Effects of nitric oxide modulators and antioxidants on endocrine and cellular markers of acute stress in rats.

The effects of nitric oxide modulators (NO-modulators) and antioxidants on acute (RSx1) restraint stress induced endocrine, cellular and oxidative/nitrosative stress markers was studied in Wistar rats. The results of our study revealed that exposure to RS(x1) enhanced malondialdehyde (MDA), heat shock protein (HSP-70), corticosterone, nuclear factor kappa B (NF-κB) levels and suppressed glutathione (GSH), superoxide dismutase (SOD) and total nitrites and nitrates (NOx) levels. NO precursor and NO synthase inhibitors were found to differentially modulate stress mechanisms, by altering NF-κB, HSP-70 and corticosterone levels. l-Ascorbic acid significantly suppressed acute stress induced elevation of NF-κB and HSP-70 levels depicting protective effects, as also evidenced by reversal of elevated plasma corticosterone levels. Therefore, modulation of oxidative and nitrosative pathways, offers an approach in modulating stress induced changes associated with various disorders.

Expatiating the molecular approaches of HMGB1 in diabetes mellitus: Highlighting signalling pathways via RAGE and TLRs.

Diabetes mellitus (DM) has become one of the major healthcare challenges worldwide in the recent times and inflammation being one of its key pathogenic process/mechanism affect several body parts including the peripheral and central nervous system. High-mobility group box 1 (HMGB1) is one of the major non-histone proteins that plays a key role in triggering the inflammatory response. Upon its release into the extracellular milieu, HMGB1 acts as an "alarmin" for the immune system to initiate tissue repair as a component of the host defense system. Furthermore, HMGB1 along with its downstream receptors like Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) serve as the suitable target for DM. The forthcoming research in the field of diabetes would potentially focus on the development of alternative approaches to target the centre of inflammation that is primarily mediated by HMGB1 to improve diabetic-related complications. This review covers the therapeutic actions of HMGB1 protein, which acts by activating the RAGE and TLR molecules to constitute a functional tripod system, in turn activating NF-κB pathway that contributes to the production of mediators for pro-inflammatory cytokines associated with DM. The interaction between TLR2 and TLR4 with ligands present in the host and the activation of RAGE stimulates various immune and metabolic responses that contribute to diabetes. This review emphasizes to elucidate the role of HMGB1 in the initiation and progression of DM and control over the inflammatory tripod as a promising therapeutic approach in the management of DM.

Assessment of Leptin Levels and Their Correlation With the Severity of Obstructive Sleep Apnea Syndrome: A Case-Control Study.

Background Obstructive sleep apnea (OSA) is characterized by a combination of structural issues in the upper airway and imbalances in the respiratory control system. While numerous studies have linked OSA with obesity, it remains uncertain whether leptin, a hormone associated with fat, plays a role in the functional and anatomical defects that lead to OSA. Therefore, the aim of this study was to investigate whether leptin levels could be used as a predictor of OSA syndrome (OSAS). Methodology A case-control observational study was conducted, enrolling study participants who reported obesity (BMI > 30) within the range of >30 to <35 kg/m2, along with a short neck and a history of snoring, excessive daytime drowsiness, fatigue, or insomnia. Leptin levels and fasting blood sugar (FBS) were measured in all individuals. Additionally, the study evaluated the severity of OSAS using indicators such as the STOP BANG scores, apnea-hypopnea index, uvula grade score, and Epworth Sleepiness Scale scores. Results A total of 80 participants (40 cases and 40 controls) were included in the study. The mean leptin and FBS levels were significantly higher in cases compared to controls. Moreover, leptin levels exhibited a significant correlation with the severity indices of OSAS. Conclusion The study findings indicate that individuals with higher leptin levels tend to exhibit more severe OSAS symptoms. Furthermore, these elevated leptin levels contribute to the worsening of various OSA symptoms. Larger controlled studies have suggested that pharmacologically restoring the altered leptin levels may serve as a beneficial adjunct to treatment for alleviating OSAS symptoms.

