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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.

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment., Graphical abstract Nanomedicine has demonstrated great potential in achieving specific targeting and amplifying therapeutic efficiency. This review focuses on the recent breakthroughs and targeting strategies to provide insights into nanomedicine for acute respiratory distress syndrome treatment.Image 1

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized., Graphical abstract Strategies including molecular modification, polymeric conjugation, formulation technologies, etc. are being developed to extend pulmonary drug exposure. Inhaled medicines with extended lung exposure could be potentially favored for therapeutic efficacy.Image 1

COVID-19 is the cause of a pandemic associated with substantial morbidity and mortality. As yet, there is no available approved drug to eradicate the virus. In this review article, we present an alternative study area that may contribute to the development of therapeutic targets for COVID-19. Growing evidence is revealing further pathophysiological mechanisms of COVID-19 related to the disregulation of inflammation pathways that seem to play a critical role toward COVID-19 complications. The NF-kB and JAK/STAT signaling pathways are highly activated in acute inflammation, and the excessive activity of these pathways in COVID-19 patients likely exacerbates the inflammatory responses of the host. A group of non-coding RNAs (miRNAs) manage certain features of the inflammatory process. In this study, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of COVID-19 disease. Furthermore, previous studies published in the online databases, namely web of science, MEDLINE (PubMed), and Scopus, were reviewed for the potential role of miRNAs in the inflammatory manifestations of COVID-19. Moreover, we disclosed the interactions of inflammatory genes using STRING DB and designed interactions between miRNAs and target genes using Cityscape software. Several miRNAs, particularly miR-9, miR-98, miR-223, and miR-214, play crucial roles in the regulation of NF-kB and JAK-STAT signaling pathways as inflammatory regulators. Therefore, this group of miRNAs that mitigate inflammatory pathways can be further regarded as potential targets for far-reaching-therapeutic strategies in COVID-19 diseases.

Graphical abstract, Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied. After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, −5, −13, −25, –33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done. BALf's eosinophils, the levels of IL-4, −5, −13, −25, –33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4. MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.

IFNγ is a key regulator of inflammatory responses but its role in influenza A virus (IAV) pathogenesis is unclear. Our studies show that infection of mice lacking the IFNγ receptor (IFNγR-/-) at a dose which caused severe disease in wild type 129 Sv/Ev (WT) mice resulted in milder clinical symptoms and significantly lower lung virus titers by 6 days post-infection (dpi). Viral spread was reduced in IFNγR-/- lungs at 2 and 4 dpi. Levels of inflammatory cytokines and chemokines were lower in IFNγR-/- mice at 2 dpi and there was less infiltration of monocyte/macrophage lineage cells than in WT mice. There was no difference in CD4+ and CD8+ T cells and alveolar macrophages in the bronchoalveolar lavage fluid (BALF) at 2 and 4 dpi but by 4 dpi IFNγR-/- mice had significantly higher percentages of neutrophils. Our data strongly suggest that IAV can use the inflammatory response to promote viral spread.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF., Graphical abstract Image 1, Highlights • Glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts lead to lung fibrosis. • Succinate contributes to metabolic dysregulation of fibroblasts by stabilizing HIF-1α. • Succinate dehydrogenase is an exciting new therapeutic target to treat IPF. • IR-780 can be a promising agent to control lung fibrosis by targeting succinate dehydrogenase.

