JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Yong-Yu Yang,Jing-Jing Qi,Si-Yi Jiang,Ling Ye
Ethnopharmacological relevance Cortex fraxini (also known as qinpi)—the bark of Fraxinus rhynchophylla Hance (Oleaceae)—is widely used as a Chinese traditional medicinal for its anti-inflammatory and anti-hyperuricemic activities. Aim of the study Obesity-induced insulin resistance (IR) is driving the rising incidence of type 2 diabetes mellitus and is related to pathological adipose tissue remodeling. Esculin, a major active component of Cortex fraxini , has anti-diabetic effects. However, whether esculin improves obesity-induced IR by regulating adipose tissue remodeling is unclear. The aims of the present study were to assess the effects of esculin on obesity-induced IR and to explore the underlying mechanisms. Materials and methods Obese IR C57BL/6J mice were treated with esculin (40 or 80 mg/kg/day) for 4 weeks. Oral glucose tolerance tests were used to assess insulin sensitivity. Histological analyses were performed to analyze the number and size distribution of adipocytes. Glucose uptake was assessed using 2-NBDG. Results Esculin had no effect on body weight gain but reduced fasting blood glucose, improved oral glucose tolerance, and increased insulin sensitivity. Esculin reduced adipocyte size and the expression levels of collagen 4A1 and tumor necrosis factor α and increased the number of adipocytes and the expression of vascular endothelial growth factor A. Esculin promoted the differentiation of 3T3-L1 cells and upregulated the mRNA expression of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ, activated the insulin receptor substrate 1 (IRS1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and enhanced the translocation of glucose transporter type 4 (GLUT4) and glucose uptake in adipocytes treated with palmitic acid. Conclusions These data suggest that esculin increases insulin sensitivity by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
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2023
·Vol. 46
·期 6
·764-772
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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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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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PHYTOMEDICINE
·
2019
·
IF 4.18
Jun-Shan Liu,Chu-Ying Huo,Hui-Hui Cao,Chun-Lin Fan,Jian-Yang Hu,Li-Juan Deng,Zi-Bin Lu,Hua-Yi Yang,Lin-Zhong Yu,Zhi-Xian Mo,Zhi-Ling Yu
Background Hepatocellular carcinoma (HCC) ranks third among the most common causes of cancer-related deaths worldwide. The chemotherapy for HCC is still insufficient, so far. In searching for effective anti-HCC agents from traditional Chinese medicine , we discovered that aloperine (ALO), a quinolizidine alkaloid from Sophora alopecuroides L., exerts anti-HCC activities. However, the effects of ALO on HCC have been rarely studied, and its underlying mechanisms remain unknown. Purpose This study aims to evaluate the anti-HCC activities of ALO and explore its underlying mechanisms. Methods MTT assay and colony formation assay were used to investigate the anti-proliferative effects of ALO on human HCC Hep3B and Huh7 cells. Hoechst 33258 staining was used to observe the morphological changes of cells after ALO treatment . Flow cytometry was used to analyze apoptosis induction, the collapse of the mitochondrial membrane potential and cell cycle distribution. Western blotting was used to examine the expression levels of proteins associated with apoptosis and cell cycle arrest , and key proteins in the PI3K/Akt signaling pathway . Small interfering RNA (siRNA) transfection was used to investigate the role of Akt in ALO-induced apoptosis and cell cycle arrest. Zebrafish tumor model was used to evaluate the anti-HCC effects of ALO in vivo. Results ALO inhibited the proliferation of Hep3B and Huh7 cells. ALO induced apoptosis in HCC cells, which was accompanied by the loss of mitochondrial potential, the release of cytochrome c into cytosol, as well as the increased cleavages of caspase-9, caspase-3 and PARP . Moreover, ALO induced G2/M cell cycle arrest by downregulating the expression levels of cdc25C, cdc2 and cyclin B1 . In addition, ALO inhibited activation of the PI3K/Akt signaling pathway by decreasing the expression levels of p110α , p85, Akt and p-Akt (Ser473) . Further study showed that inhibition of Akt by siRNA augmented ALO-mediated apoptosis and G2/M cell cycle arrest in HCC cells. Critically, ALO inhibited the growth of Huh7 cells in vivo. Conclusion We first demonstrated that ALO induced apoptosis and G2/M cell cycle arrest in HCC cells through inhibition of the PI3K/Akt signaling pathway. This study provides a rationale for ALO as a potential chemotherapeutic agent for HCC.
