Frontiers in Pharmacology
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2024
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IF 4.4
Huang Yuechang,Zhang Xingmin,Li Qian,Zheng Wende,Wu Panpan,Wu Rihui,Chen Wen-Hua,Li Chen
Type 2 diabetes mellitus is regarded as a chronic metabolic disease characterized by hyperglycemia. Long-term hyperglycemia may result in oxidative stress, damage pancreatic β-cell function and induce insulin resistance. Herein we explored the anti-hypoglycemic effects and mechanisms of action of N-p-coumaroyloctopamine (N-p-CO) in vitro and in vivo. N-p-CO exhibited high antioxidant activity, as indicated by the increased activity of SOD, GSH and GSH-Px in HL-7702 cells induced by both high glucose (HG) and palmitic acid (PA). N-p-CO treatment significantly augmented glucose uptake and glycogen synthesis in HG/PA-treated HL-7702 cells. Moreover, administration of N-p-CO in diabetic mice induced by both high-fat diet (HFD) and streptozotocin (STZ) not only significantly increased the antioxidant levels of GSH-PX, SOD and GSH, but also dramatically alleviated hyperglycemia and hepatic glucose metabolism in a dose-dependent manner. More importantly, N-p-CO upregulated the expressions of PI3K, AKT and GSK3β proteins in both HG/PA-induced HL-7702 cells and HFD/STZ-induced mice. These findings clearly suggest that N-p-CO exerts anti-hypoglycemic and anti-oxidant effects, most probably via the regulation of a PI3K/AKT/GSK3β signaling pathway. Thus, N-p-CO may have high potentials as a new candidate for the prevention and treatment of diabetes.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Lianhua Tang,Juan Deng,Pi Shi,Siyuan Zou,Hongyan Ran,Fei Yin,Jianhui Liu
Rosmarinic acid (RA), a polyphenolic compound, exhibits diverse pharmacological activities, including anti-inflammatory, antioxidant, and antitumor effects. Despite its therapeutic potentials, the mechanisms underlying its efficacy in ulcerative colitis (UC), a chronic inflammatory bowel disease characterized by intestinal epithelial barrier dysfunction, remain incompletely elucidated. This study investigates RA's protective effects in UC using complementary in vivo and in vitro models. In a dextran sulfate sodium (DSS)-induced murine colitis model, RA administration significantly attenuated disease severity, mitigating weight loss, preventing colon shortening, and reducing histopathological inflammatory infiltration. RA restored intestinal barrier integrity via upregulation of key tight junction proteins such as ZO-1, occludin, claudin-1 in colonic tissues. Mechanistic analyses in lipopolysaccharide (LPS)-stimulated NCM460 human colonic epithelial cells revealed that RA inhibited phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, as evidenced by reducing AKT phosphorylation (p-AKT), while enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological PI3K inhibition with LY294002 abolished RA-induced upregulation of Nrf2 and TJPs, confirming the PI3K/AKT/Nrf2 axis as the central signaling cascade mediating RA's protective effects. Collectively, these findings elucidate a novel mechanism by which RA preserves intestinal barrier integrity through PI3K/AKT/Nrf2 axis modulation and propose a targeted therapeutic strategy for UC management.
