Research progress of RP1L1 gene in disease.

Retinitis pigmentosa 1-like 1 (RP1L1) is a component of photoreceptor cilia. Pathogenic variants in RP1L1 cause photoreceptor diseases, suggesting that RP1L1 plays an important role in photoreceptor biology, although its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (cone degeneration) and retinitis pigmentosa (rod degeneration). Here, we summarize the reported RP1L1-associated photoreceptor pathogenic mutations. The association between RP1L1 and other diseases (mainly several tumors) is also summarized and RP1L1 is included in a wider range of diseases. Finally, it is necessary to further explore the influence mechanism of RP1L1 gene on the health of photoreceptors and how it participates in the occurrence and development of tumors.

A Closer Look at the Perivascular Unit in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus.

The recently described perivascular unit (PVU) resides immediately adjacent to the true capillary neurovascular unit (NVU) in the postcapillary venule and contains the normal-benign perivascular spaces (PVS) and pathological enlarged perivascular spaces (EPVS). The PVS are important in that they have recently been identified to be the construct and the conduit responsible for the delivery of metabolic waste from the interstitial fluid to the ventricular cerebrospinal fluid for disposal into the systemic circulation, termed the glymphatic system. Importantly, the outermost boundary of the PVS is lined by protoplasmic perivascular astrocyte endfeet (pvACef) that communicate with regional neurons. As compared to the well-recognized and described neurovascular unit (NVU) and NVU coupling, the PVU is less well understood and remains an emerging concept. The primary focus of this narrative review is to compare the similarities and differences between these two units and discuss each of their structural and functional relationships and how they relate not only to brain homeostasis but also how they may relate to the development of multiple clinical neurological disease states and specifically how they may relate to obesity, metabolic syndrome, and type 2 diabetes mellitus. Additionally, the concept and importance of a perisynaptic astrocyte coupling to the neuronal synapses with pre- and postsynaptic neurons will also be considered as a perisynaptic unit to provide for the creation of the information transfer in the brain via synaptic transmission and brain homeostasis. Multiple electron microscopic images and illustrations will be utilized in order to help explain these complex units.

The Brain Endothelial Cell Glycocalyx Plays a Crucial Role in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus.

The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may be considered as the first barrier of a tripartite blood-brain barrier (BBB) consisting of (1) ecGCx; (2) BECs; and (3) an extravascular compartment of pericytes, the extracellular matrix, and perivascular astrocytes. Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally derived leukocytes into the perivascular spaces (PVS) which result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the fifth review of a quintet series that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids, and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are increasingly being regarded as a marker of cerebrovascular and neurodegenerative pathology.

Brain Injury: Response to Injury Wound-Healing Mechanisms and Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus.

Embryonic genetic mechanisms are present in the brain and ready to be placed into action upon cellular injury, termed the response to injury wound-healing (RTIWH) mechanism. When injured, regional brain endothelial cells initially undergo activation and dysfunction with initiation of hemostasis, inflammation (peripheral leukocytes, innate microglia, and perivascular macrophage cells), proliferation (astrogliosis), remodeling, repair, and resolution phases if the injurious stimuli are removed. In conditions wherein the injurious stimuli are chronic, as occurs in obesity, metabolic syndrome, and type 2 diabetes mellitus, this process does not undergo resolution and there is persistent RTIWH with remodeling. Indeed, the brain is unique, in that it utilizes its neuroglia: the microglia cell, along with peripheral inflammatory cells and its astroglia, instead of peripheral scar-forming fibrocytes/fibroblasts. The brain undergoes astrogliosis to form a gliosis scar instead of a fibrosis scar to protect the surrounding neuropil from regional parenchymal injury. One of the unique and evolving remodeling changes in the brain is the development of enlarged perivascular spaces (EPVSs), which is the focus of this brief review. EPVSs are important since they serve as a biomarker for cerebral small vessel disease and also represent an impairment of the effluxing glymphatic system that is important for the clearance of metabolic waste from the interstitial fluid to the cerebrospinal fluid, and disposal. Therefore, it is important to better understand how the RTIWH mechanism is involved in the development of EPVSs that are closely associated with and important to the development of premature and age-related cerebrovascular and neurodegenerative diseases with impaired cognition.

Phosphate Toxicity and Vascular Calcification in Chronic Kidney Disease: A Closer Look Utilizing Transmission Electron Microscopy.

