Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement.

Circular RNAs: emerging players in asthma and COPD.

Circular RNAs (circRNAs) belong to a unique class of endogenously expressed non-protein-coding RNAs with a distinct circularized structure, characterized by the absence of 5'-cap and 3'-polyadenylate ends. They are generally formed through back-splicing from pre-mRNAs. They serve as regulators of transcription and splicing, and act as sponges for microRNAs (miRNAs) and RNA-binding proteins, thereby modulating the expression of target genes. As a result, they exert a substantial impact on a diverse array of cellular and biological processes, including cell proliferation, migration, inflammation, and oxidative stress. Asthma and COPD are chronic airway conditions that currently have no cure. In recent years, emerging evidence suggests that altered expression of circRNAs in airway, bronchial and immune cells is involved in asthma and COPD pathogenesis. Studies exploring circRNA dysregulation in asthma have showcased their involvement in regulating the proliferation, migration, and inflammation of airway smooth muscle and bronchial epithelial cells, as well as impacting goblet cell metaplasia, Th2 cell differentiation, and macrophage activation, primarily through interactions with miRNAs. Similarly, in COPD, circRNAs have shown altered expression patterns in the blood and lungs of patients, and these changes have been linked to modulating inflammation, oxidative stress, and airway remodeling in preclinical models. Furthermore, certain circRNAs have demonstrated promising potential as diagnostic and prognostic biomarkers for both asthma and COPD. This review delves into the current understanding of the function and molecular mechanisms of circRNAs in asthma and COPD, along with exploring their potential as biomarkers in these respiratory conditions.

Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined a multi-tissue full lifespan microbial biogeography for healthy Fischer 344 rats. Microbial community profiling data was extracted and integrated with host transcriptomic data from the Sequencing Quality Control (SEQC) consortium. Unsupervised machine learning, Spearman's correlation, taxonomic diversity, and abundance analyses were performed to determine and characterize the rat microbial biogeography and the identification of four inter-tissue microbial heterogeneity patterns (P1-P4). The 11 body habitats harbor a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundances progressively declined in lungs from breastfeed newborn to adolescence/adult and was below detectable levels in elderly rats. LAB's presence and levels in lungs were further evaluated by PCR in the two validation datasets. The lung, testes, thymus, kidney, adrenal, and muscle niches were found to have age-dependent alterations in microbial abundance. P1 is dominated by lung samples. P2 contains the largest sample size and is enriched for environmental species. Liver and muscle samples were mostly classified into P3. Archaea species were exclusively enriched in P4. The 357 pattern-specific microbial signatures were positively correlated with host genes in cell migration and proliferation (P1), DNA damage repair and synaptic transmissions (P2), as well as DNA transcription and cell cycle in P3. Our study established a link between metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures would be useful for microbiome therapeutic approaches to human health and good quality of life.

Emerging role of long non-coding RNA MALAT1 related signaling pathways in the pathogenesis of lung disease.

Long non-coding RNAs (lncRNAs) are endogenously expressed RNAs longer than 200 nt that are not translated into proteins. In general, lncRNAs bind to mRNA, miRNA, DNA, and proteins and regulate gene expression at various cellular and molecular levels, including epigenetics, transcription, post-transcription, translation, and post-translation. LncRNAs play important roles in many biological processes, such as cell proliferation, apoptosis, cell metabolism, angiogenesis, migration, endothelial dysfunction, endothelial-mesenchymal transition, regulation of cell cycle, and cellular differentiation, and have become an important topic of study in genetic research in health and disease due to their close link with the development of various diseases. The exceptional stability, conservation, and abundance of lncRNAs in body fluids, have made them potential biomarkers for a wide range of diseases. LncRNA MALAT1 is one of the best-studied lncRNAs in the pathogenesis of various diseases, including cancers and cardiovascular diseases. A growing body of evidence suggests that aberrant expression of MALAT1 plays a key role in the pathogenesis of lung diseases, including asthma, chronic obstructive pulmonary diseases (COPD), Coronavirus Disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), lung cancers, and pulmonary hypertension through different mechanisms. Here we discuss the roles and molecular mechanisms of MALAT1 in the pathogenesis of these lung diseases.

