Macrophages are exceptionally diversified cell types and perform unique features and functions when exposed to different stimuli within the specific microenvironment of various kidney diseases. In instances of kidney tissue necrosis or infection, specific patterns associated with damage or pathogens prompt the development of pro-inflammatory macrophages (M1). These M1 macrophages contribute to exacerbating tissue damage, inflammation, and eventual fibrosis. Conversely, anti-inflammatory macrophages (M2) arise in the same circumstances, contributing to kidney repair and regeneration processes. Impaired tissue repair causes fibrosis, and hence macrophages play a protective and pathogenic role. In response to harmful stimuli within the body, inflammasomes, complex assemblies of multiple proteins, assume a pivotal function in innate immunity. The initiation of inflammasomes triggers the activation of caspase 1, which in turn facilitates the maturation of cytokines, inflammation, and cell death. Macrophages in the kidneys possess the complete elements of the NLRP3 inflammasome, including NLRP3, ASC, and pro-caspase-1. When the NLRP3 inflammasomes are activated, it triggers the activation of caspase-1, resulting in the release of mature proinflammatory cytokines (IL)-1β and IL-18 and cleavage of Gasdermin D (GSDMD). This activation process therefore then induces pyroptosis, leading to renal inflammation, cell death, and renal dysfunction. The NLRP3–ASC–caspase-1–IL-1β–IL-18 pathway has been identified as a factor in the development of the pathophysiology of numerous kidney diseases. In this review, we explore current progress in understanding macrophage behavior concerning inflammation, injury, and fibrosis in kidneys. Emphasizing the pivotal role of activated macrophages in both the advancement and recovery phases of renal diseases, the article delves into potential strategies to modify macrophage functionality and it also discusses emerging approaches to selectively target NLRP3 inflammasomes and their signaling components within the kidney, aiming to facilitate the healing process in kidney diseases.

Visceral leishmaniasis (VL) or kala-azar is a vector-borne dreaded protozoal infection that is caused by the parasite Leishmania donovani. With increases in the dramatic infection rates, present drug toxicity, resistance, and the absence of an approved vaccine, the development of new antileishmanial compounds from plant sources remains the keystone for the control of visceral leishmaniasis. In this study, we evaluated the leishmanicidal effect of thymoquinone against L. donovani with an in vitro and ex vivo model. Thymoquinone exhibited potent antipromastigote activity with IC₅₀ and IC₉₀ concentrations achieved at 6.33 ± 1.21 and 20.71 ± 2.15 μM, respectively, whereas the IC₅₀ and IC₉₀ concentrations were found to be 7.83 ± 1.65 and 27.25 ± 2.20 μM against the intramacrophagic form of amastigotes, respectively. Morphological changes in promastigotes and growth reversibility study following treatment confirmed the leishmanicidal effect of thymoquinone. Further, thymoquinone exhibited leishmanicidal activities against L. donovani promastigote through cytoplasmic shrinkage, membrane blebbing, chromatin condensation, cellular and nuclear shrinkage, and DNA fragmentation, as observed under scanning and transmission electron microscopy analyses. The antileishmanial activity was exerted via programmed cell death as proved by exposure of phosphatidylserine, DNA nicking by TUNEL assay, and loss of mitochondrial membrane potential. Thymoquinone at a concentration of 200 μM was devoid of any cytotoxic effects against mammalian macrophage cells. Thymoquinone showed strong leishmanicidal activity against L. donovani, which is mediated via an apoptosis mode of parasitic cell death, and accordingly, thymoquinone may be the source of a new lead molecule for the cure of VL.

The re-emergence of Chikungunya virus (CHIKV) infection in humans with no approved antiviral therapies or vaccines is one of the major problems with global significance. In the present investigation, we screened 80 in-house quinoline derivatives for their anti-CHIKV activity by computational techniques and found 4-hydroxy-1-methyl-3-(3-morpholinopropanoyl)quinoline-2(1H)-one (QVIR) to have potential binding affinities with CHIKV nsP2 and E2 glycoproteins. QVIR was evaluated in vitro for its anti-CHIKV potential. QVIR showed strong inhibition of CHIKV infection with an EC₅₀ (50% effective concentration) value of 2.2 ± 0.49 μM without significant cytotoxicity (CC₅₀ > 200 μM) and was chosen for further elucidation of its antiviral mechanism. The infectious viral particle formation was abolished by approximately 72% at a QVIR concentration of 20 μM during infection in the BHK-21 cell line, and the CHIKV RNA synthesis was diminished by 84% for nsP2 as well as 74% for E2, whereas the levels of viral proteins were decreased by 69.9% for nsP2 and 53.9% for E2. Flow cytometry analysis confirmed a huge decline in the expression of viral nsP2 and E2 proteins by 71.84 and 67.7%, respectively. Time of addition experiments indicated that QVIR inhibited viral infection at early and late stages of viral replication cycle, and the optimal inhibition was observed at 16 h post infection. The present study advocates for the first time that QVIR acts as a substantial and potent inhibitor against CHIKV and might be as an auspicious novel drug candidate for the development of therapeutic agents against CHIKV infections.

Emerging evidence indicates that activation of complement system leading to the formation of the membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3^−/−; 2. C7^−/−; and 3. Cd59ab^−/−) to evaluate the role of complement in severe COVID-19 pathogenesis. C3 deficient mice lack a key common component of all three complement activation pathways and are unable to generate C3 and C5 convertases. C7 deficient mice lack a complement protein needed for MAC formation. Cd59ab deficient mice lack an important inhibitor of MAC formation. We also used anti-C5 antibody to block and evaluate the therapeutic potential of inhibiting MAC formation. We demonstrate that inhibition of complement activation (in C3^−/−) and MAC formation (in C3^−/−. C7^−/−, and anti-C5 antibody) attenuates severe COVID-19; whereas enhancement of MAC formation (Cd59ab^−/−) accelerates severe COVID-19. The degree of MAC but not C3 deposits in the lungs of C3^−/−, C7^−/− mice, and Cd59ab^−/− mice as compared to their control mice is associated with the attenuation or acceleration of SARS-CoV-2-induced disease. Further, the lack of terminal complement activation for the formation of MAC in C7 deficient mice protects endothelial dysfunction, which is associated with the attenuation of diseases and pathologic changes. Our results demonstrated the causative effect of MAC in severe COVID-19 and indicate a potential avenue for modulating the complement system and MAC formation in the treatment of severe COVID-19.