Coriolus versicolor alleviates diabetic cardiomyopathy by inhibiting cardiac fibrosis and NLRP3 inflammasome activation

Coriolus versicolor (CV) is a traditional medicine and food mushroom. Our previous study demonstrated that CV extract exhibited anti‐hyperglycemia and anti‐insulin resistance effects. However, the effect of CV on cardiac function in diabetic cardiomyopathy (DCM) remains unclear. Therefore, we aimed to investigate the effect of CV on cardiac function in diabetes mellitus (DM) rats. We found that the cardiac dysfunction of DM rats was markedly improved by CV extract treatment. CV extract administration significantly attenuated cardiac fibrosis in DM rats, which was accompanied by suppressed transforming growth factor beta 1 (TGF‐β1)/Smad signaling as indicated by decreased levels of TGF‐β1, p‐Smad2, and p‐Smad3 and increased Smad7 expression. Moreover, CV extract treatment significantly alleviated cardiac inflammation as shown by decreased levels of NLRP3 receptor, cleaved caspase‐1, IL‐1β, and IL‐18 in DM rats at least partly due to the inhibition of the NF‐κB. In addition, high‐glucose treatment induced cardiac fibrosis and increased cardiac inflammation in cardiac fibroblast cells, but these effects were ameliorated by CV extract treatment. Therefore, we conclude that the protective effect of CV on DCM is associated with the suppression of TGF‐β1/Smad signaling and attenuation of NLRP3 inflammasome activation, suggesting that CV extract may be a potential therapeutic agent for DCM.     

桑叶提取物调控IRS-1/PI3K/GLUT4通路影响2型糖尿病胰岛素抵抗机制研究

目的:提取桑叶中的黄酮类及多酚类物质,观察其对2型糖尿病(T2DM)模型大鼠降血糖及改善胰岛素抵抗(IR的作用,并探讨其分子机制。方法:取雄性SD大鼠,分为正常组、模型组、二甲双胍组、桑叶提取物组,除正常组以外建立T2DM模型,灌胃干预4周,观察药物对模型大鼠一般情况、生化指标、骨骼肌病理等的影响。测定胰岛素受体底物-1 (IRS-1)、磷脂酰肌醇3-激酶(PI3K)中的p85α、葡萄糖转运体-4 (GLUT4)在骨骼肌组织中的信使核糖核酸(mRNA)及蛋白表达水平。结果:与正常组比较,模型组空腹血糖(FBG)、IR稳态模型指数(HOMA-IR)、血清胰岛素、总胆固醇、甘油三酯、低密度脂蛋白水平升高(P<0.05);IRS-1、PI3K p85α、GLUT4的mRNA及蛋白表达明显下降(P<0.05)。与模型组比较,桑叶提取物组FBG、HOMA-IR、总胆固醇、甘油三酯、低密度脂蛋白水平下降(P<0.05);IRS-1、PI3K p85α、GLUT4的mRNA及蛋白表达明显升高(P<0.05);二甲双胍组FBG有所下降,但差异无统计学意义,血清胰岛素及HOMA-...     

Potent Effects of the Total Saponins from Dioscorea nipponica Makino Against Streptozotocin‐Induced Type 2 Diabetes Mellitus in Rats

The aim of the present paper was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against type 2 diabetes mellitus. Streptozotocin (STZ) with high‐fat diet induced type 2 diabetes mellitus (T2DM) rats were treated with TSDN. Some biochemical parameters, target proteins and genes were investigated. The results showed that TSDN decreased the levels of food/water intake, fasting blood glucose and serum lipid parameters, ameliorated oral glucose and insulin tolerance test levels, markedly increased body weight and serum insulin, reduced excess free radicals and affected ossification and renal protection. Histopathological examination indicated that TSDN increased liver glycogen, decreased the production of lipid vacuoles and lightened liver damage. Further investigation showed that TSDN down‐regulated the protein expressions of NF‐κB, GRP78, ATF6, eIF2 and the levels of MAPK phosphorylation and up‐regulated the protein expressions of IRS‐1, GLUT‐4, p‐Akt and p‐AMPK. In addition, TSDN obviously decreased the gene expressions of TNF‐a, IL‐6, PEPCK, G6Pase, GSK‐3β and GSK‐3β activity, and increased the gene expressions of PFK, PK and GK activity. These findings show the anti‐diabetic activity of total saponins from D. nipponica Makino, which should be developed as a new potent drug for treatment of diabetes mellitus in future. Copyright © 2014 John Wiley & Sons, Ltd.     

