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Background The traditional Chinese Medicine (TCM) herbal formula Lian Hua Qing Wen (LHQW) improves the results of COVID-19 treatment. Three very recent studies analyzed with network pharmacology some working mechanisms of LHQW. However, we used more techniques and also included Angiotensin converting enzyme 2 (ACE2) (a SARS-CoV receptor, possibly the viral entry point in alveolar lung cells) and the immune system, as cytokine storm is essential in the late phase. Purpose Extensive detailed Network Pharmacology analysis of the LHQW- treatment mechanism in COVID-19. Methods TCM-herb-meridian and protein interaction network (PIN) of LHQW, based on LHQW herbs meridian information and the protein-protein interaction (PPI) information of the LHQW-component targets. Hub and topological property analyses to obtain crucial targets and construct the crucial LHQW-PIN. Functional modules determination using MCODE, GO and KEGG pathway analysis of biological processes and pathway enrichment. Intersection calculations between the LHQW-proteins and ACE2 co-expression-proteins. Results LHQW herbs have relationships to Stomach-, Heart-, Liver- and Spleen-systems, but most (10 of the 13 herbs) to the Lung system, indicating specific effects in lung diseases. The crucial LHQW PIN has the scale-free property, contains 2,480 targets, 160,266 PPIs and thirty functional modules. Six modules are enriched in leukocyte-mediated immunity, the interferon-gamma-mediated signaling pathway, immune response regulating signaling pathway, interleukin 23 mediated signaling pathway and Fc gamma receptor-mediated phagocytosis (GO analysis). These 6 are also enriched in cancer, immune system-, and viral infection diseases (KEGG). LHQW shared 189 proteins with ACE2 co-expression proteins. Conclusions Detailed network analysis shows, that LHQW herbal TCM treatment modulates the inflammatory process, exerts antiviral effects and repairs lung injury. Moreover, it also relieves the “cytokine storm” and improves ACE2-expression-disorder-caused symptoms. These innovative findings give a rational pharmacological basis and support for treating COVID-19 and possibly other diseases with LHQW., Graphical abstract Image, graphical abstract

Background: COVID-19 commonly presents with upper respiratory symptoms; however, studies have shown that SARS-CoV-2 infection affects multiple organ systems. Here, we review the pathophysiology and imaging characteristics of SARS-CoV-2 infection in organ systems throughout the body and explore commonalities. Objective: Familiarity with the underlying pathophysiology and imaging characteristics is essential for the radiologist to recognize these findings in patients with COVID-19 infection. Though pulmonary findings are the most prevalent presentation, COVID-19 may have multiple manifestations and recognition of the extrapulmonary manifestations is especially important because of the potential serious and long-term effects of COVID-19 on multiple organ systems.

The healthy gut is achieved and maintained through a balanced relationship between the mucosal immune system, microbial communities resident in the lumen, and the intestinal epithelium. The intestinal epithelium plays an exceptionally important role in harmonizing the interaction between the host immunity and the luminal residents, as this selectively permeable barrier separates but also allows interchange between the 2 environments. Interleukin (IL)-10 has been well established to play an important role in maintaining gut homeostasis by imparting diverse effects on a variety of cell types in this relationship. In the intestine, the source and the target of IL-10 include leukocytes and epithelial cells. Given that both the epithelium and IL-10 are essential players in supporting homeostasis, we discuss the relationship between these 2 factors, focusing on epithelial sources of IL-10 and the effects of IL-10 on the intestinal epithelium. Insight into this relationship reveals an important aspect of the innate immune function of intestinal epithelial cells.

Graphical abstract, Highlights • SARS-CoV-2 could interact with nAChRs triggering Nicotinic Cholinergic anti-inflammatory system dysregulation. • The α7 nAChRs and SARS-CoV-2 S1 interaction is significantly disturbed by the binding of AChRs agonists. • AChRs may be an intriguing therapeutic approach for the COVID-19s' pandemic., SARS-CoV-2 infection was announced as a pandemic in March 2020. Since then, several scientists have focused on the low prevalence of smokers among hospitalized COVID-19 patients. These findings led to our hypothesis that the Nicotinic Cholinergic System (NCS) plays a crucial role in the manifestation of COVID-19 and its severe symptoms. Molecular modeling revealed that the SARS-CoV-2 Spike glycoprotein might bind to nicotinic acetylcholine receptors (nAChRs) through a cryptic epitope homologous to snake toxins, substrates well documented and known for their affinity to the nAChRs. This binding model could provide logical explanations for the acute inflammatory disorder in patients with COVID-19, which may be linked to severe dysregulation of NCS. In this study, we present a series of complexes with cholinergic agonists that can potentially prevent SARS-CoV-2 Spike glycoprotein from binding to nAChRs, avoiding dysregulation of the NCS and moderating the symptoms and clinical manifestations of COVID-19. If our hypothesis is verified by in vitro and in vivo studies, repurposing agents currently approved for smoking cessation and neurological conditions could provide the scientific community with a therapeutic option in severe COVID-19.

Background & Aims Tissue-resident memory T (Trm) cells, both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease. However, data are conflicting regarding the profile of human CD8+ Trm cells, with studies suggesting both proinflammatory and regulatory functions. It is crucial to understand the functional profile of these cells in the context of (new) therapeutic strategies targeting (trafficking of) gut Trm cells. Methods Here, we performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103+/–CD69+CD8+ Trm cells in healthy control subjects and patients with active ileal Crohn’s disease. Results Our data revealed that lamina propria CD103+CD69+CD8+ T cells have a classical Trm cell profile with active pathways for regulating cell survival/death and cytokine signaling, whereas intraepithelial CD103+CD69+CD8+ T cells display tightly regulated innate-like cytotoxic profile. Furthermore, within lamina propria CD8+CD103– Trm cells, an Itgb2+GzmK+KLRG1+ population distinct from CD103+ CD8+ Trm cells is found. During chronic inflammation, especially intraepithelial CD103+CD69+CD8+ T cells displayed an innate proinflammatory profile with concurrent loss of homeostatic functions. Conclusions Altogether, these compartmental and inflammation-induced differences indicate that therapeutic strategies could have a different impact on the same immune cells depending on the local compartment and presence of an inflammatory milieu, and should be taken into account when investigating short- and long-term effects of new gut T cell–targeting drugs.

