INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
·
IF 4.7
Wenyang Zhou,Zhenhao Liu,Xichuan Qiu,Minghao Tian,Baoqiang He,Chao Tang,Qiang Tang,Rupei Ye,Dejun Zhong,Yehui Liao
Following spinal cord injury (SCI), pyroptosis plays a significant role in regulating neuroinflammation during the secondary phase of injury. Although 1,8-cineole possesses anti-inflammatory effects, its role in SCI and underlying molecular mechanisms remains unclear. This study revealed that 1,8-cineole promoted motor function recovery in spinal cord-injured rats, reduced NLRP3 inflammasome-mediated microglial pyroptosis and activation, enhanced neuronal regeneration, and suppressed neuronal apoptosis and glial scar formation. Network pharmacology analysis showed that 1,8-cineole targets the PI3K/AKT and P38 MAPK pathways to inhibit microglial activation and pyroptosis. Finally, using a conditional co-culture system, we demonstrated that 1,8-cineole-treated microglia facilitated neuronal regeneration while inhibiting apoptosis. These findings indicate that 1,8-cineole promotes functional recovery post-SCI by protecting neurons by suppressing microglial pyroptosis and activation through the PI3K/AKT and P38 MAPK axes.
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CELL BIOLOGY INTERNATIONAL
·
2022
·Vol. 46
·期 12
·2220-2231
·
IF 4.473
Maomao Miao,Yang Zhang,Xuping Wang,Shanshan Lei,Xiaowen Huang,Luping Qin,Dan Shou
Diabetic osteoporosis (DOP) is a disorder of bone metabolism induced by multiple mechanisms. Previous studies have revealed that microRNAs (miRNAs) play crucial roles in bone metabolism. MiRNA-144-5p has been proven to participate in the regulation of osteoblast activities; however, its specific mechanism in DOP has not been elucidated. This study investigated whether high glucose (HG) inhibited osteoblasts by regulating miRNA-144-5p. Our results showed that HG inhibited bone formation not only in vivo but also in vitro. We observed that HG severely hindered the migration, proliferation and mineralization of osteoblasts, while miRNA-144-5p was upregulated by way of the cell counting kit-8 assay, wound healing assay, alkaline phosphatase (ALP) activity assay and alizarin red staining. Double luciferase reporter experiments showed that miRNA-144-5p directly targeted insulin receptor substrate 1 (IRS1). The IRS1/AKT signaling pathway is closely related to osteoblasts' migration, proliferation, and mineralization. Silencing miRNA-144-5p promoted the mRNA, and protein expression of IRS1, thereby letting the expression of total AKT down, and then preventing phosphorylation of AKT into the nucleus to regulate migration, proliferation, and mineralization genes of osteoblasts. In conclusion, this study indicated that HG regulated the migration, proliferation, and mineralization of osteoblasts via the miRNA-144-5p/IRS1/AKT axis, which suggested a possible mechanism for DOP pathology.
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CELL PROLIFERATION
·
2020
·Vol. 54
·期 1
·e12955
·
IF 5.753
Jun Ma,Lei Zhu,Zhibin Zhou,Tengfei Song,Lei Yang,Xu Yan,Aimin chen,Tian Wen Ye
Objectives Calcium ion signals are important for osteoclast differentiation. Transient receptor potential vanilloid 6 (TRPV6) is a regulator of bone homeostasis. However, it was unclear whether TRPV6 was involved in osteoclast formation. Therefore, the aim of this study was to evaluate the role of TPRV6 in bone metabolism and to clarify its regulatory role in osteoclasts at the cellular level. Materials and methods Bone structure and histological changes in Trpv6 knockout mice were examined using micro-computed tomography and histological analyses. To investigate the effects of Trpv6 on osteoclast function, we silenced or overexpressed Trpv6 in osteoclasts via lentivirus transfection, respectively. Osteoclast differentiation and bone resorption viability were measured by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays. The expression of osteoclast marker genes, including cathepsin k, DC-STAMP, Atp6v0d2 and TRAP, was measured by qRT-PCR. Cell immunofluorescence and Western blotting were applied to explore the mechanisms by which the IGF-PI3K-AKT pathway was involved in the regulation of osteoclast formation and bone resorption by Trpv6. Results We found that knockout of Trpv6 induced osteoporosis and enhanced bone resorption in mice, but did not affect bone formation. Further studies showed that Trpv6, which was distributed on the cell membrane of osteoclasts, acted as a negative regulator for osteoclast differentiation and function. Mechanistically, Trpv6 suppressed osteoclastogenesis by decreasing the ratios of phosphoprotein/total protein in the IGF–PI3K–AKT signalling pathway. Blocking of the IGF–PI3K–AKT pathway significantly alleviated the inhibitory effect of Trpv6 on osteoclasts formation. Conclusions Our study confirmed the important role of Trpv6 in bone metabolism and clarified its regulatory role in osteoclasts at the cellular level. Taken together, this study may inspire a new strategy for the treatment of osteoporosis.
