Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry.

Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.

ACE2 and energy metabolism: the connection between COVID-19 and chronic metabolic disorders.

The renin-angiotensin system (RAS) has currently attracted increasing attention due to its potential function in regulating energy homeostasis, other than the actions on cellular growth, blood pressure, fluid, and electrolyte balance. The existence of RAS is well established in metabolic organs, including pancreas, liver, skeletal muscle, and adipose tissue, where activation of angiotensin-converting enzyme (ACE) - angiotensin II pathway contributes to the impairment of insulin secretion, glucose transport, fat distribution, and adipokines production. However, the activation of angiotensin-converting enzyme 2 (ACE2) - angiotensin (1-7) pathway, a novel branch of the RAS, plays an opposite role in the ACE pathway, which could reverse these consequences by improving local microcirculation, inflammation, stress state, structure remolding, and insulin signaling pathway. In addition, new studies indicate the protective RAS arm possesses extraordinary ability to enhance brown adipose tissue (BAT) activity and induces browning of white adipose tissue, and consequently, it leads to increased energy expenditure in the form of heat instead of ATP synthesis. Interestingly, ACE2 is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is threating public health worldwide. The main complications of SARS-CoV-2 infected death patients include many energy metabolism-related chronic diseases, such as diabetes. The specific mechanism leading to this phenomenon is largely unknown. Here, we summarize the latest pharmacological and genetic tools on regulating ACE/ACE2 balance and highlight the beneficial effects of the ACE2 pathway axis hyperactivity on glycolipid metabolism, as well as the thermogenic modulation.

Virome-wide serological profiling reveals association of herpesviruses with obesity.

The relationship between viral infection and obesity has been known for several decades but epidemiological data is limited to only a few viral pathogens. The association between obesity and a wide range of viruses was assessed using VirScan, a pan-viral serological profiling tool. Serum specimens from 457 Qatari adults (lean = 184; obese = 273) and 231 Qatari children (lean = 111; obese = 120) were analyzed by VirScan. Associations with obesity were determined by odds ratio (OR) and Fisher's test (p values), and by multivariate regression analysis to adjust for age and gender. Although there was no association of viral infections with obesity in the pediatric population, a nominal association of obesity with seropositivity to members of the Herpesviridae family is observed for the adult population (OR = 1.5-3.3; p < 0.05). After adjusting p values for multiple comparisons (Bonferroni correction) the odds of being obese is significantly higher in herpes simplex virus 1 (HSV-1) seropositive Qatari adults (OR = 3.3; 95% CI 2.15-4.99; p = 2.787E - 08). By VirScan, the sero-prevalence of HSV1 is 81.3% and 57.1% among Qatari obese and lean adult populations, respectively. Higher prevalence of antibodies against several peptide epitopes of HSV-1/2 is positively associated with obesity (OR = 2.35-3.82; p ≤ 3.981E - 05). By multivariate regression analysis, HSV-1 was independently associated with obesity irrespective of age and gender. Our results suggest that obesity among Qataris may be associated with a higher prevalence of herpesvirus infections, in particular HSV-1. Furthermore, the high prevalence of antibodies against peptide antigens specific to HSV-1 and -2 in the obese population suggests that these viral peptides may play a role in adipogenesis. Further studies with these candidate peptides in cell culture or animal models may confirm their adipogenic roles.

Human Immunodeficiency Virus Infection and the Endocrine System.

In the current era of effective antiretroviral therapies (ARTs), human immunodeficiency virus (HIV) infection became a chronic disorder that requires long term follow-up. Among other medical issues, these patients may develop endocrine problems, specific to HIV infection and its treatment. The purpose of this review is to give an overview of common endocrine complications associated with HIV infection, and to propose diagnostic and therapeutic strategies. HIV can affect the endocrine system at several levels. Adrenal and gonadal dysfunction, osteoporosis with increased fracture risk, dyslipidemia with increased cardiovascular risk, are some of the endocrine disorders prevalent in HIV-infected patients that may negatively influence quality of life, and increase morbidity and mortality. While ARTs have dramatically increased life expectancy in the HIV-infected population, they are not devoid of adverse effects, including endocrine dysfunction. Physicians caring for HIV-infected patients should be knowledgeable and exercise a high index of suspicion for the diagnosis of endocrine abnormalities, and in particular be aware of those that can be life threatening. Endocrine evaluation should follow the same strategies as in the general population, including prevention, early detection, and treatment.

