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Naringin attenuates alcoholic liver injury by reducing lipid accumulation and oxidative stress

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: Alcoholic liver disease (ALD) is a leading health risk worldwide, which can induce hepatic steatosis, progressive fibrosis, cirrhosis and even carcinoma. As a potential therapeutic drug for ALD, naringin, an abundant flavanone in grapefruit, could improve resistance to oxidative stress and inflammation and protects against multiple organ injury. However, the specific mechanisms responsible for protection against alcoholic injury remain not fully understood. In this study, we aim to investigate the effect and the regulatory mechanisms of naringin in the liver and whole body after alcohol exposure under zebrafish larvae system. Main methods: At 96 h post fertilization (hpf), larvae from wild-type (WT) and transgenic zebrafish, with liver-specific eGFP expression (Tg(lfabp10 alpha: eGFP)), were exposed to 2% ethanol for 32 h to establish an ALD model. Different endpoints, such as morphological changes in liver shape and size, histological changes, oxidative stress-related free radical levels, apoptosis and the expression of certain genes, were chosen to verify the essential impact of naringin in alcohol-induced liver lesions. Key findings: Subsequent experiments, including Oil red O, Nile red, pathological hematoxylin and eosin (H&E), and TUNEL staining and qPCR, revealed that naringin treatment reduced alcoholic hepatic steatosis, and this inhibitory effect was dose dependent. Specifically, a 25 mg/L dose resulted in an almost normal response. Significance: This finding suggested that naringin may inhibit alcoholic-induced liver steatosis and injury by attenuating lipid accumulation and reducing oxidative stress and apoptosis.

IF:3.45

Development and characterization of late-stage diabetes mellitus and -associated vascular complications

期刊: LIFE SCIENCES, 2019; 216 ()

Preclinical investigation is the key mark of medical research, as the major breakthroughs including treatment of devastating diseases in biomedical research have been led by animal studies. Type 2 diabetes mellitus (T2DM) is a predominant metabolic disorder having high prevalence of morbidity worldwide which create an urgent need to understand the pathogenesis, complication and other possible influences by development of appropriate animal model. High-fat diet (HFD) fed animals (21 days) were treated with single cycle of repetitive dose (SCRD) of streptozotocin (STZ; 40, 30 and 20 mg/kg/per day in three respective group at 1st, 3rd, and 5th day) and double cycle of repetitive dose (DCRD) of streptozocin (STZ) (20, 10 and 5 mg/kg/per day in three respective group at 1st, 3rd, and 5th day in one cycle and 21st, 23rd, 25th day in second cycle of treatment) to induce late-stage diabetic complications. Induction of hyperglycemia was assessed by fasting and postprandial blood glucose, HbA1c, insulin, C-peptide, pancreatic beta-cells and dyslipidaemia up to 12 weeks. Combined treatment of HFD and STZ (20 mg/kg) in the DCRD manner were significantly induced late-stage diabetic complication with sustained hyperglycaemia, no mortality, increased HbA1c and dyslipidaemia, reduced insulin, C-peptide and beta cells. Moreover, biochemical and histological assessment of micro and macrovascular tissues confirmed the significant cardio-renal injury, endothelial and hepatic damage. The study confirmed the development of chronic diabetic model in rat mimicked to clinical pathology with associated micro and macrovascular abnormalities which can further explore the molecular aspects of diseases.

