FEBS LETTERS
·
2018
·Vol. 593
·期 2
·175-186
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IF 2.999
Shengnan Yang,Yuan Zhang,Fukui Shen,Xiaoyao Ma,Man Zhang,Yuanyuan Hou,Gang Bai
Baicalin is one of the main flavonoids of the dried root of Scutellaria baicalensis Georgi and is reported to exert beneficial effects on the regulation of glucose/lipid metabolism. However, understanding its specific target and unique mechanism for improving glucose utilization is a challenge. In this paper, target fishing with a baicalin probe reveals that baicalin interacts with AKT. An immunofluorescence assay further demonstrates the colocalization of baicalin with AKT in the cytoplasm. A competitive test and virtual docking show that baicalin might bind to the pleckstrin homology domain of AKT. This specific binding hampers AKT membrane translocation, activates the phosphorylation of AKT on Ser473, induces the downstream glycogen synthase kinase 3β activation, and affects glycogen synthesis.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yassmin Raafat Hassan,Riham A. El-Shiekh,Hala M. El Hefnawy,Osama G. Mohamed,Karema Abu-Elfotuh,Ahmed M. Hamdan,Alshaymaa Darwish,Ayah M.H. Gowifel,Ashootosh Tripathi,Camilia George Michael
Ethnopharmacological relevance Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as “African mango” or “bush mango”, belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health. Aim of the study The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction . Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat , metformin , and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways. Materials and methods Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days. Results More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 μg Gallic acid equivalent/mg extract and 8.039 ± 0.53 μg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways. Conclusion Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3β/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.
研究领域:
民族药理学
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药理学
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神经科学
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代谢组学
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分子生物学
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Journal of Functional Foods
·
2021
·
IF 4.451
Ge Fang,Chuanjing Cheng,Manqian Zhang,Xiaoyao Ma,Shengnan Yang,Xiaotao Hou,Jiagang Deng,Yuanyuan Hou,Gang Bai
Kaempferol and quercetin, as dietary flavonoids, are beneficial to diabetes risk reduction. Clarifying the mechanism of dietary flavonoids in improving glucose metabolism may meet the functional and nutritional requirements. In this paper, PCA revealed two glucuronides, kaempferol-3-glucuronide (K-3-G) and quercetin-3-glucuronide (Q-3-G), which were the primary metabolites. Target prediction, enzymatic activity, and AKT plasma translocation assays indicated that K-3-G and Q-3-G could target the AKT PH domain. Fluorescence spectrometry was used to measure the dissociation constants of K-3-G (K D = 27.6 μM) and Q-3-G (K D = 10.8 μM). Molecular docking provided interaction insights for K-3-G and Q-3-G with the AKT PH domain. K-3-G and Q-3-G activated the AKT/GSK3β phosphorylation, thereby improving glucose consumption. Our study demonstrates that the glucuronide metabolites of flavonoids directly target the AKT PH domain and activate AKT/GSK3β signal pathway, thereby improving glucose metabolism.
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International Journal of Electrochemical Science
·
2023
·
IF 1.5
Xia Wang,Li Hou,Ling-long Xu,Xiong Li,Huan Jiang,Wen-jie Zhou
In this paper, an inorganic-organic composite modification of nano-TiO 2 has been carried out using aluminum sulfate octahydrate and γ-aminopropyltriethoxysilane (KH550) to obtain AKT with good dispersion performance. The AKT-WPU composite coating with different amounts of nano-TiO 2 added was prepared by blending AKT with waterborne polyurethane (WPU). The nano-TiO 2 , before and after modification, was analyzed by Fourier transform infrared spectroscopy and indicates that alumina and KH550 can be successfully grafted onto the surface of nano-TiO 2 . Our thermogravimetric analysis shows that the heat resistance of the AKT-WPU composite coating was improved. The corrosion resistance of the AKT-WPU composite coatings was investigated by electrochemical impedance spectroscopy and polarization curves. Our results show that the addition of AKT significantly improves the corrosion resistance of the composite coating. The resistive modulus of the composite coating with 0.7% AKT addition amounted to 5.05×10 6 Ω. The corrosion current density is 5.21×10 -9 A, which is more than two orders of magnitude lower than that with the pure WPU coating. The corrosion inhibition efficiency can reach 99.54%. The coating was subjected to a long-term immersion test and observed by a scanning electron microscope. After immersion for 360 h, our results show that the coating still protected the stainless steel.
