Validating the temporal performance of genetic biomarkers in an animal model of recurrence/ non-recurrence myocardial infarction persuades by bioinformatics tools.

With a global towering prevalence of index acute myocardial infarction (nonrecurrent MI, NR-MI), a high incidence of recurrent MI (R-MI) has emerged in recent decades. Despite the extensive occurrence, the promising predictors of R-MI have been elusive within the cohort of survivors. This study investigates and validates the involvement of distinct gene expressions in R-MI and NR-MI. Bioinformatics tools were used to identify DEGs from the GEO dataset, functional annotation, pathway enrichment analysis, and the PPI network analysis to find hub genes. The validation of proposed genes was conceded by qRT-PCR and Western Blot analysis in experimentally induced NR-MI and R-MI models on a temporal basis. The temporal findings based on RT-PCR consequences reveal a significant and constant upregulation of the UBE2N in the NR-MI model out of the proposed three DEGs (UBE2N, UBB, and TMEM189), while no expression was reported in the R-MI model. Additionally, the proteomics study proposed five DEGs (IL2RB, NKG7, GZMH, CXCR6, and GZMK) for the R-MI model since IL2RB was spotted for significant and persistent downregulation with different time points. Further, Western Blot analysis validated these target genes' expressions temporally. I/R-induced NR-MI and R-MI models were confirmed by the biochemical parameters (CKMB, LDH, cTnI, serum nitrite/nitrate concentration, and inflammatory cytokines) and histological assessments of myocardial tissue. These results underscore the importance of understanding genetic mechanisms underlying MI and highlight the potential of UBE2N and IL2RB as biomarkers for non-recurrent and recurrent MI, respectively.

Amelioration of endothelial integrity by 3,5,4'-trihydroxy-trans-stilbene against high-fat-diet-induced obesity and -associated vasculopathy and myocardial infarction in rats, targeting TLR4/MyD88/NF-κB/iNOS signaling cascade.

Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.

Integrative experimental validation of concomitant miRNAs and transcription factors with differentially expressed genes in acute myocardial infarction.

Identification of concomitant miRNAs and transcription factors (TFs) with differential expression (DEGs) in MI is crucial for understanding holistic gene regulation, identifying key regulators, and precision in biomarker and therapeutic target discovery. We performed a comprehensive analysis using Affymetrix microarray data, advanced bioinformatic tools, and experimental validation to explore potential biomarkers associated with human pathology. The search strategy includes the identification of the GSE83500 dataset, comprising gene expression profiles from aortic wall punch biopsies of MI and non-MI patients, which were used in the present study. The analysis identified nine distinct genes exhibiting DEGs within the realm of MI. miRNA-gene/TF and TF-gene/miRNA regulatory relations were mapped to retrieve interacting hub genes to acquire an MI miRNA-TF co-regulatory network. Furthermore, an animal model of I/R-induced MI confirmed the involved gene based on quantitative RT-PCR and Western blot analysis. The consequences of the bioinformatic tool substantiate the inference regarding the presence of three key hub genes (UBE2N, TMEM106B, and CXADR), a central miRNA (hsa-miR-124-3p), and sixteen TFs. Animal studies support the involvement of predicted genes in the I/R-induced myocardial infarction assessed by RT-PCR and Western blotting. Thus, the final consequences suggest the involvement of promising molecular pathways regulated by TF (p53/NF-κB1), miRNA (hsa-miR-124-3p), and hub gene (UBE2N), which may play a key role in the pathogenesis of MI.

Spectrum of infections in different regimens of post-induction chemotherapy in acute myeloid leukemia (de-novo): A comparative retrospective study.

