Alcohol consumption leads to neuroinflammation and blood‒brain barrier (BBB) damage, resulting in neurological impairment. We previously demonstrated that ethanol-induced disruption of barrier function in human brain endothelial cells was associated with mitochondrial injury, increased ATP and extracellular vesicle (EV) release, and purinergic receptor P2 × 7R activation. Therefore, we aimed to evaluate the effect of P2 × 7R blockade on peripheral and neuro-inflammation in ethanol-exposed mice. In a chronic intermittent ethanol (CIE)-exposed mouse model, P2 × 7R was inhibited by two different methods: Brilliant Blue G (BBG) or gene knockout. We assessed blood ethanol concentration (BEC), brain microvessel gene expression by using RT2 PCR array, plasma P2 × 7R and P-gp, serum ATP, EV-ATP, number of EVs, and EV mtDNA copy numbers. An RT2 PCR array of brain microvessels revealed significant upregulation of proinflammatory genes involved in apoptosis, vasodilation, and platelet activation in CIE-exposed wild-type animals, which were decreased 15–50-fold in BBG-treated–CIE-exposed animals. Plasma P-gp levels and serum P2 × 7R shedding were significantly increased in CIE-exposed animals. Pharmacological or genetic suppression of P2 × 7R decreased receptor shedding to levels equivalent to those in control group. The increase in EV number and EV-ATP content in the CIE-exposed mice was significantly reduced by P2 × 7R inhibition. CIE mice showed augmented EV-mtDNA copy numbers which were reduced in EVs after P2 × 7R inhibition or receptor knockout. These observations suggested that P2 × 7R signaling plays a critical role in ethanol-induced brain injury. Increased extracellular ATP, EV-ATP, EV numbers, and EV-mtDNA copy numbers highlight a new mechanism of brain injury during alcohol exposure via P2 × 7R and biomarkers of such damage. In this study, for the first time, we report the in vivo involvement of P2 × 7R signaling in CIE-induced brain injury.

The emergence of drug-resistant mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), poses an increasing global threat that urgently demands the development of new potent anti-mycobacterial drugs. One of the approaches toward the identification of new drugs is fragment-based drug discovery (FBDD), which is the most ingenious among other drug discovery models, such as structure-based drug design (SBDD) and high-throughput screening. Specialized techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and many others, are part of the drug discovery approach to combat the Mtb and NTM global menaces. Moreover, the primary drawbacks of traditional methods, such as the limited measurement of biomolecular toxicity and uncertain bioavailability evaluation, are successfully overcome by the FBDD approach. The current review focuses on the recognition of fragment-based drug discovery as a popular approach using virtual, computational, and biophysical methods to identify potent fragment molecules. FBDD focuses on designing optimal inhibitors against potential therapeutic targets of NTM and Mtb (PurC, ArgB, MmpL3, and TrmD). Additionally, we have elaborated on the challenges associated with the FBDD approach in the identification and development of novel compounds. Insights into the applications and overcoming the challenges of FBDD approaches will aid in the identification of potential therapeutic compounds to treat drug-sensitive and drug-resistant NTMs and Mtb infections.

Tuberculosis (TB) remains a global health problem and the emergence of HIV has further worsened it. Long chemotherapy and the emergence of drug-resistance strains of Mycobacterium tuberculosis as well as HIV has aggravated the problem. This demands urgent the need to develop new anti-tuberculosis and antiretrovirals to treat TB and HIV. The lack of diversity in drugs designed using traditional approaches is a major disadvantage and limits the treatment options. Therefore, new technologies and approaches are required to solve the current issues and enhance the production of drugs. Interestingly, fragment-based drug discovery (FBDD) has gained an advantage over high-throughput screenings as FBDD has enabled rapid and efficient progress to develop potent small molecule compounds that specifically bind to the target. Several potent inhibitor compounds of various targets have been developed using FBDD approach and some of them are under progression to clinical trials. In this review, we emphasize some of the important targets of mycobacteria and HIV. We also discussed about the target-based druggable molecules that are identified using the FBDD approach, use of these druggable molecules to identify novel binding sites on the target and assays used to evaluate inhibitory activities of these identified druggable molecules on the biological activity of the targets.

Human lymphatic filariae have evolved numerous immune evasion strategies to secure their long-term survival in a host. These strategies include regulation of pattern recognition receptors, mimicry with host glycans and immune molecules, manipulation of innate and adaptive immune cells, induction of apoptosis in effector immune cells, and neutralization of free radicals. This creates an anti-inflammatory and immunoregulatory milieu in the host: a modified Th2 immune response. Therefore, targeting filarial immunomodulators and manipulating the filariae-driven immune system against the filariae can be a potential therapeutic and prophylactic strategy. Filariae-derived immunosuppression can also be exploited to treat other inflammatory diseases and immunopathologic states of parasitic diseases, such as cerebral malaria, and to prevent leishmaniasis. This paper reviews immunomodulatory mechanisms acquired by these filariae for their own survival and their potential application in the development of novel therapeutic approaches against parasitic and inflammatory diseases. Insight into the intricate network of host immune-parasite interactions would aid in the development of effective immune-therapeutic options for both infectious and immune-pathological diseases.

Objective: Immunomodulation by helminth proteins has potential therapeutic implications in inflammatory bowel disease. In the present study, we have explored the therapeutic effect of a RAL family protein of filarial parasite Wuchereria bancrofti i.e., rWbL2 protein against DSS induced colitis in a mouse model. Materials and methods: Anti-inflammatory activity of rWbL2 on mice peritoneal exudate cells was analyzed under in vitro condition. The colitis mice were treated intraperitoneally (i.p.) with rWbL2 in increasing doses (10 µg, 25 µg, and 50 µg) on days 4, 5, and 6. Disease severity was assessed by disease activity index (DAI), macroscopic and histopathological scores, and enzyme myeloperoxidase activity (MPO) in the colon. The response of the cultured splenocytes from treated mice to Con-A stimulation, in terms of ELISA-based assessment of the protein followed by the assessment of mRNA expression of cytokines, was measured by real-time PCR analysis. Result: rWbL2 protein showed anti-inflammatory activity in vitro. Treatment with rWbL2 (at 25 µg/dose) effectively attenuated disease severity by reducing weight loss, DAI, mucosal edema, colon damage, and MPO activity. This therapeutic effect was found to be associated with increased release of anti-inflammatory cytokine IL-10 and decreased release of pro-inflammatory cytokine IFN-γ and TNF-α by the splenocytes of treated mice followed by stimulation with Con-A. Conclusions: These results provide evidence of the strong immunomodulatory potential of rWbL2 protein implicating its therapeutic application against ulcerative colitis.