Hepatitis C Virus Manipulates Humans as its Favorite Host for a Long-Term Relationship.

Chronic hepatitis C virus (HCV) infection-associated liver disease is a global health problem. HCV often causes silent disease, and eventually progresses to end-stage liver disease. HCV infects hepatocytes; however, initial manifestation of liver disease is mostly displayed in hepatic stellate cells (HSCs), causing fibrosis/cirrhosis, and is believed to occur from inflammation in the liver. It remains unclear why HCV is not spontaneously cleared from infected liver in the majority of individuals and develops chronic infection with progressive liver disease. Direct-acting antivirals (DAAs) show excellent results in controlling viremia, although beneficial consequence in advanced liver disease remains to be understood. In this review, we highlight the current knowledge that has contributed to our understanding of the role of HCV in inflammation, immune evasion, metabolic disorders, liver pathogeneses, and efforts in vaccine development.

Outcome of children with rhinovirus detection prior to allogeneic hematopoietic cell transplant.

Rhinoviruses are commonly detected in symptomatic and asymptomatic children prior to HCT. Unlike pre-HCT detection of other respiratory viruses, it is not known whether RV detection, with or without clinical symptoms, is associated with worse outcomes in children post-HCT. In a retrospective study of children undergoing allogeneic HCT from January 2009 to February 2015, 91 children underwent allogeneic HCT, and 62 children had RPP testing within 30 days pre-HCT. Fifty-six (90%) children had either no pathogen (n = 34, 55%) or single RV detection (n = 22, 35%), which was the most common pathogen identified. Compared with virus negative children, children with pre-HCT RV detection were not more likely to require ventilated support and did not have longer length of stay, higher mortality, or less days alive and out of the hospital within the first 100 days post-HCT. In a secondary analysis of all 56 patients with RPP testing and no pathogen or RV alone detected, the seven children with LRTI had less days alive and out of the hospital within the first 100 days post-HCT compared with the 49 children who were either asymptomatic or had URTI (10 vs 60 days, P = 0.002). In a bootstrapped regression model, presence of LRTI, not RV detection, was significantly associated with decreased days alive and out of the hospital within the first 100 days post-HCT. Thus, pre-HCT detection of RV, without associated LRTI, does not always warrant HCT delay.

Metabolic Dysregulation in Hepacivirus Infection of Common Marmosets (Callithrix jacchus).

Chronic hepatitis C has been associated with metabolic syndrome that includes insulin resistance, hepatic steatosis and obesity. These metabolic aberrations are risk factors for disease severity and treatment outcome in infected patients. Experimental infection of marmosets with GBV-B serves as a tangible, small animal model for human HCV infection, and while virology and pathology are well described, a full investigation of clinical disease and the metabolic milieu is lacking. In this study six marmosets were infected intravenously with GBV-B and changes in hematologic, serum biochemical and plasma metabolic measures were investigated over the duration of infection. Infected animals exhibited signs of lymphocytopenia, but platelet and RBC counts were generally stable or even increased. Although most animals showed a transient decline in blood glucose, infection resulted in several fold increases in plasma insulin, glucagon and glucagon-like peptide 1 (GLP-1). All infected animals experienced transient weight loss within the first 28 days of infection, but also became hypertriglyceridemic and had up to 10-fold increases in adipocytokines such as resistin and plasminogen activator inhibitor 1 (PAI-1). In liver, moderate to severe cytoplasmic changes associated with steatotic changes was observed microscopically at 168 days post infection. Collectively, these results suggest that GBV-B infection is accompanied by hematologic, biochemical and metabolic abnormalities that could lead to obesity, diabetes, thrombosis and atherosclerosis, even after virus has been cleared. Our findings mirror those found in HCV patients, suggesting that metabolic syndrome could be conserved among hepaciviruses, and both mechanistic and interventional studies for treating HCV-induced metabolic complications could be evaluated in this animal model.

Human Microbiome and its Association With Health and Diseases.

Human microbiota are distinct communities of microorganisms that resides at different body niches. Exploration of the human microbiome has become a reality due to the availability of powerful metagenomics and metatranscriptomic analysis technologies. Recent advances in sequencing and bioinformatics over the past decade help provide a deep insight into the nature of the host-microbial interactions and identification of potential deriver genes and pathways associated with human health, well-being, and predisposition to different diseases. In the present review, we outline recent studies devoted to elucidate the possible link between the microbiota and various type of diseases. The present review also highlights the potential utilization of microbiota as a potential therapeutic option to treat a wide array of human diseases. J. Cell. Physiol. 231: 1688-1694, 2016. © 2015 Wiley Periodicals, Inc.