Oxidative Stress in Wistar Rats Under Acute Restraint Stress and Its Modulation by Antioxidants and Nitric Oxide Modulators.

BACKGROUND: Several pathogenic conditions leading to morbidity, including cancer, aging, diabetes, reperfusion injury, cardiovascular disease, and neurological disorders, are known to be exacerbated by oxidative stress. Antioxidant therapy is effective in the treatment of such disorders and appears to be a potential therapeutic technique to reduce oxidative stress. The aim of our study is to investigate the antioxidant effects of L-ascorbic acid and nitric oxide (NO) modulators on rats suffering from oxidative stress induced by acute restraint stress (RSx1). METHODOLOGY: In this in vivo study, Wistar rats were subjected to one hour of restraint stress on day 21 to induce oxidative stress. Superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase, glutathione (GSH), and malondialdehyde (MDA) were used to assess the antioxidant effects. IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp. was used for data analysis. RESULTS: Compared to vehicle groups, acute restraint stress (RSx1) dramatically increased MDA levels while decreasing GSH, SOD, total antioxidant capacity, and catalase. L-NAME, 7-NI, AG (50 mg/kg each), and L-ascorbic acid (200 mg/kg) reversed the changes in SOD, MDA, GSH, total antioxidant capacity, and catalase levels. The NO precursor L-arginine (1000 mg/kg) and NO synthase inhibitors followed the same trend. CONCLUSION: Our study findings highlight the complex role of antioxidants and NO modulators in the pathogenesis of diseases, as evidenced by the reversal of oxidative stress indicators. Antioxidant therapy, with its potential to mitigate oxidative stress, emerges as a viable treatment option for a range of pathological conditions associated with oxidative stress.

Understanding the Association Between Obesity and Obstructive Sleep Apnea Syndrome: A Case-Control Study.

Introduction Obstructive sleep apnea (OSA) represents a sleep-related impairment linked to upper airway function. The question of whether OSA drives obesity or if shared underlying factors contribute to both conditions remains unresolved. Hence, this present study aims to understand the interplay between obstructive sleep apnea syndrome (OSAS) and obesity through in-depth analysis of anthropometric data within control subjects and OSA patients. Methodology A case-control study was conducted, which included 40 cases and 40 matched healthy controls. Study participants with reported symptoms of snoring, daytime drowsiness, or both were included in the study. All the study participants underwent comprehensive anthropometric assessments such as height, weight, body mass index (BMI), neck circumference, waist circumference, hip circumference, waist-to-hip ratio, skin-fold thickness, and thickness measurements of biceps, triceps, suprailiac, and subscapular muscles. Results Within the OSA group, significant disparities emerged in mean age, waist circumference, waist-to-hip ratio, and diverse fat accumulations encompassing visceral, subcutaneous, trunk, and subcutaneous leg fat. Notably, skin-fold thickness at specific sites - biceps, triceps, subscapula, and suprailiac - demonstrated considerable augmentation relative to the control group. Furthermore, mean values associated with height, weight, BMI, neck circumference, fat percentage, subcutaneous arm fat, entire arm composition, and trunk skeletal muscle either equaled or exceeded those in the control group. However, statistical significance was not attained in these comparisons. Conclusion This investigation underscored a pronounced correlation between numerous endpoints characterizing OSA patients and markers of obesity. Consequently, addressing altered levels of obesity-linked anthropometric variables through pharmacological interventions might hold promise as a pivotal strategy for improving symptoms associated with OSA.

Effects of NO modulators and antioxidants on endocrine and cellular markers in rats under repetitive restraint stress.

