Recent Advances in Inflammation & Allergy Drug Discovery (Volume 20 - Issue 2)

Pharmacological Management of Psoriasis: Current Landscape and Future Perspectives

2025-03-16

Psoriasis is a relapsing, chronic, and inflammatory disease of the skin. However, its impact goes beyond just pathophysiology and takes a toll on the physical and psychological aspects of the health of the afflicted, lowering the quality of life significantly. It is also a mechanistically complex disease with a substantial immune component. Therefore, ongoing treatment strategies focus on targeting at least one immune component associated with the disease development and progression by employing biological agents like IL-1 inhibitors, IL-23 inhibitors, IL-36 inhibitors, and TNF-α inhibitors. Psoriasis-induced disruptions in cellular signalling pathways have drawn significant attention as novel drug targets. Numerous novel synthetic agents, such as JAK/STAT inhibitors (ruxolitinib, peficitinib), TYK2 inhibitors [zasocitinib, ropsacitinib], RORγT inhibitors (cedirogant), A3AR agonists (piclodenoson), and CXCR2 antagonists (vimnerixin) are undergoing extensive clinical trials and have demonstrated beneficial outcomes in multiple phases of these trials. Deucravacitinib, an orally administered TYK2 inhibitor, has recently received FDA approval for the treatment of moderate to severe plaque psoriasis. These synthetic agents hold promise to change the outlook of psoriasis management by modulating specific molecular targets associated with the dysregulated immune response observed in psoriasis. Moreover, these pathways can be exploited to personalize anti-psoriatic therapy, minimize side effects, and maximize therapeutic outcomes. Altogether, the integration of biological agents and synthetic agents can overcome the challenges associated with the management of the repertoire of psoriatic pathophysiology and symptoms.

Unseen Dangers: The Effects of Micro- and Nanoplastics on Human Reproductive Health - A Narrative Review

2025-03-16

Micro(nano)plastics (MNPs) have become pervasive environmental pollutants due to widespread use and inadequate waste management practices. These tiny particles infiltrate various ecosystems, including the human body, raising significant concerns about their potential health effects. Of particular concern is their impact on human reproductive health, with emerging research indicating MNPs' ability to breach biological barriers, accumulate in reproductive organs, and potentially reach the placenta. A comprehensive literature search spanning from July 2015 to July 2024 was conducted across prominent electronic databases, including Pub- Med, Scopus, Web of Science, and Google Scholar. Key search terms such as \"micro and nanoplastics,\" \"microplastics and male reproductive health,\" \"microplastics and female reproductive health,\" \"transgenerational spread of microplastics,\" and \"microplastics and fetal health\" were used to identify relevant studies published in peer-reviewed journals, books, and reputable conference proceedings. Selection criteria favoured review articles, original research papers, metaanalyses, and authoritative texts published in English. Synthesized findings from these studies were critically analysed to underscore their potential impacts on reproductive health. The accumulating evidence emphasizes the urgent need for further research to fully grasp the risks posed by MNPs to human reproductive health. Effective mitigation strategies are essential to minimize exposure and mitigate potential long-term consequences. Policy interventions aimed at enhancing waste management practices and regulating plastic usage are crucial to curb the environmental spread of MNPs and safeguard human reproductive health effectively.

Recent Advances in Medicinal Chemistry of Phosphodiesterase 7 Inhibitors and their Potential Therapeutic Applications

2025-03-16

Introduction: Phosphodiesterase 7 (PDE7) is a key enzyme in the PDE superfamily responsible for degrading cyclic adenosine monophosphate (cAMP) in pro-inflammatory and immunomodulatory cells. Elevated PDE7 activity is associated with inflammatory processes and various diseases. Suppression of PDE7 raises cAMP levels, reducing mucous secretion, cellular inflammation, and airway obstruction. This review provides an overview of the role of PDE7 in inflammatory disorders and highlights recent advances in the development of selective PDE7 inhibitors for therapeutic applications.

Methods: The review consolidates findings on the structure-activity relationships of PDE7 inhibitors. Key structural classes of small molecule inhibitors, including quinazolinone derivatives, thiadiazines, pyrimidines, and others, are discussed alongside preclinical and clinical data on selective inhibitors such as BRL50481 and OMS527.

Results: Selective PDE7 inhibitors have shown exposed potential in animal models to reduce cAMP degradation, leading to decreased inflammation and airway obstruction. BRL50481 remains the only commercially available selective PDE7 inhibitor, while OMS527 has progressed to clinical trials, demonstrating promise in treating inflammatory, neurological disorders, and leukemias.

Conclusion: Selective PDE7 inhibitors represent a novel therapeutic class for inflammatory and neurodegenerative diseases. Further research is characterised by immune dysregulation.

Screening of Phytocompounds Against the NF-kB Pathway Genes and Lung Elevated Proteins Associated with Acute Respiratory Distress Syndrome

2025-03-16

Introduction: Acute Respiratory Distress Syndrome (ARDS) is the pathophysiologic state of the inflammatory response to lung injury characterized by alveolar epithelial cell damage and increased cytokine production and accumulation in the lungs.

Objectives: The current study was performed to identify the molecular mechanisms of ARDS related to the proteins elevated in the lung (PEL) and NF-κB pathway regulatory genes (GRNF). In addition, the phytocompounds were screened to inhibit the representative target genes and proteins associated with ARDS.

Materials and Methods: We implemented STRING v11.5 and Network Analyst 3.0 to construct the protein-protein interactions (PPI) network. CytoScape v3.8.2 and DisGeNet v7.3.0 were utilized to visualize and identify genes involved in respiratory diseases. The Cytohubba module was utilized to identify the hub genes from the constructed PPI network. Autodock Vina and Discovery Studio Visualizer v19.1.0.1828 were utilized for the molecular docking analysis.

