Effect of long-term inorganic nitrate administration on myocardial ischemia-reperfusion injury in ovariectomized rats.

Introduction: Menopause is associated with reduced nitric oxide (NO) bioavailability and lower tolerance against myocardial ischemia-reperfusion (IR) injury. This study investigated whether long-term nitrate administration provides resistance against myocardial IR injury in ovariectomized (OVX) rats. Method: After ovariectomy, female rats were assigned to the OVX and the OVX + nitrate groups (n = 14/group); the latter group consumed nitrate (100 mg/L) for 9 months. At month 9, each group was divided into two subgroups (n = 7/subgroup), of which one subgroup was exposed to myocardial IR (IR+ hearts) and the other was not exposed (IR- hearts). The hearts of rats were isolated, and NO metabolite (NOx), oxidative stress indices, and mRNA expressions of endothelial (eNOS), inducible (iNOS), and neuronal (nNOS) NO synthases, as well as markers of apoptosis, were measured in the IR- and IR+ hearts. In the IR+ hearts, cardiac function indices (CFI) and the infarct size were also measured. Results: Nitrate increased catalase activity (97%) and eNOS expression (2.94-fold) in the IR- hearts. In the IR+ hearts, nitrate reduced left ventricular (LV) end-diastolic pressure (11.6%) and infarct size (26.2%) and increased recovery of LV developed pressure (44.0%) and peak rate of positive (28.9%) and negative (15.4%) changes in LV pressure. In addition, in the IR+ hearts, nitrate increased eNOS and B-cell lymphoma-2 (Bcl-2) as well as decreased iNOS, Bcl-2 associated X protein (Bax), caspase-3, caspase-8, caspase-9, and tumor necrosis factor-α (TNF-α) expression. Nitrate increased total antioxidant capacity (TAC) and catalase (CAT) activity and decreased malondialdehyde (MDA) levels at month nine in serum and IR+ hearts. Conclusion: The favorable effects of nitrate against IR injury were associated with higher eNOS and Bcl-2 expression, CAT activity, TAC, and lower iNOS, Bax, caspase-3, caspase-8, caspase-9 and TNF-α expression, and MDA in the heart tissue. Nitrate preconditioning alleviated IR-induced myocardial injury in OVX rats; this effect was associated with eNOS upregulation before IR and the blunting of OVX-induced eNOS downregulation, iNOS upregulation, apoptosis, and oxidative stress in heart tissue after IR.

Adipose organ dysfunction and type 2 diabetes: Role of nitric oxide.

Adipose organ, historically known as specialized lipid-handling tissue serving as the long-term fat depot, is now appreciated as the largest endocrine organ composed of two main compartments, i.e., subcutaneous and visceral adipose tissue (AT), madding up white and beige/brown adipocytes. Adipose organ dysfunction manifested as maldistribution of the compartments, hypertrophic, hypoxic, inflamed, and insulin-resistant AT, contributes to the development of type 2 diabetes (T2D). Here, we highlight the role of nitric oxide (NO·) in AT (dys)function in relation to developing T2D. The key aspects determining lipid and glucose homeostasis in AT depend on the physiological levels of the NO· produced via endothelial NO· synthases (eNOS). In addition to decreased NO· bioavailability (via decreased expression/activity of eNOS or scavenging NO·), excessive NO· produced by inducible NOS (iNOS) in response to hypoxia and AT inflammation may be a critical interfering factor diverting NO· signaling to the formation of reactive oxygen and nitrogen species, resulting in AT and whole-body metabolic dysfunction. Pharmacological approaches boosting AT-NO· availability at physiological levels (by increasing NO· production and its stability), as well as suppression of iNOS-NO· synthesis, are potential candidates for developing NO·-based therapeutics in T2D.

