Short-Chain Fatty Acids Attenuate Renal Fibrosis and Enhance Autophagy of Renal Tubular Cells in Diabetic Mice Through the HDAC2/ULK1 Axis

Ma, Xiaoying; Wang, Qiong

doi:10.3803/enm.2021.1336

Cited by 14 publications

(8 citation statements)

References 41 publications

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“…Surprisingly, in the light of the fact that the activation of the gene program responsible for the for autophagosomes formation was upregulated after NSD1 knockdown, ULK1 gene was consistently positively regulated by NSD1 at both mRNA and protein levels. Some studies before described the epigenetic regulation of ULK1 by histone-methylation modifiers (42, 43). Here, we showed that mechanistically, ULK1 expression is directly and positively regulated by NSD1 and K36me 2 .…”

Section: Discussionmentioning

confidence: 99%

NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma

Topchu,

Bychkov,

Gursel

et al. 2023

Preprint

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in therapeutic management and immunotherapy, the five-year survival rate for head and neck cancer remains at ~66% of all diagnosed cases. A better definition of drivers of HPV-negative HNSCC that are targetable points of tumor vulnerability could lead to significant clinical advances. NSD1 is a histone methyltransferase which catalyzes histone H3 lysine 36 di-methylation (H3K36me2); mutations inactivating NSD1 have been linked to improved outcomes in HNSCC. In this study, we show that NSD1 induces H3K36me2 levels in HNSCC, and that the depletion of NSD1 reduces HNSCC of cell growth in vitro and in vivo. We also find that NSD1 strongly promotes activation of the Akt/mTORC1 signaling pathway. NSD1 depletion in HNSCC induces an autophagic gene program activation, causes accumulation of the p62 and LC3B-II proteins, and decreases the autophagic signaling protein ULK1 at both protein and mRNA levels. Reflecting these signaling defects, knockdown of NSD1 disrupts autophagic flux in HNSCC cells. Taken together, these data identify positive regulation of Akt/mTORC1 signaling and autophagy as novel NSD1 functions in HNSCC, suggesting that NSD1 may be of value as a therapeutic target in this cancer.

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Section: Discussionmentioning

confidence: 99%

NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma

Topchu,

Bychkov,

Gursel

et al. 2023

Preprint

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“…Lactobacillus and Parabacteroides were bacteria that can produce short-chain fatty acids (SCFAs) (43). SCFAs can enhance the autophagy of renal tubular cells and attenuate the renal fibrosis in diabetic mice (44). Bacteroides is also believed to produce SCFAs by degrading cellulose in food, which can improve some metabolic diseases, such as diabetes and obesity, and inhibit the inflammatory responses of renal tissue in DKD (45).…”

Section: Discussionmentioning

confidence: 99%

Sacubitril/Valsartan contributes to improving the diabetic kidney disease and regulating the gut microbiota in mice

et al. 2022

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BackgroundDiabetic kidney disease (DKD), as a serious microvascular complication of diabetes, has limted treatment options. It is reported that the Sacubitril/Valsartan (Sac/Val) can improve kidney function, and the disordered gut microbiota and part of its metabolites are related to the development of DKD. Therefore, we aim to explore whether the effect of Sac/Val on DKD is associated with the gut microbiota and related plasma metabolic profiles.MethodsMale C57BL/6J mice were randomly divided into 3 groups: Con group (n = 5), DKD group (n = 6), and Sac/Val group (n = 6) . Sac/Val group was treated with Sac/Val solution. The intervention was given once every 2 days for 6 weeks. We measured the blood glucose and urine protein level of mice at different times. We then collected samples at the end of experiment for the 16s rRNA gene sequencing analysis and the untargeted plasma metabonomic analysis.ResultsWe found that the plasma creatinine concentration of DKD-group mice was significantly higher than that of Con-group mice, whereas it was reduced after the Sac/Val treatment. Compared with DKD mice, Sac/Val treatment could decrease the expression of indicators related to EndMT and renal fibrosis like vimentin, collagen IV and fibronectin in kidney. According to the criteria of LDA ≥ 2.5 and p<0.05, LefSe analysis of gut microbiota identified 13 biomarkers in Con group, and 33 biomarkers in DKD group, mainly including Prevotella, Escherichia_Shigella and Christensenellaceae_R_7_group, etc. For the Sac/Val group, there were 21 biomarkers, such as Bacteroides, Rikenellaceae_RC9_gut_group, Parabacteroides, Lactobacillus, etc. Plasma metabolomics analysis identified a total of 648 metabolites, and 167 important differential metabolites were screened among groups. KEGG pathway of tryptophan metabolism: M and bile secretion: OS had the highest significance of enrichment.ConclusionsSac/Val improves the renal function of DKD mice by inhibiting renal fibrosis. This drug can also regulate gut microbiota in DKD mice.

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“…In the development of diabetic retinopathy, overexpressed histone HIST1H1C/H1.2, an important variant of the linker histone H1, upregulates SIRT1 and HDAC1 to maintain the deacetylation of H4K16, leads to ATG proteins expression, and then promotes autophagy, inflammation and cell toxicity. 93 Small-chain fatty acids treatment-reduced HDAC2 upregulates H3K27ac on ULK1 promoter, reduces ULK1 expression and autophagy flux and thus alleviate diabetic renal fibrosis 94 (Fig. 3 ).…”

Section: Epigenetic Modifications and Autophagy-related Diseasesmentioning

confidence: 99%

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

Shu

Han

et al. 2023

Sig Transduct Target Ther

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Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis. However, the physiological effect of autophagy appears to be multifaced. On the one hand, autophagy functions as a cytoprotective mechanism, protecting against multiple diseases, especially tumor, cardiovascular disorders, and neurodegenerative and infectious disease. Conversely, autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells. During disorder onset and progression, the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes (ATGs) are abnormally regulated, giving rise to imbalanced autophagy flux. However, the detailed mechanisms and molecular events of this process are quite complex. Epigenetic, including DNA methylation, histone modifications and miRNAs, and post-translational modifications, including ubiquitination, phosphorylation and acetylation, precisely manipulate gene expression and protein function, and are strongly correlated with the occurrence and development of multiple diseases. There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation, resulting in alterations in autophagy levels, which subsequently induces disease or affects the therapeutic effectiveness to agents. In this review, we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets. In addition, the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed, providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.

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Short-Chain Fatty Acids Attenuate Renal Fibrosis and Enhance Autophagy of Renal Tubular Cells in Diabetic Mice Through the HDAC2/ULK1 Axis

Cited by 14 publications

References 41 publications

NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma

NSD1 supports cell growth and regulates autophagy in HPV-negative head and neck squamous cell carcinoma

Sacubitril/Valsartan contributes to improving the diabetic kidney disease and regulating the gut microbiota in mice

Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets

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