Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases.

High levels of cholesterol are generally considered to be associated with atherosclerosis. In the past two decades, however, a number of studies have shown that excess cholesterol accumulation in various tissues and organs plays a critical role in the pathogenesis of multiple diseases. Here, we summarize the effects of excess cholesterol on disease pathogenesis, including liver diseases, diabetes, chronic kidney disease, Alzheimer's disease, osteoporosis, osteoarthritis, pituitary-thyroid axis dysfunction, immune disorders, and COVID-19, while proposing that excess cholesterol-induced toxicity is ubiquitous. We believe this concept will help broaden the appreciation of the toxic effect of excess cholesterol, and thus potentially expand the therapeutic use of cholesterol-lowering medications.

Emerging nanomaterials applied for tackling the COVID-19 cytokine storm.

During the global outbreak of coronavirus disease 2019 (COVID-19), a hyperinflammatory state called the cytokine storm was recognized as a major contributor to multiple organ failure and mortality. However, to date, the diagnosis and treatment of the cytokine storm remain major challenges for the clinical prognosis of COVID-19. In this review, we outline various nanomaterial-based strategies for preventing the COVID-19 cytokine storm. We highlight the contribution of nanomaterials to directly inhibit cytokine release. We then discuss how nanomaterials can be used to deliver anti-inflammatory drugs to calm the cytokine storm. Nanomaterials also play crucial roles in diagnostics. Nanomaterial-based biosensors with improved sensitivity and specificity can be used to detect cytokines. In summary, emerging nanomaterials offer platforms and tools for the detection and treatment of the COVID-19 cytokine storm and future pandemic.

A potential impact of SARS-CoV-2 on pituitary glands and pituitary neuroendocrine tumors.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effects of SARS-CoV-2 on normal pituitary glands function or pituitary neuroendocrine tumors (PitNETs) have not yet been elucidated. Thus, the present study aimed to investigate the potential risks of SARS-CoV-2 infection on the impairment of pituitary glands and the development of PitNETs. METHODS: PitNETs tissues were obtained from 114 patients, and normal pituitary gland tissues were obtained from the autopsy. The mRNA levels of ACE2 and angiotensin II receptor type 1 (AGTR1) were examined by quantitative real-time PCR. Immunohistochemical staining was performed for ACE2 in 69 PitNETs and 3 normal pituitary glands. The primary tumor cells and pituitary cell lines (MMQ, GH3 and AtT-20/D16v-F2) were treated with diminazene aceturate (DIZE), an ACE2 agonist, with various dose regimens. The pituitary hormones between 43 patients with SARS-CoV-2 infection were compared with 45 healthy controls. RESULTS: Pituitary glands and the majority of PitNET tissues showed low/negative ACE2 expression at both the mRNA and protein levels, while AGTR1 showed high expression in normal pituitary and corticotroph adenomas. ACE2 agonist increased the secretion of ACTH in AtT-20/D16v-F2 cells through downregulating AGTR1. The level of serum adrenocorticotropic hormone (ACTH) was significantly increased in COVID-19 patients compared to normal controls (p < 0.001), but was dramatically decreased in critical cases compared to non-critical patients (p = 0.003). CONCLUSIONS: This study revealed a potential impact of SARS-CoV-2 infection on corticotroph cells and adenomas.

