BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Cheng Cao,Mubin Sun,Jiabao Li,Zhenyu Yuan,Yuwei Gu,Yufan Shao,Lisheng Wang,Xiaohua Jin,Yijie Cheng,Bo Fan
Urate transporter 1 (URAT1, encoded by SLC22A12 ) is a key mediator of renal urate reabsorption and an important pharmacological target for urate-related disorders. Sodium butyrate (BuNa), a gut microbiota derived short-chain fatty acid, has been implicated in host metabolic regulation, but its role in renal urate transport remains unclear. Here, using molecular docking, cellular thermal shift assays, immunoprecipitation-mass spectrometry and multi-omics analyses, we identified free fatty acid receptor 2 (FFAR2) as a direct target of BuNa in renal proximal tubular HK2 cells . BuNa binding upregulated FFAR2 and promoted URAT1 expression and urate uptake via an FFAR2-dependent pathway. Mechanistically, BuNa/FFAR2 signaling acts via GNAQ to activate PLCβ, generating diacylglycerol and engaging a PKC-dependent p38 MAPK/ELK1 cascade that upregulates arrestin beta 2 (ARRB2). ARRB2 directly binds to IκB, preventing its phosphorylation-dependent degradation, thereby stabilizing IκB and inhibiting NF-κB nuclear translocation. Within the SLC22A12 promoter, NF-κB (RELA/p50) and hepatocyte nuclear factor 1 beta (HNF1β) compete for overlapping binding sites. By blocking NF-κB nuclear entry, BuNa relieves this competition, permitting HNF1β-driven SLC22A12 transcription. Thus, BuNa enhances URAT1-mediated urate reabsorption in HK2 cells via an FFAR2/GNAQ/p38 MAPK/ELK1/ARRB2 axis that stabilizes IκB, suppresses NF-κB, and relieves the competitive binding between NF-κB and HNF1β on the SLC22A12 promoter. These findings establish a previously unrecognized gut microbiota–kidney axis linking microbial BuNa to renal urate homeostasis through a novel transcriptional regulatory circuit.
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高影响因子
TISSUE & CELL
·
2025
·
IF 2.5
Yujie Ma,Runqiang Liu,Juan Zhan,Yihan Lai,Sicheng Li,Wei Wang,Yisen Shao,Lin Jiang
The incidence of tongue squamous cell carcinoma (TSCC) has been increasing annually. Type 2 diabetes mellitus (T2DM) is one of the risk factors for TSCC, with hyperglycemia being a hallmark of T2DM that promotes the development of oral cancer and results in poorer prognoses for TSCC patients who also have T2DM. Oleic acid (OA), a component of Brucea javanica oil emulsion, exhibits both anti-cancer and anti-diabetic properties. However, the precise regulatory mechanisms of OA on tongue squamous cell carcinoma (TSCC) under high glucose conditions have yet to be fully elucidated. Our findings demonstrated that high glucose significantly enhanced the migratory, invasive, and proliferative capabilities of TSCC cells. Notably, OA treatment effectively reversed these high glucose-induced enhancements in TSCC cellular activities. Furthermore, our research revealed that OA exerted its anti-tumor effects by stabilizing its binding with S100A9, which modulated the glycolytic pathway. Ultimately, we confirmed that the anti-tumor mechanism of OA in TSCC patients with T2DM was associated with the inactivation of the S100A9-HK2/PKM2-SOD2 pathway. In summary, OA inhibited the proliferation, migration, and invasion of TSCC cells under high glucose conditions through the regulation of the S100A9-HK2/PKM2-SOD2 pathway.
