Biochemical investigation of association of arsenic exposure with risk factors of diabetes mellitus in Pakistani population and its validation in animal model.

Arsenic is one of the naturally occurring heavy metal that has been reported to cause damaging effects on different body organs. This study was aimed to determine the arsenic level in different water sources and investigate the effect of arsenic exposure on risk factors of diabetes mellitus (DM) in human participants and experimental animals. We recruited 150 participants to investigate the arsenic exposure in their urine and from drinking water. We found that males contained significantly higher (P < 0.001) concentrations of urinary arsenic as compared with that of their female counterparts. Similarly, urinary arsenic concentration was high and showed significant association in the age of ≥ 60 years (P < 0.05), illiterate (P < 0.001), smokers (P < 0.0001), and diabetic (P < 0.0001) participants. Moreover, urinary arsenic exposure was also associated with higher levels of fasting (P < 0.001) and random blood glucose (P < 0.001), HbA1c (P < 0.001), AST, ALT, MDA, IL-6, CRP, blood urea nitrogen, and creatinine in arsenic-exposed diabetics as compared with that of unexposed diabetics. Further, we also exposed the white albino rats with arsenic in drinking water for 30 days and their blood glucose was measured at 15th and 30th days of treatment that was significantly higher (P < 0.001) in arsenic-exposed animals as compared with that of unexposed animals. Similarly, arsenic-exposed animals failed to tolerate exogenously administered glucose (P < 0.001) as compared with that of unexposed animals. Likewise, insulin and glutathione concentrations were also significantly decreased (P < 0.001) in arsenic-exposed animals as compared with that of unexposed animals. The alterations in normal values of glucose, insulin, and glutathione exhibited the damaging effects of arsenic exposure in experimental rats. This study showed that arsenic exposed to human beings and animals through drinking water resulted in the disruption of pancreatic ß-cell functioning that provoked the risk factor for development of DM. This study also suggested that long-term arsenic exposure induces hyperglycemia, inflammation, and oxidative stress that may lead to the onset of development of DM.

Prevalence of exposure of heavy metals and their impact on health consequences.

Even in the current era of growing technology, the concentration of heavy metals present in drinking water is still not within the recommended limits as set by the regulatory authorities in different countries of the world. Drinking water contaminated with heavy metals namely; arsenic, cadmium, nickel, mercury, chromium, zinc, and lead is becoming a major health concern for public and health care professionals. Occupational exposure to heavy metals is known to occur by the utilization of these metals in various industrial processes and/or contents including color pigments and alloys. However, the predominant source resulting in measurable human exposure to heavy metals is the consumption of contaminated drinking water and the resulting health issues may include cardiovascular disorders, neuronal damage, renal injuries, and risk of cancer and diabetes. The general mechanism involved in heavy metal-induced toxicity is recognized to be the production of reactive oxygen species resulting oxidative damage and health related adverse effects. Thus utilization of heavy metal-contaminated water is resulting in high morbidity and mortality rates all over the world. Thereby, feeling the need to raise the concerns about contribution of different heavy metals in various health related issues, this article has discussed the global contamination of drinking water with heavy metals to assess the health hazards associated with consumption of heavy metal-contaminated water. A relationship between exposure limits and ultimate responses produced as well as the major organs affected have been reviewed. Acute and chronic poisoning symptoms and mechanisms responsible for such toxicities have also been discussed.

In Silico Study of a Small Bioactive Molecule Targeting Topoisomerase II and P53-MDM2 Complex in Triple-Negative Breast Cancer.

Treatment of triple-negative breast cancer (TNBC) is very challenging as only few therapeutic options are available, including chemotherapy. Thus, a constant search for new and effective approaches of therapy that could potentially fight against TNBC and mitigate side effects is "turn-on". Recently, multitarget therapy has come up with huge possibilities, and it may possibly be useful to overcome several concurrent challenges in cancer therapy. Herein, we proposed the inhibition of both Topoisomerase II enzyme and p53-MDM2 (p53 cavity in MDM2) protein complex by the same bioactive molecules for multitarget therapy. RNA-seq analysis was performed to get a network of essential proteins involved in the apoptosis pathway by considering the triple-negative breast cancer cell line (MDA-MB-231). All of the untreated duplicate sample data were retrieved from NCBI (GSC149768). Further, via in silico screening, potent bioactive molecules were screened out to target both Topo II and the p53-MDM2 complex. The results of ligand-based screening involving docking, MMGBSA, ADME/T, MD simulation, and PCA suggested that resveratrol, a plant bioactive molecule, showed more potential binding in the same cavity of target proteins compared with doxorubicin for Topo IIα (5GWK) and etoposide for the second protein target (p53-MDM2 complex; 4OQ3) as the control drug. This is also evident from the in vitro validation in case of triple-negative breast cancer cell lines (MDA-MB-231) and Western blotting analysis. Thus, it paves the scope of multitargeting against triple-negative breast cancer.

Clinical and Etiological Exploration of Ventilator-Associated Pneumonia in the Intensive Care Unit of a Developing Country.

Background Ventilator-associated pneumonia (VAP) is a critical concern in the intensive care unit (ICU), with significant implications for patient outcomes. This retrospective cross-sectional study aimed to determine the prevalence of VAP in an ICU of a developing country, identify the predominant etiological factors, assess patient outcomes, and underscore the need for tailored interventions in high-risk patient groups. Methods This retrospective cross-sectional study included 589 ICU patients who underwent ventilator-assisted breathing for over 48 hours. Among them, 151 developed VAP. The diagnosis was made on clinical, laboratory, and radiological findings, and tracheal aspirate cultures. Exclusions included pediatric patients, less than 48 hours of ventilation, and pre-existing lung infections. Patient data encompassed gender, age, comorbidities, outcomes, admission reasons, isolated microorganisms, and clinical findings. Results 151 patients out of the 589 developed VAP. The age of the patients ranged between 31 to 69 years and the mean age was 45.43 ± 8.92 years. Clinical diagnoses upon ICU admission varied, including sepsis, trauma, stroke, and metabolic disorders. Chest X-rays commonly revealed atelectasis (19.2%), consolidation (21.9%), pleural effusion (11.9%), and lobar pneumonia (45.7%). Tracheal aspirate cultures predominantly isolated multidrug-resistant gram-negative rods, with methicillin-resistant gram-positive cocci and fungal pneumonia prevalent in neutropenic sepsis cases. Notably, only 54 (35.8%) of patients survived, with significantly poorer outcomes observed in sepsis, neutropenic sepsis, and stroke cases compared to trauma and post-operative admissions. Conclusion Multidrug-resistant organisms and the spread of nosocomial infections are the predominant causes of VAP in the ICU. This emphasizes the urgent need for multifaceted interventions to prevent and manage VAP effectively. Developing and implementing targeted strategies, considering the unique challenges faced in resource-constrained healthcare settings can aid in decreasing the mortality associated with it.