Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 21, Issue 9, 2021

There is close interdependence between cell survival, cell senescence, events of the cell cycle, apoptosis, malignancy development, and tumor responses to cancer treatment. Intensive studies and elaborate researches have been conducted on the functional aspects of oncogenes, tumor suppressor genes, apoptotic genes, and members guiding cell cycle regulation. These disquisitions have put forward the existence of a highly organized response pathway termed as a DNA-damage response network. The pathways detecting DNA damage and signaling are intensively linked to the events of cell-cycle arrest, cell proliferation, apoptosis, and cell senescence. DNA damage responses are complex systems that incorporate specific “sensor” and “transducer” proteins, for assessment of damage and signal transmission, respectively. These signals are thereafter relayed upon various “effector” proteins involved in different cellular pathways. It may include those governing cell-cycle checkpoints, participating in DNA repair, cell senescence, and apoptosis. This review discusses the role of the tumour suppressor gene, oncogenes, cell cycle checkpoint regulators during DNA damage response and regulation.

The novel pandemic of Coronavirus disease 2019 (COVID-19) has become a public health issue since March 2020, with more than 30 million people found to be infected worldwide. Men may be considered to be at a higher risk of poor prognosis or death once the infection occurred. Concerns surfaced regarding the risk of a possible testicular injury due to SARS-CoV-2 infection. Several data support the existence of a bivalent role of testosterone (T) in driving poor prognosis in patients with COVID-19. On the one hand, this is attributable to the fact that T may facilitate SARS-CoV-2 entry in human cells by means of an enhanced expression of transmembrane serine-protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2). At the same time, a younger man with normal testicular function compared to a woman of similar age is prone to develop a blunted immune response against SARS-CoV-2, being exposed to less viral clearance and more viral shedding and systemic spread of the disease. Conversely, low levels of serum T observed in hypogonadal men predispose them to a greater background systemic inflammation, cardiovascular and metabolic diseases, and immune system dysfunction, hence driving harmful consequences once SARS-CoV-2 infection occurred. Finally, SARS-CoV-2, as a systemic disease, may also affect testicles with possible concerns for current and future testicular efficiency. Preliminary data suggested that the SARS-CoV-2 genome is not normally found in gonads and gametes. Therefore, transmission through sex could be excluded as a possible way to spread the COVID-19. Most data support a role of T as a bivalent risk factor for poor prognosis (high/normal in younger; lower in elderly) in COVID-19. However, the impact of medical treatment aimed to modify T homeostasis for improving the prognosis of affected patients is unknown in this clinical setting. In addition, testicular damage may be a harmful consequence of the infection, even if it occurred asymptomatically. Still, no long-term evidence is currently available to confirm and quantify this phenomenon. Different authors excluded the presence of SARS-CoV-2 in sperm and oocytes, thus limiting worries about both a potential sexual and gamete-to-embryos transmission of COVID-19. Despite these evidence, long-term and well-designed studies are needed to clarify these issues.

Chronic kidney disease is a serious co-morbidity of patients with diabetes, which amplifies the global burden of this disease, affects the quality of their life, and significantly increases both morbidity and mortality. Therefore, there is a high unmet clinical need to develop therapeutic strategies in order to prevent, delay, or even reverse its evolution. EMPA-REG OUTCOME trial has fundamentally changed the therapeutic landscape of patients with type 2 diabetes and signified a new era in which treatment approaches should be tailored based on end-organ protection and patient comorbidities rather than focusing only on their antihyperglycemic effects. This paper discusses the seminal EMPA-REG OUTCOME trial, focusing on its renal outcomes, and explores extensively the possible pathophysiological mechanisms governing the nephroprotective activity of empagliflozin both in in vitro and in vivo (animal models and humans) studies during a diabetic state. It also discusses the safety of empagliflozin therapy and its future role in order to ameliorate the global burden of CKD both in patients with and without diabetes.

Background: The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL, ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis of multiple sclerosis (MS). KW-2449 could modulate immune cells, but the immunomodulatory effects of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model. Methods: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution and compared with EAE and control mice. Following the treatment, histological analyses were performed on the brain and cerebellum to evaluate the pathological score. The gene expression levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA). Results: The results indicated that the clinical score, the infiltration of inflammatory cells and the demyelination in EAE mice treated with KW-2449 decreased significantly compared to control groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines, and MMP-2 in both brain mRNA expressions and serum levels of EAE mice. Conclusion: The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in the brain or in plasma and reduces EAE pathogenesis manifestation.

