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Highlights • Purinergic signaling is involved in the pathogenesis of neuroinfectious disease. • P2 receptors have pro-inflammatory and deleterious effects in viral Neuroinfections. • ATP-P2X7 receptor signaling contributes to sepsis-associated encephalopathy. • Adenosine favors brain parasite persistence in cerebral toxoplasmosis., The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.

Astrocytes are the major glia cells in the central nervous system (CNS). Increasing evidence indicates that more than to be safe-guard and supporting cells for neurons, astrocytes play a broad spectrum of neuroprotective and pathological functions. Thus, they are compelling models to decipher mechanistic insights of glia cells to CNS insults and for the development of drugs. Edaravone is a free radical scavenger with the capacity to eliminate hydroxyl radicals and lipid peroxides. In this study, we examined the neuroprotective effects of edaravone in rat astrocytes challenged by hydrogen peroxide (H2O2) or bacterial lipopolysaccharides (LPS), respectively. We discovered that edaravone attenuated H2O2-induced oxidative stress by reactivating the Akt signaling axis and antagonistically restoring the expression of apoptosis associated regulators such as Bcl-2 and Caspase-3. Consistently, inhibition of Akt signaling by LY294002 attenuated the anti-oxidative activity of edaravone. In addition, edaravone mitigated LPS-induced morphological changes in astrocytes and alleviated the inflammatory activation and expression of TNF-α, IL-1β, IL-6 and NOS2. In summary, our data suggested that edavarone effectively protects astrocytes from oxidative stress or infectious insults, which may pave a new avenue for its application in preclinical research and human disease therapeutics.

Graphical abstract, Highlights • MC significantly increased and decrease the kidney levels of MDA and NO respectively after 14 and 21 days. • MC administration resulted in the disorganization of the renal redox system. • MC significantly increased the kidney levels of TNF-α and IL-6 after 7, 14 and 21 days, and IL-1β after 14 and 21 days. • MC significantly increased kidney p53, Bax, and caspase-3 after 14 and 21 days, and decreased Bcl-2 after 14 and 21 days. • MC significantly increased the kidney levels of c-Myc and K-Ras after 7, 14 and 21 days., Methyl cellosolve (MC) is used in production of textile, paints, stains, inks, surface coatings, and anti-icing additive in hydraulic fluids and jet fuel. Consequently, the present study investigated its effect on renal cells, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of MC for a period of 7, 14, and 21 days. Following 7 days of administration of MC, there was a significant increase in the levels of K-Ras, c-Myc, TNF-α, IL-6 and NO, while GSH level and SOD activity were significantly reduced compared with control. At the end of 14 days exposure, RKW, GSH, NO, and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1β, IL-6, MDA and GPx activity were significantly increased compared with control. After 21 days of MC administration, RKW, GSH, NO, IL-10 and Bcl-2 levels were significantly decreased, while levels of K-Ras, c-Myc, p53, Bax, caspase-3, TNF-α, IL-1β, IL-6, MDA and GST activity were significantly increased compared with control. Exposures to MC in any way should be strictly avoided as it could trigger renal damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats.

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

Background & Aims GPBAR1, also known as TGR5, is a G protein–coupled receptor activated by bile acids. Hepatic innate immune cells are involved in the immunopathogenesis of human liver diseases and in several murine hepatitis models. Here, by using genetic and pharmacological approaches, we provide evidence that GPBAR1 ligation attenuates the inflammation in rodent models of hepatitis. Material and methods Hepatitis was induced by concanavalin A (Con A) or α-galactosyl-ceramide (α-GalCer). 6b-Ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501), a selective agonist of GPBAR1, was administrated by o.s. Results In the mouse models of hepatitis, the genetic ablation of Gpabar1 worsened the severity of liver injury and resulted in a type I NKT cells phenotype that was biased toward a NKT1, a proinflammatory, IFN-γ producing, NKT cells subtype. Further on, NKT cells from GPBAR1–/– mice were sufficient to cause a severe hepatitis when transferred to naïve mice. In contrast, GPBAR1 agonism rescued wild-type mice from acute liver damage and redirects the NKT cells polarization toward a NKT10, a regulatory, IL-10 secreting, type I NKT cell subset. In addition, GPBAR1 agonism significantly expanded the subset of IL-10 secreting type II NKT cells. RNAseq analysis of both NKT cells type confirmed that IL-10 is a major target for GPABR1. Accordingly, IL-10 gene ablation abrogated protection afforded by GPBAR1 agonism in the Con A model. Conclusion Present results illustrate a role for GPBAR1 in regulating liver NKT ecology. Because NKT cells are an essential component of liver immune system, our data provide a compelling evidence for a GPBAR1-IL-10 axis in regulating of liver immunity., Graphical abstract