The emerging diagnostic and therapeutic roles of small nucleolar RNAs in lung diseases.

Small nucleolar RNAs (snoRNAs) are non-coding RNA molecules that range from 60 to 300 nucleotides in length and are primarily located in the nucleoli of cells. They play a critical role in modifying ribosomal RNA and can also regulate alternative splicing and posttranscriptional modification of mRNA. Alterations in snoRNA expression can affect numerous cellular processes, including cell proliferation, apoptosis, angiogenesis, fibrosis, and inflammation, making them a promising target for diagnostics and treatment of various human pathologies. Recent evidence suggests that abnormal snoRNA expression is strongly associated with the development and progression of several lung diseases, such as lung cancer, asthma, chronic obstructive pulmonary disease, and pulmonary hypertension, as well as COVID-19. While few studies have shown a causal relationship between snoRNA expression and disease onset, this research field presents exciting opportunities for identifying new biomarkers and therapeutic targets in lung disease. This review discusses the emerging role and molecular mechanisms of snoRNAs in the pathogenesis of lung diseases, focusing on research opportunities, clinical studies, biomarkers, and therapeutic potential.

PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension.

Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling, we used a siRNA-mediated high-throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as readout for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in healthy human pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients, and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.

Decreasing ELK3 expression improves Bone Morphogenetic Protein Receptor 2 signaling and pulmonary vascular cell function in PAH.

ELK3 is upregulated in blood and pulmonary vascular cells of PAH patients and may play a significant role in PAH potentially through modulating BMPR2 signaling.

Nutraceuticals and COVID-19: A mechanistic approach toward attenuating the disease complications.

Nutraceuticals have emerged as potential compounds to attenuate the COVID-19 complications. Precisely, these food additives strengthen the overall COVID treatment and enhance the immunity of a person. Such compounds have been used at a large scale, in almost every household due to their better affordability and easy access. Therefore, current research is focused on developing newer advanced formulations from potential drug candidates including nutraceuticals with desirable properties viz, affordability, ease of availability, ease of administration, stability under room temperature, and potentially longer shelf-lives. As such, various nutraceutical-based products such as compounds could be promising agents for effectively managing COVID-19 symptoms and complications. Most importantly, regular consumption of such nutraceuticals has been shown to boost the immune system and prevent viral infections. Nutraceuticals such as vitamins, amino acids, flavonoids like curcumin, and probiotics have been studied for their role in the prevention of COVID-19 symptoms such as fever, pain, malaise, and dry cough. In this review, we have critically reviewed the potential of various nutraceutical-based therapeutics for the management of COVID-19. We searched the information relevant to our topic from search engines such as PubMed and Scopus using COVID-19, nutraceuticals, probiotics, and vitamins as a keyword. Any scientific literature published in a language other than English was excluded. PRACTICAL APPLICATIONS: Nutraceuticals possess both nutritional values and medicinal properties. They can aid in the prevention and treatment of diseases, as well as promote physical health and the immune system, normalizing body functions, and improving longevity. Recently, nutraceuticals such as probiotics, vitamins, polyunsaturated fatty acids, trace minerals, and medicinal plants have attracted considerable attention and are widely regarded as potential alternatives to current therapeutic options for the effective management of various diseases, including COVID-19.

Impact of ecDNA: A mechanism that directs tumorigenesis in cancer drug Resistance-A review.

Extrachromosomal DNA (ecDNA) is often found in cancerous cells, and numerous scientific investigations have already shown that ecDNA-mediated oncogene amplification which contributes to cancer therapy resistance. This ecDNA is found to be essential for enhancing gene transcription and resistance to chemotherapeutic drugs, as well as promoting tumor heterogeneity and reversing tumor phenotypes, suggesting that it plays a key role in carcinogenesis. The ecDNA induces tumors to become hostile which results in a lower survival rate and chemotherapy tolerance. It also holds the potential as a target for treatment or diagnostic procedure of tumors. The review describes the properties and origins of ecDNA, as well as how it affects carcinogenesis, its function in cancer etiology and progression, and its therapeutic value. Propagation of oncogenes and resistance genes situated in extra-chromosomal DNA has been discovered to become one of the primary causes of intra-tumor genetic heterogeneity and may result in a threshold of probable evolutionary adaptation in many investigations.