The first confirmed case of novel Coronavirus Disease 2019 (COVID-19) in the United States was reported on January 20, 2020. As of November 24, 2020, close to 12.2 million cases of COVID-19 was confirmed in the US, with over 255,958 deaths. The rapid transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), its unusual and divergent presentation has strengthened the status of COVID-19 as a major public health threat. In this review, we aim to 1- discuss the epidemiological data from various COVID-19 patient cohorts around the world and the USA as well the associated risk factors; 2- summarize the pathophysiology of SARS-CoV-2 infection and the underlying molecular mechanisms for the respiratory and cardiovascular manifestations; 3- highlight the potential treatments and vaccines as well as current clinical trials for COVID-19., Graphical abstract Unlabelled Image, Highlights • COVID-19 represents a great threat to people's health worldwide with a high transmission rate and socioeconomic impacts. • Respiratory and cardiovascular conditions showed higher risks of complications and mortality of COVID-19 patients • Efficacy and safety of investigational drugs and other potential treatments for COVID-19.

Backgroud Coronavirus disease (COVID-19) is a new respiratory infectious disease, and there is no vaccine currently. Previous studies have found that BCG vaccination can provide extensive protection against respiratory infectious diseases. Methods Herein, we obtained the latest data from the World Health Organization (WHO) as of August 12, 2020, and determined the relationship between three parameters (including the BCG vaccination coverage, human development index (HDI), and transmission classifications) and the incidence rate and mortality of COVID-19. Results The results showed that the morbidity and mortality of COVID-19 in countries with BCG vaccination recommendation were significantly lower than these in countries without BCG vaccination recommendation, and countries with lower HDI have lower morbidity and mortality. In addition, we also found that the mode of virus transmission is also related to the morbidity and mortality of COVID-19. Conclusions Although our data supports the hypothesis that BCG vaccination is beneficial in reducing the morbidity and mortality of COVID-19, the data supporting this result may be inaccurate due to many confounders such as PCR testing rate, population characteristics, and protection strategies, the reliability of this result still needs to be verified by clinical trials., Highlights • The morbidity and mortality of COVID-19 in countries with BCG vaccination recommendation were significantly lower. • The mode of virus transmission is also related to the morbidity and mortality of COVID-19. • The results may be inaccurate due to many confounders, the reliability still needs to be verified by clinical trials. • The role of BCG in COVID-19 should be confirmed by clinical trials.

The sudden emergence of severe respiratory disease, caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently become a public health emergency. Genome sequence analysis of SARS-CoV-2 revealed its close resemblance to the earlier reported SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). However, initial testing of the drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. The present study highlights the genomic, proteomic, pathogenesis, and therapeutic strategies in SARS-CoV-2 infection. We have carried out sequence analysis of potential drug target proteins in SARS-CoV-2 and, compared them with SARS-CoV and MERS viruses. Analysis of mutations in the coding and non-coding regions, genetic diversity, and pathogenicity of SARS-CoV-2 has also been done. A detailed structural analysis of drug target proteins has been performed to gain insights into the mechanism of pathogenesis, structure-function relationships, and the development of structure-guided therapeutic approaches. The cytokine profiling and inflammatory signalling are different in the case of SARS-CoV-2 infection. We also highlighted possible therapies and their mechanism of action followed by clinical manifestation. Our analysis suggests a minimal variation in the genome sequence of SARS-CoV-2, may be responsible for a drastic change in the structures of target proteins, which makes available drugs ineffective., Graphical abstract Schematic representation of novel corona virus showing target proteins and its mechanism of host entry.Unlabelled Image, Highlights • The recent exposure to SARS-CoV-2 has affected entire world, resulted >0.4 million deaths. • Potential drug targets of SARS-CoV-2 are highly conserved. • A slight structural difference makes available drugs ineffective against SARS-CoV-2. • Cytokine storm during SARS-CoV-2 infection may be targeted to handle COVID-19 patients. • Many FDA approved drugs are showing positive effects in clinical trials but further validation in large subject groups is required.

Highlights • Subpopulations of cisplatin-resistant cells are cross-resistant to anti-microtubule drugs. • Resistance mechanisms in cisplatin-resistant ovarian cancer cells are diverse. • Increased TNF and NFκB signaling found in cisplatin-resistant subpopulations treated with anti-microtubule drugs., Although the first line of therapy for epithelial ovarian cancer typically consists of taxane-platinum combination therapy, many patients develop a platinum-resistant tumor within a year. Several previous studies have looked at this cross-resistance between cisplatin and anti-microtubule drugs, but their findings have been somewhat conflicting. Here, we developed cisplatin-resistant cell lines that are resistant to low and high levels of cisplatin and explored the effects of three anti-microtubule drugs (paclitaxel, vincristine, and colchicine) on the parental and cisplatin-resistant cells. We found that cells resistant to lower levels of cisplatin were no more resistant to anti-microtubule drugs than parental cells, while cells that were resistant to higher levels of cisplatin had a subpopulation of cells that were cross-resistant to anti-microtubule drugs, clarifying discrepancies within the field. We then isolated this subpopulation by applying selective pressure with anti-microtubule drugs and performed RNA sequencing and gene set enrichment analysis to identify resistance mechanisms. This subpopulation was found to express increased levels of pro-survival TNF/NFκB signaling, among other enriched pathways, suggesting that cross-resistance was due to more general survival mechanisms found in the cisplatin-selected cells.