Graphical abstract, Highlights • Blueberry leaf may contain multiple compounds with beneficial effects, but limited about the safety. • Powdered blueberry leaf has no toxic event at oral dose of daily 500, 1000 and 2500 mg/kg for 90 days in SD rats. • No significant changes in food consumption, body weight gain and organ weights. • A daily dose up to 2,500 mg/kg body weight in both the sexes rats may indicate a NOAEL. • An acceptable daily intake of blueberry leaf powder for humans is calculated to be 25 mg in dry weight per kg body weight., Blueberry leaf may contain multiple compounds with beneficial effects. We conducted a 90-day toxicity study in rats to evaluate the safety of consuming the leaves of rabbiteye blueberry (Vaccinium virgatum Aiton; RB species). Powdered leaves were administered daily by oral gavage at doses of 500, 1000, and 2500 mg/kg body weight to male and female Sprague-Dawley rats for 90 days. Treatment did not result in death or changes in the behavior and external appearance of the animals. No alterations were observed in hematological and serum chemical parameters, urinalysis, food consumption, body weight gain, or absolute and relative organ weights at the end of the treatment period, with the exception of some leukocyte percentages in male rats treated with 500 and 1000 mg/kg blueberry leaf powder. The findings indicate that rabbiteye blueberry leaf is safe for consumption and should be investigated as a candidate functional food.

Background Atherosclerosis is a hyperlipidemia-induced condition affecting the arterial wall that damages healthy endothelial cell (EC) function, leading to enhanced risk of atherothrombotic events. Certain microRNAs regulate EC dysfunction in response to hyperlipidemia and may be suitable therapeutic targets to combat atherosclerosis. Methods miRNA expression in human ECs was analyzed under various conditions to identify key microRNAs. High-cholesterol diet (HCD)-fed Mir652−/−Apoe−/− (Mir652−/−) mice and matching Mir652+/+Apoe−/− (Mir652+/+) mice were subjected to carotid injury to analyze the effects of miR-652 knockdown on endothelial repair. In silico analysis followed by in vitro and in vivo experiments were applied to identify miR-652's target gene Ccnd2 and investigate the pair's effects on ECs. miR-652-5p and miR-652-3p antagomir therapies were tested in Mir652+/+ mice under normal and HCD diet to assess their effect on endothelial repair. Findings miR-652-3p, which is upregulated in human and murine atherosclerotic plaques, suppresses expression of the endothelial repair gene Ccnd2, thereby enhancing atherosclerotic lesion formation. Post-denudation recovery of ECs was promoted in Mir652−/− mice due to enhanced EC proliferation attributable to de-repression of miR-652-3p's (but not miR-652-5p's) regulation of Ccnd2 expression. Under hyperlipidemic conditions at non-predilection sites, miR-652-3p produces anti-proliferative effects in ECs, such that Mir652−/− mice display reduced atherosclerotic progression. In contrast, neither miR-652-3p nor Ccnd2 displayed significant effects on the endothelium at predilection sites or under disturbed flow conditions. Administration of a miR-652-3p antagomir rescued the proliferation of ECs in vivo, thereby limiting atherosclerotic development. Interpretation miR-652-3p blockade may be a potential therapeutic strategy against atherosclerosis., Highlights • miR-652-3p is upregulated in human and murine atherosclerotic plaques. • miR-652 knockdown promotes endothelial repair in injured arteries. • miR-652-3p suppresses expression of the endothelial repair gene Ccnd2. • miR-652-3p antagomir rescues EC proliferation under hyperlipidemic stress.

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

Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible for the brain's innate immune response, the aim of this study was to understand the role of microglial HO-1 under inflammatory conditions in aged mice. For this purpose, aged wild type (WT) and LysMCreHmox1△△ (HMOX1M-KO) mice that lack HO-1 in microglial cells, were used. Aged WT mice showed higher basal expression levels of microglial HO-1 in the brain than adult mice. This increase was even higher when exposed to an inflammatory stimulus (LPS via i.p.) and was accompanied by alterations in different iron-related metabolism proteins, resulting in an increase of iron deposits, oxidative stress, ferroptosis and cognitive decline. Furthermore, microglia exhibited a primed phenotype and increased levels of inflammatory markers such as iNOS, p65, IL-1β, TNF-α, Caspase-1 and NLRP3. Interestingly, all these alterations were prevented in aged HMOX1M-KO and WT mice treated with the HO-1 inhibitor ZnPPIX. In order to determine the effects of microglial HO-1-dependent iron overload, aged WT mice were treated with the iron chelator deferoxamine (DFX). DFX caused major improvements in iron, inflammatory and behavioral alterations found in aged mice exposed to LPS. In conclusion, this study highlights how microglial HO-1 overexpression contributes to neurotoxic iron accumulation providing deleterious effects in aged mice exposed to an inflammatory insult., Graphical abstract Image 1, Highlights • Microglial HO-1 increases with aging and under an acute inflammatory stimulus. • LPS-dependent microglial HO-1 upregulation during aging leads to iron overload. • Microglial HO-1-dependent iron accumulation leads to ferroptosis. • HO-1-dependent iron alterations lead to neuroinflammation. • HO-1 inhibitors/iron chelators reduce iron accumulation and neuroinflammation.

