CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Zhongting Lv,Xiang Li,Hanning Wu,Xiaowen Zhang,Wangyang Hu,Yong Xu,Jie Zhang,Li Ren
Chronic stress is a major contributor to hippocampal neurotoxicity and cognitive dysfunction. However, mechanism-oriented interventions remain limited. Bilobalide is a chemically defined sesquiterpene lactone from Ginkgo biloba with reported neuroprotective activity. Nevertheless, its effect on chronic stress-induced cognitive injury and its relationship to glucocorticoid receptor (GR) signaling remain unclear. Here, we evaluated bilobalide in chronic restraint stress (CRS) mice and in corticosterone (CORT)-challenged HT22 hippocampal neurons. Bilobalide improved short-term recognition, long-term recognition, and spatial memory in CRS mice, and alleviated neuronal injury in the hippocampal CA1, CA3, and dentate gyrus regions. These effects were accompanied by reduced lipid peroxidation, recovery of antioxidant capacity, attenuation of systemic inflammatory cytokine release and hippocampal inflammatory gene expression, suppression of apoptosis-related signaling, and preservation of dendritic architecture, synaptic ultrastructure, and synaptic proteins. Bilobalide also restored hippocampal BDNF/TrkB/PI3K/Akt signaling. In vivo and in vitro fractionation/immunofluorescence experiments showed that bilobalide restrained stress-enhanced GR nuclear translocation, and GRE-reporter assays showed reduced GR transactivation. Molecular docking and cellular thermal shift assay supported cellular target engagement of GR by bilobalide. Importantly, GR knockdown blunted bilobalide-mediated rescue of oxidative injury and of BDNF/TrkB/PI3K/Akt-associated synaptic signaling in CORT-injured HT22 cells. These data indicate that bilobalide protects against chronic stress-induced hippocampal neurotoxicity and memory impairment, at least in part, by limiting maladaptive GR signaling and preserving neurotrophic-synaptic homeostasis. Bilobalide therefore merits further evaluation as a mechanistically defined lead compound for stress-associated cognitive dysfunction.
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BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Yu-jia Huo,Miao Wei,Xiao Fan,Li-wen Peng,Jing-chang Yuan,Si-si Tan,Xiao-chen Wang,Ruo-tong Ou-yang,Yi-jing Zhou,Yan-yu Pu,Xi Gao,Jun-qin Lei,Hong Li
Glaucoma is a prominent global cause of irreversible vision loss, fundamentally driven by the continuous degeneration and ultimate death of retinal ganglion cells (RGCs), in which persistent oxidative stress plays a pivotal role. While selenium (Se) offers robust endogenous antioxidant defense, the severe toxicity and narrow therapeutic window of inorganic selenium strictly limit its application. To overcome this critical bottleneck, chitosan-functionalized selenium nanoparticles (CS-SeNPs) are engineered. This strategic nanomodification effectively shields the inherent toxicity of free selenium while conferring improved colloidal stability and biocompatibility. Clinically, systemic Se levels in patients with primary open-angle glaucoma (POAG) are found to be significantly diminished compared to healthy controls. Mechanistically, transcriptome sequencing reveals that CS-SeNPs function through the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway to upregulate the downstream nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant axis, reducing intracellular oxidative stress and apoptosis. In vivo, an intravitreal administration strategy for CS-SeNPs is established. In a rat model of acute ocular hypertension (AOH), this targeted local delivery reduces oxidative damage, preserves retinal hierarchical architecture, and restores visual electrophysiological function. These findings identify systemic Se deficiency as a clinical hallmark of POAG and demonstrate that intravitreal CS-SeNPs offer a promising, intraocular pressure-independent nanotherapeutic strategy for glaucomatous neuroprotection.