Hyperphosphatemia is independently linked with vascular calcification, cardiovascular disease, bone-mineral disease, progression of renal insufficiency, and all-cause mortality in chronic kidney disease (CKD) and end-stage renal disease (ESRD). The emerging importance of fibroblast growth factor-23 (FGF-23) and its co-factor Klotho play very important roles as phosphaturic hormones; however, phosphate levels rise due to a loss of renal Klotho production and the phosphaturic effects of the FGF-23/Klotho axis. Hyperphosphatemia is also associated with calciphylaxis, acceleration of renal tubulointerstitial disease, renal osteodystrophy, and uremic cardiomyopathy. This review incorporates ultrastructural remodeling of the thoracic aorta to provide a different perspective on vascular calcification. Nine-week-old male heterozygous (mRen2) 27 (Ren2) rat models of hypertension, insulin resistance, vascular oxidative stress and albuminuria are utilized to demonstrate aortic remodeling associated with vascular calcification. Nine-week-old male Zucker obese (fa/fa) rat models are utilized to better understand nephrolith formation. Phosphate homeostasis, toxicity, multiple metabolic and uremic toxicities, renal osteodystrophy, and vascular calcification are also discussed. Additionally, the role of the endothelium, vascular smooth muscle cells, inflammatory monocytes/macrophages and mast cells, pericytes, oxidative stress, hydrogen sulfide, and extraosseous calcification in the kidney are discussed as they relate to CKD, ESRD and calciphylaxis.

Brain Endothelial Cells Play a Central Role in the Development of Enlarged Perivascular Spaces in the Metabolic Syndrome.

Brain capillary endothelial cell(s) (BECs) have numerous functions, including their semipermeable interface-barrier (transfer and diffusion of solutes), trophic (metabolic homeostasis), tonic (vascular hemodynamics), and trafficking (vascular permeability, coagulation, and leukocyte extravasation) functions to provide brain homeostasis. BECs also serve as the brain's sentinel cell of the innate immune system and are capable of antigen presentation. In metabolic syndrome (MetS), there are two regions resulting in the proinflammatory signaling of BECs, namely visceral adipose tissue depots supplying excessive peripheral cytokines/chemokines (pCCs) and gut microbiota dysbiotic regions supplying excessive soluble lipopolysaccharide (sLPS), small LPS-enriched extracellular vesicle exosomes (lpsEVexos), and pCCs. This dual signaling of BECs at their receptor sites results in BEC activation and dysfunction (BECact/dys) and neuroinflammation. sLPS and lpsEVexos signal BECs' toll-like receptor 4, which then signals translocated nuclear factor kappa B (NFkB). Translocated NFkB promotes the synthesis and secretion of BEC proinflammatory cytokines and chemokines. Specifically, the chemokine CCL5 (RANTES) is capable of attracting microglia cells to BECs. BEC neuroinflammation activates perivascular space(s) (PVS) resident macrophages. Excessive phagocytosis by reactive resident PVS macrophages results in a stagnation-like obstruction, which along with increased capillary permeability due to BECact/dys could expand the fluid volume within the PVS to result in enlarged PVS (EPVS). Importantly, this remodeling may result in pre- and post-capillary EPVS that would contribute to their identification on T2-weighted MRI, which are considered to be biomarkers for cerebral small vessel disease.

Why Are Perivascular Spaces Important?

Perivascular spaces (PVS) and their enlargement (EPVS) have been gaining interest as EPVS can be visualized non-invasively by magnetic resonance imaging (MRI) when viewing T-2-weighted images. EPVS are most commonly observed in the regions of the basal ganglia and the centrum semiovale; however, they have also been identified in the frontal cortex and hippocampal regions. EPVS are known to be increased in aging and hypertension, and are considered to be a biomarker of cerebral small vessel disease (SVD). Interest in EPVS has been significantly increased because these PVS are now considered to be an essential conduit necessary for the glymphatic pathway to provide the necessary efflux of metabolic waste. Metabolic waste includes misfolded proteins of amyloid beta and tau that are known to accumulate in late-onset Alzheimer's disease (LOAD) within the interstitial fluid that is delivered to the subarachnoid space and eventually the cerebral spinal fluid (CSF). The CSF acts as a sink for accumulating neurotoxicities and allows clinical screening to potentially detect if LOAD may be developing early on in its clinical progression via spinal fluid examination. EPVS are thought to occur by obstruction of the PVS that associates with excessive neuroinflammation, oxidative stress, and vascular stiffening that impairs flow due to a dampening of the arterial and arteriolar pulsatility that aids in the convective flow of the metabolic debris within the glymphatic effluxing system. Additionally, increased EPVS has also been associated with Parkinson's disease and non-age-related multiple sclerosis (MS).

Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease.