Effect on the Akt2 in skeletal muscle of rats with insulin resistance treated by acupuncture

目的：观察针刺对胰岛素抵抗模型大鼠骨骼肌Akt2mRNA表达的影响。方法：将24只SD大鼠随机分为空白组、模型组和针刺组,用葡萄糖氧化酶法、ELISA、实时荧光定量PCR等方法,检测比较各组大鼠空腹血糖（Fasting Plasma Glucose,FPG）、血浆胰岛素（FastingInsulin,FINS）、胰岛素敏感性指数（InsulinSensitivityIndex,ISI）、血清c-肽（cPeptide,C—P）和骨骼肌Akt2mRNA的表达。结果：模型组大鼠的FPG、FINS、C—P较空白组显著升高（P〈O．01）,ISI和骨骼仙Akt2mRNA表达显著降低（P〈0．01,P〈0．05）;针刺组的FPG、FINS、C—P较模型组显著降低（P〈0．01,P〈0．01,P〈0．05）,ISI和骨骼肌Akt2mRNA表达显著升高（P〈0．01）。结论：针刺治疗胰岛素抵抗的作用机理可能与上调Akt2mRNA的表达,改善PI3K通路的信号转导有关。     

Ginsenoside Rg1 promotes glucose uptake through activated AMPK pathway in insulin-resistant muscle cells

Ginsenoside Rg1, a protopanaxatriols saponin, is one of the major active constituents from Panax ginseng and possesses various biological activities. A recent study reported that insulin resistance in skeletal muscle is a major contributor to the development of type 2 diabetes mellitus (T2DM). We examined the effects of ginsenoside Rg1 on glucose uptake and the associated molecular mechanisms of the glucose transport system in insulin-resistant muscle cells. The insulin resistance of the muscle cell was induced by treatment of differentiated C2C12 cells with chronic insulin. The results showed that chronic treatment of insulin resulted in reduced glucose uptake in the muscle cells. The treatment of ginsenoside Rg1 significantly enhanced glucose uptake in the differentiated muscle cells and the relative abundance of GLUT4 through the adenosine-monophosphate-activated protein kinase pathway. These results suggest that ginsenoside Rg1 improved the insulin resistance in C2C12 muscle cells, which might be useful for prevention of T2DM and metabolic syndromes.     

山柰酚对2型糖尿病小鼠骨骼肌PI3K-AKTGLUT4信号通路的影响

目的：探讨山柰酚对KKAy小鼠骨骼肌PI3K/AKT/GLUT4信号通路的影响。方法：以自发型2型糖尿病KKAy小鼠为动物模型,通过对糖尿病小鼠进行为期6周的山柰酚灌胃给药治疗,利用生化、免疫组织化学及免疫印迹法等检验方法,检测PI3K-AKT-GLUT4信号通路重要靶点的表达,探讨山柰酚改善糖尿病KKAy小鼠骨骼肌胰岛素敏感性及对胰岛素信号转导通路PI3K-AKT-GLUT4的影响。结果：山柰酚具有显著降低KKAy小鼠体重、空腹血糖、随机血糖的作用,ITT实验结果说明：山柰酚能够显著降低胰岛素注射30min时的血糖,显著降低ITT曲线下面积,改善胰岛素抵抗。此外,山柰酚能够显著上调KKAy小鼠骨骼肌PI3K、AKT、GLUT4基因的表达,能够上调AKT、GLUT4蛋白的表达。结论：山柰酚具有显著降低KKAy小鼠血糖、体重的作用,能够改善胰岛素抵抗,其作用机制可能与上调骨骼肌PI3K-AKTGLUT4信号通路有关。     

