience.com/article/1372182024-03-28Background: Pancreatic fibrosis is a hallmark feature of chronic pancreatitis (CP), resulting in persistent damage to the pancreas. The sustained activation of pancreatic stellate cells (PSCs) plays a pivotal role in the progression of pancreatic fibrosis and is a major source of extracellular matrix (ECM) deposition during pancreatic injury.

Methods: Calpain is a calcium-independent lysosomal neutral cysteine endopeptidase and was found to be correlated to various fibrotic diseases. Studies have revealed that calpeptin, a calpain inhibitor, can improve the fibrosis process of multiple organs. This study investigated the effect of the calpain inhibitor, calpeptin, on fibrosis in experimental CP and activation of cultured PSCs in mice. CP was induced in mice by repeated injections of cerulein for four weeks in vivo, and the activation process of mouse PSCs was isolated and cultured in vitro. Then, the inhibitory effect of calpeptin on pancreatic fibrosis was confirmed based on the histological damage of CP, the expression of α-smooth muscle actin (α-SMA) and collagen-Iα1(Col1α1), and the decrease in mRNA levels of calpain-1 and calpain-2.

Results: In addition, it was revealed that calpeptin can inhibit the activation process of PSCs and induce significant PSCs apoptosis by downregulating the expression of calpain-1, calpain-2 and TGF-β1, and the expression and phosphorylation of smad3 in vitro.

Conclusion: These results suggest that the calpain inhibitor, calpeptin, plays a key role in the regulation of PSC activation by inhibiting the TGF-β1/smad3 signaling pathway, which supports the potential of calpeptin as an inhibitor of pancreatic fibrosis in mice by interfering with calpain.

]]>
<![CDATA[An Essential Role of c-Fos in Notch1-mediated Promotion of Proliferation of KSHV-Infected SH-SY5Y Cells]]>https://www.benthamscience.com/article/1372192024-03-28Background: This study aimed to investigate the influence of Notch1 on c-Fos and the effect of c-Fos on the proliferation of Kaposi's sarcoma-associated herpesvirus (KSHV)-infected neuronal cells.

Methods: Real-time PCR and western blotting were used to determine c-Fos expression levels in KSHV-infected (SK-RG) and uninfected SH-SY5Y cells. C-Fos levels were measured again in SK-RG cells with or without Notch1 knockdown. Next, we measured c-Fos and p-c-Fos concentrations after treatment with the Notch1 γ-secretase inhibitor LY-411575 and the Notch1 activator Jagged-1. MTT and Ki-67 staining were used to evaluate the proliferation ability of cells after c-Fos levels downregulation. CyclinD1, CDK6, and CDK4 expression levels and cell cycle were analyzed by western blotting and flow cytometry, respectively. After the c-Fos intervention, the KSHV copy number and gene expression of RTA, LANA and K8.1 were analyzed by real-time TaqMan PCR.

Results: C-Fos was up-regulated in KSHV-infected SK-RG cells. However, the siRNA-mediated knockdown of Notch1 resulted in a significant decrease in the levels of c-Fos and p-c-Fos (P <0.01, P <0.001). Additionally, a decrease in Cyclin D1, CDK6, and CDK4 was also detected. The Notch1 inhibitor LY-411575 showed the potential to down-regulate the levels of c-Fos and p-c-Fos, which was consistent with Notch1 knockdown group (P <0.01), whereas the expression and phosphorylation of c-Fos were remarkably up-regulated by treatment of Notch1 activator Jagged-1 (P <0.05). In addition, our data obtained by MTT and Ki-67 staining revealed that the c-Fos down-regulation led to a significant reduction in cell viability and proliferation of the SK-RG cells (P <0.001). Moreover, FACS analysis showed that the cell cycle was arrested in the G0/G1 stage, and the expressions of Cyclin D1, CDK6, and CDK4 were down-regulated in the c-Fos-knockdown SK-RG cells (P <0.05). Reduction in total KSHV copy number and expressions of viral genes (RTA, LANA and K8.1) were also detected in c-Fos down-regulated SK-RG cells (P <0.05).