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PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Jian Hua,Hao Guan,Xue-Jian Li,Hong-Hui Liao,Xiao-Lin He,Chen-Huan Yu,Ping Huang
Diabetic nephropathy (DN) is a common microvascular complication with limited effective interventions in diabetic patients. Linderae Radix is a traditional herbal tonic used to treat various kidney and metabolic diseases. In this study, we evaluated the efficacy and mechanism of the main bioactive components, sesquiterpene lactones in L. Radix (SLR), on DN. The results showed that treatment with SLR reduced the levels of apoptotic rates, ROS, TNF-α, IL-6, and IL-1β, but increased the activities of SOD and GSH-Px in high glucose-treated HK2 cells. Furthermore, SLR improved renal dysfunction but increased the activities of SOD and GSH-Px in the renal tissues of DN mice. Mechanistically, SLR upregulated the expressions of Nrf2 and HO-1 but downregulated NF-κB in high glucose-treated HK2 cells by targeting PPAR, which could be reversed by the PPARγ inhibitor SR202. Therefore, SLR improved DN by reducing oxidative stress, cell apoptosis, and inflammatory response through activating PPARγ/Nrf2 pathway.
研究领域:
药理学
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肾病学
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分子生物学
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中药学
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高影响因子
PHYTOTHERAPY RESEARCH
·
2024
·
IF 6.1
Meng Wang,Qiurui Li,Shang Wang,Ling Zuo,Yang Hai,Su Yuan,Xuezhi Li,Xuekuan Huang,Congwen Yang,Ling Yao,Wenfu Cao,Guoqing Zuo,Jianwei Wang
Tubular injury and oxidative stress are involved in the pathogenesis of diabetic kidney disease (DKD). Astragaloside IV (ASIV) is a natural antioxidant. The effects and underlying molecular mechanisms of ASIV on DKD have not been elucidated. The db/db mice and high-glucose-stimulated HK2 cells were used to evaluate the beneficial effects of ASIV in vivo and in vitro. Succinylated proteomics was used to identify novel mechanisms of ASIV against DKD and experimentally further validated. ASIV alleviated renal dysfunction and proteinuria, downregulated fasting blood glucose, and upregulated insulin sensitivity in db/db mice. Meanwhile, ASIV alleviated tubular injury, oxidative stress, and mitochondrial dysfunction in vivo and in vitro. Mechanistically, ASIV reversed downregulated 17beta-hydroxysteroid dehydrogenase type 10 (HSD17B10) lysine succinylation by restoring carnitine palmitoyl-transferase1alpha (Cpt1a or CPT1A) activity in vivo and in vitro. Molecular docking and cell thermal shift assay revealed that ASIV may bind to CPT1A. Molecular dynamics simulations demonstrated K99 succinylation of HSD17B10 maintained mitochondrial RNA ribonuclease P (RNase P) stability. The K99R mutation of HSD17B10 induced oxidative stress and disrupted its binding to CPT1A or mitochondrial ribonuclease P protein 1 (MRPP1). Importantly, ASIV restored the interaction between HSD17B10 and MRPP1 in vivo and in vitro. We also demonstrated that ASIV reversed high-glucose-induced impaired RNase P activity in HK2 cells, which was suppressed upon K99R mutation of HSD17B10. These findings suggest that ASIV ameliorates oxidative stress-associated proximal tubular injury by upregulating CPT1A-mediated K99 succinylation of HSD17B10 to maintain RNase P activity.
