p38 MAPK signaling in chronic obstructive pulmonary disease pathogenesis and inhibitor therapeutics.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar remodeling. Although the abnormalities are primarily prompted by chronic exposure to inhaled irritants, maladjusted and self-reinforcing immune responses are significant contributors to the development and progression of the disease. The p38 isoforms are regarded as pivotal hub proteins that regulate immune and inflammatory responses in both healthy and disease states. As a result, their inhibition has been the subject of numerous recent studies exploring their therapeutic potential in COPD. MAIN BODY: We performed a systematic search based on the PRISMA guidelines to find relevant studies about P38 signaling in COPD patients. We searched the PubMed and Google Scholar databases and used "P38" AND "COPD" Mesh Terms. We applied the following inclusion criteria: (1) human, animal, ex vivo and in vitro studies; (2) original research articles; (3) published in English; and (4) focused on P38 signaling in COPD pathogenesis, progression, or treatment. We screened the titles and abstracts of the retrieved studies and assessed the full texts of the eligible studies for quality and relevance. We extracted the following data from each study: authors, year, country, sample size, study design, cell type, intervention, outcome, and main findings. We classified the studies according to the role of different cells and treatments in P38 signaling in COPD. CONCLUSION: While targeting p38 MAPK has demonstrated some therapeutic potential in COPD, its efficacy is limited. Nevertheless, combining p38 MAPK inhibitors with other anti-inflammatory steroids appears to be a promising treatment choice. Clinical trials testing various p38 MAPK inhibitors have produced mixed results, with some showing improvement in lung function and reduction in exacerbations in COPD patients. Despite these mixed results, research on p38 MAPK inhibitors is still a major area of study to develop new and more effective therapies for COPD. As our understanding of COPD evolves, we may gain a better understanding of how to utilize p38 MAPK inhibitors to treat this disease. Video Abstract.

We wanted to determine what studies have been done on how a protein called p38 affects a lung disease called COPD. COPD is a condition that makes it hard to breathe and can cause coughing, wheezing, and chest infections. p38 is a protein that helps cells to respond to stress and inflammation, but it may also play a role in causing or worsening COPD. We searched two main online databases for studies that met our criteria. We looked for studies that involved humans, studies that used animals or cells in the lab, studies that reported new findings, studies that were written in English, and studies that focused on p38 and COPD. We did not include studies that were reviews, summaries, opinions, or letters or studies that were not related to p38 or COPD. We found 361 studies that matched our criteria. We read the titles and summaries of these studies and checked the full texts for quality and relevance. We collected information from each study, such as who did it, when and where it was done, how many people were involved, what type of cells were studied, what treatment was given, what outcome was measured, and what the main results were. We grouped the studies based on the type of cells and type of treatment they studied. We found that different types of cells (such as lung cells, immune cells, and blood cells) and different types of treatment can affect how p38 works in COPD.

Exploring Co-occurrence patterns and microbial diversity in the lung microbiome of patients with non-small cell lung cancer.