Background & Aims Genome-wide association studies (GWAS) and transcriptome analyses have been performed to better understand the pathogenesis of ulcerative colitis (UC). However, current studies mainly focus on European ancestry, highlighting a great need to identify the key genes, pathways and cell types in colonic mucosal cells of adult UC patients from other ancestries. Here we aimed to identify key genes and cell types in colonic mucosal of UC. Methods We performed Single-cell RNA sequencing (scRNA-seq) analysis of 12 colon biopsies of UC patients and healthy controls from Chinese Han ancestry. Results Two novel plasma subsets were identified. Five epithelial/stromal and three immune cell subsets show significant difference in abundance between inflamed and non-inflamed samples. In general, UC risk genes show consistent expression alteration in both Immune cells of inflamed and non-inflamed tissues. As one of the exceptions, IgA defection, marking the signal of immune dysfunction, is specific to the inflamed area. Moreover, Th17 derived activation was observed in both epithelial cell lineage and immune cell lineage of UC patients as compared to controls , suggesting a systemic change of immune activities driven by Th17. The UC risk genes show enrichment in progenitors, glial cells and immune cells, and drug-target genes are differentially expressed in antigen presenting cells. Conclusions Our work identifies novel population-specific plasma cell molecular signatures of UC. The transcriptional signature of UC is shared in immune cells from both inflamed and non-inflamed tissues, whereas the transcriptional response to disease is a local effect only in inflamed epithelial/stromal cells., Graphical abstract

Inflammation, a common feature of many diseases, is an essential immune response that enables survival and maintains tissue homeostasis. However, in some conditions, the inflammatory process becomes detrimental, contributing to the pathogenesis of a disease. Targeting inflammation by using nanomedicines (i.e. nanoparticles loaded with a therapeutic active principle), either through the recognition of molecules overexpressed onto the surface of activated macrophages or endothelial cells, or through enhanced vasculature permeability, or even through biomimicry, offers a promising solution for the treatment of inflammatory diseases. After providing a brief insight on the pathophysiology of inflammation and current therapeutic strategies, the review will discuss, at a pre-clinical stage, the main innovative nanomedicine approaches that have been proposed in the past five years for the resolution of inflammatory disorders, finally focusing on those currently in clinical trials., Graphical Abstract Unlabelled Image, Highlights • Inflammation is an essential immune response that enables survival and maintains tissue homeostasis. • Sometimes the inflammatory process becomes detrimental, contributing to a disease development. • Conventional pharmacological treatments may result in off-target side effects and toxicity. • Innovative nanomedicines show significant therapeutic improvements in pre-clinical models. • Clinical translation remains limited due to the complexity of both inflammatory diseases and nanomedicines development.

2-methoxyethanol (2-ME) is an organic solvent widely used in the manufacture of brake fluids, paints, resins, varnish, nail polish, acetate cellulose, wood coloring, and as a plasticizer in plastics manufacturing. We therefore, investigated its effect on the liver, in a time-course study in male Wistar rats. Animals were orally administered 50 mg/kg body weight of 2-ME for a period of 7, 14, and 21 days. Following 7 days of administration of 2-ME, there was a significant increase in the level of Bax, c-Myc, K-Ras, TNF-α, IL-1β, IL-6, MDA and GPx activity, while the levels of Bcl-2, NO and GSH were significantly reduced compared with control. At the end of 14 days exposure, Bcl-2, and GSH levels, as well as GST activity, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, TNF-α, IL-1β, IL-6, MDA and NO were significantly increased compared with control. After 21 days of 2-ME administration, Bcl-2, IL-10, and GSH levels, as well as SOD and GST activities, were significantly decreased, while levels of Bax, c-Myc, K-Ras, caspase-3, p53, TNF-α, IL-1β, IL-6, MDA and NO were significantly increased compared with control. Lastly, liver histopathology confirmed and corroborated the biochemical findings reported above. We therefore, advised that exposures to 2-ME should be strictly avoided as it could trigger hepatic damage through the disorganization of the antioxidant system, up-regulation of inflammatory, apoptotic, and oncogenic markers in rats., Highlights • 2-ME significantly increased the liver levels of MDA and NO. • 2-ME administration resulted in the disorganization of the redox systems. • 2-ME significantly increased the liver levels of TNF-α, IL-1β, IL-6. • 2-ME significantly increased the liver levels of Bax and caspase-3 and significantly decreased Bcl-2 level. • 2-ME significantly increased the liver levels of c-Myc and K-Ras.