Graphical abstract, Asthma as chronic airway disease has high prevalence in children and imbalance of Th1/Th2 is a critical mechanism in pathogenesis of the asthma. Baicalein as a cell protective and anti-inflammatory flavonoid may have anti-asthma effect. Therefore, for better using lung, baicalein was used in chitosan-nanoparticle as anti-asthma treatment. Baicalein was loaded and encapsulated in chitosan nanoparticle. The morphology, physical characters (particle size, zeta potential and FT-IR) were analyzed. Drug encapsulation and loading capacity, accumulative release-time were studied. After asthma model producing, the mice were treated with L-B-NP and E-B-NP. At least, MCh challenge test, Cytokines measurement and Lung Histopathology were done. Nanoparticles had average size 285 ± 25 nm with negative charge −2.5 mV. The L-B-NP decreased penh value and E-B-NP decreased inflammation. Both nanoparticles increased IL-12 and decreased IL-5. Also, L-B-NP decreased mucus secretion in bronchi. L-B-NP and E-B-NP control immune-allergo-inflammatory response of asthma. L-B-NP controlled AHR and E-B-NP controlled inflammation that can be used as controlling anti-asthma drug.

PMID: 34438017 WOS:000702705800007 The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.

The sudden outbreak of COVID-19 has once again shrouded people in the enormous threat of RNA virus. Extracellular vesicles (EVs), eukaryotic cells-derived small bi-layer vesicles mainly consisting of exosomes and microvesicles, share many properties with RNA viruses including structure, size, generation, and uptake. Emerging evidence has implicated the involvement of EVs in the pathogenesis of infectious diseases induced by RNA viruses. EVs can transfer viral receptors (e.g., ACE2 and CD9) to recipient cells to facilitate viral infection, directly transport infectious viral particles to adjacent cells for virus spreading, and mask viruses with a host structure to escape immune surveillance. Here, we examine the current status of EVs to summarize their roles in mediating RNA virus infection, together with a comprehensive discussion of the underlying mechanisms.

Mass spectrometry imaging (MSI) visualises molecular distributions throughout tissues but is blind to dynamic metabolic processes. Here, MSI with high mass resolution together with multiple stable isotope labelling provided spatial analyses of phosphatidylcholine (PC) metabolism in mouse lungs. Dysregulated surfactant metabolism is central to many respiratory diseases. Metabolism and turnover of therapeutic pulmonary surfactants were imaged from distributions of intact and metabolic products of an added tracer, universally13C-labelled dipalmitoyl PC (U[13C]DPPC). The parenchymal distributions of newly synthesised PC species were also imaged from incorporations ofmethyl-D9-choline. This dual labelling strategy demonstrated both lack of inhibition of endogenous PC synthesis by exogenous surfactant and location of acyl chain remodelling processes acting on the U[13C]DPPC-labelled surfactant, leading to formation of polyunsaturated PC lipids. This ability to visualise discrete metabolic events will greatly enhance our understanding of lipid metabolism in diverse tissues, and has potential application to both clinical and experimental studies.

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.

Background : SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide; therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives : This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method : We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Results : We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion : Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment., Graphical Abstract Image, graphical abstract

SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the "cytokine storm", the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible "immune signature" in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow "dated" in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic.

Graphical abstract, Highlights • Pulmonary fibrosis is high probably a major complication in COVID-19 patients. • 16 kinds of polysaccharides possess significant anti-pulmonary fibrosis activities. • TGF-β is an important target for anti-pulmonary fibrosis effect of polysaccharides., Pulmonary fibrosis (PF) is a lung disease with highly heterogeneous and mortality rate, but its therapeutic options are now still limited. Corona virus disease 2019 (COVID-19) has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients.

Graphical abstract, The coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), appears with a wide spectrum of mild-to-critical clinical complications. Many clinical and experimental findings suggest the role of inflammatory mechanisms in the immunopathology of COVID-19. Hence, cellular and molecular mediators of the immune system can be potential targets for predicting, monitoring, and treating the progressive complications of COVID-19. In this review, we assess the latest cellular and molecular data on the immunopathology of COVID-19 according to the pathological evidence (e.g., mucus and surfactants), dysregulations of pro- and anti-inflammatory mediators (e.g., cytokines and chemokines), and impairments of innate and acquired immune system functions (e.g., mononuclear cells, neutrophils and antibodies). Furthermore, we determine the significance of immune biomarkers for predicting, monitoring, and treating the progressive complications of COVID-19. We also discuss the clinical importance of recent immune biomarkers in COVID-19, and at the end of each section, recent clinical trials in immune biomarkers for COVID-19 are mentioned.