Conclusion: Our findings strongly indicate that c-Fos plays a crucial role in the promotion of cell proliferation through Notch1 signaling in KSHV-infected cells. Furthermore, our results suggest that the inhibition of expression of key viral pathogenic proteins is likely involved in this process.

]]>
<![CDATA[The Regulatory Mechanism of Hypoxia-inducible Factor 1 and its Clinical Significance]]>https://www.benthamscience.com/article/1372252024-03-28 <![CDATA[Molecular Insight into the Apoptotic Mechanism of Cancer Cells: An Explicative Review]]>https://www.benthamscience.com/article/1374022024-03-28Mitosis of somatic cells produces a daughter cell. Apoptosis, a naturally programmed cellular death mechanism, kills abnormal cells produced by mitosis. Cancer can develop when this equilibrium is disrupted, either by an upsurge in cell propagation or a reduction in tissue demise. Cancer therapy aims to cause cancer cells to die while inflicting little harm to healthy cells. This review of apoptotic mechanism processes improves our understanding of how certain malignancies begin and develop. The current cancer treatments can operate either by inducing apoptosis or causing direct cell damage. An insight into the resistance to apoptosis may explicate why malignancy treatments fail in some situations. New therapies grounded on our understanding of apoptotic processes are being developed to induce apoptosis of cancer cells while limiting the simultaneous death of normal cells. Various biological activities require redox equilibrium to function properly.

Antineoplastic medications that cause oxidative stress by raising ROS and blocking antioxidant mechanisms have recently attracted much interest. The rapid accumulation of ROS impairs redox balance and damages cancer cells severely. Here, we discuss ROS-instigating malignancy therapy and the antineoplastic mechanism used by prooxidative drugs.

]]>
<![CDATA[Anticancer Properties of Baicalin against Breast Cancer and other Gynecological Cancers: Therapeutic Opportunities based on Underlying Mechanisms]]>https://www.benthamscience.com/article/1380032024-03-28 <![CDATA[Depression-like Behavior Induced by Repeated Administration of Dexamethasone to Lipopolysaccharide-inflamed Mice]]>https://www.benthamscience.com/article/1380222024-03-28Background: Over the years, animal models of depression have been developed by loading chronic stress, inducing neuroinflammation, or administering drugs that induce depression; however, these results have poor reproducibility. Therefore, it is necessary to develop animal models that exhibit definitive symptoms of depression for studies on potential therapeutics.

Objective: This study was aimed at investigating depression-like symptoms and their pathogenesis in lipopolysaccharide (LPS)-inflamed mice treated with dexamethasone (DEX).

Methods: Male ICR mice were injected with LPS, followed by injection with DEX a day later and each day for 6 consecutive days. Depression-like behavior, expression of the glial markers glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1), and the number of the immature neuronal marker doublecortin (DCX)-positive cells were assessed using tail-suspension test (TST), forced swim test (FST), western blot analysis, and immunohistochemical analysis.

Results: Mice in the LPS+DEX group had significantly longer immobility time in the TST and FST than did those in the LPS- or DEX-only and control groups on day 7 post-LPS administration. GFAP and Iba1 expression was significantly elevated in the hippocampus of mice in the LPS group than in those of mice in the control group. Moreover, a significantly lower number of DCX-positive cells was observed in the hippocampal dentate gyrus of mice in the LPS+DEX group compared with that in mice in the LPS- or DEX-only and control groups on day 7 after LPS administration.

Conclusion: Repeated DEX administration to LPS-inflamed mice may induce definitive depression-like symptoms by decreasing the number of immature neurons in the hippocampal dentate gyrus. This novel mouse model of depression was produced by repeated administration of steroids to inflamed mice.