基于PI3K/Akt通路的中药治疗糖尿病研究进展

糖尿病是一组以高血糖为特征的代谢性疾病,发病率极高,并发症较多,目前已成为世界范围内日益严重的公共健康问题,严重影响人民的生活质量。磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(Akt)信号通路是胰岛素信号转导的主要途径,也是调控血糖的主要信号通道,其信号分子的异常可引起信号转导途径异常,从而影响相应组织器官细胞的增殖、凋亡、转移和侵袭,导致疾病的发生。研究PI3K/Akt信号通道对于考察中药是否具有明确而稳定的降血糖作用具有积极的意义。目前,治疗糖尿病的中药、西药相对较多,但多数药物尤其是西药对于并发症的控制相对较差,为了解中药在治疗糖尿病方面的进展,以期更好地研究中药在糖尿病方面的综合治疗作用及机制,进一步发挥中医药在糖尿病治疗方面的多靶点、多途径、多通道、标本兼治的优势与特色,本文就近年来基于PI3K/Akt信号通路的中药治疗糖尿病体内、外研究进行了较为系统的分析,包括基于该信号通道的对糖尿病产生直接原因的胰岛素分泌的影响、对胰岛素3个主要靶器官(肝、骨骼肌、脂肪)及对糖尿病4个主要并发症相应部位(脑、肾、心、睾丸)的影响,也为研究中药单味药及复方的降血糖机制研究提供一定的思路及指导。     

银杏叶提取物对2型糖尿病大鼠骨骼肌GLUT4 mRNA表达的影响

 目的通过观察银杏叶提取物(ginkgo biloba extract,EGB)对2型糖尿病大鼠模型骨骼肌中葡萄糖转运因子4(GLUT4)的mRNA表达的影响,研究EGB对2型糖尿病的改善作用及探讨其机制。方法以高脂高糖饮食加链脲佐菌素制作2型糖尿病胰岛素抵抗大鼠模型,观察EGB对大鼠葡萄糖耐量(oral glucose tolerance test,OGTT)、血胰岛素含量(serum insulin, INS)以及计算胰岛素抵抗指数(insulin resistance index,HOMA-IR),运用RT-PCR方法检测大鼠模型骨骼肌中GLUT4的mRNA表达。结果EGB可明显改善糖尿病大鼠的OGTT,降低INS,增加大鼠模型骨骼肌中GLUT4的mRNA表达,使HOMA-IR降低。结论EGB具有较好的降血糖、降胰岛素、改善胰岛素抵抗、防治糖尿病及其并发症的作用。     

Caffeoylserotonin Protects Human Keratinocyte HaCaT Cells against H2O2‐Induced Oxidative Stress and Apoptosis through Upregulation of HO‐1 Expression via Activation of the PI3K/Akt/Nrf2 Pathway

Caffeoylserotonin (CaS) has strong radical scavenging activity as well as antioxidant activities, protecting cells from lipid peroxidation, intracellular reactive oxygen species generation, DNA damage, and cell death. The molecular mechanism by which CaS protects against oxidative stress is not well understood. Here, we analyzed the cytoprotective activity of CaS in hydrogen peroxide (H₂O₂)‐treated keratinocyte HaCaT cells. H₂O₂ induced apoptosis in the cells through activation of pro‐apoptotic p21, Bax, and caspase‐3. Pretreatment with CaS inhibited apoptotic gene expression and activated the anti‐apoptotic gene, Bcl‐xL. Although CaS did not directly affect heme oxygenase‐1 (HO‐1) expression, pretreatment with CaS augmented HO‐1 expression through an increase in NF‐E2‐related factor (Nrf2) stability and stimulation of Nrf2 translocation to the nucleus upon H₂O₂ exposure. H₂O₂ also induced the phosphorylation and subsequent activation of ERK, p38 MAPK, and Akt. Analysis using specific inhibitors of p38 MAPK and Akt demonstrated that only Akt activation was involved in HO‐1 and Nrf2 expressions. In addition, PI3K and PKC inhibitors suppressed HO‐1/Nrf2 expression and Akt phosphorylation. These results demonstrate that CaS protects against oxidative stress‐induced keratinocyte cell death in part through the activation of Nrf2‐mediated HO‐1 induction via the PI3K/Akt and/or PKC pathways, but not MAPK signaling. Copyright © 2013 John Wiley & Sons, Ltd.     

Polymethoxyflavonoids Tangeretin and Nobiletin Increase Glucose Uptake in Murine Adipocytes

Tangeretin and nobiletin are polymethoxyflavonoids that are contained in citrus fruits. Polymethoxyflavonoids are reported to have several biological functions including anti‐inflammatory, anti‐atherogenic, or anti‐diabetic effects. However, whether polymethoxyflavonoids directly affect glucose uptake in tissues is not well understood. In the current study, we investigated whether tangeretin and nobiletin affect glucose uptake in insulin target cells such as adipocytes. We observed that treatment with tangeretin or nobiletin significantly increased the uptake of [³H]‐deoxyglucose in differentiated 3T3‐F442A adipocytes in a concentration‐dependent manner. Data showed that phosphatidyl inositol 3 kinase, Akt1/2, and the protein kinase A pathways were involved in the increase in glucose uptake induced by polymethoxyflavonoids. These data suggest that the anti‐diabetic action of polymethoxyflavonoids is partly exerted via these signaling pathways in insulin target tissues. Copyright © 2012 John Wiley & Sons, Ltd.     

