Aromatic hydrocarbon receptors in mitochondrial biogenesis and function.

Mitochondria are ubiquitous membrane-bound organelles that not only play a key role in maintaining cellular energy homeostasis and metabolism but also in signaling and apoptosis. Aryl hydrocarbons receptors (AhRs) are ligand-activated transcription factors that recognize a wide variety of xenobiotics, including polyaromatic hydrocarbons and dioxins, and activate diverse detoxification pathways. These receptors are also activated by natural dietary compounds and endogenous metabolites. In addition, AhRs can modulate the expression of a diverse array of genes related to mitochondrial biogenesis and function. The aim of the present review is to analyze scientific data available on the AhR signaling pathway and its interaction with the intracellular signaling pathways involved in mitochondrial functions, especially those related to cell cycle progression and apoptosis. Various evidence have reported the crosstalk between the AhR signaling pathway and the nuclear factor κB (NF-κB), tyrosine kinase receptor signaling and mitogen-activated protein kinases (MAPKs). The AhR signaling pathway seems to promote cell cycle progression in the absence of exogenous ligands, whereas the presence of exogenous ligands induces cell cycle arrest. However, its effects on apoptosis are controversial since activation or overexpression of AhR has been observed to induce or inhibit apoptosis depending on the cell type. Regarding the mitochondria, although activation by endogenous ligands is related to mitochondrial dysfunction, the effects of endogenous ligands are not well understood but point towards antiapoptotic effects and inducers of mitochondrial biogenesis.

Development of a PCR-RFLP method for detection of D614G mutation in SARS-CoV-2.

In late 2019, an outbreak of respiratory disease named COVID-19 started in the world. To date, thousands of cases of infection are reported worldwide. Most researchers focused on epidemiology and clinical features of COVID-19, and a small part of studies was performed to evaluate the genetic characteristics of this virus. Regarding the high price and low availability of sequencing techniques in developing countries, here we describe a rapid and inexpensive method for the detection of D614G mutation in SARS-CoV-2. Using bioinformatics databases and software, we designed the PCR-RFLP method for D614G mutation detection. We evaluated 144 SARS-CoV-2 positive samples isolated in six months in Northeastern Iran. Our results showed that the prevalent type is S-D in our isolates, and a small number of isolated belongs to the S-G type. Of 144 samples, 127 (88.2%) samples have belonged to type S-D, and 13 (9%) samples typed S-G. The first S-G type was detected on 2020 June 10. We have little information about the prevalence of D614G mutation, and it seems that the reason is the lack of cheap and fast methods. We hope that this method will provide more information on the prevalence and epidemiology of D614G mutations worldwide.

The prophylaxis and treatment potential of supplements for COVID-19.

The global impact of the new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infection that caused COVID-19 has been evident in the last few months from the unprecedented socioeconomic disruption to more than 600,000 deaths. The lack of vaccine and effective therapeutic agents for the disease prompted world-wide effort to test those antiviral therapeutics already in use for other diseases. Another interesting approach has been based on the pathological sequel of the disease that involve severe inflammatory reaction (or the cytokine storm) associated with pneumonia in critically ill patients. This article outlines the prophylaxis therapeutic potential of supplements vitamins and micronutrients in COVID-19. By ameliorating the inflammatory and oxidative stress associated with the disease and some direct antiviral effects, the application of these agents as adjuvants and other alternative approaches are discussed. Available clinical trials including those currently registered on these supplements are scrutinized.

Pharmacological treatments of COVID-19.

The viral infection due to the new coronavirus or coronavirus disease 2019 (COVID-19), which was reported for the first time in December 2019, was named by the World Health Organization (WHO) as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2), because of the very similar genome and also its related symptoms to SARS-CoV1. The ongoing COVID-19 pandemic with significant mortality, morbidity, and socioeconomic impact is considered by the WHO as a global public health emergency. Since there is no specific treatment available for SARS-CoV2 infection, and or COVID-19, several clinical and sub-clinical studies are currently undertaken to find a gold-standard therapeutic regimen with high efficacy and low side effect. Based on the published scientific evidence published to date, we summarized herein the effects of different potential therapies and up-to-date clinical trials. The review is intended to help readers aware of potentially effective COVID-19 treatment and provide useful references for future studies.