Myocardial infarct size is reduced by nitrite and nitrate administration: a systematic review and meta-analysis of animal studies.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide and can be complicated by myocardial infarction (MI), leading to cardiac failure. Inorganic nitrite and nitrate, which release nitric oxide (NO), can protect the heart against myocardial injury. This animal systematic review and meta-analysis aims to assess whether the administration of nitrite/nitrate decreases myocardial infarct size. We systematically searched PubMed, Scopus, and Web of Science databases until October 2023; 15 eligible animal studies (35 study arms for in-vivo and 10 for in-vitro studies) published between 1989 and 2023 were included. In-vivo studies were conducted on rats, mice, cats, and dogs, and in-vitro studies on rats and mice with an overall exposure of 0.03 to 12713 mg/kg to nitrate/nitrite administrated before, after, or during ischemia mainly by intravenous single bolus or by oral over 270 days. All in-vitro studies used nitrite/nitrate before ischemia, with the concentration ranging between 0.34 to 201 µM. MI was induced by occlusion of the left anterior diagonal or left circumflex arteries in in-vitro studies and by isoproterenol in in-vivo studies. Infarct size was measured by direct staining of the sliced heart sections. In in-vivo studies, nitrite (overall effect size (ES)=-17.0 %, 95 % confidence interval (CI)=-21.3, -12.8, P<0.001) and nitrate (overall ES= -9.6 %, 95 % CI=-15.7, -3.4, P=0.002) reduced myocardial infarct size. In in-vitro studies, nitrite (overall ES=-15.8 %, 95 % CI=-25.5, -6.2, P=0.001) reduced the infarct size. Sensitivity analysis showed that the overall effect of nitrite on myocardial infarct size was unaffected by doses or health conditions in in-vivo and in-vitro studies. In conclusion, our meta-analysis showed that nitrite/nitrate administration can effectively reduce myocardial infarct size. However, these results should be approached with caution because of the limitations of animal studies and the existing high heterogeneity.

Anti-obesity and anti-diabetic effects of L-citrulline are sex-dependent.

AIMS: Anti-diabetic and anti-obesity effects of L-citrulline (Cit) have been reported in male rats. This study determined sex differences in response to Cit in Wistar rats. MAIN METHODS: Type 2 diabetes (T2D) was induced using a high-fat diet followed by low-dose of streptozotocin (30 mg/kg) injection. Male and female Wistar rats were divided into 4 groups (n = 6/group): Control, control+Cit, T2D, and T2D + Cit. Cit (4 g/L in drinking water) was administered for 8 weeks. Obesity indices were recorded, serum fasting glucose and lipid profile were measured, and glucose and pyruvate tolerance tests were performed during the Cit intervention. White (WAT) and brown (BAT) adipose tissues were weighted, and the adiposity index was calculated at the end of the study. KEY FINDINGS: Cit was more effective in decreasing fasting glucose (18 % vs. 11 %, P = 0.0100), triglyceride (20 % vs. 14 %, P = 0.0173), and total cholesterol (16 % vs. 11 %, P = 0.0200) as well as decreasing gluconeogenesis and improving glucose tolerance, in females compared to male rats with T2D. Following Cit administration, decreases in WAT weight (16 % vs. 14 % for gonadal, 21 % vs. 16 % for inguinal, and 18 % vs. 13 % for retroperitoneal weight, all P < 0.0001) and increases in BAT weight (58 % vs. 19 %, for interscapular and 10 % vs. 7 % for axillary, all P < 0.0001) were higher in females than male rats with T2D. The decrease in adiposity index was also higher (11 % vs. 9 %, P = 0.0007) in females. SIGNIFICANCE: The anti-obesity and anti-diabetic effects of Cit in rats are sex-dependent, with Cit being more effective in female than male rats.

Dissolving sodium hydrosulfide in drinking water is not a good source of hydrogen sulfide for animal studies.