Purpose Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. Hypothesis A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID- 19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin and the antimalarial drugs chloroquine and hydroxychloroquine has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin or hydroxychloroquine alone, and/or nutraceuticals that have been published to support immune function including Vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and “cytokine storm syndrome” with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to “acute respiratory distress syndrome” (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NFKappa B and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID 19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. Conclusion and Implications a three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with hydroxychloroquine and/or ivermetin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NFKappaB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/ or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.

The human gastrointestinal tract (GI) harbors a diverse population of microbial life that continually shapes host pathophysiological responses. Despite readily available abundant metagenomic data, the functional dynamics of gut microbiota remain to be explored in various health and disease conditions. Microbiota generate a variety of metabolites from dietary products that influence host health and pathophysiological functions. Since gut microbial metabolites are produced in close proximity to gut epithelium, presumably they have significant impact on gut barrier function and immune responses. The goal of this review is to discuss recent advances on gut microbial metabolites in the regulation of intestinal barrier function. While the mechanisms of action of these metabolites are only beginning to emerge, they mainly point to a small group of shared pathways that control gut barrier functions. Amidst expanding technology and broadening knowledge, exploitation of beneficial microbiota and their metabolites to restore pathophysiological balance will likely prove to be an extremely useful remedial tool.

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.

Primary and secondary hypertension is associated with kidney redox imbalance resulting in enhanced reactive oxygen species (ROS) and enzymes dependent phospholipid metabolism. The fatty acid amide hydrolase inhibitor, URB597, modulates the levels of endocannabinoids, particularly of anandamide, which is responsible for controlling blood pressure and regulating redox balance. Therefore, this study aimed to compare the effects of chronic URB597 administration to spontaneously hypertensive rats (SHR) and rats with secondary hypertension (DOCA-salt rats) on the kidney metabolism associated with the redox and endocannabinoid systems. It was shown fatty acid amide hydrolase (FAAH) inhibitor decreased the activity of ROS-generated enzymes what resulted in a reduction of ROS level. Moreover varied changes in antioxidant parameters were observed with tendency to improve antioxidant defense in SHR kidney. Moreover, URB597 administration to hypertensive rats decreased pro-inflammatory response, particularly in the kidneys of DOCA-salt hypertensive rats. URB597 had tendency to enhance ROS-dependent phospholipid oxidation, estimated by changes in neuroprostanes in the kidney of SHR and reactive aldehydes (4-hydroxynonenal and malondialdehyde) in DOCA-salt rats, in particular. The administration of FAAH inhibitor resulted in increased level of endocannabinoids in kidney of both groups of hypertensive rats led to enhanced expression of the cannabinoid receptors type 1 and 2 in SHR as well as vanilloid receptor 1 receptors in DOCA-salt rats. URB597 given to normotensive rats also affected kidney oxidative metabolism, resulting in enhanced level of neuroprostanes in Wistar Kyoto rats and reactive aldehydes in Wistar rats. Moreover, the level of endocannabinoids and cannabinoid receptors were significantly higher in both control groups of rats after URB597 administration. In conclusion, because URB597 disturbed the kidney redox system and phospholipid ROS-dependent and enzymatic-dependent metabolism, the administration of this inhibitor may enhance kidney disorders depending on model of hypertension, but may also cause kidney disturbances in control rats. Therefore, further studies are warranted., Graphical abstract fx1, Highlights • URB597 has tendency to decrease kidney oxidative conditions. • URB597 differentiates Nrf2 pathway response in kidney of SHR and DOCA-salt rats. • URB597 enhances level of phospholipid peroxidation products and endocannabinoids. • URB597 reduces pro-inflammatory response particularly in kidney of DOCA-salt rats.

Background Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. Methodology PWCF homozygous for the ΔF508 mutation or heterozygous for the G551D mutation were recruited (n = 48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and μ-calpain assays. Findings Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating μ-calpain. In vivo and in vitro, increased μ-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. Interpretation Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion., Highlights • This study explored neutrophil adhesion in cystic fibrosis. • Altered membrane cholesterol lead to increased adhesion. • Circulating inflammatory mediators caused increased calpain activity and reduced membrane cholesterol content. In patients with cystic fibrosis (CF), chronic inflammation in the circulation, in part originating from the pulmonary compartment, leads to decreased membrane cholesterol in circulating neutrophils, resulting in increased cell adhesion. The mechanism of action involves proteolytic down-regulation of the cholesterol trafficking protein caveolin-1. The overall effect of lung transplant therapy, or CFTR potentiator treatment, was to significantly diminish the circulating inflammatory burden thereby permitting caveolin-1 expression, with concomitant decreased CF cell adhesion and significant clinical improvement.

Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit – the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals., Graphical abstract fx1, Highlights • Adipose tissue dysfunction is a major cause of metabolic diseases. • Adipose tissue function is determined by three hallmarks: adipogenesis, metabolism and signaling. • Small non-coding RNAs (particularly microRNAs) are causally linked to these hallmarks in adipose tissue. • Changes in microRNA expression in adipose tissue occur in physiological conditions and in disease. • Adipose tissue microRNAs control whole body metabolism and organismal homeostasis.

Wilms' tumors (WT), which accountfor 6% of all childhood cancers, arise from dysregulated differentiation of nephrogenic progenitor cells from embryonic kidneys. Though there is an improvement in the prognosis of WT, still 10% of patients with WT die due to recurrence. Thus more effective treatment approaches are necessary. We previously characterized the inflammatory microenvironment in human WT and observed the robust expression of COX-2. The aim of this study was to extend our studies to analyze the role of COX-2 pathway components in WT progression using a mouse model of WT. Herein, COX-2 pathway components such as COX-2, HIF1-α, p-ERK1/2, and p-STAT3 were upregulated in mouse and human tumor tissues. In our RPPA analysis, COX-2 was up-regulated in M15 cells after Wt1 gene was knocked down. Flow cytometry analysis showed the increased infiltration of immune suppressive inflammatory cells such as pDC's and Treg cells in tumors. The chemotactic chemokines responsible for the infiltration of these cells were also induced in CCR5 and CXCR4 dependent manner respectively. The immunosuppressive cytokines IL-10, TGF-β, and TNF-α were also up-regulated. Furthermore, more pronounced Th2 and Treg induced cytokine response was observed than Th1 response in tumors. Basing on all these evidences it is speculated that COX-2 pathway may be a beneficial target for the treatment of WT. It may be most effective as an adjuvant therapy together with other inhibitors. Thus, our current study provides a good rationale for initiating animal studies to confirm the efficacy of COX-2 inhibitors in decreasing tumor cell growth in vivo.

Highlights • Astrocytes and microglia key fulfil homeostatic and immune functions in the CNS. • Dysfunction of these cell types is implicated in neurodegenerative diseases. • Understanding cellular autonomy and early pathogenic changes is a key goal. • New human iPSC models will inform on disease mechanisms and therapy development., Both astrocytes and microglia fulfil homeostatic and immune functions in the healthy CNS. Dysfunction of these cell types have been implicated in the pathomechanisms of several neurodegenerative diseases. Understanding the cellular autonomy and early pathological changes in these cell types may inform drug screening and therapy development. While animal models and post-mortem tissue have been invaluable in understanding disease processes, the advent of human in vitro models provides a unique insight into disease biology as a manipulable model system obtained directly from patients. Here, we discuss the different human in vitro models of astrocytes and microglia and outline the phenotypes that have been recapitulated in these systems.

Highlights • COVID-19 is typified by SARS-CoV-2 replication and excessive inflammatory response. • PTC299 is small orally available DHODH inhibitor that blocks pyrimidine synthesis. • PTC299 is potent inhibitor of the replication of SARS-CoV-2 and other RNA viruses. • PTC299 also reduces production of cytokines associated with COVID-19 inflammation. • PTC299 may be a promising therapeutic for COVID-19., The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.

Graphical abstract, Highlights • This paper summarized 159 natural compounds against ALI. • The paper summed up the protective effects of all products on ALI in vivo and vitro. • This paper clarified the underlying mechanism of natural compounds against ALI., Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. With increasing in-depth studies of ALI/ARDS, significant breakthroughs have been made, however, there are still no effective pharmacological therapies for treatment of ALI/ARDS. Especially, the novel coronavirus pneumonia (COVID-19) is ravaging the globe, and causes severe respiratory distress syndrome. Therefore, developing new drugs for therapy of ALI/ARDS is in great demand, which might also be helpful for treatment of COVID-19. Natural compounds have always inspired drug development, and numerous natural products have shown potential therapeutic effects on ALI/ARDS. Therefore, this review focuses on the potential therapeutic effects of natural compounds on ALI and the underlying mechanisms. Overall, the review discusses 159 compounds and summarizes more than 400 references to present the protective effects of natural compounds against ALI and the underlying mechanism.