Background: The prevalence of diabetes mellitus in Vietnam is relatively low compared to other Asian countries, but it is accelerating with the economic and cultural transition. This study aimed to estimate the current prevalence and clinical profile of undiagnosed diabetes mellitus in a tertiary hospital in the south of Vietnam. Methods: A cross-sectional investigation was conducted to recruit 1, 250 participants, who were at least 18 year-old and randomly sampled from Cho Ray Hospital, Ho Chi Minh City, Vietnam. Fasting plasma glucose concentration and HbA1c were measured for each individual. The American Diabetes Association criteria were used to diagnose diabetes. Demographic data and other clinical characteristics of diabetes were also documented, including age, sex, residence, educational status, weight, height, waist and hip circumferences, blood pressure, familial history of diabetes, and lipid profile. Results: The prevalence of undiagnosed diabetes mellitus was 7.5% in the population studied. Age, waist circumference, waist-hip ratio, body mass index, and hypertension, as well as dyslipidaemia were well-correlated with the diabetes rate. Conclusion: The prevalence of undiagnosed diabetes mellitus is increasing far more than expected. Newly diagnosed diabetic patients usually presented with multiple comorbidities, including overweight/ obesity, hypertension, and dyslipidaemia.

Background: A new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) (COVID-19) infection was reported in Wuhan, China, becoming a global health emergency. Literature shows how nursing work is particularly stressful and how this condition is closely connected to the development of anxiety disorders, sleep quality and can also influence eating behavior with consequent variations in BMI values. Objective: The study aims to investigate and correlate the levels of anxiety, insomnia and Body Mass Index among nurses directly involved in the care of patients in the intensive care units with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection. Method: An observatory study was conducted assessing and correlating the anxiety and insomnia levels and BMI values of each nurse before (until December 2019) and during (until May 2020) the pandemic. Results: In total, 291 Italian nurses joined the study. There are no statistically significant differences between female nurses and male nurses for both groups of participants with or without anxiety (p=0.655). Female nurses with mild, moderate and severe insomnia levels were statistically more than male nurses (p=0.025). For the same BMI differences, the levels of anxiety and insomnia were statistically significant between them (p<0.001). Conclusion: Nurses engaged in the treatment of the most serious patients with Covid-19 are subjected to very high levels of stress due to the nature of the nursing job, shifting, poor rest, anxiety due to health emergency period and weight gain.

Background: There is moderate-to-high evidence that the Mediterranean diet prevents increases in body weight and waist circumference in non-obese individuals, but less is known about its effects in overweight and obese subjects. The present study was focused on exploring the cross-sectional association among the adherence to a Mediterranean diet and the most commonly used variables of metabolic and cardiovascular risk factors in a cohort of overweight subjects from a typical Mediterranean region, Apulia, in Southern Italy. Methods: The study was performed in a cohort of 1214 individuals, all overweight or obese but with no other clinical condition. We investigated the association with adherence to a Mediterranean diet, assessed using the PREDIMED score, and anthropometric parameters [namely body mass index (BMI), WC, waist to height ratio (WHtR) and neck circumference (NC)], fasting serum levels of glucose, insulin, uric acid and lipids (triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol), and blood pressure and insulin resistance, measured by HOMA-IR. Results: The waist to height ratio was negatively associated with a PREDIMED score ≥7 (p<0.04), whereas HDL cholesterol was positively associated with a PREDIMED score ≥7 (p<0.04). Conclusion: This study suggests that body fat distribution and HDL-cholesterol are the parameters most strongly influenced by MedDiet in Apulian subjects.

