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Tramadol (TR), a commonly prescribed pain reliever for moderate to severe pain, has been associated with kidney damage. This study investigates TR‐induced nephrotoxicity mechanisms, focusing on its effects on renal proximal tubular cells (PTCs). The study findings demonstrate that TR disrupts PTC bioenergetic processes, leading to oxidative stress and inflammation. Significant toxicity to PTCs was observed with estimated effective concentration 50 values of 9.8 and 11.5 µM based on 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. TR also interferes with the function of PTC transporters, including organic cation uptake transporter 1, organic cation transporter 2, P‐glycoprotein, and multidrug resistance protein 2. Furthermore, bioenergetics assays showed that TR reduced the activities of mitochondrial complexes I and III, adenosine triphosphate production, mitochondrial membrane potential, and oxygen consumption rate while increasing lactate release. TR also increased the production of reactive oxygen species, lipid peroxidation thiobarbituric acid reactive substances end products, and the expression of the NRf2 gene while decreasing reduced glutathione (GSH‐R) stores and catalase and superoxide dismutase antioxidant activities. Additionally, TR increased the production of inflammatory cytokines (TNF‐α and IL‐6) and their coding genes expression. Interestingly, the study found that antioxidants like GSH‐R, inhibitors of IL‐6 and TNF‐α, and mitochondrial activating Co‐Q10 could protect cells against TR‐induced cytotoxicity. The study suggests that TR causes nephrotoxicity by disrupting bioenergetic processes, causing oxidative stress and inflammation, but antioxidants and agents targeting mitochondria may have protective and curative potential. [ABSTRACT FROM AUTHOR]

Byline: Elhassan. Eltom, Mohanad. Mahmoud Ibrahim, Ekramy. Elmorsy Sir, Tropicamide is a widely used short-acting mydriatic with antimuscarinic properties. It is mainly used to dilate the eye pupils for proper [...]

Simple Summary: Lung cancer (LC) is considered one of the most common cancers globally. Numerous studies have determined the relations between E-cigarette, or vaping, products (EVPs) and many proven environmental toxicants in LC development. Even though tobacco smoke remains the chief cause of LC, there is increasing concern that EVPs use could also increase LC risk. Consumption of EVPs has been dramatically increasing world-wide, particularly among younger people and non-smokers. This review seeks to consolidate the known environmental toxicants and EVPs contributing to LC to ensure that future research endeavors may identify key focus areas. Thus, EVPs are a highly potential risk factor for LC and an area of significant concern for the future. Since these factors have been linked to the development of LC, more research is needed to determine the mechanisms by which they affect lung pathology. Discovering the pathophysiology of EVPs use and environmental toxicant exposure in LC development can facilitate the adoption of exposure reduction strategies. Lung cancer (LC) is the second-most prevalent tumor worldwide. According to the most recent GLOBOCAN data, over 2.2 million LC cases were reported in 2020, with an estimated new death incident of 1,796,144 lung cancer cases. Genetic, lifestyle, and environmental exposure play an important role as risk factors for LC. E-cigarette, or vaping, products (EVPs) use has been dramatically increasing world-wide. There is growing concern that EVPs consumption may increase the risk of LC because EVPs contain several proven carcinogenic compounds. However, the relationship between EVPs and LC is not well established. E-cigarette contains nicotine derivatives (e.g., nitrosnornicotine, nitrosamine ketone), heavy metals (including organometal compounds), polycyclic aromatic hydrocarbons, and flavorings (aldehydes and complex organics). Several environmental toxicants have been proven to contribute to LC. Proven and plausible environmental carcinogens could be physical (ionizing and non-ionizing radiation), chemicals (such as asbestos, formaldehyde, and dioxins), and heavy metals (such as cobalt, arsenic, cadmium, chromium, and nickel). Air pollution, especially particulate matter (PM) emitted from vehicles and industrial exhausts, is linked with LC. Although extensive environmental exposure prevention policies and smoking reduction strategies have been adopted globally, the dangers remain. Combined, both EVPs and toxic environmental exposures may demonstrate significant synergistic oncogenicity. This review aims to analyze the current publications on the importance of the relationship between EVPs consumption and environmental toxicants in the pathogenesis of LC. [ABSTRACT FROM AUTHOR]