Hydrogen sulfide (H2S) has many physiological and pathological roles in the human body. Sodium hydrosulfide (NaHS) is widely used as a pharmacological tool for assessing H2S effects in biological experiments. Although H2S loss from NaHS solution is a matter of minutes, some animal studies use NaHS in solution as an H2S-donating compound in drinking water. This study addresses whether 30 µM NaHS in drinking water prepared in rat/mouse water bottles remains stable for at least 12-24 h, as presumed by some authors. NaHS solutions (30 µM) were prepared in drinking water and immediately transferred to rat/mice water bottles. Samples were obtained from the tip of water bottles and from inside of the bottles at 0, 1, 2, 3, 4, 5, 6, 12, and 24 h for sulfide measurement using the methylene blue method. Furthermore, NaHS (30 µM) was administered to male and female rats for two weeks, and serum sulfide concentrations were measured every other day in the first week and at the end of the second week. NaHS solution was unstable in the samples obtained from the tip of water bottles; it declined by 72% and 75% after 12 and 24 h, respectively. In the samples obtained from the inside of the water bottles, the decline in the NaHS was not significant until 2 h; however, it decreased by 47% and 72% after 12 and 24 h, respectively. NaHS administration did not affect serum sulfide levels in male and female rats. In conclusion, NaHS solution prepared in drinking water can not be used for H2S donation as the solution is unstable. This route of administration exposes animals to variable and lower-than-expected amounts of NaHS.

Long-term inorganic nitrate administration protects against myocardial ischemia-reperfusion injury in female rats.

BACKGROUND: The favorable effects of nitrate against myocardial ischemia-reperfusion injury (MIRI) have primarily focused on male rats and in short term. Here we determine the impact of long-term nitrate intervention on baseline cardiac function and the resistance to MIRI in female rats. METHODS: Female Wistar rats were randomly divided into untreated and nitrate-treated (100 mg/L sodium nitrate in drinking water for 9 months) groups (n = 14/group). At intervention end, levels of serum progesterone, nitric oxide metabolites (NOx), heart NOx concentration, and mRNA expressions of NO synthase isoforms (NOS), i.e., endothelial (eNOS), neuronal (nNOS), and inducible (iNOS), were measured. Isolated hearts were exposed to ischemia, and cardiac function indices (CFI) recorded. When the ischemia-reperfusion (IR) period ended, infarct size, NO metabolites, eNOS, nNOS, and iNOS expression were measured. RESULTS: Nitrate-treated rats had higher serum progesterone (29.8%, P = 0.013), NOx (31.6%, P = 0.035), and higher heart NOx (60.2%, P = 0.067), nitrite (131%, P = 0.018), and eNOS expression (200%, P = 0.005). Nitrate had no significant effects on baseline CFI but it increased recovery of left ventricular developed pressure (LVDP, 19%, P = 0.020), peak rate of positive (+ dp/dt, 16%, P = 0.006) and negative (-dp/dt, 14%, P = 0.014) changes in left ventricular pressure and decreased left ventricular end-diastolic pressure (LVEDP, 17%, P < 0.001) and infarct size (34%, P < 0.001). After the IR, the two groups had significantly different heart nitrite, nitrate, NOx, and eNOS and iNOS mRNA expressions. CONCLUSIONS: Long-term nitrate intervention increased the resistance to MIRI in female rats; this was associated with increased heart eNOS expression and circulating progesterone before ischemia and blunting ischemia-induced increased iNOS and decreased eNOS after MIRI.

Vascular nitric oxide resistance in type 2 diabetes.

Vascular nitric oxide (NO•) resistance, manifested by an impaired vasodilator function of NO• in both the macro- and microvessels, is a common state in type 2 diabetes (T2D) associated with developing cardiovascular events and death. Here, we summarize experimental and human evidence of vascular NO• resistance in T2D and discuss its underlying mechanisms. Human studies indicate a ~ 13-94% decrease in the endothelium (ET)-dependent vascular smooth muscle (VSM) relaxation and a 6-42% reduced response to NO• donors, i.e., sodium nitroprusside (SNP) and glyceryl trinitrate (GTN), in patients with T2D. A decreased vascular NO• production, NO• inactivation, and impaired responsiveness of VSM to NO• [occurred due to quenching NO• activity, desensitization of its receptor soluble guanylate cyclase (sGC), and/or impairment of its downstream pathway, cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)] are the known mechanisms underlying the vascular NO• resistance in T2D. Hyperglycemia-induced overproduction of reactive oxygen species (ROS) and vascular insulin resistance are key players in this state. Therefore, upregulating vascular NO• availability, re-sensitizing or bypassing the non-responsive pathways to NO•, and targeting key vascular sources of ROS production may be clinically relevant pharmacological approaches to circumvent T2D-induced vascular NO• resistance.

