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Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr–/– mice (Taconic) were fed a control diet and exposed to 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (Cyp1a1 and Cyp1a2) in WT but not Ahr–/–. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr–/–. The liver proteome was impacted more so by Ahr–/– genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr-dependent. Ahr principally regulated liver metabolism (e.g., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (e.g., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease., Graphical abstract The aryl hydrocarbon receptor regulated liver metabolism and endocrine function impacting systemic energy homeostasis and body composition. This regulation appeared to involve both direct and indirect mechanisms.Image 1

Background Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. Methods Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. Results Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P, Highlights • We examined psychotic symptoms in adolescents from a population-based birth cohort. • Common positive symptoms were paranoid ideation, visual and auditory hallucinations. • Negative symptoms were correlated with depressive and positive symptoms. • CRP was similarly associated with positive and negative symptom dimension scores. • CRP was specifically associated with auditory hallucinations and anhedonia.

COVID-19, caused by SARS-CoV-2, is a highly infectious disease, and clinical laboratory detection has played important roles in its diagnosis and in evaluating progression of the disease. Nucleic acid amplification testing or gene sequencing can serve as pathogenic evidence of COVID-19 diagnosing for clinically suspected cases, and dynamic monitoring of specific antibodies (IgM, IgA, and IgG) is an effective complement for false-negative detection of SARS-CoV-2 nucleic acid. Antigen tests to identify SARS-CoV-2 are recommended in the first week of infection, which is associated with high viral loads. Additionally, many clinical laboratory indicators are abnormal as the disease evolves. For example, from moderate to severe and critical cases, leukocytes, neutrophils, and the neutrophil-lymphocyte ratio increase; conversely, lymphocytes decrease progressively but are over activated. LDH, AST, ALT, CK, high-sensitivity troponin I, and urea also increase progressively, and increased D-dimer is an indicator of severe disease and an independent risk factor for death. Severe infection leads to aggravation of inflammation. Inflammatory biomarkers and cytokines, such as CRP, SAA, ferritin, IL-6, and TNF-α, increase gradually. High-risk COVID-19 patients with severe disease, such as the elderly and those with underlying diseases (cardiovascular disease, diabetes, chronic respiratory disease, hypertension, obesity, and cancer), should be monitored dynamically, which will be helpful as an early warning of serious diseases.

Background Prurigo pigmentosa (PP) is a rare inflammatory dermatosis characterized by pruritic erythematous papules that coalesce to form a reticulate pattern. PP is often misdiagnosed, and patients are treated with ineffective therapies. Although the majority of reports about PP are from East Asia, patients of all backgrounds can be affected. Objectives To perform a systematic review of reported PP cases with the purpose of summarizing the clinical presentation and treatment of PP. Methods MEDLINE and Embase were searched for original articles describing PP. We identified 115 studies from 24 countries representing 369 patients to include in the analysis. Results Of the 369 patients included in the analysis, the mean age was 25.6 years (range: 13-72 years) with 72.1% (266 of 369) female. Risk factors or aggravating factors were described in 52.3% (193 of 369) of patients and included dietary changes (25.5%, 94 of 369), friction (8.4%, 31 of 369), sweat (7.6%, 28 of 369), and ketonuria (5.1%, 19 of 369). Of those patients who experienced PP following dietary changes, 40.4% (38 of 94) started a ketogenic diet. Minocycline monotherapy was the most frequently prescribed treatment for PP (20.9%, 77 of 369), achieving complete resolution in 48.1% (37 of 77) of patients. Conclusions PP is sometimes associated with ketogenic diets and can be effectively managed with oral tetracyclines.

Splanchnic venous thrombosis is a rare type of venous thromboembolism, and its actual incidence is still unknown. Splenic infarction develops due to splenic vein (SV) thrombosis. Patients with COVID-19 may be exposed to a risk of thrombotic events, and the system affected at the highest level by coagulopathy is the respiratory system. The case presented here is splenic infarction that developed because of SV thrombosis, which is a rare form of venous thromboembolism.

The sudden outbreak and global spread of COVID-19 demanded a tremendous amount of attention for viral respiratory infections (VRIs) in modern times. Evidence accumulated over the past few decades increasingly suggests the importance of recognizing the background and context of lifestyle factors in the prevention of VRIs recurrence. The focus of attention has specifically been on how to optimize respiratory barrier function and immune function during the period of the pandemic outbreak. This viewpoint discusses the impact of a healthy lifestyle on VRIs and demonstrates a practical approach to preventing the occurrence of VRIs based on contemporary evidence.

A growing number of studies on coronavirus disease 2019 (COVID-19) are becoming available, but a synthesis of available data focusing on the critically ill population has not been conducted. We performed a scoping review to synthesize clinical characteristics, treatment, and clinical outcomes among critically ill patients with COVID-19. Between 1/1/2020 and 5/15/2020, we identified high-quality clinical studies describing critically ill patients with a sample size >20 patients by performing daily searches of the World Health Organization and LitCovid databases on COVID-19. Two reviewers independently reviewed all abstracts (2785 unique articles), full-text (218 articles), and abstracted data (92 studies). 92 studies were included, including 61 from Asia, 16 from Europe, 10 from North and South America, as well as 5 multinational studies. Notable similarities among critically ill populations across all regions included a higher proportion of older males infected and with severe illness, high frequency of co-morbidities (hypertension, diabetes, and cardiovascular disease), abnormal chest imaging findings, and death secondary to respiratory failure. Differences in regions included newly identified complications (e.g., pulmonary embolism) and epidemiologic risk factors (e.g., obesity), less chest computed tomography imaging performed, and increased use of invasive mechanical ventilation (70-100% vs. 15-47% of ICU patients) in Europe and the US compared to Asia. Future research directions should include proof-of-mechanism studies to better understand organ injuries and large-scale collaborative clinical studies to evaluate the efficacy and safety of antivirals, antibiotics, IL-6 receptor blockers, and interferon. The current established predictive models require further verification in other regions outside China., Article Highlights: 1. This scoping review is the first of its kind to synthesize the current literature focusing on COVID-19 patients with critical illness by analyzing 92 included studies from Asia, Europe, and North/South America. 2. Scoping reviews are valuable for summarizing existing knowledge, highlighting gaps in our understanding, and guiding future research directions. 3. Notable similarities among critically ill populations across all regions included a higher proportion of older males infected and with severe illness, high frequency of co-morbidities, abnormal chest imaging findings, and death secondary to respiratory failure. Differences in regions included newly identified complications (e.g., pulmonary embolism) and epidemiologic risk factors (e.g., obesity), and a longer stay in the ICU, less chest computed tomography imaging performed and increased use of mechanical ventilation (70-100% vs. 15-47% of ICU patients) in Europe and the US compared to China. 4. Future research directions include a need for studies to confirm the mechanism of organ injuries and large-scale collaborative clinical studies to evaluate the efficacy and safety of drugs. The current established predictive models require further verification in other regions outside China.

