Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy

Naringin prevents HIV-1 protease inhibitors-induced metabolic complications in vivo.

Insulin resistance, glucose intolerance and overt diabetes are known metabolic complications associated with chronic use of HIV-Protease Inhibitors. Naringin is a grapefruit-derived flavonoid with anti-diabetic, anti-dyslipidemia, anti-inflammatory and anti-oxidant activities.The study investigated the protective effects of naringin on glucose intolerance and impaired insulin secretion and signaling in vivo.Male Wistar rats were divided into six groups (n = 6) and were daily orally treated with distilled water {3.0 ml/kg body weight (BW)}, atazanavir (133 mg/kg BW), saquinavir (333 mg/kg BW) with or without naringin (50 mg/kg BW), respectively for 56 days. Body weights and water consumption were recorded daily. Glucose tolerance tests were carried out on day 55 of the treatment and thereafter, the rats were sacrificed by halothane overdose.Atazanavir (ATV)- or saquinavir (SQV)-treated rats exhibited significant weight loss, polydipsia, elevated Fasting blood glucose (FBG), reduced Fasting Plasma Insulin (FPI) and expression of phosphorylated, Insulin Receptor Substrate-1 (IRS-1) and Akt proteins, hepatic and pancreatic glucokinase levels, and also increasing pancreatic caspase-3 and -9 as well as UCP2 protein expressions compared to controls, respectively. These effects were completely reversed by naringin treatment.Naringin prevents PI-induced glucose intolerance and impairment of insulin signaling and as nutritional supplement it could therefore alleviate metabolic complications associated with antiretroviral therapy

Naringin Reduces Hyperglycemia-Induced Cardiac Fibrosis by Relieving Oxidative Stress.

INTRODUCTION:Hyperglycemia promotes myocardial fibrotic lesions through upregulation of PKC and p38 in response to redox changes. The effects of naringin on hyperglycemia-induced myocardial fibrotic changes and its putative effects on PKC-β and p38 protein expression in type 1 rat model of diabetes are hereby investigated. METHODS:Male Sprague-Dawley rats were divided into six groups I-VI. Groups I and II, were orally treated with distilled water {3.0 ml/kg body weight (BW)} and naringin (50 mg/kg BW), respectively. Groups III, IV, V and VI were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg, BW) and were similarly treated with subcutaneous insulin (8.0 I.U/kg BW, twice daily), naringin (50 mg/kg BW), distilled water (3.0 ml/Kg BW) and ramipril (3.0 mg/kg/BW), respectively. The animals were sacrificed after 56 days by halothane overdose; blood and heart samples removed for further analysis. RESULTS:The untreated diabetic rats exhibited significantly increased oxidative stress, NADPH oxidase activity, increased cardiac fibrosis, PKC-β and p38 mitogen activated protein kinase expression compared to controls. Naringin treatment significantly ameliorated these changes in diabetic rats compared to the untreated diabetic controls. CONCLUSIONS:Naringin's amelioration of myocardial fibrosis by modulating p38 and PKC-β protein expression possibly through its known antioxidant actions and may therefore be useful in retarding the progression of fibrosis in a diabetic heart

Synergism Potentiates Oxidative Antiproliferative Effects of Naringenin and Quercetin in MCF-7 Breast Cancer Cells

Breast cancer (BC) is the most frequently diagnosed type of cancer as of 2020. Quercetin (Que) and Naringenin (Nar) are predominantly found in citrus fruits and vegetables and have shown promising antiproliferative effects in multiple studies. It is also known that the bioactive effects of these flavonoids are more pronounced in whole fruit than in isolation. This study investigates the potential synergistic effects of Que and Nar (CoQN) in MCF-7 BC cells. MCF-7 cells were treated with a range of concentrations of Que, Nar or CoQN to determine cell viability. The IC50 of CoQN was then used to investigate caspase 3/7 activity, Bcl-2 gene expression, lipid peroxidation and mitochondrial membrane potential to evaluate oxidative stress and apoptosis. CoQN treatment produced significant cytotoxicity, reduced Bcl-2 gene expression and increased caspase 3/7 activity compared to either Nar or Que. Furthermore, CoQN significantly increased lipid peroxidation and reduced mitochondrial membrane potential (MMP) compared to either Nar or Que. Therefore, CoQN treatment has potential pharmacological application in BC chemotherapy by inducing oxidative stress and apoptosis in MCF-7 BC cells. The results of this study support the increased consumption of whole fruits and vegetables to reduce cell proliferation in cancer

Changes in live body weights between days 0 and 56 of treatment.

<p>(^#p = 0.0153 compared to control, * p = 0.0153 compared to ATV and SQV, respectively).</p

Naringin prevents HIV-1 protease inhibitors-induced metabolic complications <i>in vivo</i> - Fig 3

<p><b>A</b>) Fasting Blood Glucose concentrations. ***p < 0.0001 compared to control and ^@p < 0.0001 compared to ATV or SQV, respectively. <b>B</b>) Calculated AUC from Glucose Tolerance Tests- time curves. (*, ***p < 0.05 compared to control, and ^&, ^@p < 0.0001 compared to ATV or SQV, respectively).</p

Total ATP concentrations in homogenized pancreatic tissues.

<p>*, *** p < 0.05 compared to controls and ^$, ^ p < 0.05 compared to ATV and SQV, respectively.</p

Glucokinase levels in homogenized.

<p><b>A)</b> Liver and <b>B)</b> Pancreatic tissues. *, ** p < 0.05 compared to control and ^$, ^ p < 0.05 compared to ATV and SQV, respectively.</p

Fasting plasma insulin concentrations.

<p>^&, ^@p < 0.0001 compared to control and *, ^#p < 0.0001 compared to ATV and SQV, respectively.</p

Genetic polymorphisms of organic cation transporters 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes mellitus : a systematic review protocol

CITATION: Mato, E. P. M. et al. 2018. Genetic polymorphisms of organic cation transporters 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes mellitus : a systematic review protocol. Systematic Reviews, 7:105, doi:10.1186/s13643-018-0773-y.The original publication is available at https://systematicreviewsjournal.biomedcentral.comBackground: Metformin is one of the most commonly used drugs for type 2 diabetes mellitus (T2DM). Despite its efficacy and safety, metformin is frequently associated with highly variable glycemic responses, which is hypothesized to be the result of genetic variations in its transport by organic cation transporters (OCTs). This systematic review aims to highlight and summarize the overall effects of OCT1 polymorphisms on therapeutic responses to metformin and to evaluate their potential role in terms of interethnic differences with metformin responses. Methods/design: We will systematically review observational studies reporting on the genetic association between OCT1 polymorphisms and metformin responses in T2DM patients. A comprehensive search strategy formulated with the help of a librarian will be used to search MEDLINE via PubMed, Embase, and CINAHL for relevant studies published between January 1990 and July 2017. Two review authors will independently screen titles and abstracts in duplicate, extract data, and assess the risk of bias with discrepancies resolved by discussion or arbitration of a third review author. Mined data will be grouped according to OCT1 polymorphisms, and their effects on therapeutic responses to metformin will be narratively synthesized. If sufficient numbers of homogeneous studies are scored, meta-analyses will be performed to obtain pooled effect estimates. Funnel plots analysis and Egger’s test will be used to assess publication bias. This study will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Discussion: This review will summarize the genetic effects of OCT1 polymorphisms associated with variabilities in glycemic responses to metformin. The findings of this study could help to develop genetic tests that could predict a person’s response to metformin treatment and create personalized drugs with greater efficacy and safety. Systematic review registration: Registration number: PROSPERO, CRD42017079978https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-018-0773-yPublisher's versio