Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System.

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of ß-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

Therapeutic mTOR blockade in systemic autoimmunity: Implications for antiviral immunity and extension of lifespan.

The mechanistic target of rapamycin (mTOR) pathway integrates metabolic cues into cell fate decisions. A particularly fateful event during the adaptive immune response is the engagement of a T cell receptor by its cognate antigen presented by an antigen-presenting cell (APC). Here, the induction of adequate T cell activation and lineage specification is critical to mount protective immunity; at the same time, inadequate activation, which could lead to autoimmunity, must be avoided. mTOR forms highly conserved protein complexes 1 and 2 that shape lineage specification by integrating signals originating from TCR engagement, co-stimulatory or co-inhibitory receptors and cytokines and availability of nutrients. If one considers autoimmunity as the result of aberrant lineage specification in response to such signals, the importance of this pathway becomes evident; this provides the conceptual basis for mTOR inhibition in the treatment of systemic autoimmunity, such as systemic lupus erythematosus (SLE). Clinical trials in SLE patients have provided preliminary evidence that mTOR blockade by sirolimus (rapamycin) can reverse pro-inflammatory lineage skewing, including the expansion of Th17 and double-negative T cells and plasma cells and the contraction of regulatory T cells. Moreover, sirolimus has shown promising efficacy in the treatment of refractory idiopathic multicentric Castleman disease, newly characterized by systemic autoimmunity due to mTOR overactivation. Alternatively, mTOR blockade enhances responsiveness to vaccination and reduces infections by influenza virus in healthy elderly subjects. Such seemingly contradictory findings highlight the importance to further evaluate the clinical effects of mTOR manipulation, including its potential role in treatment of COVID-19 infection. mTOR blockade may extend healthy lifespan by abrogating inflammation induced by viral infections and autoimmunity. This review provides a mechanistic assessment of mTOR pathway activation in lineage specification within the adaptive and innate immune systems and its role in health and autoimmunity. We then discuss some of the recent experimental and clinical discoveries implicating mTOR in viral pathogensis and aging.

Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes.

Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.

COVID-19 and diabetes mellitus: how one pandemic worsens the other.

In light of the most challenging public health crisis of modern history, COVID-19 mortality continues to rise at an alarming rate. Patients with co-morbidities such as hypertension, cardiovascular disease, and diabetes mellitus (DM) seem to be more prone to severe symptoms and appear to have a higher mortality rate. In this review, we elucidate suggested mechanisms underlying the increased susceptibility of patients with diabetes to infection with SARS-CoV-2 with a more severe COVID-19 disease. The worsened prognosis of COVID-19 patients with DM can be attributed to a facilitated viral uptake assisted by the host's receptor angiotensin-converting enzyme 2 (ACE2). It can also be associated with a higher basal level of pro-inflammatory cytokines present in patients with diabetes, which enables a hyperinflammatory "cytokine storm" in response to the virus. This review also suggests a link between elevated levels of IL-6 and AMPK/mTOR signaling pathway and their role in exacerbating diabetes-induced complications and insulin resistance. If further studied, these findings could help identify novel therapeutic intervention strategies for patients with diabetes comorbid with COVID-19.

Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

The Mechanistic Target of Rapamycin (mTOR): Novel Considerations as an Antiviral Treatment.

Multiple viral pathogens can pose a significant health risk to individuals. As a recent example, the ß-coronavirus family virion, SARS-CoV-2, has quickly evolved as a pandemic leading to coronavirus disease 2019 (COVID-19) and has been declared by the World Health Organization as a Public Health Emergency of International Concern. To date, no definitive treatment or vaccine application exists for COVID-19. Although new investigations seek to repurpose existing antiviral treatments for COVID-19, innovative treatment strategies not normally considered to have antiviral capabilities may be critical to address this global concern. One such avenue that may prove to be exceedingly fruitful and offer exciting potential as new antiviral therapy involves the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), and AMP activated protein kinase (AMPK). Recent work has shown that mTOR pathways in conjunction with AMPK may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction, and the onset of hyperinflammation, a significant disability associated with COVID-19. Furthermore, pathways that can activate mTOR may be necessary for anti-hepatitis C activity, reduction of influenza A virus replication, and vital for type-1 interferon responses with influenza vaccination. Yet, important considerations for the development of safe and effective antiviral therapy with mTOR pathways exist. Under some conditions, mTOR can act as a double edge sword and participate in virion replication and virion release from cells. Future work with mTOR as a potential antiviral target is highly warranted and with a greater understanding of this novel pathway, new treatments against several viral pathogens may successfully emerge.