Introduction The severity of coronavirus disease (COVID-19) in Japanese patients is unreported. We retrospectively examined significant factors associated with disease severity in symptomatic COVID-19 patients (COVID-Pts) admitted to our institution between February 20 and April 30, 2020. Methods All patients were diagnosed based on the genetic detection of severe acute respiratory syndrome coronavirus 2. Information on the initial symptoms, laboratory data, and computed tomography (CT) images at hospitalization were collected from the patients’ records. COVID-Pts were categorized as those with critical or severe illness (Pts-CSI) or those with moderate or mild illness (Pt-MMI). All statistical analyses were performed using R software. Results Data from 61 patients (16 Pt–CSI, 45 Pt-MMI), including 58 Japanese and three East Asians, were analyzed. Pt–CSI were significantly older and had hypertension or diabetes than Pt-MMI (P

Highlights • Definition and pathogenesis of metabolic syndrome is briefly described. • Sesquiterpene lactones isolated from medicinal plants used in traditional medicine. • In vivo and in vitro biological activities of sesquiterpene lactones are considered. • Chemical and biological properties of natural sesquiterpene lactones are documented., Metabolic syndrome comprises a cluster of metabolic disorders related to the development of cardiovascular disease and type 2 diabetes mellitus. In latter years, plant secondary metabolites have become of special interest because of their potential role in preventing and managing metabolic syndrome. Sesquiterpene lactones constitute a large and diverse group of biologically active compounds widely distributed in several medicinal plants used for the treatment of metabolic disorders. The structural diversity and the broad spectrum of biological activities of these compounds drew significant interests in the pharmacological applications. This review describes selected sesquiterpene lactones that have been experimentally validated for their biological activities related to risk factors of metabolic syndrome, together with their mechanisms of action. The potential beneficial effects of sesquiterpene lactones discussed in this review demonstrate that these substances represent remarkable compounds with a diversity of molecular structure and high biological activity, providing new insights into the possible role in metabolic syndrome management.

Since emerging from Wuhan, China, in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has infected >3.2 million individuals worldwide and ∼1 million in the United States (as of April 29, 2020).1 , 2 Despite the institution of measures designed to “flatten the curve,” COVID-19 has claimed the lives of >225,000 individuals worldwide and >60,000 individuals in the United States alone (as of April 29, 2020).2 Of note, mortality estimates in some of the hardest hit regions have already or may need to be revised to account for a spike in sudden deaths occurring at home.3 , 4 Although most of these deaths are likely directly attributable to COVID-19 (eg, pulseless electrical activity/respiratory arrests), many of the same regions within the United States have also seen the outpatient prescription volume of COVID-19–directed heart rate–corrected QT interval (QTc)–prolonging drug(s), specifically hydroxychloroquine, rise by as much as 22,700% compared to the same time period (March 15–31) in 2019.5 Importantly, recent studies have shown that between 11% and 25% of hospitalized patients with COVID-19 treated with chloroquine or hydroxychloroquine and azithromycin had QTc values rise above the critical 500 ms threshold.6 , 7 As a result, a substantial number of patients with COVID-19, prescribed these so-called corona cocktails, may be at an increased risk of developing drug-induced long QT syndrome (DI-LQTS), which could deteriorate into drug-induced torsades de pointes (DI-TdP) or worse drug-induced sudden cardiac death (DI-SCD).8 , 9 Therefore, it stands to reason that the same phenomenon (DI-LQTS/DI-TdP) that has already halted 1 chloroquine/hydroxychloroquine clinical trial7 and led the Food and Drug Administration to caution against the use of chloroquine/hydroxychloroquine outside the hospital setting/clinical trial10 could also be contributing, at least in small part, to the increase in sudden deaths observed in some COVID-19 epicenters. In addition, the COVID-19 pandemic has already highlighted alarming health disparities in the United States. For example, in Illinois where age, sex, and racial demographic data are reported for all COVID-19 cases, African Americans account for 26% of confirmed COVID-19 cases but 43% of COVID-19 deaths.11 A similar trend has been observed across the United States where COVID-19 mortality rates in predominantly black counties are 6-fold higher than that in predominantly white counties.12 Although this phenomenon is likely explained by the convergence of multiple cultural and socioeconomic factors,12 an underlying genetic susceptibility to SARS-CoV-2 infection, its sequelae (such as hypoxia and inflammation), or the potentially lethal side effects of COVID-19–directed therapies (ie, DI-TdP and DI-SCD), assuming equal exposure to these medications, could also contribute. Current evidence supports the notion that the common ion channel variants p.Asp85Asn-KCNE1 and p.Ser1103Tyr-SCN5A confer an increased risk of DI-LQTS and DI-SCD (Table 1 ).13 Importantly, p.Ser1103Tyr-SCN5A is seen almost exclusively in individuals of African descent and its frequency in that population (∼8%) is higher than that of p.Asp85Asn-KCNE1 (0.2%–2.5% depending on ancestry; 0.2% in individuals of African origin) (Table 1).13 Furthermore, unlike p.Asp85Asn-KCNE1 whose proarrhythmic potential is largely limited to DI-LQTS risk, the modest increase in late/persistent sodium current generated by p.Ser1103Tyr-SCN5A is accentuated markedly by hypoxia/acidosis and has been linked to an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in African Americans across the age spectrum.13, 14, 15, 16 Table 1 Epidemiological and functional data supporting a role for p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 in DI-LQTS risk

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions., Graphical abstract In this article, we discuss the physiological, therapeutic and pathophysiological relevance of cytochrome P450 protein degradation. Employing mice with genetic ablation of CHIP and gp78/AMFR E3 ubiquitin-ligases that stabilize hepatic CYP2E1, we document why this stabilization not always leads to non-alcoholic fatty liver disease: It requires concomitantly enhanced hepatic lipogenesis.Image 1

Background: Leukocyte-associated immunoglobulin like receptor-1 (LAIR1) is a transmembrane inhibitory receptor that influences susceptibility to a myriad of inflammatory diseases. Our recent investigations of severe malarial anemia (SMA) pathogenesis in Kenyan children discovered that novel LAIR1 genetic variants associated with decreased LAIR1 enhanced the longitudinal risk of SMA and all-cause mortality. Methods: To further characterize LAIR1 expression and identify novel molecular mechanisms, at least in part, responsible for reduced LAIR1 in severe malaria, we conducted a series of experiments in samples from children with malaria, followed by in vitro investigations driven by the in vivo findings. Findings: Kenyan children with SMA had elevated circulating levels of soluble LAIR1 (sLAIR1) relative to non-SMA (1.69-fold P

