A novel coronavirus, which has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in December 2019 in Wuhan China and causes the highly infectious disease referred to as COVID-19. COVID-19 has now spread worldwide to become a global pandemic affecting over 24 million people as of August 26th, 2020 and claimed the life of more than 800,000 people worldwide. COVID-19 is asymptomatic for some individuals and for others it can cause symptoms ranging from flu-like to acute respiratory distress syndrome (ARDS), pneumonia and death. Although it is anticipated that an effective vaccine will be available to protect against COVID-19, at present the world is relying on social distancing and hygiene measures and repurposed drugs. There is a worldwide effort to develop an effective vaccine against SARS-CoV-2 and, as of late August 2020, there are 30 vaccines in clinical trials with over 200 in various stages of development. This review will focus on the eight vaccine candidates that entered Phase 1 clinical trials in mid-May, including AstraZeneca/Oxford's AZD1222, Moderna's mRNA-1273 and Sinovac's CoronaVac vaccines, which are currently in advanced stages of vaccine development. In addition to reviewing the different stages of vaccine development, vaccine platforms and vaccine candidates, this review also discusses the biological and immunological basis required of a SARS-CoV-2 vaccine, the importance of a collaborative international effort, the ethical implications of vaccine development, the efficacy needed for an immunogenic vaccine, vaccine coverage, the potential limitations and challenges of vaccine development. Although the demand for a vaccine far surpasses the production capacity, it will be beneficial to have a limited number of vaccines available for the more vulnerable population by the end of 2020 and for the rest of the global population by the end of 2021.

Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocytesecreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor a (PPARa) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARa KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARa KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signalrelated kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.Hepatic gluconeogenesis is tightly controlled by counterregulatory hormones such as glucagon, cortisol, and insulin, via regulating the expression of key gluconeogenic enzymes, including glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Fibroblast growth factor 21 (FGF21), a metabolic regulator mainly secreted from the liver in response to fasting and starvation under the control of the nuclear receptor peroxisome proliferatoractivated receptor a (PPARa), plays a critical role in maintaining energy homeostasis and insulin sensitivity in both rodents and nonhuman primates (1-6). A therapeutic dose of FGF21 decreased blood glucose in diabetic animals without causing hypoglycemia (4). FGF21 has also been shown to act as a key downstream effector of PPARa, mediating several metabolic adaptation responses to starvation, including hepatic fatty acid oxidation, ketogenesis, and growth hormone resistance (1,2,7). In addition, FGF21 is implicated in hepatic gluconeogenesis, although it remains controversial whether hepatocytes are a direct action site of FGF21 (8,9). There is an obvious dichotomy between the effects of endogenous FGF21 and pharmacological actions of the recombinant peptide with respect to hepatic metabolism (4,6,9).FGF21 can cross the blood-brain barrier (10) and is detectable in both human and rodent cerebrospinal fluid (10,11). Continuous intracerebroventricular injection of FGF21 into obese rats increases energy e...

Background and PurposeEndothelial dysfunction can be detected at an early stage in the development of diabetes-related microvascular disease and is associated with accelerated endothelial senescence and ageing. Hyperglycaemia-induced oxidative stress is a major contributing factor to the development of endothelial dysfunction. Clinical data indicate that the hypoglycaemic agent, metformin, has an endothelial protective action; however, its molecular and cellular mechanisms remain elusive. In the present study, we have investigated the protective effect of metformin during hyperglycaemia-induced senescence in mouse microvascular endothelial cells (MMECs).Experimental ApproachMMECs were cultured in normal glucose (11 mM) and high glucose (HG; 40 mM) in the presence and absence of metformin (50 μM) for 72 h. The expression of sirtuin-1 (SIRT1) and senescence/apoptosis-associated markers was determined by immunoblotting and immunocyto techniques. SIRT1 expression was inhibited with appropriate siRNA.Key ResultsExposure of MMECs to HG significantly reduced SIRT1 protein expression, increased forkhead box O1 (FoxO-1) and p53 acetylation, increased p21 and decreased Bcl2 expression. In addition, senescence-associated β-galactosidase activity in MMECs was increased in HG. Treatment with metformin attenuated the HG-induced reduction of SIRT1 expression, modulated the SIRT1 downstream targets FoxO-1 and p53/p21, and protected endothelial cells from HG-induced premature senescence. However, following gene knockdown of SIRT1 the effects of metformin were lost.Conclusions and ImplicationsHG-induced down-regulation of SIRT1 played a crucial role in diabetes-induced endothelial senescence. Furthermore, the protective effect of metformin against HG-induced endothelial dysfunction was partly due to its effects on SIRT1 expression and/or activity.

The endothelium, although only a single layer of cells lining the vascular and lymphatic systems, contributes in multiple ways to vascular homeostasis. Subsequent to the 1980 report by Robert Furchgott and John Zawadzki, there has been a phenomenal increase in our knowledge concerning the signalling molecules and pathways that regulate endothelial - vascular smooth muscle communication. It is now recognised that the endothelium is not only an important source of nitric oxide (NO), but also numerous other signalling molecules, including the putative endothelium-derived hyperpolarizing factor (EDHF), prostacyclin (PGI(2)), and hydrogen peroxide (H(2)O(2)), which have both vasodilator and vasoconstrictor properties. In addition, the endothelium, either via transferred chemical mediators, such as NO and PGI(2), and (or) low-resistance electrical coupling through myoendothelial gap junctions, modulates flow-mediated vasodilatation as well as influencing mitogenic activity, platelet aggregation, and neutrophil adhesion. Disruption of endothelial function is an early indicator of the development of vascular disease, and thus an important area for further research and identification of potentially new therapeutic targets. This review focuses on the signalling pathways that regulate endothelial - vascular smooth muscle communication and the mechanisms that initiate endothelial dysfunction, particularly with respect to diabetic vascular disease.

COVID-19 emerged from China in December 2019 and during 2020 spread to every continent including Antarctica. The coronavirus, SARS-CoV-2, has been identified as the causative pathogen, and its spread has stretched the capacities of healthcare systems and negatively affected the global economy. This review provides an update on the virus, including the genome, the risks associated with the emergence of variants, mode of transmission, immune response, COVID-19 in children and the elderly, and advances made to contain, prevent and manage the disease. Although our knowledge of the mechanics of virus transmission and the immune response has been substantially demystified, concerns over reinfection, susceptibility of the elderly and whether asymptomatic children promote transmission remain unanswered. There are also uncertainties about the pathophysiology of COVID-19 and why there are variations in clinical presentations and why some patients suffer from long lasting symptoms—“the long haulers.” To date, there are no significantly effective curative drugs for COVID-19, especially after failure of hydroxychloroquine trials to produce positive results. The RNA polymerase inhibitor, remdesivir, facilitates recovery of severely infected cases but, unlike the anti-inflammatory drug, dexamethasone, does not reduce mortality. However, vaccine development witnessed substantial progress with several being approved in countries around the globe.