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Cells
·
2025
·Vol. 14
·期 13
·940
·
IF 5.2
Xuelian Zhang,Mengyang Zhang,Chunzhi Wang,Qingchuan Song,Haiyan Yang,Qi Tang,Qiaoling Zhao,Jing Wang,Chuanying Pan
Chlorpyrifos (CPF) has been extensively utilized in recent decades due to its highly efficient insecticidal properties. However, the widespread use of pesticides has posed new challenges to male reproduction. This study aims to explore the potential molecular mechanisms of male reproductive decline induced by CPF. We employ flow cytometry, qRT-PCR, Western blot, RNA sequencing, and bioinformatics analysis to investigate the potential molecular mechanisms involved in CPF-induced male reproductive damage in GC2spdcells. Our results revealed that after 24 h of CPF treatment, the cell viability, cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation of GC2spdcells were significantly affected in vitro. RNA sequencing analysis data indicated that a total of 626 genes were differentially expressed compared to the DMSO group, especially forEfcab6,Nox3, andCmpk2. These differential genes were mainly enriched in signaling pathways such as PI3K-AKT and glutamine metabolism. In addition, further validation through qRT-PCR, Western blot, and experiments involving the inhibition of intracellular ROS generation with N-acetylcysteine collectively confirmed that CPF induces male reproductive damage through the ROS/AKT/Efcab6 pathway. These studies elucidate potential targets and molecular mechanisms underlying CPF-induced male infertility, providing a theoretical basis for the prevention of male reproductive damage caused by pesticide residues.
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CELL BIOLOGY INTERNATIONAL
·
2019
·Vol. 44
·期 2
·402-411
·
IF 2.127
Guiling Zhu,Bin Ma,Penghong Dong,Junjun Shang,Xiaochuan Gu,Ying Zi
Melatonin has been reported to participate in bone metabolism in recent studies. However, the underlying mechanism in melatonin-mediated osteoblastic differentiation remains largely unknown. The aim of this study is to investigate the role of melatonin in osteoblastic differentiation. In the present study, additional melatonin significantly promoted osteoblastic differentiation of MC3T3-E1 cells as evidenced by increased messenger RNA (mRNA) levels of osteogenic markers, alkaline phosphatase (ALP), collagen type I α1 chain, osteocalcin, and runt-related transcription factor 2 (Runx2). It was noteworthy that the expression level of platelet-derived growth factor subunit B (PDGFB) and content of its homodimer PDGF-BB were remarkably increased after melatonin administration. Moreover, the mRNA levels of phosphorylated PDGFRβ (PDGF receptor β) and Akt, a serine/threonine-specific protein kinase, were significantly upregulated in melatonin-treated MC3T3-E1 cells determined by a real-time polymerase chain reaction. Besides, by performing alizarin red staining, osteoblastic differentiation of MC3T3-E1 cells was conspicuously promoted by melatonin, which could be partially attenuated by crenolanib, a PDGFR inhibitor. Similarly, results from immunofluorescence and western blot assay showed that melatonin-induced upregulation of Runx2 and phosphorylated Akt was suppressed by crenolanib. Akt inhibition by MK-2206 also suppressed osteoblastic differentiation. Furthermore, by in vivo assay, additional melatonin promoted osteoblastic differentiation in mice with femoral fracture, and obvious callus formation was observed in melatonin-treated mice 5 weeks after fracture. Melatonin supplement also inhibited osteoclastic differentiation in mice. All statistical analysis was performed using GraphPad Prism and a P < 0.05 was deemed to be significant. To summarize, we demonstrate that melatonin promotes osteoblastic differentiation in MC3T3-E1 cells and enhances fracture healing in mouse femoral fracture model and regulates PDGF/AKT signaling pathway.
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CELLULAR AND MOLECULAR LIFE SCIENCES
·
2024
·Vol. 81
·期 1
·1-14
·
IF 6.2
Ren Xuan,Huang Shihai,Xu Jianchun,Xue Qingsong,Xu Tairan,Shi Deshun,Ma Shinan,Li Xiangping
BRG1 has been found to promote the generation of induced pluripotent stem cells (iPSCs) by regulating epigenetic modifications or binding to transcription factors, however, the role of BRG1 on the cellular metabolism during reprogramming has not been reported. In this study, we found that BRG1 improved the efficiency of porcine iPSC generation, and upregulated the expression of pluripotency-related factors. Further analysis revealed that BRG1 promoted cellular glycolysis, and increased levels of glycolysis-related metabolites. It enhanced the transcriptional activity of glycolysis-related gene HK2, PKM2, and PFK-1 promoters, and decreased the enrichment of H3K9me3 in glycolysis- and pluripotency-related gene promoters. BRG1 also increased the phosphorylation level at the Ser473 site of AKT protein. The specific PI3K/AKT signaling pathway inhibitor, LY294002, impaired the generation of porcine iPSCs, downregulated the expression of pluripotency-related factors, and inhibited cellular glycolysis, overexpressing BRG1 rescued those changes caused by LY294002 treatment. In addition, the glycolysis inhibitor 2-DG and BRG1 inhibitor PFI-3 had similar effects to LY294002. The above results suggest that overexpression of BRG1 promotes the generation of porcine iPSCs by facilitating glycolytic reprogramming through the PI3K/AKT signaling pathway.