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BIOFACTORS
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2024
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IF 5
Yining Lei,Manqin Li,Xinran Liu,Lu Zhang,Ruyi Zhang,Fei Cai
Despite the observation of diabetes-induced brain tissue damage and impaired learning and memory, the underlying mechanism of damage remains elusive, and effective, targeted therapeutics are lacking. Notably, the NLRP3 inflammasome is highly expressed in the hippocampus of diabetic individuals. Nerolidol, a naturally occurring compound with anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic option for metabolic disorders. However, the ameliorative capacity of nerolidol on diabetic hippocampal injury and its underlying mechanism remain unclear. Network pharmacology and molecular docking was used to predict the signaling pathways and therapeutic targets of nerolidol for the treatment of diabetes. Then established a diabetic rat model using streptozotocin (STZ) combined with a high-fat diet and nerolidol was administered. Morris water maze to assess spatial learning memory capacity. Hematoxylin and eosin and Nissl staining was used to detect neuronal damage in the diabetic hippocampus. Transmission electron microscopy was used to detect the extent of damage to mitochondria, endoplasmic reticulum (ER) and synapses. Immunofluorescence was used to detect GFAP, IBA1, and NLRP3 expression in the hippocampus. Western blot was used to detect apoptosis (Bcl-2, BAX, and Cleaved-Caspase-3); synapses (postsynaptic densifying protein 95, SYN1, and Synaptophysin); mitochondria (DRP1, OPA1, MFN1, and MFN2); ER (GRP78, ATF6, CHOP, and caspase-12); NLRP3 inflammasome (NLRP3, ASC, and caspase-1); inflammatory cytokines (IL-18, IL-1β, and TNF-α); AKT (P-AKT); and mitogen-activated protein kinase (MAPK) pathway (P-ERK, P-p38, and P-JNK) related protein expression. Network pharmacology showed that nerolidol's possible mechanisms for treating diabetes are the MAPK/AKT pathway and anti-inflammatory effects. Animal experiments demonstrated that nerolidol could improve blood glucose, blood lipids, and hippocampal neuronal damage in diabetic rats. Furthermore, nerolidol could improve synaptic, mitochondrial, and ER damage in the hippocampal ultrastructure of diabetic rats by potentially affecting synaptic, mitochondrial, and ER-related proteins. Further studies revealed that nerolidol decreased neuroinflammation, NLRP3 and inflammatory factor expression in hippocampal tissue while also decreasing MAPK pathway expression and enhancing AKT pathway expression. However, nerolidol improves hippocampal damage in diabetic rats cannot be shown to improve cognitive function. In conclusion, our study reveals for the first time that nerolidol can ameliorate hippocampal damage, neuroinflammation, synaptic, ER, and mitochondrial damage in diabetic rats. Furthermore, we suggest that nerolidol may inhibit NLRP3 inflammasome and affected the expression of MAPK and AKT. These findings provide a new experimental basis for the use of nerolidol to ameliorate diabetes-induced brain tissue damage and the associated disease.
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高影响因子
Journal of Translational Medicine
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2024
·Vol. 22
·期 1
·1-19
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IF 6.1
Liu Nannan,Fan Xuefei,Shao Yubao,Chen Suhuan,Wang Taorong,Yao Tao,Chen Xiaoyu
Background and purposeInterstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway.Methods We established an arthritis model by combining chicken type II collagen and complete Freund’s adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD.Results Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD.Conclusion In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.Graphical Abstract
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高影响因子
BIOLOGICAL PROCEDURES ONLINE
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2024
·Vol. 26
·期 1
·1-15
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IF 3.7
Wang Huizhi,Min Jingyu,Ding Yuntao,Yu Zhengyue,Zhou Yujing,Wang Shunyu,Gong Aihua,Xu Min
Background Gastric cancer (GC) is a common malignancy and a leading cause of cancer-related death with high morbidity and mortality. Methyl-CpG binding domain protein 3 (MBD3), a key epigenetic regulator, is abnormally expressed in several cancers, participating in progression and metastasis. However, the role of MBD3 in GC remains unknown. Methods MBD3 expression was assessed via public databases and validated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The prognosis of MBD3 was analysed via bioinformatics based on the TCGA dataset. The migration, invasion and proliferation of GC cells were examined by transwell, wound healing, cell counting kit (CCK)-8, colony-formation and xenograft mouse models. Epithelial-mesenchymal transition (EMT) and phosphatidylinositide 3-kinases/ protein Kinase B (PI3K/AKT) pathway markers were evaluated by Western blotting. RNA sequencing was used to identify the target of MBD3. Results MBD3 expression was higher in GC tissues and cells than in normal tissues and cells. Additionally, high MBD3 levels were associated with poor prognosis in GC patients. Subsequently, we proved that MBD3 enhanced the migration, invasion and proliferation abilities of GC cells. Moreover, western blot results showed that MBD3 promoted EMT and activated the PI3K/AKT pathway. RNA sequencing analysis showed that MBD3 may increase actin γ1 (ACTG1) expression to promote migration and proliferation in GC cells. Conclusion MBD3 promoted migration, invasion, proliferation and EMT by upregulating ACTG1 via PI3K/AKT signaling activation in GC cells and may be a potential diagnostic and prognostic target.