Cerebral palsy (CP) is a group of motor disorders caused by non-progressive lesions of the premature brain with lifelong pathophysiological consequences that include dysregulation of innate immunity. Persistent inflammation with increased levels of circulating pro-inflammatory tumor necrosis factor alpha (TNF-a) is negatively associated with rehabilitation outcome in children with CP. Because of the crosstalk between innate and adaptive immunity, we investigated the effect of CP and rehabilitation exercises on the adaptive immune system in children with CP by measuring the levels of CD3+, CD4+, CD8+ Т-cells, and CD22+ B-cells and the levels of immunoglobulins. Children with CP had higher levels of CD3+, CD4+, CD8+ Т-cells, and CD22+ B-cells compared to healthy children, and the rehabilitation exercise programs produced better outcomes in terms of increased gains in motor function at an earlier age. Rehabilitation exercises performed over a month resulted in significantly decreased levels of IgA in serum and reduced numbers of B-lymphocytes and reduced IgM levels. Our study suggests that rehabilitation programs with a focus on neuroplasticity and physical exercises in children with CP can reduce both cellular and humoral immune responses., Highlights • Children with CP demonstrate increased levels of T and B cells. • Rehabilitation exercises helped balance immune responses.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been led to a pandemic emergency. So far, different pathological pathways for SARS-CoV-2 infection have been introduced in which the excess release of pro-inflammatory cytokines (such as interleukin 1 β [IL-1β], IL-6, and tumor necrosis factor α [TNFα]) has earned most of the attentions. However, recent studies have identified new pathways with at least the same level of importance as cytokine storm in which endothelial cell (EC) dysfunction is one of them. In COVID-19, two main pathologic phenomena have been seen as a result of EC dysfunction: hyper-coagulation state and pathologic angiogenesis. The EC dysfunction-induced hypercoagulation state seems to be caused by alteration in the levels of different factors such as plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF) antigen, soluble thrombomodulin, and tissue factor pathway inhibitor (TFPI). As data have shown, these thromboembolic events are associated with severity of disease severity or even death in COVID-19 patients. Other than thromboembolic events, pathologic angiogenesis is among the recent findings. Furthermore, over-expression/higher levels of different proangiogenic factors such as vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1 α (HIF-1α), IL-6, TNF receptor super family 1A and 12, and angiotensin-converting enzyme 2 (ACE2) have been found in the lung biopsies/sera of both survived and non-survived COVID-19 patients. Also, there are some hypotheses regarding the role of nitric oxide in EC dysfunction and acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection. It has been demonstrated that different pathways involved in inflammation are generally common with EC dysfunction and angiogenesis. Altogether, considering the common possible upstream pathways in cytokine storm, pathologic angiogenesis, and EC dysfunction, it seems that targeting these molecules (such as nuclear factor κB) could be more effective in the management of patients with COVID-19., Graphical abstract Unlabelled Image

Background Posttraumatic epilepsy (PTE) is a serious and debilitating consequence of traumatic brain injury (TBI). Sometimes, the management of PTE becomes a challenging task on account of its resistance to existing antiepileptic drugs and often contributes to poor functional and psychosocial outcomes after TBI. We investigated the role of inflammatory markers interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interferon γ (INF-γ) in predicting the development of PTE. Methods A prospective analysis was performed of 254 patients who were admitted with head injury to our hospital, 35 of whom had posttraumatic epilepsy (32 males and 3 females); 30 adults (28 men, 2 women) with a similar demographic profile were selected randomly as control individuals. Blood levels of TNF-α, IL-6, and INF-γ were evaluated in all participants. Results IL-6 levels were significantly higher in the PTE group (121.36 pg/mL; standard deviation [SD], 89.23) than in the nonseizure group (65.30 pg/mL; SD, 74.75; P = 0.01), whereas there was no significant difference between the seizure group (11.42 pg/mL; SD, 7.84) and the nonseizure groups (10.58 pg/mL; SD, 7.84) in terms of TNF-α level (P = 0.343). The level of INF-γ in the seizure group tended to be higher (mean, 1.88 pg/mL, SD, 2.13 in seizure group vs. 1.10 pg/mL, SD, 1.45 in the nonseizure group); however, no statistically significant difference was detected among the 2 groups (P = 0.09). Conculsions Posttraumatic epilepsy has a strong association with an increased level of IL-6 in the blood. INF-γ may or may not be associated with PTE. However, TNF-α was not associated with PTE.

Background Cytokine storm-related hypercoagulation may be important in the pathogenesis of stent thrombosis in patients with SARS-CoV-2. Whether stent polymers behave differently under such conditions has never been explored. Methods Fluorinated polymer-nanocoated and uncoated COBRA stents (CeloNova), BioLinx-polymer-coated Resolute Onyx stents (Medtronic), and Synergy stents (Boston Scientific), which are abluminally coated with a bioabsorbable polymer, were exposed to human blood from healthy donors which was supplemented with 400 pg/mL IL-6 and 100 pg/mL TNF-α, similar to what is seen in cytokine storm caused by SARS-CoV-2. Platelet adhesion and neutrophil activation, assessed by immunofluorescence, were compared under cytokine storm and control conditions (untreated blood) (n = 4 experimental runs). Results Platelet adhesion values, defined as %platelet-covered area x staining intensity, were significantly lower in coated and uncoated COBRA and in Resolute Onyx than in Synergy under control conditions (1.28 × 107 ± 0.43 × 107 vs. 2.92 × 107 ± 0.49 × 107 vs. 3.57 × 107 ± 0.73 × 107 vs. 9.94 × 107 ± 0.99 × 107; p ≤0.0001). In cytokine storm, platelet adhesion values remained low in coated COBRA-PzF (1.78 × 107 ± 0.38 × 107) compared to all other devices (uncoated COBRA: 5.92 × 107 ± 0.96 × 107; Resolute Onyx: 7.27 × 107 ± 1.82 × 107; Synergy: 11.28 × 107 ± 1.08 × 107; p ≤0.0001). Although cytokine storm conditions significantly increased neutrophil activation in all stents, it was significantly less in coated and uncoated COBRA, and in Resolute Onyx than in Synergy. Conclusions Blood-biomaterials interactions may determine the thrombogenic potential of stents. Under simulated cytokine storm conditions, fluoropolymer-coated stents showed the most favorable anti-thrombogenic and anti-inflammatory properties., Graphic abstract Severe COVID-19 infection is associated with overproduction of cytokines by macrophages, activated T-cells, and neutrophils. Especially IL-6 and TNF-α trigger hypercoagulation, potentially playing a role in the pathogenesis of MI. PCI in this situation holds an increased risk of ST. Under in vitro simulated cytokine storm conditions, stents with fluoropolymer coatings had less platelet adhesion and neutrophil activation than uncoated and BioLinx polymer-coated stents and compared with stents abluminally coated with bioabsorbable polymers.Unlabelled Image

Graphical abstract, Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. Main Findings This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.

Graphical abstract, Highlights • In the same content, Nano-HO could effectively enhance the bioactivity of HO remarkably and prolonged its circulation time in rats. • Nano-HO improved cognitive deficits in TgCRND8 mice. • Nano-HO suppressed neuroinflammatory response (TNF-α, IL-Iβ, IL-6) inhibited the activation of microglia, astrocyte and A-β plaque burdens in TgCRND8 mice. • Nano-HO ameliorated AD through regulating APP processing, preventing tau hyperphosphorylation and modulating JNK/CDK5/GSK-3β pathway. • Nano-HO regulated the composition and structure of gut microbiota to protect the gut microflora and its stability., Introduction Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer’s disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. Objectives A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined. Methods Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT). Results Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO. Conclusion Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Purpose Researches revealed that probiotics maybe a potential strategy for COVID-19, whereas there is a lack of related evidence. This study aims to analyze the role of probiotics on severe COVID-19 patients. Methods In the current retrospective single-center study, we collected data of 311 consecutive severe patients with confirmed COVID-19 in Wuhan Union Hospital from Feb 3rd to Feb 20th, 2020. Epidemiological, clinical and medication characteristics were compared and analyzed between patients with or without probiotics. Results In total, 93 of the 123 patients (75.61%) who were treated with probiotics survived to hospital discharge with the median inpatient day of 32 days and mean virus clearance time of 23 days, which were significantly longer than those of patients without probiotics. There were no bias in laboratory parameters, except for IL-6 and ESR, which were significantly higher in patients treated probiotics. We tracked the dynamic changes of 8 selected laboratory parameters (IL-6, CRP, total T lymphocytes, NK cells, B lymphocyte, CD4 + T cells, CD8 + T cells and CD4/CD8 ratio) and found that probiotics could not reduce the increased IL-6 levels but possessed the ability to moderate the immunity and decreased the incidence of secondary infection in COVID-19 patients. Conclusions Probiotics could be an effective strategy for the treatment of COVID-19 patients to reduce the secondary infection and moderated the immunity.