The novel Coronavirus disease of 2019 (nCOV-19) is a viral outbreak noted first in Wuhan, China. This disease is caused by Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2. In the past, other members of the coronavirus family, such as SARS and Middle East Respiratory Syndrome (MERS), have made an impact in China and the Arabian peninsula respectively. Both SARS and COVID-19 share similar symptoms such as fever, cough, and difficulty in breathing that can become fatal in later stages. However, SARS and MERS infections were epidemic diseases constrained to limited regions. By March 2020 the SARS-CoV-2 had spread across the globe and on March 11th, 2020 the World Health Organization (WHO) declared COVID-19 as pandemic disease. In severe SARS-CoV-2 infection, many patients succumbed to pneumonia. Higher rates of deaths were seen in older patients who had co-morbidities such as diabetes mellitus, hypertension, cardiovascular disease (CVD), and dementia. In this review paper, we discuss the effect of SARS-CoV-2 on CNS diseases, such as Alzheimer's-like dementia, and diabetes mellitus. We also focus on the virus genome, pathophysiology, theranostics, and autophagy mechanisms. We will assess the multiorgan failure reported in advanced stages of SARS-CoV-2 infection. Our paper will provide mechanistic clues and therapeutic targets for physicians and investigators to combat COVID-19., Graphical abstract Unlabelled Image, Highlights • SARS-CoV-2 and Dementia, Multiple Sclerosis, Encephalitis, and Parkinson's disease • SARS-CoV-2 and Diabetes Mellitus Coronaviruses and Autophagy • Protease Inhibitors and Repurposed Drugs for SARS-CoV-2 USFDA approved drugs-HCQ and Remdesivir. • SARS-CoV-2 diagnostics

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Graphical abstract Unlabelled Image

Highlights • B cells regulate atherosclerotic plaque formation through production of antibodies and cytokines, and effects are subset specific (B1 and B2). • Putative human atheroprotective B1 cells function similarly to murine B1 in their spontaneous IgM antibody production. However, marker strategies in identifying human and murine B1 are different. • IgM antibody to oxidation specific epitopes produced by B1 cells associate with human coronary artery disease. • Neoantigen immunization may be a promising strategy for atherosclerosis vaccine development, but further study to determine relevant antigens still need to be done. • B-cell–targeted therapies, used in treating autoimmune diseases as well as lymphoid cancers, might have potential applications in treating cardiovascular diseases. Short- and long-term cardiovascular effects of these agents need to be assessed., Central Illustration, Summary Because atherosclerotic cardiovascular disease is a leading cause of death worldwide, understanding inflammatory processes underpinning its pathology is critical. B cells have been implicated as a key immune cell type in regulating atherosclerosis. B-cell effects, mediated by antibodies and cytokines, are subset specific. In this review, we focus on elaborating mechanisms underlying subtype-specific roles of B cells in atherosclerosis and discuss available human data implicating B cells in atherosclerosis. We further discuss potential B cell–linked therapeutic approaches, including immunization and B cell–targeted biologics. Given recent evidence strongly supporting a role for B cells in human atherosclerosis and the expansion of immunomodulatory agents that affect B-cell biology in clinical use and clinical trials for other disorders, it is important that the cardiovascular field be cognizant of potential beneficial or untoward effects of modulating B-cell activity on atherosclerosis.

Background COVID-19 patients can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome (ARDS) requiring invasive mechanical ventilation (IMV). Since interleukin-6 (IL-6) is a relevant cytokine in ARDS, the blockade of its receptor with Tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. Objective To determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. Methods Retrospective observational study performed in hospitalized patients diagnosed of COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with pre- and post-administration of TCZ. Multivariable logistic and linear regressions, and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio (PaO2/FiO2) or mortality. Results One hundred and forty-six patients were studied, predominantly male (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels>30 pg/ml was the best predictor for IMV (OR:7.1; p30 pg/ml predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration., Baseline IL-6 serum levels>30 pg/ml identify severe COVID-19 patients and should be used to guide the intervention with IL-6R inhibitors, aiming to improve their use in an uncertain and evolving therapeutic scenario.

Graphical abstract, Introduction Recently, Nrf2/HO-1 has received extensive attention as the main regulatory pathway of intracellular defense against oxidative stress and is considered an ideal target for alleviating endothelial cell (EC) injury. Objectives This paper aimed to summarized the natural monomers/extracts that potentially exert protective effects against oxidative stress in ECs. Methods A literature search was carried out regarding our topic with the keywords of “atherosclerosis” or “Nrf2/HO-1” or “vascular endothelial cells” or “oxidative stress” or “Herbal medicine” or “natural products” or “natural extracts” or “natural compounds” or “traditional Chinese medicines” based on classic books of herbal medicine and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science, GoogleScholar, BaiduScholar, and others. Then, we analyzed the possible molecular mechanisms for different types of natural compounds in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress. In addition, perspectives for possible future studies are discussed. Results These agents with protective effects against oxidative stress in ECs mainly include phenylpropanoids, flavonoids, terpenoids, and alkaloids. Most of these agents alleviate cell apoptosis in ECs due to oxidative stress, and the mechanisms are related to Nrf2/HO-1 signaling activation. However, despite continued progress in research on various aspects of natural agents exerting protective effects against EC injury by activating Nrf2/HO-1 signaling, the development of new drugs for the treatment of atherosclerosis (AS) and other CVDs based on these agents will require more detailed preclinical and clinical studies. Conclusion Our present paper provides updated information of natural agents with protective activities on ECs against oxidative stress by activating Nrf2/HO-1. We hope this review will provide some directions for the further development of novel candidate drugs from natural agents for the treatment of AS and other CVDs.

Highlights • Chronic intake of alcohol initiates a pathogenic process that involves the production of protein-aldehyde adducts, and release of cytokines. • Involved gene polymorphisms may include alcohol dehydrogenase, cytochrome P4502E1, and those associated with alcoholism. • Alcohol ingestion could be correlated to the risk of preterm births, there is no exact dose-response relationship. • Oral drugs of pentoxifylline have reduced the severity of steatohepatitis in alcohol-use patients., One of the global burdens of health care is an alcohol-associated liver disease (ALD) and liver-related death which is caused due to acute or chronic consumption of alcohol. Chronic consumption of alcohol damage the normal defense mechanism of the liver and likely to disturb the gut barrier system, mucosal immune cells, which leads to decreased nutrient absorption. Therapy of ALD depends upon the spectrum of liver injury that causes fatty liver, hepatitis, and cirrhosis. The foundation of therapy starts with abstinence from alcohol. Corticosteroids are used for the treatment of ALD but due to poor acceptance, continuing mortality, and identification of tumor necrosis factor-alpha as an integral component in pathogenesis, recent studies focus on pentoxifylline and, antitumor necrosis factor antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidants also play a significant role in the treatment but till today there is no universally accepted therapy available for any stage of ALD. The treatment aspects need to restore the gut functions and require nutrient-based treatments to regulate the functions of the gut system and prevent liver injury. The vital action of saturated fatty acids greatly controls the gut barrier. Overall, this review mainly focuses on the mechanism of alcohol-induced metabolic dysfunction, contribution to liver pathogenesis, the effect of pregnancy, and targeted therapy of ALD.

