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Introduction
Interleukin-17A (IL-17A) is a well-established pro-inflammatory cytokine, which plays a pivotal role in immune and autoimmune diseases including psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. Three currently approved monoclonal antibodies (mAbs) are in clinical practice for the treatment of multiple immune diseases....
Contexts in source publication
Context 1
... DNA-encoded library (DEL) synthesis technology, a plentiful macrocycle library was developed for screening IL-17 inhibitors. Most macrocycles with general structure 1 ( Figure 3) are claimed to have excellent binding to IL-17A [17,18]. These macrocycles mostly use -CH 2 -(1,4-phenylene)-as a linker to connect the large cyclic amide ring and the aromatic motif. ...
Context 2
... example, compound 4 and its derivatives 5 and 6 were measured through enzyme-linked immunosorbent assay (ELISA), SPR assay, HT-29 cell-based functional assay and a rheumatoid arthritis synovial fibroblast (RASF) cell assay. (Figure 3). Notably, macrocycle 4, 5, and 6 were shown to bind to IL-17A with very good binding affinities K d < 100 nM. ...
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Citations
... Prdx4 is an important anti-inflammatory and antioxidant molecule, and its expression is decreased in AP group, which is more likely to be used as a therapeutic target [22,23]. Using Autodock Vina 1.1.2 ...
... Over the past few years, many important breakthroughs have been made in identifying small molecule compounds with therapeutic potential for a variety of diseases [22]. Small molecule compounds have the advantage of high tissue penetration, adjustable half-life, oral bioavailability, etc., which can produce better multiple therapeutic effects [23]. The compounds C42H60N4O6 and C28H29F3N4O5S can significantly improve AP damage in vitro and in vivo by inhibiting Fig. 6 Docking diagram of small molecule drugs with targets. ...
Acute pancreatitis (AP) is a common systemic inflammatory disease resulting from the activation of trypsinogen by various incentives in ICU. The annual incidence rate is approximately 30 out of 100,000. Some patients may progress to severe acute pancreatitis, with a mortality rate of up to 40%. Therefore, the goal of this article is to explore the key genes for effective diagnosis and treatment of AP. The analysis data for this study were merged from two GEO datasets. 1357 DEGs were used for functional enrichment and cMAP analysis, aiming to reveal the pathogenic genes and potential mechanisms of AP, as well as potential drugs for treating AP. Importantly, the study used LASSO and SVM-RFE machine learning to screen the most likely AP occurrence biomarker for Prdx4 among numerous candidate genes. A receiver operating characteristic of Prdx4 was used to estimate the incidence of AP. The ssGSEA algorithm was employed to investigate immune cell infiltration in AP. The biomarker Prdx4 gene exhibited significant associations with a majority of immune cells and was identified as being expressed in NKT cells, macrophages, granulocytes, and B cells based on single-cell transcriptome data. Finally, we found an increase in Prdx4 expression in the pancreatic tissue of AP mice through immunohistochemistry. After treatment with recombinant Prdx4, the pathological damage to the pancreatic tissue of AP mice was relieved. In conclusion, our study identified Prdx4 as a potential AP hub gene, providing a new target for treatment.
... In addition, we plan to explore the IL-17/IL-17RA pathway as a therapeutic target using humanized antibodies (secukinumab, ixekizumab, brodamulab) or small molecule inhibitors (S011806, LY3509754, LEO 153339) in mouse model and clinical trial. 55,56 AUTHOR CONTRIBUTIONS Jeng-Kai Jiang: Conceptualization (lead); funding acquisition (equal); project administration (equal); resources (lead); supervision (equal). Chi-Hung Lin: Conceptualization (equal); project administration (equal); resources (equal); supervision (equal). ...
Background
Interleukin‐17 (IL‐17) is a pro‐inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL‐17 binds to interleukin‐17 receptor A (IL‐17RA); however, the role of IL‐17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL‐17RA in human CRC tissues and the progression of CRC in humans and mice.
Methods
The expressions of IL‐17RA and epithelial‐mesenchymal transition (EMT)‐related genes were examined in CRC cells and tissue samples by quantitative real‐time polymerase chain reaction. The role of IL‐17RA in pathogenesis and prognosis was evaluated using a Chi‐squared test, Kaplan–Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor‐bearing mice model was executed to evaluate the role of IL‐17RA in tumor growth, vascularity and population of infiltrating immune cells.
Results
IL‐17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL‐17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL‐17RA expression exhibited significantly worse overall and CRC‐specific survival than those with low IL‐17RA expression. Functional assessment suggested that the knockdown of IL‐17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT‐related gene expression. In a tumor‐bearing mouse model, decreased IL‐17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid‐derived suppressor cells (MDSCs).
Conclusion
Reduced IL‐17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL‐17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL‐17RA expression was identified to be independently associated with the prognosis of patients with CRC.
... During the last few decades, small-molecular drugs targeting a series of diseases have achieved great success. 51,52 Several merits, including high tissue penetration, a tunable half-life, and oral bioavailability, have made small-molecular drugs more effective in conducting precise medication. Using CMAP analysis, several small-molecule drugs for the precise medication of patients in Cluster B were screened based on key genes included in both subsets (up-regulated genes and crucial module genes of Cluster B), whereas further trials are needed for assessing the therapeutic effects of those drugs in ameliorating kidney function of DN patients in Cluster B. ...