BACKGROUND: It has been demonstrated in the literature that a dysbiotic microbiome could have a negative impact on the host immune system and promote disease onset or exacerbation. Co-occurrence networks have been widely adopted to identify biomarkers and keystone taxa in the pathogenesis of microbiome-related diseases. Despite the promising results that network-driven approaches have led to in various human diseases, there is a dearth of research pertaining to key taxa that contribute to the pathogenesis of lung cancer. Therefore, our primary goal in this study is to explore co-existing relationships among members of the lung microbial community and any potential gained or lost interactions in lung cancer. RESULTS: Using integrative and network-based approaches, we integrated four studies assessing the microbiome of lung biopsies of cancer patients. Differential abundance analyses showed that several bacterial taxa are different between tumor and tumor-adjacent normal tissues (FDR adjusted p-value < 0.05). Four, fifteen, and twelve significantly different associations were found at phylum, family, and genus levels. Diversity analyses suggested reduced alpha diversity in the tumor microbiome. However, beta diversity analysis did not show any discernible pattern between groups. In addition, four distinct modules of bacterial families were detected by the DBSCAN clustering method. Finally, in the co-occurrence network context, Actinobacteria, Firmicutes, Bacteroidetes, and Chloroflexi at the phylum level and Bifidobacterium, Massilia, Sphingobacterium, and Ochrobactrum at the genus level showed the highest degree of rewiring. CONCLUSIONS: Despite the absence of statistically significant differences in the relative abundance of certain taxa between groups, it is imperative not to overlook them for further exploration. This is because they may hold pivotal central roles in the broader network of bacterial taxa (e.g., Bifidobacterium and Massilia). These findings emphasize the importance of a network analysis approach for studying the lung microbiome since it could facilitate identifying key microbial taxa in lung cancer pathogenesis. Relying exclusively on differentially abundant taxa may not be enough to fully grasp the complex interplay between lung cancer and the microbiome. Therefore, a network-based approach can offer deeper insights and a more comprehensive understanding of the underlying mechanisms.

The controversial effect of smoking and nicotine in SARS-CoV-2 infection.

The effects of nicotine and cigarette smoke in many diseases, notably COVID-19 infection, are being debated more frequently. The current basic data for COVID-19 is increasing and indicating the higher risk of COVID-19 infections in smokers due to the overexpression of corresponding host receptors to viral entry. However, current multi-national epidemiological reports indicate a lower incidence of COVID-19 disease in smokers. Current data indicates that smokers are more susceptible to some diseases and more protective of some other. Interestingly, nicotine is also reported to play a dual role, being both inflammatory and anti-inflammatory. In the present study, we tried to investigate the effect of pure nicotine on various cells involved in COVID-19 infection. We followed an organ-based systematic approach to decipher the effect of nicotine in damaged organs corresponding to COVID-19 pathogenesis (12 related diseases). Considering that the effects of nicotine and cigarette smoke are different from each other, it is necessary to be careful in generalizing the effects of nicotine and cigarette to each other in the conducted researches. The generalization and the undifferentiation of nicotine from smoke is a significant bias. Moreover, different doses of nicotine stimulate different effects (dose-dependent response). In addition to further assessing the role of nicotine in COVID-19 infection and any other cases, a clever assessment of underlying diseases should also be considered to achieve a guideline for health providers and a personalized approach to treatment.

Oral and nasal probiotic administration for the prevention and alleviation of allergic diseases, asthma and chronic obstructive pulmonary disease.

Interaction between a healthy microbiome and the immune system leads to body homeostasis, as dysbiosis in microbiome content and loss of diversity may result in disease development. Due to the ability of probiotics to help and modify microbiome constitution, probiotics are now widely used for the prevention and treatment of different gastrointestinal, inflammatory, and, more recently, respiratory diseases. In this regard, chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma and allergic rhinitis are among the most common and complicated respiratory diseases with no specific treatment until now. Accordingly, many studies have evaluated the therapeutic efficacy of probiotic administration (mostly via the oral route and much lesser nasal route) on chronic respiratory diseases. We tried to summarise and evaluate these studies to give a perspective of probiotic therapy via both the oral and nasal routes for respiratory infections (in general) and chronic respiratory diseases (specifically). We finally concluded that probiotics might be useful for allergic diseases. For asthmatic patients, probiotics can modulate serum cytokines and IgE and decrease eosinophilia, but with no significant reduction in clinical symptoms. For COPD, only limited studies were found with uncertain clinical efficacy. For intranasal administration, although some studies propose more efficiency than the oral route, more clinical evaluations are warranted.

Distinguishing drug/non-drug-like small molecules in drug discovery using deep belief network.

