Heavy metal Chromium (Cr), can adversely affect humans and their health if accumulated in organs of the body, such as the lungs, liver, and kidneys. Cr (VI) is highly toxic and has a higher solubility in water than Cr (III). One of the most common routes for Cr exposure is through inhalation and is associated with liver, lung, kidney damage, widespread dermatitis, GI tract damage, human lung cancer, cardiomyopathies, and cardiovascular disease. The increase in ROS production has been attributed to most of the damage caused by Cr toxicity. Cr-induced ROS-mediated oxidative stress has been seen to cause a redox imbalance affecting the antioxidant system balance in the body. The Nrf2 pathway dysregulation has been implicated in the same. Deregulation of histone acetylation and methylation has been observed, together with gene methylation in genes such as p16, MGMT, APC, hMLH1, and also miR-143 repression. Several ultra-structural changes have been observed following Cr (VI)-toxicity, including rough ER dilation, alteration in the mitochondrial membrane and nuclear membrane, pycnotic nuclei formation, and cytoplasm vacuolization. A significant change was observed in the metabolism of lipid, glucose, and the metabolism of protein after exposure to Cr. Cr-toxicity also leads to immune system dysregulations with changes seen in the expression of IL-8, IL-4, IgM, lymphocytes, and leukocytes among others. P53, as well as pro-and anti-apoptotic proteins, are involved in apoptosis. These Cr-induced damages can be alleviated via agents that restore antioxidant balance, regulate Nrf-2 levels, or increase anti-apoptotic proteins while decreasing pro-apoptotic proteins.

Toxic heavy metals (THMs) are non-essential hazardous environmental pollutants with intractable health challenges in humans and animals. Exposure to lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), and chromium (Cr) are ubiquitous and unavoidable due to food contamination, mining, and industrial mobilization. They are triggers of tissue impairment and aberrant signaling pathways that cascade into several toxicities and pathologies. Each of Pb, Cd, Hg, As, Ni, and Cr aggravate oxidative inflammation, protein dysregulation, apoptotic induction, DNA damage, endocrine deficits, and mitochondrial dysfunction contributing to the pathophysiology of diseases. Hesperidin (HSD) and hesperetin (HST) are flavonoids from citrus fruits, and systematic investigations suggest their potential to combat the molecular alterations and toxicities induced by THMs. They mitigate heavy metal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic effects via scavenging free radicals and modulation of ATPases, cell cycle proteins, and various cellular signaling pathways, including Nrf2/HO-1/ARE, PI3K/mTOR/Akt, MAPK/caspase-3/Bax/Bcl-2, iNOS/NF-κB/TNF-α/COX-2. This review summarized the mechanistic effects of heavy metal toxicity and the insights on molecular mechanisms underlying mitigation of heavy metal toxicity by HSD and HST. Hesperidin and hesperetin are potential flavonoids for the modulation of pathological signaling networks associated with THMs. Therefore, HSD and HST can be suggested as natural dietary agents and blockers of harmful effects of THMs.

The ever-increasing rate of pollution has attracted considerable interest in research. Several anthropogenic activities have diminished soil, air, and water quality and have led to complex chemical pollutants. This review aims to provide a clear idea about the latest and most prevalent pollutants such as heavy metals, PAHs, pesticides, hydrocarbons, and pharmaceuticals—their occurrence in various complex mixtures and how several environmental factors influence their interaction. The mechanism adopted by these contaminants to form the complex mixtures leading to the rise of a new class of contaminants, and thus resulting in severe threats to human health and the environment, has also been exhibited. Additionally, this review provides an in-depth idea of various in vivo, in vitro, and trending biomarkers used for risk assessment and identifies the occurrence of mixed contaminants even at very minute concentrations. Much importance has been given to remediation technologies to understand our current position in handling these contaminants and how the technologies can be improved. This paper aims to create awareness among readers about the most ubiquitous contaminants and how simple ways can be adopted to tackle the same.

