As breast cancer is the leading cause of cancer-related deaths in women population worldwide, ongoing endeavor has been made for alternative regimens with improved efficacy but fewer adverse effects. ...Recently, active components from the spores of
have attracted much attention for their versatile biological activities owing to the advance in sporoderm-breaking technology. Here, anticancer potential of an extract derived from the sporoderm-breaking spores of
(ESG) was explored in a 4T1-breast cancer xenograft mice model. Results showed that ESG was able to suppress 4T1 tumor growth
rather than
. Flowcytometry analysis revealed that ESG could significantly increase both cytotoxic T cell (Tc) population and the ratio of Tc to helper T cell (Th) in peripheral blood of the tumor-bearing mouse; similar promotion on Tc was also found in tumor-infiltrating lymphocyte. Moreover, ESG evidently downregulated the two immune checkpoints, programmed cell death protein-1 (PD-1, in the spleen) and cytotoxic T lymphocyte antigen-4 (CTLA-4, in the tumor), suggesting that ESG could effectively restore the T cell paradigm by recovering the exhaustion status
suppressing the co-inhibitory checkpoints. By 16S rRNA gene sequence analysis on the fecal microbiota, it was found that ESG would remodeling the overall structure of the samples from tumor-bearing mice toward that of the normal counterparts, including 18 genera in 5 phyla, together with regulations on several genes that are responsible for signaling pathways involved in metabolism, cellular processes, and environmental information processing. Collectively, this study demonstrated that ESG would serve as a natural anticancer adjuvant
a restoration on the exhausted Tc, highlighting important clinical implications for the treatment of breast cancer.
Renal tubulointerstitial fibrosis (TIF), characterized by epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, is the typical pathological alteration in diabetic nephropathy. ...Gentiopicroside (GPS), a natural compound with anti-inflammatory activity, has been demonstrated to alleviate glomerulosclerosis, whereas whether GPS inhibits TIF
via
regulating inflammation remains unclear. In this study, diabetic db/db mice and high glucose (HG)-stimulated renal tubular epithelial cells (NRK-52E) were applied to explore the effects and mechanisms of GPS on TIF. The results
in vivo
showed that GPS effectively improves glycolipid metabolism disorder, renal dysfunction, and TIF. In particular, GPS treatment reversed the abnormal expressions of EMT marker proteins including elevated α-smooth muscle actin and vimentin and decreased E-cadherin in the kidney of db/db mice. Moreover, GPS treatment also inhibited protein expressions of angiotensinⅡ type 1 receptor (AT1R) and CK2α and the activation of the NF-κB pathway. Importantly, the aforementioned effects of GPS acted
in vivo
were further observed
in vitro
in HG-stimulated NRK-52E cells, which were independent of its effects on glucose and lipid-lowering activity but were reversed by AT1R over-expression. Together, our results indicate that GPS that directly inhibits the CK2/NF-κB inflammatory signaling pathway
via
AT1R may also contribute to the amelioration of TIF in diabetes.
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can ...negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.
Gentiopicroside (GPS) decreased progestin and adipoQ receptor 3 (PAQR3) expression by promoting DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Importantly, GPS bound directly to PAQR3 and spatially inhibited the combination between PAQR3 and P110α to restore PI3K/AKT signaling. Display omitted
The multiple roles of TGR5 in the regulation of glucose metabolism, inflammation, and oxidative stress have drawn attention as therapeutic candidates for diabetes-related kidney disease. However, ...diabetes induces downregulation of renal TGR5 protein expression, and the regulatory mechanisms have not been clarified. Here, we identify that Smurf1, an E3 ubiquitin ligase, is a critical interactor of TGR5 and mediates the ubiquitination and proteasomal degradation of TGR5 under high glucose stimulation in glomerular mesangial cells. Genetic deficiency of Smurf1 restores TGR5 protein expression and attenuates renal injuries in diabetic mice. Mechanistically, Smurf1 interacts with the TGR5 ICL2 region by its HECT domain and induces K11/K48-linked polyubiquitination of TGR5 at K306 residue. Moreover, restoration of TGR5 protects db/db mice from diabetic nephropathy. These observations elucidate the critical role of Smurf1 in regulating TGR5 stability, suggesting that pharmacological targeting of the interaction between Smurf1 and TGR5 could serve as a promising therapeutic strategy against diabetic nephropathy.
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•Renal TGR5 is downregulated via ubiquitin-proteasome pathway under HG stimulation•Restoration of TGR5 attenuates renal injuries in diabetic mice•Smurf1 is a negative regulator of TGR5 through its ubiquitination activity•Smurf1 interacts with TGR5 ICL2 region by its HECT domain
TGR5 has drawn attention as a therapeutic candidate for diabetic nephropathy. However, diabetes induces downregulation of renal TGR5 expression. Lin et al. show that TGR5 undergoes ubiquitination and degradation induced by Smurf1 in diabetic nephropathy. They find that genetic deficiency of Smurf1 and restoration of TGR5 attenuate renal injuries in diabetic mice.
