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Project description:Aims: We have previously demonstrated hepatic, cardiac, and skin inflammation in high-fat diet-induced steatotic liver disease model. However, the molecular mechanism in the kidney in this model is still not clear. It has been recently reported that SGLT2 inhibitors improved chronic kidney disease (CKD). Therefore, we evaluated the effect of tofogliflozin on renal lipid metabolism and inflammation in this model. Methods: Male 8-10-week-old C57Bl/6 mice were fed high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or HF/HC/HS/BA diet alone (Cont group). After eight weeks, serum lipid profiles and histology, lipid content, mRNA/microRNA and protein expression levels in the kidney were examined. Results: The Tofo group showed significant reduction in body weight (26.9±0.9 vs 24.5±1.0 g; p<0.001) and kidney weight compared to the Cont group. Renal cholesterol (9.1±1.6 vs 7.5±0.7 mg/g; p<0.05) and non-esterified fatty acid (NEFA) (12.0±3.0 vs 8.4±1.5 µEq/g; p<0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed a decreasedd number of lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. microRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Interestingly, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and CPT1 in the Tofo group. Conclusions: Tofogliflozin decreased renal cholesterol and NEFA content and improved inflammation through the regulation of PPARα and miR-21a.
2025-02-05 | GSE251738 | GEO
Project description:Aims: We have previously demonstrated hepatic, cardiac, and skin inflammation in high-fat diet-induced steatotic liver disease model. However, the molecular mechanism in the kidney in this model is still not clear. It has been recently reported that SGLT2 inhibitors improved chronic kidney disease (CKD). Therefore, we evaluated the effect of tofogliflozin on renal lipid metabolism and inflammation in this model. Methods: Male 8-10-week-old C57Bl/6 mice were fed high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or HF/HC/HS/BA diet alone (Cont group). After eight weeks, serum lipid profiles and histology, lipid content, mRNA/microRNA and protein expression levels in the kidney were examined. Results: The Tofo group showed significant reduction in body weight (26.9±0.9 vs 24.5±1.0 g; p<0.001) and kidney weight compared to the Cont group. Renal cholesterol (9.1±1.6 vs 7.5±0.7 mg/g; p<0.05) and non-esterified fatty acid (NEFA) (12.0±3.0 vs 8.4±1.5 µEq/g; p<0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed a decreasedd number of lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. microRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Interestingly, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and CPT1 in the Tofo group. Conclusions: Tofogliflozin decreased renal cholesterol and NEFA content and improved inflammation through the regulation of PPARα and miR-21a.
2025-02-05 | GSE251737 | GEO
Project description:Tofogliflozin Attenuates Renal Lipid Deposition and Inflammation via PPARα restoration in Diet-induced Steatohepatitic mice
| PRJNA1055144 | ENA
Project description:Tofogliflozin Attenuates Renal Lipid Deposition and Inflammation via PPARα restoration in Diet-induced Steatohepatitic mice. (microRNA-Seq)
| PRJNA1055152 | ENA
Project description:Tofogliflozin Attenuates Renal Lipid Deposition and Inflammation via PPARα restoration in Diet-induced Steatohepatitic mice. (RNA-Seq)
| PRJNA1055151 | ENA
Project description:BackgroundHistologically, cytoplasmic deposits of lipids and glycogen are common in clear cell renal cell carcinoma (ccRCC). Owing to the significance of lipid deposition in ccRCC, numerous trials targeting lipid metabolism have shown certain therapeutic potential. The agonism of peroxisome proliferator-activated receptor-α (PPARα) via ligands, including WY-14,643, has been considered a promising intervention for cancers.MethodsFirst, the effects of WY-14,643 on malignant behaviors were investigated in ccRCC in vitro. After RNA sequencing, the changes in lipid metabolism, especially neutral lipids and glycerol, were further evaluated. Finally, the underlying mechanisms were revealed.ResultsPhenotypically, the proliferation and migration of ccRCC cells treated with WY-14,643 were significantly inhibited in vitro. A theoretical functional mechanism was proposed in ccRCC: WY-14,643 mediates lipid consumption by recognizing carnitine palmitoyltransferase 1 A (CPT1A). Activation of PPARα using WY-14,643 reduces lipid deposition by increasing the CPT1A level, which also suppresses the NF-κB signaling pathway. Spatially, WY-14,643 binds and activates PPARα by targeting Gly335.ConclusionOverall, WY-14,643 suppresses the biological behaviors of ccRCC in terms of cell proliferation, migration, and cell cycle arrest. Furthermore, its anticancer properties are mediated by the inhibition of lipid accumulation, at least in part, through the PPARα/CPT1A axis by targeting Gly335, as part of the process, NF-κB signaling is also suppressed. Pharmacological activation of PPARα might offer a new treatment option for ccRCC.