Objective: Our previous studies showed the antihypertensive effect of Ribes khorassanicum (R. khorassanicum), a medicinal herb growing in the North Khorasan Province of Iran. For further evaluation, the present study investigated the effect of n-hexane (HX), ethyl acetate (EA), and aqueous (AQ) fractions of hydroalcoholic R. khorassanicum extract on cardiovascular responses in angiotensin II (AngII) and NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Methods: Wistar rats were randomly divided into 11 groups (n=5): 1) control, 2) AngII (50 ng/kg, i.v), 3) AngII + losartan (Los, 10 mg/kg, i.p), 4) L-NAME (10 mg/kg, i.v), 5) L-NAME+ sodium nitroprusside (SNP) (50 mg/kg, i.p), 6, 7, 8) one dose of each fraction of R. khorassanicum (AQ/EA/HX (50 mg/kg, i.p)) +AngII, Los 9, 10, 11) one dose of each fraction of R. khorassanicum (AQ/EA/HX (50 mg/kg, i.p)) + L-NAME. Treated rats received three fractions 30 min before the injection of L-NAME and AngII in separate groups. The cardiovascular parameters were recorded by the Power Lab instrument via an angiocath inserted into the femoral artery. The peak changes (Δ) of Mean Arterial Pressure (MAP), Systolic Blood Pressure (SBP), and Heart Rate (HR) in treated groups were compared with those of the hypertensive and control groups. Result: AngII and L-NAME significantly increased ΔMAP and ΔSBP and attenuated by pretreatment of Los and SNP, respectively. Pretreatment with polar (AQ) and semipolar (EA) fractions of R. khorassanicum reduced the peak changes of MAP and SBP in both AngII and L-NAME-treated groups. Only the fraction of the herb attenuated the HR increased in the L-NAME group. The HR in other groups did not demonstrate any significant difference. Conclusion: All fractions of R. khorassanicum have an antihypertensive effect. However, the effect of polar fractions is more salient. It is also conceivable that the antihypertensive effect of fractions is mostly mediated by the inhibition of AngII.

Background and Objective: The effects of hypothyroidism during pregnancy and lactation on carbohydrate metabolism have been mostly studied in male animals. The aim of this study is, therefore, to investigate the effect of fetal and neonatal hypothyroidism (FH and NH) on glucose tolerance in middle-aged female rat offsprings. Methods: Pregnant female rats were divided into three groups: Rats in the control group consumed tap water, while those in the FH and NH groups consumed 250 mg/L of 6-propyl-2-thiouracil (PTU) in their drinking water during gestation or lactation periods, respectively. After weaning, the female offspring were separated and divided into 3 groups (n=8/group): Control, FH, and NH. Bodyweight was recorded monthly and an intravenous glucose tolerance test (IVGTT) was performed at month 12. Results: Compared to controls, female rats in the FH group had significantly higher plasma glucose levels than controls throughout the IVGTT except at min 60. Values at min 5 of the FH and control group were 196.1±1.9 and 155.3±5.9 mg/dL, respectively (P<0.05). In the NH group, plasma glucose levels were significantly higher only at min 5 (185.7±14.1 vs. 155.3±5.9 mg/dL, P<0.05). Conclusion: Hypothyroidism during fetal or neonatal periods caused glucose intolerance in middle- aged female offspring rats.

Background: Asthenospermia is defined as the forward motility of sperm less than 32%. Aim/Objective: This study aimed to establish a mouse model of asthenospermia through triggering D-galactose mediated oxidative stress. Methods: A total of 40 Kunming male mice were randomly divided into control group, low-dose group (administrating D-galactose at 60 mg/kg), high-dose group (administrating D-galactose at 120 mg/kg), and high-dose+feed addition group (administrating D-galactose at 120 mg/kg together with oral D-galactose). The testicular weight, testicular organ coefficient, sperm viability, sperm concentration, and survival rate of the tail of epididymis were measured. Oxidative damage of D-- galactose to the reproductive system of mice was evaluated by measuring superoxide dismutase (SOD) and malondialdehyde (MDA) in the testicular homogenate of mice. Results: The sperm motility, motility rate, concentration, and survival rate of low-dose, high-dose and high-dose+feed addition group were decreased, compared to that in the control group. However, there background:was a significant difference between high-dose group/high dose+feed group and the control group (p<0.05): the forward motile sperm motility rate and total motility rate are accorded with critical criteria of asthenospermia. As compared with the control group, the activity of SOD of model group mice significantly decreased, and MDA concentration significantly increased (p<0.05), except for low-dose versus control group for SOD activity. This suggests that testicular tissues suffered from oxidative damage. Conclusion : This study successfully established a mouse asthenospermia model through D-galactose mediated oxidative stress injury. The establishment of asthenospermia model in this study would provide new promising insight and act as a potential approach for studying asthenospermia in vivo levels.

