BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
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2024
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IF 1.4
Wu Tao,Wu Ji,Liu Li,Song Hongping
Lipopolysaccharide (LPS) causes inflammatory cholestasis in sepsis. We investigated the role of PDZK1 in the repression of ABC transporters in LPS-induced cholestasis. Lentiviral gene transfer of PDZK1 to rats was conducted to explore its influence on cholestasis induced by LPS. And the effect of lentivirus-mediated shRNA targeting PDZK1 on ABC transporters in rat liver BRL-3A cells was evaluated. Lentiviral vector encoding rat PDZK1 was administered to rats by tail intravenous injection. Obviously elevated serum total bile acid (TBA) level and liver biochemical markers in cholestatic rats were decreased by the Lv-PDZK1 delivery. Also Lv-PDZK1 delivery stimulated the suppressed hepatic ABC transporters expression. In vitro, after the lentiviral vector LV3/PDZK1 shRNA transfection, no expression of PDZK1 and mild expression of ABC transporters were detected in BRL-3A cells by Western blotting. Our results indicate that the lentiviral-mediated hepatocyte PDZK1 expression ameliorates LPS-induced cholestasis in rats by rescuing hepatic ABC transporters expression.
研究领域:
分子生物学
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肝病学
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基因治疗
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DOI
PubMed
高影响因子
MOLECULAR MEDICINE
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2025
·Vol. 31
·期 1
·1-14
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IF 6.4
Jin Shengkai,Zhou Yuhua,Lv Jing,Lu Yichen,Zhang Yuwei,Li Menglu,Feng Ninghan
Background A close relationship exists between castration-resistant prostate cancer (CRPC) and histidine metabolism by gut microbes. However, the effects of the histidine metabolite imidazole propionate (IMP) on prostate cancer (PCa) and its underlying mechanisms are not well understood.Methods We first assessed the effects of IMP on cell proliferation and migration at the cellular level. Subsequently, we investigated the mechanism of action of IMP using transcriptome sequencing, qPCR, and Western blot analysis. Finally, we validated our findings in vivo using a mouse model.Results Histidine had no effect on PCa cell proliferation; however, IMP significantly inhibited the proliferation and migration of PC3 and DU145 cells. Mechanistic studies indicate that IMP exerts its effects by upregulating PDZK1 expression, which subsequently inhibits the phosphorylation of the PI3K-AKT pathway.Conclusion sIn conclusion, IMP significantly inhibits the progression of PCa, offering new insights into potential treatments for CRPC.
研究领域:
肿瘤学
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微生物学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Shuanghui Lu,Xiu Chen,Yujia Chen,Yingqiong Zhang,Jun Luo,Huidi Jiang,Luo Fang,Hui Zhou
Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of renal tubular cells promotes renal fibrosis and the progression of chronic kidney disease (CKD). PDZ domain-containing 1 (PDZK1) is highly expressed in renal tubular epithelial cells; however, its role in TGF-β1-induced EMT remains poorly understood. The present study showed that PDZK1 expression was extremely downregulated in fibrotic mouse kidneys and its negative correlation with TGF-β1 expression and the degree of renal fibrosis. In addition, TGF-β1 downregulated the mRNA expression of PDZK1 in a time- and concentration-dependent manner in vitro . The downregulation of PDZK1 exacerbated TGF-β1-induced EMT upon oxidative stress, while the overexpression of PDZK1 had the converse effect. Subsequent investigations demonstrated that TGF-β1 downregulated PDZK1 expression via p38 MAPK or PI3K/AKT signaling in vitro , but independently of ERK/JNK MAPK signaling. Meanwhile, inhibition of the p38/JNK MAPK or PI3K/AKT signaling using chemical inhibitors restored the PDZK1 expression, mitigated renal fibrosis, and elevated renal levels of endogenous antioxidants carnitine and ergothioneine in adenine-induced CKD mice. These findings provide the first evidence suggesting a negative correlation between PDZK1 and renal fibrosis, and identifying PDZK1 as a novel suppressor of renal fibrosis in CKD through ameliorating oxidant stress.
研究领域:
肾病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Host & Microbe
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2024
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IF 20.6
Ying-Xi Xu,Lu-Di Liu,Jiang-Yuan Zhu,Shan-Shan Zhu,Bing-Qi Ye,Jia-Lu Yang,Jing-Yi Huang,Zhi-Hao Huang,Yi You,Wen-Kang Li,Jia-Lin He,Min Xia,Yan Liu
Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.