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Frontiers in Pharmacology
·
2024
·
IF 4.4
Chencen Lai,Shuo Zhang,Zhiyu Chen,Xiaoyu Fu,Min Zhang,Pengjiao Wang,Xiuli Gao
Pyroptosis induced by oxidative stress is a significant contributor to mental health disorders, including depression (+)-Catechin (CA), a polyphenolic compound prevalent in various food sources, has been substantiated by prior research to exhibit potent antioxidant properties and potential antidepressant effects. Nonetheless, the precise antidepressive mechanisms and effects of CA remain incompletely elucidated. In this study, we employed corticosterone (CORT) and PC12 cells to develop a cellular model of depression, aiming to investigate the protective effects of CA against CORT-induced cellular damage. Our objective was to elucidate the underlying mechanisms of protective action. We utilized transcriptomic analysis to identify differentially expressed genes and employed bioinformatics approaches to predict the potential mechanisms of CA’s protective effects in PC12 cells. These transcriptomic predictions were subsequently validated through western blot analysis. The findings indicated that CA possesses the capacity to mitigate oxidative stress and suppress pyroptosis in PC12 cells via the activation of the PI3K/AKT signaling pathway. This activation subsequently modulates the Nrf2/HO1/NF-κB pathways, thereby providing protection to PC12 cells against damage induced by CORT. Furthermore, we investigated the interaction between CA and the Keap1 protein employing molecular docking and protein thermal shift assays. We propose that CA can activate Nrf2 through two mechanisms to decrease reactive oxygen species (ROS) levels and inhibit pyroptosis: one mechanism involves the activation of the PI3K/AKT signaling pathway, and the other involves direct binding to Keap1, leading to an increase in p-Nrf2.
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American Journal of Cancer Research
·
2022
·
IF 5.942
Guangyu Cheng,Lin Li,Qingjie Li,Shulin Lian,Hongbo Chu,Yunlu Ding,Chikun Li,Yan Leng
Multi-drug resistance remains a critical issue in cancer treatment that hinders the effective use of chemotherapeutic drugs. The active components of traditional Chinese medicine have been applied as adjuvants to accentuate the anticancer properties of conventional drugs such as cisplatin. However, their application requires further validation and optimization. This study explored the anticancer activity of β-elemene, a natural component of traditional Chinese medical formulations. The effect of β-elemene on the anticancer properties of cisplatin was evaluated in A549 and NCI-H1650 lung cancer cells. Cell apoptosis, stem-like properties, glucose metabolism, multi-drug resistance, and PI3K/AKT/mTOR activation were assessed via flow cytometry, tumorsphere formation, and western blotting. The target genes of β-elemene were predicted using bioinformatics tools and validated in both cell lines. A xenograft model of lung cancer was established in nude mice to evaluate the combined effects of β-elemene and cisplatin in vivo . We found that β-elemene acted synergistically with cisplatin against non-small cell lung cancer cells by promoting apoptosis and impairing glucose metabolism, multi-drug resistance, and stemness maintenance. These effects were mediated by the inhibition of PI3K/AKT/mTOR activation. Bioinformatics analysis revealed that RB1 and TP53 are common target genes associated with lung cancer and β-elemene. The anti-tumorigenic properties of β-elemene were confirmed in vivo , wherein β-elemene, along with cisplatin, significantly suppressed tumor growth in a mouse xenograft model of non-small cell lung cancer. As such, β-elemene acted as an inhibitor of PI3K/AKT/mTOR signaling and enhanced the anticancer effect of cisplatin by targeting tumor metabolism, chemoresistance, and stem-like behavior. Thus, β-elemene is an effective anticancer adjuvant agent with potential clinical applications.
