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1.
FASEB J ; 36(12): e22625, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36331546

RESUMO

Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney disease (CKD), ultimately predisposes patients to end-stage renal disease. However, there is no effective therapy for renal fibrosis. Our earlier studies proved that RIP3-mediated necroptosis might be an important mode of renal tubular cell death in rats with chronic renal injury. Under transmission electron microscopy (TEM), we found morphological changes in the necrosis of human renal tissue, and the percentage of necrotic cells increased significantly in patients with stages 2 and 3a CKD. Immunofluorescence analyses showed that the percentages of TUNEL+ /RIP3+ double-positive and TUNEL+ /MLKL+ double-positive tubular epithelial cells in renal tubules of patients with stages 2 and 3a CKD were significantly increased compared to those in control patients without renal disease. Immunohistochemistry analyses of renal biopsy specimens from patients with CKD revealed RIP3, MLKL, and p-MLKL upregulation in patients with stages 2 and 3a CKD, suggesting that necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. We showed that profibrotic factor proteins (TGF-ß1, Smad2 and Smad3) and fibroblast activation markers (α-SMA and Vimentin) were specifically upregulated in stage 2 and 3a CKD patients. In addition, Pearson correlation analysis showed that the percentage of necroptotic renal tubular epithelial cells was positively correlated with TGF-ß1 and collagen-I. We also showed that RIP1/3 or MLKL inhibitors decreased the expression of RIP3, MLKL, TGF-ß1, and Smad3 in HK-2 cells treated with TNF-α. FGF-2, α-SMA, Vimentin and FN were overexpressed in the hRIFs cultured with the supernatant of necroptotic HK-2 cells, whereas necroptosis blockers (Nec-1s, GSK'872 and NSA) and TGF-ß1/Smad3 pathway antagonists (LY364947 and SIS3) reduced FGF-2, α-SMA, Vimentin and FN levels. Collectively, necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. Renal tubular epithelial cell necroptosis mediates renal tubulointerstitial fibrosis in patients with chronic kidney disease, which is related to the TGF-ß1/Smad3 signaling pathway.


Assuntos
Insuficiência Renal Crônica , Fator de Crescimento Transformador beta1 , Humanos , Ratos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Necroptose , Vimentina/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fibrose , Células Epiteliais/metabolismo , Insuficiência Renal Crônica/metabolismo , Rim/metabolismo , Necrose/patologia
2.
EBioMedicine ; 45: 108-123, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262715

RESUMO

BACKGROUND: Hydrogen Sulfide (H2S), a third member of gasotransmitter family along with nitric oxide (NO) and carbon monoxide (CO), exerts a wide range of cellular and molecular actions in our body. There is a large body of evidence suggesting that H2S plays an important role in cancer metastasis; however, the molecular mechanisms of H2S-mediated acceleration of cancer metastasis remain unknown. METHODS: We examined the promote effects of H2S on phenotype of gastric cancer (GC) cells (including those of express wild type CD36 and mutant CD36) in vitro and in vivo. GC patients' samples were used for clinical translational significance evaluation. FINDINGS: H2S triggered lipid metabolism reprogramming by significantly up-regulating the expression of the fatty-acid receptor CD36 (CD36) and directly activating CD36 in GC cells. Mechanistically, a disulfide bond located between cysteine (Cys)333 and Cys272 within the CD36 protein structure that was labile to H2S-mediated modification. The long chain-fatty acid (LC-FA) binding pocket was capped by a turn in the CD36 protein, located between helical and sheet structures that were stabilized by the Cys333-Cys272. This limited the secondary binding between LC-FAs and lysine (Lys)334. Breaking the Cys333-Cys272 disulfide bond restored the second LC-FA binding conformation of CD36. Targeting CD36 in vivo blocked H2S-promoted metastasis and improved animal survival. INTERPRETATION: These findings identify that the Cys333-Cys272 disulfide bond disrupted the integrity of the second LC-FA binding conformation of CD36. Therefore, CD36 can directly activate LC-FA access to the cytoplasm by acting as a direct target molecule for H2S.


Assuntos
Antígenos CD36/genética , Proliferação de Células/genética , Cisteína/genética , Neoplasias Gástricas/metabolismo , Animais , Proteínas de Artrópodes , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Cisteína/metabolismo , Dissulfetos/metabolismo , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Xenoenxertos , Humanos , Sulfeto de Hidrogênio/metabolismo , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Óxido Nítrico/genética , Domínios Proteicos/genética , Receptores Odorantes/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
3.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 32(2): 177-180, 2016 Feb 08.
Artigo em Zh | MEDLINE | ID: mdl-29931872

RESUMO

OBJECTIVE: To study the protective effect and the underlying mechanism of trillium tschonoskii maxim (TTM, Traditional Chinese Medicine) on myocardial injury of diabetic rats induced by high-fat diet and streptozotocin (STZ), which will lay a theoretical foundation for further exploring its pharmacological effect. METHODS: SD male rats received high fat diet and STZ (35 mg/kg) via tail vein injection were modeled into diabetic rats, the levels of brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) in serum, the contents of superoxide (SOD), glutathione peroxidase (GPX),malondialdehyde (MDA) in cardiac tissues, and cardiac myocyte apoptosis index were tested in all groups after the last administration. RESULTS: Compared with that in the model group, SOD and GPX activities were significantly increased and levels of BNP、cTnI、cardiac weight index (CWI)、apoptosis index (AI) were decreased in TTM and metformin (Met) group. The effects of TTM were better than traditional medicine metformin in enhancing GPX activity and decreasing collagen level. CONCLUSIONS: TTM can inhibit myocardial apoptosis by reducing oxidative stress responses in diabetic rats, which can slow down collagen fiber production to protect the myocardial cell injury.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Coração/efeitos dos fármacos , Extratos Vegetais/farmacologia , Trillium/química , Animais , Apoptose , Glutationa Peroxidase/metabolismo , Masculino , Malondialdeído/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/sangue , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Troponina I/sangue
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