Airway inflammation is a critical feature of lower respiratory tract infections caused by viruses such as respiratory syncytial virus (RSV). A growing body of literature has demonstrated the importance of extracellular matrix changes such as the accumulation of hyaluronan (HA) and versican in the subepithelial space in promoting airway inflammation; however, whether these factors contribute to airway inflammation during RSV infection remains unknown. To test the hypothesis that RSV infection promotes inflammation via altered HA and versican production, we studied an ex vivo human bronchial epithelial cell (BEC)/human lung fibroblast (HLF) coculture model. RSV infection of BEC/HLF cocultures led to decreased hyaluronidase expression by HLFs, increased accumulation of HA, and enhanced adhesion of U937 cells as would be expected with increased HA. HLF production of versican was not altered following RSV infection; however, BEC production of versican was significantly downregulated following RSV infection. In vivo studies with epithelial-specific versican-deficient mice [SPC-Cre(+) Vcan-/-] demonstrated that RSV infection led to increased HA accumulation compared with control mice, which also coincided with decreased hyaluronidase expression in the lung. SPC-Cre(+) Vcan-/- mice demonstrated enhanced recruitment of monocytes and neutrophils in bronchoalveolar lavage fluid and increased neutrophils in the lung compared with SPC-Cre(-) RSV-infected littermates. Taken together, these data demonstrate that altered extracellular matrix accumulation of HA occurs following RSV infection and may contribute to airway inflammation. In addition, loss of epithelial expression of versican promotes airway inflammation during RSV infection further demonstrating that versican's role in inflammatory regulation is complex and dependent on the microenvironment.

Purpose The pathophysiology theories of COVID-19 attach the injury of target organs to faulty immune responses and occasionally hyper-inflammation. The damage frequently extends beyond the respiratory system, accompanying cardiovascular, renal, central nervous system, and/or coagulation derangements. Tumor necrosis factor-α (TNF-α) and interleukins (IL)-1 and − 6 suppression may improve outcomes, as experimentally shown. Targeted therapies have been proposed, but mild therapeutic hypothermia—a more multifaceted approach—could be suitable. Findings According to evidence derived from previous applications, therapeutic hypothermia diminishes the release of IL-1, IL-6, and TNF-α in serum and at the tissue level. PaCO2 is reduced and the PaO2/FiO2 ratio is increased, possibly lasting after rewarming. Cooling might mitigate both ventilator and infectious-induced lung injury, and suppress microthrombi development, enhancing V/Q mismatch. Improvements in microhemodynamics and tissue O2 diffusion, along with the ischemia-tolerance heightening of tissues, could be reached. Arrhythmia incidence diminishes. Moreover, hypothermia may address the coagulopathy, promoting normalization of both hypo- and hyper-coagulability patterns, which are apparently sustained after a return to normothermia. Conclusions As per prior therapeutic hypothermia literature, the benefits regarding inflammatory response and organic damage might be seen. Following the safety-cornerstones of the technique, the overall infection rate and infection-related mortality are not expected to rise, and increased viral replication does not seem to be a concern. Therefore, the possibility of a low cost and widely available therapy being capable of improving COVID-19 outcomes deserves further study.

Highlights • CCL17, IFN- l 3, IL-6, IP-10, and CXCL9 were predictor for COVID-19 prognosis. • CCL17 were showed strong association with the development of severe pneumonia. • A flare-up of IFN- l 3, IL-6, IP-10, and CXCL9 were a trigger for severe symptom. • The downregulation of CCL17 could be unique in COVID-19., COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9–1.0, p

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.

