MICROCHEMICAL JOURNAL
·
2022
·
IF 5.304
Qingqing Yao,Jiahuan Chen,Xuechao Li,Wen Yang,Jianan Ning,Qi Liang,Qian Li
The development of site-selective covalent protein immobilization strategies is crucial for many protein-based bioanalytical assays. Herein, we proposed a label-free, site-selective, covalent immobilization strategy for the functionalization of PPARγ on GW9662 modified macroporous silica gels . The gels were characterized by X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM). Molecular docking in combination with competitive study, adsorption energy distribution (AED) calculation, and frontal analysis were used to investigate the binding of ligands with GW9662 occupied PPARγ. Docking results indicated that rosiglitazone , pioglitazone , and gensenoside Rh1 could cooperatively bind to the receptor with GW9662. Competitive studies revealed that the three ligands bond with PPARγ through the same site in the presence of GW9662. AED calculation showed one type of binding site for the three ligands on the receptor. Due to the presence of GW9662, the affinities of the three ligands ((2.35 ± 0.05) × 10 5 M −1 for rosiglitazone, (1.27 ± 0.02) × 10 5 M −1 for pioglitazone, and (3.18 ± 0.13) × 10 5 M −1 for gensenoside Rh1) with PPARγ were one or two orders of magnitude smaller than the literature reported values. The good performance of the immobilized PPARγ provided an opportunity for application in receptor-ligand interactions and cooperative partner screening. Our strategy is, therefore, a promising way to realize the label-free, covalent immobilization of functional proteins.
研究领域:
生物化学
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分析化学
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分子生物学
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蛋白质工程
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色谱学
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产品关联
DOI
高影响因子
Journal of Functional Foods
·
2024
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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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DOI
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2024
·Vol. 43
·期 1
·1-27
·
IF 11.4
Shan Junqi,Li Xinyu,Sun Runqi,Yao Yao,Sun Yan,Kuang Qin,Dai Xianling,Sun Yanlai
Background The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients. Methods Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. Results To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis. Conclusions We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.
研究领域:
癌症生物学
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分子生物学
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脂质代谢
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Pei-Yu Dong,Shuai Yuan,Yu-Mei Chen Yan,Yu Chen,Yue Bai,Yang Dong,Yin-Yin Li,Wei Shen,Xi-Feng Zhang
Iron deficiency is a common nutritional issue that seriously affects male reproductive health. Lotus root polysaccharide iron (LRPF), a novel nutritional supplement, may ameliorate the damage caused by iron deficiency, however, the mechanism is unclear. In this study, we comprehensively determined the benefits of LRPF on reproduction in iron-deficient mice by integrating transcriptomics, microbiomics and serum metabolomics. Microbiomics showed that LRPF could restore changes to the intestinal microbiota caused by iron deficiency. Metabolomics results showed that LRPF stabilised steroid hormone and fatty acid metabolism in iron-deficient mice, reduced the content of ethyl chrysanthemumate (EC) and ameliorated the reproductive impairment. The transcriptomic analysis showed that LRPF regulated steroid hormone synthesis and the peroxisome proliferator-activated receptor (PPAR) signalling pathway in iron-deficient mice. In vitro experiments showed that LRPF could promote steroid hormone synthesis in Leydig cells by activating PPARγ. In conclusion, this study highlights the advantage of LRPF to improve testicular development.