The aim of the study was to evaluate the effects of NO modulators and antioxidant treatments on endocrine (plasma corticosterone), cellular (heat shock protein 70 [HSP-70] and nuclear factor κB [NF-κB]), and oxidative stress markers in repetitively stressed rats. Repetitive (restraint) stress (RS 1hr/day × 21 days) enhanced the levels of cellular and endocrine stress markers in the rat blood and altered pro-oxidant-antioxidant balance differentially in the control and test groups. Exposure to repetitive RS enhanced malondialdehyde (MDA) levels, lowered reduced glutathione (GSH), and superoxide dismutase (SOD) levels as well as nitric oxide (NOx) levels. NO precursor L-arginine and NO synthase inhibitors were found to differentially modulate stress-induced mechanism in altering NF-κB, HSP-70, and corticosterone levels. The antioxidant L-ascorbic acid (L-AA) significantly suppressed RS(×21)-induced elevation of NF-κB and HSP-70 levels, depicting protective effects, as also evidenced by reversal of elevated corticosterone levels. The results suggest that NO modulators and antioxidants differentially influence repetitive stress-induced changes in endocrine and cellular markers, and the complex interaction between NO and cellular markers like HSP70 and NF-κB plays a crucial modulatory role in this phenomenon.

Role of UPP pathway in amelioration of diabetes-associated complications.

Type 2 diabetes (T2D) is one of the most widely spread metabolic disorder also called as "life style" disease. Due to the alarming number of patients, there is great need to therapies targeting functions which can help in maintaining the homeostasis of glucose levels and improving insulin sensitivity. Detailed analysis was done through various research and review papers which was searched using MEDLINE, BIOSIS, and EMBASE using various keywords. This search retrieved the most appropriate content on these molecules targeting UPP pathway. From this extensive review involving UPP pathway, it was concluded that the role of ubiquitin's is not only limited to neurodegenerative disorders but also plays a critical role in progression of diabetes including obesity, insulin resistance, and various neurogenerative disorders but it also targets proteasomal degradation including mediation of cellular signaling pathways. Thus, drugs targeting UPP not only may show effect against diabetes but also are therapeutically beneficial in the treatment of diabetes-associated complications which may be obtained. Thus, based on the available information and data on UPP functions, it can be concluded that regulation of UPP pathway via downstream regulators mainly E1, E2, and E3 may bring promising results. Drugs targeting these transcriptional factors may emerge as a novel therapy in the treatment of diabetes and diabetes-associated complications.

The dual impact of ACE2 in COVID-19 and ironical actions in geriatrics and pediatrics with possible therapeutic solutions.

The novel corona virus disease has shaken the entire world with its deadly effects and rapid transmission rates, posing a significant challenge to the healthcare authorities to develop suitable therapeutic solution to save lives on earth. The review aims to grab the attention of the researchers all over the globe, towards the role of ACE2 in COVID-19 disease. ACE2 serves as a molecular target for the SARS-CoV-2, to enter the target cell, by interacting with the viral glycoprotein spikes. However, the complexity began when numerous studies identified the protective response of ACE2 in abbreviating the harmful effects of vasoconstrictor, anti-inflammatory peptide, angiotensin 2, by mediating its conversion to angiotensin-(1-7), which exercised antagonistic actions to angiotensin 2. Furthermore, certain investigations revealed greater resistance among children as compared to the geriatrics, towards COVID-19 infection, despite the elevated expression of ACE2 in pediatric population. Based upon such evidences, the review demonstrated possible therapeutic interventions, targeting both the protective and deleterious effects of ACE2 in COVID-19 disease, primarily inhibiting ACE2-virus interactions or administering soluble ACE2. Thus, the authors aim to provide an opportunity for the researchers to consider RAAS system to be a significant element in development of suitable treatment regime for COVID-19 pandemic.

Possible role of free radicals in theophylline-induced seizures in mice.

