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Graphical abstract, Several plants have traditionally been used since antiquity to treat various gastroenteritis and respiratory symptoms similar to COVID-19 outcomes. The common symptoms of COVID-19 include fever or chills, cold, cough, flu, headache, diarrhoea, tiredness/fatigue, sore throat, loss of taste or smell, asthma, shortness of breath, or difficulty breathing, etc. This study aims to find out the plants and plant-derived products which are being used by the COVID-19 infected patients in Bangladesh and how those plants are being used for the management of COVID-19 symptoms. In this study, online and partially in-person survey interviews were carried out among Bangladeshi respondents. We selected Bangladeshi COVID-19 patients who were detected Coronavirus positive (+) by RT-PCR nucleic acid test and later recovered. Furthermore, identified plant species from the surveys were thoroughly investigated for safety and efficacy based on the previous ethnomedicinal usage reports. Based on the published data, they were also reviewed for their significant potentialities as antiviral, anti-inflammatory, and immunomodulatory agents. We explored comprehensive information about a total of 26 plant species, belonging to 23 genera and 17 different botanical families, used in COVID-19 treatment as home remedies by the respondents. Most of the plants and plant-derived products were collected directly from the local marketplace. According to our survey results, greatly top 5 cited plant species measured as per the highest RFC value are Camellia sinensis (1.0) > Allium sativum (0.984) > Azadirachta indica (0.966) > Zingiber officinale (0.966) > Syzygium aromaticum (0.943). Previously published ethnomedicinal usage reports, antiviral, anti-inflammatory, and immunomodulatory activity of the concerned plant species also support our results. Thus, the survey and review analysis simultaneously reveals that these reported plants and plant-derived products might be promising candidates for the treatment of COVID-19. Moreover, this study clarifies the reported plants for their safety during COVID-19 management and thereby supporting them to include in any future pre-clinical and clinical investigation for developing herbal COVID-19 therapeutics.

Background: The decreased renal function is known to be associated with biological aging, of which the main pathological features are chronic inflammation and renal interstitial fibrosis. In previous studies, we reported that total saponins from Panax japonicus (SPJs) can availably protect acute myocardial ischemia. We proposed that SPJs might have similar protective effects for aging-associated renal interstitial fibrosis. Thus, in the present study, we evaluated the overall effect of SPJs on renal fibrosis. Methods: Sprague-Dawley (SD) aging rats were given SPJs by gavage beginning from 18 months old, at 10 mg/kg/d and 60 mg/kg/d, up to 24 months old. After the experiment, changes in morphology, function and fibrosis of their kidneys were detected. The levels of serum uric acid (UA), β2-microglobulin (β2-MG) and cystatin C (Cys C) were assayed with ELISA kits. The levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), inflammatory factors and changes of oxidative stress parameters were examined. Results: After SPJs treatment, SD rats showed significantly histopathological changes in kidneys accompanied by decreased renal fibrosis and increased renal function; As compared with those in 3-month group, the levels of serum UA, Cys C and β2-MG in 24-month group were significantly increased (p

To discover immune factors that can predict the progression of COVID-19, we evaluated circulating immune cells and plasma cytokines in COVID-19 patients. We found that T cells, including CD4+ T cells and CD8+ T cells, were significantly decreased in severe COVID-19 symptoms but not in mild symptoms, in comparison with healthy people. T cells remained at a low level after recovery from severe COVID-19. CD4+CD25+CD127low Treg-enriched cells were significantly increased in either mild or severe COVID-19 patients, regardless of recovery or not. Moreover, in either mild or severe COVID-19 patients, Treg-enriched cells up-regulated CD25 and down-regulated CD127. After recovery, CD25 was partially down-regulated but still higher than the normal level, while CD127 returned to the normal level in mild patients but not severe patients. B cells were decreased in mild patients and further decreased in severe patients, and remained low after recovery. NK cells were decreased only in severe COVID-19, with a tendency to return to the normal level after recovery. Plasma IL-6 and IL-10 were both elevated in severe patients but not in mild patients. After recovery, IL-6 remained higher than its normal level, while IL-10 returned to the normal level. Binary logistic regression analysis indicated that CD4+ T cells, B cells, IL-6, and IL-10 were significantly associated with COVID-19 severity. Therefore, these parameters are indicators of COVID-19 severity. Dynamic monitoring of these parameters would benefit therapy planning and prognosis evaluation.