Inflammatory co-morbidities in HIV+ individuals: learning lessons from healthy ageing.

Increased life expectancy due to improved efficacy of cART has uncovered an increased risk of age-related morbidities in HIV+ individuals and catalyzed significant research into mechanisms driving these diseases. HIV infection increases the risk of non-communicable diseases common in the aged, including cardiovascular disease, neurocognitive decline, non-AIDS malignancies, osteoporosis, and frailty. These observations suggest that HIV accelerates immunological ageing, and there are many immunological similarities with the aged, including shortened telomeres, accumulation of senescent T cells and altered monocyte phenotype/function. However, the most critical similarity between HIV+ individuals and the elderly, which most likely underpins the heightened risk of non-communicable diseases, is chronic inflammation and associated immune activation. Here, we review the similarities between HIV+ individuals and the aged regarding the pathogenesis of inflammatory diseases, the current evidence for mechanisms driving these processes and discuss current and potential therapeutic strategies for addressing inflammatory co-morbidity in HIV+ infection.

Metabolic disease in HIV infection.

The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin-glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs.

Endocrine and metabolic disorders in HTLV-1 infected patients

Human T-cell leukemia virus type 1 (HTLV-1) infection is endemic in Japan and several countries in South America, Caribbean and Africa. Endocrine and metabolic disorders have been variably reported to be associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Therefore, the aim of this article was to critically evaluate the current knowledge of the endocrine and metabolic disorders associated with HTLV-1 infection. The literature search used PubMed, Web of Science, and LILACS databases in the past 10 years, utilizing, in various combinations, the following keywords: HTLV-1, adult T-cell leukemia, diabetes mellitus, GLUT-1, osteoporosis, hypercalcemia, autoimmune thyroid disorders, diabetes insipidus, inappropriate antidiuretic hormone secretion; pseudohypoparathyroidism; pseudopseudohypoparathyroidism. The proven endocrine manifestations of the HTLV-1 infection are calcium disorders which occur in some patients with acute HTLV-1/Adult T-cell leukemia/lymphoma. The few reports about thyroid, parathyroid, antidiuretic hormone and diabetes mellitus are insufficient to prove a causal association with HTLV-1 infection. The evidence for an association between endocrine disorders and HTLV-1 infection in general, and in asymptomatic patients is lacking. Given all these uncertainties, the endocrine expression of the HTLV-1 infection composes a promising research line for understanding the pathophysiology of this infection.

Endocrine and metabolic disorders in HTLV-1 infected patients.

Human T-cell leukemia virus type 1 (HTLV-1) infection is endemic in Japan and several countries in South America, Caribbean and Africa. Endocrine and metabolic disorders have been variably reported to be associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Therefore, the aim of this article was to critically evaluate the current knowledge of the endocrine and metabolic disorders associated with HTLV-1 infection. The literature search used PubMed, Web of Science, and LILACS databases in the past 10 years, utilizing, in various combinations, the following keywords: HTLV-1, adult T-cell leukemia, diabetes mellitus, GLUT-1, osteoporosis, hypercalcemia, autoimmune thyroid disorders, diabetes insipidus, inappropriate antidiuretic hormone secretion; pseudohypoparathyroidism; pseudopseudohypoparathyroidism. The proven endocrine manifestations of the HTLV-1 infection are calcium disorders which occur in some patients with acute HTLV-1/Adult T-cell leukemia/lymphoma. The few reports about thyroid, parathyroid, antidiuretic hormone and diabetes mellitus are insufficient to prove a causal association with HTLV-1 infection. The evidence for an association between endocrine disorders and HTLV-1 infection in general, and in asymptomatic patients is lacking. Given all these uncertainties, the endocrine expression of the HTLV-1 infection composes a promising research line for understanding the pathophysiology of this infection.

Human immunodeficiency virus and highly active antiretroviral therapy-associated metabolic disorders and risk factors for cardiovascular disease.

