ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
·
2025
·
IF 4.8
Xiaoqiang Liu,Luojia Liu,Qiaoling Wang,Lufan Xia,Fangqing Zuo,Jinrui Yang,Kaibang Zheng,Yunfan Tang,Jingjing Guo,Xiaoping Yu,Boye Qi,Hanghang Zhou,Ying Chen,Jiaping Zhang,Xuanfen Zhang
Skin cutaneous melanoma (SKCM), the most aggressive form of cutaneous malignancy globally, remains poorly understood in terms of its molecular drivers. Although the copper metabolism MURR1 domain (COMMD) protein family has been associated with oncogenesis, its functional relevance in SKCM is undefined. In this study, we identified COMMD4 as a prognostic biomarker of SKCM and showed that it is positively correlated with the adverse clinical outcomes of patients. COMMD4 gene knockout (COMMD4-KO) impaired the proliferative, migratory, and invasive capacities of SKCM cells in vitro and suppressed xenograft tumor growth in vivo. Mechanistically, COMMD4-KO induced G2/M phase arrest by disrupting p21-CDK1-cyclinB1 and impeded epithelial-mesenchymal transition (EMT) by reversing the E/N cadherin switch. We also demonstrate that COMMD4 activates PI3K-AKT signaling by binding PI3K-p85 to release PI3K-p110, thereby driving G2/M transition and EMT. Reactivation of PI3K-AKT signaling in COMMD4-KO cells rescued oncogenic phenotypes. By integrative Connectivity Map analysis and functional validation, we identified triamterene as a pharmacological inhibitor targeting the COMMD4-PI3K-AKT axis, which suppressed the progression of SKCM effectively in vitro and vivo. Our findings establish the COMMD4-PI3K-AKT axis as a novel and critical regulator of SKCM progression and repurpose triamterene as a promising therapeutic agent against SKCM. Graphical COMMD4 activates the PI3K-AKT signaling through binding PI3K-p85 to release PI3K-p110, driving the G2/M phase transition via p21-CDK1/cyclin B1 axis and facilitating the EMT by switching cadherin expression from the E to the N type, ultimately promoting the progression of SKCM.
研究领域:
肿瘤学
·
分子生物学
·
癌症信号通路
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药理学
·
皮肤病学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
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
·
化学
·
分子生物学
·
炎症研究
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
·
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
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
Materials Today Bio
·
2024
·
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
·
组织工程
·
免疫学
·
再生医学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
·
IF 3.118
Yan-dan Zhou,Jin-gang Hou,Wei Liu,Shen Ren,Ying-ping Wang,Rui Zhang,Chen Chen,Zi Wang,Wei Li
Although ginsenoside Rg3 was isolated as a major component of Korea red ginseng and confirmed to exert potential hepatoprotective effect on acetaminophen (APAP)-induced liver injury via induction of glutathione S-transferase (GST) in vitro, the in vivo hepatoprotective effect of Rg3 and the underlying molecular mechanism of action remain unclear. The current study was aimed to explore whether 20( R )-Ginsenoside Rg3 (20( R )-Rg3) could alleviate acetaminophen-induced liver injury in mice and to determine the involvement of PI3K/AKT signaling pathway . Our findings demonstrated that a single injection of APAP (250 mg/kg) increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β); such increases were attenuated by pretreatment of mice with 20( R )-Rg3 for seven days. The depletion of glutathione (GSH), generation of malondialdehyde (MDA) and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP exposure were also inhibited by 20( R )-Rg3 pretreatment. Moreover, 20( R )-Rg3 pretreatment significantly alleviated APAP-induced apoptosis , necrosis, and inflammatory infiltration in liver tissues. Importantly, 20( R )-Rg3 effectively attenuated APAP-induced liver injury in part via activating PI3K/AKT signaling pathway. In summary, 20( R )-Rg3 exerted liver protection against APAP-caused hepatotoxicity evidenced by inhibition of oxidative stress and inflammatory response, alleviation of hepatocellular necrosis and apoptosis via activation of PI3K/AKT signaling pathway, showing potential as a novel therapeutic agent to prevent liver damage.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
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
·
神经科学
·
代谢组学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ARCHIVES OF MICROBIOLOGY
·
2024
·Vol. 206
·期 6
·1-11
·
IF 2.3
Zhuang Cuicui,Zhang Ruoqing,Bai Jiangang,Zhang Xinying,Zhao Jinhui
Escherichia coli ( E. coli ) can induce severe clinical bovine mastitis, which is to blame for large losses experienced by dairy farms. Macrophage polarization into various states is in response to pathogen infections. Lycopene, a naturally occurring hydrocarbon carotenoid, relieved inflammation by controlling M1/M2 status of macrophages. Thus, we wanted to explore the effect of lycopene on polarization states of macrophages in E. coli -induced mastitis. Macrophages were cultivated with lycopene for 24, before E. coli inoculation for 6 h. Lycopene (0.5 μmol/L) significantly enhanced cell viabilities and significantly reduced lactic dehydrogenase (LDH) levels in macrophages, whereas 2 and 3 μmol/L lycopene significantly enhanced LDH activities. Lycopene treatment significantly reduced the increase in LDH release, iNOS, CD86, TNF-α, IL-1β and phosphatase and tensin homolog (PTEN) expressions in E. coli group. 0.5 μmol/L lycopene significantly increased E. coli -induced downregulation of CD206, arginase I (ARG1), indoleamine 2,3-dioxygenase (IDO), chitinase 3-like 3 (YM1), PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, jumonji domain-containing protein-3 (JMJD3) and interferon regulatory factor 4 (IRF4) levels. Moreover, Ginkgolic acid C17:1 (a specific PTEN inhibitor), 740YPDGFR (a specific PI3K activator), SC79 (a specific AKT activator) or CHPG sodium salt (a specific NF-κB activator) significantly decreased CD206, AGR1, IDO and YM1 expressions in lycopene and E. coli -treated macrophages. Therefore, lycopene increased M2 macrophages via inhibiting NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to E. coli infection in macrophages. These results contribute to revealing the pathogenesis of E. coli -caused bovine mastitis, providing the new angle of the prevention and management of mastitis.
研究领域:
免疫学
·
微生物学
·
药理学
·
细胞生物学
·
兽医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
·
内分泌学
·
代谢
·
鱼类生理学
✓ 已验证
DOI
高影响因子
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2023
·Vol. 26
·期 5
·106558-106558
·
IF 5.8
Xuelian Zhang,Ming Li,Wenjie Li,Linxiu Yue,Taiyuan Zhang,Qi Tang,Naidan Zhang,Xianyong Lan,Chuanying Pan
Chlorpyrifos (CPF) has been shown to have male reproductive toxicity in mice and rat. However, the association of CPF and male reproduction in pigs remains unknown. Therefore, this study attempts to investigate the damage of CPF on male reproduction in pigs and its potential molecular mechanisms. First, ST cells and porcine sperms were treated with CPF and then cell proliferation, apoptosis, motility of sperm, and oxidative stress levels were examined, respectively. Meanwhile, RNA sequencing was performed on ST cells before and after the treatment of CPF. The results of experiments in vitro showed that CPF had broad-spectrum toxic effects on ST cells and porcine sperms. The RNA-sequencing data and WB results indicated that CPF may regulate cell survival through the PI3K-AKT pathway. In conclusion, this study may lay the foundation for improving male fertility in pigs and provide theoretical information for human infertility.
研究领域:
生殖毒理学
·
分子生物学
·
动物科学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）