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 Myeloperoxidase (MPO) anti-neutrophil cytoplasm autoantibody (ANCA)-associated vasculitis commonly causes life-threatening pulmonary alveolar hemorrhage or fibrosis. Only a limited number of candidate gene variants have been explored, but hitherto, are not widely confirmed. In the present study, we investigated the importance of energy homeostasis associated gene (Enho) mutations and adropin deficiency in the development of MPO-ANCA associated lung injury. Methods We analyzed the peripheral blood mononuclear cells from 152 unrelated patients and 220 population-matched healthy individuals for genetic variations in Enho. Functional studies with adropin knockout (AdrKO) on C57BL/6J mice were also performed. Findings Sequencing revealed six patients with p.Ser43Thr and that five patients shared Cys56Trp amino acid substitution in Enho. Serum concentration of adropin was significantly lower in patients than that of the healthy subjects (P, Graphical Abstract Adropin-deficiency causes ANCA vasculitis. Adropin-deficiency plays a critical role in activating endothelial cells during neutrophil recruitment and neutrophil-endothelium cell interactions under IL-1 and TNF-α-induced vascular inflammation. Neutrophil extracellular trap (NET) formation, also termed as NETosis, has been linked to develop autoantibodies against endothelial cell, such as VCAM-1. Then, VCAM-1 mediates the adhesion of lymphocytes and monocytes to vascular endothelium.Image 1, Highlights • Enho mutations result in adropin deficiency. • Adropin deficiency cause MPO-ANCA-related pulmonary hemorrhage or lung fibrosis. • Adropin knockout (AdrKO) mice exhibit reduced eNOS (Ser1177) and Akt1 (Ser473) phosphorylation and loss of Treg cells in lung tissue. • PR3-AAV and MPO-AAV may be the two independent disease subtypes and have their different susceptibility genes.

Highlights • Mental disorders in COVID-19 patients and survivors revealed that the COVID-19 had immune dysfunction. • Analysing the symptoms of COVID-19, TCM syndrome of the depression, anxiety and PTSD was interpreted as internal heat and Yin deficiency. • Depression, anxiety and PTSD pertains the category of “lily disease”, “hysteria” and “deficient dysphoria” in TCM. • Lily Bulb and Rehmannia Decoction, Lily Bulb and Anemarrhenae Decoction and Ganmai Dazao Decoction were used to treat the depression., Purpose The aim of this study is to explore the possible benefits of traditional Chinese medicine on the pathogenesis of psychological and mental health of COVID-19 survivors. Methods A literature search was conducted to confirm the effects of COVID-19 on psychological and mental health of survivors. In addition to this, on the basis of signs and symptoms, TCM were used on treat mental disorder as per suggested clinical and animal experimental data plus relevant records in classical Chinese medicine books written by Zhang Zhongiing during Han Dynasty. A series of treatment plans were prescribed for COVID-19 survivors with psychological and mental disorders. Results According to previous extensive studies focusing on effects on mental health of survivors, high incidence was observed in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) survivors. During investigations of mental health of COVID-19 patients and survivors, it is observed that they also had symptoms of mental disorders and immune dysfunction. Furthermore, it was also proposed that depression, anxiety and post-traumatic stress disorder (PTSD) were most common mental disorders requiring special attention after the recovery from COVID-19. The symptoms of COVID-19 were analyzed, and the TCM syndrome of the depression, anxiety and PTSD after recovered from COVID19 was interpreted as internal heat and Yin deficiency. These three mental disorders pertains the category of “Lily disease”, “hysteria” and “deficient dysphoria” in TCM. Conclusion Lily Bulb, Rhizoma Anemarrhena Decoction and Ganmai Dazao Decoction were used to treat depression. Suanzaoren Decoction, Huanglian Ejiao Decoction and Zhizi Chi Decoction were suggested for anxiety. Moreover, Lily Bulb, Rehmannia Decoction and Guilu Erxian Decoction were the formula for PTSD.

Background & Aims Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. Methods We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf–/–, Lta–/–, and Ltb–/– mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. Results Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp–/– mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte–derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. Conclusions Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

COVID-19 initially an epidemic caused by SARS-CoV-2 has turned out to be a life- threatening global pandemic with increased morbidity and mortality. The presence of cytokine storm has been linked with the pathogenesis of severe lung injury as evinced in COVID-19. Aquaporins (AQPs) are molecular water channels, facilitating water transport across the cell membrane in response to osmotic gradients. Impairment in alveolar fluid clearance due to altered functional expression of respiratory AQPs highlight their pathophysiological significance in pulmonary edema associated respiratory illness. Therefore, we hypothesize that targeted modulation of AQPs in lungs in the intervening period of time, could diminish the dreadful effects of inflammation- induced comorbidity in COVID-19.