Results: The PPI network was constructed with the GRNF genes. Fifty-four genes are identified as biomarkers involved in respiratory diseases (BMRD). About 191 PEL were identified from the human protein atlas database and constructed the PPI network. The interactions between the PPI network of BMRD and PEL were analyzed. The top 100 hub genes and the signaling genes were identified. Based on the identified signaling genes through the PPI network of BMRD and PEL, the metabolic pathway was elucidated, which causes ARDS via NF-κB activation. The ARDS targets (ACVRL1, IKKβ, ITGAL, ITGB2, TGFβR1, and TGFβR2) were selected for the molecular docking study. One hundred and thirty-five chemical compounds from Allium sativum, Alstonia scholaris, Ammi visnaga, Artemisia vulgaris Linn., Houttuynia cordata, and Ocimum gratissimum Linn. were retrieved and used for docking against selected ARDS targets. Among them, genkdaphine from A. sativum inhibited ACVRL1 (binding affinity of -9.2 kcal/mol, and RMSD of 2.607Å), ITGAL (binding affinity of -9.1 kcal/mol, and RMSD of 1.69Å), ITGB2 (binding affinity of -7.9 kcal/mol, and RMSD of 2.184Å), TGFβRI (binding affinity of -8.5 kcal/mol, and RMSD of 1.807Å), and TGFβRII (binding affinity of -8.2 kcal/mol, and RMSD of 1.647Å). Edulisin III from A. visnaga inhibited the IKKβ (binding affinity of -7.4 kcal/mol, and RMSD of 2.223Å).

Conclusion: Genkdaphine and edulisin III may be the therapeutics for treating ARDS. However, further studies are needed to warrant the benefits of genkdaphine and edulisin III in treating ARDS. The study's findings may aid in developing new therapeutic approaches to improve the health status of ARDS-affected patients.

Evaluation of Toxoplasma gondii Perforin-like Proteins (PLPs) to Find the Potential Epitopes for Immunization through in silico Approach

2025-03-16

Introduction: Toxoplasma gondii (T. gondii) is a widespread apicomplexan parasite that affects approximately one-third of the global population, posing particular risks to pregnant women and individuals with weakened immune systems. Despite its significant impact, there is currently no vaccine available for humans.

Objective: This study employs computational methods (in silico) to investigate the physicochemical, antigenic, and structural properties of Perforin-like proteins (PLPs) from T. gondii, as well as to identify immunogenic epitopes within these antigens.

Methods: For this aim, amino acid sequences of TgPLP1 and TgPLP2 were retrieved and submitted to the ProtParam (physicochemical), VaxiJen v2.0 (antigenicity), NetSurfP-6.0 (2D structure), Robetta (3D structure) web servers, along with the IEDB server to decipher the immunogenic epitopes. Subcellular characteristics such as signal peptide, transmembrane domain, post-translational modifications (PTMs), and cellular localization were also predicted.

Results: Both proteins had a high MW of 125.50 and 92.21, respectively, with an alkaline pI, a 30 hours half-life in mammalian reticulocytes, good thermotolerance (high aliphatic index), and hydrophilicity properties (negative GRAVY). They also showed good antigenicity (0.7021 [PLP1] vs 0.5701 [PLP2]), while they were non-allergenic. Both proteins were extracellular with numerous post-translational modification sites (phosphorylation, glycosylation, and acetylation), and a transmembrane domain was only present in TgPLP1, with no signal peptide in both. Furthermore, numerous immunogenic B- and T-cell epitopes were identified within the TgPLPs sequences, suggesting their potential for inclusion in multi-epitope vaccine designs.

Conclusion: Further studies are needed to confirm these findings and assess the efficacy of the proposed vaccine constructs.

An Assessment of BHLHE40 Transcription Factor Level and its Target Cytokines in Patients with Rheumatoid Arthritis

2025-03-16

Introduction: Basic helix-loop-helix protein 40 (BHLHE40) can function as both a transcriptional activator and repressor. Recent studies have reported its regulatory functions in T helper (Th)1 and Th17 immune responses. Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which joints are involved. Both Th1 and Th17 contribute to the pathogenesis of the disease. In the present study, the levels of BHLHE40, interleukin 17 (IL-17), and interferon-gamma (IFN-γ) were assessed in the RA patients.

Methods: Two groups, including RA patients and healthy individuals, were included in the study. The relative expression levels of BHLHE40, IL-17, and IFN-γ were quantified in peripheral blood mononuclear cells (PBMCs) using real-time PCR.

Results: The results showed that the level of BHLHE40 was significantly higher in RA patients compared to the healthy control (P < 0.001) (11.1-fold increase). Accordingly, a significant increase in the levels of IL-17 (8.1 folds increase) (P < 0.021) and IFN-γ (12.7 folds) (P < 0.001) was observed.

Discussion: Given the rapid pace of research showing the importance of Bhlhe40 in anti-tumor, anti-pathogen, and autoimmune responses, it is anticipated that Bhlhe40 might be leveraged either as a putative biomarker or as a candidate target for therapy in a variety of human diseases.

Conclusion: Evaluation of the expression level of BHLHE40 in RA patients showed a significant increase. In line with the elevated level of BHLHE40, a significant increase in the expression level of IL-17 and IFN-γ was also detected. These findings point to the possible role of BHLHE40 in the disease course or severity by elevating the levels of inflammatory cytokines, including IL-17 and IFN-γ. Therefore, BHLHE40 might be considered either as a putative biomarker or as a candidate for therapy in a variety of human diseases.