The coronavirus disease 2019 (COVID-19) pandemic has changed life on a global scale. The numbers of transplantations have plummeted as a result of fear of disease transmission, recipient coronavirus disease 2019 infection, priority shift, and resource limitations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complicates transplantation because donor testing, (re)allocation of limited resources, and recipient testing may exceed permissible ischemia times. Normothermic machine perfusion (NMP) helps safely prolong liver preservation up to 38 hours. Additional time is essential under the current circumstances. Here we present the case of a 29-year-old liver transplant recipient in whom prolonged liver preservation required for SARS-CoV-2 screening was accomplished through NMP. Donor and recipient test results for SARS-CoV-2 were negative, and intensive care unit capacity was eventually available. The surgical procedure and postoperative course were uneventful. NMP can extend preservation times in liver transplantation while awaiting SARS-CoV-2 test results and available intensive care unit capacity.

Background The COVID-19 pandemic has led to surges of patients presenting to emergency departments (ED) and potentially overwhelming health systems. Objective This study aimed to assess the predictive accuracy of host biomarkers at clinical presentation to the ED for adverse outcome. Methods Prospective observational study of PCR-confirmed COVID-19 patients in the ED of a Swiss hospital. Concentrations of inflammatory and endothelial dysfunction biomarkers were determined at clinical presentation. We evaluated the accuracy of clinical signs and these biomarkers in predicting 30-day intubation/mortality, and oxygen requirement by calculating the area under the receiver operating characteristic curve (AUROC) and by classification and regression tree analysis. Results Of 76 COVID-19 patients included, 24 were outpatients or hospitalized without oxygen requirement, 35 hospitalized with oxygen requirement and 17 intubated/died. We found that soluble triggering receptor expressed on myeloid cells (sTREM-1) had the best prognostic accuracy for 30-day intubation/mortality (AUROC 0.86; 95% CI 0.77-0.95) and interleukin-6 (IL-6) measured at presentation to the ED had the best accuracy for 30-day oxygen requirement (AUROC 0.84; 95% CI 0.74-0.94) .An algorithm based on respiratory rate and sTREM-1 predicted 30-day intubation/mortality with 94% sensitivity and 0.1 NLR. An IL-6-based algorithm had 98% sensitivity and 0.04 negative likelihood ratio (NLR) for 30-day oxygen requirement. Conclusion sTREM-1 and IL-6 concentrations in COVID-19 in the ED have good predictive accuracy for intubation/mortality and oxygen requirement. sTREM-1- and IL-6-based algorithms are highly sensitive to identify patients with adverse outcome and could serve as early triage tools., Capsule summary: To our knowledge, this is the first study evaluating sTREM-1 in the context of COVID-19 risk-stratification. Our results suggested we could use it as triage tool in emergency department.

Graphical abstract, COVID-19, the greatest public health emergency of the 21st century, has affected 215 countries and territories around the world resulting in 15,151,738 confirmed cases and 621,121 deaths. The outbreak has continued at breakneck pace despite stringent public health measures, ravaging the global economy and causing profound human casualties. Vaccination is currently the best bet for the prevention of COVID-19. Still, in its absence, there has been considerable interest in repurposing existing therapeutic agents to reduce the severity of the illness and ease the burden on the already strained healthcare systems. This review outlines the current evidence regarding proposed treatments- experimental or repurposed, for COVID-19, and gives an insight into the clinical trial landscape for drugs as well as vaccines.

While the liver demonstrates remarkable resilience during aging, there is growing evidence that it undergoes all the cellular hallmarks of aging, which increases the risk of liver and systemic disease. The aging process in the liver is driven by alterations of the genome and epigenome that contribute to dysregulation of mitochondrial function and nutrient sensing pathways, leading to cellular senescence and low-grade inflammation. These changes promote multiple phenotypic changes in all liver cells (hepatocytes, liver sinusoidal endothelial, hepatic stellate and Küpffer cells) and impairment of hepatic function. In particular, age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease., Graphical Abstract Unlabelled Image, Highlights • Liver aging is driven by transcription and metabolic epigenome alterations. • This leads to cellular senescence and low-grade inflammation. • Hepatocyte, sinusoidal endothelial, stellate and Küpffer cells undergoes the hallmarks of aging. • Each cell type demonstrates phenotypical cellular changes with age.

Currently, treating coronavirus disease 2019 (COVID19) patients, particularly those afflicted with severe pneumonia, is challenging, as no effective pharmacotherapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Severe pneumonia is recognized as a clinical syndrome, characterized by hyper induction of proinflammatory cytokine production, which can induce organ damage followed by edema, dysfunction of air exchange, acute respiratory distress syndrome, acute cardiac injury, secondary infection, and increased mortality. Owing to the immunoregulatory and differentiation potential of mesenchymal stem cells (MSCs), we aimed to outline current insights into the clinical application of MSCs in the patients of COVID19. Based on results from preliminary clinical investigations, one predicts that MSCs therapy for SARS-CoV-2 infected patients is safe and effective although multiple clinical trials with a protracted follow-up will be necessary to determine the long term effects of the treatment on COVID19 patients.

Graphical abstract, Highlights • miRNAs are key regulators of gene expression at both transcription and translation. • The role of miRNAs in xenobiotic toxicity and its potential as biomarkers are being explored. • In spite of numerous studies, the complex mechanism of miRNA biogenesis and its regulation remains unclear., The advent of new technologies has paved the rise of various chemicals that are being employed in industrial as well as consumer products. This leads to the accumulation of these xenobiotic compounds in the environment where they pose a serious threat to both target and non-target species. miRNAs are one of the key epigenetic mechanisms that have been associated with toxicity by modulating the gene expression post-transcriptionally. Here, we provide a comprehensive view on miRNA biogenesis, their mechanism of action and, their possible role in xenobiotic toxicity. Further, we review the recent in vitro and in vivo studies involved in xenobiotic exposure induced miRNA alterations and the mRNA-miRNA interactions. Finally, we address the challenges associated with the miRNAs in toxicological studies.