Highlights • Adipose tissue secretes bioactive peptides/proteins, known as adipocytokines. • Adipocytokines are involved in the pathogenesis of diseases in nearly all body systems. • Adipocytokines had an impact on metabolic, oncologic, and rheumatologic disorders., Introduction Adipose tissue secretes various bioactive peptides/proteins, immune molecules and inflammatory mediators which are known as adipokines or adipocytokines. Adipokines play important roles in the maintenance of energy homeostasis, appetite, glucose and lipid metabolism, insulin sensitivity, angiogenesis, immunity and inflammation. Enormous number of studies from all over the world proved that adipocytokines are involved in the pathogenesis of diseases affecting nearly all body systems, which raises the question whether we can always blame adipocytokines as the triggering factor of every disease that may hit the body. Objective Our review targeted the role played by adipocytokines in the pathogenesis of different diseases affecting different body systems including diabetes mellitus, kidney diseases, gynecological diseases, rheumatologic disorders, cancers, Alzheimer’s, depression, muscle disorders, liver diseases, cardiovascular and lung diseases. Methodology We cited more than 33 recent literature reviews that discussed the role played by adipocytokines in the pathogenesis of different diseases affecting different body systems. Conclusion More evidence is being discovered to date about the role played by adipocytokines in more diseases and extra research is needed to explore hidden roles played by adipokine imbalance on disease pathogenesis.

Urticaria is defined as the sudden appearance of erythematous, itchy wheals of variable size, with or without angioedema (AE) (swelling of the deeper layers of the skin). Its classification depends on time course of symptoms and the presence of eliciting factors. When it lasts less than 6 weeks it is classified as acute urticaria (AU), and if the symptoms persist for more than 6 weeks, it is classified as chronic urticaria (CU). Current International Guidelines also classify CU as chronic spontaneous urticaria (CSU) and inducible urticarial, according to the absence or presence of environmental triggering factors. CSU is defined as urticaria and/or angioedema in which there is no evidence of a specific eliciting factor. CSU is associated with autoimmunity in 30–45% of the cases, sharing some immunological mechanisms with other autoimmune diseases, and is associated with autoimmune thyroid disease (ATD) in about 4.3%–57.4% patients. Several studies suggest that adequate therapy with anti-thyroid drugs or levothyroxine in early stages of ATD and CSU, may help to remit the latter; but there is still a lack of double-blind, placebo-controlled studies that support this hypothesis in patients without abnormal thyroid hormone levels. The objective of this review is to describe the pathophysiology of chronic spontaneous urticaria and its association with autoimmune thyroid disease. Keywords: Autoimmunity, Chronic urticaria, Histamine, Levothyroxine, Urticaria, Thyroid disease

Celiac Disease (CeD) is defined as a chronic small intestinal immune-mediated enteropathy that is precipitated by exposure to dietary gluten in genetically predisposed individuals. CeD is one of the most common autoimmune disorders affecting around 1% of the population worldwide. Currently, the only acceptable treatment for CeD is strict, lifelong adherence to a gluten-free diet (GFD) which can often present a challenging task. A GFD alone is not sufficient to control symptoms and prevent mucosal damage that can result from unintentional gluten exposure. Moreover, long-term complications can occur in many patients. Consequently, there is an unmet need for non-dietary therapies for the management of CeD. Such therapies could serve as an adjunct to the GFD but eventually may replace it. This review will focus on and discuss non-dietary therapies currently in clinical development for the management of CeD. METHODOLOGY: We searched clinicaltrials.gov and PubMed to extract articles about celiac disease. We used keywords including, but not limited to, "celiac disease," "non-dietary," "therapeutics," "pathophysiology," "Endopeptidases," "tight junction modulators," "vaccine," and "Nexvax2". We focused mainly on articles that conducted pathophysiologic and therapeutic research in human trials.

Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD., Graphical abstract fx1, Highlights • A novel mouse model with conditional ablation of Gpx4 in forebrain neurons was generated. • Conditional ablation of Gpx4 in forebrain neurons resulted in progressive cognition impairment. • The cognitively impaired mice with Gpx4 ablation in forebrain neurons showed neurodegeneration in hippocampus. • Neurodegeneration in mice with Gpx4 ablation in forebrain neurons exhibited features of ferroptosis.

Summary Background & aims Mortality resulting from influenza (flu) virus infections occurs primarily in the elderly through declining immunity. Studies in mice have suggested beneficial effects of selenium (Se) supplementation on immunity to flu but similar evidence is lacking in humans. A dietary intervention study was therefore designed to test the effects of Se-supplementation on a variety of parameters of anti-flu immunity in healthy subjects aged 50–64 years. Methods A 12-week randomized, double-blinded, placebo-controlled clinical trial (ClinicalTrials.govNCT00279812) was undertaken in six groups of individuals with plasma Se levels

Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα), a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− as well as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM) mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context Alternative (M2-type) macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression., Highlights • IL-4Rα is considered a central switch for alternative macrophage polarization. • IL-4Rα on macrophages is shown to differentially regulate liver fibrosis progression vs reversal. • Therapeutic IL-4Rα antisense oligonucleotides replicate these findings. • MMP-12 induced via macrophage IL-4Rα is a key promoter of fibrosis reversal.