Background: Patients diagnosed with acute myeloid leukemia (AML) face a heightened susceptibility to infections, which significantly elevates their risk of mortality and disability. The intensity of the chemotherapy treatment and its specific focus on inhibiting myeloid cell divisions render patients especially vulnerable, particularly during the early stages of chemotherapy. This vulnerability is compounded by the occurrence of repeated episodes of prolonged neutropenia, leaving patients highly susceptible to infections. The compromised immune systems of these individuals make them more susceptible to infections, which adversely affect their physical health and overall well-being. Consequently, our study aimed to investigate the range of infections experienced by patients with newly diagnosed AML undergoing different induction chemotherapy. Methods: This was a comparative retrospective study, conducted at a tertiary hospital providing comprehensive cancer care in North India. All newly diagnosed patients with AML, who received induction chemotherapy from January 1, 2012 to November 1, 2022, were identified from the hospital database and included in this study. Results: Four hundred and twenty AML patients treated with either high-intensity or low-intensity induction chemotherapy was observed in this study. It was found that patients who received high-intensity treatment had a higher rate of clinically and microbiologically documented infections, fever without a known cause, and more cases of febrile neutropenia than those who got low-intensity treatment. These differences between the two groups were particularly evident on day 14 (p = 0.0002) and persisted through day 28 (p = 0.005). Conclusions: These findings underscore the effectiveness and downside of high-intensity induction chemotherapy regimens, as evidenced by the higher incidence of infections observed. Further investigation through prospective clinical studies is warranted to better evaluate and validate the efficacy of this approach.

Preparation of novel S-allyl cysteine chitosan based nanoparticles for use in ischemic brain treatment.

Objective: To enhance the brain bioavailability of S-allyl-l-cysteine (SC) by developing novel S-allyl-l-cysteine chitosan nanoparticles (SC CS NPs) and examining the quantity of SC by developing a novel method of ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in ischemic rat brain treatment. Methods: The ionotropic gelation method was used to develop S-allyl cysteine-loaded CS NPs. The 4-factor, 5-level central composite design was optimized to determine the effect of independent variables, i.e., particle size, polydispersity index (PDI), zeta potential, EE, and loading capacity, together with their characterization, followed by drug release and intranasal permeation to enhance the brain bioavailability and examination of their neurobehavioral and biochemical parameters with their histopathological examination. Results: SC CS NPs were optimized at the particle size of 93.21 ± 3.31 nm (PDI: 0.317 ± 0.003), zeta potential of 44.4 ± 2.93, and drug loading of 41.23 ± 1.97% with an entrapment efficiency of 82.61 ± 4.93% having sustain and controlled release (79.92 ± 3.86%) with great permeation (>80.0%) of SC. SC showed the retention time of 1.021 min and 162.50/73.05 m/z. SC showed good linearity in the range of 5.0-1300.0 ng mL-1, % inter-and-intraday accuracy of 96.00-99.06% and CV of 4.38-4.38%. We observed significant results, i.e., p < 0.001 for improved (AUC)0-24 and Cmax delivered via i.v. and i.n. dose. We also observed the highly significantly observations of SC CS NPs (i.n.) based on their treatment results for the biochemical, neurobehavioral, and histopathological examination in the developed ischemic MCAO brain rat model. Conclusion: The excellent significant role of mucoadhesive CS NPs of SC was proven based on the enhancement in the brain bioavailability of SC via i.n. delivery in rats and easy targeting of the brain for ischemic brain treatment followed by an improvement in neuroprotection based on a very small dose of SC.

Chlorogenic Acid Restores Ovarian Functions in Mice with Letrozole-Induced Polycystic Ovarian Syndrome Via Modulation of Adiponectin Receptor.

Around the world, polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic condition that typically affects 6-20% of females. Our study's major goal was to examine how chlorogenic acid (CGA) affected mice with endocrine and metabolic problems brought on by letrozole-induced PCOS. Group I served as the control for 81 days; Group II was given Letrozole (LETZ) orally at a dose of 6 mg/kg bw for 21 days to induce PCOS; Group III was given LETZ (6 mg/kg) for 21 days, followed by treatment with CGA (50 mg/kg bw daily) for 60 days. The study indicated that LETZ-treated mice displayed symptoms of PCOS, such as dyslipidemia, hyperinsulinemia, elevated testosterone, increases in inflammatory markers and malonaldehyde, and a decline in antioxidants (Ar, lhr, fshr, and esr2) in the ovaries. These alterations were affected when the mice were given CGA and were associated with reduced levels of adiponectin. Adiponectin showed interactions with hub genes, namely MLX interacting protein like (MLXIPL), peroxisome proliferator-activated receptor gamma Coactivator 1- alpha (PPARGC1), peroxisome proliferator-activated receptor gamma (Pparg), and adiponectin receptor 1 (Adipor1). Lastly, the gene ontology of adiponectin revealed that adiponectin was highly involved in biological processes. The findings from our research suggest that adiponectin has direct impacts on metabolic and endocrine facets of PCOS.