The novel SARS-CoV-2 virus outbreak is the major cause of a respiratory disease known as COVID-19. It has caused a global pandemic and has resulted in mortality in millions. The primary mode of infection is respiratory ailments, however, due to multi-organ complications, COVID-19 patients displays a greater mortality numbers. Due to the 3Rs Principle (Refine, Reduce, Replacement), the scientific community has shifted its focus to 3D organoid models rather than testing animal models. 3D organoid models provide a better physiological architecture as it mimics the real tissue microenvironment and is the best platform to recapitulate organs in a dish. Hence, the organoid approach provides a more realistic drug response in comparison to the traditional 2D cellular models, which lack key physiological relevance due to the absence of proper surface topography and cellular interactions. Furthermore, an adverse outcome pathway (AOPs) provides a best fit model to identify various molecular and cellular events during the exposure of SARS-CoV-2. Hence, 3D organoid research provides information related to gene expression, cell behavior, antiviral studies and ACE2 expression in various organs. In this review, we discuss state-of-the-art lung, liver and kidney 3D organoid system utilizing the AOPs to study SARS-CoV-2 molecular pathogenesis. Furthermore, current challenges are discussed for future application of 3D organoid systems for various disease states.

Highlights • The HSE-RFP reporter detects primarily- and secondarily-damaged neural cells in spinal cord injury. • The HSE-RFP reporter detects primarily- and secondarily-damaged neural cells in sciatic nerve injury. • Reporter-positive secondarily-injured neurons show altered physiological properties., Spinal cord and peripheral nerve injury results in extensive damage to the locally injured cells as well as distant cells that are functionally connected to them. Both primary and secondary damage can cause a broad range of clinical abnormalities, including neuropathic pain and cognitive and memory dysfunction. However, the mechanisms underlying these abnormalities remain unclear, awaiting new methods to identify affected cells to enable examination of their molecular, cellular and physiological characteristics. Here, we report that both primary and secondary damage to cells in mouse models of spinal cord and peripheral nerve injury can be detected in vivo using a novel fluorescent reporter system based on the immediate stress response via activation of Heat Shock Factor 1. We also provide evidence for altered electrophysiological properties of reporter-positive secondarily-injured neurons. The comprehensive identification of injured, but surviving cells located both close and at distant locations from the injury site in vivo will provide a way to study their pathophysiology and possibly prevention of their further deterioration.

In some types of human cancer, aldehyde dehydrogenases represent stemness markers and their expression is associated with advanced disease stages and poor prognosis. Although several biological functions are mediated by their product Retinoid acid, the molecular mechanism is tissue-dependent and only partially understood. In this review, we summarize the current knowledge about the role of ALDH in solid tumours, especially ALDH1A1 and ALDH1A3 isoforms, regarding the molecular mechanism of their transcription and regulation, and their crosstalk with main molecular pathways resulting in the excessive proliferation, chemoresistance, stem cells properties and invasiveness. The recent knowledge of the regulatory effect of lnRNA on ALDH1A1 and ALDH1A3 is discussed too., Highlights • Aldehyde dehydrogenases are important stem cell markers in many human cancer types. • ALDH1A1 or ALDH1A3 activation participates in tumour progression, chemoresistance, stem-cell properties and invasiveness. • ALDH1A1 interacts with oncogenic pathways Notch, NRF, CXCR4, Polycomb, MDR, and HOX.

Graphical abstract, Despite endorsed and exponential research to improve diagnostic and therapeutic strategies, efforts have not yet converted into a better prospect for patients infected with the novel coronavirus (2019nCoV), and still, the name of SARS-CoV-2 is coupled with numerous unanswered questions. One of these questions is concerning how this respiratory virus reduces the number of platelets (PLTs)? The results of laboratory examinations showed that about a quarter of COVID-19 cases experience thrombocytopenia, and more remarkably, about half of these patients succumb to the infection due to coagulopathy. These findings have positioned PLTs as a pillar in the management as well as stratifying COVID-19 patients; however, not all the physicians came into a consensus about the prognostic value of these cells. The current review aims to unravel the contributory role of PLTs s in COVID-19; and also to summarize the original data obtained from international research laboratories on the association between COVID-19 and PLT production, activation, and clearance. In addition, we provide a special focus on the prognostic value of PLTs and their related parameters in COVID-19. Questions on how SARS-CoV-2 induces thrombocytopenia are also responded to. The last section provides a general overview of the most recent PLT- or thrombocytopenia-related therapeutic approaches. In conclusion, since SARS-CoV-2 reduces the number of PLTs by eliciting different mechanisms, treatment of thrombocytopenia in COVID-19 patients is not as simple as it appears and serious cautions should be considered to deal with the problem through scrutiny awareness of the causal mechanisms.

Background & Aims The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection. Methods We performed gene expression profiling of primary human hepatocytes infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real-time polymerase chain reaction and Western blotting. Activation of signal transducer and activator of transcription (STAT3) was examined in HBV-replicating human hepatocytes, HBV-replicating mice, and liver tissue from HBV-infected individuals using Western blotting, STAT3-luciferase reporter assay, and immunohistochemistry. The consequences of STAT3 activation on HBV infection and cell survival were studied by chemical inhibition of STAT3 phosphorylation and small interfering RNA–mediated knockdown of STAT3. Results Gene expression profiling of HBV-infected primary human hepatocytes detected no interferon response, while genes encoding for acute phase and antiapoptotic proteins were up-regulated. This gene regulation was confirmed in liver tissue samples of patients with chronic HBV infection and in HBV-related hepatocellular carcinoma. Pathway analysis revealed activation of STAT3 to be the major regulator. Interleukin-6–dependent and –independent activation of STAT3 was detected in HBV-replicating hepatocytes in cell culture and in vivo. Prevention of STAT3 activation by inhibition of Janus tyrosine kinases as well as small interfering RNA–mediated knockdown of STAT3-induced apoptosis and reduced HBV replication and gene expression. Conclusions HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells. This very likely supports HBV-related carcinogenesis., Graphical abstract

Atherosclerosis involves interactions between inflammation system and dyslipidemia. MCPIP1 (Monocyte Chemotactic Protein induced Protein-1) is induced by proinflammatory molecules and serves as a negative feedback loop in regulating inflammatory responses. Our current study was designed to test the role of MCPIP1 in maintaining lipid homeostasis, the latter a pivotal factor that contributes to the pathogenesis of atherosclerosis. We found that MCPIP1 knockout mice displayed a decrease in levels of serum HDL-cholesterol and total triglycerides but an increase in serum LDL/VLDL-cholesterol levels when compared to wild-type mice. Additionally, ApoA-1 expression was reduced but LPL expression was upregulated in plasma from MCPIP1 knockout mice. The livers from the MCPIP1 knockout mice revealed a decrease in hepatocyte number and an increase in collagen deposition when compared to wild-type mice. These findings suggest that MCPIP1 deficiency can induce liver fibrosis, alter the expression of lipoproteins, and affect transportation and metabolism of lipids, indicating that MCPIP1 is involved in maintaining lipid homeostasis, possibly via negatively regulating inflammatory responses., Graphical abstract Image 1, Highlights • Atherosclerosis is the result of interaction between inflammation and dyslipidemia. • MCPIP1 is a negative regulator in inflammatory responses. • MCPIP1 is upregulated in the atherosclerotic plaques. • MCPIP1 deficiency induces dyslipidemia and hepatic remodeling. • MCPIP1 deficiency may increase the risk of atherosclerosis.