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ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 44
·期 6
·1262-1276
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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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EXPERIMENTAL ANIMALS
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2022
·
IF 1.798
Guangquan Hu,Xiaojie Ding,Feng Gao,Jiehua Li
Myocardial infarction (MI) is a severe coronary artery disease resulted from substantial and sustained ischemia. Abnormal upregulation of calcium and integrin binding protein 1 (CIB1) has been found in several cardiovascular diseases. In this study, we established a mouse model of MI by permanent ligation of the left anterior descending coronary artery. CIB1 was upregulated in the heart of MI mice. Notably, CIB1 knockdown by intramuscular injection of lentivirus-mediated short hairpin RNA (shRNA) targeting Cib1 improved cardiac function and attenuated myocardial hypertrophy and infarct area in MI mice. MI-induced upregulation of α-SMA, vimentin, Collagen I, and Collagen III, which resulted in collagen production and myocardial fibrosis, were regressed by CIB1 silencing. In vitro, cardiac fibroblasts (CFs) isolated from mice were subjected to angiotensin II (Ang II) treatment. Inhibition of CIB1 downregulated the expression of α-SMA, vimentin, Collagen I, and Collagen III in Ang II-treated CFs. Moreover, CIB1 knockdown inhibited Ang II-induced phosphorylation of PI3K-p85 and Akt in CFs. The effect of CIB1 knockdown on Ang II-induced cellular injury was comparable to that of LY294002, a specific inhibitor of the PI3K/Akt pathway. We demonstrated that MI-induced cardiac hypertrophy, myocardial fibrosis, and cardiac dysfunction might be attributed to the upregulation of CIB1 in MI mice. Downregulation of CIB1 alleviated myocardial fibrosis and cardiac dysfunction by decreasing the expression of α-SMA, vimentin, Collagen I, and Collagen III via inhibiting the PI3K/Akt pathway. Therefore, CIB1 may be a potential target for MI treatment.
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EUROPEAN JOURNAL OF NEUROSCIENCE
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2022
·Vol. 56
·期 3
·4045-4059
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IF 3.698
Huqing Wang,Ming Chen,Tao Zhang,Zhen Gao,Yu Gong,Xiaorui Yu,Haiqin Wu
In vitro cell experiments have suggested that recombinant human erythropoietin (rhEPO) and peroxisome proliferator activated receptor γ (PPARγ) activation exert protective effects on neurons. This study observed the learning and memory ability, antioxidant capacity and the ratio of apoptotic cells after rhEPO intervention and investigated the relationship among rhEPO, PI3K/Akt and PPARγ in the anti-neural oxidative stress injury process in vivo. The results showed that rhEPO significantly improved the learning and memory abilities of rats subjected to oxidative stress, enhanced the antioxidant capacity of cells, and reduced neuronal apoptosis. Then, the PI3K/Akt and PPARγ pathways were inhibited, and TUNEL staining were used to observe the changes in the effect of rhEPO. After the PI3K/Akt and PPARγ pathways were inhibited, the effect of rhEPO on rats subjected to oxidative stress was significantly weakened, suggesting that both the PI3K/Akt and PPARγ pathways are involved in the process by which rhEPO protects neurons. Finally, Western blotting and immunofluorescence staining were used to observe the changes in PI3K/Akt and PPARγ signalling proteins in the neurons after the rhEPO intervention and to explore the relationship among the three. The results showed that rhEPO significantly increased the levels of the p-Akt and PPARγ proteins and the level of the PPARγ protein in the nucleus, indicating that the PI3K/Akt pathway was located upstream of and regulates PPARγ. In conclusion, this study suggested that rhEPO activates the PI3K/Akt to upregulate PPARγ, enhance the cellular antioxidant capacity, and protect neurons in rats subjected to oxidative stress.