Objective To clarify what future problems must be resolved and how clinical findings of SARS-CoV-2 infection differ from those of cHCoV infection. Methods Patients and Methods Clinical characteristics of 14 patients with laboratory-confirmed Coronavirus disease 2019 (COVID-19) and 5 patients with cHCoV pneumonia admitted to our institution and treated up to March 8, 2020, were retrospectively analyzed. Results On admission, 10 patients had pneumonia, 5 of whom had pulmonary shadows detectable only via computed tomography (CT). During hospitalization, another patient with no pulmonary shadows on admission developed pneumonia. In total, 11 (78.6%) of the 14 patients developed pneumonia, indicating its high prevalence in COVID-19. During hospitalization, the patients' symptoms spontaneously relapsed and resolved, and gastrointestinal symptoms were frequently found. C-reactive protein values showed correlation with the patients’ clinical courses. Ritonavir/lopinavir were administered to 5 patients whose respiratory conditions worsened during admission, all of whom improved. However, the pneumonia in the 6 other patients improved without antivirals. None of the 14 patients died, whereas 5 other patients with cHCoV pneumonia were in respiratory failure on admission, and one patient (20%) died. Conclusion Both SARS-CoV-2 and cHCoV can cause severe pneumonia. Problems for future resolution include whether antiviral agents administered in cases of mild or moderate severity can reduce the number of severe cases, and whether antivirals administered in severe cases can reduce mortality.

Drug-induced lung injury (DLI) has become more common because of the increasing number of therapeutic agents in use. Mesalazine, also known as 5-aminosalicylic acid (5-ASA), is one of the key drugs for the treatment of ulcerative colitis (UC). Although mesalazine-induced lung injury has been previously reported, few cases have included severe respiratory failure. In this report, we present a case of mesalazine-induced lung injury with severe respiratory failure, which was improved by discontinuation of mesalazine and introduction of corticosteroid therapy and ventilation support with non-invasive positive pressure ventilation (NPPV). We also review the previous literature on mesalazine-induced lung injury.

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19., Graphical abstract Chinese herbal medicines and natural compounds possess promising antiviral effects against Human coronaviruses (HCoVs) and provide a rich resource for novel antiviral drug development. This review provides an update on natural compounds against HCoVs and summarizes the active natural compounds and their possible action mechanisms.Image 1

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, Highlights • Entecavir and imipenem alleviated LPS-induced cytokine storm syndrome. • Entecavir and imipenem mitigated LPS-induced acute lung injury. • Entecavir and imipenem inhibited LPS-stimulated TNF-α and IL-10 in hPBMC. • Entecavir and imipenem attenuated LPS-activated NF-κB., Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-κB activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-α and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.

Pulmonary drug delivery has attracted increasing attention in biomedicine, and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs. However, the existing methods for preparing porous particles using porogens have several drawbacks, such as the inhomogeneous and uncontrollable pores, drug leakage, and high risk of fragmentation. In this study, a series of cyclodextrin-based metal-organic framework (CD-MOF) particles containing homogenous nanopores were delicately engineered without porogens. Compared with commercial inhalation carrier, CD-MOF showed excellent aerosolization performance because of the homogenous nanoporous structure. The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments, including cytotoxicity assay, hemolysis ratio test, lung function evaluation, in vivo lung injury markers measurement, and histological analysis. The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs. Therefore, all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery. This study may throw light on the nanoporous particles for effective pulmonary administration., Graphical abstract The nanoporous CD-MOF particles were delicately engineered for pulmonary drug delivery. Compared with commercial inhalation carrier, CD-MOF showed better aerodynamic behavior and higher lung deposition rate because of the homogenous nanoscale pores. Moreover, CD-MOF exhibited good biocompatibility, which would not affect the lung function and cause inflammatory response.Image 1