The current study aims to assess the protective effects of dapagliflozin (Dapa; a sodium-glucose cotransporter-2 inhibitor) and/or liraglutide (Lira; a glucagon-like peptide 1 agonist) in an experimental model of diabetic cardiomyopathy (DCM). A single dose of streptozotocin (STZ) was administrated to male Sprague–Dawley rats by intraperitoneal injection at a dose of 50 mg/kg to induce diabetes mellitus (DM). Dapa (1 mg/kg, orally), Lira (0.4 mg/kg, s.c.), and Dapa–Lira combination were administrated for 8 weeks once-daily. Blood samples were evaluated for glucose level and biochemical markers of cardiac functions. Cardiac tissue was dissected and assessed for redox homeostasis (malondialdehyde (MDA), glutathione (GSH), and catalase (CAT)), pro-inflammatory mediators (NF-κB and tumor necrosis factor-α (TNF-α)), and apoptotic effectors (caspase-3). Moreover, the effect of treatments on the cardiac cellular structure was studied. Dapa and/or Lira administration resulted in significant improvement of biochemical indices of cardiac function. Additionally, all treatment groups demonstrated restoration of oxidant/antioxidant balance. Moreover, inflammation and apoptosis key elements were markedly downregulated in cardiac tissue. Also, histological studies demonstrated attenuation of diabetes-induced cardiac tissue injury. Interestingly, Dapa–Lira combination treatment produced a more favorable protective effect as compared to a single treatment. These data demonstrated that Dapa, Lira, and their combination therapy could be useful in protection against DM-accompanied cardiac tissue injury, shedding the light on their possible utilization as adjuvant therapy for the management of DM patients.

Hepatic encephalopathy (HE) is a neurological disarray manifested as a sequel to chronic and acute liver failure (ALF). A potentially fatal consequence of ALF is brain edema with concomitant astrocyte enlargement. This study aims to outline the role of astrocytes in acute HE and shed light on the most critical mechanisms driving this role. Rats were allocated into two groups. Group 1, the control group, received the vehicle. Group 2, the TAA group, received TAA (300 mg/kg) for 3 days. Serum AST, ALT, and ammonia were determined. Liver and cerebral cortical sections were processed for hematoxylin and eosin staining. Additionally, mRNA expression and immunohistochemical staining of cortical GFAP, TNFα, Kir4.1, and AQP4 were performed. Cortical sections from the TAA group demonstrated neuropil vacuolation and astrocytes enlargement with focal gliosis. GFAP, TNFα, and AQP4 revealed increased mRNA expression, positive immunoreactivity, and a positive correlation to brain water content. In contrast, Kir 4.1 showed decreased mRNA expression and immunoreactivity and a negative correlation to brain water content. In conclusion, our findings revealed altered levels of TNFα, Kir 4.1, GFAP, and AQP4 in HE-associated brain edema. A more significant dysregulation of Kir 4.1 and TNFα was observed compared to AQP4 and GFAP.

The clinical application of cyclosporine A (CsA) as an immunosuppressive agent is limited by its organ toxicity. We aimed to evaluate the effectiveness of α-lipoic acid against CsA-induced hepatotoxicity and to delineate the underlying molecular mechanisms. Male Wistar rats (n = 24, 8 per each group) received the vehicle, CsA (25 mg/kg) and/or ALA (100 mg/kg, p.o.) for 3 weeks. Biochemical markers of liver function (serum ALT, AST, ALP < GGT), oxidative stress (MDA, TAC, SOD, GSH, Nrf2/HO-1), inflammation (NF-κB, CD68, iNOS, NO, COX-2), and apoptosis (caspase-3) were assessed in serum and tissue. Liver histological analysis using H&E and Sirius red was performed. The development of liver injury in CsA-treated animals was indicated by elevated levels of liver enzymes, oxidants/antioxidants imbalance, inflammatory cells infiltration, up-regulated expression of inflammatory mediators, and apoptosis. These changes were associated with altered architecture of hepatic cells and fibrous connective tissue. ALA co-administration protected against CsA-induced liver damage and ameliorated biochemical changes and cellular injury. In conclusion, ALA demonstrated hepatoprotective potential against CsA-induced liver injury through combating oxidative stress, inflammation, and apoptosis, highlighting ALA as a valuable adjunct to CsA therapy.