Liver fibrosis induces intrahepatic microcirculation disorder and hypoxic stress. Hypoxic stress has the potential for an increase in the possibility of more liver fibrosis and carcinogenesis. Liver biopsy is a standard method that evaluates of intrahepatic hypoxia, however, is invasive and has a risk of bleeding as a complication. Here, we investigated the hypoxia reactive gene expressions in peripheral blood mononuclear cells (PBMC) from chronic liver disease patients to evaluate intrahepatic hypoxia in a non-invasive manner. The subjects enrolled for this study were composed of 20 healthy volunteers (HV) and 48 patients with chronic liver disease (CLD). CLD patients contained 24 patients with chronic hepatitis（CH）and 24 patients with liver cirrhosis (LC). PBMC were isolated from heparinized peripheral blood samples. We measured the transcriptional expression of hypoxia reactive genes and inflammatory cytokines by quantitative RT-PCR. mRNA expression of adrenomedullin (AM), vascular endothelial growth factor A (VEGFA) superoxide dismutase (SOD), glutathione peroxidase (GPx) (p, Highlights • The hypoxia reactive genes in PBMC were elevated in patients with chronic liver disease. •Angiogenic genes were upregulated and correlated with liver fibrosis in patients with chronic liver disease. •Adrenomedullin mRNA expression in PBMC was correlated with liver function. •mRNA expression of adrenomedullin in PBMC could be the biomarker of intrahepatic hypoxia.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions., Graphical abstract This review discusses common pitfalls in studies of acetaminophen hepatotoxicity.Image 1

The COVID-19 global epidemic caused by coronavirus has affected the health and other aspects of life for more than one year. Despite the current pharmacotherapies, there is still no specific treatment, and studies are in progress to find a proper therapy with high efficacy and low side effects. In this way, Traditional Persian Medicine (TPM), due to its holistic view, can provide recommendations for the prevention and treatment of new diseases such as COVID-19. The muco-obstruction of the airway, which occurs in SARS-CoV-2, has similar features in TPM textbooks that can lead us to new treatment approaches. Based on TPM and pharmacological studies, Cinnamomum verum (Darchini)'s potential effective functions can contribute to SARS-CoV-2 infection treatment and has been known to be effective in corona disease in Public beliefs. From the viewpoint of TPM theories, Cinnamon can be effective in SARS-CoV-2 improvement and treatment through its anti-obstructive, diuretic, tonic and antidote effects. In addition, there is pharmacological evidence on anti-viral, anti-inflammatory, antioxidant, organ-o-protective and anti-depression effects of Cinnamon that are in line with the therapeutic functions mentioned in TPM.Overall, Cinnamon and its ingredients can be recommended for SARS-CoV2 management due to multi-targeting therapies. This review provides basic information for future studies on this drug's effectiveness in preventing and treating COVID-19 and similar diseases., Graphical Abstract ga1

Summary Background & Aims Cholangiocyte senescence is important in the pathogenesis of primary sclerosing cholangitis (PSC). We found that CDKN2A (p16), a cyclin-dependent kinase inhibitor and mediator of senescence, was increased in cholangiocytes of patients with PSC and from a PSC mouse model (multidrug resistance 2; Mdr2-/-). Given that recent data suggest that a reduction of senescent cells is beneficial in different diseases, we hypothesised that inhibition of cholangiocyte senescence would ameliorate disease in Mdr2-/- mice. Methods We used 2 novel genetic murine models to reduce cholangiocyte senescence: (i) p16Ink4a apoptosis through targeted activation of caspase (INK-ATTAC)xMdr2-/-, in which the dimerizing molecule AP20187 promotes selective apoptotic removal of p16-expressing cells; and (ii) mice deficient in both p16 and Mdr2. Mdr2-/- mice were also treated with fisetin, a flavonoid molecule that selectively kills senescent cells. p16, p21, and inflammatory markers (tumour necrosis factor [TNF]-α, IL-1β, and monocyte chemoattractant protein-1 [MCP-1]) were measured by PCR, and hepatic fibrosis via a hydroxyproline assay and Sirius red staining. Results AP20187 treatment reduced p16 and p21 expression by ~35% and ~70% (p >0.05), respectively. Expression of inflammatory markers (TNF-α, IL-1β, and MCP-1) decreased (by 60%, 40%, and 60%, respectively), and fibrosis was reduced by ~60% (p >0.05). Similarly, p16-/-xMdr2-/- mice exhibited reduced p21 expression (70%), decreased expression of TNF-α, IL-1β (60%), and MCP-1 (65%) and reduced fibrosis (~50%) (p >0.05) compared with Mdr2-/- mice. Fisetin treatment reduced expression of p16 and p21 (80% and 90%, respectively), TNF-α (50%), IL-1β (50%), MCP-1 (70%), and fibrosis (60%) (p >0.05). Conclusions Our data support a pathophysiological role of cholangiocyte senescence in the progression of PSC, and that targeted removal of senescent cholangiocytes is a plausible therapeutic approach. Lay summary Primary sclerosing cholangitis is a fibroinflammatory, incurable biliary disease. We previously reported that biliary epithelial cell senescence (cell-cycle arrest and hypersecretion of profibrotic molecules) is an important phenotype in primary sclerosing cholangitis. Herein, we demonstrate that reducing the number of senescent cholangiocytes leads to a reduction in the expression of inflammatory, fibrotic, and senescence markers associated with the disease., Graphical abstract, Highlights • p16 and p21 are major mediators of cellular senescence and are highly expressed in cholangiocytes in a Mdr2-/- murine model of PSC. • The senescence-associated secretory phenotype markers are all increased in cholangiocytes of Mdr2-/- mice. • Genetic and pharmacological elimination of senescent cholangiocytes reduces peribiliary inflammation and fibrosis in Mdr2-/- mice. • Preclinical work suggests that fisetin, a naturally occurring and safe senolytic flavonoid, has the potential to be tested in patients with PSC.