研究领域:
营养学
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生殖生物学
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分子生物学
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转录组学
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代谢组学
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微生物组学
✓ 已验证
DOI
PubMed
高影响因子
CELL CYCLE
·
2022
·
IF 5.173
Feng Zhang,Peng Liu,Zhaopeng He,like Zhang,Xinqi He,Feng Liu,Jinsheng Qi
Crocin (CRO) is feasible in alleviating atherosclerosis (AS), the mechanism of which was therefore explored in the study. High-fat diet (HFD)-induced apolipoprotein E-deficient (ApoE−/−) mice and lysophosphatidic acid (LPA)-treated macrophages received CRO treatment. Treated macrophage viability was determined via MTT assay. In both murine and macrophage, the lipid level and total Cholesterol/Cholesteryl l Ester (TC/CE) levels were quantified by oil-red-O staining and ELISA, respectively. Lipid droplet, aortic plaque formation and collagen deposition were detected via Oil-red-O staining, hematoxylin–eosin staining and Masson staining, respectively. Liver X Receptor-α (LXR-α), Peroxisome Proliferator-Activated Receptor γ (PPARγ), CD68, PCSK9, CD36, ATP Binding Cassette Subfamily A Member 1 (ABCA1), phosphorylated (p)-AKT, and AKT expressions were detected via Western blot, the former three also being detected using Immunohistochemistry and the first being measured by qRT-PCR. CRO decreased HFD-induced weight gain, ameliorated the abnormal serum lipid levels of HFD-treated mice, and inhibited aortic plaque formation and lipid deposition, and increased collagen fibers, with upregulated high-density lipoprotein-cholesterol (HDL-C) and downregulated TC and low-density lipoprotein-cholesterol (LDL-C). CRO alleviated the HFD-induced upregulations of CD68, PCSK9 and CD36 as well as downregulations of PPARγ/LXR-α, ABCA1 and AKT phosphorylation. In LPA-treated macrophages, CRO alone exerted no effect on the viability yet inhibited the lipid droplets formation and downregulated TC/CE levels. Silent LXR-α reversed the effect of CRO on the lipid droplets formation and levels of lipid metabolism-related factors. CRO ameliorated AS by inhibiting foam cells formation and promoting reverse cholesterol transport via PPARγ/LXR-α.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Open Life Sciences
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2024
·Vol. 19
·期 1
·
IF 1.7
Jingxin Cui,Liwei Xu,Yimeng Sun,Lingfei Dai,Yuxiu Mo,Keli Yun,Yifei Chen,Linglin Chen
Neuroinflammation, characterized by microglial activation and the subsequent secretion of inflammatory cytokines, plays a pivotal role in neurodegenerative diseases and brain injuries, often leading to neuronal damage and death. Alleviating neuroinflammation has thus emerged as a promising strategy to protect neurons and ameliorate neurodegenerative disorders. While peroxisome proliferator-activated receptor gamma (PPARγ) agonists have demonstrated potential therapeutic actions on neuroinflammation, their prolonged use, such as with rosiglitazone, can lead to cardiac risks and lipid differentiation disorders. In this study, we investigated the effects of a newly synthesized PPARγ agonist, VSP-2, on secretion of inflammatory cytokines in BV2 cells. Treatment with VSP-2 significantly reduced the mRNA and protein levels of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Furthermore, VSP-2 attenuated the phosphorylation of nuclear factor kappa B (NF-κB) (65 kD) and IκBα, as well as the nuclear translocation of NF-κB (65 kD). Additionally, the use of PPARγ small interfering RNA was able to attenuate the effects of VSP-2 on proinflammatory cytokines and the NF-κB pathway. In conclusion, our findings suggest that VSP-2 effectively suppressed the expressions of IL-1β, IL-6, and TNF-α via the PPARγ/NF-κB signaling pathway. Given its potential therapeutic benefits, VSP-2 may emerge as a promising candidate for the treatment of neurodegenerative diseases or brain injuries associated with neuroinflammation.
研究领域:
神经科学
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药理学
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炎症
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神经退行性疾病
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DOI
PubMed
高影响因子
JOURNAL OF ANIMAL SCIENCE
·
2024
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IF 2.7
Ma Zifeng,Li Qiao,Xu Hongmei,Li Yueyue,Wang Shujin,Xiong Yan,Lan Daoliang,Li Jian,Xiong Xianrong,Fu Wei
Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 μM and 20 μM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.
研究领域:
兽医学
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毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2025
·
IF 6.1
Wenhui Yan,Xin Cui,Tingli Guo,Na Liu,Zhuanzhuan Wang,Yuzhuo Sun,Yuanrui Shang,Jieyun Liu,Yuanyuan Zhu,Yangyang Zhang,Lina Chen
Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD.Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway.Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 00, 000–000.