IF:3.45

IGF-1 and somatocrinin trigger islet differentiation in human amniotic membrane derived mesenchymal stem cells

期刊: LIFE SCIENCES, 2019; 216 ()

Aim: To induce differentiation of human amniotic membrane derived mesenchymal stem cells (hAMMSCs) into insulin producing cells (IPCs) by treating with somatocrinin or growth hormone releasing hormone (GHRH) and Insulin-like growth factor-1 (IGF-1). Main method: In this investigation, we cultivated and characterized hAMMSCs and then treated with IGF-1 and somatocrinin to find out whether this combination gives better yield of insulin producing cells. We showed that hAMMSCs can give rise to IPCs on exposure to serum-free defined media containing specific growth factors and differentiating agents in presence of IGF-1 and somatocrinin. Key finding: A combination of IGF-1 and somatocrinin lead to differentiation of large number of IPCs from hAMMSCs. These IPCs were found to be positive for dithizone indicating their insulin secretory mechanism. Moreover these cells were also found to be positive for C-peptide. IPCs released insulin in response to glucose challenge. Gene expression analysis exhibited significant up-regulation of pancreatic transcription factor GLUT2 and Insulin. Significance: Our data thus demonstrates for the first time that somatocrinin and IGF-1 synergistically enhance the differentiation of hAMMSCs into IPCs.

IF:3.45

Involvement of inducible nitric oxide synthase and estrogen receptor ESR2 (ER beta) in the vascular dysfunction in female type 1 diabetic rats

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: Inflammation is involved in diabetes-related vascular dysfunction. Estrogen receptor ESR2/ER beta induces the expression of inducible nitric oxide (NO) synthase (iNOS) and inflammation. The present study investigated the effect of alloxan-induced type 1 diabetes on the iNOS and ESR2 expression and the effect of the chronic iNOS inhibition on the vascular smooth muscle dysfunction in diabetic female rats. In addition, we evaluated the involvement of ESR2 in iNOS expression. Main methods: Alloxan-induced diabetic female rats were treated or not with iNOS inhibitor (L-NIL). iNOS and ESR2 immunostaining, S-nitrosylated proteins and IL-1 beta protein expression in aorta and plasmatic NO levels were analyzed. Contractile response to noradrenaline was analyzed in endothelium-denuded aorta. iNOS mRNA expression was analyzed in isolated aortic smooth muscle cells (ASMCs) of female rats, incubated with 22 mM glucose and an ESR2 antagonist. Key findings: Aortic iNOS and ESR2 immunostaining, S-nitrosylated proteins, IL-1 beta protein expression and plasmatic NO levels were all increased, whereas noradrenaline-induced contraction was reduced in aorta of diabetic female rats. With the exception of iNOS and ESR2 immunostaining, all these parameters were corrected by L-NIL treatment. High glucose increased iNOS mRNA expression in ASMCs, which was reduced by an ESR2 antagonist. Significance: We demonstrated that increased iNOS-NO contributed to the impairment of the contractile response of aortic smooth muscle cells in female type 1 diabetic rats and that increased expression of iNOS may involve the participation of ESR2/ER beta.

IF:3.45

miR-141 alleviates LPS-induced inflammation injury in WI-38 fibroblasts by up-regulation of NOX2

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: The roles of miR-141 in various types of cancers and inflammatory bowel diseases are researched, whereas, little information about its function in lung inflammation is available. This study was designed to explore the effect of miR-141 on inflammation injury in WI-38 cells, possibly providing basis for targeted therapeutic strategy for treatment of infantile pneumonia. Main methods: WI-38 cells were treated with LPS to construct cell model with inflammation injury. Expressions of miR-141 and NOX2 were altered by transfection assay and expressions of them were detected by qRT-PCR or Western blot. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry, respectively. The tested pro-inflammatory factors were analyzed by qRT-PCR and Western blot; and their productions were quantified by ELISA. Main proteins participating in regulation of apoptosis, p38 MAPK pathway and NF-kappa B pathway were analyzed by Western blot. Key findings: miR-141 was down-regulated in LPS-treated cells and elevating miR-141 level reduced inflammation extent of WI-38 cells by promoting viability, inhibiting apoptosis, and inhibiting production of tested pro-inflammatory cytokines. NOX2 was up-regulated by miR-141 overexpression. NOX2 silence impaired the cell-protective effect of miR-141. miR-141 inhibited LPS-induced activations of p38 MAPK and NF-kappa B pathways, which was also mediated by NOX2. Significance: miR-141 alleviated LPS-induced inflammation injury in WI-38 fibroblasts by up-regulating NOX2 and further inhibiting p38 MAPK and NF-kappa B pathways.