Objective
Diabetic nephropathy (DN) represents the principal cause of end-stage renal diseases worldwide, lacking effective therapies. Fatty acid (FA) serves as the primary energy source in the kidney and its dysregulation is frequently observed in DN. Nevertheless, the roles of FA metabolism in the occurrence and progression of DN have not been fully elucidated.
Methods
Three DN datasets (GSE96804/GSE30528/GSE104948) were obtained and combined. Differentially expressed FA metabolism-related genes were identified and subjected to DN classification using “ConsensusClusterPlus”. DN subtypes-associated modules were discovered by “WGCNA”, and module genes underwent functional enrichment analysis. The immune landscapes and potential drugs were analyzed using “CIBERSORT” and “CMAP”, respectively. Candidate diagnostic biomarkers of DN were screened using machine learning algorithms. A prediction model was constructed, and the performance was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The online tool “Nephroseq v5” was conducted to reveal the clinical significance of the candidate diagnostic biomarkers in patients with DN. A DN mouse model was established to verify the biomarkers’ expression.
Results
According to 39 dysregulated FA metabolism-related genes, DN samples were divided into two molecular subtypes. Patients in Cluster B exhibited worse outcomes with a different immune landscape compared with those in Cluster A. Ten potential small-molecular drugs were predicted to treat DN in Cluster B. The diagnostic model based on PRKAR2B/ANXA1 was created with ideal predictive values in early and advanced stages of DN. The correlation analysis revealed significant association between PRKAR2B/ANXA1 and clinical characteristics. The DN mouse model validated the expression patterns of PRKAR2B/ANXA1.
Conclusion
Our study provides new insights into the role of FA metabolism in the classification, immunological pathogenesis, early diagnosis, and precise therapy of DN.
... 54 Interesting, accumulated literature clarified that the IL-17/T-helper 17 (Th17) axis, a wellestablished proinflammatory cytokine, is involved in the pathophysiology of psoriasis. 55,56 We detected the level of IL-17A in clinical patient samples by Luminex and found that the secretion level of IL-17A increased gradatim with the prolongation of the disease course (Supplement Figure 1). We did not find the change tendency of IL-17A mRNA in HaCaT cells treated with TNF-α, IL-22, and LPS compared with normal control cells. ...
Background
The traditional Matricaria chamomilla L. has been used to treat dermatitis for thousands of years. Due to emerging trends in alternative medicine, patients prefer natural remedies to relieve their symptoms. Therefore, finding safe and effective plant medicines for topical applications on the skin is an important treatment strategy for dermatologists. German chamomile (Matricaria chamomilla L.) from the Compositae family is a famous medicinal plant, often known as the “star of medicinal species.”However, the function of Matricaria chamomilla essential oil on skin inflammation has not been thoroughly examined in earlier research.
Methods
GC-MS analyzed the components of MCEO, and this study explored the anti-inflammation effects of MCEO on psoriasis with network pharmacological pathway prediction. Following this, we used clinical samples of psoriasis patients to confirm the secretory characteristic of relative inflammatory markers. The therapeutic effect of MCEO on skin inflammation was detected by examination of human keratinocytes HaCaT. At the same time, we prepared imiquimod-induced psoriatic-like skin inflammation in mice to investigate thoroughly the potential inhibition functions of MCEO on psoriatic skin injury and inflammation.
Results
MCEO significantly reduced interleukin-22/tumor necrosis factor α/lipopolysaccharide-stimulated elevation of HaCaT cell inflammation, which was correlated with downregulating PI3K/Akt/mTOR and p38MAPK pathways activation mediated by MCEO in HaCaT cells treated with IL-22/TNF-α/LPS. Skin inflammation was evaluated based on the PASI score, HE staining, and relative inflammatory cytokine levels. The results showed that MCEO could significantly contribute to inflammatory skin disease treatment.
Conclusion
MCEO inhibited inflammation in HaCaT keratinocytes induced by IL-22/TNF-α/LPS, the potential mechanisms associated with inhibiting excessive activation and crosstalk between PI3K/Akt/mTOR and p38MAPK pathways. MCEO ameliorated skin injury in IMQ-induced psoriatic-like skin inflammation of mice by downregulating the levels of inflammatory cytokines but not IL-17A. Thus, anti-inflammatory plant drugs with different targets with combined applications were a potential therapeutic strategy in psoriasis.
... However, all monoclonal antibodies targeting the IL-17-IL-17R pathway and approved as treatments have several disadvantages, such as non-oral administration, poor tissue penetration, and various adverse effects as an escalation of the immune system's inflammatory response. Indeed, intensive research is being performed to discover potent small molecules targeting the IL-17A/IL-17 RA protein-protein interaction to modulate immune responses as an attractive approach for immunotherapy [130]. These new small-molecule drugs (SMDs), which are orally bioavailable, are beneficial in terms of production cost, convenience of delivery, and potentially higher efficacy. ...