Graphical abstract, Highlights • Systemic oxidative stress and inflammation are significant outcomes of SARS-CoV-2 infection. • Activated Gsk-3 following SARS-CoV-2 infection provoke the oxidative stress and inflammation in the host. • Gsk-3 phosphorylates nucleocapsid protein of SARS-CoV-2 and helps in disease progression. • Inhibition of Gsk-3 can be a suitable target in curbing of COVID-19 pandemic., The coronavirus disease 19 (COVID-19) outbreak caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had turned out to be highly pathogenic and transmittable. Researchers throughout the globe are still struggling to understand this strain's aggressiveness in search of putative therapies for its control. Crosstalk between oxidative stress and systemic inflammation seems to support the progression of the infection. Glycogen synthase kinase-3 (Gsk-3) is a conserved serine/threonine kinase that mainly participates in cell proliferation, development, stress, and inflammation in humans. Nucleocapsid protein of SARS-CoV-2 is an important structural protein responsible for viral replication and interferes with the host defence mechanism by the help of Gsk-3 protein. The viral infected cells show activated Gsk-3 protein that degrades the Nuclear factor erythroid 2-related factor (Nrf2) protein, resulting in excessive oxidative stress. Activated Gsk-3 also modulates CREB-DNA activity, phosphorylates NF-​κB, and degrades β-catenin, thus provokes systemic inflammation. Interaction between these two pathophysiological events, oxidative stress, and inflammation enhance mucous secretion, coagulation cascade, and hypoxia, which ultimately leads to multiple organs failure, resulting in the death of the infected patient. The present review aims to highlight the pathogenic role of Gsk-3 in viral replication, initiation of oxidative stress, and inflammation during SARS-CoV-2 infection. The review also summarizes the potential Gsk-3 pathway modulators as putative therapeutic interventions in combating the COVID-19 pandemic.

Mononuclear phagocytes are a widely distributed family of cells contributing to innate and adaptive immunity. Circulating monocytes and tissue macrophages participate in all stages of SARS COVID-19. They contribute to comorbidities predisposing to clinical infection, virus resistance and dissemination, and to host factors that determine disease severity, recovery and sequelae. Assays are available to detect viral infection and antibody responses, but no adequate tests have been developed to measure the activation level of monocytes and tissue macrophages, and the risk of progression to a fatal hyperinflammatory syndrome. Blood monocytes provide a window on the systemic immune response, from production to tissue recruitment, reflecting the impact of infection on the host. Ready availability of blood makes it possible to monitor severity and the risk of potentially lethal complications, by developing tests to assess the status of monocyte activation and its potential for further inflammatory dysregulation after recruitment to tissues and during recovery.

Background & Aims Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon. Methods We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4–10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly or SER-287 once daily. Clinical endpoints included safety and clinical remission (modified Mayo score ≤ 2; endoscopic subscores 0 or 1). Microbiome endpoints included SER-287 engraftment (dose species detected in stool after, but not before, SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo. Results Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P=.024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P

Background & Aims Defining the genetic heterogeneity of intrahepatic biliary epithelial cells (BECs) is challenging, and tools for identifying BEC subpopulations are limited. Here, we characterize the expression of a Sox9EGFP transgene in the liver and demonstrate that green fluorescent protein (GFP) expression levels are associated with distinct cell types. Methods Sox9EGFP BAC transgenic mice were assayed by immunofluorescence, flow cytometry, and gene expression profiling to characterize in vivo characteristics of GFP populations. Single BECs from distinct GFP populations were isolated by fluorescence-activated cell sorting, and functional analysis was conducted in organoid forming assays. Intrahepatic ductal epithelium was grown as organoids and treated with a Yes-associated protein (Yap) inhibitor or bile acids to determine upstream regulation of Sox9 in BECs. Sox9EGFP mice were subjected to bile duct ligation, and GFP expression was assessed by immunofluorescence. Results BECs express low or high levels of GFP, whereas periportal hepatocytes express sublow GFP. Sox9EGFP+ BECs are differentially distributed by duct size and demonstrate distinct gene expression signatures, with enrichment of Cyr61 and Hes1 in GFPhigh BECs. Single Sox9EGFP+ cells form organoids that exhibit heterogeneous survival, growth, and HNF4A activation dependent on culture conditions, suggesting that exogenous signaling impacts BEC heterogeneity. Yap is required to maintain Sox9 expression in biliary organoids, but bile acids are insufficient to induce BEC Yap activity or Sox9 in vivo and in vitro. Sox9EGFP remains restricted to BECs and periportal hepatocytes after bile duct ligation. Conclusions Our data demonstrate that Sox9EGFP levels provide readout of Yap activity and delineate BEC heterogeneity, providing a tool for assaying subpopulation-specific cellular function in the liver., Graphical abstract

Epithelial cells in the liver (known as hepatocytes) are high-performance engines of myriad metabolic functions and versatile responders to liver injury. As hepatocytes metabolize amino acids, alcohol, drugs, and other substrates, they produce and are exposed to a milieu of toxins and harmful byproducts that can damage themselves. In the healthy liver, hepatocytes generally divide slowly. However, after liver injury, hepatocytes can ramp up proliferation to regenerate the liver. Yet, on extensive injury, regeneration falters, and liver failure ensues. It is therefore critical to understand the mechanisms underlying liver regeneration and, in particular, which liver cells are mobilized during liver maintenance and repair. Controversies continue to surround the very existence of hepatic stem cells and, if they exist, their spatial location, multipotency, degree of contribution to regeneration, ploidy, and susceptibility to tumorigenesis. This review discusses these controversies. Finally, we highlight how insights into hepatocyte regeneration and biology in vivo can inform in vitro studies to propagate primary hepatocytes with liver regeneration-associated signals and to generate hepatocytes de novo from pluripotent stem cells.