Uncontrolled blood pressure among hypertensive adults with rheumatoid arthritis in Saudi Arabia: A cross-sectional study.

ABSTRACT: Despite the availability and advancement of diagnostic and treatments with demonstrated benefits in minimizing cardiovascular morbidity and mortality, hypertension control rates remain suboptimal. Therefore, this research aimed to determine the prevalence of uncontrolled BP in rheumatoid arthritis (RA) patients and understand all potential risk factors for uncontrolled BP.We conducted a cross-sectional study on RA patients in 2 rheumatology clinics in 2 public hospitals in Riyadh. Patients' information such as demographics, comorbidities, drug use, and other clinical data were captured through a review of medical records and supplemented by patient interviews. Multivariate logistic regression was utilized for the analysis to identify the significant factors of uncontrolled BP (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg).In total, 834 subjects with RA and concomitant BP were involved in this cross-sectional study. The prevalence of uncontrolled BP was found to be 31.65% among all the study population. Multivariate analysis showed that males, subjects above 60 years of age, and smokers had a distinctly higher occurrence of uncontrolled BP. Among the patients with comorbid conditions, those with obesity, hyperlipidemia, diabetes, anemia, cancer, and reflex or gastroesophageal reflux disease also showed a significantly higher risk of uncontrolled BP (P < .05).The rate of uncontrolled BP was found to be alarmingly high in the study population. Age, gender, smoking, diabetes, obesity, hyperlipidemia, cancer, gastroesophageal reflux disease, and osteoporosis are independently linked with lack of BP control.

Development and validation of an automated solid-phase extraction-LC-MS/MS method for the bioanalysis of fluoxetine in human plasma.

A wide-range, specific, and precise liquid chromatography tandem mass spectrometric (LC-MS/MS)technique for quantifying fluoxetine (FLX) in human plasma was developed using the RapidTrace® automated solid-phase extraction (SPE) method; the analyte and internal standard (IS) were extricated on Oasis MCX SPE cartridges. Acetonitrile and 5 mM ammonium formate buffer (90:10 v/v) were used as mobile phase to achieve chromatographic separation on the reverse phase (C18 column). The analyte and IS were ionized using +ve electrospray ionization approach which was further traced by multiple-reaction monitoring on a tandem mass spectrometer. To quantify the FLX and FLX-d5, the parent-to-daughter ion transition of m/z of 310.0/44.1 and 315.0/44.0 was used, respectively. The method demonstrated a linear active limit of 0.20-30 ng/ml with recoveries ranging from 63.04% to 79.39% for quality control samples and 61.25% for IS samples. The concentrations over the calibration range demonstrated acceptable precision and accuracy. Due to the high inconsistency of the FLX concentration data, the minimum threshold of the assay was kept at 0.20 ng/ml. The flow rate was maintained at 500 µL/min, and the time for sample analysis for each injection was 3.5 min. The method was found to be specific, sensitive, and faster with minimum utilization of organic solvents and was utilized further for metabolic and pharmacokinetic studies.

Changes in Hematological Parameters by Quantifying HRCT Chest Results in Patients With COVID-19 in Tertiary Care Hospital.

AIM: To find changes in hematologic parameters in patients who are COVID-19-positive with respect to high resolution computed tomography (HRCT) chest scan so that the exact picture of the disease course can be identified and an adequate treatment protocol can be planned to combat the COVID-19 pandemic. METHODS: Patients' health-related data including age, gender, symptomatology, associated co-morbidities, laboratory test results and HRCT results were collected. RESULTS: The radiologic findings showed ground glass opacities (GGOs) was the most common manifestation. Analysis of HRCTs of patients with COVID-19 showed that lesions were mainly confined to the right and left lower lobes, suggesting that the COVID-19 virus is mainly harbored in the basal areas of the lungs. CONCLUSION: Radiologic and laboratory investigations can greatly help in early detection of COVID-19, thus allowing for timely interventions.