Graphical abstract A positive activation loop between TMEM16A and the IP3R/Ca2+/NFκB/IL-6 pathway is important for Ca2+ elevation, NFκB activation and IL-6 release, and thus cooperatively promotes the pathogenesis of AP., TMEM16A Ca2+-activated Cl− channels are expressed in pancreatic acinar cells and participate in inflammation-associated diseases. Whether TMEM16A contributes to the pathogenesis of acute pancreatitis (AP) remains unknown. Here, we found that increased TMEM16A expression in the pancreatic tissue was correlated with the interleukin-6 (IL-6) level in the pancreatic tissue and in the serum of a cerulein-induced AP mouse model. IL-6 treatment promoted TMEM16A expression in AR42J pancreatic acinar cells via the IL-6 receptor (IL-6R)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. In addition, TMEM16A was co-immunoprecipitated with the inositol 1,4,5-trisphosphate receptor (IP3R) and was activated by IP3R-mediated Ca2+ release. TMEM16A inhibition reduced the IP3R-mediated Ca2+ release induced by cerulein. Furthermore, TMEM16A overexpression activated nuclear factor-κB (NFκB) and increased IL-6 release by increasing intracellular Ca2+. TMEM16A knockdown by shRNAs reduced the cerulein-induced NFκB activation by Ca2+. TMEM16A inhibitors inhibited NFκB activation by decreasing channel activity and reducing TMEM16A protein levels in AR42J cells, and it ameliorated pancreatic damage in cerulein-induced AP mice. This study identifies a novel mechanism underlying the pathogenesis of AP by which IL-6 promotes TMEM16A expression via IL-6R/STAT3 signaling activation, and TMEM16A overexpression increases IL-6 secretion via IP3R/Ca2+/NFκB signaling activation in pancreatic acinar cells. TMEM16A inhibition may be a new potential strategy for treating AP.

Summary Liver resection is one of the main curative options for early hepatocellular carcinoma (HCC) in patients with cirrhosis and is the treatment of choice in non-cirrhotic patients. However, careful patient selection is required to balance the risk of postoperative liver failure and the potential benefit on long-term outcomes. In the last decades, improved surgical techniques and perioperative management, as well as better patient selection, have enabled the indications for liver resection to be expanded. In this review, we aim to describe the main indications for liver resection in the management of HCC, its role compared to percutaneous ablation and liver transplantation in the therapeutic algorithm, as well as the recent advances in liver surgery that could be used to improve the prognosis of patients with HCC.

Sleep is a recurrent physiologic and fundamental process in every human being, regardless of ethnicity, gender, birthplace, or occupation; however, the features of sleep are swayed by genetic background and environmental influences. All these factors have an intricate relationship, and arise from a complex and assorted genetic repertoire in the alleles that promote a higher genetic variation in human populations. Sleep disorders have become an uprising public health problem in the modern society; in addition, the correlation between sleep disorders and the development of late chronic diseases has been extensively studied, finding an important causality between them. Therefore, an adequate evaluation of the current situation in a developing continent such as Africa is essential to develop satisfactory health policies. In this review, we will reprise several aspects that influence the sleep-wake cycle in individuals with African heritage (including African Americans and sub-Saharan Africans), such as genetic background, HIV infection, tropical diseases, immunological markers, cultural aspects, and place them into Africa's context in order to have a better comprehension of its situation., Highlights • African genes predispose to obstructive sleep apnea and short sleep. • CRP and IL-6 induce a pro-inflammatory state and sleep disturbances.

Background Macrophages regulate the inflammatory response and affect re-endothelialization. Inflammation and macrophages play important roles in promoting tissue repair, but p38α mitogen-activated protein kinase's role in re-endothelialization is unknown. Methods and results Wire injuries of carotid arteries and Evans blue staining were performed in macrophage-specific p38α-knockout (p38αfl/flLysMCre+/-) mice and control mice (p38αfl/fl). Re-endothelialization of the carotid arteries at 3, 5 and 7 days was significantly promoted in p38αfl/flLysMCre+/- mice. In vitro experiments indicated that both the proliferation and migration of endothelial cells were enhanced in conditioned medium from peritoneal macrophages of p38αfl/flLysMCre+/- mice. Interleukin-6 (IL-6) level was decreased significantly in macrophages of p38αfl/flLysMCre+/- mice and an IL-6-neutralizing antibody promoted endothelial cell migration in vitro and re-endothelialization in p38αfl/fl mice in vivo. Phosphoproteomics revealed that the phosphorylation level of S544/T545/S549 sites in megakaryocytic leukemia 1 (MKL1) was decreased in p38αfl/flLysMCre+/- mice. The mutation of either S544/S549 or T545/S549 sites could reduce the expression of IL-6 and the inhibition of MKL1 reduced the expression of IL-6 in vitro and promoted re-endothelialization in vivo. Conclusion p38α in macrophages aggravates injury of arteries by phosphorylating MKL1, and increasing IL-6 expression after vascular injury., Graphical abstract Image 1, Highlights • Re-endothelialization of the carotid arteries is significantly promoted when p38α is knocked out in macrophages. • Inhibiting IL-6 activity by a neutralizing antibody promotes re-endothelialization. • p38α mediates S544/S549 and T545/S549 phosphorylation motif in MKL1 which regulates the expression of IL-6 in mouse.

Highlights • IL-6 has been associated with poorer facial emotion recognition. • fMRI was performed during a faces task and IL-6 measured from blood samples. • IL-6 predicted increased neural response during facial emotion recognition., Background Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. Methods Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. Results Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p

The C1q and TNF related 4 (C1QTNF4) protein is a structurally unique member of the C1QTNF family, a family of secreted proteins that have structural homology with both complement C1q and the tumor necrosis factor superfamily. C1QTNF4 has been linked to the autoimmune disease systemic lupus erythematosus through genetic studies; however, its role in immunity and inflammation remains poorly defined and a cell surface receptor of C1QTNF4 has yet to be identified. Here we report identification of nucleolin as a cell surface receptor of C1QTNF4 using mass spectrometric analysis. Additionally, we present evidence that the interaction between C1QTNF4 and nucleolin is mediated by the second C1q-like domain of C1QTNF4 and the C terminus of nucleolin. We show that monocytes and B cells are target cells of C1QTNF4 and observe extensive binding to dead cells. Imaging flow cytometry experiments in monocytes show that C1QTNF4 becomes actively internalized upon cell binding. Our results suggest that nucleolin may serve as a docking molecule for C1QTNF4 and act in a context-dependent manner through coreceptors. Taken together, these findings further our understanding of C1QTNF4's function in the healthy immune system and how dysfunction may contribute to the development of systemic lupus erythematosus.

Inflammasomes are macromolecular complexes involved in the host response to external and endogenous danger signals. Inflammasome-mediated sterile inflammation plays a central role in several human conditions such as autoimmune diseases, type-2 diabetes, and neurodegenerative disorders, indicating inflammasomes could be appealing therapeutic targets. Previous work has demonstrated that inhibiting the ATPase activity of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3), disrupts inflammasome assembly and function. However, there is a necessity to find new potent compounds with therapeutic potential. Here we combine computational modeling of the target and virtual screening to discover a group of novel compounds predicted to inhibit NLRP3. We characterized the best compounds and determined their potency, specificity, and ability to inhibit processes downstream from NLRP3 activation. Moreover, we analyzed in mice the competence of a lead candidate to reduce lipopolysaccharide-induced inflammation. We also validated the active pharmacophore shared among all the NLRP3 inhibitors, and through computational docking, we clarify key structural features for compound positioning within the inflammasome ATP-binding site. Our study sets the basis for rational design and optimization of inflammasome-targeting probes and drugs.