]]>
<![CDATA[Curcumin and Berberine Arrest Maturation and Activation of Dendritic Cells Derived from Lupus Erythematosus Patients]]>https://www.benthamscience.com/article/1380292024-03-28Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease recognized by elevated activity of autoimmune cells, loss of tolerance, and decreased regulatory T cells producing inhibitory cytokines. Despite many efforts, the definitive treatment for lupus has not been fully understood. Curcumin (CUR) and berberine (BBR) have significant immunomodulatory roles and anti-inflammatory properties that have been demonstrated in various studies. This study aimed to investigate the anti-inflammatory properties of CUR and BBR on human monocyte-derived dendritic cells (DCs) with an special focus on the maturation and activation of DCs.

Methods: Human monocytes were isolated from the heparinized blood of SLE patients and healthy individuals, which were then exposed to cytokines (IL-4 and GM-CSF) for five days to produce immature DCs. Then, the obtained DCs were characterized by FITC-uptake assay and then cultured in the presence of CUR, BBR, or lipopolysaccharide (LPS) for 48 h. Finally, the maturation of DCs was analyzed by the level of maturation using flow cytometry or real-time PCR methods.

Results: The results showed promising anti-inflammatory effects of CUR and BBR in comparison with LPS, supported by a significant reduction of not only co-stimulatory and antigen-presenting factors such as CD80, CD86, CD83, CD1a, CD14, and HLA-DR but also inflammatory cytokines such as IL-12.

Conclusion: CUR and BBR could arrest DC maturation and develop a tolerogenic DC phenotype that subsequently promoted the expression of inhibitory cytokines and reduced the secretion of proinflammatory markers.

]]>
<![CDATA[Impact of Nicosulfuron on Sperm Quality: Insights into Testicular Cell Apoptosis and NF-κB Signaling Pathway in Mice Testes]]>https://www.benthamscience.com/article/1381482024-03-28Background: Nicosulfuron, a widely used herbicide in crops, has raised concerns due to its escalating presence as an environmental pollutant, particularly in soil and water. The potential adverse effects of nicosulfuron on animals, including reproductive toxicity, have garnered attention.

Objective: The study aimed to evaluate the reproductive toxicity of nicosulfuron in male mice.

Methods: Male mice were orally administrated with three different concentration gradients (350, 700, and 1400 mg/kg) of nicosulfuron for 35 days. The investigation delved into sperm quality, testicular structures, and expression of cleaved caspase-3 and NF-κB p65 of the testes.

Results: The finding unveiled a correlation between nicosulfuron exposure and detrimental effects on sperm quality and alteration of testicular structure. Notably, parameters, such as sperm survival rate (SUR) and sperm motility (MOT), exhibited a decline in relation to increasing nicosulfuron dosages. Moreover, in the mice subjected to higher doses of nicosulfuron, elevated expression of cleaved caspase-3 and NF-κB p65 was observed in the testes. Interestingly, we also observed an increase of NF-κB p65 expression in the mice exposed to the nicosulfuron.

Conclusion: Our research revealed that exposure to nicosulfuron resulted in compromised sperm quality and alterations in testicular structure. The correlation between nicosulfuron and apoptosis, especially via the NF-κB pathway, provided significant insights into the mechanisms underpinning these detrimental effects. These findings significantly enhance our comprehension of the potential hazards associated with nicosulfuron exposure and its impacts on the reproductive health of animals.

]]>
<![CDATA[Advancements in the Research of GEF-H1: Biological Functions and Tumor Associations]]>https://www.benthamscience.com/article/1381532024-03-28 <![CDATA[Nrf2 Mediates Effect of Resveratrol in Ischemia-reperfusion Injury]]>https://www.benthamscience.com/article/1381582024-03-28 <![CDATA[Sanguinarine Attenuates Lung Cancer Progression via Oxidative Stress-induced Cell Apoptosis]]>https://www.benthamscience.com/article/1382872024-03-28Background: Lung cancer (LC) incidence is rising globally and is reflected as a leading cause of cancer-associated deaths. Lung cancer leads to multistage carcinogenesis with gradually increasing genetic and epigenetic changes.

