ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE
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2024
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IF 1.9
Guo Z,Qin Y,Li Y,Tang P
Objective Given the crucial role of the PI3K/Akt signaling pathway in chondrocyte survival and inflammation in osteoarthritis (OA), this study aimed to investigate the effects of Gu Bi Tang on chondrocyte proliferation, apoptosis, and inflammatory factor expression in a rat model of OA, with a focus on the PI3K/Akt signaling pathway. Methods Forty-five specific pathogen-free (SPF) C57 mice were randomly divided into three groups: the model group (Group A), the Gu Bi Tang group (Group B), and the Amfenac group (Group C), with 15 rats in each group. All 45 rats underwent anterior cruciate ligament transection (ACLT) surgery to establish an OA model. The ACLT procedure is a well-established method for inducing OA in rodents, as it leads to the destabilization of the knee joint and the development of degenerative changes characteristic of human OA. After 8 weeks of modeling, Group A rats received an equivalent volume of normal saline by gastric lavage, Group B rats were administered 13 mL/kg of Gu Bi Tang, and Group C rats received 19.5 mg/kg of Amfenac solution by gastric lavage. The dosages of Gu Bi Tang and Amfenac were selected based on previous studies examining the therapeutic effects of these interventions in rodent OA models. The gastric lavage frequency for all three groups was maintained at twice daily. The researchers analyzed cartilage morphological changes using toluidine blue staining, chondrocyte proliferation and apoptosis using the TUNEL method, and the expression of PI3K/AKT/mTOR proteins in chondrocytes using Western blotting. Additionally, the expression of inflammatory factors (TNF-α and IL-1β) in serum was measured using ELISA. Results Staining: Compared to the model group (Group A), both the Gu Bi Tang group (Group B) and the Amfenac group (Group C) showed significant improvement in cartilage tissue, with deeper toluidine blue staining. Toluidine blue staining is a marker of cartilage integrity and glycosaminoglycan content, indicating improved cartilage structure and composition in the treatment groups. Chondrocyte proliferation and apoptosis: Compared to the model group (Group A), both the Gu Bi Tang group (Group B) and the Amfenac group (Group C) significantly reduced chondrocyte apoptosis (P < .05). This reduction in chondrocyte death contributes to a healthier cartilage environment and helps prevent further cartilage degradation. Protein expression: In comparison to the model group (Group A), the expression of PI3K, AKT, and mTOR proteins in the joint cartilage of the Gu Bi Tang group (Group B) and the Amfenac group (Group C) significantly decreased, with the Amfenac group showing a greater reduction than the Gu Bi Tang group (P < .05). The inhibition of this detrimental PI3K/AKT/mTOR signaling pathway promotes chondrocyte survival and a more favorable cartilage homeostasis. Inflammatory factor expression: Prior to treatment, there was no significant difference in the expression levels of the inflammatory factors TNF-α and IL-1β in serum among the three groups (P > .05). However, after treatment, both the Gu Bi Tang group (Group B) and the Amfenac group (Group C) showed a significant reduction in the serum expression of TNF-α and IL-1β compared to the model group (Group A), with the Amfenac group showing a greater reduction than the Gu Bi Tang group (P < .05). This is important, as TNF-α and IL-1β are key pro-inflammatory cytokines that drive the destructive processes in osteoarthritis. Conclusion In summary, this study demonstrates that Gu Bi Tang exerts protective effects on chondrocytes in a rat model of osteoarthritis. Specifically, Gu Bi Tang was shown to inhibit chondrocyte apoptosis, reduce the expression of key proteins in the PI3K/AKT/mTOR signaling pathway, and decrease the levels of the pro-inflammatory cytokines TNF-α and IL-1β. These findings suggest that Gu Bi Tang could offer a novel therapeutic approach for osteoarthritis by modulating key signaling pathways and inflammatory responses. The ability of Gu Bi Tang to preserve chondrocyte viability and maintain a more favorable cartilage homeostasis makes it a promising candidate for further investigation as a potential treatment for osteoarthritis. Future studies should explore the precise mechanisms by which Gu Bi Tang exerts its beneficial effects and evaluate its efficacy in additional animal models and clinical settings.
