Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(27)

Published: June 28, 2021

Significance A single acute kidney injury event increases the risk of progression to chronic disease (CKD). Combining single-nucleus RNA sequencing with genetic tracing injured proximal tubule cells identified a spatially dynamic, evolving response following ischemia–reperfusion injury. Failed repair leads persistence profibrotic, proinflammatory Vcam1 + / Ccl2 cell type exhibiting senescence-associated secretory phenotype and marked transcriptional activation NF-κB AP-1 pathway signatures, but no signs G 2 /M cycle arrest. Insights from this study can inform strategies improve renal prevent CKD progression.

Language: Английский

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Increased expression of lncRNA CASC9 promotes tumor progression by suppressing autophagy-mediated cell apoptosis via the AKT/mTOR pathway in oral squamous cell carcinoma

Cell Death and Disease, Journal Year: 2019, Volume and Issue: 10(2)

Published: Jan. 17, 2019

Recent studies showed that lncRNA CASC9 was upregulated and acted as an oncogene in a variety of tumors. However, the expression biological functions oral squamous cell carcinoma (OSCC) remain unknown. In this study, we found for first time remarkably OSCC tissues lines compared with paired noncancerous normal epithelial cells. Highly expressed is strongly associated tumor size, clinical stage, regional lymph node metastasis overall survival patients. vitro, knockdown cells SCC15 CAL27 significantly promotes autophagy apoptosis, while inhibiting proliferation. Moreover, levels p-AKT, p-mTOR, P62 BCL-2 were decreased, BAX LC3BII/LC3BI ratio increased CASC9-knockdown After addition AKT activator SC79 cells, apoptosis rescued. Furthermore, rescued treated inhibitor Autophinib. addition, depletion suppressed growth vivo. conclusion, our findings demonstrate progression through enhancing proliferation suppressing autophagy-mediated via AKT/mTOR pathway. could potentially be used valuable biomarker diagnosis prognosis.

Language: Английский

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Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3219 - 3219

Published: Feb. 6, 2023

Ubiquitination and deubiquitination are reversible processes that modify the characteristics of target proteins, including stability, intracellular localization, enzymatic activity. Ubiquitin-specific proteases (USPs) constitute largest deubiquitinating enzyme family. To date, accumulating evidence indicates several USPs positively negatively affect metabolic diseases. USP22 in pancreatic β-cells, USP2 adipose tissue macrophages, USP9X, 20, 33 myocytes, USP4, 7, 10, 18 hepatocytes, hypothalamus improve hyperglycemia, whereas USP19 adipocytes, USP21 USP2, 14, 20 hepatocytes promote hyperglycemia. In contrast, USP1, 5, 9X, 15, 22, 36, 48 modulate progression diabetic nephropathy, neuropathy, and/or retinopathy. ameliorates non-alcoholic fatty liver disease (NAFLD), while hepatic 11, 19, exacerbate it. The roles USP7 22 disorders controversial. 17, vascular cells postulated to be determinants atherosclerosis. Moreover, mutations

Language: Английский

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Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115670 - 115670

Published: Oct. 13, 2023

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as major contributor to end-stage renal disease. The glomerular filtration barrier, composed podocytes, endothelial cells, the basement membrane, plays vital role maintaining function. Disruptions podocyte function, including hypertrophy, shedding, reduced density, apoptosis, can impair integrity resulting elevated proteinuria, abnormal rate, increased creatinine levels. Hence, recent research increasingly focused on injury DN, with growing emphasis exploring therapeutic interventions targeting injury. Studies have revealed that factors such lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, impaired autophagy contribute This review aims summarize underlying mechanisms DN provide an overview current status regarding experimental drugs DN. findings presented herein may offer potential targets strategies for management associated

Language: Английский

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mTOR in programmed cell death and its therapeutic implications

Cytokine & Growth Factor Reviews, Journal Year: 2023, Volume and Issue: 71-72, P. 66 - 81

Published: June 1, 2023

Mechanistic target of rapamycin (mTOR), a highly conserved serine/threonine kinase, is involved in cellular metabolism, protein synthesis, and cell death. Programmed death (PCD) assists eliminating aging, damaged, or neoplastic cells, indispensable for sustaining normal growth, fighting pathogenic microorganisms, maintaining body homeostasis. mTOR has crucial functions the intricate signaling pathway network multiple forms PCD. can inhibit autophagy, which part PCD regulation. Cell survival affected by through autophagy to control reactive oxygen species production degradation pertinent proteins. Additionally, regulate an autophagy-independent manner affecting expression levels related genes phosphorylating Therefore, acts both autophagy-dependent -independent pathways It conceivable that exerts bidirectional regulation PCD, such as ferroptosis, according complexity networks, but underlying mechanisms have not been fully explained. This review summarizes recent advances understanding mTOR-mediated regulatory Rigorous investigations into PCD-related provided prospective therapeutic targets may be clinically beneficial treating various diseases.

