Spotlight on amino acid changing mutations in the JAK-STAT pathway: from disease-specific mutation to general mutation databases

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 20, 2025

The JAK-STAT pathway is central to cytokine signaling and controls normal physiology disease. Aberrant activation via mutations that change amino acids in proteins of the can result diseases. While disease-centric databases like COSMIC catalog cancer, their prevalence healthy populations remains underexplored. We systematically studied such genes by comparing population-focused All Us database. Our analysis revealed frequent all JAK STAT domains, particularly among white females. further identified three categories: Mutations uniquely found were associated with cancer literature but could not be COSMIC, underscoring COSMIC's limitations. unique underline potential as drivers due absence general population. present both databases, e.g., JAK2Val617Phe/V617F - widely recognized a driver hematopoietic cells, without disease associations Us, raising possibility combinatorial SNPs might responsible for development. These findings illustrate complementarity understanding mutation impacts underscore need multi-mutation analyses uncover genetic factors underlying complex diseases advance personalized medicine.

Language: Английский

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Crosstalk between ferroptosis and innate immune in diabetic kidney disease: mechanisms and therapeutic implications

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 28, 2025

Diabetic kidney disease (DKD) is a prevalent complication of diabetes mellitus (DM), and its incidence increasing alongside the number cases. Effective treatment long-term management DKD present significant challenges; thus, deeper understanding pathogenesis essential to address this issue. Chronic inflammation abnormal cell death in closely associate with development. Recently, there has been considerable attention focused on immune infiltration into renal tissues inflammatory response’s role progression. Concurrently, ferroptosis—a novel form death—has emerged as critical factor pathogenesis, leading increased glomerular filtration permeability, proteinuria, tubular injury, interstitial fibrosis, other pathological processes. The cardiorenal benefits SGLT2 inhibitors (SGLT2-i) patients have demonstrated through numerous large clinical trials. Moreover, further exploratory experiments indicate these drugs may ameliorate serum urinary markers inflammation, such TNF-α, inhibit ferroptosis models. Consequently, investigating interplay between innate responses for guiding future drug This review presents an overview within context DKD, beginning core mechanisms delving potential roles We will also analyze how aberrant cells, molecules, signaling pathways contribute Finally, we discuss interactions responses, well targeted therapeutic agents, based current evidence. By analyzing immunity aim provide insights development area.

Language: Английский

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Ameliorative effects of wine-steamed Songaria Cynomorium Herb: Chemical characterization by UPLC-Q-TOF-MS and modulation of pathophysiology and JAK/STAT signaling pathway in kidney-Yang deficient rats

Fitoterapia, Journal Year: 2025, Volume and Issue: 182, P. 106478 - 106478

Published: March 12, 2025

Language: Английский

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Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Abstract At the convergence point of multiple cytokine signals, signal transducer and activator transcription 3 (STAT3) is a highly promising therapeutic target for diabetic nephropathy. Isoquercitrin, natural small‐molecule inhibitor STAT3, may have beneficial effects on nephropathy; however, underlying mechanism remains unclear. Isoquercitrin significantly mitigated renal inflammation fibrosis by inhibiting STAT3 activity in mice with Moreover, direct molecular isoquercitrin, which as corroborated tight stable noncovalent binding between them. This interaction mechanistically supported affinity isoquercitrin Ser668–Gln635–Gln633 region within pY+1 pocket SH2 domain. obstructs pivotal processes like phosphorylation dimerization, thereby suppressing its transcriptional function. Finally, kidney‐targeted nanocarrier, Iso@PEG‐GK, developed to load thus enhancing precision Iso@PEG‐GK improved absorption distribution isoquercitrin. study first demonstrate that exerts significant protective effect against nephropathy provide novel drug this disease.

Language: Английский

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Diabetic Kidney Disease: Disease Progression Driven by Positive Feedback Loops and Therapeutic Strategies Targeting Pathogenic Pathways

Diabetes Metabolic Syndrome and Obesity, Journal Year: 2025, Volume and Issue: Volume 18, P. 1073 - 1085

Published: April 1, 2025

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, with its pathogenesis intricately regulated by dynamic feedback mechanisms. This comprehensive review systematically analyzes the hierarchical networks driving DKD progression, spanning from systemic interactions to molecular cross-talks. We reveal that self-amplifying positive loops dominate process, manifested through three key dimensions: (1) The triad hyperglycemia-hypertension-proteinuria establishes vicious cycle accelerating renal dysfunction; (2) Cellular homeostasis collapse cross-amplified cell death modalities (apoptosis, pyroptosis, ferroptosis) and dysregulation; (3) Molecular cascades centered on AGE/RAGE signaling fuel chronic inflammation fibrotic transformation. Collectively, these form loop where PKC activation, oxidative stress propagation, TGF-β-mediated fibrosis induced hyperglycemia lead progressive deterioration fibrosis. Therapeutically, we propose dual intervention strategy targeting both acute phase axis inhibition, coupled via precision modulation pathways. These findings redefine progression as self-reinforcing network disorder, providing roadmap for developing multi-target therapies disrupt pathological while preserving repair