研究领域:
药理学
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风湿病学
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骨科
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分子生物学
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炎症
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Du Hongxu,Li Zhangxun,Su Lijuan,He Zhengke,Tan Xiaoyan,Hou Fengzhi,He Tanjie,Pan Yu,Xu Shuang,Cao Liting,Dong Shiqi,Ma Yue
Objective: To investigate the anti-inflammatory activity and mechanism of Baicalin derivative (Baicalin butyl ester, BE).Methods: BE was synthesized and identified using UV-Vis spectroscopy, FT-IR spectroscopy, mass spectrometry (MS) and high-performance liquid chromatography (HPLC) methods. Its anti-inflammatory potential was explored by an in vitro inflammation model. Network pharmacology was employed to predict the anti-inflammatory targets of BE, construct protein-protein interaction (PPI) networks, and analysis topological features and KEGG pathway enrichment. Additionally, molecular docking was conducted to evaluate the binding affinity between BE and its core targets. qRT-PCR analysis was conducted to validate the network pharmacology results. The organizational efficiency was further evaluated through octanol-water partition coefficient and transmembrane activity analysis.Results: UV-Vis, FT-IR, MS, and HPLC analyses confirmed the successfully synthesis of BE with a high purity of 93.75%. In vitro anti-inflammatory research showed that BE could more effectively suppress the expression of NO, COX-2, IL-6, IL-1β, and iNOS. Network pharmacology and in vitro experiments validated that BE’s anti-inflammatory effects was mediated through the suppression of SRC, HSP90AA1, PIK3CA, JAK2, AKT1, and NF-κB via PI3K-AKT pathway. Molecular docking results revealed that the binding affinities of BA to the core targets were lower than those of BE. The Log p-value of BE (1.7) was markedly higher than that of BA (−0.5). Furthermore, BE accumulated in cells at a level approximately 200 times greater than BA.Conclusion: BE exhibits stronger anti-inflammatory activity relative to BA, possibly attributed to its better lipid solubility and cellular penetration capabilities. The anti-inflammatory mechanism of BE may be mediated through the PI3K-AKT pathway.
研究领域:
药理学
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化学
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分子生物学
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炎症研究
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DOI
PubMed
高影响因子
Food Bioscience
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2024
·
IF 4.8
Jindan Xiao,Liuming Xie,Bing Zheng,Wenjie Ma,Yi Chen,Jianhua Xie,Xiaobo Hu,Qiang Yu
Autophagy is pivotal for the management of intestinal homeostasis, modulation of intestinal immunity response and anti-microbial protection. Previous studies have documented the protective function of Polygonatum cyrtonema Saponin (PCS) against intestinal injury, but whether PCS modulated autophagy and its associated responses remained unknown. A model of dextran sodium sulfate (DSS)- elicited intestinal injury was employed to confirm this hypothesis. The results showed that PCS effectively relieved the typical symptoms of DSS-induced weight reduction, shortened colon length, and augmented disease activity index score, down-regulated organ indices, reduced hepatic oxidative stress, and inhibited excessive inflammatory mediators. Meanwhile, PCS intervention ameliorated the intestinal barrier dysfunction via promoting the differentiation of goblet cells and augmenting the expression of tight junction proteins (TJs). It also suppressed apoptosis in intestinal cells by altering the Bcl-2/Bax ratios and diminishing the expressions of Caspase-9 and Caspase-3. Additionally, PCS remarkably enhanced autophagy by modulating the PI3K/AKT/mTOR signal pathway. More importantly, the classical autophagy inducer rapamycin augmented the beneficial effects of PCS. In contrast, the autophagy inhibitor 3-methyladenine essentially eliminated the above effects, revealing a role for autophagy in the response. Further studies have demonstrated that PCS intervention improved the diversities of the intestinal flora, increased occupancy of beneficial bacteria in Lachnospiraceaeae and Akkermansia , which was closely associated with autophagy. Taken together, these findings demonstrated that PCS is a potential supplier of prebiotics by modulating immunity, repairing intestinal mucosal injury, regulating autophagy and intestinal flora, and autophagy is a key target for PCS-mediated intestinal barrier protection.