Fourty-nine years old woman co-infected with SARS-CoV-2 and Mycoplasma: A case report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new virus responsible for the outbreak of respiratory illness known as coronavirus disease 2019 (CoVID-19). Mycoplasma is an uncommon co-infected pathogen with SARS-CoV-2 and has not yet been reported. Computed tomography (CT), used as an accessory examination, may play a more significant role in this co-infection. CASE SUMMARY: A 49-year-old female presented with a cough, expectoration and chest congestion followed by elevated C-reactive protein and erythrocyte sedimentation rate. CT images showed ground-glass opacities in bilateral lower lobes and a patchy and striate shadow in the right upper lobe. Immunoglobulin M antibody of Mycoplasma pneumoniae was positive and real-time fluorescence polymerase chain reaction of sputum was positive for SARS-CoV-2 nucleic acid. The diagnosis of CoVID-19 was made based on laboratory results, chest CT images, clinical manifestations and epidemiologic characteristics. She was treated with combination therapy for 17 d and showed a marked reCoVery. CONCLUSION: Co-infection with SARS-CoV-2 and Mycoplasma in CoVID-19 patients appears to be uncommon. CT is an acceptable method for the primary diagnosis and treatment should be initiated as soon as possible. Combination therapy with antiviral, anti-inflammatory, traditional Chinese herbal medicine and interferon inhalation may be a reference for further progress in treating this co-infection.

Differences in the Clinical and Hematological Characteristics of COVID-19 Patients with and without Type 2 Diabetes.

OBJECTIVE: To examine whether comorbidity with type 2 diabetes (T2D) affects the clinical and hematological parameters of coronavirus disease 2019 (COVID-19) patients. METHODS: We retrospectively investigated the clinical, imaging, and laboratory characteristics of patients with confirmed COVID-19 who were hospitalized from January 30, 2020 to March 17, 2020, at the Renmin Hospital of Wuhan University. A detailed clinical record was kept for each subject, including the medical history of COVID-19 and physical and laboratory examinations. A total of 164 subjects were eligible for the study, among which 40 patients were comorbid with T2D. Further analysis was conducted in two subcohorts of sex- and age-matched patients with and without T2D to identify hematological and biochemical differences. The laboratory tests, including routine blood tests, serum biochemistry, and coagulation function, were performed upon admission. RESULTS: The two groups showed no significant differences in baseline parameters, including age, sex, chest X-ray, or computed tomography (CT) findings, upon admission. However, patients with T2D showed an increased incidence of diarrhea. T2D patients required more recovery time from pneumonia, as shown by follow-up CT findings, which might contribute to the prolonged hospitalization. Comorbidity with T2D also increased risk of secondary bacterial infection during COVID-19. The T2D group had significantly higher white blood cell and neutrophil counts compared with the nondiabetic group, but T2D patients suffered from more severe lymphocytopenia and inflammation (P < 0.05). Most biochemical parameters showed no significant differences between the two groups (P > 0.05). However, patients with T2D seemed to have a significantly higher risk of developing hyperlactatemia, hyponatremia, and hypocalcemia. CONCLUSIONS: COVID-19 patients comorbid with T2D demonstrated distinguishing clinical features and hematological parameters during the infection. It is necessary to develop a different clinical severity scoring system for COVID-19 patients with T2D. This study may provide helpful clues for the assessment and management of COVID-19 in T2D patients.

Gastrointestinal Symptoms Associated With Unfavorable Prognosis of COVID-19 Patients: A Retrospective Study.

Background and Aim: The global pandemic of COVID-19 has posed an enormous threat to the economy and people's lives across various countries. Patients with COVID-19 most commonly present with respiratory symptoms. However, gastrointestinal (GI) symptoms can also occur. We aimed to study the relationship between GI symptoms and disease prognosis in patients with COVID-19. Methods: In a single-center and retrospective cohort study, the outcomes in COVID-19 patients with or without GI symptoms were compared. The propensity score is a conditional probability of having a particular exposure (COVID-19 patients with GI symptoms vs. without GI symptoms) given a set of baseline measured covariates. Survival was estimated using the Kaplan-Meier method, and any differences in survival were evaluated with a stratified log-rank-test. To explore the GI symptoms associated with ARDS, non-invasive ventilator treatment, tracheal intubation, tracheotomy, and CRRT, univariable and multivariable COX regression models were used. Results: Among 1,113 eligible patients, 359 patients with GI symptoms and 718 without GI symptoms had similar propensity scores and were included in the analyses. Patients with GI symptoms, as compared with those without GI symptoms, were associated with a similar risk of death, but with higher risks of ARDS, non-invasive mechanical ventilation in COVID-19 patients, respectively. Conclusions: The presence of GI symptoms was associated with a high risk of ARDS, non-invasive mechanical ventilation and tracheal intubation in patients with COVID-19 but not mortality.