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npj Science of Food
·
2026
·
IF 9.7
Shen Linyuan,Ma Jianfeng,Liang Shuang,Yang Yiting,Liao Tianci,Lei Yuhang,Chen Lei,Wang Yan,Zhao Ye,Niu Lili,Gan Mailin,Zhu Li
Diet derived extracellular vesicles (EV) can be absorbed and influence physiological processes. Herein, this study investigates the potential health impacts of extracellular vesicles in meat products. Experimental results showed the extracellular vesicles derived from cooked red meat (RM-EV) and white meat (WM-EV) were successfully isolated via ultra-high speed centrifugation. The median particle size of RM-EV is 137.5 nm and that of WM-EV is 116.1 nm. RM-EV and WM-EV are added to the drinking water of mice for ten weeks. The mice developed insulin resistance and abnormal lipid metabolism in the liver. The influences of RM-EV are more pronounced for mice than WM-EV. High-throughput sequencing indicated that ssc-miR-1 (52.05%) and scc-miR-133a-3p (14.21%) are the most abundant microRNA in RM-EV. However, the highest content of microRNA is gga-miR-133a-3p (44.16%) in WM-EV, followed by gga-miR-1 (21.58%). Therefore, the most abundant ssc-miR-1 in red meat EV (RM-EV-miR-1) was selected for in vitro studies. In vitro experiments revealed that RM-EV-miR-1 inhibited cell proliferation by targeting IGF1 in NCTC1469 liver cell. Besides, RM-EV-miR-1 exacerbates insulin resistance in NCTC1469 insulin resistance cell model by targeting PI3K/AKT signaling pathway. Our findings show that the differential health impacts of red and white meat may be partially attributed to the presence of EV. These results provide novel insights into dietary health from the perspective of EV.
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EUROPEAN JOURNAL OF MEDICAL RESEARCH
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2025
·Vol. 30
·期 1
·1-11
·
IF 3.4
Zhang Zihao,Ren Jiayi,Tang Ke,Hu Xinyi,Liu Jinhui,Li Chunming
Background Oral cancer (OC) is one of the major types of cancer and the most common cause of cancer-related mortality in Asia. In recent years, matrix stiffness in the tumor microenvironment has been found to play an important role in regulating tumor cell behavior. However, the regulatory mechanisms associated with matrix stiffness in OC cells remain unclear. Methods In this study, polyacrylamide gels with different stiffness were prepared to simulate low versus high matrix stiffness environments in tumor tissues by adjusting the acrylamide and cross-linker concentrations. Subsequently, the effects of different stiffness on OC cell survival, migration, invasion and invadopodia formation were explored based on cell counting kit-8 (CCK-8), Transwell and confocal microscopy. Meanwhile, the levels of markers relevant to phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), apoptosis (BAX and BCL2) as well as metastasis (Cadherin-1, CDH1; Cadherin-2, and CDH2) were calculated via western blotting and real-time quantitative PCR. Results According to the results, high matrix stiffness was seen to contribute to the increased number of migrated and invaded cells as well as the enhanced viability of OC cells, along with the aggravated invadopodia formation and the up-regulation in CDH2 and BCL2 levels yet the down-regulation in CDH1 and BAX levels. Elevated PI3K/AKT phosphorylation levels were also seen in high matrix stiffness-mediated OC cells, and the intervention using LY294002 could visibly overturned the effects of high matrix stiffness on the cell migration, invasion and invadopodia formation of OC cells. Conclusions This study reveals that matrix stiffness may enhance the invasiveness and anti-apoptotic ability of OC cells by activating the PI3K/AKT pathway, which provides a new idea for exploring the microenvironmental regulation of tumor mechanics and targeted intervention strategies.