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LIFE SCIENCES
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2019
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IF 3.448
Zhaopeng Yan,Bin Zang,Xiaoying Gong,Jiangyue Ren,Rui Wang
Aims Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. Main methods Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. Key findings MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. Significance MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.
研究领域:
分子生物学
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病理学
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药理学
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Biomaterials Research
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2025
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IF 9.6
Jian Wu,Minghui Liu,Meng Gao,Yongchao Li,Youjie Zhang,Liang Tang,Hao Yu,Zhangcheng Liao,Yu Cui,Feng Zeng,Hequn Chen,Zewu Zhu
Although tea consumption has been suggested to affect kidney stone formation, epidemiological evidence remains inconsistent, and the underlying molecular mechanisms are unclear. To assess the association between tea intake and kidney stone risk, we initially conducted a prospective cohort analysis of 481,393 participants from the UK Biobank and a 2-sample Mendelian randomization (MR) analysis. Our findings revealed that heavy tea drinkers (>5 cups/day) had a significantly reduced risk of kidney stones (hazard ratio: 0.79, 95% confidence interval [CI]: 0.72 to 0.86, P < 0.001), and MR analyses confirmed a causal association (inverse variance weighted OR: 0.45, 95% CI: 0.32 to 0.62, P < 0.001). We next explored the effect of epigallocatechin gallate (EGCG), the main bioactive component in tea, on calcium oxalate (CaOx) stone formation. EGCG was found to inhibit the glucose-regulated protein 94/phosphatidylinositol 3-kinase/protein kinase B (GRP94/PI3K/AKT) pathway in human proximal renal tubular epithelial cells, thereby attenuating CaOx crystal-induced oxidative stress and inflammation, and inhibiting crystal-cell adhesion. This finding aligned with the observation that the activated GRP94/PI3K/AKT pathway was positively associated with inflammation-related molecules in renal papillary tissues of CaOx stone formers. Moreover, to enhance renal targeting and therapeutic potential, we synthesized cell membrane-coated EGCG-loaded poly(lactic-co-glycolic acid) (TP-EGCG) nanoparticles, which enhanced renal EGCG delivery and substantially reduced CaOx crystal deposition in a mouse model of CaOx nephrolithiasis. In conclusion, tea consumption protects against kidney stone formation, an effect exerted by EGCG through the GRP94/PI3K/AKT axis, and our novel TP-EGCG nanoparticles show strong potential for targeted prevention and treatment.
研究领域:
肾脏病学
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分子生物学
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药理学
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营养流行病学
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纳米医学
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信号转导
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高影响因子
CELL AND TISSUE RESEARCH
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2019
·Vol. 378
·期 1
·113-125
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IF 3.36
Zheng Rongzong,Huang Shuming,Zhu Junkun,Lin Wei,Xu Huan,Zheng Xiang
Rotator cuff tears (RCTs), the most common tendon injury, are always accompanied by muscle atrophy, which is characterized by excessive protein degradation. Autophagy–lysosome systems are the crucial proteolytic pathways and are activated in atrophying muscle. Thus, inhibition of the autophagy–lysosome pathway might be an alternative way to minimize skeletal muscle atrophy. In this present study, combined with a tendon transection-induced rat model of massive rotator cuff tears, HE staining and transmission electron microscopy methods, we found leucine supplementation effectively prevented muscle atrophy, muscle injury and autophagosome formation. Utilizing immunoblotting, we discovered that leucine supplementation is able to inhibit the rise in autophagy-related protein expression (including LC3, Atrogin-1, MuRF1, Bnip3 and FoxO3) driven by tendon transection. The PI3K/AKT/mTOR pathway that was essential in autophagosome formation and autophagy was blocked in atrophying muscle and reactivated in the presence of leucine. Once administrated with LY294002 (PI3K inhibitor) and Rapamycin (mTOR inhibitor), leucine mediated by the anti-atrophic effects was nearly blunted. These results suggest that leucine potentially attenuates tendon transection-induced muscle atrophy through autophagy inhibition via activating the PI3K/AKT/mTOR pathway.