A Novel Extract of Gymnema sylvestre Improves Glucose Tolerance In Vivo and Stimulates Insulin Secretion and Synthesis In Vitro

Herbal medicines, especially plant‐derived extracts, have been used to treat Type 2 diabetes mellitus (T2DM) for many centuries, and offer the potential of cheap and readily available alternatives to conventional pharmaceuticals in developing countries. Extracts of Gymnema sylvestre (GS) have anti‐diabetic activities and have been used as a folk medicine in India for centuries. We have investigated the effects of a novel high molecular weight GS extract termed OSA® on glucose tolerance in insulin‐resistant ob/ob mice, and on insulin secretion and synthesis by isolated mouse islets. Single administration of OSA® (500 mg/kg) to ob/ob mice 30 min before an intraperitoneal glucose load improved their abnormal glucose tolerance. In vitro studies indicated that OSA® (0.25 mg/ml) initiated rapid and reversible increases in insulin secretion from isolated mouse islets at substimulatory (2 mM) and stimulatory (20 mM) glucose concentrations. In addition, prolonged treatment (24–48 h) of mouse islets with OSA® elevated the expression of preproinsulin mRNA and maintained the total insulin content of mouse islets in the presence of stimulated insulin secretion. These effects of OSA® are consistent with its potential use as a therapy for the hyperglycemia associated with obesity‐related T2DM. Copyright © 2012 John Wiley & Sons, Ltd.     

MDG-1, a polysaccharide from Ophiopogon japonicus exerts hypoglycemic effects through the PI3K/Akt pathway in a diabetic KKAy mouse model

Ethnopharmacological relevance

Ophiopogon japonicus is a traditional Chinese medicine that might be helpful for the treatment of type 2 diabetes. Recent studies have confirmed its beneficial properties, but not the mechanism of action.

Aim of study

In this study, we examined the effects of a water-soluble β-d-fructan (MDG-1) from O. japonicus on type 2 diabetes through the PI3K/Akt pathway in a diabetic KKAy mouse model.

Materials and methods

MDG-1 was extracted from the tube root of O. japonicus and purified as described previously ( Xu et al., 2005). The KKAy mice were gavaged once daily with either distilled water, MDG-1or rosiglitazonefor 8 weeks. Blood glucose levels were tested regularly for the fed and fasted mice. In order to evaluate the effect of MDG-1 on disease progression, the proteins of InsR/IRS-1/PI3K/Akt/GSK-3/Glut-4 were detected by Western blotting and serum TG, TC, HDL-C, LDL-C were also dertermined.

Results

MDG-1 reduced the hyperglycemia, hyperinsulinemia and hyperlipidemia in the KKAy mice. The oral glucose tolerance test (OGTT) and the level of insulin in the serun showed that insulin resistance in KKAy mice was ameliorated after MDG-1 treated. After 8 weeks treatment with 300 mg/kg MDG-1, the content of triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) the serum decreased significantly. Meanwhile high density lipoprotein cholesterol (HDL-C) content increased notably. MDG-1 did not have any effect on total cholesterol (TC) content in the serum, whereas rosiglitazone significantly decreased the TC content. In addition, MDG-1 upregulates the phosphoinositide 3-kinase p85 subunit, Akt, insulin receptor (InsR), insulin receptor substrate-1 (IRS-1) and Glut-4 expression, but downregulates glycogen synthase kinase 3β expression.

Conclusions

These data indicate that MDG-1 has remarkable anti-diabetic activity through the InsR/IRS-1/PI3K/Akt/GSK-3/Glut-4 signaling pathway. We believe that MDG-1 is a promising anti-diabetic compound that will be helpful for the treatment of T2DM.     