IF:3.45

Alpinumisoflavone causes DNA damage in Colorectal Cancer Cells via blocking DNA repair mediated by RAD51

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: Colorectal Cancer (CRC) accounts for 6.1% incidence and 9.2% mortality worldwide. The current study aimed to investigate the effect of alpinumisoflavone (AIF) on CRC and its possible molecular mechanism. Methods: HCT-116 and SW480 cells were chosen as cell model to study the anti-cancer activity of AIF in vitro experiments. Cells proliferative capacity and clonogenicity were examined by CCK-8 assay and colony formation assay, while cell apoptosis was detected by Hoechst 33258 staining and Flow cytometer. The protein expression levels of related gene were examined by western blotting. Transcriptome analyses were conducted to identify the differentially expressed genes in CRC cells, following AIF treatment. DNA damage was examined by gamma H2AX foci assay. The anti-cancer effect of AIF in vivo was validated in CRC xenograft model. Key findings: We found that AIF inhibited CRC cell proliferation and promoted apoptosis in a dose-dependent manner, as well as increased the number of gamma-H2AX foci. In addition, microarray analysis showed that the DNA-double strand break (DSB) repair gene RAD51 was aberrantly overexpressed in CRC tissues, and was positively correlated with lymph node metastasis, TNM stage and poor outcomes. Both in vitro and in vivo experiments confirm that AIF treatment significantly decreased RAD51 levels. Knockdown RAD51 could enhance the anticancer activity of AIF against CRC, while abrogated by RAD51 overexpression. Significance: These findings suggest that AIF can be regarded as a potential anti-cancer drug and provide new insights into CRC treatment.

IF:3.45

Emerging role of Unfolded Protein Response (UPR) mediated proteotoxic apoptosis in diabetes

期刊: LIFE SCIENCES, 2019; 216 ()

Endoplasmic reticulum (ER) is a crucial single membrane organelle that acts as a quality control system for cellular proteins as it is intricately involved in their synthesis, folding and trafficking to the respective targets. Type 2 diabetes is characterized by enhanced blood glucose level that promotes insulin resistance and hampers cellular glucose metabolism. Hyperglycemia provokes mitochondrial ROS production and glycation of proteins which exert a tremendous load on ER for conventional refolding of misfolded/unfolded and nascent proteins that perturb ER homeostasis resulting in apoptotic cell death. Impairment in ER functions is suspected to be through specific ER membrane-bound proteins known as Unfolded Protein Response (UPR) sensor proteins. Conformational changes in these proteins induce oligomerization and cross-autophosphorylation which facilitate processes required for the restoration of ER homeostatic imbalance. Multiple studies have reported the involvement of UPR mediated autophagy and apoptotic pathways in the progression of metabolic disorders including diabetes, cardiac ischemia/reperfusion injury and hypoxia-mediated cell death. In this review, the involvement of UPR pathways in the progression of diabetes associated complications have been addressed, which underscores molecular crosstalks during neuropathy, nephropathy, hepatic injury and retinopathy. A better understanding of these molecular interventions may reveal advanced therapeutic approaches for preventing diabetic comorbidities. The article also highlights the importance of phytochemicals that are emerging as novel ER stress inhibitors and are being explored for targeted interaction in preventing cell death responses during diabetes.