Cerebroprotective effect of pterostilbene against global cerebral ischemia in rats.

AIM OF THE STUDY: The role of pterostilbene against induced neurobehavioral alterations in global cerebral ischemia-reperfusion and oxidative damage was studied. MATERIALS AND METHODS: Male SD rats (180-200 g) were exposed for 30 min to bilateral carotid artery occlusion accompanied by 60 min reperfusion to cause cerebral injury. Pretreatment with pterostilbene (200 and 400 mg/kg, orally) was given to the animals for ten days followed by ischemia-reperfusion injury. Various behavioral tests (locomotor activity, neurological score, transfer latency, hanging wire test) were studied. The brain tissues of animals were used for both the biochemical parameters (lipid peroxidation, reduced glutathione, superoxide dismutase, catalase activity) and histopathological study. RESULT: The pterostilbene as given orally significantly improved neurobehavioral alterations compared to control ischemia-reperfusion. Treatment with pterostilbene (200, and 400 mg/kg, orally) also significantly attenuated oxidative damage as indicated by reduced lipid peroxidation, nitrite concentration, restored reduced glutathione, and catalase activity as compared to control (ischemia-reperfusion) animals. Overall, pterostilbene treated animals showed non significant histological alteration as compared to ischemia-reperfusion control. CONCLUSION: This work suggests the beneficial effect of pterostilbene and its therapeutic potential against reperfusion-induced ischemia and associated behavioral changes in rats due to the stabilization of DNA damage with significant free radical scavenging properties.

Clinical Characteristics and Outcomes Among COVID-19 Hospitalized Patients with Chronic Conditions: A Retrospective Single-Center Study.

PURPOSE: Evidence to date suggests that having chronic conditions increases the probability of severe illness from severe coronavirus disease 2019 (COVID-19). Thus, it is essential to identify the features of those patients. The purpose of this research was to identify the clinical characteristics and outcomes of COVID-19 patients with chronic conditions. PATIENTS AND METHODS: A retrospective cross-sectional single-center study was conducted using electronic medical records of hospitalized COVID-19 patients between March 1, 2020, and May 20, 2020. Patients' basic information, laboratory test, clinical data, medications, and outcome data have been extracted and compared among three groups: patients without chronic conditions, patients with one chronic condition, and patients with two or more chronic conditions. Chi-square, Fisher's exact test, Student's t-test, and the Mann-Whitney U-test were used. RESULTS: The study population was 458 patients, with an average age of 38.8 years (standard deviation (SD) 12.8). There were 398 (86.9%) males in the study population, most of them with one chronic condition. There were 14 (14.3%) smokers, and the majority of them were among patients with two or more chronic conditions. Longer hospital stay and time in the intensive care unit (ICU), a higher probability of ICU admission, and the need for mechanical ventilation were identified among patients with two or more chronic conditions. Dyspnea, an increased level of platelet counts, and a reduction in hemoglobin levels were discovered among patients with two or more chronic conditions. CONCLUSION: Patients with more chronic conditions were at higher risk of yielding poor clinical outcomes. Prevention and treatment of infections in these patients merit more attention.

Cichorium intybus attenuates streptozotocin induced diabetic cardiomyopathy via inhibition of oxidative stress and inflammatory response in rats.

The aim of the present study was to investigate the effects of Cichorium intybus on lipid peroxidation activities of both enzymatic and non-enzymatic antioxidants, inflammatory mediators, myocardial enzymes and histopathology of cardiac tissues in experimental diabetic cardiomyopathy (DCM). DCM was induced by single intraperitoneal injection of streptozotocin (STZ) (40 mg/kg) combined with high energy intake in rats. Seed extract of Cichorium intybus (CIE) (250 mg/kg & 500 mg/kg) was administered orally once a day for 3 weeks. Phytochemical investigations of seed extract revealed presence of some active ingredients such as alkaloids, tannins, saponin, phenols, glycosides, steroids, terpenoids and flavonoids. Seed extract of Cichorium intybus confirmed a significant potency towards restoring the blood glucose, an elevation of the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), blood glutathione (GSH), TNF-α and IL-6 and a reduction in the levels of catalase (CAT) was observed following the STZ treatment. Oxidative stress was accompanied by myocardial degeneration as evidenced by histopathological examination of cardiac tissues. Administration of CIE reduced the lipid peroxides level in heart. Serum levels of AST, GSH, LDH and SOD were brought down to physiological levels by CIE in STZ induced DCM rats. CIE also markedly down-regulated serum TNF-α and IL-6 levels. Catalase that was reduced in serum was brought back to near normal level. The extensive necrotic changes of cardiac tissue by STZ was minimized to normal morphology upon CIE administration. The study demonstrates the cardioprotective effect of CIE via inhibition of oxidative stress and pro-inflammatory cytokines.