研究领域:
肝病学
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内分泌学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Shufeng Wu,Xiang Kuang,Haizhao Song,Zhigang Liu,Ling Xiong,Bo Ren,Fang Wang,Xinchun Shen,Luanfeng Wang
Limosillactobacillus reuteri ( L. reuteri ) is known to play a beneficial role in various aspects of human health, including diabetes, inflammatory bowel disease, and neurological disorders. However, its role in regulating obesity-induced metabolic disorders remains poorly understood. We demonstrate that administering L. reuteri C501 to male mice for 10 weeks significantly alleviates high-fat diet (HFD)-induced obesity and related metabolic disorders. Treatment with L. reuteri C501 led to reduced body weight gain, improved insulin sensitivity, and attenuated inflammatory responses. Moreover, the treatment activated the aryl hydrocarbon receptor (AhR) and the circadian rhythm regulator brain and muscle ARNT-like protein 1 (Bmal1)-two key players in immune function and energy metabolism-thereby influencing lipid metabolism in HFD-fed mice. In addition, L. reuteri C501 modulated gut microbiota composition and enhanced the production of indole derivatives. Supplementation with indole-3-lactic acid (ILA), one such derivative, also improved obesity outcomes in HFD-fed mice. Notably, administering L. reuteri C501 at zeitgeber time 0 (ZT0, the beginning of the light cycle) resulted in stronger therapeutic effects, suggesting that timing of intake may critically influence its efficacy. These findings highlight L. reuteri C501 as a promising probiotic intervention for obesity, with chronobiological factors playing a key role in optimizing its metabolic benefits.
研究领域:
微生物学
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代谢病学
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免疫代谢
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分子营养学
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昼夜节律生物学
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肠道微生物组学
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转化医学
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产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Chenying Zeng,Linjian Chen,Jiajie Lin,Zipeng Xiao,Qingqiang Tu,Wenhui Yu,Weihao Zhang,Qibo Li,Yanfeng Wu,Zhongyu Xie,Ziji Zhang
Background The shift in BMSC differentiation potential toward adipogenesis at the expense of osteogenesis is a critical mechanism underlying reduced bone formation in osteoporosis. Necroptosis has been implicated as a key driver of bone-fat imbalance in osteoporosis, though its mechanisms remain unclear. Taraxasterol (TAX), a bioactive triterpenoid derived from Taraxacum officinale , exhibits antitumor, antioxidant, and immunomodulatory properties. However, its potential role in osteoporosis has not yet been explored. Objective This study aimed to investigate whether TAX alleviates osteoporosis by regulating necroptosis and osteogenic–adipogenic differentiation in BMSCs, and to elucidate the underlying molecular mechanisms. Methods An ovariectomized (OVX) mouse model of osteoporosis was established for in vivo evaluation. Treatment groups received daily oral administration of TAX (5 or 20 mg/kg), with estradiol (E₂, 10 μg/kg) serving as a positive control. Bone microarchitecture and therapeutic response were assessed via micro-CT and immunohistochemistry, while femoral necroptosis and differentiation markers were evaluated by immunostaining. For in vitro studies, BMSCs isolated from osteoporosis patients were treated with the necroptosis inducer TSZ (TNF-α, SM-164, Z-VAD-FMK), with or without TAX. Flow cytometry was used to analyze the phenotype of MSCs. To identify molecular targets and mechanisms, an integrated approach combining network pharmacology, RNA sequencing, SPR assays, and molecular docking was employed. Subsequent analyses included western blotting, PI staining, and RNA interference to assess TAX-regulated necroptosis and PI3K/AKT/PPARγ pathway activity. ARS and ORO staining were employed to analyze osteogenic and adipogenic differentiation, respectively, and mitochondrial function was evaluated with TMRE and MitoSOX Red probes. Results TAX (20 mg/kg) significantly ameliorated bone loss in OVX mice, suppressed femoral necroptotic signaling, and reversed osteogenic–adipogenic imbalance in OVX-derived BMSCs. In vitro , TAX pretreatment attenuated TSZ-induced differentiation imbalance and necroptosis in patient-derived BMSCs and mitigated mitochondrial damage. Integrated network pharmacology and RNA sequencing revealed that TAX targets the PI3K/AKT/PPARγ axis. Immunohistochemical analysis demonstrated upregulation of the PI3K/AKT/PPARγ axis in the femurs of OVX mice following TAX administration. Molecular docking and SPR assays confirmed effective binding between TAX and PI3K. The protective effects of TAX were abolished by the PI3K inhibitor LY294002. Furthermore, TAX enhanced the rebalancing of osteogenic–adipogenic differentiation in PPARγ-silenced BMSCs. Conclusion Our study reveals for the first time that TAX restores osteogenic-adipogenic equilibrium in OP-BMSCs and promotes bone regeneration through PI3K/AKT/PPARγ activation and mitochondrial protection-mediated suppression of necroptosis. These results position TAX as a promising therapeutic candidate for osteoporosis.