Background and aims Overall obesity has recently been established as an independent risk factor for critical illness in patients with coronavirus disease 2019 (COVID-19). The role of fat distribution and especially that of visceral fat, which is often associated with metabolic syndrome, remains unclear. Therefore, this study aims at investigating the association between fat distribution and COVID-19 severity. Methods Thirty patients with COVID-19 and a mean age of 65.6 ± 13.1 years from a level-one medical center in Berlin, Germany, were included in the present cross-sectional analysis. COVID-19 was confirmed by polymerase chain reaction (PCR) from nasal and throat swabs. A severe clinical course of COVID-19 was defined by hospitalization in the intensive care unit (ICU) and/or invasive mechanical ventilation. Fat was measured at the level of the first lumbar vertebra on routinely acquired low-dose chest computed tomography (CT). Results An increase in visceral fat area (VFA) by ten square centimeters was associated with a 1.37-fold higher likelihood of ICU treatment and a 1.32-fold higher likelihood of mechanical ventilation (adjusted for age and sex). For upper abdominal circumference, each additional centimeter of circumference was associated with a 1.13-fold higher likelihood of ICU treatment and a 1.25-fold higher likelihood of mechanical ventilation. Conclusions Our proof-of-concept study suggests that visceral adipose tissue and upper abdominal circumference specifically increase the likelihood of COVID-19 severity. CT-based quantification of visceral adipose tissue and upper abdominal circumference in routine chest CTs may therefore be a simple tool for risk assessment in COVID-19 patients., Highlights • Previous studies suggested an association between obesity and severe COVID-19. • So far, research focused exclusively on body mass index as a measure of obesity. • Routine chest CTs allow quantification of subcutaneous and visceral abdominal fat. • We found a positive association between visceral fat tissue and COVID-19 severity. • Chest CTs may be a simple tool for risk assessment in patients with COVID-19.

Neural stem cell (NSC) grafting in conditions such as aging, brain injury, and neurodegenerative diseases promotes regeneration, plasticity and functional recovery. Recent studies have revealed that administration of NSC-derived extracellular vesicles (NSC-EVs) via non-invasive approaches can also afford therapeutic benefits. This review confers the properties and therapeutic promise of EVs secreted by NSCs. NSC-EVs enriched with specific miRNAs mediate multiple functions in physiological and pathological conditions, which include modulation of the proximate microenvironment, facilitating the entry of viruses into cells, functioning as independent metabolic units, operating as a microglial morphogen and influencing the diverse aspects of brain function in adulthood including the process of aging. Due to their anti-inflammatory, neurogenic and neurotrophic effects, NSC-EVs are also useful for treating multiple neurodegenerative diseases. Although only a few studies have demonstrated the efficacy of NSC-EVs to treat brain impairments, the promise is enormous. Moving forward, the use of well-characterized NSC-EVs generated in specific culture conditions and NSC-EVs that are engineered to carry the desired miRNAs, mRNAs and proteins have great promise for treating brain injury and neurogenerative diseases. Notably, the possibility of targeting NSC-EVs to specific neuronal types or brain regions would enable managing of diverse neurodegenerative conditions with minimal side effects., Highlights • Extracellular vesicles hold a cargo comprising proteins, miRNAs, mRNAs, and DNA • Neural stem cell derived extracellular vesicles are enriched with specific miRNAs • Neural stem cell derived extracellular vesicles can function as independent metabolic units • Extracellular vesicles released from hypothalamic neural stem cells influence aging • Neural stem cell derived extracellular vesicles promote brain repair in models of stroke

Prunus cerasus (P. cerasus) is an alternative-medicine used traditionally for amelioration of chronic-ailments marked by elevation in oxidative-stress like neuropathy. The oxidative-stress control was reported to ameliorate the inflammatory-process. This study aimed to phytochemically-investigate P. cerasus most-active phytochemicals utilizing in-vivo biological models to explore their gastroprotective, anti-inflammatory, and antinociceptive potentials and their possible mechanisms of action. Sonication with EtAc was used to extract P. cerasus fruit (Scf), and seed (Scs). The phytochemical-investigation of Scf was performed by RP-HPLC, while that of Scs was explored utilizing GC-FID. A bio-guided-fraction and isolation method was done utilizing column-chromatography, and have shown that cyanidin-3-glucoside (Cy3G) was the most-active constituent in Scf, while linoleic-acid (LA) was the most-active constituent in Scs. Scf, Scs, Cy3G, and LA significantly (p ˂ 0.05) protected the gastric-mucosa against HCl/EtOH-induced gastric-lesions. Scs (200 mg/kg) has shown the most gastroprotective-potentials, and had comparable-results to ranitidine (50 mg/kg). Scf, Scs, Cy3G, and LA have shown significant anti-inflammatory and antinociceptive potentials against carrageenan induced-edema and nociceptive-pain, respectively, where Scs (200 mg/kg) has shown the most anti-inflammatory and antinociceptive potentials, and had comparable results to ibuprofen (100 mg/kg). Scf, Scs, Cy3G, and LA have counter-acted carrageenan-induced oxidative-stress markers, with increased serum-catalase and reduced-glutathione levels, and decreased lipid-peroxidation. Histopathological-studies demonstrated gastroprotective potentials, regeneration and improvement of the spleen-structural architecture when treated with highest doses of Scs and Scf. The reduction of the pro-inflammatory TNF-alpha and IL-6, and elevation the anti-inflammatory factor IL-10 levels, spleen regenerative-capacity and oxidative-stress amelioration might be the main-mechanism responsible for P. cerasus anti-inflammatory potentials. P. cerasus appears to aid in ameliorating the inflammatory process, and reducing pain-thresholds while preserving the stomach., Graphical abstract Image 1

Highlights • At symptom level, IL-6 is associated with diurnal variation in mood, concentration difficulties, fatigue and sleep disturbances. • These are so-called somatic/neurovegetative symptoms of depression. • At dimension level, IL-6 is associated with both somatic/neurovegetative and psychological symptom dimensions. • Somatic/neurovegetative symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression., Background Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood. Methods In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores. Results Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13–2.69) for diurnal mood variation, 1.50 (95% CI, 1.11–2.02) for concentration difficulties, 1.31 (95% CI, 1.12–1.54) for fatigue, and 1.24 (95% CI, 1.01–1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (β = 0.059, SE = 0.024, P = 0.013) and psychological (β = 0.056, SE = 0.023, P = 0.016) scores. Conclusions Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression.