Theophylline is a methylxanthine bronchodilator with a narrow therapeutic index and is prone to induce seizures, the mechanisms for which are not clearly defined. Free radicals have considerable neurotoxic potential and the present study evaluated the possible involvement of these bioactive moieties in aminophylline-induced seizures in mice. Aminophylline (50-250 mg/kg) induced convulsions and mortality in mice in a dose-dependent manner. The anti-oxidants, melatonin (25-100 mg/kg) and N-actylcysteine (100 and 200 mg/kg) attenuated aminophylline seizures and mortality. Similar antagonism of aminophylline seizures was also observed after pretreatments with nitric oxide (NO) synthase inhibitors, L-NAME (3 and 10 mg/kg) and 7-nitroindazole (10 and 30 mg/kg). Further, combined treatment with otherwise sub-effective doses of melatonin and L-NAME or 7-nitroindazole produced marked protective effects against these seizures. Aminophylline-induced seizures enhanced malondialdehyde (MDA) concentrations and NO metabolite (NOx) levels in the brain homogenates of mice, and these were attenuated by melatonin and L-NAME pretreatments. The results are suggestive of the possible involvement of free radicals (reactive oxygen and reactive nitrogen species) in the convulsiogenic effects of aminophylline.

Establishment of the enzymatic protein acetylation independent of acetyl CoA: recombinant glutathione S-transferase 3-3 is acetylated by a novel membrane-bound transacetylase using 7,8-diacetoxy-4-methyl coumarin as the acetyl donor.

The current knowledge on biological protein acetylation is confined to acetyl CoA-dependent acetylation of protein catalyzed by specific acetyl transferases and the non-enzymatic acetylation of protein by acetylated xenobiotics such as aspirin. We have discovered a membrane-bound enzyme catalyzing the transfer of acetyl groups from the acetyl donor 7,8-diacetoxy-4-methyl coumarin (DAMC) to glutathione S-transferase 3-3 (GST3-3), termed DAMC:protein transacetylase (TAase). The purified enzyme was incubated with recombinant GST3-3 subunit and DAMC, the modified protein was isolated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in gel digested with trypsin and the tryptic digest was analyzed by mass spectrometry. The N-terminus and six lysines, Lys-51, -82, -124, -181, -191 and -210, were found to be acetylated. The acetylation of GST3-3 described above was not observed in the absence of either DAMC or TAase. These results clearly establish the phenomenon of protein acetylation independent of acetyl CoA catalyzed by a hitherto unknown enzyme (TAase) utilizing a certain xenobiotic acetate (DAMC) as the active acetyl donor.

Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part 9: comparison of acetoxy 4-methylcoumarins and other polyphenolic acetates reveal the specificity to acetoxy drug: protein transacetylase for pyran carbonyl group in proximity to the oxygen heteroatom.

The evidences for the possible enzymatic transfer of acetyl groups (catalyzed by a transacetylase localized in microsomes) from an acetylated compound (acetoxy-4-methylcoumarins) to enzyme proteins leading to profound modulation of their catalytic activities was cited in our earlier publications in this series. The investigations on the specificity for transacetylase (TA) with respect to the number and positions of acetoxy groups on the benzenoid ring of coumarin molecule revealed that acetoxy groups in proximity to the oxygen heteroatom (at C-7 and C-8 positions) demonstrate a high degree of specificity to TA. These studies were extended to the action of TA on acetates of other polyphenols, such as flavonoids and catechin with a view to establish the importance of pyran carbonyl group for the catalytic activity. The absolute requirement of the carbonyl group in the pyran ring of the substrate for TA to function was established by the observation that TA activity was hardly discernible when catechin pentacetate and 7-acetoxy-3,4-dihydro-2,2-dimethylbenzopyran (both lacking pyran ring carbonyl group) were used as the substrates. Further, the TA activity with flavonoid acetates was remarkably lower than that with acetoxycoumarins, thus suggesting the specificity for pyran carbonyl group in proximity to the oxygen heteroatom. The biochemical properties of flavonoid acetates, such as irreversible activation of NADPH cytochrome C reductase and microsome-catalyzed aflatoxin B(1) binding to DNA in vitro were found to be in tune with their specificity to TA.