The effect of edelfosine on GRA1 and MIC3 expressions in acute toxoplasmosis.

Phosphoinositide-dependent phospholipase-C (PI-PLC) triggers the calcium signaling pathway which plays an important role in dense granule and microneme secretion and pathogenesis of Toxoplasma gondii (T. gondii). There are limited data about the effects of phospholipid analogues against T. gondii. The current study assessed the effect of edelfosine, as a phospholipid analogue, on GRA1 and MIC3 expressions using in vitro and in vivo models of acute toxoplasmosis. Infected Vero cells were treated by edelfosine in two subgroups: 24 h following the cell infection and treatment at the same time of cell infection. Animal study was performed on forty mice in four groups including non-infected, infected untreated, infected edelfosine-treated, and infected pyrimethamine-treated. Gene and protein expression analyses were done using quantitative real-time PCR and western blot, respectively. Edelfosine significantly reduced the GRA1 (P < 0.01) and MIC3 (P < 0.01) mRNA and protein expressions in 24 h following the cell infection and at the same time of cell infection groups. In vivo study showed that the edelfosine significantly reduced the GRA1 expression in eye, and MIC3 expression in brain and liver. Moreover, the edelfosine-treated infected mice had significant higher survival rate compared with uninfected mice. The reducing effect of edelfosine on GRA1 and MIC3 mRNA and protein levels 24 h following the cell infection was more than treatment at the same time of cell infection group. Moreover, the effect of edelfosine on GRA1 and MIC3 expression in animal tissues was variable. These data showed that the edelfosine may decrease the T. gondii excretory/secretory antigens through inhibition of PI-PLC.

Reducing effect of insulin resistance on alpha-synuclein gene expression in skeletal muscle.

BACKGROUND: Alpha-synuclein (SNCA) as the presynaptic protein is expressed in different tissues and prevents insulin-resistance (IR) through increasing glucose-uptake by adipocytes and muscles. However, the effect of insulin metabolism on SNCA expression has scarcely elucidated. In present study we assessed the probable effect of insulin resistance on SNCA expression in muscle C2C12 cells and also skeletal muscle tissues of type 2 diabetic mice. MATERIALS AND METHODS: Sixteen male C57BL/6 mice were divided into two experimental groups, including control and type 2 diabetic mice with IR (induced by high-fat diet + low-dose streptozotocin). The animals of the study involved the measurements of fasting blood glucose, oral-glucose-tolerance-test, as well as fasting plasma insulin. Moreover, insulin-resistant and insulin-sensitive muscle C2C12 cells were prepared. The insulin-resistance was confirmed by the glucose-uptake assay. Comparative quantitative real time PCR was used to assess the SNCA expression. RESULTS: The obtained results have showed a significant ~ 27% decrease in SNCA expression level in muscle tissue of diabetic mice (P = 0.022). Moreover, there was a significant change of SNCA expression in insulin-resistant C2C12 cells (P < 0.001). CONCLUSION: Type 2 diabetes due to insulin-resistance can decrease SNCA gene expression in muscles. In addition to the role of SNCA in cell susceptibility to insulin and glucose uptake, the SNCA expression can also be affected by insulin metabolism.

Effect of insulin-glucose metabolism compared with obesity on adipose omentin gene expression in different models of diabetic C57BL/6 mice.