Graphical abstract, Highlights • A year since the first report of the SARS-CoV-2, over 57 million cases have been diagnosed, and over 1.37 million have died worldwide. • An uncontrolled inflammatory response linked to a cytokine storm has been associated with pulmonary inflammation severity. • The genetic drifting of SARS-CoV-2 has been extremely slow, increasing the prospect of designing vaccines against all viral clades. • None of the therapeutic approaches currently used appears to be decisive for the treatment of COVID-19. • Three vaccines have demonstrated efficacy superior to 90%. Two of these vaccines, BNT162b2 and mRNA-1273, were based on an RNA platform, while Sputnik V was based on a non-replicating viral vector platform., Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) results in diverse outcomes. The symptoms appear to be more severe in males older than 65 and people with underlying health conditions; approximately one in five individuals could be at risk worldwide. The virus’s sequence was rapidly established days after the first cases were reported and identified an RNA virus from the Coronaviridae family closely related to a Betacoronavirus virus found in bats in China. SARS-CoV-2 is the seventh coronavirus known to infect humans, and with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), the only ones to cause severe diseases. Lessons from these two previous outbreaks guided the identification of critical therapeutic targets such as the spike viral proteins promoting the virus’s cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor expressed on the surface of multiple types of eukaryotic cells. Although several therapeutic agents are currently evaluated, none seems to provide a clear path for a cure. Also, various types of vaccines are developed in record time to address the urgency of efficient SARS-CoV-2 prevention. Currently, 58 vaccines are evaluated in clinical trials, including 11 in phase III, and 3 of them reported efficacy above 90%. The results so far from the clinical trials suggest the availability of multiple effective vaccines within months.

Background Korean Red Ginseng (KRG) is a traditional herb that has several beneficial properties including anti-aging, anti-inflammatory, and autophagy regulatory effects. However, the mechanisms of these effects are not well understood. In this report, the underlying mechanisms of anti-inflammatory and autophagy-promoting effects were investigated in aged mice treated with KRG-water extract (WE) over a long period. Methods The mechanisms of anti-inflammatory and autophagy-promoting activities of KRG-WE were evaluated in kidney, lung, liver, stomach, and colon of aged mice using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR), and western blot analysis. Results KRG-WE significantly suppressed the mRNA expression levels of inflammation-related genes such as interleukin (IL)-1β, IL-8, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 in kidney, lung, liver, stomach, and colon of the aged mice. Furthermore, KRG-WE downregulated the expression of transcription factors and their protein levels associated with inflammation in lung and kidney of aged mice. KRG-WE also increased the expression of autophagy-related genes and their protein levels in colon, liver, and stomach. Conclusion The results suggest that KRG can suppress inflammatory responses and recover autophagy activity in aged mice., Graphical abstract Image 1

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a potentially life-threatening disease, defined as Coronavirus Disease 19 (COVID-19). The most common signs and symptoms of this pathological condition include cough, fever, shortness of breath, and sudden onset of anosmia, ageusia, or dysgeusia. The course of COVID-19 is mild or moderate in more than 80% of cases, but it is severe or critical in about 14% and 5% of infected subjects respectively, with a significant risk of mortality. SARS-CoV-2 related infection is characterized by some pathogenetic events, resembling those detectable in other pathological conditions, such as sepsis and severe acute pancreatitis. All these syndromes are characterized by some similar features, including the coexistence of an exuberant inflammatory- as well as an anti-inflammatory-response with immune depression. Based on current knowledge concerning the onset and the development of acute pancreatitis and sepsis, we have considered these syndromes as a very interesting paradigm for improving our understanding of pathogenetic events detectable in patients with COVID-19. The aim of our review is: 1)to examine the pathogenetic mechanisms acting during the emergence of inflammatory and anti-inflammatory processes in human pathology; 2)to examine inflammatory and anti-inflammatory events in sepsis, acute pancreatitis, and SARS-CoV-2 infection and clinical manifestations detectable in patients suffering from these syndromes also according to the age and gender of these individuals; as well as to analyze the possible common and different features among these pathological conditions; 3)to obtain insights into our knowledge concerning COVID-19 pathogenesis. This approach may improve the management of patients suffering from this disease and it may suggest more effective diagnostic approaches and schedules of therapy, depending on the different phases and/or on the severity of SARS-CoV-2 infection.

Introduction In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy. Methods Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc). Results For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence. Conclusion Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations.