Aims: Sanguinarine (sang) mediated the anticancer effect in LCC lines by involving the stimulation of reactive oxygen species (ROS), impeding Bcl2, and enhancing Bax and other apoptosis-associated protein Caspase-3, -9, and -PARP, subsequently inhibiting the LC invasion and migration.

Objective: This study was conducted to investigate the apoptotic rate and mechanism of Sang in human LC cells (LCC) H522 and H1299.

Methods: MTT assay to determine the IC50, cell morphology, and colony formation assay were carried out to show the sanguinarine effect on the LC cell line. Moreover, scratch assay and transwell assay were performed to check the migration. Western blotting and qPCR were done to show its effects on targeted proteins and genes. ELISA was performed to show the VEGF effect after Sanguinarine treatment. Immunofluorescence was done to check the interlocution of the targeted protein.

Results: Sang significantly inhibited the growth of LCC lines in both time- and dose-dependent fashions. Flow cytometry examination and Annexin-V labeling determined that Sang increased the apoptotic cell percentage. H522 and H1299 LCC lines treated with Sang showed distinctive characteristics of apoptosis, including morphological changes and DNA fragmentation.

Conclusion: Sang exhibited anticancer potential in LCC lines and could induce apoptosis and impede the invasion and migration of LCC, emerging as a promising anticancer natural agent in lung cancer management.

]]>
<![CDATA[Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes]]>https://www.benthamscience.com/article/1386432024-03-28Aim: To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes.

Methods: An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs).

Results: GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs.

Conclusion: GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.

]]>
<![CDATA[IMPDH2 Positively Impacts the Proliferation Potential of Hepatoblastoma Cells by Activating JunB Signaling Pathway]]>https://www.benthamscience.com/article/1386452024-03-28Background: Amplification of inosine monophosphate dehydrogenase II, EC 1,1,1,205 (IMPDH2) has been reported in various cancers, which results in transformation and tumorigenicity. In our current work, we have explored the oncogenic properties and the underlying pathophysiology of IMPDH2 in hepatoblastoma (HB).

Methods: To investigate IMPDH2 expression in HB tissues and prognostic significance in HB patients, gene expression profiling interactive analysis (GEPIA) has been adopted. Immunohistochemistry has also helped to validate the protein expression of IMPDH2 in HB tissues. The effect of IMPDH2 overexpression or depletion on the proliferation of Hepatoblastoma cells in vitro has been evaluated by CCK8 assays and colony formation assays. Xenograft tumor growth of mice has been detected. Luciferase reporter assays have been conducted to determine the interaction of IMPDH2 and JunB, which was further asserted by pharmacological inhibition of JunB.

Results: IMPDH2 was highly expressed in HB tissues. Experimentally, the proliferation and colony formation of HuH6 cells were increased by IMPDH2 overexpression. Conversely, genetic inactivation of IMPDH2 impaired the proliferative efficiency and colony-forming rate of HepG2 cells. Besides, the luciferase reporter assay validated IMPDH2 overexpression to be associated with enhanced JunB transcriptional activity, while its activity was diminished in the case of IMPDH2 depletion. JunB inhibitor neutralized the IMPDH2-mediated increased phosphorylation of JunB.

Conclusion: Our findings, thus, suggest that IMPDH2 exhibits its oncogenic role in HB partially via JunB-dependent proliferation.

]]>
<![CDATA[RNA Interference-based Therapies for the Reduction of Cardiovascular Risk]]>https://www.benthamscience.com/article/1388472024-03-28 <![CDATA[A Promising Breakthrough: The Potential of VORASIDENIB in the Treatment of Low-grade Glioma]]>https://www.benthamscience.com/article/1388832024-03-28Background: This commentary explores the potential of Vorasidenib, also known as AG-881. This emerging small-molecule inhibitor has garnered substantial attention within the realm of oncology due to its unique mechanism of action and potential therapeutic applications.

