Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons.

Hypoglycemia-associated autonomic failure (HAAF) is a well-established complication of diabetes. Although HAAF has serious outcomes such as recurrent morbidity, coma, and death, the mechanisms of HAAF and its pathological components are largely unknown. Our previous studies have revealed that hypoglycemia is associated with the upregulation of an immediate early gene - FOS. In addition, it is documented that glucose deprivation activates neuronal autophagic activities. Therefore, the present study aimed to identify the role of FOS and one of the core components of the autophagy pathway, Beclin-1 (encoded by the BECN1 gene), in the regulation of autophagic mechanisms in embryonic hypothalamic neurons in response to hypoglycemic conditions. Embryonic Mouse Hypothalamic Cell Line N39 (mHypoE-N39 or N39) was cultured in reduced concentrations of glucose (2000, 900, 500, and 200 mg/L). Gene and protein expression, as well as immunofluorescence studies on autophagy were conducted under different reduced glucose concentrations in N39 hypothalamic neurons with and without FOS and BECN1 gene knockdowns (KD). The outcomes of the present study have demonstrated a significant increase in autophagosome formation and subsequent lysosomal degradation in the hypothalamic neurons in response to reduced glucose concentrations. This hypoglycemic response appears to be lowered to a similar extent in the FOS KD and BECN1 KD cells, albeit insignificantly from the negative control, is indicative of the involvement of FOS in the autophagic response of hypothalamic neurons to hypoglycemia. Moreover, the KD cells exhibited a change in morphology and reduced cell viability compared with the control cells. Our findings suggest that reduced FOS expression could potentially be associated with impaired autophagic activities that are dependent on BECN1, which could lead to decreased or blunted hypothalamic activation in response to hypoglycemia, and this, in turn, may contribute to the development of HAAF.

Nucleic acid sensor STING drives remodeling and its inhibition enhances steroid responsiveness in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is progressive and irreversible chronic lung inflammatory disease. Cigarette smoke, the main cause of COPD, is often associated with double-stranded DNA release which potentially activates DNA-sensing pathways, such as STING. This study, therefore, analyzed the role of STING pathway in inducing pulmonary inflammation, steroid resistance, and remodeling in COPD. METHODS: Primary cultured lung fibroblasts were isolated from healthy non-smoker, healthy smoker, and smoker COPD individuals. The expression of STING pathway, remodeling, and steroid resistance signatures were investigated in these fibroblasts upon LPS stimulation and treatment with dexamethasone and/or STING inhibitor, at both mRNA and protein levels using qRT-PCR, western blot, and ELISA. RESULTS: At baseline, STING was elevated in healthy smoker fibroblasts and to a higher extent in smoker COPD fibroblasts when compared to healthy non-smoker fibroblasts. Upon using dexamethasone as monotherapy, STING activity was significantly inhibited in healthy non-smoker fibroblasts but showed resistance in COPD fibroblasts. Treating both healthy and COPD fibroblasts with STING inhibitor in combination with dexamethasone additively inhibited STING pathway in both groups. Moreover, STING stimulation triggered a significant increase in remodeling markers and a reduction in HDAC2 expression. Interestingly, treating COPD fibroblasts with the combination of STING inhibitor and dexamethasone alleviated remodeling and reversed steroid hyporesponsiveness through an upregulation of HDAC2. CONCLUSION: These findings support that STING pathway plays an important role in COPD pathogenesis, via inducing pulmonary inflammation, steroid resistance, and remodeling. This raises the possibility of using STING inhibitor as a potential therapeutic adjuvant in combination with common steroid treatment.

Continuous positive airway pressure therapy suppresses inflammatory cytokines and improves glucocorticoid responsiveness in patients with obstructive sleep apnea and asthma: A case-control study.