Acute eosinophilic pneumonia (AEP) is an eosinophilic lung disease associated with environmental substances including smoking. Although the etiology of AEP has not been fully elucidated, it has been hypothesized that IL-33 plays a central role in the pathogenesis of AEP. Turpentine oil, from resins of pine trees, is not only used in paints, but also utilized in experimental animal models of inflammation because it leads to the production of inflammatory cytokines including IL-33. Here, we report the first case of AEP following turpentine oil inhalation. A 67-year-old woman reported using urushiol with turpentine oil to repair home goods. She had fever and persistent cough after turpentine inhalation over a very short period of time. The chest X-ray image showed consolidation in the upper right lung field. Laboratory findings indicated that there was no evidence of infection, collagen vascular diseases, and other allergic diseases that cause pneumonia, but analysis of the bronchoalveolar lavage fluid revealed 29% eosinophils with a small number of lipid-laden macrophages. With these findings, the diagnostic criteria of AEP was met. We rendered a diagnosis of AEP by inhalation of turpentine because no other cause for AEP was identified even with a structured questionnaire survey. The manifestations resolved immediately after steroid therapy. This is the first report of a case of AEP caused by the inhalation of turpentine oil.

The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu Decoction (XFBD) as one of the “three medicines and three prescriptions” for the clinically effective treatment of COVID-19 in China, shows unique advantages in the control of symptomatic transition from moderate to severe disease states. However, the roles of XFBD to against hyper-inflammatory response and its mechanism remain unclear. Here, we established acute lung injury (ALI) model induced by lipopolysaccharide (LPS), presenting a hyperinflammatory process to explore the pharmacodynamic effect and molecular mechanism of XFBD on ALI. The in vitro experiments demonstrated that XFBD inhibited the secretion of IL-6 and TNF-α and iNOS activity in LPS-stimulated RAW264.7 macrophages. In vivo, we confirmed that XFBD improved pulmonary injury via down-regulating the expression of proinflammatory cytokines such as IL-6, TNF-α and IL1-β as well as macrophages and neutrophils infiltration in LPS-induced ALI mice. Mechanically, we revealed that XFBD treated LPS-induced acute lung injury through PD-1/IL17A pathway which regulates the infiltration of neutrophils and macrophages. Additionally, one major compound from XFBD, i.e. glycyrrhizic acid, shows a high binding affinity with IL17A. In conclusion, we demonstrated the therapeutic effects of XFBD, which provides the immune foundations of XFBD and fatherly support its clinical applications., Graphical Abstract ga1

We report a case of recurrent idiopathic pulmonary hemosiderosis after a long-term remission presented with Sjögren's syndrome. The patient was diagnosed with IPH due to repeated pneumonia and blood sputum in his childhood. He was admitted to our hospital due to exertional dyspnea and dry cough with bilateral ground-glass opacity in chest computed tomography at the age of 32. Video-assisted thoracoscopic surgery was performed and the specimens showed nonspecific interstitial pneumonia pattern with diffuse, chronic alveolar hemorrhage, suggesting recurrence of IPH. He was also diagnosed with Sjögren's syndrome. Further immunological studies will reveal the pathogenesis of IPH. Keywords: Idiopathic pulmonary hemosiderosis, Sjögren's syndrome

A 67-year-old woman with fever and cough was diagnosed with eosinophilic pneumonia because of eosinophilia and increased eosinophil levels in the bronchoalveolar lavage fluid and transbronchial biopsy lung specimens. However, prednisolone therapy at a previous hospital was ineffective. Histological findings from thoracoscopic lung and lymph node biopsies were consistent with multicentric Castleman's disease (MCD). Since specimens also showed prominent eosinophil and IgG4-positive plasma cell infiltration, it was difficult to distinguish IgG4-related disease (IgG4-RD) from MCD. Administration of prednisolone plus tocilizumab improved the symptoms and lung lesions, and prednisolone administration was successfully reduced and then terminated. The present case highlights the difficulty in diagnosing MCD and IgG4-RD, and suggests that combined administration of tocilizumab and prednisolone might be effective in such a case.