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 • COVID-19 is a common pathology that may affect diverse organs, including the central and peripheral nervous system. • Coronaviruses have important neurotropic potential and they cause neurological alterations that range from mild to severe. • CoV may affect any age group; the main symptoms are headache, dizziness, and altered consciousness. • The neurological symptoms caused by CoV (MERS-CoV, SARS-CoV and SARS-CoV2) are similar., Objective To describe the main neurological manifestations related to coronavirus infection in humans. Methodology A systematic review was conducted regarding clinical studies on cases that had neurological manifestations associated with COVID-19 and other coronaviruses. The search was carried out in the electronic databases PubMed, Scopus, Embase, and LILACS with the following keywords: “coronavirus” or “Sars-CoV-2” or “COVID-19” and “neurologic manifestations” or “neurological symptoms” or “meningitis” or “encephalitis” or “encephalopathy,” following the Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Seven studies were included. Neurological alterations after CoV infection may vary from 17.3% to 36.4% and, in the pediatric age range, encephalitis may be as frequent as respiratory disorders, affecting 11% and 12% of patients, respectively. The Investigation included 409 patients diagnosed with CoV infection who presented neurological symptoms, with median age range varying from 3 to 62 years. The main neurological alterations were headache (69; 16.8%), dizziness (57, 13.9%), altered consciousness (46; 11.2%), vomiting (26; 6.3%), epileptic crises (7; 1.7%), neuralgia (5; 1.2%), and ataxia (3; 0.7%). The main presumed diagnoses were acute viral meningitis/encephalitis in 25 (6.1%) patients, hypoxic encephalopathy in 23 (5.6%) patients, acute cerebrovascular disease in 6 (1.4%) patients, 1 (0.2%) patient with possible acute disseminated encephalomyelitis, 1 (0.2%) patient with acute necrotizing hemorrhagic encephalopathy, and 2 (1.4%) patients with CoV related to Guillain-Barré syndrome. Conclusion Coronaviruses have important neurotropic potential and they cause neurological alterations that range from mild to severe. The main neurological manifestations found were headache, dizziness and altered consciousness.

The COVID-19-, SARS- and MERS-related coronaviruses share many genomic and structural similarities. However, the SARS-CoV-2 is less pathogenic than SARS-CoV and MERS-CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID-19-, SARS- and MERS. Monocytes and macrophages may be infected by SARS-CoV-2 through ACE2-dependent and ACE2-independent pathways. SARS-CoV-2 can effectively suppress the anti-viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs) act as antigen presenting cells (APCs), the infection of these cells by SARS-CoV-2 impairs the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS-CoV-2-infected monocytes and macrophages can produce large amounts of numerous types of pro-inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development of COVID-19-related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID-19 patients. Here, we describe the monocytes and macrophage responses during severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage-related inflammatory reactions in possible approaches for COVID-19 treatment., Graphical abstract Unlabelled Image, Highlights • A subset of monocytes and macrophages may be infected by SARS-CoV-2. • Coronavirus-infected monocyte can migrate to tissue and become infected macrophage. • Coronavirus-infected monocyte/macrophage produces high level of inflammatory factors. • Monocyte/macrophage-related cytokines promote organ inflammation and cytokine storm. • Local tissue inflammation and cytokine storm cause multi-organ failure in COVID-19.

Graphical abstract Molecular targets modulated by artemisinins in respiratory diseases., Artemisinins are sesquiterpene lactones with a peroxide moiety that are isolated from the herb Artemisia annua. It has been used for centuries for the treatment of fever and chills, and has been recently approved for the treatment of malaria due to its endoperoxidase properties. Progressively, research has found that artemisinins displayed multiple pharmacological actions against inflammation, viral infections, and cell and tumour proliferation, making them effective against diseases. Moreover, it has displayed a relatively safe toxicity profile. The use of artemisinins against different respiratory diseases has been investigated in lung cancer models and inflammatory-driven respiratory disorders. These studies revealed the ability of artemisinins in attenuating proliferation, inflammation, invasion, and metastasis, and in inducing apoptosis. Artemisinins can regulate the expression of pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), promote cell cycle arrest, drive reactive oxygen species (ROS) production and induce Bak or Bax-dependent or independent apoptosis. In this review, we aim to provide a comprehensive update of the current knowledge of the effects of artemisinins in relation to respiratory diseases to identify gaps that need to be filled in the course of repurposing artemisinins for the treatment of respiratory diseases. In addition, we postulate whether artemisinins can also be repurposed for the treatment of COVID-19 given its anti-viral and anti-inflammatory properties.

Highlights • Principal component analysis (PCA) can create scores from collinear markers. • This study shows a PCA-derived score can combine cytokines in AMI patients. • An IL-6-IL-8 score using PCA independently predicts poor outcomes in AMI., Introduction Many studies have shown that elevated biomarkers of inflammation following acute myocardial infarction (AMI) are associated with major adverse cardiovascular events (MACE). However, the optimal way of measuring the complex inflammatory response following AMI has not been determined. In this study we explore the use of principal component analysis (PCA) utilising multiple inflammatory cytokines to generate a combined cytokine score that may be predictive of MACE post-AMI. Methods Thirteen inflammatory cytokines were measured in plasma of 317 AMI patients, drawn 48–72 h following symptom onset. Patients were followed-up for one year to determine the incidence of MACE. PCA was used to generate a combined score using six cytokines that were detectable in the majority of patients (IL-1β, -6, -8, and -10; MCP-1; and RANTES), and using a subset of cytokines that were associated with MACE on univariate analysis. Multivariate models using baseline characteristics, elevated individual cytokines and PCA-derived scores determined independent predictors of MACE. Results IL-6 and IL-8 were significantly associated with MACE on univariate analysis and were combined using PCA into an IL-6-IL-8 score. The combined cytokine score and IL-6-IL-8 PCA-derived score were both significantly associated with MACE on univariate analysis. In multivariate models IL-6-IL-8 scores (OR = 2.77, p = 0.007) and IL-6 levels (OR = 2.18, p = 0.035) were found to be independent predictors of MACE. Conclusion An IL-6-IL-8 score derived from PCA was found to independently predict MACE at one year and was a stronger predictor than any individual cytokine, which suggests this may be an appropriate strategy to quantify inflammation post-AMI. Further investigation is required to determine the optimal set of cytokines to measure in this context.