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Journal of Functional Foods
·
2024
·
IF 3.8
Xiaotian Xu,Xinhui Li,Xingshu Wei,Xiaoqun Duan,Yuhui Wang
Passion fruit peel fermentation extract (PFPFE) increased gastrointestinal transport power and fecal moisture content, protected the structural integrity of colon tissue, and reduced inflammatory infiltration. PFPFE also increased secretion of the ET-1, GAS, MTL, and SP, and decreased secretion of the inhibitory SS and VIP. In addition, PFPFE alleviated perirectal redness and hemorrhage in hemorrhoid mice, and downregulated levels of the serum inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). In this study, we also analyzed the main active components and core targets of PFPFE for alleviating constipation and hemorrhoids through network pharmacology, and predicted its mechanism of action. Finally, we carried out Western blot experiments to verify that PFPFE and its active component kae alleviates constipation and hemorrhoids in mice by downregulating ESR1 and PI3K/Akt pathways. These results provide a scientific basis for the development of PFPFE as a functional food for alleviating constipation and hemorrhoids.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Meng-xiao Wang,Ke-ke Luo,Meng-yao Tian,Wen-ya Gao,Shan Jiang,Yan Zhang,Jian Yang,Nan Si,Shi-lan Ding,Xiao-lu Wei,Yu-yang Liu,Bao-lin Bian,Yan-yan Zhou,Hong-jie Wang
The diagnosis and treatment of chronic glomerulonephritis (CGN) during childhood pose distinct challenges. Acteoside (ACT) is the primary active ingredient extracted from the leaves of Rehmannia glutinosa by our research group, accounting for 2.15 %, which possess multiple biological activities, especially for nephropathy treatment. However, its mechanism intervention on CGN in children remains obscure. In this study, we established a model of purinomycin aminonucleoside (PAN)-induced CGN in childhood rats to assess the potential therapeutic effect and underlying mechanisms of ACT. Leveraging network pharmacology and multi-omics technology, we delved into the effects and mechanisms of ACT intervention on CGN. And these findings were further corroborated through qRT-PCR, western blot and targeted metabolomics. Our results demonstrated that ACT had significantly efficient in the treatment of CGN in childhood rats by improving the key indicators and pathological changes. Further, ACT could significantly regulate differences in endogenous small molecules and genes based on non-target metabolomics and transcriptomics. Meanwhile, target capture analysis found the crucial targets of ACT treatment in CGN. Integrated analysis of multi-omics study indicated that PI3K/Akt signaling pathway and its downstream amino acid metabolism were significantly enriched, hinting at the essential regulatory pathway for ACT in treating of CGN. Finally, through qRT-PCR, western blot and targeted metabolomics, it was verified that ACT could ameliorate CGN through Cxcr4-PI3K-Akt-eNOS signaling pathway, thereby regulating amino acid metabolism. The collective results were consistent with those of multi-omics analysis. Our study illuminated that ACT had notable curative effect on CGN rats, and preliminarily elucidated its mechanism of action. Our research will provide solid basis for the treatment of chronic glomerulonephritis in children with ACT and developing it into innovative traditional Chinese medicine.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
·
IF 5.895
Sinan Chen,Fanhua Wu,Chenchen Yang,Cheng Zhao,Ni Cheng,Wei Cao,Haoan Zhao