Abstract Background Heart failure (HF) is characterized by a disorder of cardiomyocyte energy metabolism. Xinbao Pill (XBW), a traditional Chinese medicine formulation integrating “Liushen Pill” and ...“Shenfu Decoction,” has been approved by China Food and Drug Administration for the treatment of HF for many years. The present study reveals a novel mechanism of XBW in HF through modulation of cardiac energy metabolism. Methods In vivo, XBW (60, 90, 120 mg/kg/d) and fenofibrate (100 mg/kg/d) were treated for six weeks in Sprague–Dawley rats that were stimulated by isoproterenol to induce HF. Cardiac function parameters were measured by echocardiography, and cardiac pathological changes were assessed using H&E, Masson, and WGA staining. In vitro, primary cultured neonatal rat cardiomyocytes (NRCMs) were induced by isoproterenol to investigate the effects of XBW on myocardial cell damage, mitochondrial function and fatty acid energy metabolism. The involvement of the SGLT1/AMPK/PPARα signalling axis was investigated. Results In both in vitro and in vivo models of ISO-induced HF, XBW significantly ameliorated cardiac hypertrophy cardiac fibrosis, and improved cardiac function. Significantly, XBW improved cardiac fatty acid metabolism and mitigated mitochondrial damage. Mechanistically, XBW effectively suppressed the expression of SGLT1 protein while upregulating the phosphorylation level of AMPK, ultimately facilitating the nuclear translocation of PPARα and enhancing its transcriptional activity. Knockdown of SGLT1 further enhanced cardiac energy metabolism by XBW, while overexpression of SGLT1 reversed the cardio-protective effect of XBW, highlighting that SGLT1 is probably a critical target of XBW in the regulation of cardiac fatty acid metabolism. Conclusions XBW improves cardiac fatty acid energy metabolism to alleviate HF via SGLT1/AMPK/PPARα signalling axis.
The immunomodulatory effect of a novel purified polysaccharide (JCH-1) isolated from Isaria cicadae Miquel had been confirmed to promote secretion of nitric oxide (NO), tumor necrosis factor-alpha ...(TNF-α) and interleukin 6 (IL-6) in our previous study. However, the immunomodulatory mechanism was still unclear. The purpose of this study was to investigate the immunomodulatory mechanism of JCH-1. Experimental data showed that JCH-1 could increase protein expression of toll-like receptor 4 (TLR4), promote the phosphorylation of mitogen-activated protein kinase (MAPK), as well as nuclear factor-kappa B (NF-κB) p65. Importantly, TLR4 inhibitor inhibited JCH-1-induced activation of MAPK-NF-κB signaling pathway, thus suppressed JCH-1-induced secretion of NO, TNF-α and IL-6. Collectively, these results indicated that JCH-1 actives RAW264.7 cells through TLR4-MAPK-NF-κB signaling pathway.
•The purified polysaccharide (JCH-1) had immunomodulatory activity.•JCH-1 performed immunomodulatory effect by promoting NO, TNF-α and IL-6 secretion.•JCH-1 could activate TLR4-MAPK-NF-κB signaling pathway.•Immunomodulatory effect of JCH-1 was related to TLR4-MAPK-NF-κB pathway.
Oxidative stress (OS) is the main cause leading to diabetic renal fibrosis. Recently, Fyn was paid much attention on OS and emerged as a pivotal player in acute kidney injury, while whether Fyn ...regulates oxidative stress in chronic diabetes nephropathy (DN) has not been clarified yet. The purpose of this study was to identify the role of Fyn in DN and elucidated its regulatory mechanism.
The db/db mice and littermate control C57BKS/J mice were injected by tail vein with Fyn interfering adenovirus or Fyn overexpressing adenovirus to investigate the role of Fyn in vivo. Primary glomerular mesangial cells (GMCs) were used for in vitro studies.
Fyn was up-regulated in high glucose (HG)-induced GMCs and kidneys of diabetic mice. Additionally, Fyn knockdown reduced the level of OS in HG-induced GMCs and kidneys of diabetic mice, thereby ameliorating diabetic renal fibrosis. While overexpression of Fyn significantly increased the level of OS in GMCs and kidney tissues, resulting in renal damage. Moreover, Fyn deficiency exerted antioxidant effects by activating the Sirt1/Foxo3a pathway. Mechanistically, Fyn facilitated the combination of c-Cbl and Sirt1 by phosphorylating c-Cbl at Tyr731, which triggered K48-linked polyubiquitination of Sirt1 at Lys377 and Lys513 by c-Cbl and promoted Sirt1 degradation, impairing the antioxidant effects of Foxo3a.
Fyn deficiency promoted Foxo3a nuclear transcription via reducing the ubiquitination of Sirt1 by c-Cbl, thereby alleviating renal oxidative damage in diabetic mice. These results identified Fyn as a potential therapeutic target against DN.