CONTEXT: Asthma and obstructive sleep apnea (OSA) are prevalent respiratory disorders that frequently coexist. Continuous positive airway pressure (CPAP) therapy is the standard treatment for OSA. However, its effects on systemic inflammation and glucocorticoid responsiveness in OSA patients with asthma are largely unknown. AIMS: To examine the potential role of CPAP therapy in reducing systemic inflammation and improving glucocorticoid responsiveness in asthmatic patients with OSA. SETTINGS AND DESIGN: A case-control study was conducted at the respiratory and sleep clinics involving patients with OSA and patients with asthma and OSA. METHODS: The levels of inflammatory asthma biomarkers (interleukin [IL]-4, IL-17A, IL-8, IL-2, and interferon-γ [IFN-γ]), and glucocorticoid receptors (GR)-α and GR-ß, were determined to compare systemic inflammation and glucocorticoid responsiveness between pre- and post-1-month CPAP treatment in both groups. STATISTICAL ANALYSIS: The Wilcoxon signed-rank test was used to compare inflammatory biomarkers before and after CPAP therapy. P < 0.05 considered statistically significant. The analysis was performed using SPSS. RESULTS: Recruited patients (n = 47), 51% (n = 24) had OSA and 49% (n = 23), had OSA with asthma. Interestingly, the blood levels of IL-17 and IL-8 were significantly decreased post-CPAP therapy in OSA patients, whereas IL-4, IL-17, and IFN-γ were significantly reduced post-CPAP treatment in OSA patients with asthma. Remarkably, CPAP therapy improved glucocorticoid responsiveness in asthmatic patients with OSA, but not in the OSA group and an increase in the GR-α/GR-ß ratio was noted post-CPAP therapy. CONCLUSIONS: Continuous positive airway pressure therapy improved responsiveness to glucocorticoid treatment and demonstrated a suppressive effect on proinflammatory cytokines in asthmatics with OSA.

Bcl10 Regulates Lipopolysaccharide-Induced Pro-Fibrotic Signaling in Bronchial Fibroblasts from Severe Asthma Patients.

Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. Current asthma medications have limited efficacy in treating fibrosis, particularly in patients with severe asthma, necessitating a deeper understanding of the fibrotic mechanisms. The NF-κB pathway is key to airway inflammation in asthma, as it regulates the activity of multiple pro-inflammatory mediators that contribute to airway pathology. Bcl10 is a well-known upstream mediator of the NF-κB pathway that has been linked to fibrosis in other disease models. Therefore, we investigated Bcl10-mediated NF-κB activation as a potential pathway regulating fibrotic signaling in severe asthmatic fibroblasts. We demonstrate here the elevated protein expression of Bcl10 in bronchial fibroblasts and bronchial biopsies from severe asthmatic patients when compared to non-asthmatic individuals. Lipopolysaccharide (LPS) induced the increased expression of the pro-fibrotic cytokines IL-6, IL-8 and TGF-ß1 in bronchial fibroblasts, and this induction was associated with the activation of Bcl10. Inhibition of the Bcl10-mediated NF-κB pathway using an IRAK1/4 selective inhibitor abrogated the pro-fibrotic signaling induced by LPS. Thus, our study indicates that Bcl10-mediated NF-κB activation signals increased pro-fibrotic cytokine expression in severe asthmatic airways. This reveals the therapeutic potential of targeting Bcl10 signaling in ameliorating inflammation and fibrosis, particularly in severe asthmatic individuals.

Recent advances in the immunopathogenesis of severe asthma.

Severe asthma is a heterogeneous disease encompassing different phenotypes and endotypes. Although patients with severe asthma constitute a small proportion of the total population with asthma, they largely account for the morbidity and mortality associated with asthma, indicating a clear unmet need. Being distinct from mild and moderate disease, new insights into the immunopathogenesis of severe asthma are needed. The disease endotypes have provided better insights into the immunopathogenic mechanisms underlying severe asthma. Current stratified approach of treating severe asthma based on phenotypes is met with shortcomings, necessitating unbiased multidimensional endotyping to cope with disease complexity. Therefore, in this review, we explore the distinct endotypes and their mechanistic pathways that characterize the heterogeneity observed in severe asthma.

Long term predictors of breathlessness, exercise intolerance, chronic fatigue and well-being in hospitalized patients with COVID-19: A cohort study with 4 months median follow-up.