IF:3.45

Tilianin mediates neuroprotection against ischemic injury by attenuating CaMKII-dependent mitochondrion-mediated apoptosis and MAPK/NF-kappa B signaling

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: Tilianin, a naturally occurring flavonoid glycoside, possesses versatile biological activities including antioxidant, anti-inflammatory, energy collecting and anti-hypoxic effects. Little is known about the mechanisms underlying the effect of tilianin against ischemic injury in neuronal cells. We aimed to determine the potential targets and mechanisms of tilianin treatment behind the crosstalk pathways induced by oxygen-glucose deprivation (OGD). Main methods: We used an in silico docking model for interaction mode analysis and in vitro models for mechanistic exploration and target verification. Protein changes were measured using cellular immunofluorescence and ELISA techniques. Key findings: The ability of tilianin to promote recovery of OGD-induced neurocytotoxic injury was demonstrated by maintenance of cell viability, membrane integrity and nuclear homogeneity. Tilianin treatment was also found to balance the concentrations of proapoptotic and antiapoptotic proteins that had been modified by OGD-induced mitochondrial dysfunction. Of these intersectional cascades, Ca2+/calmodulin-dependent protein kinase II (CaMKII) was found to bind efficiently with tilianin. This presented a certain binding score along with down-regulation of ox-CaMKII and p-CaMKII in SH-SY5Y cells affected by OGD. Importantly, after utilizing KN93, one specific CaMKII inhibitor, tilianin-mediated neuroprotection against OGD was abolished. This effect was accompanied by upregulation of mitochondrial function. Thus, the beneficial effects of tilianin toward mitochondrion-mediated apoptosis and p38/JNK/NF-kappa B-associated inflammatory pathways were reversed following CaMKII inhibition. Significance: Our study indicated that attenuation of CaMKII-linked signaling mediated through mitochondria and p38/JNK/NF-kappa B inflammatory pathways is a key mechanism by which tilianin exerts its neuroprotective effects against cerebral ischemia.

IF:3.45

Reduced TIPE2 expression is inversely associated with proinflammatory cytokines and positively correlated with bone mineral density in patients with osteoporosis

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: The tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) participates in multiple inflammatory diseases. However, its underlying mechanism in osteoporosis has not been elucidated. The aim of current study is to preliminarily clarify the function of TIPE2 in the pathogenesis of osteoporosis. Main methods: TIPE2 expression in patients with osteoporosis was measured by Western blot and qRT-PCR methods. Proinflammatory cytokines including TNF-alpha, IL-1 and IL-6 were assessed via enzyme-linked immunosorbent assay. Serum fasting PINP and beta-CTX were measured by the chemiluminescence method. Simple logistic regression analysis was performed for the odds ratio (OR) for TIPE2. Key findings: TIPE2 expression in patients with osteoporosis was dramatically decreased and negatively correlated with proinflammatory cytokines. Furthermore, TIPE2 level was negatively correlated with fasting beta-CTX, but not PINP, indicating that TIPE2 participates in the pathogenesis of osteoporosis dominantly by supression of bone resorption. Interestingly, TIPE2 expression level was positively correlated with bone mineral density (BMD), and its expression level can predict the risk of bone fracture using the simple logistic regression assay. Significance: Our findings clarify that TIPE2 alleviates the pathogenesis of osteoporosis by suppressing the inflammatory status and the ability of TIPE2 for predicts bone fracture further demonstrated that TIPE2 might serve as a novel diagnostic marker and a therapeutic target for osteoporosis.

IF:3.45

Diosmetin as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive activity in mice

期刊: LIFE SCIENCES, 2019; 216 ()