Background: Neonatal hyperbilirubinemia is a serious neonatal problem which has hazardous effects on the neonates when the level of indirect bilirubin is increased to the levels that could cause kernicterus. Aims: The aim of this research is to study the cord blood levels of erythropoietin (EPO), bilirubin and reticulocyte count (RC) as early predictors of neonatal hyperbilirubinemia. Methods: This is a case-control study, which was conducted at Tanta University Hospital (TUH) from July 2016 to March 2018 on 90 neonates. The studied neonates were divided into 2 groups: Group 1 (45 neonates) who developed pathological hyperbilirubinemia and required treatment and group 2(45 neonates) who did not develop pathological hyperbilirubinemia and did not require treatment. Cord blood levels of EPO, bilirubin and RC were measured in all the studied neonates in both groups. Results: There was a significant difference between both groups with regard to cord blood bilirubin (CBB), hemoglobin, EPO and RC levels where the P. value is 0.001*,0.027, *0.001* & 0.001*respectively. There was a significant positive correlation between cord blood EPO levels and both CBB and cord blood RC with r=0.610 and 0.579, respectively and P. value is 0.001* & 0.001* respectively. With regard to ROC curve, there were high cord blood EPO levels where the cut off value was 22.5 mIU/ml while the sensitivity and specificity were 96 and89, respectively. In the cord blood RC, the cut off value was 5.7% while the sensitivity and specificity were 93 and 85, respectively, and lastly, CBB where the cut off value was 1.8 mg/dl while the sensitivity and specificity were 89 and 78 respectively. Conclusion: Cord blood levels of EPO, bilirubin and RC were increased in cases of pathological neonatal hyperbilirubinemia. Recommendation: Cord blood levels of EPO, bilirubin and RC could be used for early prediction of pathological neonatal hyperbilirubinemia.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 has affected millions of people, and especially in adult patients with underlying diseases lead to death. Meanwhile pediatric patients with inherited defects of T cell should be prone to viral diseases. Case Presentation: Herein, we report an infant with severe combined immunodeficiencies, who were affected and died because of COVID-19. Conclusion: Considering the importance of finding how immune system can affect the viral infection, presentation of COVID-19 in immune deficient patients can be valuable.

Background: The beneficial effects of vitamin D, together with the high prevalence of vitamin D deficiency, have led to an expanding use of vitamin D analogues. While inappropriate consumption is a recognized cause of harm, the determination of doses at which vitamin D becomes toxic remains elusive. Case Presentation: A 56-year woman was admitted to our Hospital following a 3-week history of nausea, vomiting, and muscle weakness. The patient had been assuming a very high dose of cholecalciferol for 20 months (cumulative 78,000,000UI, mean daily 130,000UI), as indicated by a non-- conventional protocol for multiple sclerosis. Before starting vitamin D integration, serum calcium and phosphorus levels were normal, while 25OH-vitamin D levels were very low (12.25 nmol/L). On admission, hypercalcemia (3.23 mmol/L) and acute kidney injury (eGFR 20 mL/min) were detected, associated with high concentrations of 25OH-vitamin D (920 nmol/L), confirming the suspicion of vitamin D intoxication. Vitamin D integration was stopped, and in a week, hypercalcemia normalized. It took about 6 months for renal function and 18 months for vitamin D values to go back to normal. Conclusion: This case confirms that vitamin D intoxication is possible, albeit with a high dose. The doses used in clinical practice are far lower than these and, therefore, intoxication rarely occurs even in those individuals whose baseline vitamin D serum levels have never been assessed. Repeated measurements of vitamin D are not necessary for patients under standard integrative therapy. However, patients and clinicians should be aware of the potential dangers of vitamin D overdose.

Background: Severe congenital neutropenia (SCN4) caused by mutations in glucose-6- phosphatase catalytic subunit 3 (G6PC3) is characterized by recurrent infections due to severe neutropenia, may be accompanied by other extra-hematopoietic manifestations; including structural heart defects, urogenital abnormalities, prominent superficial venous markings, growth retention, and inflammatory bowel diseases with rare incidence. The homozygous or compound heterozygous mutations of G6PC3 are responsible for most cases of autosomal recessive SCN4. Herein, we present two cases of SCN4 affected by novel mutations in the G6PC3, in addition to a summarized list of variants in G6PC3 gene that are reported as pathogenic and related to the SCN4 phenotype. Case Presentation: Herein, we present two cases of SCN4; the first case was a three-months old boy with severe neutropenia and prior history of hospitalization due to umbilical separation, umbilical herniation, omphalitis, and pyelonephritis; and the second case was an eight-year-old with a history of neutropenia, recurrent and severe episodes of intractable diarrhea, refractory rectovaginal and rectoperineal fistula, congenital inguinal hernia, and ASD type 2. Whole exome sequencing was performed for both cases, which revealed two novel homozygous missense mutations in G6PC3 that were predicted to be deleterious; c.337G>A, p. Gly113Arg in the first case and c.479C>T; P. Ser160Leu in the second case. To our knowledge, both of these two mutations have not been reported in the G6PDC3 gene. Conclusion: In patients with severe neutropenia with varying extra hematopoietic syndrome, mutation of G6PC3 should be suspected after ruling out other mutations related to neutropenia. This study pointed toward novel G6PC3 mutations that should be considered in order to diagnose patients with severe congenital neutropenia.

