Recent Advances in Inflammation & Allergy Drug Discovery最新文献

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], RORꝩT 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.

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.

The physiological process of wound healing is complicated and involves extensive connections between biological, molecular, and cellular pathways. Acute and chronic wounds pose a serious socioeconomic burden by impacting millions of people each year globally, which has significantly increased the problem of amputations, longer hospital stays, and mortality. Despite tremendous progress, in aging populations, associated conditions like diabetes and growing antibiotic resistance make chronic wounds even more clinically challenging. Recent developments in science and technology and research at cellular and molecular levels have opened up new possibilities for wound healing by laying the foundation for new technologies, techniques, and information. This review provides an in-depth knowledge of phases of wound healing, innovative methods, and combining technology for wound repair for successful therapies. This study reveals the associated challenges with wound healing dressings, including traditional, advanced, and biotechnology-based dressings. Moreover, this study also includes herbal remedies for wound repair, wound assessment techniques, and experimental wound healing models. This report additionally includes new treatment technologies, such as smart wound dressings capable of real-time monitoring and delivery of drugs at a controlled rate. Finally, an extremely inventive and futuristic approach that adds a new horizon in wound healing is the use of nanobots, and new analytical tools based on machine learning and artificial intelligence (AI) are also considered.

Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease with difficult management, affecting the quality of life. Stem cell therapy has been proven to have regenerative ability. Using the existing stem cell therapy and modifying it, the current study aims to evaluate the effect of umbilical cord-derived mesenchymal stem cells (UCMSC), condition media (CM), and UCMSC and CM preconditioned with methotrexate, reservetrol, and vitamin D for its ability to manage T1DM in Swiss albino mice.

Materials & methods: Disease condition was established in the animals by using a diabetesinducing agent streptozotocin (STZ). Then the animals were grouped into normal control, disease control, standard, and test groups; and the treatments were given accordingly. The total study period for this experiment was 28 days. During this period, the animals were supervised for blood glucose levels, food-water intake, and body weight twice a week. At the end of 28 days, the biochemical estimations for serum insulin level, C-peptide, pro-inflammatory cytokines, and anti-inflammatory cytokines level were done. Also, histopathology of the pancreas was performed.

Results: The test groups showed a significant decline in the blood glucose level, an increase in C-peptide level, and a decrease in pro-inflammatory cytokines as compared to the disease group. A statistically significant change was not observed within the groups in terms of serum insulin and anti-inflammatory cytokine levels. There were improvements in diabetic symptoms in treatment groups, such as polyphagia, polydipsia, and weight loss. Treatment groups also showed pancreatic regeneration, indicating improved insulin secretion.

Conclusion: In the present study, we concluded that UCMSC, CM, and UCMSC and CM preconditioned with synthetic and natural immunosuppressants and immunomodulators have the ability to regenerate damaged pancreatic beta cells and have an antidiabetic activity, along with an immunomodulating effect. This therapy is a promising choice for future research.

This study provides a comprehensive bibliometric analysis of global research on urticaria, aiming to chart its progression, assess its relevance, and explore the roles of oxidative stress, inflammation, and immunity in its pathogenesis. Additionally, by analyzing data from PubMed and Scopus, we mapped research trends, identified leading authors and institutions, and examined global collaboration patterns. We also evaluated the impact of oxidative stress, inflammation, and immunity on urticaria and assessed the roles of both conventional and traditional medicine in its management. The results highlight the evolution of urticaria research, key contributors, thematic developments, and collaborative networks. This study offers a detailed bibliometric profile and thematic map, including insights into effective authors, prominent keywords, and significant research patterns. The findings are valuable for medical researchers, providing an updated overview of current themes and gaps, and are also beneficial for healthcare decision-makers by summarizing relevant information for strategic planning and fostering new collaborations. Additionally, the study integrates biological aspects related to urticaria with insights into traditional treatments, contributing to both research and practical management strategies.