BACKGROUND: Post-acute COVID-19 syndrome (PACS) is an emerging healthcare burden. We therefore aimed to determine predictors of different functional outcomes after hospital discharge in patients with COVID-19. METHODS: An ambidirectional cohort study was conducted between May and July 2020, in which PCR-confirmed COVID-19 patients underwent a standardized telephone assessment between 6 weeks and 6 months post discharge. We excluded patients who died, had a mental illness or failed to respond to two follow-up phone calls. The medical research council (MRC) dyspnea scale, metabolic equivalent of task (MET) score for exercise tolerance, chronic fatigability syndrome (CFS) scale and World Health Organization-five well-being index (WHO-5) for mental health were used to evaluate symptoms at follow-up. RESULTS: 375 patients were contacted and 153 failed to respond. The median timing for the follow-up assessment was 122 days (IQR, 109-158). On multivariate analyses, female gender, pre-existing lung disease, headache at presentation, intensive care unit (ICU) admission, critical COVID-19 and post-discharge ER visit were predictors of higher MRC scores at follow-up. Female gender, older age >67 years, arterial hypertension and emergency room (ER) visit were associated with lower MET exercise tolerance scores. Female gender, pre-existing lung disease, and ER visit were associated with higher risk of CFS. Age, dyslipidemia, hypertension, pre-existing lung disease and duration of symptoms were negatively associated with WHO-5 score. CONCLUSIONS: Several risk factors were associated with an increased risk of PACS. Hospitalized patients with COVID-19 who are at risk for PACS may benefit from a targeted pre-emptive follow-up and rehabilitation programs.

Therapeutic effect of statins on airway remodeling during asthma.

INTRODUCTION: Asthma is a chronic inflammatory disease of the airways, which is usually characterized by remodeling, hyperresponsiveness and episodic obstruction of the airways. The underlying chronic airway inflammation leads to pathological restructuring of both the large and small airways. Since the effects of current asthma medications on airway remodeling have been met with contradictions, many therapeutic agents have been redirected from their primary use for the treatment of asthma. Such treatments, which could target several signaling molecules implicated in the inflammatory and airway remodeling processes of asthma, would be an ideal choice. AREAS COVERED: Statins are effective serum cholesterol-lowering agents that were found to have potential anti-inflammatory and anti-remodeling properties. Literature search was done for the past 10 years to include research and review articles in the field of statins and asthma complications. In this review, we discuss the role of statins in airway tissue remodeling and their potential therapeutic modalities in asthma. EXPERT OPINION: With improved understanding of the role of statins in airway remodeling and inflammation, statins represent a potential therapeutic option for various asthma phenotypes. Further research is warranted to optimize statins for asthma therapy through inhalation as a possible route of administration.

Prevalence and predictors of Post-Acute COVID-19 Syndrome (PACS) after hospital discharge: A cohort study with 4 months median follow-up.

BACKGROUND: Post-acute COVID-19 syndrome (PACS) is an emerging healthcare burden. The risk factors associated with PACS remain largely unclear. The aim of this study was to evaluate the frequency of new or persistent symptoms in COVID-19 patients post hospital discharge and identify associated risk factors. METHODS: Our prospective cohort comprised of PCR-confirmed COVID-19 patients admitted to King Fahad Medical City, Riyadh, Saudi Arabia between May and July 2020. The patients were interviewed through phone calls by trained physicians from 6 weeks up to 6 months post hospital discharge. Multivariate Cox proportional hazards and logistic regression models were used to examine for predictors associated with persistence of symptoms and non-return to baseline health. RESULTS: 222 COVID-19 patients responded to follow-up phone interviews after a median of 122 days post discharge. The majority of patients were men (77%) with mean age of 52.47 (± 13.95) years. 56.3% of patients complained of persistent symptoms; 66 (29.7%) experiencing them for >21 days and 64 (28.8%) reporting not having returned to their baseline health. Furthermore, 39 patients (17.6%) reported visiting an emergency room post discharge for COVID-19-related symptoms while 16 (7.2%) had required re-hospitalization. Shortness of breath (40.1%), cough (27.5%) and fatigue (29.7%) were the most frequently reported symptoms at follow-up. After multivariable adjustments, female gender, pre-existing hypertension and length of hospital stay were associated with an increased risk of new or persistent symptoms. Age, pre-existing lung disease and emergency room visits increased the likelihood of not fully recovering from acute COVID-19. Patients who were treated with interferon ß-1b based triple antiviral therapy during hospital stay were less likely to experience new or persistent symptoms and more likely to return to their baseline health. CONCLUSIONS: COVID-19 survivors continued to suffer from dyspnea, cough and fatigue at 4 months post hospital discharge. Several risk factors could predict which patients are more likely to experience PACS and may benefit from individualized follow-up and rehabilitation programs.

Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets.

Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.

Innate Lymphoid Cells and Natural Killer Cells in Bacterial Infections: Function, Dysregulation, and Therapeutic Targets.

Infectious diseases represent one of the largest medical challenges worldwide. Bacterial infections, in particular, remain a pertinent health challenge and burden. Moreover, such infections increase over time due to the continuous use of various antibiotics without medical need, thus leading to several side effects and bacterial resistance. Our innate immune system represents our first line of defense against any foreign pathogens. This system comprises the innate lymphoid cells (ILCs), including natural killer (NK) cells that are critical players in establishing homeostasis and immunity against infections. ILCs are a group of functionally heterogenous but potent innate immune effector cells that constitute tissue-resident sentinels against intracellular and extracellular bacterial infections. Being a nascent subset of innate lymphocytes, their role in bacterial infections is not clearly understood. Furthermore, these pathogens have developed methods to evade the host immune system, and hence permit infection spread and tissue damage. In this review, we highlight the role of the different ILC populations in various bacterial infections and the possible ways of immune evasion. Additionally, potential immunotherapies to manipulate ILC responses will be briefly discussed.

Vitamin D Regulates the Expression of Glucocorticoid Receptors in Blood of Severe Asthmatic Patients.

PURPOSE: Vitamin D (VitD) deficiency is a significant public health concern in many areas around the globe and has been associated with many immune-mediated diseases, including asthma. Severe asthma has been linked to a decreased glucocorticoid receptor (GR) ratio (GR-α/GR-ß ratio), indicating steroid hyporesponsiveness. Using a combination of in silico and in vivo approaches, we aimed to explore the immunomodulatory effect of VitD on asthmatic patients diagnosed with hypovitaminosis D. METHODS: In silico tools were used to identify the regulatory effect of VitD supplementation on GR genes. We measured the expression levels of GR-α and the inactive isoform, GR-ß, in the blood of adult asthmatics diagnosed with hypovitaminosis D before and after VitD supplementation. Moreover, the blood levels of inflammatory cytokines associated with asthma severity were determined. RESULTS: Using an in silico approach, we identified specific genes commonly targeted by VitD as well as corticosteroids, the mainstay of asthma therapy. NR3C1 gene encoding GR was found to be significantly upregulated on Th2 CD4 cells and NK cells. Interestingly, blood expression level of NR3C1 was lower in severe asthmatics compared to nonsevere asthmatics and healthy controls, while the blood level of VitD receptor (VDR) was higher. Upon VitD supplementation of severe asthmatic patients, there was a significant increase in the blood levels of GR-α with no change in GR-ß mRNA expression. VitD supplementation also suppressed the blood levels of IL-17F and IL-4. CONCLUSION: VitD may enhance steroid responsiveness by upregulating the expression of steroid receptor GR-α.

Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19.

More than one year since its emergence, corona virus disease 2019 (COVID-19) is still looming large with a paucity of treatment options. To add to this burden, a sizeable subset of patients who have recovered from acute COVID-19 infection have reported lingering symptoms, leading to significant disability and impairment of their daily life activities. These patients are considered to suffer from what has been termed as "chronic" or "long" COVID-19 or a form of post-acute sequelae of COVID-19, and patients experiencing this syndrome have been termed COVID-19 long-haulers. Despite recovery from infection, the persistence of atypical chronic symptoms, including extreme fatigue, shortness of breath, joint pains, brain fogs, anxiety and depression, that could last for months implies an underlying disease pathology that persist beyond the acute presentation of the disease. As opposed to the direct effects of the virus itself, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to be largely responsible for the appearance of these lasting symptoms, possibly through facilitating an ongoing inflammatory process. In this review, we hypothesize potential immunological mechanisms underlying these persistent and prolonged effects, and describe the multi-organ long-term manifestations of COVID-19.