Novel Insight into the Effect of Probiotics in the Regulation of the Most Important Pathways Involved in the Pathogenesis of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is considered one of the most common disorders worldwide. Although several treatment modalities have been developed, the existing interventions have not yielded the desired results. Therefore, researchers have focused on finding treatment choices with low toxicity and few adverse effects that could control T2DM efficiently. Various types of research on the role of gut microbiota in developing T2DM and its related complications have led to the growing interest in probiotic supplementation. Several properties make these organisms unique in terms of human health, including their low cost, high reliability, and good safety profile. Emerging evidence has demonstrated that three of the most important signaling pathways, including nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and nuclear factor erythroid 2-related factor 2 (Nrf2), which involved in the pathogenesis of T2DM, play key functions in the effects of probiotics on this disease. Hence, we will focus on the clinical applications of probiotics in the management of T2DM. Then, we will also discuss the roles of the involvement of various probiotics in the regulation of the most important signaling pathways (NF-κB, PI3K/Akt, and Nrf2) involved in the pathogenesis of T2DM.

Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Protective effects of long-term nitrate administration against ovariectomy-induced kidney dysfunction in rats.

BACKGROUND: Menopause is associated with higher risks of chronic kidney disease. We determined the effect of nitrate on ovariectomy-induced kidney dysfunction METHODS: Control, ovariectomized (OVX), control + nitrate, and OVX + nitrate female Wistar rats (n = 10/group); sodium nitrate (100 mg/L) administered in drinking water for 9 months. Glomerular filtration rate (GFR) and albumin excretion rate (AER) were calculated from serum and urine parameters. At month 9, serum and kidney levels of nitric oxide (NO) metabolites (NOx), oxidative stress indices, and mRNA expression of endothelial NO synthase (eNOS) were measured; with histological analyses of the kidney. RESULTS: Compared to controls, OVX rats had lower GFR (31%, p = 0.0079), higher glomerular tuft volume (30%, p = 0.0402), and Bowman's capsule space (39%, p = 0.0224). OVX rats had lower serum NOx (33%, p = 0.0061) and kidney eNOS mRNA expression (34%, p = 0.0368). Nitrate administration to: (i) control rats increased serum NOx (59%, p < 0.0001), with no effect on other parameters; (ii) OVX rats increased serum (85%, p < 0.0001) and kidney (106%, p = 0.0008) NOx values, and restored kidney eNOS expression to normal value. Nitrate administration to OVX rats increased GFR (36%, p = 0.0361) and restored glomerular tuft volume and Bowman's capsule space to normal values. In OVX rats, it also increased serum catalase (CAT) activity, serum and kidney total antioxidant capacity (TAC), and decreased serum malondialdehyde (MDA). CONCLUSIONS: Low-dose long-term nitrate administration protects against ovariectomy-induced kidney dysfunction in rats. This effect is associated with reducing ovariectomy-induced oxidative stress and restoring eNOS-derived NO deficiency in systemic circulation and the kidney.

Anti-oxidant effect of nitrite in the pancreatic islets of type 2 diabetic male rats.