•This study reported the role of Fyn in diabetic nephropathy (DN).•We proposed Fyn as a potential therapeutic target against DN.•Fyn deficiency exerted antioxidant effects by activating the Sirt1/Foxo3a pathway.•Fyn facilitated the bond of c-Cbl and Sirt1 by phosphorylation at Tyr731 of c-Cbl.•c-Cbl promoted K48-linked polyubiquitination at Lys377 and Lys513 of Sirt1.
•Ostrea rivularis polysaccharide (ORP) had antioxidant and spermatogenic activity.•ORP could reduce testicular oxidative stress damage via Keap1-Nrf2/ARE pathway.•ORP could promote production of ...corresponding antioxidative enzymes and protein.•ORP could ameliorate testicular oxidative stress damage to the normal level.
The purpose of this study was to investigate the effects of Ostrea rivularis polysaccharide (ORP) against testicular oxidative stress injury via kelch-like ECH-associated protein 1-nuclear erythroid 2-related factor 2/antioxidant response element (Keap1-Nrf2/ARE) pathway. In pharmacological experiments in vivo, ORP administration could dose-dependently inhibit body and testicular weight loss, ameliorate epididymal sperm quality and protect reproductive impairment in cyclophosphamide-induced male Balb/c mice. Moreover, the mechanism in vivo might be elucidated that ORP could increase expression level of Nrf2 and its downstream ARE gene battery in the testis, promote production of corresponding antioxidative enzymes and protein, and enhance Keap1-Nrf2/ARE signaling pathway to avoid male reproductive dysfunction. In addition, ORP treatment could improve survival capacity of H2O2-induced TM4 cells and its antioxidant mechanism in vitro also had been verified to activate Keap1-Nrf2/ARE signaling pathway. Overall, these results showed that ORP as a potent antioxidant could reduce reproductive oxidative stress damage related to Keap1-Nrf2/ARE pathway.
Renal tubulointerstitial fibrosis (RIF), featured by epithelial-to-mesenchymal-transition (EMT) of renal tubular epithelial cells and collagen deposition in the renal interstitial region, is the main ...pathological change of diabetic nephropathy (DN). Fraxin, the main active component of Fraxinus rhynchophylla Hance with anti-inflammatory activity, has been demonstrated to ameliorate glomerulosclerosis. However, the regulatory role of Fraxin on diabetic RIF remains unclear. In this study, we investigated the renal protective benefits of Fraxin against diabetic RIF and elucidated its mechanisms. In vitro, Fraxin inhibited the abnormal expression of EMT-related markers and proinflammatory cytokines, improved cellular morphology, and subsequently reduced the extracellular matrix (ECM) production in high glucose (HG)-induced NRK-52E cells. In vivo, Fraxin effectively ameliorated renal function, inhibited the abnormal expression of EMT-related markers and proinflammatory cytokines, and reduced ECM deposition in renal tubule interstitium in db/db mice. Notably, Fraxin could directly bind to epidermal growth factor receptor (EGFR), which contributed to the inhibition of EGFR phosphorylation and counteracted the activation of c-Src/NF-κB pathway, eventually ameliorating RIF. Thus, Fraxin may be a potential drug candidate for treating DN.
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The suppression of the fibroblast growth factor 21/fibroblast growth factor receptor 1 (FGF21/FGFR1) signaling pathway is considered as a vital factor in the type 2 diabetes mellitus (T2DM) ...progression. Our previous study showed that gentiopicroside (GPS), the main active compound present in Gentiana macrophylla Pall., has the capacity to control disorders related to glucose and lipid metabolism in individuals with T2DM. Nevertheless, the specific mechanism remains unclear.
In light of the fact that the PharmMapper database suggests FGFR1 as the target of GPS, our investigation aims to determine if GPS can enhance glucose and lipid metabolism issues in T2DM by modulating the FGF21/FGFR1 signaling pathway.
In this study, we used palmitic acid (PA)-induced HepG2 cells and db/db mice to investigate the function and mechanism of GPS in the FGF21/FGFR1 signaling pathway. To examine the interaction between GPS and FGFR1, researchers performed Cellular Thermal Shift Assay (CETSA) and Surface Plasmon Resonance (SPR) analysis.
The results suggest that GPS activates the traditional metabolic pathways, including PI3K/AKT and AMPK, which are the subsequent stages of the FGF21/FGFR1 pathway. This activation leads to the enhancement of glucose and lipid metabolism issues in PA-treated HepG2 cells and db/db mice. Furthermore, the depletion of FGFR1 has been noticed to oppose the stimulation of PI3K/AKT and AMPK pathways by GPS in HepG2 cells subjected to PA. Notability, our research affirms that GPS binds directly to FGFR1, hindering the ubiquitinated degradation of FGFR1 by neural precursor cells expressing developmentally decreased protein 4 (NEDD4) and ultimately promoting FGF21 signal transduction.
This study demonstrates that GPS targeting FGFR1 activates the PI3K/AKT and AMPK pathways, which is an important mechanism for its treatment of T2DM.
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