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

Background Severe immunopathology may drive the deleterious manifestations that are observed in the advanced stages of coronavirus disease 2019 (COVID-19) but are poorly understood. Objective Our aim was to phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). Methods We consecutively included patients less than 72 hours after intubation following informed consent from their next of kin. Bronchoalveolar lavage fluid was evaluated by microscopy; bronchoalveolar lavage fluid and blood were assessed by 10-color flow cytometry and a multiplex cytokine panel. Results Four mechanically ventilated patients (aged 40-75 years) with moderate-to-severe COVID-19 ARDS were included. Immature neutrophils dominated in both blood and lungs, whereas CD4 and CD8 T-cell lymphopenia was observed in the 2 compartments. However, regulatory T cells and TH17 cells were found in higher fractions in the lung. Lung CD4 and CD8 T cells and macrophages expressed an even higher upregulation of activation markers than in blood. A wide range of cytokines were expressed at high levels both in the blood and in the lungs, most notably, IL-1RA, IL-6, IL-8, IP-10, and monocyte chemoattactant protein-1, consistent with hyperinflammation. Conclusion COVID-19 ARDS exhibits a distinct immunologic profile in the lungs, with a depleted and exhausted CD4 and CD8 T-cell population that resides within a heavily hyperinflammatory milieu., Graphical abstract

Graphical abstract, Highlights • According to WHO, COVID-19 pandemic belongs to very high-risk category. • Potentially lethal manifestations of COVID-19 are due to cytokine storm syndrome. • Cytokine storm in COVID-19 patients with co-morbidities is associated with elevated cytokine synergism. • Exacerbation of ‘cytokine storm’ in high risk patients could be responsible for the high mortality. • Antiviral state imparted by BCG vaccine confers early protection against SARS-CoV2. • Trained immunity of BCG vaccine involves the release of cytokine IL-1β, TNF-α and IL-6 from epigenetically modified monocytes., The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses like SARS-CoV and MERS-CoV, which are established to cause lower respiratory tract infection. The viral infection can be fatal as the disease advances to pneumonia followed by acute respiratory distress syndrome (ARDS). Increasingly higher cytokine concentration on account of over-stimulated immune response against the virus, or the ‘cytokine storm’, is the reason behind the manifestation of lethal clinical symptoms. In this article, we discuss the immune pathogenesis of cytokine storm and its relation with SARS-CoV2/COVID-19 risk factors. People with underlying risk factors are more susceptible to fatal complications of COVID-19 infection leading to poor clinical outcome. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 to a Cytokine Super Cyclone. We also overviewed antiviral immune response provided by BCG vaccine involving the IL-1β, IL-6 and TNF-α secretion via ‘trained monocytes’, which confers early protection against SARS-CoV2.

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 and Aims GAS6 signaling, through the TAM receptor tyrosine kinases AXL and MERTK, participates in chronic liver pathologies. Here, we addressed GAS6/TAM involvement in Non-Alcoholic SteatoHepatitis (NASH) development. Methods GAS6/TAM signaling was analyzed in cultured primary hepatocytes, hepatic stellate cells (HSC) and Kupffer cells (KCs). Axl-/-, Mertk-/- and wild-type C57BL/6 mice were fed with Chow, High Fat Choline-Deficient Methionine-Restricted (HFD) or methionine-choline-deficient (MCD) diet. HSC activation, liver inflammation and cytokine/chemokine production were measured by qPCR, mRNA Array analysis, western blotting and ELISA. GAS6, soluble AXL (sAXL) and MERTK (sMERTK) levels were analyzed in control individuals, steatotic and NASH patients. Results In primary mouse cultures, GAS6 or MERTK activation protected primary hepatocytes against lipid toxicity via AKT/STAT-3 signaling, while bemcentinib (small molecule AXL inhibitor BGB324) blocked AXL-induced fibrogenesis in primary HSCs and cytokine production in LPS-treated KCs. Accordingly; bemcentinib diminished liver inflammation and fibrosis in MCD- and HFD-fed mice. Upregulation of AXL and ADAM10/ADAM17 metalloproteinases increased sAXL in HFD-fed mice. Transcriptome profiling revealed major reduction in fibrotic- and inflammatory-related genes in HFD-fed mice after bemcentinib administration. HFD-fed Mertk-/- mice exhibited enhanced NASH, while Axl-/- mice were partially protected. In human serum, sAXL levels augmented even at initial stages, whereas GAS6 and sMERTK increased only in cirrhotic NASH patients. In agreement, sAXL increased in HFD-fed mice before fibrosis establishment, while bemcentinib prevented liver fibrosis/inflammation in early NASH. Conclusion AXL signaling, increased in NASH patients, promotes fibrosis in HSCs and inflammation in KCs, while GAS6 protects cultured hepatocytes against lipotoxicity via MERTK. Bemcentinib, by blocking AXL signaling and increasing GAS6 levels, reduces experimental NASH, revealing AXL as an effective therapeutic target for clinical practice., Graphical abstract