Triterpenoids‐Enriched Extract from the Aerial Parts of Salvia miltiorrhiza Regulates Macrophage Polarization and Ameliorates Insulin Resistance in High‐Fat Fed Mice

Adipose tissue inflammation and macrophage polarization are tightly associated with the development of obesity‐associated insulin resistance. Our previous studies have demonstrated the triterpenoids‐enriched extract from the aerial parts of Salvia miltiorrhiza (TTE) could significantly improve atherosclerosis in LDLR^?/? mice. However, its molecular mechanisms of TTE ameliorating insulin resistance remain unclear. In the present study, obesity model with insulin resistance induced by feeding high‐fat diet (HFD) was established. Dietary TTE attenuated hyperlipidemia, improved glucose intolerance in mice and mediated the activation of IRS‐1/PI3K/Akt insulin signaling pathway. Meanwhile, dietary TTE also attenuated macrophage infiltrations into adipose tissue and modified the phenotype ratio of M1/M2 macrophages. Furthermore, our results showed that TTE regulated the polarization of macrophages partly via adenosine monophosphate‐activated kinase (AMPK). Taken together, these findings suggested that TTE has a potential clinical utility in improving insulin resistance. Its mechanisms might be contributed to its beneficial effects on macrophage polarization via AMPK. Copyright © 2016 John Wiley & Sons, Ltd.     

Tinospora cordifolia preserves pancreatic beta cells and enhances glucose uptake in adipocytes to regulate glucose metabolism in diabetic rats

The purpose of this study was to evaluate the pancreatic beta cell protective and glucose uptake enhancing effect of the water extract of Tinospora cordifolia stem (TCSE) by using rat insulinoma (RIN)‐m5F cells and 3 T3‐L1 adipocytes. RIN‐m5F cells were stimulated with interleukin‐1β and interferon‐γ, and the effect of TCSE on insulin secretion and cytokine‐induced toxicity was measured by ELISA and MTT assay, respectively. The glucose uptake and protein expression were measured by fluorometry and western blotting. Antidiabetic effect of TCSE was measured using streptozotocin‐induced diabetic rats. TCSE dose dependently increased cell viability and insulin secretion in RIN‐m5F cells. In addition, TCSE increased both the glucose uptake and glucose transporter 4 translocation in 3 T3‐L1 adipocytes via PI3K pathway. Finally, TCSE significantly lowered blood glucose and diet intake and increased body weight in streptozotocin‐induced diabetic rats. The level of serum insulin and hepatic glycogen was increased, whereas the level of serum triglyceride, total cholesterol, dipeptidyl peptidase‐4, and thiobarbituric acid reactive substances was decreased in TCSE‐administered rats. TCSE also increased glucose transporter 4 protein expression in the adipose tissue and liver of TCSE‐fed diabetic rats. Our results suggested that TCSE preserved RIN‐m5F cells from cytokine‐induced toxicity and enhanced glucose uptake in 3 T3‐L1 adipocytes, which may regulate glucose metabolism in diabetic rats.     

The Beneficial Effect of Anthocyanidin‐Rich Vitis vinifera L. Grape Skin Extract on Metabolic Changes Induced by High‐Fat Diet in Mice Involves Antiinflammatory and Antioxidant Actions

We hypothesized that a polyphenol‐rich extract from Vitis vinifera L. grape skin (GSE) may exert beneficial effects on obesity and related metabolic disorders induced by a high‐fat diet (HFD). C57/BL6 mice were fed a standard diet (10% fat, control, and GSE groups) or an HFD (60% fat, high fat (HF), and HF + GSE) with or without GSE (200 mg/kg/day) for 12 weeks. GSE prevented weight gain; dyslipidemia; insulin resistance; the alterations in plasma levels of leptin, adiponectin, and resistin; and the deregulation of leptin and adiponectin expression in adipose tissue. These beneficial effects of GSE may be related to a positive modulation of insulin signaling proteins (IR, pIRS, PI3K, pAKT), pAMPK/AMPK ratio, and GLUT4 expression in muscle and adipose tissue. In addition, GSE prevented the oxidative damage, evidenced by the restoration of antioxidant activity and decrease of malondialdehyde and carbonyl levels in muscle and adipose tissue. Finally, GSE showed an anti‐inflammatory action, evidenced by the reduced plasma and adipose tissue inflammatory markers (TNF‐α, IL‐6). Our results suggest that GSE prevented the obesity and related metabolic disorders in HF‐fed mice by regulating insulin sensitivity and GLUT4 expression as well as by preventing the oxidative stress and inflammation in skeletal muscle and adipose tissue. Copyright © 2017 John Wiley & Sons, Ltd.     