The advent of computational methods for efficient prediction of the druglikeness of small molecules and their ever-burgeoning applications in the fields of medicinal chemistry and drug industries have been a profound scientific development, since only a few amounts of the small molecule libraries were identified as approvable drugs. In this study, a deep belief network was utilized to construct a druglikeness classification model. For this purpose, small molecules and approved drugs from the ZINC database were selected for the unsupervised pre-training step and supervised training step. Various binary fingerprints such as Macc 166 bit, PubChem 881 bit, and Morgan 2048 bit as data features were investigated. The report revealed that using an unsupervised pre-training phase can lead to a good performance model and generalizability capability. Accuracy, precision, and recall of the model for Macc features were 97%, 96%, and 99%, respectively. For more consideration about the generalizability of the model, the external data by expression and investigational drugs in drug banks as drug data and randomly selected data from the ZINC database as non-drug were created. The results confirmed the good performance and generalizability capability of the model. Also, the outcomes depicted that a large proportion of misclassified non-drug small molecules ascertain the bioavailability conditions and could be investigated as a drug in the future. Furthermore, our model attempted to tap potential opportunities as a drug filter in drug discovery.

The identification of co-expressed gene modules in Streptococcus pneumonia from colonization to infection to predict novel potential virulence genes.

BACKGROUND: Streptococcus pneumonia (pneumococcus) is a human bacterial pathogen causing a range of mild to severe infections. The complicated transcriptome patterns of pneumococci during the colonization to infection process in the human body are usually determined by measuring the expression of essential virulence genes and the comparison of pathogenic with non-pathogenic bacteria through microarray analyses. As systems biology studies have demonstrated, critical co-expressing modules and genes may serve as key players in biological processes. Generally, Sample Progression Discovery (SPD) is a computational approach traditionally used to decipher biological progression trends and their corresponding gene modules (clusters) in different clinical samples underlying a microarray dataset. The present study aimed to investigate the bacterial gene expression pattern from colonization to severe infection periods (specimens isolated from the nasopharynx, lung, blood, and brain) to find new genes/gene modules associated with the infection progression. This strategy may lead to finding novel gene candidates for vaccines or drug design. RESULTS: The results included essential genes whose expression patterns varied in different bacterial conditions and have not been investigated in similar studies. CONCLUSIONS: In conclusion, the SPD algorithm, along with differentially expressed genes detection, can offer new ways of discovering new therapeutic or vaccine targeted gene products.

Involvement of microRNAs in physiological and pathological processes in asthma.

Asthma is the most common respiratory disease accompanied by lung inflammatory disorders. The main symptoms are airway obstruction, chronic inflammation due to mast cell and eosinophil activity, and the disturbance of immune responses mostly mediated by the Th2 response. Genetic background and environmental factors also contribute to the pathogenesis of asthma. Today, microRNAs (miRNAs) are known as remarkable regulators of gene expression. As a small group of noncoding single-strand RNAs, mature miRNAs (~21 nucleotides) modulate the gene expression by targeting complement RNAs at both transcriptional and posttranscriptional levels. The role of miRNAs in the pathogenesis of many diseases such as allergies, asthma, and autoimmunity has been vastly studied. This review provides a thorough research update on the role of miRNAs in the pathogenesis of asthma and their probable role as diagnostic and/or therapeutic biomarkers.

Pneumococcal Disease and the Effectiveness of the PPV23 Vaccine in Adults: A Two-Stage Bayesian Meta-Analysis of Observational and RCT Reports.

