Heavy metal bioaccumulation triggers oxystress, genotoxicity and immunomodulation in head kidney macrophages of Channa punctatus Bloch.

Studies on heavy metal induced toxicity have been conducted in many water bodies across the globe and such effects have been evaluated in various fish species. The present study was designed to determine the load of some heavy metals in select sites in Southern Assam, India, along with estimating their concentration in tissues of Channa punctatus Bloch. inhabiting those niches. The effect of heavy metals in oxystress generation, genotoxicity and subsequent immune response in fish was also evaluated. In all of these sites, the concentration of Hg, Cd, Pb and Cr were above the permissible ranges while their concentrations were several folds higher in the piscine tissues due to bioaccumulation and possible biomagnification. Kidney showed the highest metal pollution index followed by liver and gills. Generation of ROS was significantly elevated and that in turn triggered oxystress, as is evident from enhanced lipid peroxidation, protein carbonylation and respiratory burst activity. These were in association with the compromised antioxidant enzyme levels with concomitant damage to DNA as evident from Comet parameters. The innate immune potential was significantly impaired as evident from the compromised cell adhesion, phagocytosis, intracellular killing activity in head kidney macrophages (HKM) along with decreased release of nitric oxide (NO) and myeloperoxidase (MPO). Immunosuppression was further validated at protein levels where compromised release of cytokines viz. TNF-α, IL-1ß, IL-6, IL-10 and IL-12 and cell signaling molecules iNOS and NF-κß were noted. Thus the present study indicates genotoxicity along with a compromise in immune status of Channa punctatus Bloch. living in a habitat laden with heavy metals.

Regional disparity of covid-19 infections: an investigation using state-level Indian data.

Using the state-level panel data for India, we establish that Covid infections are clustered in more urbanized, and prosperous states. Poverty lowers cases showing evidence of herd immunity of poor which stands in sharp contrast with the developed part of the world. Our dynamic panel regression results indicate that Covid infections are persistent across states and unlocking has aggravated the infections. We also find that richer and more urbanised states with better health infrastructure and governance perform more tests. The policy lesson from this exercise is that the authorities should monitor immunization and Covid protocols in densely populated urban areas.

Cadmium exposure induces inflammation through the canonical NF-κΒ pathway in monocytes/macrophages of Channa punctatus Bloch.

A vast range of research related to the toxicity of the heavy metal cadmium (Cd) has been carried out in a wide variety of fish species. However, Cd induced immunomodulation in monocytes/macrophages of Channa punctatus Bloch. has rarely been explored. The present study was designed to determine Cd induced immune response, role of NF-κB (nuclear factor kappa B) pathway and the subsequent downstream molecular responses in monocytes/macrophages of C. punctatus. Fish were sampled and acclimatized, with one group treated with cadmium chloride (CdCl2) (1.96 mg/L) and another kept as untreated control group, both under observation for 7 days. Exposure to CdCl2 was found to alter hematological profile of C. punctatus in addition to incurring histo-architectural damages in the HK (head kidney) and ultrastructural changes in the monocytes/macrophages. The innate immune potential was found to be significantly compromised as evident from decreased phagocytosis, intracellular killing, cell adhesion and reduced release of nitric oxide (NO) and myeloperoxidase (MPO) in Cd intoxicated group. Also Cd triggered ROS generation, reduced cellular NO levels by forming peroxynitrite along with the upregulated expression of the inflammatory marker iNOS (inducible nitric oxide synthase) in monocytes/macrophages, both at mRNA and protein levels, indicating inflammation. Inflammation is further verified from the upregulated expression of proinflammatory cytokines viz. TNF-α, IL-1ß, IL-6, IL-12 along with a central inflammatory mediator NF-κΒ and downregulation of the anti-inflammatory cytokine IL-10, both at mRNA and protein levels. It can be concluded that, a sub-lethal exposure of Cd in C. punctatus for 7 days caused significant alterations in the hematological, histological and ultrastructural profile in monocytes/macrophages; impaired innate immune parameters, triggers ROS generation and inflammation as validated from the upregulated expression of NF-κΒ, iNOS, TNF-α, IL-1ß, IL-6, IL-12 and IL-10 downregulation.

Cadmium induced oxystress alters Nrf2-Keap1 signaling and triggers apoptosis in piscine head kidney macrophages.

Cadmium (Cd) with no known functional role in any life-form has myriad of harmful effects. The present study was designed to elucidate the mechanism of Cd-induced oxystress generation and its impact on antioxidant and apoptosis signaling pathways in head kidney macrophage (HKM) of Channa punctatus Bloch. Fish were sampled and acclimatized with one group treated with cadmium chloride (CdCl2) (1.96 mg/L) and another as untreated control group, both kept under observation for 7 days. Exposure to Cd caused ultrastructural changes along with reduced head kidney somatic index (HKSI). Significantly increased levels of reactive oxygen species (ROS), respiratory burst activity, lipid peroxidation, DNA fragmentation and superoxide dismutase were found in the HKM from the treated group as compared to control. In contrast, antioxidant enzymes like catalase and reduced glutathione activity decreased in the Cd exposed group. The suppressed antioxidant activity was further confirmed and corroborated from the altered expression of Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) genes, the major player of antioxidant pathway. Cd induced alteration in Nrf2-Keap1 signaling pathway was also validated by the diminished levels of Nrf2 dependent expression of protein like heme oxygenase-1 (HO-1). The flow cytometry analysis supported the event of apoptosis in Cd exposed group as compared to control, which was further confirmed by the upregulated expression of caspase-3, caspase-8, caspase-9, TNF-α and p53 genes from the real-time gene expression study. In addition, altered protein level of cytochrome C validates the incidence of apoptosis. Altogether, our results demonstrate that exposure to Cd caused oxidative stress in HKM of Channa punctatus Bloch. by compromising the antioxidant enzyme activities via the down regulation of expression of genes related to antioxidant signaling pathway besides encouraging apoptosis via both mitochondrial and death receptor pathway.

Gold­manganese oxide nanocomposite suppresses hypoxia and augments pro-inflammatory cytokines in tumor associated macrophages.

The tumor microenvironment, essentially hypoxic, is sustained by the hypoxia inducing factor (HIF), released from the pro-tumorigenic tumor associated macrophages (TAMs), functionally identical to the M2 phenotype macrophages. Stability of HIF mainly depends on molecular oxygen and an iron-dependent enzyme prolyl hydroxylase, while its activity may be inhibited by high levels of reactive oxygen species and nitric oxide. The present work showcases a novel approach utilizing the anti-tumorigenic potential of a gold-manganese oxide nanocomposite material in the tumor microenvironment that affects tumor hypoxia, exploring the possibility of restoring the immunoregulatory nature of TAMs from their pro-tumorigenic state. Along with the biochemical markers, ELISA and FACS analyses have also confirmed the potential of these nanoparticles in reverting back the M2 phenotype of TAMs to their classically activated M1 phenotype.