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this “unique” cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy., Graphical Abstract ga1

The coronavirus disease 19 (COVID-19) has turned out to be a pandemic in short period of time due to the high transmissibility of its causative agent, severe acute respiratory syndrome coronavirus 2. Various reports have suggested the promising link between overexpression of angiotensin converting enzyme 2 (ACE2) and COVID-19 pathogenesis. The severity of COVID-19 pathophysiology is greatly depended on several comorbidities, like hypertension, diabetes mellitus (DM), respiratory and cardiovascular disease, out of which DM has emerged as a major risk factor. The current review focuses on the link among the expression of ACE2, use of ACE inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), and risk of COVID-19 pathogenesis in DM. The review also emphasizes on synergistic detrimental effect of DM and COVID-19 on the immune system in provoking uncontrolled cytokine storm which eventually leads to lethal consequences. Finally, several possible therapeutic strategies have been highlighted to reduce the excess of risk associated with COVID-19 in people with DM.

Background & Aims The circadian clock is crucial for physiological homeostasis including gut homeostasis. Disorder of the circadian clock may contribute to many diseases including inflammatory bowel disease (IBD). However, the role and the mechanisms of circadian clock involvement in IBD still are unclear. Methods Disorder of the circadian clock including chronic social jet lag and circadian clock gene deficiency mice (Bmal1-/-, and Per1-/-Per2-/-) were established. Dextran sulfate sodium (DSS) and/or azoxymethane were used to induce mouse models of colitis and its associated colorectal cancer. Flow cytometry, immunohistochemistry, immunofluorescence, Western blot, and reverse-transcription quantitative polymerase chain reaction were used to analyze the characteristics of immune cells and their related molecules. Results Mice with disorders of the circadian clock including chronic social jet lag and circadian clock gene deficiency were susceptible to colitis. Functionally, regulatory B (Breg) cells highly expressing Programmed cell death 1 ligand 1 (PDL1) in intestinal intraepithelial lymphocytes (IELs) helped to alleviate the severity of colitis after DSS treatment and was dysregulated in DSS-treated Bmal1-/- mice. Notably, interleukin 33 in the intestinal microenvironment was key for Bmal1-regulated PDL1+ Breg cells and interleukin 33 was a target of Bmal1 transcriptionally. Dysregulated PDL1+ B cells induced cell death of activated CD4+ T cells in DSS-treated Bmal1-/- mice. Consequently, circadian clock disorder was characterized as decreased numbers of Breg+ PDL1+ cells in IELs and dysfunction of CD4+ T cells promoted colitis-associated colorectal cancer (CRC) in mice. In clinical samples from CRC patients, low expression of Bmal1 gene in paracancerous tissues and center area of tumor was associated closely with a poorer prognosis of CRC patients. Conclusions Our study uncovers the importance of the circadian clock regulating PDL1+ Breg+ cells of IELs in IBD and IBD-associated CRC., Graphical abstract

Highlights • Oral exposure to BPA relevant to human exposure aggravated allergic asthma. • Low dose BPA with allergen reduced lung mRNA levels of hormone receptors. • Low dose BPA with allergen altered lymph node and bone marrow microenvironments., Bisphenol A (BPA) is widely used in many consumer products and has adverse effects on human health including allergic diseases. We investigated the effects of low dose BPA, comparable to actual human oral exposure, on allergic asthma in mice. C3H/HeJ male mice were fed a chow diet containing BPA (equivalent to 0.09, 0.90, or 9.01 μg/kg/day) and were intratracheally administered ovalbumin (OVA, 1 μg/animal) every two weeks from 5–11 weeks of age. All doses of BPA plus OVA enhanced pulmonary inflammation and airway hyperresponsiveness, and increased lung mRNA levels of Th2 cytokine/chemokine, and serum OVA-specific IgE and IgG1 compared to OVA alone, with greater effects observed in the middle- and high-dose BPA plus OVA groups. Furthermore, high-dose BPA with OVA decreased lung mRNA levels of ERβ and AR compared with OVA. Furthermore, BPA enhanced OVA-restimulated cell proliferation and protein levels of IL-4 and IL-5 in mediastinal lymph node (MLN) cells in OVA-sensitized mice. In bone marrow (BM) cells, middle-dose BPA with OVA increased Gr-1 expression. In conclusion, oral exposure to low-dose BPA at levels equivalent to human exposure can aggravate allergic asthmatic responses through enhancement of Th2-skewed responses, lung hormone receptor downregulation, and MLN and BM microenvironment change.