The successful introduction of highly active antiretroviral therapy (HAART), a combination of potent antiretroviral agents, including protease inhibitors, nucleoside reverse transcriptase inhibitors, and nonnucleoside reverse transcriptase inhibitors, has impacted positively on morbidity and mortality among human immunodeficiency virus (HIV)-positive patients. Over time, HAART has been associated with a number of metabolic and anthropometric abnormalities, including dyslipidemia and insulin resistance as well as subcutaneous fat loss and abdominal obesity, potentially contributing to cardiovascular risk. Recent studies have more firmly established that both HIV infection and HAART might increase the risk of clinical cardiovascular events. Furthermore, whereas HIV/HAART is associated with multiple aspects of endocrine dysfunction, there has been less focus on bone disease, although some studies indicate a higher prevalence of osteoporosis among HIV-positive subjects compared to HIV-negative controls. The relationship between bone and fat metabolism under HIV-positive conditions deserves further attention, and available data suggest the possibility of an intriguing connection. In the future, an increasing population of aging HIV-positive patients with a spectrum of antiretroviral therapies and accumulation of endocrine abnormalities and conventional cardiovascular risk factors will present preventive and therapeutic challenges to our health-care system.

Hormonal contraception and HIV-positive women: metabolic concerns and management strategies.

As HIV-positive women live longer lives, and as testing for HIV becomes more routine, clinicians can expect to see more HIV-positive women in their practices. The need to be aware of management issues particular to this population becomes increasingly important. Metabolic dysregulation is a common, long-term complication associated with HIV and is one of the most difficult to manage. Hormonal contraception also is associated with metabolic dysregulation. As more HIV-positive women choose long-term, reversible contraception, the potential for concomitant and additive side effects, and the need for careful, proactive management strategies to avoid these complications, will become more important. This article reviews research detailing the metabolic dysfunction associated with hormonal contraception and with HIV-seropositivity. It highlights reasons for concern regarding the potential, although as yet theoretical, increased risk for metabolic dysfunction when hormonal contraception is used in the presence of HIV. Suggestions for management strategies for women living with HIV who choose to use hormonal contraception are presented. These strategies should be viewed as suggestions for management until substantitive research becomes available.

Metabolic syndromes in human immunodeficiency virus infection.

Infection with human immunodeficiency virus (HIV) is associated with marked disturbance of metabolism affecting the metabolism of carbohydrates, fats and proteins. In the first decade of clinical experience of HIV, the primary clinical manifestation of such disturbed metabolism was wasting. Such wasting was often severe and contributed significantly to the morbidity and mortality of AIDS. Mechanistic studies demonstrated that in addition to the effects of altered intermediary metabolism, reduced food intake played a major role in the causation of AIDS-related wasting. More recently, potent anti-retroviral drugs have dramatically changed the clinical consequences of HIV infection. Wasting has become far less frequent among infected patients and occurs in only a small percentage of subjects on effective anti-retroviral therapy. However, a new constellation of metabolic syndromes has become apparent characterized by altered body fat distribution ('lipodystrophy'), lactic acidosis and evidence of mitochondrial dysfunction. The mechanistic basis for such syndromes is currently unclear, but is the subject of ongoing research.

A pilot study of L-methionine for the treatment of AIDS-associated myelopathy.

The pathogenesis of AIDS-associated vacuolar myelopathy (VM) may be related to abnormality of transmethylation mechanisms in the nervous system. To evaluate the safety and potential efficacy of the methyl-group donor L-methionine in AIDS-associated VM, we conducted a pilot clinical trial in 12 patients with VM. Seven of the nine patients who completed the study had clinical and electrophysiologic improvement. Controlled studies may be indicated to assess the efficacy and safety of L-methionine in AIDS-associated VM.

Congenital cytomegalovirus infection in a northern Italian region. NEOCMV Group.

Knowledge of the prevalence of congenital cytomegalovirus infection is necessary to evaluate the need for prevention. We performed a multicentre one-year study involving 11 neonatology divisions to ascertain the prevalence in Lombardy. Cytomegalovirus was isolated by culturing saliva samples from all babies born (n = 1268) of two 15-day sample periods and from 185 neonates with suspected congenital CMV based on clinical and laboratory findings and the history. The overall prevalence of congenital infection was 0.47% (6/1268) in the sample period group and 5% (9/185) in the second group. Clinical monitoring revealed sequelae in two of three children with symptomatic infection and no asymptomatic child at age two years. In a subgroup of 205 babies including 14 of the infected infants we also evaluated a test to detect cytomegalovirus DNA in the Guthrie cards obtained in neonatal screening for genetic and metabolic disorders. The test's sensitivity was 100% and specificity 98.5%, encouraging its use for early identification of infected neonates and for large epidemiological studies.