Vitis vinifera (grape) seed extract and resveratrol alleviate bisphenol‐A‐induced metabolic syndrome: Biochemical and molecular evidences

The mechanisms of bisphenol‐A (BPA)‐induced metabolic syndrome as well as the protective role of grape seed extract (GSE) and resveratrol were investigated. Rats were treated with BPA (0 and 35 mg·kg^?1·day^?1, gavage) plus resveratrol (25, 50, and 100 mg·kg^?1·day^?1, i.p.) or GSE (3, 6, 12 mg·kg^?1·day^?1, i.p.) or vitamin E (200 IU/kg/every other day, i.p.). After 2 months, mean systolic blood pressure, serum lipid profile, glycaemia, and fat index were examined. By enzyme‐linked immunosorbent assay, the serum concentrations of insulin, leptin, adiponectin, and paraoxonase 1, and by real‐time polymerase chain reaction as well as western blotting, key liver elements in cholesterol hemostasis (LDLR, CYP7A1, ABCG5 and 8) and insulin signaling (p‐Akt/Akt and p‐PI3K/PI3K) were measured. BPA increased mean systolic blood pressure, total cholesterol, and low‐density lipoprotein cholesterol and reduced paraoxonase1 and the hepatic expression of both ABCG5 and ABCG8. It increased the body fat index, leptin, adiponectin, insulin, and glycaemia level and decreased the hepatic protein expression of p‐Akt/Akt and p‐PI3K/PI3k. GSE, resveratrol, or vitamin E coadministration along with BPA restored the detrimental effects of BPA in some levels. Herein, the predisposing effects of BPA‐induced metabolic syndrome were restored by GSE and resveratrol, linked to the regulation of insulin signaling, ABCG8 expression, and their antioxidant properties.     

Arctium lappa contributes to the management of type 2 diabetes mellitus by regulating glucose homeostasis and improving oxidative stress: A critical review of in vitro and in vivo animal‐based studies

Diabetes is a metabolic disease highly widespread worldwide, and the most common form is the type 2 diabetes mellitus (T2DM). A large number of synthetic drugs are currently available for the treatment of diabetes; however, they present various side effects and, for this reason, people are increasingly inclined to search natural alternative treatments. Among these, Arctium lappa (A. lappa) has interesting anti‐diabetic activities, exerted by improving glucose homeostasis and reducing insulin‐resistance. In addition, A. lappa exerts a marked antioxidant activity, an effect known to play a pivotal role in the treatment of T2DM. The purpose of this review is to analyse scientific evidence in order to evaluate the role of A. lappa and its bioactive compounds in management of T2DM. The literature search performed provided only in vitro and animal‐based studies. No clinical studies have been conducted in order to investigate the effect of A. lappa on T2DM patients. However, available literature provides evidence for further clinical trials in order to confirm these claimed activities on humans.     

Poncirin downregulates ATP‐binding cassette transporters to enhance cisplatin sensitivity in cisplatin‐resistant osteosarcoma cells

Poncirin, a flavanone glycoside with bitter taste extracted from dried immature fruit of Poncirus trifoliate, exhibits multiple biological activities including anti‐tumor activity. Our study aimed to determine the effect and potential mechanism of poncirin on cisplatin resistance in osteosarcoma (OS) cells. CCK‐8, flow cytometry analysis, and caspase‐3/7 activity assays were used to evaluate cisplatin sensitivity. The expression changes of multidrug resistance 1 (MDR1), multidrug resistance‐associated protein (MRP1), breast cancer resistance protein (BCRP), and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway‐related proteins were detected by RT‐qPCR or western blot analyses. Results showed that poncirin exposure enhanced cisplatin sensitivity, promoted apoptosis, and increased caspase‐3/7 activity in cisplatin‐resistant OS cells. Poncirin decreased the expression levels of MDR1, MRP1, and BCRP, and inhibited the PI3K/Akt signaling in OS cells. Rescue experiments suggested that activation of the PI3K/Akt signaling by 740Y‐P abolished poncirin‐induced expression reduction of MDR1, MRP1, and BCRP, and attenuated the facilitative effects of poncirin on cisplatin sensitivity and apoptosis in cisplatin‐resistant OS cells. In summary, poncirin suppressed cisplatin resistance in cisplatin‐resistant OS cells by downregulating the expression of MDR1, MRP1, and BCRP through inhibiting the PI3K/Akt pathway.