Insulin resistance (IR) is the central link to metabolic syndrome (MS), and IR prevention has become the key to overcoming this worldwide public health problem. A diet rich in simple sugars is an important pathogenic factor in IR development. To investigate the effect of honey on IR compared to the sugar-water diet, we analyzed phenolics and oligosaccharides in jujube honey and rape honey based on LC-MS and silane derivatization/GC–MS. The effects of different diets on glucose and lipid profile, histopathology and IR-related mechanism pathways were analyzed and compared by equal sugar levels intervention of fructose, fructose + glucose and two kinds of unifloral honey (high-/low-dose) in rats. The results suggested that sugar-equivalent honey, which differs from sugar solution, especially 17.1 g/kg BW jujube honey rich in phenolics (1.971 mg/100 g of isoquercitrin) and oligosaccharides (2.18 g/100 g of turanose), suppressed IR via maintaining glucose (OGTT and ITT) and lipid (TC, TG, LDL-C, HDL-C, and NEFA) homeostasis, improving histological structural abnormalities of the liver, adipose and skeletal muscle, reducing oxidative stress (GSH-Px and MDA) and inflammation (IL-6 and TNF-α), modulating the NF-κB (NF-κB gene expression was down-regulated to 0.94) and IRS/PI3K/AKT signaling pathways (e.g., AKT and GLUT2 expression in liver increased by 4.56 and 13.37 times, respectively) as well as reshaping the gut microbiota. These revealed a potential nutritional contribution of substituting honey for simple sugar in the diet, providing a theoretical basis for controlling IR development via dietary modification and supplementation.
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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.
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Pharmaceuticals
·
2025
·Vol. 18
·期 6
·817
·
IF 4.8
Luqi Qin,Yixia Zhou,Bei Fan,Jiahuan Zheng,Rao Diao,Jiameng Liu,Fengzhong Wang
Background/Objectives: Endophytes can produce bioactive metabolites similar to their host plants. CM-YJ44 ( Pseudomonas protegens CHA0, 99.24% similarity), an endophyte from Dendrobium officinale , has not yet validated hypoglycemic potential. This study aimed to evaluate its anti-insulin resistance (IR) activity and metabolite profile. Methods: The fermentation broth of CM-YJ44 was separated into three fractions (CM-YJ44-1, -2, and -3) using semi-preparative high-performance liquid chromatography (pre-HPLC). An IR HepG2 cell model was constructed to evaluate their glucose uptake capacity. CM-YJ44-3 was further tested for oxidative stress, inflammatory, and insulin signaling pathway activation. Metabolites in CM-YJ44-3 were preliminarily identified using the Q Exactive Focus LC-MS system (QE), and the dendrobine content was quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Molecular docking was performed to predict the binding affinities between dendrobine and target proteins. Results: Among the three fractions, CM-YJ44-3 significantly reduced nitric oxide (NO) and reactive oxygen species (ROS) levels in IR cells, enhanced glycogen synthesis, upregulated the activities of pyruvate kinase (PK) and hexokinase (HK), and suppressed the expression of inflammatory factors. Its mechanism of action was mainly through activation of the IRS1/PI3K/Akt/GSK3β/GLUT4 signaling pathway. QE analysis preliminarily identified 24 metabolites in CM-YJ44-3. Quantitative analysis by UPLC-MS/MS showed that the dendrobine content was 78.73 ± 4.29 ng/mL. Molecular docking results indicated that dendrobine exhibited binding energies below −5 kcal/mol with multiple target proteins involved in this signaling pathway, suggesting it may be a key bioactive component responsible for the anti-IR effect. Conclusions: This study provides the first evidence of hypoglycemic bioactive metabolite production by strain CM-YJ44, indicating its potential as a novel microbial candidate for alleviating IR.