Hydrogen sulfide (H2S) has emerged as a critical mediator of multiple physiological processes in mammalian systems. The pathways involved in the production, consumption, and mechanism of action of H2S appear to be sensitive to alterations in the cellular redox state and O2 tension. Indeed, the catabolism of H2S through a putative oxidation pathway, the sulfide quinone oxido-reductase system, is highly dependent on O2 tension. Dysregulation of H2S homeostasis has also been implicated in numerous pathological conditions and diseases. In this review, the chemistry and the main physiological actions of H2S are presented. Some examples highlighting the cytoprotective actions of H2S within the context of cardiovascular disease are also reported. Elucidation of the redox biology of H2S will enable the development of new pharmacological agents based on this intriguing new redox cellular signal., Graphical abstract Highlights ► Hydrogen sulfide (H2S) is an endogenously produced cell signaling molecule, which plays a key role in multiple physiological processes including vasodilation, angiogenesis, and inflammation. ► The production and consumption of H2S in vivo is redox sensitive. ► Dysregulation of H2S production and consumption contributes to disease pathogenesis. ► Cytoprotective properties of H2S may be due, in part, to restoration of cellular redox status and upregulation of antioxidant defenses.

Recently we described a co-culture model of periodontal ligament (PDL) fibroblasts and SCC-25 lingual squamous carcinoma cells, which resulted in conversion of normal fibroblasts into carcinoma-associated fibroblasts (CAFs), and in epithelial–mesenchymal transition (EMT) of SCC-25 cells. We have found a constitutive high interleukin-1β (IL1-β) expression in SCC-25 cells in normal and in co-cultured conditions. In our hypothesis a constitutive IL1-β expression in SCC-25 regulates gene expression in fibroblasts during co-culture. Co-cultures were performed between PDL fibroblasts and SCC-25 cells with and without dexamethasone (DEX) treatment; IL1-β processing was investigated in SCC-25 cells, tumor cells and PDL fibroblasts were treated with IL1-β. IL1-β signaling was investigated by western blot and immunocytochemistry. IL1-β-regulated genes were analyzed by real-time qPCR. SCC-25 cells produced 16 kD active IL1-β, its receptor was upregulated in PDL fibroblasts during co-culture, which induced phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear translocalization of NFκBα. Several genes, including interferon regulatory factor 1 (IRF1) interleukin-6 (IL-6) and prostaglandin-endoperoxide synthase 2 (COX-2) were induced in CAFs during co-culture. The most enhanced induction was found for IL-6 and COX-2. Treatment of PDL fibroblasts with IL1-β reproduced a time- and dose-dependent upregulation of IL1-receptor, IL-6 and COX-2. A further proof was achieved by DEX inhibition for IL1-β-stimulated IL-6 and COX-2 gene expression. Constitutive expression of IL1-β in the tumor cells leads to IL1-β-stimulated gene expression changes in tumor-associated fibroblasts, which are involved in tumor progression., Graphical abstract SCC-25 cells produce active, processed IL1-β. PDL fibroblasts possess receptor for IL1-β, and its expression is increased 4.56-times in the presence of SCC-25 tumor cells. IL1-β receptor expression in fibroblasts, especially in CAFs represents a major option in coordination of fibroblast and tumor behavior. A key event in IL1-β signaling, the phosphorylation of IRAK1, occurred in co-cultured fibroblasts, which has lead to nuclear translocation of NFκBα, and finally to induction of several genes, including BDNF, IRF1, IL-6 and COX-2. The most enhanced induction was found for IL-6 and COX-2.

Summary Lipolysis is the biochemical pathway responsible for the catabolism of triacylglycerol (TAG) stored in cellular lipid droplets. The hydrolytic cleavage of TAG generates non-esterified fatty acids, which are subsequently used as energy substrates, essential precursors for lipid and membrane synthesis, or mediators in cell signaling processes. Consistent with its central importance in lipid and energy homeostasis, lipolysis occurs in essentially all tissues and cell types, it is most abundant, however, in white and brown adipose tissue. Over the last 5 years, important enzymes and regulatory protein factors involved in lipolysis have been identified. These include an essential TAG hydrolase named adipose triglyceride lipase (ATGL) [annotated as patatin-like phospholipase domain-containing protein A2], the ATGL activator comparative gene identification-58 [annotated as α/β hydrolase containing protein 5], and the ATGL inhibitor G0/G1 switch gene 2. Together with the established hormone-sensitive lipase [annotated as lipase E] and monoglyceride lipase, these proteins constitute the basic “lipolytic machinery”. Additionally, a large number of hormonal signaling pathways and lipid droplet-associated protein factors regulate substrate access and the activity of the “lipolysome”. This review summarizes the current knowledge concerning the enzymes and regulatory processes governing lipolysis of fat stores in adipose and non-adipose tissues. Special emphasis will be given to ATGL, its regulation, and physiological function.