Objectives: Nitrite, a nitric oxide (NO) donor, increases insulin secretion from pancreatic islets and has positive metabolic effects in type 2 diabetes (T2D). Here, we test the hypothesis of whether nitrite-induced insulin secretion is due to blunting of diabetes-induced oxidative stress in the islets. Materials and Methods: T2D was created in male rats using a combination of streptozotocin at 25 mg/kg and a high-fat diet. Wistar rats were assigned to 3 groups (n=6 in each group), including control, T2D, and T2D+nitrite; the latter group consumed drinking water containing sodium nitrite (50 mg/l) for eight weeks. At the end of the study, mRNA levels of NADPH oxidase (Nox1, 2, 3, and 4), superoxide dismutase (SOD1, 2, and 3), glutathione peroxides (GPX1 and 7), glutathione reductase (GR), catalase, thioredoxin (TXN1 and 2), and thioredoxin reductase (TXNRD1) were measured in the isolated pancreatic islets. Results: In the islets of diabetic rats, mRNA expressions of Nox1, 2, and 4 were higher, whereas expressions of SOD1, 2, catalase, GPX1, 7, GR, and TXN1 were lower than controls. Nitrite significantly (all P-values<0.05) decreased gene expression of Nox1 (0.39-fold) and Nox4 (0.23-fold) and increased gene expression of SOD1 (2.2-fold), SOD2 (2.8-fold), catalase (2.7-fold), GPX1 (2.2-fold), GPX7 (6.0-fold), GR (3.0-fold), TXN1 (2.1-fold), and TXNRD1 (2.3-fold) in diabetic rats. Conclusion: Nitrite decreased oxidative stress in isolated pancreatic islets of rats with T2D by suppressing oxidants and augmenting anti-oxidants. These findings favor the notion that nitrite-induced insulin secretion is partially due to decreased oxidative stress.

Scientific Publishing in Biomedicine: A Brief History of Scientific Journals.

Scientific publishing, with about 350-year historical background, has played a central role in advancing science by disseminating new findings, generalizing accepted theories, and sharing novel ideas. The number of scientific journals has exponentially grown from 10 at the end of the 17th century to 100,000 at the end of the 20th century. The publishing landscape has dramatically changed over time from printed journals to online publishing. Although scientific publishing was initially non-commercial, it has become a profitable industry with a significant global financial turnover, reaching $28 billion in annual revenue before the COVID-19 pandemic. However, scientific publishing has encountered several challenges and is suffering from unethical practices and some negative phenomena, like publish-or-perish, driven by the need to survive or get a promotion in academia. Developing a global landscape with collaborative non-commercial journals and platforms is a primary proposed model for the future of scientific publishing. Here, we provide a brief history of the foundation and development of scientific journals and their evolution over time. Furthermore, current challenges and future perspectives of scientific publishing are discussed.

Streptozotocin as a tool for induction of rat models of diabetes: a practical guide.

Streptozotocin (STZ) is the most used diabetogenic chemical for creating rat models of type 1 and type 2 diabetes. Despite ~60 years of using STZ in animal diabetes research, some prevailing views about STZ preparation and use are not supported by evidence. Here, we provide practical guides for using STZ to induce diabetes in rats. Susceptibility to the diabetogenic effect of STZ is inversely related to age, and males are more susceptible to STZ than females. Wistar and Sprague-Dawley rats, the most commonly-used rat strains, are sensitive to STZ, but some strains (e.g., Wistar-Kyoto rats) are less sensitive. STZ is mostly injected intravenously or intraperitoneally, but its intravenous injection produces more stable hyperglycemia. Despite the prevailing view, no fasting is necessary before STZ injection, and injection of its anomer-equilibrated solutions (i.e., more than 2 hours of dissolving) is recommended. Mortality following the injection of diabetogenic doses of STZ is due to severe hypoglycemia (during the first 24 h) or severe hyperglycemia (24 h after the injection and onwards). Some measures to prevent hypoglycemia-related mortality in rats include providing access to food soon after the injection, administration of glucose/sucrose solutions during the first 24-48 h after the injection, administration of STZ to fed animals, and using anomer-equilibrated solutions of STZ. Hyperglycemia-related mortality following injection of high doses of STZ can be overcome with insulin administration. In conclusion, STZ is a valuable chemical for inducing diabetes in rats, but some practical guides should be considered to perform well-conducted and ethical studies.

Altered sialin mRNA gene expression in type 2 diabetic male Wistar rats: implications for nitric oxide deficiency.

