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AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.
Assuntos
Ácido Clorogênico , Nefropatias Diabéticas , Fibrose , Rim , Metabolismo dos Lipídeos , Receptor Notch1 , Fator de Transcrição STAT3 , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Receptor Notch1/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Animais , Transdução de Sinais/efeitos dos fármacos , Fibrose/tratamento farmacológico , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Humanos , Camundongos , Masculino , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Camundongos Endogâmicos C57BL , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Linhagem CelularRESUMO
Perovskites based on CsPbX3 (X = Cl, Br, I) have promising applications in solar cells, light-emitting diodes, and photodetectors. In this paper, the phase stability of inorganic metal halide perovskite CsPbCl3 under hydrostatic pressure and anion substitution is studied using density functional theory (DFT), and this modification is explained by the interaction of the octahedrons and transformation of the bond-orbital coupling. In addition, two space groups, P4/mbm and Amm2, which are stable under stress, are subjected to anion substitution; then, the structural stability and band gap change of CsPbCl3-yXy (X = Br, I; y = 0, 1, 2, 3) are analyzed after applying stress; finally, the electronic structures and optical properties of the six most stable components are presented. The effect of stress and anions on the components' optoelectronic properties is closely linked with the crystal's structural alteration mechanism. These results show that stress and anion modulation can significantly change the optoelectronic properties of materials, which make these materials have broad application prospects. Furthermore, stress can be used as an effective tool for screening the most stable material structure.
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Delayed wound healing is one of the most prominent clinical manifestations of diabetes and lacks satisfactory treatment options. Persistent inflammation occurs in the late phase of wound healing and impairs the healing process in mice with diabetes mellitus (DM). In this study, we observed that the late wound healing in streptozotocin (STZ)-induced DM mice could be improved by (-)-epigallocatechin gallate (EGCG). The macrophage accumulation, inflammation response, and Notch signaling can be inhibited by EGCG in the skin wounds of DM mice. Furthermore, we found that the LPS-induced inflammation response including overactivated Notch signaling, was inhibited by EGCG in mouse macrophages. Moreover, we confirmed that EGCG could directly bind with mouse Notch-1. In addition, our studies indicated that diabetic wound healing was improved by EGCG treatment before or after the inflammation phase by targeting the Notch signaling pathway, which suggests that the pre-existing diabetic wound healing can be improved by EGCG. To summarize, wound healing can be improved by EGCG through targeting Notch in STZ-induced DM mice. Our findings provide insight into the therapeutic strategy for diabetic wounds and offer EGCG as a novel potential medicine to treat chronic wounds.-Huang, Y.-W., Zhu, Q.-Q., Yang, X.-Y., Xu, H.-H., Sun, B., Wang, X.-J., Sheng, J. Wound healing can be improved by (-)-epigallocatechin gallate through targeting Notch in streptozotocin-induced diabetic mice.
Assuntos
Catequina/análogos & derivados , Diabetes Mellitus Experimental/metabolismo , Receptores Notch/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Catequina/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Feminino , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Células RAW 264.7 , Transdução de Sinais , Pele/metabolismo , Estreptozocina , Cicatrização/fisiologiaRESUMO
Renal fibrosis is a characteristic of diabetic nephropathy, which is a serious complication of diabetes. It has been reported that (-)-epigallocatechin gallate (EGCG) attenuates renal fibrosis. However, the molecular mechanism of regulation by EGCG in this process remains unclear. Previous studies showed that abnormal activation of Notch signaling contributes to the development of renal fibrosis. Previous studies have demonstrated that EGCG attenuates Notch1 expression. In this study, we found that the levels of fibronectin and Notch1 expression were decreased in human embryonic kidney cells after treatment with EGCG. We also observed that the type II transforming growth factor beta receptor (TGFßRII) and Smad3 pathway were inhibited in kidney cells by treatment with EGCG. In the diabetic kidney, we found that the activation of Notch signaling was attenuated by administration of EGCG. Moreover, TGFßRII and Smad3 phosphorylation could be inhibited by treatment with EGCG in the kidney. These results indicated that EGCG may improve renal fibrosis by targeting Notch via inhibition of the TGFß/Smad3 pathway in diabetic mice. Our findings provide insight into the therapeutic strategy for diabetes-induced renal fibrosis, and suggest EGCG to be a novel potential medicine for the treatment of chronic kidney disease in patients with diabetes.
Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Diabetes Mellitus Experimental/prevenção & controle , Insuficiência Renal Crônica/prevenção & controle , Animais , Antioxidantes/administração & dosagem , Catequina/administração & dosagem , Catequina/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/prevenção & controle , Feminino , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos ICR , Distribuição Aleatória , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/complicações , Transdução de Sinais , Proteína Smad3/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Green tea (Camelliasinensis [L.] Kuntze) belongs to the plant family Theaceae and is mainly distributed in East Asia, the Indian subcontinent and Southeast Asia. This plant has been proven to be beneficial to human health, and green tea is the second most consumed beverage in the world after water. However, until now, the effect of green tea aqueous extract (GTE) upon postmenopausal osteoporosis has remained unclear. In this study, we investigated the therapeutic effects of GTE on estrogen deficiency-induced osteoporosis and explored the possible mechanisms in vivo and in vitro. MATERIALS AND METHODS: Ovariectomized (OVX) female rats were orally administered with GTE at doses of 60, 120, and 370 mg kg-1 for 13 consecutive weeks. The biochemical parameters, bone gla protein, alkaline phosphatase, acid phosphatase, estrogen, interleukin-1ß, and interleukin-6 in blood samples were detected, and histological change in bones was analyzed by hematoxylin and eosin staining. Meanwhile, the mechanisms of GTE on osteoclast formation were explored in RAW 264.7 cells induced by receptor activation of the nuclear factor kappa B ligand (RANKL). RESULTS: The results showed that GTE could increase bone mass and inhibit trabecular bone loss in OVX rats. Furthermore, real-time quantitative reverse transcription polymerase chain reaction analysis from in vitro experiments also showed that GTE reduced the mRNA expression of osteoclast-associated genes such as cathepsin K (cath-K), c-Fos, matrix metalloproteinase 9, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and tartrate-resistant acid phosphatase. In addition, GTE caused a reduction in the protein levels of NFATc1, c-Fos, c-src and cath-K. CONCLUSION: Evidence from both animal models and in vitro experiments suggested that GTE might effectively ameliorate the symptoms of osteoporosis in OVX rats and inhibit RANKL-induced osteoclast-specific gene and protein expression.
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AIMS: Dendrobium candidum (DC) and black tea, are traditional chinese drinks, which contain multiple active ingredients. However, whether or not the combination of these two ingredients can improve osteoporosis remains unknown. This study therefore aimed to examine the effects of the combination of DC and black tea extract (BTE) on osteoporosis. MAIN METHODS: Ovariectomy (OVX)-induced osteoporosis in vivo as well as receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in vitro was selected. KEY FINDINGS: Results showed that OVX rats that were treated orally with a DC and BTE combination for 12â¯weeks maintained their calcium (Ca) and phosphorus (P) homeostasis and exhibited significantly enhanced estradiol (E2) and OPG levels. This combination treatment also simultaneously reduced levels of interleukin (IL)-1ß, IL-6 and improved the organ coefficients of the uterus and femur as well as BMD and BMC in OVX rats. In addition, this DC and BTE combination suppressed osteoclast differentiation in the RANKL-stimulated osteoclastogenesis of RAW 264.7 cells and effectively inhibited the expression of osteoclast-associated genes and proteins. The results of this study further highlight the fact that a combination of DC and BTE improved ovariectomy-induced osteoporosis in rats and suppressed RANKL-stimulated osteoclastogenesis in RAW 264.7 cells. SIGNIFICANCE: This combination also significantly alleviated osteoporosis when compared to the alternative sole treatments above, due to synergistic effects among components. One partial mechanism of this combination might be the inhibition of osteoclast proliferation and the regulation of NFATC1/c-Fos expression.