Diosmetin is an O-methylated flavone found naturally in citrus fruit, and it was identified in Amphilophium crucigerum (L.), a plant popularly used as an analgesic. This compound had different pharmacological effects and presented a chemical structure like the flavonoid eriodyctiol that exhibited antinociceptive effects by TRPV1 antagonism. However, the possible antinociceptive effect of this compound was not well documented. Thus, the goal of the present study was to evaluate the antinociceptive effect of diosmetin and its mechanism of action. The diosmetin effect on different pain models and its possible adverse effects were assessed on adult Swiss male mice (25-30 g). Mice spinal cord samples were used on calcium influx and binding assays using TRPV1 agonists. First, it was observed that the diosmetin reduced calcium influx mediated by capsaicin in synaptosomes and displace the specific binding to [H-3]-resiniferatoxin in membrane fractions from the spinal cord of mice. Diosmetin (0.15 to 1.5 mg/kg, intragastric, i.g.) presented antinociceptive and antiedematogenic effect in the capsaicin intraplantar test and induced antinociception in a noxious heat test (48 degrees C). Also, treatment with diosmetin reduced mechanical and heat hypersensitivity observed in a model of inflammatory or neuropathic pain. Acute diosmetin administration in mice did not induce locomotor or body temperature changes, or cause liver enzyme abnormalities or alter renal function. Moreover, there were no observed changes in gastrointestinal transit or induction of ulcerogenic activity after diosmetin administration. In conclusion, our results support the antinociceptive properties of diosmetin which seems to occur via TRPV1 antagonist in mice.

IF:3.45

Modulation of inducible nitric oxide synthase pathway by eugenol and telmisartan in carbon tetrachloride-induced liver injury in rats

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: Inducible nitric oxide synthase (iNOS) pathway has been in the limelight since its discovery as a key mediator in the process of liver fibrogenesis. Therefore, the objective of the current study was to elucidate the in vivo molecular mechanism underlying the hepatic preventive relevance of eugenol (EUG) and telmisartan (TEL) through iNOS pathway modulation against carbon tetrachloride (CCl4)-induced hepatic injury. Methods: Sixty healthy male albino rats were used in this study. Serum aminotransferases activities and NO levels were assessed. Hepatic malondialdehyde (MDA), total nitrite/nitrate content and reduced glutathione (GSH) concentration were estimated. Liver NF-kB, TNF-alpha, IL-6 and iNOS proteins expressions were investigated by western blot assay. Histopathological examination was done. Key findings: CCl4 resulted in damage to centrilobular regions of the liver, elevation of serum aminotransferases, rise in oxidative parameters level, and up-regulation of NF-kB, TNF-alpha, IL-6 as well as iNOS proteins expressions. Treatment of fibrotic rats with either EUG or TEL significantly alleviated CCl4-induced biochemical, inflammatory and histopathological changes. Moreover, the combined administration of EUG with TEL has an ameliorative effect which is greater than either of them alone. Significance: In conclusion, the combination therapy between EUG and TEL is more effective than either drug alone which is attributed to suppression of NO production and iNOS protein expression. The results support that use of EUG and TEL exerts beneficial effects in the attenuation of CCl4-induced liver fibrosis in rats.

IF:3.45

Histone deacetylase 2 regulates the doxorubicin (Dox) resistance of hepatocarcinoma cells and transcription of ABCB1

期刊: LIFE SCIENCES, 2019; 216 ()

Histone deacetylases (HDACs) can regulate cell-cycle, differentiation, and apoptosis of hepatocarcinoma (HCC) cells, while their roles in drug sensitivity remain unclear. Our results showed that the expression of HDAC2 was significantly increased in HCC doxorubicin (Dox) resistant cells as compared with their corresponding control cells. Over expression of HDAC2 can increase the cell viability and decrease the Dox sensitivity. Kaplan-Meier Plotter assay revealed that HCC patients with higher levels of HDAC2 had significantly poor prognosis than that of the lower expression patients. Mechanistically studies revealed that HDAC2 can regulate the transcription of ABCB1 via directly binding with its promoter and increasing its expression in Dox resistant HCC cells. Knockdown of HDAC2 significantly inhibited the expression of ABCB1. Co-immunoprecipitation revealed that HDAC2 can bind with c-fos, an important transcription factor of ABCB1, in HCC/Dox cells. Knockdown of c-Fos decreased the binding between HDAC2 and promoter of ABCB1 in HCC/Dox cells. Collectively, our data revealed that HDAC2 can regulate Dox sensitivity of HCC cells and the transcription of ABCB1.