Background Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma. Objectives Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis. Methods The authors investigated ISR’s role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes. Results The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis. Conclusions These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles’ responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis., Central Illustration

Background Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. Findings 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q, Graphical abstract Image, graphical abstract

Background Throughout the 5000-year history of China, more than 300 epidemics were recorded. Traditional Chinese herbal medicine (TCM) has been used effectively to combat each of these epidemics’ infections, and saved many lives. To date, there are hundreds of herbal TCM formulae developed for the purpose of prevention and treatment during epidemic infections. When COVID-19 ravaged the Wuhan district in China in early January 2020, without a deep understanding about the nature of COVID-19, patients admitted to the TCM Hospital in Wuhan were immediately treated with TCM and reported later with >90% efficacy. Approach We conducted conduct a systematic survey of various TCM herbal preparations used in Wuhan and to review their efficacy, according to the published clinical data; and, secondly, to find the most popular herbs used in these preparations and look into the opportunity of future research in the isolation and identification of bioactive natural products for fighting COVID-19. Results Although bioactive natural products in these herbal preparations may have direct antiviral activities, TCM employed for fighting epidemic infections was primarily based on the TCM theory of restoring the balance of the human immune system, thereby defeating the viral infection indirectly. In addition, certain TCM teachings relevant to the meridian system deserve better attention. For instance, many TCM herbal preparations target the lung meridian, which connects the lung and large intestine. This interconnection between the lung, including the upper respiratory system, and the intestine, may explain why certain TCM formulae showed excellent relief of lung congestion and diarrhea, two characteristics of COVID-19 infection. Conclusion There is good reason for us to learn from ancient wisdom and accumulated clinical experience, in combination with cutting edge science and technologies, to fight with the devastating COVID-19 pandemic now and emerging new coronaviruses in the future.

Background & Aims TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs). Methods Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions. Results TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1high CD8+ TILs. PD1high TIGIT+ CD8+ TILs co-expressed exhaustion markers TIM3 and LAG3 and demonstrated higher TOX expression. Furthermore, this subset showed decreased capacity to produce IFN-γ and TNF-α. Expression of TIGIT-ligand CD155 was up-regulated on tumor cells compared with hepatocytes in TFL. Whereas single PD1 blockade preferentially enhanced ex vivo functions of CD8+ TILs from tumors with PD1high CD8+ TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8+ TILs from tumors enriched for PD1int CD8+ TILs (low PD1 expressers). Importantly, ex vivo co-blockade of TIGIT/PD1 improved proliferation, cytokine production, and cytotoxicity of CD8+ TILs compared with single PD1 blockade. Conclusions Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8+ TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients., Graphical abstract

Background Community-acquired pneumonia (CAP) guidelines have improved the management and outcomes of patients with CAP, primarily by standardization of initial empiric therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no concensus regarding the initial management of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the management of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiological work-up, general principles of empiric therapy, and empiric therapy for specific pathogens. Interpretation This document offer general suggestions for the initial management of the immunocompromised patient who arrives at the hospital with pneumonia.

Highlights • COVID-19 pandemic is raging worldwide and is putting health-care systems under severe strain. • The “cytokine storm” and the subsequent Acute Respiratory Distress Syndrome results from the effects of a combination of several immune-active molecules. • the “cytokine storm” appears as one of the most dangerous and potentially life-threatening event related to COVID-19 sustaining its major clinical consequences. • The chemokine system appears to be deeply involved in the pathogenesis of severe clinical sequelae of COVID-19, similarly to what was observed in SARS and MERS epidemics., In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.

Visual Abstract, Highlights • Electrospun polycaprolactone surfaces were immobilized with a monolayer of the cytokine interleukin-4 to create a “bioactive” immunomodulatory surface capable of influencing the phenotype of macrophages responding to the material surface in vivo. • Bioactive surfaces, evaluated in vitro by using macrophage culture, exhibited upregulation of anti-inflammatory M2 genes and facilitated morphological changes consistent with macrophage activation. • As a subcutaneous implant in a 14-day model of acute inflammation, bioactive surfaces polarized macrophages from their M1 pro-inflammatory to M2 anti-inflammatory phenotypes, leading to a significant reduction in the local immune-driven foreign body response. • As vascular grafts in a 28-day mouse carotid interposition model, bioactive grafts maintained their macrophage polarization and immunomodulatory effects, significantly reducing adventitial encapsulation and neointimal hyperplasia development., Summary Cardiovascular disease is an inflammatory disorder that may benefit from appropriate modulation of inflammation. Systemic treatments lower cardiac events but have serious adverse effects. Localized modulation of inflammation in current standard treatments such as bypass grafting may more effectively treat CAD. The present study investigated a bioactive vascular graft coated with the macrophage polarizing cytokine interleukin-4. These grafts repolarize macrophages to anti-inflammatory phenotypes, leading to modulation of the pro-inflammatory microenvironment and ultimately to a reduction of foreign body encapsulation and inhibition of neointimal hyperplasia development. These resulting functional improvements have significant implications for the next generation of synthetic vascular grafts.

Background Oral submucous fibrosis (OSMF) is one of the common oral potentially malignant disorders that can result in severe morbidity. Depending upon the stage of disease, multiple management therapies exist which include medicinal and surgical approaches. Although the surgical approach is preferred in severe conditions, numerous studies have reported its post-surgical deteriorating outcomes including increased fibrotic changes. To reduce these post-surgical complications, Light amplification by stimulated emission of radiation (Laser) has been introduced and studied as a non-invasive technique to treat oral submucous fibrosis. However, there exists a lack of knowledge about ‘which laser shows a better post-treatment outcome’. Accordingly, this review aims to answer this question. Materials and methods A systematic review of the published literature was performed using an electronic search in PubMed/Medline, Science Direct, Web of Science, Embase, J- STAGE, Google Scholar, and Scopus databases, from 1952 till 2019 using keywords like, ‘Oral submucous fibrosis’, ‘Treatment’, ‘Laser’, ‘Trismus’, ‘ Fibrosis’, ‘Surgical’, ‘Non-invasive’, and ‘Postoperative results’. Results The search strategy revealed 20 relevant published studies in which laser had been used to treat 250 patients of OSMF. Effective results were found without any complications in all the cases after follow up. Conclusion Observing the current literature, it can be concluded that laser might be used as a potential non-invasive approach in the management of OSMF, however, large scale studies are required to investigate the efficacy and other effects of this technology.