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Results in Chemistry
·
2025
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IF 4.2
Dongqing He,Dongjun Liu,Zhuoyan Wu,Ruiguang Xiao,Wenjie Ruan,Zeqiang Lin,Qiuxia Chen,Chanling Yuan,Qiong Wu,Wenjie Mei
Acne is a chronic inflammatory skin disease that is highly prevalent in adolescents, and its recurrent flare-ups can affect facial aesthetics, severely impacting adolescents' mental health and quality of life. Screening for safer, more effective fruit acid molecules for daily acne treatment is crucial. This work examined potential mandelic acid derivatives. In a zebrafish model, mandelic acid showed a 78.17 % rate of inflammatory cell aggregation, outperforming supramolecular salicylic acid (86.96 % aggregation) at the same concentration. In a P. acnes -induced cell model, MMP9 protein expression was significantly upregulated in the model group. After treatment with mandelic acid, MMP9 expression decreased by 72.84 % compared to the model group, a better effect than that of supramolecular salicylic acid (36.78 %). Further mechanistic investigations indicate that mandelic acid may inhibit the PI3K/AKT signaling pathway activated by P. acnes , thereby blocking MAPK signaling and modulating MMP9 protein production, thereby averting the development of NLRP3 inflammatory vesicles. Mandelic acid has a favourable safety profile and notable anti-inflammatory properties, which can be further harnessed to mitigate acne in sensitive skin demographics, offering a novel approach to acne treatment.
研究领域:
皮肤病学
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炎症研究
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分子生物学
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药理学
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 5.4
Bin Yang,Qingqing Xia,Xinyu Ji,Ke Su,Tao Yu,Zihan Xiao,Chen Shi,Zichen Luo,Xuan Wang,Weichen Xu,Yanan Gao,Haibin Hua,Jinjun Shan
Ethnopharmacological relevance Ganjie Decoction (GJD), a traditional Chinese medicine (TCM) formula commonly used for respiratory diseases, has shown therapeutic potential against RSV pneumonia. However, its pharmacological mechanisms against respiratory syncytial virus (RSV) pneumonia are not fully understood. Aim of study This study aimd to characterize the active components of GJD and systematically investigate its therapeutic effects and underlying mechanisms in RSV-induced pneumonia. Materials and methods To evaluate the therapeutic efficacy of GJD in RSV-infected mice, we monitored body weight, performed qPCR, and conducted histopathological examination of lung tissues. The chemical constituents of GJD were characterized using UPLC-MS. Key bioactive compounds and their potential targets were predicted using network pharmacology and molecular docking. The underlying mechanisms were further elucidated using immunohistochemistry and western blotting. The interactions between GJD and the gut microbiota were explored using antibiotic depletion, fecal microbiota transplantation (FMT), metagenomic sequencing, and in vitro co-culture assays. Untargeted metabolomics was employed to assess GJD-induced metabolic alterations. Finally, the role of 4-hydroxyphenylacetic acid (4-HPA) was investigated through cell viability assays, immunofluorescence staining, and western blot analysis in vitro . Results GJD significantly mitigated weight loss, attenuated pulmonary viral load, and suppressed inflammation in RSV-infected mice. Network pharmacology and molecular docking revealed that specific compounds in GJD target the PI3K/AKT signaling pathway. This finding was validated by western blotting and immunohistochemistry, which demonstrated that GJD suppresses PI3K/AKT pathway activation, thereby attenuating apoptosis and ameliorating RSV-induced pneumonia. Notably, these protective effects were markedly attenuated in mice with depleted gut microbiota. Furthermore, the therapeutic effects of GJD against RSV pneumonia were transferable via gut microbiota transplantation. GJD restored RSV-induced dysbiosis of the gut microbiota, with Lactobacillus reuteri emerging as one of the most enriched microbes following treatment. Metabolomics analysis identified 4-HPA as a microbiota-dependent metabolite significantly upregulated by GJD. Remarkably, administration of 4-HPA reproduced GJD’s therapeutic effects in RSV-infected mice and activated the KEAP1/NRF2 antioxidant pathway, suggesting that 4-HPA functions as a key mediator of GJD’s anti-RSV activity. Conclusions These findings suggest that GJD alleviates RSV pneumonia through a synergistic mechanism that modulates the PI3K/AKT–apoptosis pathway, restores gut microbial balance, and normalizes metabolic disturbances. This study systematically elucidates the mechanistic basis underlying the therapeutic effects of GJD against RSV pneumonia.