Background The impact of viral infections on acute exacerbations in idiopathic pulmonary fibrosis (IPF) and/or non-IPF interstitial lung disease (ILDs) has been scarcely described. Objectives To elucidate the frequency of virus infections in patients with IPF or non-IPF ILDs including idiopathic interstitial pneumonia (IIP) or connective tissue disease (CTD)-associated pneumonia, and its influence on their short-term mortality. Methods We prospectively enrolled adult patients with acute exacerbation of IPF and non-IPF ILDs who were admitted to the hospital during the last 3 years, and examined the respiratory samples obtained from nasopharyngeal, sputum, and bronchoalveolar lavage fluid. Results A total of 78 patients were identified, consisting of 27 patients with acute exacerbation of IPF and 51 patients with non-IPF ILDs (IIP: n = 27, CTD-associated IP: n = 24). Of all patients, 15 (19.2%) had viruses detected in their respiratory samples including the human herpesvirus 7 (HHV7; n = 4) and cytomegalovirus (CMV) plus HHV7 (n = 3). The proportion of virus infections in the IPF and non-IPF ILDs groups was comparable. The Kaplan-Meier survival curves over 60 days revealed a lower survival probability in the virus positive group (n = 15, 60%) than in the virus negative group (n = 60, 83.3%, p

Allergic asthma is a chronic inflammatory disorder of the pulmonary airways. Gelam honey has been proven to possess anti-inflammatory property with great potential to treat an inflammatory condition. However, the effect of ingestion of Gelam honey on allergic asthma has never been studied. This study aimed to investigate the efficacy of Gelam honey on the histopathological changes in the lungs of a mice model of allergic asthma. Forty-two Balb/c mice were divided into seven groups: control, I, II, III, IV, V and VI group. All groups except the control were sensitized and challenged with ovalbumin. Mice in groups I, II, III, IV, and V were given honey at a dose of 10% (v/v), 40% (v/v) and 80% (v/v), dexamethasone 3 mg/kg, and phosphate buffered saline (vehicle) respectively, orally once a day for 5 days of the challenged period. Mice were sacrificed 24 h after the last OVA challenged and the lungs were evaluated for histopathological changes by light microscopy. All histopathological parameters such as epithelium thickness, the number of mast cell and mucus expression in Group III significantly improved when compared to Group VI except for subepithelial smooth muscle thickness (p, Graphical abstract

Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases and could occur in severe COVID-19 patients. Re-Du-Ning injection (RDN) is a tradition Chinese medicine preparation which has been clinically used for treatment of respiratory diseases including COVID-19. Purpose To elucidate the potential mechanisms of RDN for the treatment of ALI. Methods Female C57BL/6J mice were used to establish ALI model by intraperitoneal injection 10 mg/kg LPS, and RDN injection was intraperitoneally administered with the dose of 5 and 10 mL/kg. The cytokines were measured by ELISA and qPCR. The data related to NETs were analyzed by ELISA, immunofluorescence, Western blotting and network pharmacological approach. Results RDN robustly alleviated LPS-induced ALI. Meanwhile, RDN downregulated the expression of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α. Specifically, RDN treatment inhibited the formation of neutrophil extracellular traps (NETs) and remarkably suppressed the protein of PAD4. The active compound from RDN decreased the phosphorylation of ERK1/2. Conclusion These findings demonstrate that RDN ameliorates LPS-induced ALI through suppressing MAPK pathway to inhibit the formation of NETs., Graphical abstract Image, graphical abstract