Psoriasis (PsR), a chronic autoimmune disorder, affects millions of individuals globally and has a substantial impact on their quality of life. This complex condition involves intricate molecular networks and signaling pathways, making the development of effective treatments a significant challenge. Moreover, to advance treatment options, precise targeting of cells through the identification of protein biomarkers in PsR has emerged as a promising field of research for both fundamental and clinical scientists. These protein components provide valuable insights into the underlying mechanisms of the disease and can serve as indicators of treatment response. Furthermore, by identifying specific biocomponents, researchers can develop targeted therapeutics that address the molecular abnormalities driving PsR. The use of biologics as potential targets for improving treatment efficacy is a significant focus in PsR research. Biologics, which include monoclonal antibodies and fusion proteins, specifically target key molecules involved in the immune response, such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL). These targeted therapies have demonstrated substantial efficacy in managing PsR by modulating the immune system and reducing inflammation. Recent advancements in moleculartargeted therapies utilizing biologics or small-molecule inhibitors have contributed to improving patient outcomes. This review aims to summarize the recent discoveries and insights regarding biocomponents and their importance in treating PsR, encompassing both its inflammatory and dermatological aspects. Furthermore, the review discusses the commercial outcomes of ongoing clinical trials for various biological-based therapeutic modalities for PsR, providing valuable insights into the evolving landscape of PsR therapeutics. These developments indicate the growing interest and investment in improving treatment options for individuals living with PsR.

Background: 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.

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.

Background: 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.

The skin, as the body's largest organ, is crucial for maintaining homeostasis and providing protection, making it susceptible to wounds from various causes. Wound healing is a complex process involving numerous cellular activities. Any interruptions can lead to chronic, non-healing wounds, which present significant challenges in healthcare. Interleukin-24 (IL-24), a cytokine within the IL-10 family, has become recognized for its significant role in wound healing due to its diverse effects on cellular processes. IL-24 can inhibit keratinocyte migration, potentially leading to chronic wounds, and promote endothelial cell migration and angiogenesis, which are vital for tissue repair. This dual role highlights IL-24's intricate involvement in wound healing, as it can hinder and aid different aspects of the process. Research indicates that IL-24 expression increases in response to inflammatory mediators and is involved in various immune responses, emphasizing its regulatory function. Further research on IL-24's mechanisms and interactions is essential for developing new therapeutic strategies to enhance tissue regeneration and treat chronic wounds and skin disorders. A deeper understanding of IL-24's functions could transform wound care, providing new approaches for effectively managing and treating conditions involving impaired healing.

Background: Timolol is a beta-adrenergic blocker that has been shown to be effective in the healing of wounds. Oral mucositis (OM), an acute inflammation of the oral mucosa, is a bothersome side effect of some regimens of chemotherapy in which the oral mucosa becomes ulcerated. The current study aimed to evaluate the prophylactic effects of timolol mouthwash in preventing OM in adult patients receiving chemotherapy compared to the placebo.

Method: This randomized, double-blind trial was conducted on 30 adult patients receiving chemotherapy regimen, including doxorubicin or 5-fluorouracil (5-FU). The patients were randomized in a 1:1 ratio to receive either timolol 0.5% (w/v) (n = 15) or placebo (n = 15) mouthwash 5 ml three times per day. The outcomes of the study were the intensity of OM evaluated by the World Health Organization (WHO) mucositis scale and OM-related pain based on the Visual Analog Scale (VAS) weekly during the seven weeks of the study period.

Results: The results of the study showed that the scores of WHO mucositis scale significantly decreased in the timolol group compared to the control group during the study [week 1: mean (SD), 0.02 (0.41) in the timolol group, and 0.67 (0.48) in the control group; week 7: mean (SD), 0.33 (0.61) in the timolol group, and 0.87 (0.74) in the control group; P-value = 0.049]. Moreover, the mean pain scores significantly decreased in the first, second, and third weeks in the timolol group compared to the control group (P-value < 0.05).

Conclusion: The results of this preliminary clinical trial demonstrated that among the patients receiving doxorubicin or 5-FU chemotherapy regimens, the preventive use of timolol mouthwash significantly diminished the severity of OM compared to the control group during the seven weeks of follow-up. The severity of pain was also significantly lower during the first three weeks of the study; however, the effect size was less than the minimal clinically important difference. Further studies are required to assess both the long-term efficacy and safety of timolol mouthwash in preventing OM.