研究领域:
微生物学
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代谢组学
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药理学
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胃肠病学
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DOI
PubMed
高影响因子
Translational Research
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2026
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IF 6.1
Liying Luo,Lei Wang,Dan Ma,Wenxiu Liu,Zhiyu Shi,Chunnan Liu,Meng Zhao,Yufeng Bai,Jiukun Lu,Jinyu Chi
Hypertension is a chronic disease accompanied by vascular remodeling. As an m6A demethylase, ALKBH5 is implicated in cardiovascular diseases. Herein, we demonstrated that ALKBH5 expression was upregulated in the aortic tissues of spontaneously hypertensive rats (SHR), with predominant localization in vascular smooth muscle cells (VSMCs). To define ALKBH5 function, we generated an SM22α-driven, VSMC-specific Alkbh5 -knockdown AAV9 vector and administered a single tail-vein injection (11 × 10¹² v.g./rat) to 4-week-old male SHRs. Alkbh5 knockdown markedly lowered arterial pressure in SHRs, ameliorated left ventricular remodeling, attenuated aortic media thickening and extracellular matrix deposition, and suppressed the contractile-to-synthetic/proliferative phenotypic switch of VSMCs. Primary thoracic aortic VSMCs were isolated from 16-week-old SHRs and Wistar-Kyoto (WKY) rats, with Alkbh5 knockdown achieved via adenoviral transduction. Separately, primary human aortic smooth muscle cells were pretreated with 1 μM angiotensin II for 24 h prior to adenoviral infection. In vitro assays further verified that ALKBH5 knockdown suppressed proliferation and the contractile-to-synthetic/proliferative phenotypic switch in VSMCs in hypertensive context. Subsequent mechanistic studies revealed that ALKBH5 knockdown enhanced the stability of TEAD3 mRNA by increasing its m6A modification; the upregulated TEAD3 could directly bind to the PDZK1 promoter and promote its transcription. Moreover, PDZK1 knockdown reversed the inhibitory effect of ALKBH5 knockdown on the abnormal proliferation of VSMCs. In conclusion, ALKBH5 knockdown inhibits the abnormal phenotypic switch of VSMCs through the TEAD3/PDZK1 axis, thereby alleviating vascular remodeling caused by hypertension. These findings suggest that ALKBH5 may serve as a potential therapeutic target for hypertension.
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Lei Wang,Yufeng Bai,Dan Ma,Wenxiu Liu,Zhiyu Shi,Chunnan Liu,Meng Zhao,Huiying Wang,Liying Luo,Jinyu Chi
Hypertension is a risk factor for cardiovascular diseases, primarily through its induction of pathological vascular and ventricular remodeling. TEA domain transcription factor 3 (TEAD3) is a transcription factor highly expressed in myocardial tissues. PDZ domain-containing 1 (PDZK1) has been reported to protect blood vessels. This study discovered decreased expression of TEAD3 and PDZK1 in the aortic tissues of spontaneously hypertensive rats (SHRs). TEAD3 overexpression in SHR vascular smooth muscle cells (VSMCs) driven by the SM22α promoter was achieved through adeno-associated virus delivery. TEAD3 overexpression alleviated aortic remodeling by reducing elastic fiber and collagen deposition. This improvement in vascular structure attenuated hypertension. Subsequently, ventricular remodeling was alleviated by reducing periaortic myocardial fibrosis and left ventricular posterior wall thickness. To elucidate the underlying mechanisms, we overexpressed TEAD3 or PDZK1 in SHR-derived VSMCs via adenoviral infection. Both interventions suppressed VSMC proliferation and migration. Crucially, TEAD3 overexpression upregulated PDZK1 expression, and DNA pull-down assays confirmed direct binding of TEAD3 protein to the PDZK1 promoter. PDZK1 knockdown abolished the anti-proliferative and anti-migratory effects of TEAD3. Further analysis suggested that PDZK1 exerted its protective role by inhibiting the phosphoinositide-3-kinase adaptor protein 1-mediated PI3K/Akt pathway. In conclusion, this study reveals that TEAD3-PDZK1 axis attenuates the abnormal proliferation and migration of VSMCs, which ameliorates aortic and left ventricular remodeling in hypertensive conditions. These findings establish a molecular basis for developing targeted therapies against hypertension-induced cardiovascular remodeling.
研究领域:
心血管研究
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分子生物学
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高血压
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转录调控
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血管生物学
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DOI
PubMed
高影响因子
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