Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway.
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SUBMITTER: Tan Z
PROVIDER: S-EPMC9240271 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: To observe the therapeutic effect of Yi-Shen-Hua-Shi (YSHS) granule in podocyte damage and diabetic nephropathy (DN) proteinuria and to explore the corresponding mechanism. Methods: The db/db mice were used to establish the DN model. Serum creatinine (SCr), blood urea nitrogen (BUN), and 24 h urinary proteinuria were detected with specific kits. Glomerular structural lesions and podocyte apoptosis were detected through HE staining, TUNEL assay, and immunofluorescence. The medicated serum of YSHS granule (YSHS-serum) or control serum was prepared. Macrophage-derived exosomes were extracted using an exosome extraction kit. Morphology and the protein concentration of exosomes were evaluated by a transmission electron microscope (TEM) and BCA kit. The activity and apoptosis of podocyte MPC5 cells, the M1 macrophage polarization, and the protein expression of an exosome marker and cleaved caspase were detected by the CCK8 experiment, flow cytometry, and Western blot, respectively. The miR-21a-5p expression in podocytes and the exosomes from macrophages were measured by qRT-PCR. The effect of YSHS granule on the infiltration of M1 macrophages in the kidney tissue in db/db mice was measured by immunofluorescence. Results: The YSHS granule could improve renal function, reduce proteinuria, and inhibit glomerular structural lesions and podocyte apoptosis in db/db mice. High-glucose (HG) stimulation and YSHS granule treatment did not affect the protein concentration in macrophage-derived exosomes. Macrophage-derived exosomes could inhibit the cell viability and increase apoptosis of podocytes, especially the exosomes from macrophages treated with HG and control serum. Compared with the exosomes secreted by macrophages after an HG treatment, the exosome from macrophages treated with HG and YSHS granule showed lower inhibitory effects on podocyte activity, accompanied by the decreased upregulating effects of macrophage-derived exosomes on the miR-21a-5p in podocytes. miR-21a-5p mimics could reduce podocyte activity and promote caspase-3 shearing. M1 polarization of macrophages could change the content of miR-21a-5p in macrophage-derived exosomes. In addition, YSHS granule could inhibit HG-induced M1 polarization of macrophages and M1 macrophage infiltration in renal tissues. Conclusion: The YSHS granule could improve the podocyte injury induced by macrophage-derived exosomes and alleviate the progression of DN. This regulation might be related to the inhibition of M1 macrophage polarization by YSHS granule and the reduction of the miR-21a-5p content in macrophage-derived exosomes.
| S-EPMC9732029 | biostudies-literature
Project description:The pathophysiology underlying the nephrotic syndrome is becoming clear for several inherited podocytopathies; the mechanisms of injury that lead to the acquired forms of this disease are not well understood. We explored these mechanisms using the mouse model of adriamycin-induced proteinuria.We estimated the fractional clearances for FITC-Ficolls, albumin, and neutral albumin in cooled, isolated,perfused kidneys (cIPK) in situ. Treatment with adriamycin led to a significant increase in the fractional clearance of albumin and of Ficoll with radii larger than 20 A. Neutral albumin (33.4 A) and similarly sized Ficoll behaved similarly to each other. In addition, adriamycin led to a significant loss of charge density and size selectivity of the glomerular barrier. The thickness of the glomerular endothelial surface layer(i.e., or the glycocalyx) in adriamycin-treated animals was only 20% of that in normal animals. Finally,several proteoglycans were downregulated in isolated glomeruli. In summary, adriamycin thins the glomerular glycocalyx, perhaps by downregulating proteoglycan synthesis, and alters glomerular charge- and size selectivity. These data suggest that the glomerular endothelium may play a role in the pathogenesis of proteinuric renal diseases.