Novel pentacyclic triterpene isolated from seeds of Euryale Ferox Salisb. ameliorates diabetes in streptozotocin induced diabetic rats.

The present research was carried out to study the effect of 2ß-hydroxybetulinic acid 3ß-oleiate (HBAO), a novel compound isolated from the seeds of Euryale ferox salisb. on glycemic control, antioxidant status and histopathological morphological alterations in the liver, pancreas, kidney and heart in streptozotocin induced type-2 diabetes in rats. HBAO was isolated from the seeds of Euryale ferox salisb. according to Lee. Isolation of the active principle HBAO was performed for the first time. To date there are no reports on the isolation and evaluation of 2ß-hydroxybetulinic acid 3ß-oleiate (HBAO) from Euryale ferox salisb. Assessment of different biochemical parameters like the effect of HBAO on glycemic control, plasma insulin, glycosylated hemoglobin, hepatic glucose-6-phosphate dehydrogenase, glucose-6-phosphatase and fructose-1-6-biphosphatase, hepatic hexokinase, lipid profile, antioxidant marker and histopathology of pancreas, liver and kidney examination was done at the end of the experimentation, i.e. on day 45. HBAO exhibited remarkable improvement in glycemic control, lipid levels, plasma insulin, glycogenic liver enzymes and antioxidant activity in diabetic rats, along with progressive enhancement of distortive histopathological morphology of liver, pancreas and kidney. The results strongly suggest that HBAO could be a potential therapeutic agent in diabetes.

The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients.

BACKGROUND AND OBJECTIVES: The selection of suitable functional excipients with low toxicity index and having P-glycoprotein inhibitory characteristics represents a major innovative step in designing a promising formulation for oral chemotherapy. This study was aimed at investigating the chemosensitizing effect of selected pharmaceutical excipients to improve the in vivo pharmacokinetic performance of VP-16. METHODS: The pharmaceutical excipients having P-glycoprotein inhibitory activity were screened by shake flask method for their VP-16 solubilization capacity. The cumulative amount of VP-16 was determined with or without the selected pharmaceutical excipients at three different concentrations (0.1 % w/v, 0.5 % w/v and 1 % w/v) by an everted gut sac technique. Moreover, pharmacokinetic studies were also performed to determine the oral bioavailability assessment of VP-16 in albino male Wistar rats. RESULTS: The absorptive transport from mucosal-to-serosal (M â†’ S) and secretory transport from serosal-to-mucosal (S â†’ M) for VP-16 solution over 90 min were found to be (3.58 ± 0.32) × 10-6 and (14.63 ± 3.11) × 10-6 cm/s, respectively, with a net efflux of 4.08. Addition of verapamil (200 µM), a P-glycoprotein inhibitor, elevated the transport from M â†’ S [Papp from (3.58 ± 0.32) to (9.66 ± 1.55) × 10-6 cm/s, p < 0.05] and lowered the S â†’ M [Papp from (14.63 ± 3.11) to (13.35 ± 2.01) × 10-6 cm/s, p < 0.01], with a net efflux of 1.38. The relative bioavailability of VP-16 following oral administration (4.5 mg/kg) in rats was increased significantly (p < 0.01) in presence of Labrasol micellar solution at a concentration of 5 % (w/v) when compared with VP-16 solution alone. CONCLUSION: The findings suggest that pharmaceutical excipients may be employed in the development of drug delivery systems to improve the oral bioavailability of drugs having low solubility and/or less permeability as a result of substantial P-glycoprotein mediated efflux.