Metabolic syndrome (MetS) is considered a metabolic disorder that has been steadily increasing globally and seems to parallel the increasing prevalence of obesity. It consists of a cluster of risk factors which traditionally includes obesity and hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia. These four core risk factors are associated with insulin resistance (IR) and, importantly, the MetS is known to increase the risk for developing cerebrocardiovascular disease and type 2 diabetes mellitus. The MetS had its early origins in IR and syndrome X. It has undergone numerous name changes, with additional risk factors and variables being added over the years; however, it has remained as the MetS worldwide for the past three decades. This overview continues to add novel insights to the MetS and suggests that leptin resistance with hyperleptinemia, aberrant mitochondrial stress and reactive oxygen species (ROS), impaired folate-mediated one-carbon metabolism with hyperhomocysteinemia, vascular stiffening, microalbuminuria, and visceral adipose tissues extracellular vesicle exosomes be added to the list of associated variables. Notably, the role of a dysfunctional and activated endothelium and deficient nitric oxide bioavailability along with a dysfunctional and attenuated endothelial glycocalyx, vascular inflammation, systemic metainflammation, and the important role of ROS and reactive species interactome are discussed. With new insights and knowledge regarding the MetS comes the possibility of new findings through further research.

Ultrastructural Remodeling of the Blood-Brain Barrier and Neurovascular Unit by Lipopolysaccharide-Induced Neuroinflammation.

The blood-brain barrier (BBB) is an interface primarily comprised of brain endothelial cells (BECs), separating the central nervous system (CNS) from the systemic circulation while carefully regulating the transport of molecules and inflammatory cells, and maintaining the required steady-state environment. Inflammation modulates many BBB functions, but the ultrastructural cytoarchitectural changes of the BBB with inflammation are understudied. Inflammation was induced in male 8-10-week-old CD-1 mice with intraperitoneal lipopolysaccharide (LPS), using a regimen (3 mg/kg at 0, 6, and 24 h) that caused robust BBB disruption but had minimal lethality at the study timepoint of 28 h. Perfusion-fixed brains were collected and the frontal cortical layer III regions were analyzed using a transmission electron microscopy (TEM). The LPS-treated mice had pronounced ultrastructural remodeling changes in BECs that included plasma membrane ruffling, increased numbers of extracellular microvesicles, small exosome formation, aberrant BEC mitochondria, increased BEC transcytosis, while tight junctions appeared to be unaltered. Aberrant pericytes were contracted with rounded nuclei and a loss of their elongated cytoplasmic processes. Surveilling microglial cells were attracted to the neurovascular unit (NVU) of BECs, and astrocyte detachment and separation were associated with the formation of a perivascular space and pericapillary edema. The LPS treatment resulted in numerous ultrastructural aberrant remodeling changes to the neurovascular unit's BECs, microglia, pericytes, and astrocytes. In summary, a disturbance of the NVU morphology is a consequence of LPS treatment.

Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice.

Widespread consumption of diets high in fat and fructose (Western diet, WD) has led to increased prevalence of obesity and diastolic dysfunction (DD). DD is a prominent feature of heart failure with preserved ejection fraction (HFpEF). However, the underlying mechanisms of DD are poorly understood, and treatment options are still limited. We have previously shown that deletion of the cell-specific mineralocorticoid receptor in endothelial cells (ECMR) abrogates DD induced by WD feeding in female mice. However, the specific role of ECMR activation in the pathogenesis of DD in male mice has not been clarified. Therefore, we fed 4-wk-old ECMR knockout (ECMRKO) male mice and littermates (LM) with either a WD or chow diet (CD) for 16 wk. WD feeding resulted in DD characterized by increased left ventricle (LV) filling pressure (E/e') and diastolic stiffness [E/e'/LV inner diameter at end diastole (LVIDd)]. Compared with CD, WD in LM resulted in increased myocardial macrophage infiltration, oxidative stress, and increased myocardial phosphorylation of Akt, in concert with decreased phospholamban phosphorylation. WD also resulted in focal cardiomyocyte remodeling, characterized by areas of sarcomeric disorganization, loss of mitochondrial electron density, and mitochondrial fragmentation. Conversely, WD-induced DD and associated biochemical and structural abnormalities were prevented by ECMR deletion. In contrast with our previously reported observations in females, WD-fed male mice exhibited enhanced Akt signaling and a lower magnitude of cardiac injury. Collectively, our data support a critical role for ECMR in obesity-induced DD and suggest critical mechanistic differences in the genesis of DD between males and females.