Objectives: The study aims to assess apoptosis, oxidative stress, and inflammation as underlying diabetogenic mechanisms in isolated CD1 mouse beta-pancreatic cells of some prescribed Antipsychotics (APs). Methods: Three types of APs were tested in different concentrations (0.1, 1, 10, and 100 µM) on adult male CD1 mice. The cytotoxicity of the tested APs was determined using different assays including MTT and Lactate Dehydrogenase (LDH) assays. Oxidative stress was assessed by and measuring Reactive oxygen species (ROS) production, lipid peroxidation, and antioxidant enzyme activities. Moreover, the effect on the inflammatory cascade was also investigated. Results: The tested APs were cytotoxic to beta cells and showed patterns dependent on both concentration and exposure, with a parallel reduction in glucose-stimulated insulin secretion of the treated cells. The APs also showed induction of oxidative stress in the treated cells by significantly increasing the ROS, lipid peroxidation, and NRf2 gene expression, together with decreased antioxidant enzyme activities. Moreover, APs showed significant increases in cytokines levels to their estimated IC50 levels. The activities of caspases 3, 8, and 9 were also significantly increased in all treated samples at their IC50s and at 10 µM concentrations of all tested APs. However, the glutathione and inhibitors of caspase-3, IL-6, and TNF-α significantly improved GSIS and the viability of the AP-treated cells. Conclusion: The results suggest a significant role for apoptosis, oxidative stress, and inflammation, in the diabetogenic effect of APs, expected role of antioxidants and anti-inflammatory drugs as therapeutics for improving the outcome in cases of long-term prescribed APs [ABSTRACT FROM AUTHOR]

Objectives: Antipsychotics (APs) are medications used for different psychological disorders. They can introduce diabetogenic effects through different mechanisms, including cyclic adenosine monophosphate (cAMP) and calcium (Ca2+) signaling pathways. However, this effect is poorly understood. Therefore, this study aimed to evaluate the effect of three widely used APs (chlorpromazine, haloperidol, and clozapine) on cAMP and Ca2+ signaling. Methods: The local bioethics committee of Northern Border University approved the study. Pancreatic β-cells were isolated from male CD1 mice, and three drug stock solutions were made in different concentrations (0.1, 1, 10, and 100 µM). The levels of glucose-stimulated insulin secretion (GSIS) and cAMP as well as the activities of adenylyl cyclase (AC), cAMP-dependent protein kinase (PKA), guanine-nucleotide exchange protein activated by cAMP (Epac 1 and 2), Ca2+ mobilization, and Ca2+/ calmodulin kinase II (CaMKII) were then determined using different methods. Results: APs were found to be cytotoxic to pancreatic β cells and caused a parallel and significant decrease in GSIS. APs significantly reduced the levels of cAMP in the treated cells, with an associated reduction in ATP production, CaMKII, PKA, and transmembrane AC activities as well as Ca2+ mobilization to variable extents. In addition, the gene expression results showed that APs significantly decreased the expression of both the active subunits AC1 and AC8, the PKA α and β subunits, Epac1 and Epac2 as well as the four main subunits of CaMKII to variable extents. Conclusion: AP-induced alterations in the cAMP and Ca2+ signaling pathways can play a significant role in their diabetogenic potential. [ABSTRACT FROM AUTHOR]

Antipsychotics (APs) are widely used medications with reported diabetogenic side effects. This study investigated the effect of commonly used APs, namely chlorpromazine (CPZ), haloperidol (HAL) and clozapine, on the bioenergetics of male CD1 mice isolated pancreatic beta cells as an underlying mechanism of their diabetogenic effects. The effect of APs on Alamar blue reduction, adenosine triphosphate (ATP) production and glucose‐stimulated insulin secretion (GSIS) of isolated beta cells was evaluated. Then, the effects of APs on the activities of mitochondrial complexes and their common coding genes expression, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and lactate production were investigated. The effects of APs on the mitochondrial membrane fluidity (MMF) and mitochondrial membrane fatty acid composition were also examined. Results showed that the tested APs significantly decreased cellular ATP production and GSIS of the beta cells. The APs significantly inhibited the activities of mitochondrial complexes and their coding gene expression, MMP and OCR of the treated cells, with a parallel increase in lactate production to different extents with the different APs. CPZ and HAL showed increased MMF and mitochondrial membrane polyunsaturated fatty acid content. In conclusion, the tested APs‐induced mitochondrial disruption can play a role in their diabetogenic side effect. [ABSTRACT FROM AUTHOR]