Background IL-35 was recently identified as an anti-inflammatory cytokine. We previously reported that recombinant fusion protein of murine IL-35 and human IgG1 Fc fragment (rIL-35) reduced Th2 cytokines (IL-4 and IL-5) in vitro. However, it is unclear whether IL-35 can attenuate nasal allergic responses and symptoms of allergic rhinitis in vivo. Methods To investigate the in vivo effect of IL-35 on allergic rhinitis in mice, mice were sensitized with ovalbumin (OVA). Intranasal administration of rIL-35 and intranasal challenge of OVA were then performed. Nasal symptoms were estimated after the last nasal challenge. Nasal tissue and cervical lymph nodes (CLN) were collected. OVA-specific IgE in sera, OVA-specific T cell response, and the production of cytokines (IL-4, IL-5, and IL-10) stimulated by the OVA antigen were measured. The transcription level of Foxp3 and the frequency of CD4+CD25+ regulatory T cells were also measured. Results rIL-35 significantly inhibited the number of sneezes and nasal rubbing movements. It also reduced the number of eosinophils in the nasal mucosa and significantly decreased the level of OVA-specific IgE, the OVA-specific T cell proliferation, and the production of IL-4 and IL-5. Furthermore, rIL-35 significantly increased the production of IL-10, the transcription level of Foxp3, and the frequency of CD4+CD25+ regulatory T cells. Conclusions This study showed for the first time that rIL-35 inhibits nasal allergic responses and symptoms in mice, and that rIL-35 increases IL-10, Foxp3, and CD4+CD25+ regulatory T cells in CLN. This study also suggests that intranasal administration of IL-35 can attenuate allergic rhinitis., Graphical abstract Image 1

We describe the case of a 73-year-old man who experienced dry cough and exertional dyspnea after dabigatran administration. Chest radiographs revealed the development of bilateral consolidative and ground glass opacity, and transbronchial lung biopsy showed organized materials in the alveolar spaces with moderate inflammatory infiltrate and focal fibrosis. Lung opacity gradually disappeared after discontinuing dabigatran. To date, there has been only one report regarding dabigatran-induced lung injury, except for alveolar hemorrhage and eosinophilic pneumonia. Therefore, we should consider that any drug can cause various types of lung injuries. Keywords: Dabigatran, Interstitial pneumonia, Drug-induced lung injury

The lungs are directly connected to the external environment, which makes them more vulnerable to infection and injury. They are protected by the respiratory epithelium and immune cells to maintain a dynamic balance. Both innate and adaptive immune cells are involved in the pathogenesis of lung diseases. Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells, which have attracted increasing attention in recent years. Although MAIT cells account for a small part of the total immune cells in the lungs, evidence suggests that these cells are activated by T cell receptors and/or cytokine receptors and mediate immune response. They play an important role in immunosurveillance and immunity against microbial infection, and recent studies have shown that subsets of MAIT cells play a role in promoting pulmonary inflammation. Emerging data indicate that MAIT cells are involved in the immune response against SARS-CoV-2 and possible immunopathogenesis in COVID-19. Here, we introduce MAIT cell biology to clarify their role in the immune response. Then we review MAIT cells in human and murine lung diseases, including asthma, chronic obstructive pulmonary disease, pneumonia, pulmonary tuberculosis and lung cancer, and discuss their possible protective and pathological effects. MAIT cells represent an attractive marker and potential therapeutic target for disease progression, thus providing new strategies for the treatment of lung diseases.

A 40-year-old Japanese man was diagnosed with systemic lupus erythematosus. Chest computed tomography showed patchy consolidation in both lungs. A cryobiopsy and bronchoalveolar lavage showed organizing pneumonia, not acute lupus pneumonia or diffuse alveolar hemorrhage. This case demonstrates the usefulness of cryobiopsy for the management of systemic lupus erythematosus interstitial lung disease.