BACKGROUND: Omentin, releasing by adipose-tissue may be related to glucose metabolism. The omentin circulating levels and the related mRNA expression in visceral adipose-tissue are different in types of diabetes and the exact function of this molecule is still unknown. The aim of this study was to examine omentin gene expression in adipose-tissues of type-1 and type-2 diabetic mice for the investigation of the effects of fat-mass and insulin-glucose metabolism. METHODS: In this study, 36 C57BL/6 mice were divided into four experimental groups, including control, type-1 diabetes (inducted by streptozotocin), type-2 diabetes with obesity (high-fat diet + low-dose-streptozotocin [HFD + STZ]), and type-2 with normal weight (normal-pellet diet + low-dose-streptozotocin [NPD + STZ]). The present study involved the measurements of oral-glucose-tolerance-test and the levels of biochemical parameters, including blood glucose, omentin, insulin, lipid-profile, as well as aminotransferases. In addition, the omentin mRNA expression was evaluated by real-time polymerase-chain-reaction. RESULTS: The results of omentin gene expression analysis showed a significant difference between mRNA expressions in the experimental groups. The plasma omentin levels were significantly higher in type-1 diabetes group and lower in type-2 diabetes with NPD + STZ; however, the plasma omentin levels were not changed in the HFD + STZ group. In addition, the findings of serum-biochemical analysis revealed significant differences, compared to the control-group. CONCLUSIONS: The omentin expression may be affected by insulin and glucose levels in different types of diabetes more than fat-mass, and due to the local activity, the serum omentin may not comply with its gene expression.

Association of Omentin rs2274907 and FTO rs9939609 gene polymorphisms with insulin resistance in Iranian individuals with newly diagnosed type 2 diabetes.

BACKGROUND: Insulin resistance (IR) and fat accumulation in visceral adipose tissue are key players in developing type 2 diabetes (T2D). Several adipose tissue derived-gene polymorphisms are related to higher body mass index (BMI), insulin resistance and T2D. The association of omentin rs2274907 (Val109Asp) and fat-mass and obesity-associated (FTO) rs9939609 gene polymorphisms with overweight/obesity and T2D is controversial. The aim of this study was to determine the association between omentin Val109Asp and FTO rs9939609 polymorphisms and insulin resistance in newly-diagnosed T2D patients. METHODS: The case-control study included 83 newly-diagnosed T2D patients and 85 healthy matched controls, aged 20-80 years. Fasting blood glucose and insulin levels were measured by the enzymatic method and enzyme-linked-immunosorbent assay, respectively. Insulin resistance was calculated using the homeostasis model assessment (HOMA) index. Genotyping was examined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: There are significant differences between both omentin Val109Asp and FTO rs9939609 polymorphisms and studied individuals (P = 0.011 and P = 0.0001, respectively). Both genetic polymorphisms of omentin Val109Asp and FTO rs9939609 (T/A) are significantly related to higher HOMA index (P = 0.030 and P = 0.046, respectively). However, omentin Val109Asp polymorphism was only related to individuals who were overweight/obese. Additionally, both omentin Val109Asp and FTO rs9939609 polymorphisms were significantly positively correlated to familial history of diabetes (P = 0.046 and P = 0.024, respectively). CONCLUSIONS: Omentin V109D and FTO rs9939609 genetic variations may change insulin metabolism and have key roles in developing T2D through insulin resistance. Thus, the evaluation of these polymorphic regions may be helpful for predicting type 2 diabetes.

Association between TPO Asn698Thr and Thr725Pro gene polymorphisms and serum anti-TPO levels in Iranian patients with subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism (SCH) is defined as high levels of TSH in the presence of normal levels of serum FT4. Since thyroid peroxidase (TPO) plays a key role in thyroid hormone synthesis, variations in the TPO gene can change the enzyme structure and result in the production of anti-TPO antibodies. The aim of this study was to examine the relationship between the Asn698Thr (A2095C) and Thr725Pro (A2173C) polymorphisms of the TPO gene and anti-TPO levels in patients with SCH. DESIGN: In this study, 150 individuals (75 cases and 75 controls), aged 19-75 years, were selected randomly by a clinician. The thyroid function tests included were FT3, FT4, TSH and anti-TPO antibodies using ELISA. The TPO gene polymorphisms were examined by PCR-RFLP. RESULTS: Anti-TPO levels in the experimental group was significantly increased (P=0.020). The A2095C genotype frequency in the experimental and control groups were 37.3% vs 34.7% for the AA healthy genotype, 20% vs 46.7% for AC and 42.7% vs 18.6% for CC, respectively (P=0.001). The A2173C genotype frequency in the experimental and control groups were 22.6% vs 68% for healthy AA, 40% vs 25.3% for AC and 37.4% vs 6.7% for CC, respectively (P <0.001). The increased anti-TPO antibodies were significantly associated with the A2173C polymorphism (P=0.035). The findings showed that the chance (odds ratio) of developing subclinical hypothyroidism in individuals who had C alleles was 1.5 and 5.6-fold higher than in individuals without these alleles in the A2095C and A2173C regions, respectively. CONCLUSIONS: Determination of anti-TPO antibody levels and exon 12 TPO gene polymorphisms in patients with SCH can be helpful for prediction of overt hypothyroidism.