Background: Acute adrenal insufficiency is a rare but potentially lethal condition, that is important to identify promptly and treat with replacement therapy. It can be consequent to adrenal hemorrhage that can occur after major orthopedic surgery. Few data are available about potential recovery of adrenal function, as well as both timing and modality of cortisone acetate withdrawal, probably due to the assumption that adrenal failure should be definitive. The extension of adrenal damage can be different, so justifying a partial, or potentially complete, recovery of adrenal function. The aim of our article is to highlight the opportunity of a periodical revaluation of adrenal reserve in order to identify those patients which are able to interrupt replacement therapy. Case Presentation: We had recently described one case of acute adrenal insufficiency, which developed short time after hip replacement; the patient was able to discontinue cortisone acetate treatment 46 months after the diagnosis and remained untreated up to five years later. We collected other two cases of acute adrenal insufficiency, developed about one week after major orthopedic surgery. We followed such patients for about three years, repeatedly reassessing adrenal imaging and cortisol response to 250 μg ACTH test, in order to ascertain the real need of lifetime substitutive treatment with cortisone acetate. Acute adrenal insufficiency partially reverted during the follow up for both patients. We observed a reduction in adrenal glands’ volume and a progressive improvement of cortisol basal levels, without response (or with a poor one) to ACTH stimulation, as well as with ACTH basal levels persistently above the normal range after 36 and 28 months respectively spent from the acute event. Conclusion: The present finding suggests the opportunity that patients developing acute adrenal insufficiency after major orthopedic surgery undergo long-term surveillance, in order to establish if steroid replacement has to be continued, or it can be safely withdrawn.

Background: Atopic dermatitis (AD) is a chronic inflammatory pruritic dermatologic disease in children. Malva sylvestris L. (M. sylvestris) is a medicinal plant, which is used as a remedy for eczema in traditional Persian medicine. Previous studies have shown the anti-ulcerogenic and anti-inflammatory activity of this plant. Objective: We designed a clinical trial to evaluate the efficacy of topical cream of the M. sylvestris extract in the management of children with AD. Methods: Fifty-one children with AD were randomly enrolled in two arms of a randomized, double- blind, controlled clinical trial. They were treated by topical cream of the M. sylvestris extract or placebo for a palm-sized surface (single fingertip unit, twice daily) for 4 weeks. The SCORing Atopic Dermatitis (SCORAD) score was set as the primary outcome measure. Results: There was a significant improvement in the severity of participants’ dermatitis regarding skin thickening score, redness score, and total SCORAD score of the M. sylvestris group as compared with the placebo group (P= 0.009, P=0.01, and P=0.03; respectively). Conclusion: According to the results of this clinical trial, it could be concluded that the topical use of M. sylvestris extract cream was effective in the reduction of AD symptoms in children. Trial Registration: This study is registered by the Iranian Registry of Clinical Trials with the code: IRCT20170107031814N2.

Background: Addictive substances are known to result in oxidative stress (OS). OS enhances the generation of free radicals and reactive oxygen species (ROS) and reduces antioxidant capacity. Peroxides and oxygen radicals, including hydrogen peroxide and superoxide and radical nitrogen species, including nitric oxide (NO), are parts of the ROS. Gene variants of the endothelial nitric oxide (eNOS) affect the plasma levels of NO. This study aimed to investigate whether there was an association between eNOS variants and substance use disorders (SUDs) risk in the Turkish population. Methods: Two eNOS variants (G894T and 27 bp VNTR 4b/a in intron 4) were examined in 216 SUD patients and 140 healthy controls. The eNOS variants were assessed with the PCR based on the RFLP analysis. Since the patient group consisted only of men, the control group was examined as a mixed and male-only. Results: The eNOS G894T homozygous T/T genotype revealed a significant association with susceptibility to SUD. The patients carrying T/T genotype had SUD risk 1.054 times as much as the controls and male controls had (p=0.004 and p=0.038, respectively). eNOS 4a/4a genotype increased in patients as compared to male controls (p=0.048). The homozygous 4b/4b genotype was higher in the male control group than in SUD patients (p=0.029). eNOS VNTR 4a allele was more prevalent in the patients than in both controls and male controls (p=0.026 and p=0.0033, respectively). Conclusion: This study is one of the first studies investigating the relationship between two eNOS gene variants and SUD in our country. Our findings show that eNOS G894T and VNTR variants may be the significant risk factor for SUDs in Turkish subjects.