Nitrate therapy has been suggested to boost nitric oxide (NO) levels in type 2 diabetes (T2D); however, little is known about nitrate transport across the membranes. This study aimed to assess changes in the mRNA expression of sialin, as a nitrate transporter, in the main tissues of rats with T2D. Rats were divided into two groups (n = 6/group): Control and T2D. A high-fat diet combined with a low dose of streptozotocin (STZ, 30 mg/kg) was used to induce T2D. At month 6, samples from the main tissues of rats were used to measure the mRNA expression of sialin and levels of NO metabolites. Rats with T2D had lower nitrate levels in the soleus muscle (66%), lung (48%), kidney (43%), aorta (30%), adrenal gland (58%), epididymal adipose tissue (eAT) (61%), and heart (37%) and had lower nitrite levels in the pancreas (47%), kidney (42%), aorta (33%), liver (28%), eAT (34%), and heart (32%). The order of sialin gene expression in control rats was: soleus muscle > kidney > pancreas > lung > liver > adrenal gland > brain > eAT > intestine > stomach > aorta > heart. Compared to controls, rats with T2D had higher sialin mRNA expressions in the stomach (2.1), eAT (2.0), adrenal gland (1.7), liver (8.9), and soleus muscle (3.4), and lower sialin expression in the intestine (0.56), pancreas (0.42), and kidney (0.44), all P values < 0.05. These findings indicate altered sialin mRNA expression in the main tissues of male T2D rats and may have implications for future NO-based treatment of T2D.

Metabolic effects of L-citrulline in type 2 diabetes.

The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L-citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L-arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic ß cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and ß-oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit-induced improved metabolic parameters in T2D.

Long-term inorganic nitrate administration protects against ovariectomy-induced osteoporosis in rats.

The risk of osteoporotic fractures increases in women after menopause. This study aims at determining the effects of long-term inorganic nitrate administration against ovariectomy-induced osteoporosis in rats. Rats were divided into 4 groups (n=6/group): Control, control+nitrate, ovariectomized (OVX), and OVX+nitrate. Sodium nitrate (100 mg/L in drinking water) was administered for 9 months. Trabecular bone quality in the proximal tibia was measured using a Micro-Computed Tomography (micro-CT) scanner at months 0, 1, 3, and 9. Levels of nitric oxide (NO) metabolites (NOx) and oxidative stress indices, and mRNA expression of endothelial NO synthase (eNOS) were measured at month 9 in the proximal tibia. Compared to controls, OVX rats had lower NOx levels by 47 %, eNOS mRNA expression by 55 %, catalase activity (CAT) by 45 %, total antioxidant capacity (TAC) by 70 %, and higher malondialdehyde (MDA) levels by 327 % in the bone tissue at month 9. OVX rats, compared to controls, had lower bone volume/tissue volume (BV/TV), trabecular number (Tb.N.), and trabecular thickness (Tb.Th.) by 32 %, 58 %, and 17 %, respectively, and higher trabecular separation (Tb.Sp.) by 123 %, at month 9. Nitrate administration to control rats increased TAC by 46 % in the bone tissue at month 9 but did not significantly affect other parameters in serum and bone tissue. Nitrate in OVX rats significantly increased NOx levels by 86 %, eNOS expression by 2.14-fold, CAT activity by 75 %, TAC by 170 %, and decreased MDA levels by 36 % at month 9 in the bone tissue. Nitrate-treated OVX rats at month 9 had higher BV/TV (42 %) and Tb.N. (61 %) and lower Tb.Sp. (15 %). Long-term inorganic nitrate administration at a low dose has protective effects against OVX-induced osteoporosis in rats; this effect is associated with increasing eNOS-derived NO and decreasing oxidative stress in the bone tissue.

Scientific Publishing in Biomedicine: Information Literacy.

The literature review is an integral part of the research process, from developing research ideas to disseminating findings. It involves explaining, interpreting, and summarizing published materials around a topic to elaborate a research hypothesis/question, synthesize new concepts, identify knowledge gaps, develop new theories, and identify new research directions. Effective reading and processing of the literature (i.e., analyzing and synthesizing) and actual writing of the literature (verbal or non-verbal output, e.g., tables and figures) are essential stages of an effective literature review. This article provides a practical guide to conducting an effective literature review. In addition, literature search and evaluation are also briefly discussed.

Quantitative aspects of nitric oxide production in the heart.