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TISSUE & CELL
·
2025
·
IF 2.5
Yanfei Yang,Lili Yang,Yabin Li,Yanfen Wang
Background The gut microbiota is essential for the bidirectional communication between the gut and the brain. However, its specific role and underlying mechanisms in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remain largely unclear. Methods An anti-NMDAR encephalitis model was induced by GluN1 peptide immunization, and brain histopathology was assessed by hematoxylin-eosin staining. Behavioral performance was assessed through the Y-maze and open field tests. Flow cytometry was employed to quantify T follicular helper (Tfh) and T follicular regulatory (Tfr) cell populations. Enzyme-linked immunosorbent assay and western blot were used to assess inflammatory cytokines and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway-related protein levels, respectively. 16S rRNA sequencing and Helicobacter rodentium gavage (1.5 mL, 1×10¹¹ CFU/mL) were used to assess microbiota composition and bacterial function. Results 16S rRNA sequencing revealed a trend toward reduced gut microbial diversity in anti-NMDAR encephalitis mice. Helicobacter rodentium colonization further exacerbated behavioral deficits and inflammatory cell infiltration in the cerebral cortex. This was accompanied by a marked increase in tumor necrosis factor alpha (TNF-α) and interleukin (IL)-21 levels and a reduction in IL-10 concentrations in both cerebrospinal fluid and serum. Moreover, the Tfh/Tfr cell ratio was further elevated following Helicobacter rodentium exposure. Targeted suppression of the PI3K/AKT pathway with LY294002 significantly restored Tfh/Tfr balance and alleviated neurobehavioral impairments and cortical inflammation. Conclusion Helicobacter rodentium exacerbates anti-NMDAR encephalitis by inducing PI3K/AKT-mediated Tfh/Tfr imbalance, highlighting a potential therapeutic target in autoimmune encephalitis.
研究领域:
神经免疫学
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微生物组研究
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自身免疫性疾病
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分子信号通路
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炎症生物学
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JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Yan Zhang,Fuqing Yi,Ying He,Yidan Ma,Xinyi Mu,Yanqing Geng,Xin Yin,Rufei Gao,Liping Yan,Xuemei Chen,Junlin He
Dibutyl phthalate (DBP), a common environmental endocrine-disrupting chemical, is known to impair female reproduction, yet its specific effects on ovarian reserve and underlying epigenetic mechanisms are not fully understood. Here, using gestational exposure models ( in vivo ) and fetal ovarian culture models ( in vitro ), we show that gestational DBP exposure disrupts the ovarian reserve through a dual assault: impairing primordial follicle formation ("input") and, more critically, driving primordial follicle premature activation ("output"). Mechanistically, DBP induces METTL14-dependent m⁶A hypermethylation, which activates the PI3K-AKT-FOXO3a signaling axis to promote aberrant follicular activation. Knockdown of Mettl14 rescues this pathway activation and the follicular disruption. Long‑term follow‑up revealed that such precocious activation leads to progressive ovarian reserve depletion, culminating in a premature ovarian insufficiency (POI)-like phenotype with hormonal dysfunction, reduced oocyte quality, and compromised fertility in adult offspring. Collectively, these findings indicate that gestational DBP exposure activates the PI3K-AKT-FOXO3a signaling pathway via METTL14-mediated m⁶A modification, causing impaired follicle formation, follicular over-activation, and ultimately ovarian reserve depletion and a POI-like phenotype in offspring. This study reveals a novel m⁶A‑mediated epigenetic mechanism in plasticizer-induced ovarian toxicity, advancing our understanding of POI etiology and highlighting a significant environmental risk to female fertility.
