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1.
Int Immunopharmacol ; 135: 112314, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38788450

ABSTRACT

We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1ß/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1ß showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1ß/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1ß, collagen I, fibronectin and α-SMA, and TGF- ß 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.


Subject(s)
Cinnamates , Depsides , Fibrosis , Indican , Inflammasomes , Kidney , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Rosmarinic Acid , Signal Transduction , Animals , Depsides/pharmacology , Depsides/therapeutic use , Cinnamates/pharmacology , Cinnamates/therapeutic use , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Inflammasomes/metabolism , Signal Transduction/drug effects , Male , Kidney/pathology , Kidney/drug effects , Kidney/metabolism , Cell Line , Mice , Interleukin-1beta/metabolism , Ureteral Obstruction/drug therapy , Ureteral Obstruction/pathology , Reactive Oxygen Species/metabolism , Disease Models, Animal , Smad2 Protein/metabolism , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/chemically induced , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/metabolism , Smad3 Protein/metabolism , Caspase 1/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/chemically induced , Kidney Diseases/pathology
2.
Tzu Chi Med J ; 36(1): 59-66, 2024.
Article in English | MEDLINE | ID: mdl-38406569

ABSTRACT

Objectives: Ellagic acid (EA), a kind of polyphenol found in numerous fruits and vegetables, has anti-inflammatory, anti-apoptotic, anti-oxidant, and anti-fibrotic effects against a variety of diseases, but its role in mediating renal fibrogenesis remains unknown. Materials and Methods: We used an in vivo mouse unilateral ureteral obstruction (UUO) model and an in vitro model with HK-2 cell lines treated with EA and transforming growth factor ß1 (TGF-ß1). The expression of epithelial-to-mesenchymal transition (EMT)-related proteins of UUO mice was examined using immunohistochemical staining. Liver function and renal function were evaluated using biochemical testing. Western blot analysis was used to determine the proteins related to EMT, and MTT assay was used to determine cell viability. Results: In UUO mice fed EA, both microscopical examination with immunohistochemical staining and western blotting protein analysis showed reduced expression of fibrotic (α-SMA, fibronectin, and collagen I)- and EMT (vimentin and N-cadherin)-related proteins, compared with sham control. In HK-2 cells treated with TGF-ß1, EA decreased motility as well as expression of α-SMA, collagen-I, fibronectin, N-cadherin, and vimentin. Conclusion: EA reduced the progression of the morphological transformations and concomitantly suppressed the expression of fibrotic- and EMT-related proteins in vitro and in vivo. These findings improved our understanding of the role of EA in suppressing renal fibrogenesis and demonstrated the promising role EA may play in the management of chronic kidney disease.

3.
Biochem Pharmacol ; 218: 115935, 2023 12.
Article in English | MEDLINE | ID: mdl-37989414

ABSTRACT

α-mangostin (α-MG), a natural derivative of coumarin, exhibits anti-inflammatory, antioxidant and anti-fibrotic effects. This study aimed to determine the effect of α-MG treatment in mediating the process of renal interstitial fibrosis. We found that α-MG could alleviate tubule-interstitial damage and decrease fibrotic (α-smooth muscle actin [α-SMA], fibronectin, and collagen I), and epithelial-mesenchymal transition (EMT) protein (N-cadherin, Snail, Slug, TGF-ß1 and vimentin) expression in unilateral ureteral obstruction (UUO) mice with chronic kidney disease. α-MG significantly decreased motility as well as inhibited expression of fibrotic- and EMT-related proteins in TGF-ß1-induced HK2 cells. To clarify the molecular mechanisms of α-MG in reducing renal interstitial fibrosis, we used a MEK inhibitor (U0126) or Smad inhibitor (SB431542) cotreatment with α-MG. This is the first study is to demonstrate the antifibrotic effects of α-MG by targeting the TGF-ß1/ERK/Smad-mediated EMT signaling pathway, is even more effective against renal interstitial fibrosis.