... These new small-molecule drugs (SMDs), which are orally bioavailable, are beneficial in terms of production cost, convenience of delivery, and potentially higher efficacy. Actually, numerous clinical trials of anti-IL-17A and IL-17RA antibodies are currently in progress [130,131]. ...
Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed world. Until recently, there were no approved antifibrotic therapies. In recent years, high levels of interleukin-17 (IL-17) have been associated with chronic inflammatory diseases with fibrotic complications that culminate in organ failure. In this review, we provide an update on the role of IL-17 in fibrotic diseases, with particular attention to the most recent lines of research in the therapeutic field represented by the epigenetic mechanisms that control IL-17 levels in fibrosis. A better knowledge of the IL-17 signaling pathway implications in fibrosis could design new strategies for therapeutic benefits.
... 50,51 Considering the potential benefits of small molecules over monoclonal antibodies, the next leap forward in treating psoriasis and PsA might be small molecule modulators targeting IL-17A/IL-17RA. 52 Exciting preliminary data confirms this leap, as deucravacitinib demonstrated superiority over apremilast in patients with psoriasis, 53 and upadacitinib was superior to adalimumab in patients with PsA. 54 Although currently available therapeutic armamentarium resulting in somewhat durable remission in patents with ulcerative colitis, the treatment goal of corticosteroid-free clinical remission was hardly achieved with biologic and small-molecule therapies targeting TNF-α, 4β7 integrin, JAK, S1P, TYK2, etc. 55 Although the effect on small bowel lesions remain unclear, risankizumab represents a promising and favorable option for patients with Crohn's disease who still have unmet needs. ...
... 50,51 Considering the potential benefits of small molecules over monoclonal antibodies, the next leap forward in treating psoriasis and PsA might be small molecule modulators targeting IL-17A/IL-17RA. 52 Exciting preliminary data confirms this leap, as deucravacitinib demonstrated superiority over apremilast in patients with psoriasis, 53 and upadacitinib was superior to adalimumab in patients with PsA. 54 Although currently available therapeutic armamentarium resulting in somewhat durable remission in patents with ulcerative colitis, the treatment goal of corticosteroid-free clinical remission was hardly achieved with biologic and small-molecule therapies targeting TNF-α, 4β7 integrin, JAK, S1P, TYK2, etc. 55 Although the effect on small bowel lesions remain unclear, risankizumab represents a promising and favorable option for patients with Crohn's disease who still have unmet needs. ...
Background The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019.
... 50,51 Considering the potential benefits of small molecules over monoclonal antibodies, the next leap forward in treating psoriasis and PsA might be small molecule modulators targeting IL-17A/IL-17RA. 52 Exciting preliminary data confirms this leap, as deucravacitinib demonstrated superiority over apremilast in patients with psoriasis, 53 and upadacitinib was superior to adalimumab in patients with PsA. 54 Although currently available therapeutic armamentarium resulting in somewhat durable remission in patents with ulcerative colitis, the treatment goal of corticosteroid-free clinical remission was hardly achieved with biologic and small-molecule therapies targeting TNF-α, 4β7 integrin, JAK, S1P, TYK2, etc. 55 Although the effect on small bowel lesions remain unclear, risankizumab represents a promising and favorable option for patients with Crohn's disease who still have unmet needs. ...
Background The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019.
... 50,51 Considering the potential benefits of small molecules over monoclonal antibodies, the next leap forward in treating psoriasis and PsA might be small molecule modulators targeting IL-17A/IL-17RA. 52 Exciting preliminary data confirms this leap, as deucravacitinib demonstrated superiority over apremilast in patients with psoriasis, 53 and upadacitinib was superior to adalimumab in patients with PsA. 54 Although currently available therapeutic armamentarium resulting in somewhat durable remission in patents with ulcerative colitis, the treatment goal of corticosteroid-free clinical remission was hardly achieved with biologic and small-molecule therapies targeting TNF-α, 4β7 integrin, JAK, S1P, TYK2, etc. 55 Although the effect on small bowel lesions remain unclear, risankizumab represents a promising and favorable option for patients with Crohn's disease who still have unmet needs. ...
Background The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019.
... 50,51 Considering the potential benefits of small molecules over monoclonal antibodies, the next leap forward in treating psoriasis and PsA might be small molecule modulators targeting IL-17A/IL-17RA. 52 Exciting preliminary data confirms this leap, as deucravacitinib demonstrated superiority over apremilast in patients with psoriasis, 53 and upadacitinib was superior to adalimumab in patients with PsA. 54 Although currently available therapeutic armamentarium resulting in somewhat durable remission in patents with ulcerative colitis, the treatment goal of corticosteroid-free clinical remission was hardly achieved with biologic and small-molecule therapies targeting TNF-α, 4β7 integrin, JAK, S1P, TYK2, etc. 55 Although the effect on small bowel lesions remain unclear, risankizumab represents a promising and favorable option for patients with Crohn's disease who still have unmet needs. ...
Background
The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019.
Methods
We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends.
Findings
In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR.
Interpretation
The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively.