Highlights • The tumour microenvironment promotes induction of mesenchymal stromal cells through the production of soluble factors. • Data from animal models indicates that mesenchymal stromal cells could accelerate pulmonary metastases, promote proliferation of sarcoma cells and increase chemoresistance. • Pre-activated and use of transduced mesenchymal stromal cells have a positive effect on bone sarcoma. • There is preliminary clinical evidence for mesenchymal stromal cell in promoting bone regeneration within large bone defects after surgical excision., Over the past few decades, there has been growing interest in understanding the molecular mechanisms of cancer pathogenesis and progression, as it is still associated with high morbidity and mortality. Current management of large bone sarcomas typically includes the complex therapeutic approach of limb salvage or sacrifice combined with pre- and postoperative multidrug chemotherapy and/or radiotherapy, and is still associated with high recurrence rates. The development of cellular strategies against specific characteristics of tumour cells appears to be promising, as they can target cancer cells selectively. Recently, Mesenchymal Stromal Cells (MSCs) have been the subject of significant research in orthopaedic clinical practice through their use in regenerative medicine. Further research has been directed at the use of MSCs for more personalized bone sarcoma treatments, taking advantage of their wide range of potential biological functions, which can be augmented by using tissue engineering approaches to promote healing of large defects. In this review, we explore the use of MSCs in bone sarcoma treatment, by analyzing MSCs and tumour cell interactions, transduction of MSCs to target sarcoma, and their clinical applications on humans concerning bone regeneration after bone sarcoma extraction.

Highlights • Patchouli alcohol (PA) is a bioactive component in essential oil extracted from Pogostemon cablin. • The present review provides the scientific mechanisms for health beneficial activities of PA in diverse disease models. • PA possesses diverse health beneficial activities., Patchouli alcohol (PA), a tricyclic sesquiterpene, is a dominant bioactive component in oil extracted from the aerial parts of Pogostemon cablin (patchouli). Diverse beneficial activities have been reported, including anti-influenza virus, anti-depressant, anti-nociceptive, vasorelaxation, lung protection, brain protection, anti-ulcerogenic, anti-colitis, pre-biotic-like, anti-inflammatory, anti-cancer and protective activities against metabolic diseases. However, detailed mechanistic studies are required to explore the possibility of developing PA as a functional food material or promising drug for the prevention and treatment of human diseases. This review highlights multiple molecular targets and working mechanisms by which PA mediates health benefits.

Background & Aims: Severe acute pancreatitis is characterized by acinar cell death and inflammation. Necroptosis is an aggressive and proinflammatory mode of cell death that can be prevented by necrostatin-1 administration or receptor-interacting protein kinase (RIP3) deletion. Methods: Mouse pancreatic acinar cells were incubated with supramaximally stimulating concentrations of caerulein or submicellar concentrations of taurolithocholic acid-3-sulfate (TLCS), and necroptosis was inhibited by either addition of necrostatin or by RIP3 deletion. Cell death was quantitated using either lactate dehydrogenase leakage from acini or propidium iodide staining of nuclei. Necrosome formation was tracked and quantitated using cell fractionation or immunoprecipitation. Pancreatitis was induced in mice by retrograde intraductal infusion of TLCS or by repetitive supramaximal stimulation with caerulein. Results: Necroptosis was found to be the most prevalent mode of acinar cell in vitro death and little or no apoptosis was observed. Acinar cell death was associated with necrosome formation and prevented by either necrostatin administration or RIP3 deletion. Both of these interventions reduced the severity of TLCS- or caerulein-induced pancreatitis. Delaying necrostatin administration until after pancreatitis already had been established did not prevent its ability to reduce the severity of TLCS-induced pancreatitis. Conclusions: Necroptosis is the predominant mode of acinar cell death in severe experimental mouse pancreatitis. The severity of pancreatitis can be reduced by administration of necrostatin, and necrostatin still can reduce the cell injury of pancreatitis even if it is administered after the disease already has been established. Inhibition of necroptosis may be an effective strategy for the treatment of severe clinical pancreatitis. Keywords: Acute Pancreatitis, Biliary Pancreatitis, Necroptosis, Apoptosis, Pancreatic Cell Death

Ischaemic diseases remain a major cause of morbidity and mortality despite continuous advancements in medical and interventional treatments. Moreover, available drugs reduce symptoms associated with tissue ischaemia, without providing a definitive repair. Cardiovascular regenerative medicine is an expanding field of research that aims to improve the treatment of ischaemic disorders through restorative methods, such as gene therapy, stem cell therapy, and tissue engineering. Stem cell transplantation has salutary effects through direct and indirect actions, the latter being attributable to growth factors and cytokines released by stem cells and influencing the endogenous mechanisms of repair. Autologous stem cell therapies offer less scope for intellectual property coverage and have limited scalability. On the other hand, off-the-shelf cell products and derivatives from the stem cell secretome have a greater potential for large-scale distribution, thus enticing commercial investors and reciprocally producing more significant medical and social benefits. This review focuses on the paracrine properties of cardiac stem cells and pericytes, two stem cell populations that are increasingly attracting the attention of regenerative medicine operators. It is likely that new cardiovascular drugs are introduced in the next future by applying different approaches based on the refinement of the stem cell secretome.