Subject(s)
Renal Insufficiency, Chronic , Ureteral Obstruction , Mice , Animals , Transforming Growth Factor beta1/metabolism , Smad Proteins/metabolism , Signal Transduction , Ureteral Obstruction/metabolism , Ureteral Obstruction/pathology , Renal Insufficiency, Chronic/metabolism , Fibrosis , Epithelial-Mesenchymal Transition , Kidney/metabolism
4.
Food Funct ; 13(8): 4641-4652, 2022 Apr 20.
Article in English | MEDLINE | ID: mdl-35373225

ABSTRACT

Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via renal fibrosis. Epithelial-mesenchymal transition (EMT) is a crucial feature of renal fibrosis. Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydroxyphenylacetic acid with a wide range of desirable biological activities. In this study, we investigated whether RA exerted anti-renal fibrosis effects and its related mechanisms in a unilateral ureteral obstruction (UUO) mouse model. C57BL/6 mice were orally administered RA (10 and 20 mg kg-1 d-1) for 7 consecutive days before and after UUO surgery. The mice were then sacrificed to collect the blood and kidneys. Hematoxylin and eosin (H&E) and Masson's trichrome staining were used to evaluate the renal injury and function. Immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR), and western blotting were used to detect the expression levels of EMT markers. In vitro studies were performed using the IS-stimulated NRK-52E cell line. Here, the pathological changes, collagen deposition, and mRNA and protein expression levels of profibrotic factors and fibrotic markers were found to be significantly elevated in the kidneys of UUO mice. We found that RA administration significantly ameliorated UUO-induced kidney damage by reversing abnormal serum creatinine and blood urea nitrogen levels. It was found that RA treatment decreased the expression levels of alpha-smooth muscle actin (α-SMA), collagen I, fibronectin, transforming growth factor (TGF)-ß1, vimentin and phosphorylated AKT (p-AKT) while increasing the E-cadherin expression in both UUO kidneys and IS-treated NRK-52E cells. Our results demonstrate that RA may be a promising therapeutic agent for renal interstitial fibrosis.


Subject(s)
Kidney Diseases , Renal Insufficiency, Chronic , Ureteral Obstruction , Animals , Cinnamates , Collagen/metabolism , Depsides , Epithelial-Mesenchymal Transition , Female , Fibrosis , Humans , Kidney , Kidney Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/metabolism , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Ureteral Obstruction/drug therapy , Ureteral Obstruction/metabolism , Ureteral Obstruction/pathology , Rosmarinic Acid
5.
Cancers (Basel) ; 15(1)2022 Dec 21.
Article in English | MEDLINE | ID: mdl-36612038

ABSTRACT

Cervical cancer is one of the most common gynecologic cancers globally that require novel approaches. Timosaponin AIII (TSAIII) is a steroidal saponin that displays beneficial effects in antitumor activities. However, the effect of TSAIII on human cervical cancer remains unknown. In this study, we found that TSAIII showed no influence on cell viability, cytotoxicity, cell cycle distribution and apoptosis induction in human cervical cancer cells. TSAIII was revealed to have a significant inhibitory effect on cell migration and invasion through the downregulation of invasion-related uPA expression and p38 MAPK activation in both human cervical cancer cells and cervical cancer stem cells (CCSCs), indicating that the p38 MAPK-uPA axis mediated the TSAIII-inhibited capacity of cellular migration and invasion. In a synergistic inhibition assay, a TSAIII plus p38 siRNA cotreatment revealed a greater inhibition of uPA expression, migration and invasion in human cervical cancer cells. In an immunodeficient mouse model, TSAIII significantly inhibited lung metastases from human cervical cancer SiHa cells without TSAIII-induced toxicity. These findings first revealed the inhibitory effects of TSAIII on the progression of human cervical cancer through its downregulation of p38 MAPK-uPA axis activation. Therefore, TSAIII might provide a potential strategy for auxiliary therapy in human cervical cancer.

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