| S-EPMC9667690 | biostudies-literature
Project description:PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.
| S-EPMC8198004 | biostudies-literature
Project description:Renal inflammation contributes to the pathogeneses of hypertension. This study was designed to determine whether B-cell lymphoma 6 (BCL6) attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used in the present study. Angiotensin (Ang) II or lipopolysaccharides (LPS) was used to induce inflammation in HK-2 cells, a human renal tubular epithelial (RTE) cell line. NLRP3 inflammasome was activated and BCL6 was downregulated in the kidneys of SHR. Either Ang II or LPS suppressed BCL6 expression in HK-2 cells. BCL6 overexpression in HK-2 cells attenuated Ang II-induced NLRP3 upregulation, inflammation and cell injury. The inhibitory effects of BCL6 overexpression on NLRP3 expression and inflammation were also observed in LPS-treated HK-2 cells. BCL6 inhibited the NLRP3 transcription via binding to the NLRP3 promoter. BCL6 knockdown with shRNA increased NLRP3 and mature IL-1β expression levels in both PBS- or Ang II-treated HK-2 cells but had no significant effects on ASC, pro-caspase-1 and pro-IL-1β expression levels. BCL6 overexpression caused by recombinant lentivirus expressing BCL6 reduced blood pressure in SHR. BCL6 overexpression prevented the upregulation of NLRP3 and mature IL-1β expression levels in the renal cortex of SHR. The results indicate that BCL6 attenuates Ang II- or LPS-induced inflammation in HK-2 cells via negative regulation of NLRP3 transcription. BCL6 overexpression in SHR reduced blood pressure, NLRP3 expression and inflammation in the renal cortex of SHR.
| S-EPMC5680929 | biostudies-literature
Project description:Fatty acid binding protein 4 (FABP4), a subtype of fatty acid-binding protein family, shows critical roles in metabolism and inflammation. However, its roles on regulating renal interstitial fibrosis (RIF) remain unclear. In this work, LPS-stimulated in vitro models on NRK-52E and NRK-49F cells, and in vivo UUO models in rats and mice were established. The results showed that comparing with control groups or sham groups, the expression levels of α-SMA, COL1A, COL3A, IL-1β, IL-6, and TNF-α in LPS-stimulated cells or UUO animals were significantly increased. Meanwhile, the levels of TC, TG, and free fatty acid were also significantly increased as well as the obvious lipid droplets, and the serum levels of BUN, Cr were significantly increased with large amounts of collagen deposition in renal tissues. Further investigation showed that compared with control groups or sham groups, the expression levels of FABP4 in LPS-stimulated cells and UUO animals were significantly increased, resulting in down- regulating the expression levels of PPARγ, upregulating the levels of p65 and ICAM-1, and decreasing the expression levels of ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1. To deeply explore the mechanism of FABP4 in RIF, FABP4 siRNA and inhibitor interfered cell models, and UUO model on FABP4 knockout (KO) mice were used. The results showed that the expression levels of α-SMA, COL1A, and COL3A were significantly decreased, the deposition of lipid droplets decreased, and the contents of TC, TG, and free fatty acids were significantly decreased after gene silencing. Meanwhile, the expression levels of PPAR-γ, ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1 were upregulated, the levels of p65 and ICAM-1 were downregulated, and the mRNA levels of IL-1β, IL-6, and TNF-α were decreased. Our results supported that FABP4 contributed to RIF via promoting inflammation and lipid metabolism, which should be considered as one new drug target to treat RIF.
| S-EPMC6522534 | biostudies-literature
Project description:Laser material deposition based restoration of high-value components can be a revolutionary technology in remanufacturing. The deposition process induces residual stresses due to thermomechanical behavior and metallurgical transformations. The presence of tensile residual stresses in the deposited layer will compromise the fatigue life of the restored component. We have developed a novel fully coupled metallurgical, thermal and mechanical (metallo-thermomechanical) model to predict residual stresses and identified a critical deposition height, which ensures compressive residual stresses in the deposited layer. Any lower deposition height will result in tensile residual stresses and higher deposition height will result in excessive dilution (substrate melting). We have validated the model using neutron and micro-focus X-ray diffraction measurements. This study highlights that the critical deposition height corresponds to the minimum cooling rate during solidification. It addresses one of the major outstanding problems of additive manufacturing and paves a way for "science-enabled-technology" solutions for sustainable restoration/remanufacturing.
| S-EPMC6170464 | biostudies-literature