| S-EPMC2615716 | biostudies-literature
Project description:San-Huang-Yi-Shen Treats Diabetic Nephropathy
| PRJEB48652 | ENA
Project description:BackgroundDiabetic nephropathy (DN), one of the most frequent complications of diabetes mellitus, is a leading cause of end-stage renal disease. However, the current treatment methods still cannot effectively halt the progression of DN. Jian-Pi-Gu-Shen-Hua-Yu (JPGS) decoction can be used for the treatment of chronic kidney diseases such as DN, but the specific mechanism of action has not been fully elucidated yet.PurposeThe aim of this study is to clarify whether JPGS alleviates the progression of diabetic nephropathy by inhibiting ferroptosis.Materials and methodsWe established a DN mouse model to investigate the therapeutic effect of JPGS in a DN mouse model. Subsequently, we examined the effects of JPGS on ferroptosis- and glutathione peroxidase 4 (GPX4) pathway-related indices. Finally, we validated whether JPGS inhibited ferroptosis in DN mice via the GPX4 pathway using GPX4 inhibitor and ferroptosis inhibitors.ResultsThe results indicate that JPGS has a therapeutic effect on DN mice by improving kidney function and reducing inflammation. Additionally, JPGS treatment decreased iron overload and oxidative stress levels while upregulating the expression of GPX4 pathway-related proteins. Moreover, JPGS demonstrated a similar therapeutic effect as Fer-1 in the context of DN treatment, and RSL3 was able to counteract the therapeutic effect of JPGS and antiferroptotic effect.ConclusionJPGS has significant therapeutic and anti-inflammatory effects on DN mice, and its mechanism is mainly achieved by upregulating the expression of GPX4 pathway-related proteins, thereby alleviating iron overload and ultimately reducing ferroptosis.
| S-EPMC10960652 | biostudies-literature
Project description:BACKGROUND:Jian-Pi-Yi-Shen Formula (JPYSF), a Chinese herbal decoction with the efficacies of 'fortify the spleen and tonify the kidney' and 'activate blood and resolve stasis', is effective for the treatment of chronic kidney disease in clinic. However, the underlying mechanism remains unclear. The aim of this study was to investigate the therapeutic effects and possible mechanisms of JPYSF on retarding chronic kidney disease progression in 5/6 nephrectomized (5/6 Nx) rats. METHODS:Perindopril (4?mg/kg/d) and JPYSF (2.72?g/kg/d) were administrated by gavage to 5/6 Nx rats daily for 6?weeks. The therapeutic effects of JPYSF were evaluated by renal function, pathological injury, and fibrosis. The protein levels associated with mitochondrial quality control network were measured by Western blot and immunofluorescence analysis. RESULTS:5/6 Nx rats showed obvious decline in renal function as evidenced by increased serum creatinine, blood urea nitrogen, and urinary protein excretion, and significant injury in kidney structure as evidenced by glomerular hypertrophy, tubular atrophy, and interstitial fibrosis. Administration of JPYSF for 6 weeks could improve renal function and ameliorate kidney structure injury in 5/6 Nx rats. Furthermore, the remnant kidneys of 5/6 Nx rats showed unbalanced mitochondrial quality control network manifested as decreased mitochondrial biogenesis, fusion, and mitophagy, and increased mitochondrial fission. Treatment of JPYSF could restore aforesaid aspects of mitochondrial quality control network. CONCLUSIONS:These results indicate that JPYSF can notably ameliorate 5/6 Nx-induced chronic kidney disease, which may be related with modulation of mitochondrial quality control network.