研究领域:
药理学
·
分子生物学
·
内分泌学
·
干细胞研究
·
骨代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NUTRITION
·
2023
·
IF 4.4
Jiabao Tang,Xiaohua Li,Wei Li,Chun Cao
Objective Enteral nutrition (EN) is the key therapy in septic patients. Different formulas of EN have various effects on gastrointestinal sepsis. Therefore, we investigated the effects of EN supplemented with octanoic acid (OA) on lipopolysaccharide (LPS) induced intestinal injury and explored the potential mechanism. Methods First, to investigate the effects of EN supplemented with OA on LPS-induced intestinal injury, rats were randomly divided into four groups: the sham, LPS, LPS + EN, and LPS + EN + OA groups. Then, to explore whether EN supplemented with OA can prevent LPS-induced intestinal injury via the PPARγ/STAT-1/MyD88 pathway, rats were randomly divided into five groups: the sham, LPS, LPS + EN + OA, LPS + EN + OA +SR202, and LPS + pioglitazone groups. All rats received nutritional support for three days. We examined the serum levels of inflammatory factors, pathological changes, goblet cell density, intestinal tight junction protein expression, and the PPARγ/STAT-1/MyD88 pathway in the ileum and colon. In addition, the effect of OA on intestinal epithelium injury was also explored in vitro. Results EN supplemented with OA significantly decreased the serum levels of inflammatory factors and prevented intestinal barrier dysfunction compared with EN alone (P < 0.05). Inhibiting the PPARγ/STAT-1/MyD88 pathway exacerbated effects of EN supplemented with OA on intestinal injury (P < 0.05). Activation of the PPARγ/STAT-1/MyD88 pathway prevented intestinal injury (P < 0.05). OA also exerted a similar effect on intestinal epithelium injury in vitro. Conclusion EN supplemented with OA prevents LPS-induced intestinal injury via the PPARγ/STAT-1/MyD88 pathway.
研究领域:
营养学
·
胃肠病学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Jianv Wang,Jing Jia,Qingqing He,Yang Xu,Hongye Liao,Xia Xiong,Li Liu,Changzhen Sun
Recent advancements in tumour-targeted therapies and immunotherapy offer hope to patients with various malignancies. However, the uncontrolled growth and metastatic infiltration of malignant tumours remain a huge therapeutic challenge. Therefore, this study aimed to develop an integrated multifunctional diagnostic and treatment reagent IR-251 that can not only be used for tumour imaging but also to inhibit tumour growth and metastasis. Besides, our results showed that IR-251 targeted and damaged the mitochondria in cancer cells via organic anion-transporting polypeptides . Mechanistically, IR-251 induced ROS overproduction by inhibiting PPARγ and then inhibiting the β-catenin signalling pathway and downstream protein molecules related to the cell cycle and metastasis. Moreover, the excellent anti-tumour proliferation and metastasis ability of IR-251 were verified in vitro/in vivo . And histochemistry staining revealed that IR-251 inhibited tumour proliferation and metastasis, which showed no significant side effect. In conclusion, this novel, multifunctional, mitochondria-targeting near-infrared fluorophore probe IR-251 has great potential in achieving accurate tumour imaging and inhibiting tumour proliferation and metastasis, and the underlying mechanism of action of IR-251 is mainly via the PPARγ/ROS/β-catenin pathway.
研究领域:
癌症生物学
·
药理学
·
分子生物学
·
免疫治疗
·
医学成像
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）