研究领域:
干细胞生物学
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代谢
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表观遗传学
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细胞重编程
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AQUACULTURE NUTRITION
·
2022
·
IF 3.781
Shaoyang Zhi,Liping Yang,Guokun Yang,Chaobin Qin,Xiao Yan,Mingming Niu,Wenlei Zhang,Mingyu Liu,Mengjuan Zhao,Guoxing Nie
Irisin plays a crucial role in the glucose metabolism of mammals and fish. However, the mechanism by which irisin regulates hepatic glucose metabolism is not entirely known. To clarify irisin’s function and underlying mechanisms in common carp glucose metabolism, the FNDC5 expression patterns were detected after insulin/glucagon injection, long-term high-glucose, and high-fat diet feeding. In vivo, the activity of PFK and the synthesis of liver glycogen were significantly increased, while the enzyme activity of PEPCK was reduced after intraperitoneal injection with irisin. In contrast, irisin siRNA attenuated the brain and liver FNDC5a and FNDC5b expression, and the serum glucose was increased. Glut2, gs, hk, and pfk were considerably downregulated in the brain and liver, while pygl, pepck, and g6pase were remarkably upregulated after siRNA treatment. In vitro, irisin activates the phosphorylation level of AMPK and PI3K/Akt in primary hepatocytes. Compound C and wortmannin inhibit AMPK and PI3K/Akt, reversing irisin-induced expression of g6pase, fbpase, pepck, gk, gs, pfk, hk, and gsk3b. At the same time, compound C attenuated irisin-induced expression of pi3k and akt. Our research reveals the mechanisms of irisinA and irisinB as glucose metabolism regulators in teleost for the first time.
研究领域:
分子生物学
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内分泌学
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代谢
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鱼类生理学
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REPRODUCTIVE BIOMEDICINE ONLINE
·
2026
·
IF 3.9
Yongfeng Wu,Xiaoye Ye,Ou Jin,Beibei Liu,Shuchen Yu,Aolin Zheng,Fei Lv,Yingling Zheng,Fengjuan Liu,Song Xu,Ke Zhang,Chunyu Jin,Jinyi Tong
Research Question Does pyruvate carboxylase (PC) drive endometriosis progression and, if so, what is the underlying mechanism? Design We examined PC expression in clinical endometrial specimens via immunohistochemistry. After PC knockdown or overexpression in immortalized human endometriotic stromal cells (ihESCs), cell proliferation and migration were assessed using 5-ethynyl-2′-deoxyuridine (EdU), colony formation and Transwell assays. Quasi-targeted metabolomics, RNA sequencing and western blotting were adopted to explore downstream molecular changes, and an allogeneic mouse endometriosis model was applied for in vivo functional verification. Results First, we found that PC expression was significantly upregulated in eutopic and ectopic endometrial tissues of patients with endometriosis compared with controls (p=0.022 and p<0.001, respectively). Then, in vitro and in vivo experiments showed that PC promoted the progression of endometriosis. In addition, quasi-targeted metabolomics showed that PC knockdown decreased the abundance of glycolytic metabolites in ihESCs. Furthermore, RNA sequencing and western blotting identified that PC enhanced the activity of the phosphoinositide 3-kinase (PI3K)-AKT pathway. Using AKT agonist (SC79) and inhibitor (AZD5363), we found that PC modulates glycolytic enzyme expression and endometriosis progression through the AKT pathway. Finally, PC inhibitors ZY-444 and octyl gallate attenuated the progression of endometriosis. Conclusions PC is significantly upregulated in eutopic and ectopic endometrial tissues from endometriosis patients, and modulates glycolytic enzyme expression as well as endometriosis progression via activation of the AKT pathway. Our findings provide mechanistic insight into the metabolic reprogramming underlying endometriosis pathogenesis.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 3.7
Shi Chenjun,Lu Conghua,Lin Caiyu,Lian Shaopan,Luo Huanyu,You Ziyin,Li Li