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CHEMISTRY & BIODIVERSITY
·
2023
·Vol. 20
·期 4
·e202200523
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IF 2.9
Zhonghua An,Xuelin Feng,Mengjia Sun,Yifan Wang,Hongbo Wang,Yanling Gong
Chamomile essential oil (CEO) is extracted from chamomile and mainly used in aromatherapy. The chemical constituents and its antitumor activity on Triple-negative breast cancer (TNBC) was explored in the present study. Gas chromatography-mass spectrometry (GC/MS) was employed to analyze the chemical constituents of CEO. The cell viability, migration and invasion of TNBC cell MDA-MB-231 were measured using MTT, wound scratch and Transwell assay, respectively. The protein expression of PI3K/Akt/mTOR signaling pathway was determined by Western blot. CEO is rich in terpenoids (63.51 %), among which the identified terpenoids and their derivatives are mainly Caryophyllene (29.57 %), d-Cadinene (12.81 %), Caryophyllene oxide (14.51 %), etc. Three concentration of CEO (1, 1.5, 2 μg/mL) significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells with a dose dependent manner. Moreover, the phosphorylation of PI3K, Akt and mTOR was inhibited by CEO. The results revealed that there was abundant terpenoids in the CEO which account for 63.51 %. CEO significantly inhibited the proliferation, migration and invasion of MDA-MB-231 cells, exhibiting antitumor effect on TNBC. The antitumor effect of CEO might attribute to its inhibition on PI3K/Akt/mTOR signaling pathway. However, further study should be conducted in more TNBC cell lines and animal models to provide further evidence for TNBC treatment by CEO.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 46
·期 6
·764-772
·
IF 2
Xin Zhang,Zhifang Liang,Ying Zhou,Fang Wang,Shan Wei,Bing Tan,Yujie Guo
Diabetic peripheral neuropathy (DPN) is an early developing complication of diabetes mellitus associated with nerve dysfunction. Artesunate (ART), a natural compound extracted from the herb Artemisia annua L., was reported to benefit neural injury. However, whether ART has a role in preventing DPN is still unknown. In this study, a rat model of DPN with a high fat diet feeding and streptozotocin (STZ) injection was established. The findings indicated that ART treatment significantly ameliorated hyperglycemia-induced hot plate reaction latency (HPRL) decline, cold sensitivity and mechanical allodynia, and nerve injury by inhibiting sciatic nerve apoptosis. Further, ART restored high glucose (HG)-induced elevated apoptosis and deficient survival in rat neuronal Schwann cells, RSC96 cells. We demonstrated that ART promoted protein kinase B (AKT) phosphorylation as well as its downstream factor mammalian target of rapamycin (mTOR) in vivo and in vitro. Of note, the protective effects of ART in RSC96 cells under HG condition could be counteracted by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Taken together, ART mitigated hyperglycemia-induced nerve injury by suppressing apoptosis and promoting the viability of Schwann cells via the PI3K/AKT/mTOR signaling pathway.
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ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 44
·期 6
·1262-1276
·
IF 7.169
Song Qi-qi,Lin Li-ping,Chen Ya-li,Qian Jia-cheng,Wei Ke,Su Jian-wei,Ding Jian-hua,Lu Ming,Liu Yang,Tan Ren-xiang,Hu Gang
Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates’ efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC 50 values of 1.97, 1.84, and 2.03 μM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg −1 ·d −1 , i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.
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PHYTOMEDICINE
·
2022
·
IF 6.656
Zhonghao Li,Qinmei Sun,Qingyang Liu,Xinru Mu,Hui Wang,Han Zhang,Fenfen Qin,Qisheng Wang,Dengyun Nie,Anlong Liu,Qian Li,Jianjian Ji,Yongwei Jiang,Shengfeng Lu,Qian Wang,Zhigang Lu
Background Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression , addiction, tolerance, and severe immunosuppression . Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistμlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. Purpose To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. Methods Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). Results Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3 , and increased those of STAT3 and T-bet in the spleen . It improved immune function and reduced MRSA-induced lung inflammation. Conclusion Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection .
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