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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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BIOMATERIALS
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2021
·
IF 12.479
Chuanchuan Lin,Ye He,Qian Feng,Kun Xu,Zhe Chen,Bailong Tao,Xuemin Li,Zengzilu Xia,Hong Jiang,Kaiyong Cai
To control the fate of mesenchymal stem cells (MSCs) in a 3D environment by adjusting the mechanical parameters of MSC-loading scaffolds, is one of the hot topics in the field of regenerative biomaterials. However, a thorough understanding of the relevant MSCs behaviors affected by viscoelasticity , a dynamic physical parameter of scaffolds, is still lacking. Herein, we established an alginate hydrogel system with constant stiffness and tunable stress relaxation rate, which is a key parameter for the viscoelastic property of material. MSCs were cultured inside three groups of alginate hydrogels with various stress relaxation rates, and then RNA-seq analysis of cells was performed. Results showed that the change of stress relaxation rates of hydrogels regulated the most of the different expression genes of MSCs, which were enriched in cell proliferation-related pathways. MSCs cultured in hydrogels with fast stress relaxation rate presented a high self-renewal proliferation profile via activating phosphatidylinositol 3- kinase (PI3K)/protein kinase B (Akt) pathway. In contrast, a slow stress relaxation rate of hydrogels induced MSCs to enter a reversible quiescence state due to the weakened PI3K/Akt activation. Combined with a further finite element analysis , we speculated that the quiescence of MSCs could be served as a positive strategy for MSCs to deal with the matrix with a low deformation to keep stemness. Based on the results, we identified that stress relaxation rate of hydrogel was a potential physical factor of hydrogel to regulate the self-renewal or quiescence of MSCs. Thus, our findings provide a significant guiding principle for the design of MSCs-encapsulated biomaterials.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2021
·
IF 3.575
Xiaobo Zhang,Jie Zhang,Yun Liu,Dongming Zhu,Dong Chen,Zhen Zhang,Yu Sun
Objective This present study aims to assess the effect of pirfenidone (PFD) on inhibiting fibroblast proliferation, migration or adhesion in vitro and reducing laminectomy-induced epidural fibrosis in vivo. Methods The effect of PFD on proliferation inhibition was evaluated with flow cytometry, CCK-8, EdU and western-blotting assays. Altered properties in migration and adhesion were confirmed by wound-scratch, transwell, immunofluorescence (IF), cell adhesion and western-blotting assays. Additionally, fifty male healthy Sprague-Dawley rats were subjected to laminectomy and then treated with various concentrations of PFD. After 4 weeks, the degree of epidural fibrosis was evaluated by histological analysis. Results In vitro, the results of flow cytometry, CCK-8, EdU and western-blotting assays showed that PFD reduced fibroblast proliferation by a dose-dependent manner. And the results of wound-scratch, transwell, IF, cell adhesion and western-blotting assays showed that the migration and adhesion of fibroblasts could be inhibited and the cytoskeleton could also be altered in a dose-dependent manner. And the inhibitory effect of PFD could be partially reversed in the PI3K overexpression experiment, which indicated that the capability of PFD to inhibit fibroblast proliferation, migration and adhesion might be through the PI3K/AKT signaling pathway . In vivo, an obvious reduction in epidural fibrosis was observed in groups topically treated with PFD. Conclusions Topical PFD application obviously suppressed laminectomy-induced epidural fibrosis, possibly by inhibiting fibroblast proliferation, migration and adhesion via the PI3K/AKT signaling pathway. PFD may be a safe and effective pharmaceutical to reduce clinical epidural fibrosis.
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BIOMEDICINE & PHARMACOTHERAPY
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2021
·
IF 6.53
Yaoxing Dou,Ronglei Huang,Qiaoping Li,Yuhong Liu,Yucui Li,Hanbin Chen,Gaoxiang Ai,Jianhui Xie,Huifang Zeng,Jiannan Chen,Chaodan Luo,Ziren Su
Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo . The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic β-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.
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JOURNAL OF DERMATOLOGICAL TREATMENT
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2020
·
IF 2.156
Yifeng Xiao
Background This study explored the function and mechanism of miR-486-5p in HSFBs.Methods Qualitative real-time-polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-486-5p in HS and hypertrophic scar fibroblasts (HSFBs). Viability, migration, invasion ability, apoptosis, and expressions of Collagen I, Collagen III, α-SMA and Cleaved caspase-3 in HSFBs after transfection with miR-486-5p mimic or inhibitor were measured by CCK-8, wound-healing, transwell, and Western blot, respectively. Interaction between miR-486-5p and IGF1 was predicted by Targetscan version 7.2 and further confirmed by dual-luciferase assay, and functional rescue experiments were conducted to verify the predicted molecular mechanism. The activation of PI3K/AKT pathway was also analyzed by Western blot.Results MiR-486-5p was low-expressed in HS and HSFBs, and that overexpression of miR-486-5p suppressed the viability, migration, invasion, and expressions of Collagen I, Collagen III, and α-SMA of HSFBs, meanwhile, it also promoted apoptosis and Cleaved caspase-3 expression in HSFBs. Moreover, IGF1 was targeted by miR-486-5p, and increased viability, migration, invasion, and collagens expressions, the activation of PI3K/Akt pathway, and decreased apoptosis and Cleaved caspase-3 induced by miR-486-5p inhibitor could be partly alleviated by siIGF1.Conclusions Overexpressed miR-486-5p inhibited the hyperproliferation and excessive production of collagen in HSFBs via IGF1/PI3K/AKT pathway.
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