研究领域:
胃肠病学
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免疫学
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分子生物学
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药理学
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DOI
高影响因子
FEBS Journal
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2019
·Vol. 287
·期 9
·1816-1829
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IF 4.739
Man Zhang,Xiaoyao Ma,Honglei Xu,Wenbo Wu,Xin He,Xiaoying Wang,Min Jiang,Yuanyuan Hou,Gang Bai
Swertiamarin (SW), a representative component in Flos Lonicerae Japonicae , has been reported to exert significant activity in preventing infections. In this research, we aim to clarify the details of SW and its target to explore SW's underlying anti-inflammatory mechanisms. An azide labeled SW probe was synthesized for protein target fishing, and the results demonstrated that AKT could be captured specifically. Immunofluorescence colocalization with AKT was implemented by a click reaction of the SW probe and alkynyl CY5. The result showed that AKT was one of the targets of SW. Then, a competitive combination experiment using a set of AKT inhibitors and a membrane translocation experiment confirmed that SW might target the pleckstrin homology (PH) domain of AKT. This specific binding directly deactivated the phosphorylation of AKT on both Ser473 and Thr308, which induced the dephosphorylation of IKK and NF-κB. Finally, proinflammatory cytokines (TNF-α, IL-6, and IL-8) were suppressed both in cells and in acute lung injury animal model by targeting AKT-PH domain. This study demonstrated that SW functions as a natural AKT inhibitor and presents significant anti-inflammatory activity by directly regulating the AKT-PH domain and inhibiting downstream inflammatory molecules.
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PubMed
高影响因子
Materials Today Bio
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2024
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IF 8.7
Xiang Han,Feiyang Wang,Yuzhuo Ma,Xuerong Lv,Kewei Zhang,Yue Wang,Ke Yan,Youmin Mei,Xiaoqian Wang
Traditional fibrous membranes employed in guided tissue regeneration (GTR) in the treatment of periodontitis have limitations of bioactive and immunomodulatory properties. We fabricated a novel nTPG/PLGA/PCL fibrous membrane by electrospinning which exhibit excellent hydrophilicity, mechanical properties and biocompatibility. In addition, we investigated its regulatory effect on polarization of macrophages and facilitating the regeneration of periodontal tissue both in vivo and in vitro. These findings showed the 0.5%TPG/PLGA/PCL may inhibit the polarization of RAW 264.7 into M1 phenotype by suppressing the PI3K/AKT and NF-κB signaling pathways. Furthermore, it directly up-regulated the expression of cementoblastic differentiation markers (CEMP-1 and CAP) in periodontal ligament stem cells (hPDLSCs), and indirectly up-regulated the expression of cementoblastic (CEMP-1 and CAP) and osteoblastic (ALP, RUNX2, COL-1, and OCN) differentiation markers by inhibiting the polarization of M1 macrophage. Upon implantation into a periodontal bone defect rats model, histological assessment revealed that the 0.5%TPG/PLGA/PCL membrane could regenerate oriented collagen fibers and structurally intact epithelium. Micro-CT (BV/TV) and the expression of immunohistochemical markers (OCN, RUNX-2, COL-1, and BMP-2) ultimately exhibited satisfactory regeneration of alveolar bone, periodontal ligament. Overall, 0.5%TPG/PLGA/PCL did not only directly promote osteogenic effects on hPDLSCs, but also indirectly facilitated cementoblastic and osteogenic differentiation through its immunomodulatory effects on macrophages. These findings provide a novel perspective for the development of materials for periodontal tissue regeneration.
研究领域:
牙科材料
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组织工程
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免疫学
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再生医学
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DOI
PubMed
高影响因子
Nutrients
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2018
·Vol. 10
·期 10
·1366
·
IF 4.196
Jie Gao,Xin He,Yuejiao Ma,Xuezhi Zhao,Xiaotao Hou,Erwei Hao,Jiagang Deng,Gang Bai
Chlorogenic acid (CGA), a bioactive component in the human diet, is reported to exert beneficial effects on the regulation of glucose metabolism. This study was designed to investigate the specific target of CGA, and explore its underlying mechanisms. Beneficial effects of CGA in glucose metabolism were confirmed in insulin-treated human hepatocarcinoma HepG2 cells. Protein fishing, via CGA-modified functionalized magnetic microspheres, demonstrated the binding of CGA with protein kinase B (AKT). Immunofluorescence using a CGA molecular probe further demonstrated the co-localization of CGA with AKT. A competitive combination test and hampering of AKT membrane translocation showed that CGA might bind to the pleckstrin homology (PH) domain of AKT. The specific binding did not lead to the membrane translocation to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), but directly activated the phosphorylation of AKT on Ser-473, induced the phosphorylation of the downstream molecules, glycogen synthase kinase 3β (GSK3β) and forkhead box O1 (FOXO1), and improved glucose metabolism. Collectively, our data demonstrate that CGA exerts regulatory effects on glucose metabolism via direct targeting the PH domain of AKT. This study clarifies the mechanism of the potential benefits of nutrients containing CGA in the complementary therapy of glucose metabolism disorders.Keywords:chlorogenic acid;glucose metabolism;protein kinase B (AKT);pleckstrin homology (PH) domain;glycogen synthase kinase 3β (GSK3β);forkhead box O1 (FOXO1)