研究领域:
肾病学
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分子生物学
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药理学
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糖尿病研究
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PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Qiang Li,Yanbin Zheng,Jianyu Zhao,Xinyi Wei,Zongxin Shi,Haonan Fan,Chenxu Ge,Minxuan Xu,Jun Tan
Diabetic kidney disease (DKD) is a major diabetic complication and a leading cause of end-stage renal disease (ESRD), but the therapeutic strategies for DKD are still limited. Red radishes ( Raphanus sativus L.) are a rich source of natural anthocyanins that have antioxidant, anti-apoptotic and anti-inflammatory activities. In this study, we attempted to explore the effects of natural pigment anthocyanin called radish red (RR) extracted from red radishes on DKD progression and the underlying molecular mechanisms. RR dose-dependently reduced the tubular cell injury, indicated by the decreased expression of kidney injury molecule 1 (KIM1). Furthermore, releases of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) stimulated by HF were strongly relieved by RR. Inflammatory response and pyroptosis were also identified to be induced by HF stimulation but were mitigated by RR in HK2 cells through repressing nuclear factor-κB (NF-κB) activation and NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. IR and lipogenesis due to HF exposure were also significantly ameliorated by RR in HK2 cells. Mechanistically, RNA-Seq analysis showed that RR strongly depressed interleukin-1 receptor-associated kinase-1 (IRAK1)-mediated NLRP3 inflammasome, pyroptosis, IR and lipid deposition. Importantly, IRAK1 overexpression almost diminished the beneficial effects of RR, while being rescued upon NLRP3 knockdown in HF-treated HK2 cells, revealing that RR performed its nephroprotective functions in diabetic kidney via inactivating the IRAK1-NLRP3 signaling pathway. Similarly, animal studies confirmed that RR supplementation efficiently ameliorated HFF-caused metabolic disturbance, IR, renal dysfunctions in mice and improved structural kidney damage. Consistently, RR consumption dramatically reduced lipid accumulation, inflammatory response and pyroptosis in kidney tissues of HFF-challenged mice mainly through repressing IRAK1-NLRP3 axis. Our results demonstrated that dietary supplementation with RR may serve as an IRAK1-NLRP3 inhibitor for preventing and treating diabetic nephropathy.
研究领域:
药理学
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分子生物学
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糖尿病学
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肾病学
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营养学
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Ping Guan,Zhaoxu Meng,Xinran Liu,Jiaxiang Mu,Zichun Gao,Xinrong Yu,He Lian
The complex, invasive, and metastatic nature of malignant tumors make the current treatment of patients challenging in advanced stages. The present study proposes a multi-effect synergistic biomimetic mineralization nanosystem ( [email protected] 4 ) to regulate tumor cell metabolism and relevant biological behaviors through glycolysis-oxidative stress-autophagy process. Bovine serum albumin complexed with lonidamine served as a template to induce the formation of iron phosphate mineralization in situ . After intratumoral administration, the released lonidamine inhibited hexokinase II and down-regulated the level of glycolysis, cutting off the energy and biosynthesis supply source for tumor growth. Ferric ions dissociated from biomineralization in acidic microenvironment converted reduced glutathione to oxidized glutathione, elevated oxidative stress and induced ferroptosis through chemokinetic reactions. The dissociated phosphate ions function as an autophagy inhibitor to block the protective autophagy cased by energy deprivation for efficacy enhancement. The up-regulation of Nrf2 and LC3 proteins, the down-regulation of HK2 and GPX4 proteins, and the increase of ROS level in tumors all confirmed this conclusion. Notably, the nanosystem also down-regulated the release of inflammatory factors (IL-6, IL-8) and metastasis-related proteins (N-Cadherine, Vimentin) simultaneously, effectively preventing distant lung metastasis of tumor. In summary, this biomineralization-based nanosystem exhibited powerful antitumor effects both in vitro and in vivo and provides a new perspective for addressing the dilemma of malignant tumor treatment.
研究领域:
癌症生物学
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药学
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纳米技术
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生物医学工程
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高影响因子
ONCOLOGY REPORTS
·
2020
·Vol. 44
·期 6
·2595-2609
·
IF 3.417
Gang Wang,Yang Yu,Yu‑Zhu Wang,Zhi‑Min Zhu,Pei‑Hao Yin,Ke Xu
Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA‑loaded nanoliposomes (BA‑NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA‑NLs in fatty acid metabolism‑mediated glycolysis, and investigate the role of key targets, such as acyl‑CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase‑1 (PFK‑1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA‑NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti‑CRC function of BA‑NLs. Moreover, the effects of BA‑NLs were further validated by demonstrating that the key targets of HK2, PFK‑1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA‑NLs, which play key roles in the inhibition of glycolysis and fatty acid‑mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.
研究领域:
肿瘤学
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药理学
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代谢
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PubMed
高影响因子
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