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Biomaterials Research
·
2025
·
IF 9.6
Anran Li,Cong Chen,Tongjia Zhang,Yuxin Tian,Yifan Cao,Xiaoming Zhao,Liping Wang
Human umbilical cord mesenchymal stem cell extracellular vesicles (hucMSC-EVs) exhibit remarkable potential for alleviating type 2 diabetes mellitus (T2DM). However, the role of hucMSC-EVs in T2DM, particularly concerning oxidative damage to pancreatic β cells, remains underexplored. This study utilized a high-fat diet and streptozotocin (STZ)-induced T2DM mouse model and an STZ-induced INS-1 cell damage model to investigate the effects and mechanisms of hucMSC-EVs. In the T2DM mouse model, hucMSC-EVs effectively lowered blood glucose levels, improved lipid metabolism disorders, and preserved liver function. Moreover, hucMSC-EVs enhanced insulin sensitivity and mitigated oxidative damage. Histological analysis confirmed that hucMSC-EVs marked alleviated liver, kidney, and pancreatic tissue damage. In vitro studies demonstrate that hucMSC-EVs enhance glucose absorption and glycogen synthesis in an insulin-resistant HepG2 model and stimulated insulin secretion in INS-1 cells under high-glucose conditions. In the STZ-induced INS-1 oxidative damage model, hucMSC-EVs protect against oxidative damage by increasing antioxidant enzyme activities, reducing reactive oxygen species production, and decreasing cell apoptosis. The effects were partially mediated by the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT and signal transducer and activator of transcription (STAT) signaling pathways, as well as the up-regulation of key antioxidant proteins such as Nrf2, SOD1, and Bcl2. Further research revealed that miR-191-5p, which is enriched in hucMSC-EVs, targets DAPK1 to activate the PI3K/AKT pathway, thereby contributing to the protective effects against oxidative damage. These findings highlight the critical role and underlying mechanisms of hucMSC-EVs in ameliorating metabolic dysfunction in T2DM, particularly the protective effects against oxidative damage, thus providing a novel strategy for the treatment of T2DM.
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Frontiers in Pharmacology
·
2026
·
IF 5.4
Shuai Zhao,Zhenyao Tan,Jiaxin Suo,Yang Bu
Introduction Colorectal cancer liver metastasis (CRLM) is the leading cause of death in colorectal cancer, and nonalcoholic fatty liver disease (NAFLD) promotes CRLM. Lycium barbarum polysaccharides (LBPs), bioactive metabolites of the traditional medicinal plant Lycium barbarum L, inhibit the progression of colorectal cancer and NAFLD by regulating gut microbiota composition. However, their roles in preventing CRLM under NAFLD conditions remain unclear. This study aimed to investigate the preventive effect of LBPs on liver metastasis of colorectal cancer in the context of NAFLD and explore its potential mechanisms. Methods An NAFLD mouse model was established, followed by prophylactic oral administration of LBPs by gavage for 28 days before splenic injection of MC38 colorectal cancer cells to establish liver metastasis. Pseudo-germ-free mice combined with fecal microbiota transplantation were constructed to explore the role of the gut microbiota in the preventive effect of LBPs on CRLM. Gut microbiota and fecal short-chain fatty acids were analyzed by 16S rRNA sequencing and liquid chromatography–mass spectrometry. Spearman’s correlation analysis was used to explore the correlation between bacterial genera and liver lipid metabolism indicators. Serum non-targeted metabolomic profiling and transcriptomic analysis of CRLM cells were performed to elucidate metabolic and molecular mechanisms. Results Under NAFLD conditions, LBPs markedly reduced hepatic metastatic burden, liver weight, and liver-to-body weight ratio. LBPs ameliorated hepatic lipid metabolism and restored colonic barrier integrity in NAFLD mice. The gut microbiota was identified as a critical mediator of LBPs-induced protection against CRLM, and depletion of the microbiota completely abrogated the anti-metastatic effects of LBPs. LBPs enhanced microbial diversity and richness, enriched of short-chain fatty acid-producing bacterial genera, such as Cryptobacteroides, Evtepia, and Bacteroides -H, and elevated colonic butyrate levels. Metabolomic profiling revealed reduced serum acylcarnitines and increased organic acids. Transcriptomic profiling showed upregulation of fibroblast growth factor 21, activation of the PI3K-AKT signaling pathway, and promotion of epithelial–mesenchymal transition in colorectal cancer cells, while LBPs reverse these changes. Discussion LBPs prevent CRLM associated with NAFLD by modulating the gut microbiota, enhancing butyrate production, improving hepatic metabolic homeostasis, and suppressing prometastatic signaling pathways. These findings highlight LBPs as promising preventive agents against CRLM in the setting of metabolic liver disease.
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