Aim The Pringle maneuver is a way to reduce blood loss during liver surgery. However, this may result in ischemia/reperfusion injury in the development of which Kupffer cells play a central role. Corticosteroids are known to have anti-inflammatory effects. Our aim was to investigate whether a conjugate of dexamethasone and antibody against the CD163 macrophage cell surface receptor could reduce ischemia/reperfusion injury in the rat liver. Methods Thirty-six male Wistar rats were used for the experiments. Animals were randomly divided into four groups of eight receiving anti-CD163-dexamethasone, high dose dexamethasone, low dose dexamethasone or placebo intravenously 18 h before laparotomy with subsequent 60 min of liver ischemia. After reperfusion for 24 h the animals had their liver removed. Bloods were drawn 30 min and 24 h post ischemia induction. Liver cell apoptosis and necrosis were analyzed by stereological quantification. Results After 24 h' reperfusion, the fraction of cell in non-necrotic tissues exhibiting apoptotic profiles was significantly lower in the high dose dexamethasone (p = 0.03) and anti-CD163-dex (p = 0.03) groups compared with the low dose dexamethasone and placebo groups. There was no difference in necrotic cell volume between groups. After 30 min of reperfusion, levels of haptoglobin were significantly higher in the anti-CD163-dex and high dose dexamethasone groups. Alanine aminotransferase and alkaline phosphatase were significantly higher in the high dose dexamethasone group compared to controls after 24 h' reperfusion. Conclusions We show that pharmacological preconditioning with anti-CD163-dex and high dose dexamethasone reduces the number of apoptotic cells following ischemia/reperfusion injury., Highlights • We investigated the effect of pharmacologic preconditioning with HDD, LDD and anti-CD163-dex on ischemia/reperfusion injury. • Liver cell apoptosis and necrosis were analyzed by stereological quantification. • Anti-CD163-dex and high dose dexamethasone reduces the number of apoptotic cells following ischemia/reperfusion injury.

Bacillus Calmette-Guerin (BCG) vaccination has been reported to protect neonates from non-tuberculous pathogens, but no biological mechanism to explain such effects is known. We hypothesised that BCG produces broad-spectrum anti-microbial protection via a hepcidin-mediated hypoferraemia, limiting iron availability for pathogens.To test this we conducted a trial in 120 Gambian neonates comparing iron status in the first 5-days of life after allocation to: (1) All routine vaccinations at birth (BCG/Oral Polio Vaccine (OPV)/Hepatitis B Vaccine (HBV)); (2) BCG delayed until after the study period (at day 5); and (3) All routine vaccinations delayed until after the study period.Vaccine regime at birth did not significantly impact on any measured parameter of iron metabolism. However, the ability to detect an effect of BCG on iron metabolism may have been limited by short follow-up time and high activation of the inflammatory-iron axis in the study population.

Objective: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. Methods: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj−/− (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. Results: High-fat diet fed-Ptprj−/− mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj−/− mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj−/− mice. Conclusion: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.

Highlights • Functional IL6R variant Asp358Ala (IL6R rs2228145; A > C) is associated with decreased risk of severe depression and/or psychosis. • The variant exerts anti-inflammatory effect downstream of IL-6. • rs2228145 is associated with increased serum IL-6 but decreased serum CRP levels. • rs2228145 is not associated with common confounders of IL-6, depression and psychosis relationship., Objective Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. Method We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. Results Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15–0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10−22) but decreased serum CRP levels (P = 3.5 × 10−5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). Conclusions The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.

The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called “hypervariable region”), a macrodomain (also named “X domain”), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro), the Nsp3 ectodomain (3Ecto, also called “zinc-finger domain”), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth., Highlights • Nonstructural protein 3 (∼200 kD) is a multifunctional protein comprising up to 16 different domains and regions. • Nsp3 binds to viral RNA, nucleocapsid protein, as well as other viral proteins, and participates in polyprotein processing. • The papain-like protease of Nsp3 is an established target for new antivirals. • Through its de-ADP-ribosylating, de-ubiquitinating, and de-ISGylating activities, Nsp3 counteracts host innate immunity. • Structural data are available for the N-terminal two thirds of Nsp3, but domains in the remainder are poorly characterized.

Passion fruit seed extract (PFSE), a product rich in stilbenes such as piceatannol and scirpusin B, has various physiological effects. It is unclear whether PFSE and its stilbene derivatives inhibit cancer cell proliferation via human glyoxalase I (GLO I), the rate-limiting enzyme for detoxification of methylglyoxal. We examined the anticancer effects of PFSE in two types of human cancer cell lines with different GLO I expression levels, NCI–H522 cells (highly-expressed GLO I) and HCT116 cells (lowly-expressed GLO I). PFSE and its stilbenes inhibited GLO I activity. In addition, PFSE and its stilbenes supressed the cancer cell proliferation of NCI–H522 cells more than HCT116 cells. These observations suggest that PFSE can provide a novel anticancer strategy for prevention and treatment., Highlights • Piceatannol, and scirpusin B inhibited GLO I activity. • Passion fruit seed extract suppressed proliferation and colony formation of NCI–H522 cells. • Passion fruit seed extract and piceatannol could exert anticancer activity via GLO I inhibition.

Cardiac oxidative stress has been implicated in the pathogenesis of hypertrophy, cardiomyopathy and heart failure. Systemic deletion of the gene encoding adipose triglyceride lipase (ATGL), the enzyme that catalyzes the rate-limiting step of triglyceride lipolysis, results in a phenotype characterized by severe steatotic cardiac dysfunction. The objective of the present study was to investigate a potential role of oxidative stress in cardiac ATGL deficiency. Hearts of mice with global ATGL knockout were compared to those of mice with cardiomyocyte-restricted overexpression of ATGL and to those of wildtype littermates. Our results demonstrate that oxidative stress, measured as lucigenin chemiluminescence, was increased ~ 6-fold in ATGL-deficient hearts. In parallel, cytosolic NADPH oxidase subunits p67phox and p47phox were upregulated 4–5-fold at the protein level. Moreover, a prominent upregulation of different inflammatory markers (tumor necrosis factor α, monocyte chemotactant protein-1, interleukin 6, and galectin-3) was observed in those hearts. Both the oxidative and inflammatory responses were abolished upon cardiomyocyte-restricted overexpression of ATGL. Investigating the effect of oxidative and inflammatory stress on nitric oxide/cGMP signal transduction we observed a ~ 2.5-fold upregulation of soluble guanylate cyclase activity and a ~ 2-fold increase in cardiac tetrahydrobiopterin levels. Systemic treatment of ATGL-deficient mice with the superoxide dismutase mimetic Mn(III)tetrakis (4-benzoic acid) porphyrin did not ameliorate but rather aggravated cardiac oxidative stress. Our data suggest that oxidative and inflammatory stress seems involved in lipotoxic heart disease. Upregulation of soluble guanylate cyclase and cardiac tetrahydrobiopterin might be regarded as counterregulatory mechanisms in cardiac ATGL deficiency., Graphical abstract, Highlights • ATGL(−/−) mice suffer from severe cardiac oxidative stress originating from upregulation of NOX2-dependent NADPH oxidase. • Inflammation markers TNFα, MCP-1, IL-6, and Mac-2 are increased in cardiac ATGL deficiency. • Activity of sGC and cardiac BH4 levels are elevated in ATGL(−/−) hearts. • Systemic treatment of ATGL(−/−) mice with the SOD mimetic MnTBAP did not ameliorate oxidative stress.