IF:3.45

Eugenol ameliorates insulin resistance, oxidative stress and inflammation in high fat-diet/streptozotocin-induced diabetic rat

期刊: LIFE SCIENCES, 2019; 216 ()

Background: Eugenol, a phenolic compound present in many plant essential oils, demonstrated anti-diabetic activity but the underlying mechanisms are not fully understood. The aim of the present study was to examine the anti-diabetic, anti-oxidative and the anti-inflammatory effect of eugenol in high-fat-diet (HFD) and streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of eugenol on the insulin sensitivity and on skeletal muscle protein contents of glucose transporter-4 (GLUT4) and AMP-activated protein kinase (AMPK) was investigated. Materials and methods: HFD/STZ-induced diabetic rats were treated orally with eugenol (10 mg/kg) for 45 days. After the end of the experiment, blood and skeletal muscle samples were collected. Metformin was used as positive control. Results: The anti-diabetic effects of eugenol were demonstrated by the significant reduction in the levels of serum glucose, triglyceride, cholesterol, Low-density lipoprotein, malondialdehyde and interleukin-6 in the treated group compared to the diabetic group. Additionally, eugenol treatment significantly restored the decreased serum levels of insulin and glutathione when compared to that of the diabetic control rats. The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower in rats treated with eugenol than in the diabetic rats. The skeletal muscle protein contents of GLUT4 and AMPK were higher in the eugenol treated group than in the diabetic control group. Conclusion: Eugenol possesses potent anti-oxidative and anti-inflammatory effect in HFD/STZ-induced diabetic rats. Moreover, eugenol facilitates insulin sensitivity and stimulate skeletal muscle glucose uptake via activation of the GLUT4-AMPK signaling pathway. Eugenol could represent a promising therapeutic agent to prevent type 2 diabetes.

IF:3.45

Geniposide protects PC-12 cells against oxygen and glucose deprivation-induced injury by up-regulation of long-noncoding RNA H19

期刊: LIFE SCIENCES, 2019; 216 ()

Aims: Hypoxic-ischemic encephalopathy (HIE) is a common brain injury disease in neonates, which can lead to neonatal disability and death. Geniposide (GEN) is a main ingredient of Gardenia jasminoides, whose anti-tumor, anti-inflammatory and anti-apoptotic effects have been reported in various diseases. However, the effect of GEN on HIE remains uninvestigated. This study aimed to clarify the protective effect of GEN on PC-12 cells against oxygen and glucose deprivation (OGD)-induced injury. Main methods: PC-12 cells were subjected to OGD treatment, cell viability, cell cycle-associated factors, apoptosis and apoptosis-associated factors were then determined. The different concentrations of GEN were used to stimulate PC-12 cells, and the effects of GEN on cell proliferation and apoptosis in OGD-treatment cells were assessed. Subsequently, relative expression level of H19 was analyzed in PC-12 cells after treatment with GEN. After this, si-H19 was transfected into PC-12 cells to explore the regulatory effect of H19 on PC-12 cells after treatment with GEN and OGD. Besides, PI3K/AKT and Wnt/beta-catenin pathways were examined by western blot assay. Key findings: OGD significantly inhibited cell viability, decreased CyclinD1, CDK4 and CDK6 expression, induced apoptosis and up-regulated Cleaved-Caspase-9/-7/-3 expression in PC-12 cells. GEN treatment obviously alleviated OGD-induced cell injury. Additionally, H19 expression was up-regulated by GEN, and H19 knockdown reversed the protective effect of GEN on PC-12 cells against OGD-induced injury. Finally, GEN activated PI3K/AKT and Wnt/beta-catenin pathways by regulating H19 in OGD-insulted PC-12 cells. Significance: The findings suggested that GEN protected PC-12 cells against OGD-induced injury by up-regulation of H19.

IF:3.45

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