COPD (chronic obstructive pulmonary disease) is caused by exposure to toxic gases and particles, most often CS (cigarette smoke), leading to emphysema, chronic bronchitis, mucus production and a subsequent decline in lung function. The disease pathogenesis is related to an abnormal CS-induced inflammatory response of the lungs. Similar to active (mainstream) smoking, second hand (sidestream) smoke exposure severely affects respiratory health. These processes can be studied in vivo in models of CS exposure of mice. We compared the acute inflammatory response of female C57BL/6 mice exposed to two concentrations [250 and 500 mg/m3 TPM (total particulate matter)] of sidestream and mainstream CS for 3 days and interpreted the biological effects based on physico-chemical differences in the gas and particulate phase composition of CS. BAL (bronchoalveolar lavage fluid) was obtained to perform differential cell counts and to measure cytokine release. Lung tissue was used to determine mRNA and protein expression of proinflammatory genes and to assess tissue inflammation. A strong acute inflammatory response characterized by neutrophilic influx, increased cytokine secretion [KC (keratinocyte chemoattractant), TNF-α (tumour necrosis factor α), MIP-2 (macrophage inflammatory protein 2), MIP-1α and MCP-1 (monocyte chemoattractant protein-1)], pro-inflammatory gene expression [KC, MIP-2 and MMP12 (matrix metalloproteinase 12)] and up-regulated GM-CSF (granulocyte macrophage colony-stimulating factor) production was observed in the mainstream model. After sidestream exposure there was a dampened inflammatory reaction consisting only of macrophages and diminished GM-CSF levels, most likely caused by elevated CO concentrations. These results demonstrate that the composition of CS determines the dynamics of inflammatory cell recruitment in COPD mouse models. Different initial inflammatory processes might contribute to COPD pathogenesis in significantly varying ways, thereby determining the outcome of the studies.

Ethnopharmacological relevance Pulmonary fibrosis (PF) is a chronic, debilitating and often lethal lung disorder. Despite the molecular mechanisms of PF are gradually clear with numerous researchers’ efforts, few effective drugs have been developed to reverse human PF or even halt the chronic progression to respiratory failure. Traditional Chinese medicine (TCM), the main component of the medical practice used for more than 5000 years especially in China, often exerts wider action spectrum than previously attempted options in treating human diseases. Recent data have shown the anti-fibrotic benefits of the active ingredients from TCM in this field, which may represent an attractive source of the drug discovery against PF. Aim of the review This review summarizes the pre-clinical and clinical evidence on the benefits of TCM and their active ingredients, and provides a comprehensive information and reliable basis for the exploration of new treatment strategies of botanical drugs in the therapy of PF. Methods The literature information was obtained from the scientific databases on ethnobotany and ethno medicines (up to Aug 2016), mainly from the Pubmed, Web of Science and CNKI databases, and was to identify the experimental studies on the anti-fibrotic role of the active agents from TCM and the involved mechanisms. The search keywords for such work included: “lung fibrosis” or “pulmonary fibrosis”, and “traditional Chinese medicine”, “extract” or “herb”. Results A number of studies have shown that the active agents of single herbs and TCM formulas, particularly the flavonoids, glycosides and alkaloids, exhibit potential benefits against PF, the mechanisms of which appear to involve the regulation of inflammation, oxidant stress, and pro-fibrotic signaling pathways, etc. Besides, the processing methods for discovering TCM in treating PF were prospectively discussed. Conclusion These research work have shown the therapeutic benefits of TCM in the treatment of PF. However, more continued researches should be undertaken to clarify the unconfirmed chemical composition and regulatory mechanisms, conduct standard clinical trials, and evaluate the possible side effects. The insights provided in present review will be needed for further exploration of botanical drugs in the development of PF therapy., Graphical abstract fx1

The purpose was to test the hypothesis that adipocytes from obese rats would exert pro-atherogenic paracrine effects on cultured endothelial cells compared to adipocytes from lean rats, and that the adverse obesity-associated paracrine effects of adipocytes would be more pronounced in visceral than subcutaneous adipose tissue. Epididymal and subcutaneous adipose tissues were harvested from 32-wk old obese Otsuka Long Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats. Cultured rat aortic endothelial cells were treated for 24 h with media conditioned with LETO subcutaneous adipocytes (LSA), OLETF subcutaneous adipocytes (OSA), LETO epididymal adipocytes (LEA), and OLETF epididymal adipocytes (OEA). The amount of key adipokines secreted by ATs was measured in the supernatant fluid with ELISA and mRNA levels of a number of pro- and anti-atherogenic genes were assessed in treated endothelial cells via quantitative real-time PCR. Compared to adipocytes from other depots, secretion of leptin and TNFα was highest and vaspin secretion was lowest from OEA. However, endothelial cells treated with OEA conditioned media exhibited lower expression of several pro-atherogenic genes. These data suggest that adipocytes isolated from obese visceral adipose tissue secrete some as-yet unidentified factor(s) that confers a beneficial effect on transcription of pro- and anti-atherogenic genes of endothelial cells.