Reactive Microgliosis in Sepsis-Associated and Acute Hepatic Encephalopathies: An Ultrastructural Study.

Sepsis and acute liver failure are associated with severe endogenous intoxication. Microglia, which are the resident immune brain cells, play diverse roles in central nervous system development, surveillance, and defense, as well as contributing to neuroinflammatory reactions. In particular, microglia are fundamental to the pathophysiology of reactive toxic encephalopathies. We analyzed microglial ultrastructure, morphotypes, and phagocytosis in the sensorimotor cortex of cecal ligation and puncture (CLP) and acetaminophen-induced liver failure (AILF) Wistar rats. A CLP model induced a gradual shift of ~50% of surveillant microglia to amoeboid hypertrophic-like and gitter cell-like reactive phenotypes with active phagocytosis and frequent contacts with damaged neurons. In contrast, AILF microglia exhibited amoeboid, rod-like, and hypertrophic-like reactive morphotypes with minimal indications for efficient phagocytosis, and were mostly in contact with edematous astrocytes. Close interactions of reactive microglia with neurons, astrocytes, and blood-brain barrier components reflect an active contribution of these cells to the tissue adaptation and cellular remodeling to toxic brain damage. Partial disability of reactive microglia may affect the integrity and metabolism in all tissue compartments, leading to failure of the compensatory mechanisms in acute endogenous toxic encephalopathies.

The Mighty Mitochondria Are Unifying Organelles and Metabolic Hubs in Multiple Organs of Obesity, Insulin Resistance, Metabolic Syndrome, and Type 2 Diabetes: An Observational Ultrastructure Study.

Mitochondria (Mt) are essential cellular organelles for the production of energy and thermogenesis. Mt also serve a host of functions in addition to energy production, which include cell signaling, metabolism, cell death, and aging. Due to the central role of Mt in metabolism as metabolic hubs, there has been renewed interest in how Mt impact metabolic pathways and multiple pathologies. This review shares multiple observational ultrastructural findings in multiple cells and organs to depict aberrant mitochondrial (aMt) remodeling in pre-clinical rodent models. Further, it is intended to show how remodeling of Mt are associated with obesity, insulin resistance, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). Specifically, Mt remodeling in hypertensive and insulin-resistant lean models (Ren2 rat models), lean mice with streptozotocin-induced diabetes, obesity models including diet-induced obesity, genetic leptin-deficient ob/ob, and leptin receptor-deficient db/db diabetic mice are examined. Indeed, aMt dysfunction and damage have been implicated in multiple pathogenic diseases. Manipulation of Mt such as the induction of Mt biogenesis coupled with improvement of mitophagy machinery may be helpful to remove leaky damaged aMt in order to prevent the complications associated with the generation of superoxide-derived reactive oxygen species and the subsequent reactive species interactome. A better understanding of Mt remodeling may help to unlock many of the mysteries in obesity, insulin resistance, MetS, T2DM, and the associated complications of diabetic end-organ disease.

Inhibition of sphingomyelinase attenuates diet - Induced increases in aortic stiffness.

Sphingomyelinases ensure ceramide production and play an integral role in cell turnover, inward budding of vesicles and outward release of exosomes. Recent data indicate a unique role for neutral sphingomyelinase (nSMase) in the control of ceramide-dependent exosome release and inflammatory pathways. Further, while inhibition of nSMase in vascular tissue attenuates the progression of atherosclerosis, little is known regarding its role on metabolic signaling and arterial vasomotor function. Accordingly, we hypothesized that nSMase inhibition with GW4869, would attenuate Western diet (WD) - induced increases in aortic stiffness through alterations in pathways which lead to oxidative stress, inflammation and vascular remodeling. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet (CD). Mice were variably treated with GW4869 (2.0 µg/g body weight, intraperitoneal injection every 48 h for 12 weeks). WD feeding increased nSMase2 expression and activation while causing aortic stiffening and impaired vasorelaxation as determined by pulse wave velocity (PWV) and wire myography, respectively. Moreover, these functional abnormalities were associated with aortic remodeling and attenuated AMP-activated protein kinase, Sirtuin 1, and endothelial nitric oxide synthase activation. GW4869 treatment prevented the WD-induced increases in nSMase activation, PWV, and impaired endothelium dependent/independent vascular relaxation. GW4869 also inhibited WD-induced aortic CD36 expression, lipid accumulation, oxidative stress, inflammatory responses, as well as aortic remodeling. These findings indicate that targeting nSMase prevents diet - induced aortic stiffening and impaired vascular relaxation by attenuating oxidative stress, inflammation and adverse vascular remodeling.

