Liposome encapsulated clodronate mediated elimination of pathogenic macrophages and microglia: A promising pharmacological regime to defuse cytokine storm in COVID-19.

The emergence of new SARS-CoV-2 variants continues to pose an enormous public health concern. The SARS-CoV-2 infection disrupted host immune response accounting for cytokine storm has been linked to multiorgan failure and mortality in a significant portion of positive cases. Abruptly activated macrophages have been identified as the key pathogenic determinant of cytokine storm in COVID-19. Besides, reactive microglia have been known to discharge a surplus amount of proinflammatory factors leading to neuropathogenic events in the brains of SARS-CoV-2 infected individuals. Considering the fact, depletion of activated macrophages and microglia could be proposed to eradicate the life-threatening cytokine storm in COVID-19. Clodronate, a non-nitrogenous bisphosphonate drug has been identified as a potent macrophage and microglial depleting agent. While recent advancement in the field of liposome encapsulation technology offers the most promising biological tool for drug delivery, liposome encapsulated clodronate has been reported to effectively target and induce prominent phagocytic cell death in activated macrophages and microglia compared to free clodronate molecules. Thus, in this review article, we emphasize that depletion of activated macrophages and microglial cells by administration of liposome encapsulated clodronate can be a potential therapeutic strategy to diminish the pathogenic cytokine storm and alleviate multiorgan failure in COVID-19. Moreover, recently developed COVID-19 vaccines appear to render the chronic activation of macrophages accounting for immunological dysregulation in some cases. Therefore, the use of liposome encapsulated clodronate can also be extended to the clinical management of unforeseen immunogenic reactions resulting from activated macrophages associated adverse effects of COVID-19 vaccines.

Testicular Atrophy and Hypothalamic Pathology in COVID-19: Possibility of the Incidence of Male Infertility and HPG Axis Abnormalities.

Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.