Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.

Urokinase-type plasminogen activator (uPA) participates in diverse (patho)physiological processes through intracellular signaling events that affect cell adhesion, migration, and proliferation, although the mechanisms by which these occur are only partially understood. Here we report that upon cell binding and internalization, single-chain uPA (scuPA) translocates to the nucleus within minutes. Nuclear translocation does not involve proteolytic activation or degradation of scuPA. Neither the urokinase receptor (uPAR) nor the low-density lipoprotein-related receptor (LRP) is required for nuclear targeting. Rather, translocation involves the binding of scuPA to the nucleocytoplasmic shuttle protein nucleolin through a region containing the kringle domain. RNA interference and mutational analysis demonstrate that nucleolin is required for the nuclear transport of scuPA. Furthermore, nucleolin is required for the induction smooth muscle ␣-actin (␣-SMA) by scuPA. These data reveal a novel pathway by which uPA is rapidly translocated to the nucleus where it might participate in regulating gene expression. (Blood. 2008;112: 100-110) IntroductionUrokinase-type plasminogen activator (uPA) is a multifunctional protein that has been implicated in several physiological and pathological processes, including cell proliferation and migration during angiogenesis, tissue regeneration, inflammatory responses, and tumor growth/metastases. These complex processes all involve intracellular signal transduction and regulation of gene transcription in addition to proteolysis (see Alfano et al 1 for review). uPA is secreted as a single-chain protein (scuPA) that consists of an N-terminal EGF-like domain (GFD), a kringle domain (KD), and a serine protease domain. Binding of uPA to its high-affinity receptor CD87 (uPAR) is mediated by the GFD. 2 Plasmin converts scuPA into a proteolytically active 2-chain enzyme (tcuPA) 3 that is rapidly inhibited primarily by plasminogen activator inhibitor-1 (PAI-1). tcuPA-PAI-1 complexes are internalized with the aid of lipoprotein receptor-related protein (LRP) 4 by clathrin-mediated endocytosis. The tcuPA-PAl-1 complexes traffic to lysosomes and are degraded, while unoccupied uPAR and LRP recycle back to the cell surface. 5 uPA-induced signal transduction occurs via uPAR-dependent and uPAR-independent pathways (reviewed in Alfano et al 1 ; Kjoller 6 ; Blasi and Carmeliet 7 ). Among the latter, we have shown that cleavage of scuPA by plasmin releases the GFD fragment, generating a form of uPA unable to bind to uPAR, 8 but that stimulates migration of smooth muscle cells (SMCs). 9 Signal transduction by this scuPA fragment may be mediated in part by LRP 10 and certain integrins. 11 However, there is limited information as to the mechanism by which uPA modifies gene transcription, [12][13][14][15] and our previous studies have provided reason to hypothesize that cells express additional uPA-binding proteins that possess distinct signal-transducing activities involved in cell contractility, migration, an...

Alterations in expression of surface adhesion molecules on resident vascular and blood-derived cells play a fundamental role in the pathogenesis of cardiovascular disease. Smooth muscle cells (SMCs) have been shown to express T-cadherin (T-cad), an unusual GPIanchored member of the cadherin family of adhesion molecules. Particular relevance for T-cad in cardiovascular tissues is indicated by our present screen (immunoblotting) of human tissues and organs whereby highest expression of T-cad was found in aorta, carotid, iliac and renal arteries and heart. To explore the (patho)physiological role for T-cad in the vasculature we performed an immunohistochemical analysis of T-cad expression in normal human aorta and atherosclerotic lesions of varying severity. T-cad was present both in the intima and media and was expressed in endothelial cells (ECs), SMCs and pericytes, but not in monocytes/macrophages, foam cells and lymphocytes. In the adventitia T-cad was present in the wall of vasa vasorum and was expressed in ECs, SMCs and pericytes. T-cad was differentially expressed in SMCs from distinct vascular layers of normal aorta (for example, high in the subendothelial (proteoglycan) layer of the intima, low in the musculoelastic intimal layer and in the media), as well as at different stag-es of lesion progression. In SMCs there was an apparent inverse relationship between the intensities of T-cad and smooth muscle α-actin expression, this being most prominent in lesions. The findings suggest a phenotypeassociated expression of T-cad which may be relevant to control of the normal vascular architecture and its remodelling during atherogenesis.

Adult stem cells that are tightly regulated by the specific microenvironment, or the stem cell niche, function to maintain tissue homeostasis and regeneration after damage. This demands the existence of specific niche components that can preserve the stem cell pool in injured tissues and restore the microenvironment for their subsequent appropriate functioning. This role may belong to mesenchymal stromal cells (MSCs) due to their resistance to damage signals and potency to be specifically activated in response to tissue injury and promote regeneration by different mechanisms. Increased amount of data indicate that activated MSCs are able to produce factors such as extracellular matrix components, growth factors, extracellular vesicles and organelles, which transiently substitute the regulatory signals from missing niche cells and restrict the injury-induced responses of them. MSCs may recruit functional cells into a niche or differentiate into missing cell components to endow a niche with ability to regulate stem cell fates. They may also promote the dedifferentiation of committed cells to reestablish a pool of functional stem cells after injury. Accumulated evidence indicates the therapeutic promise of MSCs for stimulating tissue regeneration, but the benefits of administered MSCs demonstrated in many injury models are less than expected in clinical studies. This emphasizes the importance of considering the mechanisms of endogenous MSC functioning for the development of effective approaches to their pharmacological activation or mimicking their effects. To achieve this goal, we integrate the current ideas on the contribution of MSCs in restoring the stem cell niches after damage and thereby tissue regeneration.

The 42- and 44-kD mitogen-activated protein kinases, also referred to as extracellular signal-related kinase (ERK) 2 and 1, respectively, may be transiently activated by stretching vascular smooth muscle cells (VSMCs). Using an organ culture model of rabbit aorta, we studied short- and long-term ERK1/2 activation by intraluminal pressure (150 mm Hg). Activation of ERK1/2 was biphasic: it reached a maximum (217.5 +/- 8.4% of control) 5 minutes after pressurizing and decreased to 120.7 +/- 5.1% of control after 2 hours. Furthermore, after 24 hours of pressurizing, ERK1/2 activity was as high (241.8 +/- 14.7% of control) as in the acute phase. Long-term pressure-induced ERK1/2 activation correlated with stimulation of tyrosine phosphorylation of proteins in the 125- to 140-kD range. Neither protein kinase C inhibitors (1 mumol/L staurosporine or 50 mumol/L bisindolylmaleimide-I) nor tyrosine kinase inhibitors (50 mumol/L tyrphostin A48 or 50 mumol/L genistein) affected pressure-induced ERK1/2 activation. However, the Src-family tyrosine kinase inhibitor herbimycin A (500 nmol/L) did reduce both 5-minute (by 92 +/- 8%) and 24-hour (by 63 +/- 7%) pressure-induced ERK1/2 activation. Thus, our results demonstrate a sustained activation of ERK1/2 and tyrosine kinases by intraluminal pressure in the arterial wall. Pressure-induced ERK1/2 activation is PKC independent and Src-family tyrosine kinase dependent and possibly includes activation of extracellular matrix-associated tyrosine kinases.