Distinguishable Immunologic Characteristics of COVID-19 Patients with Comorbid Type 2 Diabetes Compared with Nondiabetic Individuals.

BACKGROUND: COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has threatened every civilian as a global pandemic. The immune system poses the critical interactive chain between the human body and the virus. Here, we make efforts to examine whether comorbidity with type 2 diabetes (T2D) affects the immunological response in COVID-19 patients. METHODS: We conducted a retrospective pilot study investigating immunological characteristics of confirmed cases of COVID-19 with or without comorbid T2D. Two subcohorts of sex- and age-matched participants were eligible for data analysis, of which 33 participants were with T2D and the remaining 37 were nondiabetic (NDM). Cellular immunity was assessed by flow cytometric determination of surface markers including CD3, CD4, CD8, CD19, CD16, and CD56 in peripheral blood. Levels of C reactive protein, immunoglobulin (IgG, IgM, IgA, and IgE), and complements (C3, C4) were detected by rate nephelometry immunoassay. And Th1/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were detected by Cytometric Bead Array. RESULTS: Neutrophil counts were found to be significantly higher in the T2D group than in the NDM group and had a significant relevance with clinical severity. Lymphocyte frequencies showed no significant differences in the two groups. However, the proportions and absolute counts of T, Tc, Th, and NK cells decreased in both groups to different degrees. An abnormal increase in neutrophil count and a decrease in lymphocyte subpopulations may represent risk factors of COVID-19 severity. The level of IgG, IgM, IgA, C3, and C4 showed no significant difference between the two groups, while the IgE levels were higher in the T2D group than in the NDM group (p < 0.05). Th1 cytokines including IFN-γ, TNF-α, and IL-6, as well as CRP, appeared significantly higher in the T2D group. CONCLUSIONS: The COVID-19 patients comorbid with T2D demonstrated distinguishable immunological parameters, which represented clinical relevancies with the predisposed disease severity in T2D.

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. FINDINGS: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. INTERPRETATION: In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. FUNDING: Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.

The impact of type 2 diabetes and its management on the prognosis of patients with severe COVID-19.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) patients with coronavirus disease 2019 (COVID-19) develop a more severe condition compared to those without diabetes, the mechanisms for this are unknown. Moreover, the impact of treatment with antihyperglycemic drugs and glucocorticoids is unclear. METHODS: From 1584 COVID-19 patients, 364 severe/critical COVID-19 patients with clinical outcome were enrolled for the final analysis, and patients without preexisting T2DM but elevated glucose levels were excluded. Epidemiological data were obtained and clinical status evaluation carried out to assess the impact of T2DM and its management on clinical outcomes. RESULTS: Of 364 enrolled severe COVID-19 inpatients, 114 (31.3%) had a history of T2DM. Twenty-seven (23.7%) T2DM patients died, who had more severe inflammation, coagulation activation, myocardia injury, hepatic injury, and kidney injury compared with non-DM patients. In severe COVID-19 patients with T2DM, we demonstrated a higher risk of all-cause fatality with glucocorticoid treatment (adjusted hazard ratio [HR], 3.61; 95% CI, 1.14-11.46; P = .029) and severe hyperglycemia (fasting plasma glucose ≥11.1 mmol/L; adjusted HR, 11.86; 95% CI, 1.21-116.44; P = .034). CONCLUSIONS: T2DM status aggravated the clinical condition of COVID-19 patients and increased their critical illness risk. Poor fasting blood glucose (≥ 11.1 mmol/L) and glucocorticoid treatment are associated with poor prognosis for T2DM patients with severe COVID-19.

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.