Introduction: Gliomas are common malignant brain tumors characterized by diffuse brain infiltration. World Health Organization grade II and grade III diffuse gliomas are considered lower-grade gliomas (LGGs) and have isocitrate dehydrogenase (IDH) mutations. LGGs are challenging due to their infiltrative nature, making them capable of progressing into higher-grade malignancies. Vorasidenib is a novel therapeutic agent targeting mutant IDH1/2, sparking interest in the field.

Mechanism of Action: Vorasidenib inhibits mutant IDH1/2 through a unique mechanism, reducing the production of the oncometabolite 2-hydroxyglutarate (2-HG). This alteration affects key enzymes and DNA methylation, impacting tumor growth and invasion.

Preclinical Evidence: Preclinical studies show vorasidenib's efficacy in inhibiting mutant IDH1/2 and 2-HG production in glioma models. It suppresses tumor growth, making it a potential treatment option.

Clinical Evidence: Early clinical trials demonstrate vorasidenib's clinical activity in non-enhancing gliomas. It reduces 2-hydroxyglutarate levels and tumor cell proliferation, with an objective response rate and prolonged progression-free survival. The drug's safety profile is favorable.

Challenges and Future Directions: Challenges include identifying predictive biomarkers and optimizing sequencing or combinations with existing therapies. Further research is needed to establish long-term effectiveness, evaluate side effects, and explore combinations with immunotherapy.

Conclusion: Vorasidenib significantly advances LGG treatment, targeting a prevalent mutation and slowing tumor growth. Promising preclinical and clinical evidence and manageable side effects suggest its potential impact on LGG management. However, more research, including large trials, is needed to confirm its efficacy and role in treatment.

]]>
<![CDATA[Quercetin Enhances 5-fluorouracil Sensitivity by Regulating the Autophagic Flux and Inducing Drp-1 Mediated Mitochondrial Fragmentation in Colorectal Cancer Cells]]>https://www.benthamscience.com/article/1388142024-03-28Background: While chemotherapy treatment demonstrates its initial effectiveness in eliminating the majority of the tumor cell population, nevertheless, most patients relapse and eventually succumb to the disease upon its recurrence. One promising approach is to explore novel, effective chemotherapeutic adjuvants to enhance the sensitivity of cancer cells to conventional chemotherapeutic agents. In the present study, we explored the effect of quercetin on the sensitivity of colorectal cancer (CRC) cells to conventional chemotherapeutic agent 5-fluorouracil (5-FU) and the molecular mechanisms.

Methods: MTT assay, colony formation assay and Hoechst staining were performed to investigate the growth inhibition effect of quercetin alone or combined with 5-FU. The expression levels of apoptosis and autophagy-related proteins were assessed by western blotting. Intracellular ROS was detected using DCFH-DA. The change in the mitochondrial membrane potential was measured by a JC-1 probe. The effect of quercetin on mitochondrial morphology was examined using a mitochondrial-specific fluorescence probe, Mito-Tracker red.

Results: The results demonstrated quercetin induced apoptosis and autophagy, as well as imbalanced ROS, decreased mitochondrial membrane potential, and Drp-1-mediated mitochondrial fission in CRC cells. Autophagy blockage with autophagy inhibitor chloroquine (CQ) enhanced quercetininduced cytotoxicity, indicating that quercetin induced cytoprotective autophagy. Meanwhile, quercetin enhanced the sensitivity of CRC cells to 5- FU via the induction of mitochondrial fragmentation, which could be further enhanced when the quercetin-induced protective autophagy was blocked by CQ.

Conclusions: The findings of the study suggested that quercetin could enhance the sensitivity of CRC cells to conventional agent 5-FU by regulating autophagy and Drp-1-mediated mitochondrial fragmentation. Therefore, quercetin may act as a chemotherapeutic adjuvant. Moreover, the regulation of autophagic flux may be a potential therapeutic strategy for colorectal cancer.

]]>