| S-EPMC6302435 | biostudies-other
Project description:AimTo investigate epigenomic and gene expression alterations during cellular senescence induced by oncogenic Raf.MethodsCellular senescence was induced into mouse embryonic fibroblasts (MEFs) by infecting retrovirus to express oncogenic Raf (RafV600E). RNA was collected from RafV600E cells as well as MEFs without infection and MEFs with mock infection, and a genome-wide gene expression analysis was performed using microarray. The epigenomic status for active H3K4me3 and repressive H3K27me3 histone marks was analyzed by chromatin immunoprecipitation-sequencing for RafV600E cells on day 7 and for MEFs without infection. These data for Raf-induced senescence were compared with data for Ras-induced senescence that were obtained in our previous study. Gene knockdown and overexpression were done by retrovirus infection.ResultsAlthough the expression of some genes including secreted factors was specifically altered in either Ras- or Raf-induced senescence, many genes showed similar alteration pattern in Raf- and Ras-induced senescence. A total of 841 commonly upregulated 841 genes and 573 commonly downregulated genes showed a significant enrichment of genes related to signal and secreted proteins, suggesting the importance of alterations in secreted factors. Bmp2, a secreted protein to activate Bmp2-Smad signaling, was highly upregulated with gain of H3K4me3 and loss of H3K27me3 during Raf-induced senescence, as previously detected in Ras-induced senescence, and the knockdown of Bmp2 by shRNA lead to escape from Raf-induced senescence. Bmp2-Smad inhibitor Smad6 was strongly repressed with H3K4me3 loss in Raf-induced senescence, as detected in Ras-induced senescence, and senescence was also bypassed by Smad6 induction in Raf-activated cells. Different from Ras-induced senescence, however, gain of H3K27me3 did not occur in the Smad6 promoter region during Raf-induced senescence. When comparing genome-wide alteration between Ras- and Raf-induced senescence, genes showing loss of H3K27me3 during senescence significantly overlapped; genes showing H3K4me3 gain, or those showing H3K4me3 loss, also well-overlapped between Ras- and Raf-induced senescence. However, genes with gain of H3K27me3 overlapped significantly rarely, compared with those with H3K27me3 loss, with H3K4me3 gain, or with H3K4me3 loss.ConclusionAlthough epigenetic alterations are partly different, Bmp2 upregulation and Smad6 repression occur and contribute to Raf-induced senescence, as detected in Ras-induced senescence.
| S-EPMC4768123 | biostudies-literature
Project description:Androgens have been linked to the onset, severity, and progression of rheumatoid arthritis (RA). In traditional Chinese medicine (TCM), the most common pattern in RA is kidney deficiency, which partly corresponds to a low sex hormone state. In this study, TCM kidney deficiency was induced in male Sprague-Dawley rats with castration surgery, and a TCM preparation, Yi Shen Juan Bi Pill (YJB), was used to treat collagen induced arthritis (CIA) rats with castration. Metabolomic technique was used to evaluate the pharmacological mechanism in castrated CIA rats treated by YJB. The results showed that castration significantly increased the severity of the arthritis in rats but was ameliorated by YJB. Its pharmacological mechanism was partially associated with lipid metabolites involving free fatty acid (FFA) and lysophosphatidylcholine (LPC). In conclusion, the experimental results demonstrate the protective effect of YJB on the TCM kidney deficiency pattern induced by androgen deficiency in CIA rats and support that YJB should be used for the clinical treatment of RA with TCM kidney deficiency pattern.
| S-EPMC3329149 | biostudies-literature
Project description:Cell senescence, an irreversible cell cycle arrest, reflects a safeguard program that limits the capacity of uncontrolled cell proliferation. Treatment of tumor cells with certain chemotherapeutic agents activates premature senescence to decrease the tumorigenecity. Here we show that sublethal concentrations of adriamycin could induce premature senescence in lung cancer cells. Adriamycin treatment resulted in the up-regulation of BMP4, which is underexpressed in NSCLC (non-small cell lung cancers). Moreover, the BMP4-Smad pathway played a key role in mediating adriamycin-induced senescence. Overexpression of BMP4 was able to induce premature senescence in lung cancer cells and this process required the participation of cyclin/cyclin-dependent kinase (cdk) inhibitors p16(INK4a) and p21(WAF1/cip1). We also show that increases of p16(INK4a) and p21(WAF1/cip1) expression in response to BMP4 were mediated by the Smad signaling pathway. Furthermore, our data revealed that p300 was recruited to P16(INK4a) and P21(WAF1/cip1) promoters by Smad1/5/8 to induce the hyperacetylation of histones H3 and H4 at the promoters. The present study provides useful clues to the evaluation of the potentiality of BMP4 as a responsive molecular target for cancer chemotherapy.