Pathogenesis of COVID-19 described through the lens of an undersulfated and degraded epithelial and endothelial glycocalyx.

The glycocalyx surrounds every eukaryotic cell and is a complex mesh of proteins and carbohydrates. It consists of proteoglycans with glycosaminoglycan side chains, which are highly sulfated under normal physiological conditions. The degree of sulfation and the position of the sulfate groups mainly determine biological function. The intact highly sulfated glycocalyx of the epithelium may repel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) through electrostatic forces. However, if the glycocalyx is undersulfated and 3-O-sulfotransferase 3B (3OST-3B) is overexpressed, as is the case during chronic inflammatory conditions, SARS-CoV-2 entry may be facilitated by the glycocalyx. The degree of sulfation and position of the sulfate groups will also affect functions such as immune modulation, the inflammatory response, vascular permeability and tone, coagulation, mediation of sheer stress, and protection against oxidative stress. The rate-limiting factor to sulfation is the availability of inorganic sulfate. Various genetic and epigenetic factors will affect sulfur metabolism and inorganic sulfate availability, such as various dietary factors, and exposure to drugs, environmental toxins, and biotoxins, which will deplete inorganic sulfate. The role that undersulfation plays in the various comorbid conditions that predispose to coronavirus disease 2019 (COVID-19), is also considered. The undersulfated glycocalyx may not only increase susceptibility to SARS-CoV-2 infection, but would also result in a hyperinflammatory response, vascular permeability, and shedding of the glycocalyx components, giving rise to a procoagulant and antifibrinolytic state and eventual multiple organ failure. These symptoms relate to a diagnosis of systemic septic shock seen in almost all COVID-19 deaths. The focus of prevention and treatment protocols proposed is the preservation of epithelial and endothelial glycocalyx integrity.

Deficient Leptin Cellular Signaling Plays a Key Role in Brain Ultrastructural Remodeling in Obesity and Type 2 Diabetes Mellitus.

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model).

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway.

Oxidized low-density lipoprotein (oxLDL) induced a foam-cell-like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression.

Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID.

Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer's disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative-redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation.

An Immediate and Long-Term Complication of COVID-19 May Be Type 2 Diabetes Mellitus: The Central Role of ß-Cell Dysfunction, Apoptosis and Exploration of Possible Mechanisms.

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was declared a pandemic by the WHO on 19 March 2020. This pandemic is associated with markedly elevated blood glucose levels and a remarkable degree of insulin resistance, which suggests pancreatic islet ß-cell dysfunction or apoptosis and insulin's inability to dispose of glucose into cellular tissues. Diabetes is known to be one of the top pre-existing co-morbidities associated with the severity of COVID-19 along with hypertension, cardiocerebrovascular disease, advanced age, male gender, and recently obesity. This review focuses on how COVID-19 may be responsible for the accelerated development of type 2 diabetes mellitus (T2DM) as one of its acute and suspected long-term complications. These observations implicate an active role of metabolic syndrome, systemic and tissue islet renin-angiotensin-aldosterone system, redox stress, inflammation, islet fibrosis, amyloid deposition along with ß-cell dysfunction and apoptosis in those who develop T2DM. Utilizing light and electron microscopy in preclinical rodent models and human islets may help to better understand how COVID-19 accelerates islet and ß-cell injury and remodeling to result in the long-term complications of T2DM.

Endothelial activation and dysfunction in metabolic syndrome, type 2 diabetes and coronavirus disease 2019.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 infection is a serious global concern. Increased morbidity and mortality is associated with older age, male gender, cardiovascular disease, diabetes, and smoking. As COVID-19 spreads from coastal borders, both state to state and country to country, our understanding of its pathophysiology has evolved. Age and type 2 diabetes mellitus (T2DM) play especially important roles in COVID-19 progression. T2DM is an age-related disease associated with metabolic syndrome, obesity, insulin resistance (hyperinsulinemia), hyperlipidemia, hypertension, hyperglycemia, and endothelial activation and dysfunction. This review evaluates the relationships and intersection between endothelial cell activation and dysfunction in T2DM and COVID-19. COVID-19 induces multiple injuries of the terminal bronchioles and alveolar blood-gas barrier and associated ultrastructural tissue remodeling. COVID-19 may unmask multiple vulnerabilities associated with T2DM including damage to the endothelial glycocalyx and multiple end-organ macro and microvascular diseases. Unmasking existing vulnerabilities in diabetic patients with COVID-19 is important. Globally, we must come together to better understand why T2DM is associated with increased COVID-19 morbidity and mortality.