House dust mites (HDMs) are a potent allergen source that are commonly found in human living environments. While HDMs are known to induce allergic diseases in humans, such as asthma, its other biological activities related to human health are less understood. Our laboratory recently purified the HDM protein PDI (protein disulfide isomerase). In this study, we assess the role of PDI in contributing to immune regulation. Using mass spectrometry, we analyzed the complexes of DEC205 and HDM extracts, and the role of PDI in the induction of tolerogenic dendritic cells (DCs) was assessed in human cell culture experiments and verified in a murine model. We found that more than 20 HDM-derived proteins, including PDI, bound to DCs by forming complexes with DEC205. Additionally, DEC205-mediated the endocytosis of PDI. HDM-derived PDI (HDM-PDI) promoted Foxp3 expression in DCs. HDM-PDI-primed DCs also showed tolerogenic properties that induced regulatory T cell development, indicating that the primed DCs were tolerogenic DCs. Our results suggested that the PDI/DEC205/TIEG1/Foxp3 signal pathway activation was involved in the HDM-PDI-induced Foxp3 expression in DCs. Finally, we found that HDM-PDI competitively counteracted the Th2 cytokines to restore DC's tolerogenicity, and administration of HDM-PDI could suppress experimental asthma. In conclusion, our data suggest that HDM-PDI contributes to immune regulation by inducing tolerogenic DC development. Administration of HDM-PDI can alleviate experimental asthma. These findings demonstrate that HDM-PDI has translational potential to be used in the treatment of immune disorders such as asthma.

Aberrant or constitutive activation of nuclear factor kappa B (NF-κB) contributes to various human inflammatory diseases and malignancies via the upregulation of genes involved in cell proliferation, survival, angiogenesis, inflammation, and metastasis. Thus, inhibition of NF-κB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase, is involved in the preferential repair of oxidized DNA bases from the transcriptionally active sequences via the transcription-coupled base excision repair pathway. We have further shown that Neil2-null mice are highly sensitive to tumor necrosis factor α (TNFα)- and lipopolysaccharide-induced inflammation. Both TNFα and lipopolysaccharide are potent activators of NF-κB. However, the underlying mechanism of NEIL2's role in the NF-κB–mediated inflammation remains elusive. Here, we have documented a noncanonical function of NEIL2 and demonstrated that the expression of genes, such as Cxcl1, Cxcl2, Cxcl10, Il6, and Tnfα, involved in inflammation and immune cell migration was significantly higher in both mock- and TNFα-treated Neil2-null mice compared with that in the WT mice. NEIL2 blocks NF-κB's binding to target gene promoters by directly interacting with the Rel homology region of RelA and represses proinflammatory gene expression as determined by co-immunoprecipitation, chromatin immunoprecipitation, and electrophoretic mobility-shift assays. Remarkably, intrapulmonary administration of purified NEIL2 via a noninvasive nasal route significantly abrogated binding of NF-κB to cognate DNA, leading to decreased expression of proinflammatory genes and neutrophil recruitment in Neil2-null as well as WT mouse lungs. Our findings thus highlight the potential of NEIL2 as a biologic for inflammation-associated human diseases.

Highlights • This is the first case report of diagnosing T. marneffei infection in a HIV-negative patient with the assistance of mNGS in North China. • The mNGS was used to diagnose T. marneffei infection much faster than traditional fungal culture. • This was a non-HIV patient who infected with T. marneffei., Talaromyces marneffei (T. marneffei), is an opportunistic pathogenic fungus commonly reported in southeast Asia. T. marneffei infection predominantly occurs in patients with immunodeficiency and can be fatal if diagnosis and treatment were delayed. Conventional diagnosis of T. marneffei infection relies heavily on tissue culture and histologic analysis, which is time consuming and has limited positive rate. Rapid and accurate diagnosis of T. marneffei remains urgent for effective therapy and prevention. This case is the first reported T. marneffei infection in non-HIV patients in north China diagnosed by mNGS. The successful diagnosis of T. marneffei infection assistant by mNGS underlies the potential of this technique in rapid etiological diagnosis.

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders., Graphical abstract Andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), significantly improved lipopolysaccharide-induced airway inflammatory cell recruitment, inflammation cytokines and lung histological alterations with a possible mechanism for negative regulation NF-κB and MAPK-mediated inflammatory response.

Graphical abstract, Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 μM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form β of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1β and TNF-α in serum. In conclusion, oral administration of crystal form β of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.