The efficacy of PPV-23 vaccine on outcomes of pneumococcal disease in adults still remains controversial due mainly to the lack of consistency between the results obtained from observational studies(OSs) and those obtained from randomized controlled trials(RCTs). As a consequence, the complexity in the structure of evidence available, in turn, generates a challenge for combining disparate pieces of evidence quantitatively. In this regard, we used a hierarchical Bayesian inference-based evidence synthesis of RCTs and observational data using a two-stage approach (in addition to a traditional random-effects meta-analysis) to examine the effectiveness of PPV-23 in adults. To this end, 21 studies were included involving 826109 adult participants. By a two-stage Bayesian meta-analysis, which was directly used for combining studies of different designs, the overall log OR (95% credible interval) for IPDs was -0.1048 (-0.3920,-0.0250), indicating a significant protective effect of the vaccination against IPDs. No significant effect of PPV-23 was found on all-cause pneumonia, pneumococcal pneumonia, and death from pneumonia, which confirmed the results obtained by a traditional method followed by stratified and sensitivity analyses. The estimated overall log OR (95% credible interval) was -0.0002 (-0.0241,0.0142), -0.0002 (-0.0110,0.0122), and -6.3912 × 10-5 (-0.0219,0.0131), respectively. The PPV-23 vaccine might be effective in preventing the most severe invasive forms of pneumococcal diseases, but not effective in preventing other clinical outcomes, in the adult population of 18 years and older.

Airway remodeling: Systems biology approach, from bench to bedside.

Airway Remodeling, a patho-physiologic process, is considered as a key feature of chronic airway diseases. In recent years, our understanding of the complex diseases has increased significantly by the use of combined approaches, including systems biology, which may contribute to the development of personalized and predictive medicine approaches. Integrative analysis, along with the cooperation of clinicians, computer scientists, research scientists, and bench scientists, has become an important part of the experimental design and therapeutic strategies in the era of omics. The airway remodeling process is the result of the dysregulation of several signaling pathways that modulate the airway regeneration; therefore, high-throughput experiments and systems biology approach can help to understand this process better. The study reviews related literature and is consistent with the existing clinical evidence.

Immunology of Chronic Obstructive Pulmonary Disease and Sulfur Mustard Induced Airway Injuries: Implications for Immunotherapeutic Interventions.

BACKGROUND: Sulfur mustard (SM)-induced airway injuries and chronic obstructive pulmonary disease (COPD) are characterized by chronic inflammation of the respiratory tract and share some similarities regarding the cellular and molecular mechanisms orchestrating airway destruction. Since available data regarding the immunobiology of COPD is much more known compared with SM-mediated injuries, and considering the similarities in the immunopathogenesis of these diseases, comparison of the immunopathogenesis of COPD and SM-induced respiratory complications can help designing new therapeutic approaches for treatment of SM-induced injuries. METHODS: A multi-database search was performed to identify articles dealing with the role of immune system function in the pathogenesis of COPD and mustard mustard-induced respiratory complications. RESULTS: This review outlines the role of different components of the immune system in the pathogenesis of COPD and mustard-induced respiratory complications, and suggests therapeutic implication for improving the management of the latter condition as the most common chronic complication of sulfur mustard exposure. CONCLUSION: Although COPD and mustard lung are overlapping phenotypes and have shared pathophysiologic features, there are certain differences between these two diseases that necessitate further scrutiny. Combination therapies to counterbalance inflammation, oxidative stress and immune imbalance hold promise for the management of SM-induced respiratory complications but the success of such combined treatments need to be confirmed in proof-ofconcept trials.

Reconstruction of Arabidopsis thaliana fully integrated small RNA pathway.

Small non-protein-coding RNAs (ncRNAs) have acquired diverse functions in plant and animals development. These riboregulators have been confirmed to cooperate in plant growth and development in the processes of moderating the levels of specific mRNAs and their translation products through to chromatin remodeling and silencing. According to the specific needs for interpreting and annotating small-RNA-based regulatory networks, it is evident that many additional components remain to be discovered and functionally characterized. Shedding light on the remaining components and uncovering the relation of the small-RNA-generating pathways with the synthesis of other components such as hormones and transcription factors define future challenges as more complicated mechanisms are expected to be characterized. In this review, we summarize our current understanding of the molecular and biological roles of ncRNAs in gene regulation/expression, describe in detail the specific and shared components for each pathway and highlight the advances in currently identified relationships and interactions between small ncRNAs. We present a fully integrated pathway connecting ncRNA entities such as miRNAs, siRNAs, ta-siRNAs, and nat-siRNAs, to each other within Arabidopsis thaliana.