Language: Английский

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Autophagy and its therapeutic potential in diabetic nephropathy

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: March 20, 2023

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is most significant microvascular complication diabetes and poses a severe public health concern due to lack effective clinical treatments. Autophagy lysosomal process that degrades damaged proteins organelles preserve cellular homeostasis. Emerging studies have shown disorder in autophagy results accumulation diabetic cells promotes development DN. regulated by nutrient-sensing pathways including AMPK, mTOR, Sirt1, several intracellular stress signaling such as oxidative endoplasmic reticulum stress. An abnormal nutritional status excess stresses caused diabetes-related metabolic disorders disturb autophagic flux, dysfunction Here, we summarized role DN focusing on modulate therapeutic interferences

Language: Английский

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Autophagy, Pyroptosis and Ferroptosis are Rising Stars in the Pathogenesis of Diabetic Nephropathy

Diabetes Metabolic Syndrome and Obesity, Journal Year: 2024, Volume and Issue: Volume 17, P. 1289 - 1299

Published: March 1, 2024

Abstract: Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes and can potentially develop into end-stage renal disease. Its pathogenesis complex not fully understood. Podocytes, glomerular endothelial cells (GECs), mesangial (GMCs) tubular epithelial (TECs) play important roles normal function glomerulus tubules, their injury involved progression DN. Although our understanding mechanisms leading to DN has substantially improved, we still need find more effective therapeutic targets. Autophagy, pyroptosis ferroptosis are programmed cell death processes that associated with inflammation closely related a variety diseases. Recently, growing number studies have reported autophagy, regulate podocytes, GECs, GMCs TECs. This review highlights contributions pyroptosis, these cells, offering potential targets for treatment. Keywords: diabetic nephropathy, ferroptosis,

Language: Английский

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The regulatory role of miRNA and lncRNA on autophagy in diabetic nephropathy

Cellular Signalling, Journal Year: 2024, Volume and Issue: 118, P. 111144 - 111144

Published: March 15, 2024

Language: Английский

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A systematic review of epigenetic interplay in kidney diseases: Crosstalk between long noncoding RNAs and methylation, acetylation of chromatin and histone

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116922 - 116922

Published: June 13, 2024

The intricate crosstalk between long noncoding RNAs (lncRNAs) and epigenetic modifications such as chromatin/histone methylation acetylation offer new perspectives on the pathogenesis treatment of kidney diseases. lncRNAs, a class transcripts longer than 200 nucleotides with no protein-coding potential, are now recognized key regulatory molecules influencing gene expression through diverse mechanisms. They modulate by recruiting or blocking enzymes responsible for adding removing methyl acetyl groups, DNA, N6-methyladenosine (m6A) histone acetylation, subsequently altering chromatin structure accessibility. In diseases acute injury (AKI), chronic disease (CKD), diabetic nephropathy (DN), glomerulonephritis (GN), renal cell carcinoma (RCC), aberrant patterns DNA/RNA/histone have been associated onset progression, revealing complex interplay lncRNA dynamics. Recent studies highlighted how lncRNAs can impact pathology affecting function genes involved in cycle control, fibrosis, inflammatory responses. This review will separately address roles diseases, particular emphasis elucidating bidirectional effects underlying mechanisms conjunction addition to potential exacerbating renoprotective pathologies. Understanding reciprocal relationships not only shed light molecular underpinnings pathologies but also present avenues therapeutic interventions biomarker development, advancing precision medicine nephrology.

Language: Английский

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The emerging role of E3 ubiquitin ligases and deubiquitinases in metabolic dysfunction-associated steatotic liver disease

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 25, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic worldwide, with a prevalence as high 32.4%. MASLD encompasses spectrum of pathologies, ranging from steatosis to metabolic steatohepatitis (MASH), fibrosis, and, in some cases, progression end-stage (cirrhosis and hepatocellular carcinoma). A comprehensive understanding pathogenesis this highly prevalent may facilitate identification novel targets for development improved therapies. E3 ubiquitin ligases deubiquitinases (DUBs) are key regulatory components ubiquitin‒proteasome system (UPS), which plays pivotal role maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression DUBs involved MASLD. Here, we review abnormalities by (1) discussing their targets, mechanisms, functions MASLD; (2) summarizing pharmacological interventions targeting these enzymes preclinical clinical studies; (3) addressing challenges future therapeutic strategies. This synthesizes current highlight strategies based on UPS progressive disease.

Language: Английский

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