Nitric oxide (NO) has essential roles in heart physiology, including the regulation of myocardial contractility and coronary blood flow, and in heart pathophysiology, particularly in the ischemic heart. NO is produced by both NO synthase (NOS)-dependent and NOS-independent pathways in the heart. This review summarizes quantitative aspects of NO production in the heart; the contribution of cardiomyocytes, endothelial cells (ECs), red blood cells (RBCs), and neurons are also discussed. Based on the available data, under normal conditions, the human heart produces about 50-70 µmol NO per day, primarily attributed to eNOS activity; ECs produce the highest amount of NO compared to other cell types in the heart. On the other hand, during ischemic conditions, NOS-independent NO production participates a significant role in the heart NO production that can exceed NOS-dependent NO generation. These data are relevant as most cardiovascular disorders are associated with NO dysfunction, and increasing NO bioavailability and signaling is a potential therapeutic approach for cardiovascular diseases.

Chronic nitrate administration increases the expression the genes involved in the browning of white adipose tissue in female rats.

Nitrate, a nitric oxide (NO) donor, has antiobesity effect in female rats. This study hypothesized that the antiobesity effect of nitrate in female rats is due to the browning of white adipose tissue (WAT). Female Wistar rats (aged 8 months) were divided into two groups (n = 10/group): the control group received tap water and the nitrate group received water containing 100 mg/L of sodium nitrate for 9 months. At months 0, 3, 6, and 9, obesity indices were measured. At month 9, gonadal adipose tissue was used to measure messenger RNA (mRNA) and protein levels of peroxisome proliferator-activated receptor-γ (PPAR-γ), PPAR-γ coactivator 1-α (PGC1-α), uncoupling protein 1 (UCP1), and adipocyte density and area. After the 9-month intervention, nitrate-treated rats had lower body weight, body mass index, thoracic circumference, and abdominal circumference by 6.4% (p = .012), 9.1% (p = .029), 6.0% (p = .056), and 5.7% (p = .098), respectively. In addition, nitrate-treated rats had higher PPAR-γ (mRNA: 1.78-fold, p = .016 and protein: 19%, p = .076), PGC1-α (mRNA: 1.69-fold, p = .012 and protein: 68%, p = .001), and UCP1 (mRNA: 2.50-fold, p = .001 and protein: 81%, p = .001) in gonadal adipose tissue. Nitrate also reduced adipocyte area by 35% (p = .054) and increased adipocyte density by 31% (p = .086). In conclusion, antiobesity effect of nitrate in female rats is associated with increased browning of gonadal adipose tissue as indicated by higher expression of PPAR-γ, PGC1-α, and UCP1 and reduced adipocyte area and increased adipocyte density.

The Epigenetic Modification of SLC5A8 in Papillary Thyroid Carcinoma and its Effects on Clinic-Pathological Features.

Background: Epigenetic alterations such as DNA methylation are known as the main cause of different types of cancers through inactivation of tumor suppressor genes, especially thyroid cancer. Identification of novel and effective markers are important in diagnosis and prevention of thyroid cancer. In the present study, the expression and methylation of Solute carrier family 5 member 8 (SLC5A8) in Papillary Thyroid Carcinoma (PTC) in comparison to multinodular goiter (MNG) have been studied. Methods: Overall, 41 patients with PTC and 36 patients affected by MNG were recruited from four hospitals in Tehran and Qazvin, Iran in 2018. Thyroid tissues were obtained during thyroidectomy. RNA and DNA were extracted from thyroid tissues. Quantitative RT-PCR assay was performed for determining the mRNA level of SLC5A8 while Methylation-Sensitive High-Resolution Methylation was applied for assessing the methylation status. Results: Methylation status of three regions composed of 52 CpG islands in the promoter of SLC5A8 gene was studied by HRM assay. SLC5A8 level in PTC tissues was significantly downregulated in average 0.4 fold in comparison with MNG tissues (P=0.05). The aberrant methylation of SLC5A8 (b) region was remarkably different in PTC and MNG cases. The promoter methylation of SLC5A8 (c) was significantly related to BRAF mutations and vascular invasion in PTC patients. Conclusion: The aberrant promoter hyper methylation of SLC5A8 was related to aggressive PTC. Therefore, there is some evidence to support the hypothesis that SLC5A8 could be a paly important role in the development of PTC.