Butyrolactone I blocks the transition of acute kidney injury to chronic kidney disease in mice by targeting JAK1

MedComm, Год журнала: 2025, Номер 6(2)

Опубликована: Янв. 21, 2025

Abstract Chronic kidney disease (CKD) is a that affects more than 850 million people. Acute injury (AKI) common cause of CKD, and blocking the AKI–CKD transition shows promising therapeutic potential. Herein, we found butyrolactone I (BLI), natural product, exerts significant nephroprotective effects, including maintenance function, inhibition inflammatory response, prevention fibrosis, in both folic acid‐ ureteral obstruction‐induced mouse models. Notably, BLI showed greater blood urea nitrogen reduction anti‐inflammatory effects telmisartan. Bioinformatics analysis target confirmation assays suggested directly binds to JAK1, kinase assay confirmed it potent JAK1inhibitor with an IC 50 0.376 µM. Experiments JAK1‐knockdown mice also proved targets JAK1 work. Furthermore, demonstrated safety comparable ivarmacitinib, well‐known inhibitor. Mechanistically, inhibits its phosphorylation JAK‐STAT activation, subsequently regulating downstream signaling pathways inhibit reactive oxygen species production, inflammation, ferroptosis, thereby preventing occurrence fibrosis process. This study demonstrates for first time inhibitor candidate delaying CKD progression, which warrants further investigation.

Язык: Английский

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Potential Modulatory Effects of Hesperidin on the JAK/STAT Pathway in Mesangial Proliferative Glomerulonephritis

Chemical Biology & Drug Design, Год журнала: 2025, Номер 105(2)

Опубликована: Фев. 1, 2025

ABSTRACT Mesangial proliferative glomerulonephritis (MsPGN) is a common type of glomerular disease characterized by immune complex deposition and inflammation in the kidney, leading to renal dysfunction. Currently, treatment options for MsPGN are limited, there need effective therapeutic interventions. Hesperidin (HSP), natural flavonoid glycoside, has shown promising anti‐inflammatory antioxidant properties various models. This study aimed investigate potential HSP explore its possible mechanism action. A male Wistar rat model was established via tail vein injection Thy‐1 monoclonal antibody, rats were divided into four groups: Control, MsPGN, + HSP, Prednisone. After 7 days intervention, effects evaluated through biochemical histological analyses. Our results demonstrated that significantly reduced levels blood urea nitrogen, serum creatinine, total cholesterol, triglycerides, improved pathology. Additionally, pro‐inflammatory cytokines, including tumor necrosis factor‐α, interleukin‐1β, interleukin‐2, monocyte chemoattractant protein‐1, markedly decreased. Immunofluorescence analysis revealed immunoglobulin G C5b‐9, along with decreased kidneys. Furthermore, downregulated phosphorylation Janus kinase 2 (JAK2) signal transducer activator transcription 3 (STAT3), suggesting modulation JAK/STAT pathway. In conclusion, might effectively alleviate injury, reduce inflammatory response, inhibit deposition, potentially suppression

Язык: Английский

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

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 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.

Язык: Английский

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

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 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.

Язык: 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, Год журнала: 2025, Номер 182, С. 106478 - 106478

Опубликована: Март 12, 2025

Язык: Английский

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Isoquercitrin Alleviates Diabetic Nephropathy by Inhibiting STAT3 Phosphorylation and Dimerization

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Апрель 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.

Язык: 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, Год журнала: 2025, Номер Volume 18, С. 1073 - 1085

Опубликована: Апрель 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

Язык: Английский

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Genistein as a renoprotective agent: mechanistic insights into antioxidant, anti-inflammatory, and fibrosis-regulating pathways

Molecular Biology Reports, Год журнала: 2025, Номер 52(1)

Опубликована: Май 24, 2025

Язык: Английский

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Exploring Inflammatory and Fibrotic Mechanisms Driving Diabetic Nephropathy Progression

Cytokine & Growth Factor Reviews, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

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Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights

Diabetology & Metabolic Syndrome, Год журнала: 2025, Номер 17(1)

Опубликована: Июнь 4, 2025

Язык: Английский

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