Effect of urotensin II on apolipoprotein B100 and apolipoprotein A-I expression in HepG2 cell line.

BACKGROUND: Increased apolipoprotein B100 (apo B) and decreased apolipoprotein A-I (apo A-I) production are important risk factors in atherosclerosis. Urotensin II (UII), as the most potent vasoconstrictor in human, is related with hypertension and probably atherosclerosis. Because of the relationship between the hypertension and lipoprotein metabolism in atherosclerosis, the aim of this study was to test the effect of urotensin II on apo B and apo A-I expression in hepatic (HepG2) cell line. MATERIALS AND METHODS: HepG2 cells were treated with 10, 50, 100, and 200 nmol/L of urotensin II (n = 6). Relative apo B and apo A-I messenger RNA (mRNA) levels in conditioned media, normalized to glyceraldehyde-3-phosphate dehydrogenase, were measured with quantitative real-time polymerase chain reaction method. In addition, apo B and apo A-I levels were also estimated and compared with the controls using the western blotting method. Data were analyzed statistically by ANOVA and non-parametric tests. RESULTS: The apo B mRNA levels were not increased significantly following the treatment with UII. However, apo B protein levels were increased significantly after the treatment with urotensin II, especially at 100 and 200 nmol/L. The apo A-I mRNA and protein levels in conditioned media also were not significantly changed. However, there was a significant decrease in apo A-I mRNA and protein levels at 200 nM UII. CONCLUSIONS: UII might increase apo B at protein level probably through participating factors in its synthesis and/ or stability/degradation. In addition, UII may have decreasing effect at more than 200 nM concentrations on apo A-I.

Relationship between PON1L55M and Q192R gene polymorphisms and high APO B/APO A-I ratios.

Elevated Apolipoprotein B Apolipoprotein A-I ratio is a risk factor for predicting coronary artery disease (CAD). Paraoxonase 1 (PON1) is a high density lipoprotein (HDL) associated serum enzyme. PON1 protects lowdensity lipoproteins (LDLs) from oxidative modifications and thus has a protective effect against CAD progression. There are two common polymorphisms, Q192R and L55M, in PON1 gene. There may be a relationship between these polymorphisms and elevated ApoB/ApoA-I ratios. Therefore, we decided to evaluate effect of these polymorphisms on individuals with high and normal ApoB/ApoA-I ratios. To evaluate Q192R and L55M polymorphisms in Iranian case group (n=75) with high ApoB/ApoA-I ratio, and control group (n=75) with normal ApoB/ApoA-I ratio, we carried out PCR using specific primers. Then, we digested PCR products by RFLP. ApoB and ApoA-I levels were determined by immunoturbidimetry method. Genotype frequencies for Q192R were determined: 49.3%QQ, 44%QR, 6.7%RR in case group, and 53.3%QQ, 33.3%QR, 13.4%RR in controls (P= 0.236). Genotype frequencies for L55M were determined: 21.3%LL, 68%LM, 10.7%MM in case group and 42.7%LL, 52%LM, 5.3%MM in controls (P= 0.016). A significant relationship between L55M polymorphism and familial history of cardiovascular disease was found (P= 0.011). In our study PON1L55M polymorphism was associated with high ApoB/ApoA-I ratios in case group. Thus, L55M polymorphism may be an independent risk factor for cardiovascular disease. Since L55M polymorphism was associated with familial history of cardiovascular disease, it is better to evaluate L55M polymorphism in younger ages even in the absence of high ApoB/ApoA-I ratios.