Graphical abstract, The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern. Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities. Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality. Up–to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs. In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19.

Highlights • Coronavirus pandemic has created a global alarming situation. • SARS-CoV shares sequence homology with bats, therefore, considered as origin. • Scientists are burning midnight's oil to discover drug or vaccine against this deleterious virus. • Medicinal plants should be explored to find a cure for this disease. • Phyto-constituents are ubiquitously synthesised in plants, effective against SARS-CoV-2. • Clinical trials for herbal formulations are promoted to find drug or vaccine. • Other armours like physical fitness, balanced diet are promoted for boosting immunity., Current scenario depicts that world has been clenched by COVID-19 pandemic. Inevitably, public health and safety measures could be undertaken in order to dwindle the infection threat and mortality. Moreover, to overcome the global menace and drawing out world from moribund stage, there is an exigency for social distancing and quarantines. Since December, 2019, coronavirus, SARS-CoV-2 (COVID-19) have came into existence and up till now world is still in the state of shock.At this point of time, COVID-19 has entered perilous phase, creating havoc among individuals, and this has been directly implied due to enhanced globalisation and ability of the virus to acclimatize at all conditions. The unabated transmission is due to lack of drugs, vaccines and therapeutics against this viral outbreak. But research is still underway to formulate the vaccines or drugs by this means, as scientific communities are continuously working to unravel the pharmacologically active compounds that might offer a new insight for curbing infections and pandemics. Therefore, the topical COVID-19 situation highlights an immediate need for effective therapeutics against SARS-CoV-2. Towards this effort, the present review discusses the vital concepts related to COVID-19, in terms of its origin, transmission, clinical aspects and diagnosis. However, here, we have formulated the novel concept hitherto, ancient means of traditional medicines or herbal plants to beat this pandemic., Graphical abstract Image, graphical abstract

Acetaminophen (APAP)-induced liver necrosis is a form of regulated cell death (RCD) in which APAP activates the mitogen-activated protein kinases (MAPKs) and specifically the c-Jun-N-terminal kinase (JNK) pathway, leading to necrotic cell death. Previously, we have shown that receptor interacting protein kinase-1 (RIPK1) knockdown is also protective against APAP RCD upstream of JNK. However, whether the kinase or platform function of RIPK1 is involved in APAP RCD is not known. To answer this question, we used genetic mouse models of targeted hepatocyte RIPK1 knockout (RIPK1HepCKO) or kinase dead knock-in (RIPK1D138N) and adult hepatocyte specific knockout of the cytoprotective protein A20 (A20HepCKO), known to interact with RIPK1, to study its potential involvement in MAPK signaling. We observed no difference in injury between WT and RIPK1D138N mice post APAP. However, RIPK1HepCKO was protective. We found that RIPK1HepCKO mice had attenuated pJNK activation, while A20 was simultaneously upregulated. Conversely, A20HepCKO markedly worsened liver injury from APAP. Mechanistically, we observed a significant upregulation of apoptosis signal-regulating kinase 1 (ASK1) and increased JNK activation in A20HepCKO mice compared with littermate controls. We also demonstrated that A20 coimmunoprecipitated (co-IP) with both RIPK1 and ASK1, and that in the presence of RIPK1, there was less A20-ASK1 association than in its absence. We conclude that the kinase-independent platform function of RIPK1 is involved in APAP toxicity. Adult RIPK1HepCKO mice are protected against APAP by upregulating A20 and attenuating JNK signaling through ASK1, conversely, A20HepCKO worsens injury from APAP.

Graphical abstract, Highlights • CS triggered by excessive inflammatory response drives the pathogenesis of COVID-19. • ASX inhibits TNFα, IL1β, IL6 via regulation of NF-kB & JAK/STAT; prevents CS & ALI/ARDS. • ASX suppresses plasma CRP, iNOS, COX2, PGE2 & ICAM-1; prevents oxidative damages. • ASX inhibits NLRP3, HIF1α, activates Nrf2, Sirtuin pathways; exerts antioxidant effect. • ASX enhances immune responses, NK cell activity, T- & B- cell population., Host excessive inflammatory immune response to SARS-CoV-2 infection is thought to underpin the pathogenesis of COVID-19 associated severe pneumonitis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Once an immunological complication like cytokine storm occurs, anti-viral based monotherapy alone is not enough. Additional anti-inflammatory treatment is recommended. It must be noted that anti-inflammatory drugs such as JAK inhibitors, IL-6 inhibitors, TNF-α inhibitors, colchicine, etc., have been either suggested or are under trials for managing cytokine storm in COVID-19 infections. Natural astaxanthin (ASX) has a clinically proven safety profile and has antioxidant, anti-inflammatory, and immunomodulatory properties. There is evidence from preclinical studies that supports its preventive actions against ALI/ARDS. Moreover, ASX has a potent PPARs activity. Therefore, it is plausible to speculate that ASX could be considered as a potential adjunctive supplement. Here, we summarize the mounting evidence where ASX is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α. We present reports where ASX is shown to prevent against oxidative damage and attenuate exacerbation of the inflammatory responses by regulating signaling pathways like NF-ĸB, NLRP3 and JAK/STAT. These evidences provide a rationale for considering natural astaxanthin as a therapeutic agent against inflammatory cytokine storm and associated risks in COVID-19 infection and this suggestion requires further validation with clinical studies.

Human coronaviruses, especially COVID-19, is an emerging pandemic infectious disease with high morbidity and mortality. Coronaviruses are associated with comorbidities, along with the symptoms of it. SARS-CoV-2 is one of the highly pathogenic coronaviruses that causes a high death rate compared to the SARS-CoV and MERS. In this review, we focused on the mechanism of coronavirus with comorbidities and impairment in multi-organ function. The main dysfunction upon coronavirus infection is damage to alveolar and acute respiratory failure. It is associated with the other organ damage such as cardiovascular risk via an increased level of hypertension through ACE2, gastrointestinal dysfunction, chronic kidney disease, diabetes mellitus, liver dysfunction, lung injury, CNS risk, ocular risks such as chemosis, conjunctivitis, and conjunctival hyperemia, cancer risk, venous thromboembolism, tuberculosis, aging, and cardiovascular dysfunction and reproductive risk. Along with this, we have discussed the immunopathology and coronaviruses at a molecular level and therapeutic approaches for the coronavirus infection. The comorbidities and multi-organ failure of COVID-19 have been explained at a molecular level along with the base of the SARS-CoV and MERS-CoV. This review would help us to understand the comorbidities associated with the coronaviruses with multi-organ damage., Graphical abstract Unlabelled Image

Graphical abstract, COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.