PRMT5 Selective Inhibitor Enhances Therapeutic Efficacy of Cisplatin in Lung Cancer Cells.

As a therapeutic approach, epigenetic modifiers have the potential to enhance the efficacy of chemotherapeutic agents. Protein arginine methyltransferase 5 (PRMT5), highly expressed in lung adenocarcinoma, was identified to be involved in tumorigenesis. In the current study, we examined the potential antineoplastic activity of PRMT5 inhibitor, arginine methyltransferase inhibitor 1 (AMI-1), and cisplatin on lung adenocarcinoma. Bioinformatic analyses identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5-associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival in lung adenocarcinoma. Combined AMI-1 and cisplatin treatment significantly reduced cell viability and induced apoptosis. Cell cycle arrest in A549 and DMS 53 cells was evident after AMI-1, and was reinforced after combination treatment. Western blot analysis showed a reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While the combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on HBEpC (normal epithelial cells). The survival of normal bronchial epithelial cells was not affected by using AMI-1. This study highlights evidence of novel selective antitumor activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells.

Derangement of cell cycle markers in peripheral blood mononuclear cells of asthmatic patients as a reliable biomarker for asthma control.

In asthma, most of the identified biomarkers pertain to the Th2 phenotype and no known biomarkers have been verified for severe asthmatics. Therefore, identifying biomarkers using the integrative phenotype-genotype approach in severe asthma is needed. The study aims to identify novel biomarkers as genes or pathways representing the core drivers in asthma development, progression to the severe form, resistance to therapy, and tissue remodeling regardless of the sample cells or tissues examined. Comprehensive reanalysis of publicly available transcriptomic data that later was validated in vitro, and locally recruited patients were used to decipher the molecular basis of asthma. Our in-silicoanalysis revealed a total of 10 genes (GPRC5A, SFN, ABCA1, KRT8, TOP2A, SERPINE1, ANLN, MKI67, NEK2, and RRM2) related to cell cycle and proliferation to be deranged in the severe asthmatic bronchial epithelium and fibroblasts compared to their healthy counterparts. In vitro, RT qPCR results showed that (SERPINE1 and RRM2) were upregulated in severe asthmatic bronchial epithelium and fibroblasts, (SFN, ABCA1, TOP2A, SERPINE1, MKI67, and NEK2) were upregulated in asthmatic bronchial epithelium while (GPRC5A and KRT8) were upregulated only in asthmatic bronchial fibroblasts. Furthermore, MKI76, RRM2, and TOP2A were upregulated in Th2 high epithelium while GPRC5A, SFN, ABCA1 were upregulated in the blood of asthmatic patients. SFN, ABCA1 were higher, while MKI67 was lower in severe asthmatic with wheeze compared to nonasthmatics with wheezes. SERPINE1 and GPRC5A were downregulated in the blood of eosinophilic asthmatics, while RRM2 was upregulated in an acute attack of asthma. Validation of the gene expression in PBMC of locally recruited asthma patients showed that SERPINE1, GPRC5A, SFN, ABCA1, MKI67, and RRM2 were downregulated in severe uncontrolled asthma. We have identified a set of biologically crucial genes to the homeostasis of the lung and in asthma development and progression. This study can help us further understand the complex interplay between the transcriptomic data and the external factors which may deviate our understanding of asthma heterogeneity.

Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts.

Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target for pharmaceutical management of severe asthma. Wnt/ß-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. Here we explored the changes in Wnt signaling associated with asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based on in silico analysis and followed by in vitro validation. In summary, the in silico analysis showed that the bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. A Th2-high phenotype is associated with upregulated Wnt-negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling member enrichment. Most of these genes are regulators of healthy lung development early in life and, if disturbed, can make people susceptible to developing asthma early in life and prone to developing a severe phenotype. Most of the Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which puts cells under stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is also dependent on Wnt signaling. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO-treated cells. In fibroblasts from asthmatic patients, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged besides other pathways that might be non-functional.