| S-EPMC2673284 | biostudies-literature
Project description:ContextYi Shen An (YSA) is an investigational composite of traditional Chinese medicine (Reference: 2010L000974) for the treatment of renal disease.ObjectiveTo investigate the protective effects of YSA against membranous glomerulonephritis (MGN).Materials and methodsMale Sprague-Dawley rats were injected with cationic bovine serum albumin (C-BSA) to create a model of MGN. Then, rats were orally treated with YSA at doses of 0.25, 0.5, 1 and 2 g/kg for 35 successive days; prednisone (5 mg/kg) was used as a positive control. At the end of the experimental period, we performed a series of tests, including 24 h urinary protein, and biochemical, immunological, antioxidative, coagulation indices, and histopathological examination.ResultsYSA-1 g/kg significantly lowered urinary protein from 68.37 to 30.74 mg (p < 0.01). Meantime, total protein (TP) and albumin (ALB) recovered from 66.26 and 20.51 g/L to 76.08 and 35.64 g/L (p < 0.01), respectively. YSA removed the deposition of immunoglobulin G (IgG) and complement 3c (C3c), prevented inter-capillary cell hyperplasia on the glomerular basement membrane (GBM), and reduced electron-dense deposits and fusion of podocytes. In addition, serum IgG and superoxide dismutase were significantly elevated. In contrast, malondialdehyde, total cholesterol, triglyceride, circulating immune complex (CIC), and immunoglobulin M decreased in the YSA-treated group. Moreover, the blood coagulation dysfunction was adjusted.Discussion and conclusionsThese findings indicate YSA may exert a therapeutic effect against MGN through the inhibition of CIC formation, and the removal of IgG and C3c deposition from the GBM, thus supporting the development of further clinical trials.
| S-EPMC8745358 | biostudies-literature
Project description:San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic nephropathy (DN) in clinic. However, the mechanisms of SHYS on DN remain unknown. In this study, we used a high-fat diet (HFD) combined with streptozotocin (STZ) injection to establish a DN rat model. Next, we used 16S rRNA sequencing and untargeted metabolomics to study the potential mechanisms of SHYS on DN. Our results showed that SHYS treatment alleviated the body weight loss, hyperglycemia, proteinuria, pathological changes in kidney in DN rats. SHYS could also inhibite the oxidative stress and inflammatory response in kidney. 16S rRNA sequencing analysis showed that SHYS affected the beta diversity of gut microbiota community in DN model rats. SHYX could also decrease the Firmicutes to Bacteroidetes (F to B) ratio in phylum level. In genus level, SHYX treatment affected the relative abundances of Lactobacillus, Ruminococcaceae UCG-005, Allobaculum, Anaerovibrio, Bacteroides and Candidatus_Saccharimonas. Untargeted metabolomics analysis showed that SHYX treatment altered the serum metabolic profile in DN model rats through affecting the levels of guanidineacetic acid, L-kynurenine, prostaglandin F1α, threonine, creatine, acetylcholine and other 21 kind of metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, tryptophan metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, tyrosine metabolism, arginine and proline metabolism, arginine and proline metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and D-glutamine and D-glutamate metabolism pathways. Spearman correlation analysis showed that Lactobacillus, Candidatus_Saccharimonas, Ruminococcaceae UCG-005, Anaerovibrio, Bacteroides, and Christensenellaceae_R-7_group were closely correlated with most of physiological data and the differential metabolites following SHYS treatment. In conclusion, our study revealed multiple ameliorative effects of SHYS on DN including the alleviation of hyperglycemia and the improvement of renal function, pathological changes in kidney, oxidative stress, and the inflammatory response. The mechanism of SHYS on DN may be related to the improvement of gut microbiota which regulates arginine biosynthesis, TCA cycle, tyrosine metabolism, and arginine and proline metabolism.
| S-EPMC8764181 | biostudies-literature