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高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2024
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IF 3.1
Sun Hui,Wang ZiTong,Tu BingHua,Shao ZiChen,Li YiDan,Han Di,Jiang YinJie,Zhang Peng,Zhang WeiChang,Wu YunYan,Wu XiaoMing,Liu Chi-Ming
Type 2 diabetes mellitus (T2DM) is a metabolic disease. Diabetes increases the risk of benign prostatic hyperplasia (BPH). Capsaicin is extracted from chili peppers and possesses many pharmacological properties, including anti-diabetic, pain-relieving, and anti-cancer properties. This study aimed to investigate the effects of capsaicin on glucose metabolism and prostate growth in T2DM mice and uncover the related mechanisms. Mice model of diabetes was established by administering a high-fat diet and streptozotocin. Oral administration of capsaicin for 2 weeks inhibited prostate growth in testosterone propionate (TP)-treated mice. Furthermore, oral administration of capsaicin (5 mg/kg) for 2 weeks decreased fasting blood glucose, prostate weight, and prostate index in diabetic and TP-DM mice. Histopathological alterations were measured using hematoxylin & eosin (H&E) staining. The protein expression of 5α-reductase type II, androgen receptor (AR), and prostate-specific antigen (PSA) were upregulated in diabetic and TP-DM mice, but capsaicin reversed these effects. Capsaicin decreased the protein expression of p-AKT, insulin-like growth factor-1 (IGF-1), IGF-1R, and the receptor for advanced glycation end products (RAGE) in diabetic and TP-DM mice. Capsaicin also regulated epithelial-mesenchymal transition (EMT) and modulated the expression of fibrosis-related proteins, including E-cadherin, N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-β1, and p-Smad in TP-DM mice. In this study, capsaicin alleviated diabetic prostate growth by attenuating EMT. Mechanistically, capsaicin affected EMT by regulating RAGE/IGF-1/AKT, AR, and TGF-β/Smad signalling pathways. These results provide with new therapeutic approach for treating T2DM or T2DM-induced prostate growth.
研究领域:
药理学
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内分泌学
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糖尿病
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前列腺健康
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信号转导
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
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IF 4.8
Kunmei Xie,Feibiao Wang,Yue Yang,Shoujie Pan,Junyao Wang,Nan Xiao,Xinyan Wang,Zhihao Ma,Xiaolong Xu,Zibo Dong
Sepsis-associated acute liver injury (ALI) is a deadly condition resulting from a systemic inflammatory response to liver cell damage and malfunction. Monotropein (MON) belongs to the iris group of compounds extracted from the natural product Mollen dae officinalis radix, which has strong anti-inflammatory and antioxidant pharmacological effects. The purpose of this study was to elucidate the underlying mechanism of MON in the treatment of sepsis ALI. In this study, an in vivo caecal ligation puncture (CLP)-induced ALI model and in vitro LPS-stimulated AML12 cells and RAW264.7 cells model were established. Additionally, a variety of experimental techniques, including CCK8, H&E staining, DHE probe labelling, biochemical, QPCR, and Western blotting and blocking tests, were used to explore the role of MON in ALI. The results showed that MON improved liver morphological abnormalities, oedema, histopathological injury, and elevated ALT and AST, providing a protective effect against ALI. MON reduced CYP2E1 expression, alleviated oxidative stress (downregulation of MDA levels and upregulation of GSH, CAT, and T-AOC levels) and ROS accumulation with the involvement of the NRF2-Keap-1 pathway. MON inhibited inflammation via the TLR4/NF-κB/NLRP3 inflammasome pathway. In addition, it activated the Akt (Ser473)/GSK3β (Ser9)/Fyn pathway and accelerated NRF2 nuclear accumulation; MK-2206 blockade reversed the NRF2 nuclear accumulation and anti-inflammatory function of MON. MON also restricted the mitochondrial apoptosis pathway, a process specifically blocked by MK-2206. In summary, we concluded that MON alleviated septic ALI by restricting oxidative stress, inflammation, and apoptosis via the AKT (Ser473)/GSK3β (Ser9)/Fyn/NRF2 pathway.
研究领域:
药理学
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免疫学
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
FEBS LETTERS
·
2018
·Vol. 593
·期 2
·175-186
·
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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DOI
PubMed
高影响因子
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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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2021
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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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高影响因子
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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高影响因子
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