Background & Aims Chemokine-mediated immune cell recruitment plays pivotal roles in liver inflammation. C-C motif chemokine ligand 5 (CCL5) has been shown to be responsible for the recruitment of monocytes/macrophages and has been implicated in various liver diseases, including nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma. Previous studies have also shown that inhibition of CCL5 appears to be a promising therapeutic approach for several chronic liver diseases. However, whether blocking CCL5 could benefit immune cell–mediated hepatitis remains largely elusive. Methods By adopting a specific agonist, alpha-galactosylceramide (α-Galcer), of invariant natural killer T cells (iNKTs), we investigated the function and mechanism of CCL5 in the iNKT induced murine hepatitis model. Results We found significantly increased CCL5 expression in α-Galcer–induced hepatitis murine model. Such an increase in CCL5 is mainly enriched in non-parenchymal cells such as macrophages and iNKTs but not in hepatocytes. Surprisingly, CCL5 blockage by genetic deletion of Ccl5 does not affect the α-Galcer–induced iNKT activation but greatly worsens α-Galcer–induced liver injury accompanied by an increased hepatic neutrophil infiltration. Mechanistically, we demonstrated that greater neutrophil accumulation in the liver is responsible for the enhanced liver injury in Ccl5-/- mice. Such an increased hepatic neutrophil infiltration is mainly caused by an enhanced CXCL1-CXCR2 signal in Ccl5-/- mice. Therapeutically, either antibody-mediated neutrophil depletion or a CXCR2 antagonist, SB225002, mediated CXCR2 signaling blockage significantly ameliorated α-Galcer–induced liver injury in Ccl5-/- mice. Conclusions Our present study demonstrates that (1) α-Galcer–induced murine hepatitis could greatly induce CCL5 production in macrophages and iNKT cells; (2) loss of CCL5 could enhance CXCL1 expression in hepatocytes and activate CXCL1-CXCR2 axis in neutrophils to augment their hepatic infiltration; and (3) neutrophil depletion or blockage of CXCL1-CXCR2 axis greatly improves α-Galcer–induced liver injury in Ccl5-/- mice. This study suggests that clinical utilization of CCL5 blockage may compensatorily induce the activation of other chemokine pathways to enhance neutrophil recruitment and liver injury in hepatitis., Graphical abstract

Background & Aims Psoriasis and inflammatory bowel disease (IBD) are both chronic inflammatory diseases occurring in the skin and gut, respectively. It is well established that psoriasis and IBD have high concordance rates, and similar changes in immune cells and microbiome composition have been reported in both conditions. To study this connection, we used a combination murine model of psoriatic dermatitis and colitis in which mice were treated topically with the Toll-like receptor 7 agonist imiquimod (IMQ) and fed dextran sulfate sodium (DSS). Methods We applied IMQ topically to B6 mice (IMQ mice) and subsequently fed them 2% DSS in their drinking water. Disease activity and immune cell phenotypes were analyzed, and the microbial composition of fecal samples was investigated using 16S ribosomal RNA sequencing. We transplanted feces from IMQ mice to germ-free IQI/Jic (IQI) mice and fed them DSS to assess the effect of the gut microbiome on disease. Results We first confirmed that IMQ mice showed accelerated DSS colitis. IMQ mice had decreased numbers of IgD+ and IgM+ B cells and increased numbers of non–cytokine-producing macrophages in the gut. Moreover, the gut microbiomes of IMQ mice were perturbed, with significant reductions of Lactobacillus johnsonii and Lactobacillus reuteri populations. Germ-free mice transplanted with feces from IMQ mice, but not with feces from untreated mice, also developed exacerbated DSS colitis. Conclusions These results suggest that skin inflammation may contribute to pathogenic conditions in the gut via immunologic and microbiological changes. Our finding of a novel potential skin–gut interaction provides new insights into the coincidence of psoriasis and IBD., Graphical abstract

Background & Aims Human norovirus infection is the leading cause of acute gastroenteritis. Genetic polymorphisms, mediated by the FUT2 gene (secretor enzyme), define strain susceptibility. Secretors express a diverse set of fucosylated histoblood group antigen carbohydrates (HBGA) on mucosal cells; nonsecretors (FUT2-/-) express a limited array of HBGAs. Thus, nonsecretors have less diverse norovirus strain infections, including resistance to the epidemiologically dominant GII.4 strains. Because future human norovirus vaccines will comprise GII.4 antigen and because secretor phenotype impacts GII.4 infection and immunity, nonsecretors may mimic young children immunologically in response to GII.4 vaccination, providing a needed model to study cross-protection in the context of limited pre-exposure. Methods By using specimens collected from the first characterized nonsecretor cohort naturally infected with GII.2 human norovirus, we evaluated the breadth of serologic immunity by surrogate neutralization assays, and cellular activation and cytokine production by flow cytometry. Results GII.2 infection resulted in broad antibody and cellular immunity activation that persisted for at least 30 days for T cells, monocytes, and dendritic cells, and for 180 days for blocking antibody. Multiple cellular lineages expressing interferon-γ and tumor necrosis factor-α dominated the response. Both T-cell and B-cell responses were cross-reactive with other GII strains, but not GI strains. To promote entry mechanisms, inclusion of bile acids was essential for GII.2 binding to nonsecretor HBGAs. Conclusions These data support development of within-genogroup, cross-reactive antibody and T-cell immunity, key outcomes that may provide the foundation for eliciting broad immune responses after GII.4 vaccination in individuals with limited GII.4 immunity, including young children., Graphical abstract

Obesity has reached epidemic proportions in the United States and in much of the westernized world, contributing to considerable morbidity. Several of these obesity-related morbidities are associated with greater risk for death with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 penetrates human cells through direct binding with angiotensin-converting enzyme 2 receptors on the cell surface. Angiotensin-converting enzyme 2 expression in adipose tissue is higher than that in lung tissue, which means that adipose tissue may be vulnerable to COVID-19 infection. Obese patients also have worse outcomes with COVID-19 infection, including respiratory failure, need for mechanical ventilation, and higher mortality. Clinicians need to be more aggressive when treating obese, especially severely obese, patients with COVID-19 infection.

Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipolysis separate from hormone or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis regulated by adrenergic or hormonal stimuli. Inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. Adipocyte-specific deletion of IRE1 in mice prevented inflammatory ligand-induced lipolysis in adipose tissue. IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. We found no role for canonical unfolded protein responses (UPR) or ABL kinases in linking ER stress to lipolysis. Lipolysis was unchanged in adipose tissue from GRP78/BiP+/- compared to littermate mice. Tyrosine kinase inhibitors (TKIs) such as imatinib, which reduce ER stress and IRE1 RNase activity, did not alter lipolysis from inflammatory stimuli. Inhibiting IRE1 kinase activity blocked adipocyte NF-κB activation and Interleukin-6 (Il6) production due to inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signalling in adipocytes. Therefore, inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. Our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation, including insulin resistance. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders.SignificanceAdipocytes maintain metabolic homeostasis by storing nutrients and releasing lipids into the blood via lipolysis. Catecholamines stimulate adrenergic-mediated lipolysis, whereas insulin inhibits lipolysis. Obesity is associated with elevated blood lipids and inflammation, which can impair insulin-mediated suppression of lipolysis (i.e. insulin resistance). It is unclear if inflammatory triggers of lipolysis require insulin resistance or if specific lipolytic triggers engage distinct cell stress components. We found that a specific ER stress response was required for inflammation-mediated lipolysis, not adrenergic-mediated lipolysis. Bacterial and cytokine-induced lipolysis required adipocyte IRE1 kinase activity, but not IRE1 RNase activity typical of the ER stress-related unfolded protein response. We propose that inflammatory triggers of lipolysis engage IRE1 kinase independent of catecholamine and hormone responses, including insulin resistance.Graphical AbstractIRE1 kinase activity promotes an inflammation-specific adipocyte lipolytic program that is separate from hormonal or adrenergic regulation of lipolysis.

Allergic rhinitis affects the quality of life of millions of people worldwide. Air pollution not only causes morbidity, but nearly 3 million people per year die from unhealthy indoor air exposure. Furthermore, allergic rhinitis and air pollution interact. This report summarizes the discussion of an International Expert Consensus on the management of allergic rhinitis aggravated by air pollution. The report begins with a review of indoor and outdoor air pollutants followed by epidemiologic evidence showing the impact of air pollution and climate change on the upper airway and allergic rhinitis. Mechanisms, particularly oxidative stress, potentially explaining the interactions between air pollution and allergic rhinitis are discussed. Treatment for the management of allergic rhinitis aggravated by air pollution primarily involves treating allergic rhinitis by guidelines and reducing exposure to pollutants. Fexofenadine a non-sedating oral antihistamine improves AR symptoms aggravated by air pollution. However, more efficacy studies on other pharmacological therapy of coexisting AR and air pollution are currently lacking. Keywords: Allergic rhinitis, Occupational rhinitis, Air pollution, Climate change, Air pollutants, Indoor air quality, Oxidative stress, Antioxidant enzymes

Visual Abstract, Highlights • Distinct from other histone deacetylases, HDAC6 primarily resides in the cytosol. • Unexpectedly, HDAC6-selective inhibition (or silencing) enhances the nuclear activity of SRF. • HDAC6 inhibition elevates acetylation and protein levels of myocardin-related transcription factor A, a cytoplasmic-nuclear shuttling co-activator of SRF. Myocardin-related transcription factor A/SRF are known to critically regulate vascular smooth muscle cell phenotypic stability. • HDAC6 inhibition prevents smooth muscle cell dedifferentiation in vitro and reduces neointima and restenosis in vivo., Summary Cellular plasticity is fundamental in biology and disease. Vascular smooth muscle cell (SMC) dedifferentiation (loss of contractile proteins) initiates and perpetrates vascular pathologies such as restenosis. Contractile gene expression is governed by the master transcription factor, serum response factor (SRF). Unlike other histone deacetylases, histone deacetylase 6 (HDAC6) primarily resides in the cytosol. Whether HDAC6 regulates SRF nuclear activity was previously unknown in any cell type. This study found that selective inhibition of HDAC6 with tubastatin A preserved the contractile protein (alpha-smooth muscle actin) that was otherwise diminished by platelet-derived growth factor-BB. Tubastatin A also enhanced SRF transcriptional (luciferase) activity, and this effect was confirmed by HDAC6 knockdown. Interestingly, HDAC6 inhibition increased acetylation and total protein of myocardin-related transcription factor A (MRTF-A), a transcription co-activator known to translocate from the cytosol to the nucleus, thereby activating SRF. Consistently, HDAC6 co-immunoprecipitated with MRTF-A. In vivo studies showed that tubastatin A treatment of injured rat carotid arteries mitigated neointimal lesion, which is known to be formed largely by dedifferentiated SMCs. This report is the first to show HDAC6 regulation of the MRTF-A/SRF axis and SMC plasticity, thus opening a new perspective for interventions of vascular pathologies.

Summary Chemical modifications to nucleosomal DNA and histone tails greatly influence transcription of adjacent and distant genes, a mode of gene regulation referred to as epigenetic control. Here, the authors summarize recent findings that have illustrated crucial roles for epigenetic regulatory enzymes and reader proteins in the control of cardiac fibrosis. Particular emphasis is placed on epigenetic regulation of stress-induced inflammation and fibroblast activation in the heart. The potential of developing innovative small molecule “epigenetic therapies” to combat cardiac fibrosis is highlighted., Central Illustration

Ustekinumab is a human interleukin (IL)12/23 antagonist with US Food and Drug Administration indications to treat moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn's disease. Because of the blockade of the IL-12/IL-13 pathway, which mediates antitumor and antiviral responses, ustekinumab has significant immunosuppressive characteristics and can lead to an increased risk of infection, reactivation of latent infection, and malignancy in patients. We present a case of a patient with psoriasis and psoriatic arthritis on ustekinumab who had disseminated verrucae shortly after initiating treatment.