Implications of preexisting asthma on COVID-19 pathogenesis.

The coronavirus disease 2019 (COVID-19) pandemic spreading at an alarming rate has taken a heavy toll on the public healthcare systems and economies worldwide. An abnormal and overactivated inflammatory response is occasionally elicited by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and this hyperinflammation is associated with worse prognosis of COVID-19. Theoretically, one would expect patients with asthma to be at a greater risk of SARS-CoV-2 infection considering their increased susceptibility to common respiratory virus-associated exacerbations. Surprisingly, current data do not consistently suggest an increased prevalence of asthma among patients with COVID-19. Considering the high global prevalence of asthma, the characteristics of the disease and/or their conventional therapy might play a role in their potential defense against COVID-19. This may be attributed to the T helper type 2 immune response predominantly seen in patients with asthma. Likewise, asthma therapeutics, including corticosteroids and biologics, may in fact benefit the patients with asthma by alleviating the development of hyperinflammation. On the other hand, elevated IL-17 levels are characteristically seen in a subset of asthma patients with severe disease as well as in patients with COVID-19. Targeting the IL-17 pathway as a treatment strategy could plausibly alleviate acute respiratory distress syndrome (ARDS) in patients with COVID-19 and asthma demonstrating a predominant T helper type 17 response. A clinical trial including a drug targeting this pathway may thus, constitute a logical addition to the global pursuit for effective therapeutics against COVID-19. The complex interplay between the asthma endotypes and COVID-19 is not very well understood and will be discussed in this mini-review.

IL-13 Augments Histone Demethylase JMJD2B/KDM4B Expression Levels, Activity, and Nuclear Translocation in Airway Fibroblasts in Asthma.

PURPOSE: Asthma is one of the most common obstructive pulmonary diseases worldwide. Epigenetic alterations, including DNA methylation and histone modifications, have been reported to contribute to asthma pathogenesis. Since the inflammation mediator and remodeling trigger, IL-13, is known to play a central role in the pathophysiology of asthma, this study was aimed to identify novel IL-13-regulated epigenetic modifiers in asthma that may contribute to subepithelial fibrosis. METHODS: Publicly available transcriptomic datasets from Gene Expression Omnibus (GEO) were used to identify differentially expressed genes on an epigenetic level upon IL-13 exposure in lung fibroblasts. Bronchial fibroblasts isolated from healthy and asthmatic individuals were assessed for the gene and protein expression levels of the identified gene at baseline and upon IL-13 treatment using qRT-PCR and western blotting, respectively. Its subcellular localization and tissue distribution were examined in bronchial fibroblasts as well as bronchial biopsies by immunofluorescence and immunohistochemical analysis, respectively. RESULTS: Bioinformatic analysis revealed the differential expression of the histone demethylase JMJD2B/KDM4B, a well-known epigenetic modulator that leads to the demethylation of different lysine residues on histones, in IL-13-treated lung fibroblasts. The baseline expression levels of JMJD2B were higher in asthmatic fibroblasts and in bronchial biopsies in comparison to healthy ones. There was also an increase in JMJD2B activity as evidenced by the demethylation of its downstream target, H3K36me3. Furthermore, IL-13 stimulation induced JMJD2B expression and further demethylation of H3K36me3 in asthmatic fibroblasts. This was accompanied by increased translocation of JMJD2B into the nucleus. CONCLUSION: This study highlights the novel pathological involvement of the histone demethylase JMJD2B/KDM4B in asthmatic airway fibroblasts that are regulated by IL-13. Clinical implications. Given that there is no single therapeutic medicine to effectively treat the various subtypes of asthma, this study provides promising insights into JMJD2B as a new therapeutic target that could potentially improve the treatment and management of asthma.

Nucleic Acid-Sensing Pathways During SARS-CoV-2 Infection: Expectations versus Reality.

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1ß and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.