Defective alveolar re-epithelialization following acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represents a critical barrier to clinical recovery. Intrinsic signals that could be harnessed to speed this repair remain poorly defined. Endogenous electric fields (EFs) arise immediately after epithelial injury and are recognized as mediators of cell migration and morphogenesis, but their impact on lung epithelial proliferation is unknown. Here we demonstrate that physiological-strength direct-current EFs (100–200 mV/mm) are potent pro-mitogenic signals for both human bronchial (BEAS-2B) and murine alveolar (MLE-12) epithelial cells. Within a custom live-cell electrotactic chamber, EFs exposure for 4 h doubled EdU incorporation, increased Ki-67 expression, and elevated real-time mitotic events without altering spindle orientation. RNA-seq analysis of BEAS-2B cells with EFs exposure identified 1,447 differentially expressed genes, with significant enrichment of the PI3K/AKT signaling pathway and immunoblotting further confirmed rapid phosphorylation of PI3K p85 (Tyr458)/p55 (Tyr199) and AKT (Ser473). Selective inhibition with Alpelisib or LY294002 abolished pathway activation and fully suppressed the pro-proliferative effect of EFs. Furthermore, EFs triggered AKT-dependent phosphorylation of glycogen synthase kinase-3β (GSK3β) at Ser9, while blockade with the GSK3β inhibitor Tideglusib or upstream PI3K inhibitors suppressed this event and attenuated EF-induced proliferation. Taken together, our findings delineate the PI3K/AKT/GSK3β signaling axis through which EFs enhance pulmonary epithelial proliferation. This work identifies physiological EFs as previously unrecognized regenerative cues in the lung and underscores bioelectric modulation as a promising therapeutic strategy to accelerate alveolar repair in ALI/ARDS.
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CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 11
·e70655
·
IF 5
Mao‐mei Song,Ting‐yan Chen,Shi‐na Song,Ying‐jie Gao,Chang‐xin Li,Sui‐yi Xu
CXCL10 activates the PI3K/AKT signaling pathway, promoting the release of inflammatory factors, including IL‐1β, IL‐6, and TNF‐α, and is thus involved in the pathogenesis of VM.
研究领域:
神经病学
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分子生物学
·
免疫学
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JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Xiao-chen Li,Shuai Wang,Xin-xin Yang,Tian-jiao Li,Jia-xing Gu,Lin Zhao,Yong-rui Bao,Xian-sheng Meng
Ethnopharmacological relevance At present, the colorectal cancer (CRC) is a malignant tumor of the colon and rectum that is often found at the junction of the two, and it will invade many visceral organs and organizations, causing very serious damage to the body of the patient. Patrinia villosa Juss. (P.V), is a well-known traditional chinese medicine (TCM), and is recorded in the Compendium of Materia Medica as a necessary article for the treatment of intestinal carbuncle . It has been incorporated into traditional cancer treatment prescriptions in modern medicine. While the mechanism of action of P.V in the treatment of CRC remains unclear. Aim of the study: To investigate P.V in treating CRC and clarify the underlying mechanism. Materials and methods This study was based on Azoxymethane (AOM) combined with the Dextran Sulfate Sodium Salt (DSS)-induced CRC mouse model to clarify the pharmacological effects of P.V. The mechanism of action was found by metabolites and metabolomics. The rationality of metabolomics results was verified through the clinical target database of network pharmacology , and find the upstream and downstream target information of relevant action pathways. Apart from that, the targets of associated pathways were confirmed, and the mechanism of action was made clear, using quantitative PCR (q-PCR) and Western blot . Results The number and the diameter of tumors were decreased when mice were treated with P.V. P.V group section results showed newly generated cells which improved the degree of colon cell injury. Pathological indicators presented a trend of recovery to normal cells. Compared to the model group, P.V groups had significantly lower levels of the CRC biomarkers CEA, CA19-9, and CA72-4. Through the evaluation of metabolites and metabolomics, it was found that a total of 50 endogenous metabolites had significant changes. Most of these are modulated and recovered after P.V treatment. It alters glycerol phospholipid metabolites, which are closely related to PI3K target, suggesting that P.V can treat CRC though the PI3K target and PI3K/Akt signaling pathway. q-PCR and Western blot results also verified that the expression of VEGF, PI3K, Akt, P38, JNK, ERK1/2, TP53, IL-6, TNF- α and Caspase-3 were significantly decreased, whereas that of Caspase-9 was increased after treatment. Conclusion P.V is dependent on PI3K target and PI3K/Akt signaling pathway for CRC treatment.
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