研究领域:
骨骼肌生物学
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药理学
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分子生物学
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高影响因子
ONCOLOGY REPORTS
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2016
·Vol. 36
·期 4
·2160-2168
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IF 2.486
Ming Liu,Jiwei Wang,Qichao Qi,Bin Huang,Anjing Chen,Xingang Li,Jian Wang
Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 µM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism. Decreases in viability and proliferation reached ~50% for both cell lines with 50 µM NC at 24 h as assessed by cell viability Cell Counting Kit-8 (CCK-8) and EdU assays. In wound closure and Transwell assays, migration and invasion were inhibited at 50 µM after 24 h (~20 and 80%, respectively; P<0.05). ATP and L-lactate levels were also decreased after treatment with NC (50 µM, 24 h; P<0.05 and P<0.01, respectively). Finally, in western blot analysis, phosphorylation of Akt and mTOR was suppressed by NC, but partially restored when cells were treated simultaneously with a novel Akt activator, SC79. Partial restoration was also observed in viability/proliferation (U251 and U87, ~15 vs. 40%; NC vs. NC + SC79; P<0.05) and invasion (U251 and U87, ~30 vs. 60%; NC vs. NC + SC79; P<0.05). Our results demonstrated that NC inhibits development of GBM by targeting the PI3K/Akt/mTOR signaling pathway and provides a potential therapeutic agent for the treatment of GBM.
研究领域:
肿瘤学
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细胞生物学
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药理学
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高影响因子
Quantitative Imaging in Medicine and Surgery
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2025
·Vol. 16
·期 1
·18
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IF 2.3
Xi Weizhe,Liu Fenfang,Zhong Guangen,Chen Fen,Xie Yin,Lai Meilian,He Qiting,Lu Yiqing,Zhang Jiping,Chen Ying,Meng Luo,Yang Lu
Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that leads to cartilage degradation and bone destruction, significantly impacting daily life. Melittin acupoint injection (MAI) is a promising traditional Chinese medicine treatment, but its molecular mechanisms are not fully understood. This study aimed to investigate the therapeutic effects of MAI on RA and elucidate its underlying mechanisms. Methods A collagen-induced arthritis (CIA) mouse model was established using bovine type II collagen, administered every other day for 28 days. The mice were randomly divided into a CIA model group (MO group), melittin acupoint subcutaneous injection group (ST group), melittin acupoint intramuscular injection group (IT group), and methotrexate group (MTX group), with an additional normal control group (NC group) established. Each group contained 8 mice, all of which were treated for 28 days. Therapeutic outcomes were assessed by measuring body weight, swollen joint count (SJC), arthritis index (AI), ankle circumference, and plantar thickness. Radiological and histological changes were analyzed with micro-computed tomography (CT) imaging and pathological staining. Cytokine levels were measured via enzyme-linked immunosorbent assay (ELISA), and autophagy levels were assessed using immunofluorescence staining. The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway and autophagy status were examined through western blot (WB) and immunofluorescence techniques. Results MAI significantly improved clinical symptoms in CIA mice by reducing plantar thickness, AI scores, and swollen joints (P<0.05). Histopathological analysis showed decreased inflammatory cell infiltration, synovial proliferation, and cartilage damage (P<0.01). Micro-CT and immunohistochemistry revealed reduced inflammation, bone destruction, and cartilage erosion, along with decreased tumor necrosis factor-α (TNF-α) expression (P<0.05). MAI also lowered serum levels of interleukin (IL)-1β (P<0.05), IL-17A, and TNF-α (P<0.01), while increasing IL-10 levels (P<0.05). Immunofluorescence indicated increased microtubule-associated protein 1 light chain 3 beta (LC3B) fluorescence intensity (P<0.05). WB analysis showed elevated levels of Unc-51-like autophagy activating kinase 1 (ULK1), beclin-1 (P<0.01), and microtubule-associated protein 1 light chain 3 II (LC3II) (P<0.05), and reduced phosphorylation of PI3K, AKT, and mTOR (P<0.05). Conclusions MAI alleviates RA symptoms by inhibiting the PI3K/AKT/mTOR pathway and promoting autophagy.