Objective: Increased level of plasma homocysteine (Hcy) is a potential risk factor for several multi-system diseases. The Methylenetetrahydrofolate reductase (MTHFR) gene C677T variant has been established as an important genetic determinant of hyperhomocysteinemia. There are conflicting reports about the effects of physical activity on plasma Hcy. Therefore, the main aim of this study was to investigate whether the MTHFR C677T variant affects elite athletic performance. Methods: This study was carried out on 214 individuals (114 elite athletes and 100 sedentary controls). Genotyping was performed using PCR- RFLP method. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Results: There was a significant difference between the athletes and the control group in genotype distribution and allele frequency of the MTHFR C677T variant. MTHFR C677T CC genotype and C allele were more prevalent in elite athletes than those in the sedentary controls (p =0.007, OR: 2.16, 95%:1.26-3.70; p=0.009, OR: 1.84, 95%:1.18-2.89, respectively). The control group had a higher MTHFR C677T CT genotype than the athletes (p=0.019, OR: 0.51, 95%:0.30-0.88). There was no deviation from HWE for the MTHFR C677T variant in the groups. Conclusion: Our findings support that there is an association between the MTHFR C677T C allele and athletic performance among the elite Turkish athletes.

Background: Osteoporosis (OP) is the most common type of systemic bone disease characterized by low bone mass and micro-structure deterioration of bone tissue, with a consequent increase in bone fragility and fracture risk. Nitric oxide (NO), produced by the enzyme endothelial nitric oxide synthase (eNOS) in endothelial cells, has considerable effects on bone cell function. The objective of this case-control study was to investigate the potential association between the eNOS gene Variable Number Tandem Repeat (VNTR) variant and susceptibility of OP, in Turkish postmenopausal female patients. Methods: One hundred and fifty female patients and 100 age-matched healthy females were enrolled in the present study. The eNOS gene VNTR variant was genotyped with a polymerase chain reaction (PCR) method. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Results: The mean age of the patients was 60.32±8.65 years. It was found that the eNOS VNTR variant genotype and allele frequencies were not significantly different between the patient and control groups (p>0.05).

Background: Many published studies attempted to elucidate the implication of glucokinase regulator gene (GCKR) polymorphisms in the susceptibility to non-alcoholic fatty liver disease (NAFLD), but the results among them were still controversial. Objective: This meta-analysis aims to precisely assess the relationship between the GCKR polymorphisms and the risk of NAFLD. Methods: Systematic computerized searches in six databases were performed and updated on April 6, 2020. Meta-analyses were conducted by calling the R programs based on accumulated epidemiological data. Odds ratio (OR) and 95% confidential interval (CI) were calculated to summarize the effect estimates. Results: In total, 25 studies including 6,598 cases and 19,954 controls were included. The pooled estimates indicated that the T allele carrier of the GCKR rs780094 polymorphism has predisposition to NAFLD (allele model: OR: 1.20, 95% CI: 1.11~1.29; homozygote model: OR: 1.38, 95% CI: 1.15~1.67; heterozygote model: OR: 1.25, 95% CI: 1.12~1.39; dominant model: OR: 1.29, 95% CI: 1.13~1.47; recessive model: OR: 1.18, 95% CI: 1.06~1.31), and the same as the rs1260326 polymorphism (allele model: OR: 1.32, 95% CI: 1.22~1.42; homozygote model: OR: 1.65, 95% CI: 1.40~1.94; heterozygote model: OR: 1.24, 95% CI: 1.07~1.43; dominant model: OR: 1.39, 95% CI: 1.21~1.59; recessive model: OR: 1.44, 95% CI: 1.28~1.62). Further stratified analyses according to age and ethnicity confirmed the statistical existence in most subgroups. Conclusion: This meta-analysis suggested that both of the GCKR rs780094 and rs1260326 polymorphisms are significantly associated with the increased risk of NAFLD.