Language: Английский

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Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation

Archives of Internal Medicine Research, Journal Year: 2024, Volume and Issue: 07(02)

Published: Jan. 1, 2024

The review delves into the methods for quantitative assessment of intracellular effectors and cellular response Receptor Advanced Glycation End products (RAGE), a vital transmembrane receptor involved in range physiological pathological processes. RAGE bind to (AGEs) other ligands, which turn activate diverse downstream signaling pathways that impact responses such as inflammation, oxidative stress, immune reactions. article discusses activated by followed differential activation across various diseases. This will ultimately guide researchers developing targeted effective interventions diseases associated with activation. Further, we have discussed how PCR, western blotting, microscopic examination molecules can be leveraged monitor, diagnose, explore involving proteins unique post-translational modifications. underscores pressing need advancements molecular approaches disease detection management RAGE.

Language: Английский

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Molecular signaling pathways in doxorubicin-induced nephrotoxicity and potential therapeutic agents

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 144, P. 113373 - 113373

Published: Nov. 19, 2024

Language: Английский

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Role of inflammation in the progression of diabetic kidney disease

Vessel Plus, Journal Year: 2024, Volume and Issue: unknown

Published: July 11, 2024

Diabetic kidney disease (DKD) is a global health burden and the leading cause of end-stage renal disease. Its clinical management focuses on controlling hyperglycemia, hypertension, hyperlipidemia. While progression DKD can be slowed with intervention, it cannot stopped or reversed yet. The pathogenesis complex, an interplay numerous signaling pathways, research continues to decipher players their role, beneficial pathogenic. Inflammation essential defense our bodies against internal external insults. injuries that trigger inflammation range from pathogenic infections wounds dysregulated metabolism. helpful only if controlled subsides after has helped defend individual insult. Uncontrolled chronic recognized as contributor diseases. Dysregulated plays role in multiple aspects DKD: glomerular hyperfiltration, mesangial expansion, podocyte injury, tubular basement membrane thickening, fibrosis, scarring. Since integral DKD, targeting for therapy also reasonable. There growing trend therapeutic approach, new targets being discovered evaluated drugs every year. exponential increase literature necessitates comprehensive summary current information, hence this review.

Language: Английский

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The Role of Autophagy in Type 2 Diabetic Kidney Disease Management

Cells, Journal Year: 2023, Volume and Issue: 12(23), P. 2691 - 2691

Published: Nov. 23, 2023

Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications type 2 diabetes mellitus (T2DM) and causes severe burden on general welfare T2DM patients around world. While several new agents have shown promise in treating this condition potentially halting progression disease, more work needed to understand complex regulatory network involved disorder. Recent studies provided insights into connection between autophagy, a physiological metabolic process known maintain cellular homeostasis, pathophysiological pathways DKD. Typically, autophagic activity plays role DKD mainly by promoting an inflammatory response tissue damage, while both overactivated downregulated autophagy worsen outcomes different stages This correlation demonstrates potential as novel therapeutic target for also highlights possibilities utilizing already available DN-related medications. In review, we summarize findings relationship DKD, impact these results clinical management strategies.

Language: Английский

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Hederagenin Improves Adriamycin-induced Nephropathy by Inhibiting the JAK/STAT Signaling Pathway

Integrative Medicine in Nephrology and Andrology, Journal Year: 2024, Volume and Issue: 11(2)

Published: April 23, 2024

ABSTRACT Background: Glomerulonephritis, a common kidney disease and major cause of end-stage renal disease, lacks effective treatment options. Hederagenin (HDG) exerts potent anti-inflammatory protective effects on the kidneys exhibits promise for glomerulonephritis. This study aimed to investigate therapeutic mechanism action hederagenin in context adriamycin-induced nephropathy (ADN). Methods: C57BL/6 mice were randomly divided into 5 groups that included control, model, low-dose HDG (20 mg/kg), high-dose (40 positive control (10 mg/kg irbesartan) groups. ADN was established by administering single injection 10 adriamycin. Renal pathology fibrosis assessed using haematoxylin eosin (H & E) Masson’s trichrome staining, whereas vitro studies conducted cultured mouse podocytes (MPC5). Immunofluorescence staining western blotting performed detect inflammation protein levels signaling pathways. Results: The results revealed significantly improved abnormal serum creatinine, albumin, urea nitrogen levels. reduced glomerular injury fibrosis, particularly at high doses. Additionally, effectively activation Janus kinase-signal transducer activator transcription (JAK/STAT) while suppressing CD4 + /CD8 cell ratios enhancing immune response. Interestingly, when JAK/STAT pathway activated an agonist, ameliorative inhibited, thus suggesting is key target HDG. Conclusion: may represent promising option glomerulonephritis inhibiting JAK/STAT-mediated immune-inflammatory responses.

Language: Английский

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