研究领域:
风湿病学
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分子医学
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中医中药
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免疫学
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信号转导
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
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IF 5.895
Xiaofei Zhou,Bowei Zhang,Xiuli Zhao,Yongxi Lin,Yuan Zhuang,Jingting Guo,Shuo Wang
Hyperuricemia is an independent hazard factor of renal injury and can induce renal fibrosis, promoting the development of chronic kidney disease (CKD). This study aimed to explore the probability of chlorogenic acid (CGA) as a potential substance for preventing hyperuricemia nephropathy (HN). Pretreatment with CGA downregulated SUA, BUN, and CR levels, relieved oxidative stress and inflammatory response, alleviated kidney fibrosis, and contributed to the prevention of HN. In the gut microbiota, Blautia, Enterococcus, and Faecalibaculum related to trimethylamine N-oxide (TMAO) synthesis were significantly increased in HN rats. In addition, it showed a significant increase in serum TMAO content in HN rats. However, CGA regulated the cascade response of the microbiota-TMAO signaling to reverse the increase of serum TMAO. CGA also decreased the protein expression of protein kinase B (AKT) phosphorylation, phosphatidylinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) by reducing the production of TMAO. CGA delayed kidney fibrosis in HN rats as evidenced by regulating the cascade response of the microbiota-TMAO-PI3K/AKT/mTOR signaling pathway. In summary, CGA can be an excellent candidate for HN prevention.
研究领域:
药理学
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肾病学
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微生物学
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分子生物学
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病理生理学
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2017
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IF 3.671
Jing-yi Zhang,Ying Guo,Jin-ping Si,Xiao-bo Sun,Gui-bo Sun,Jing-jing Liu
Dendrobium officinale is one valuable traditional Chinese medicine, which has skyscraping medicinal value. Polysaccharide is the main active ingredient in D. officinale ; its antioxidant activity is a hot research topic nowadays. Oxidative stress plays an important role in the pathological progress of a variety of cardiovascular disease, as one of key factors of cardiomyocyte apoptosis. This research adopts a model of H 2 O 2 induction-H9c2 cardiomyocytes apoptosis, aiming to study the effect of Dendrobium officinale Polysaccharide (DOP-GY) for cardiomyocyte apoptosis caused by oxidative stress and its possible mechanism. Our results showed that pretreatment of DOP-GY (low dose: 6.25 μg/mL, medium dose: 12.5 μg/mL, high dose: 25 μg/mL) followed by a 2 h incubation with 200 μM H 2 O 2 elevated the survival rate, cutted the LDH leakage, reduced lipid peroxidation damage, improved the activity of the endogenous antioxidant enzymes. In addition, the pretreatment of DOP-GY significantly inhibited the production of ROS, declined of the mitochondrial membrane potential, down-regulated pro-apoptosis protein and up-regulated anti-apoptosis protein. The protective effect was correlated with the PI3K/Akt and MAPK signal pathway. Collectively, these observations suggest that DOY-GY has the potential to exert cardioprotective effects against H 2 O 2 -induced H9c2 cardiomyocyte apoptosis.
研究领域:
药理学
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心脏病学
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分子生物学
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高影响因子
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