The role of circular RNAs in pulmonary hypertension.

Circular RNAs (circRNAs) are endogenous, covalently circularised, non-protein-coding RNAs generated from back-splicing. Most circRNAs are very stable, highly conserved, and expressed in a tissue-, cell- and developmental stage-specific manner. circRNAs play a significant role in various biological processes, such as regulation of gene expression and protein translation via sponging of microRNAs and binding with RNA-binding proteins. circRNAs have become a topic of great interest in research due to their close link with the development of various diseases. Their high stability, conservation and abundance in body fluids make them promising biomarkers for many diseases. A growing body of evidence suggests that aberrant expression of circRNAs and their targets plays a crucial role in pulmonary vascular remodelling and pulmonary arterial hypertension (group 1) as well as other forms (groups 3 and 4) of pulmonary hypertension (PH). Here we discuss the roles and molecular mechanisms of circRNAs in the pathogenesis of pulmonary vascular remodelling and PH. We also highlight the therapeutic and biomarker potential of circRNAs in PH.

Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COPD overlap (ACO). Patients characterized with ACO have increased disease severity; however, the mechanisms driving this have not been widely studied. OBJECTIVES: This study sought to characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite antigen and cigarette smoke exposure. METHODS: Female BALB/c mice were chronically exposed to house dust mite antigen for 11 weeks to induce experimental asthma, cigarette smoke for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Lung inflammation, structural changes, and lung function were assessed. RNA-sequencing was performed on separated airway and parenchyma lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313. RESULTS: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition, and increased airway hyperresponsiveness. Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchyma samples in experimental asthma, COPD, and ACO. Upstream driver analysis revealed increased expression of the transcription factor Spi1. Pharmacological inhibition of SPI1 using DB2313, reduced airway remodeling and airway hyperresponsiveness in experimental ACO. CONCLUSIONS: A new experimental model of ACO featuring chronic dual exposures to house dust mite and cigarette smoke mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy.

The Role of Zinc in the Pathogenesis of Lung Disease.

Lung diseases, such as asthma, chronic obstructive pulmonary diseases (COPD), and cystic fibrosis (CF), are among the leading causes of mortality and morbidity globally. They contribute to substantial economic burdens on society and individuals. Currently, only a few treatments are available to slow the development and progression of these diseases. Thus, there is an urgent unmet need to develop effective therapies to improve quality of life and limit healthcare costs. An increasing body of clinical and experimental evidence suggests that altered zinc and its regulatory protein levels in the systemic circulation and in the lungs are associated with these disease's development and progression. Zinc plays a crucial role in human enzyme activity, making it an essential trace element. As a cofactor in metalloenzymes and metalloproteins, zinc involves a wide range of biological processes, such as gene transcription, translation, phagocytosis, and immunoglobulin and cytokine production in both health and disease. Zinc has gained considerable interest in these lung diseases because of its anti-inflammatory, antioxidant, immune, and metabolic modulatory properties. Here we highlight the role and mechanisms of zinc in the pathogenesis of asthma, COPD, CF, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, and pulmonary hypertension.

Aim2 suppresses cigarette smoke-induced neutrophil recruitment, neutrophil caspase-1 activation and anti-Ly6G-mediated neutrophil depletion.

Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) and absent in melanoma-2 (AIM2) inflammasomes in cigarette smoke-induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2-/- mice in cigarette smoke-induced experimental COPD. MCC950 treatment had minimal effects on disease development and/or progression. Aim2-/- mice had increased airway neutrophils with decreased caspase-1 levels, independent of changes in lung neutrophil chemokines. Suppressing neutrophils with anti-Ly6G in experimental COPD in wild-type mice reduced neutrophils in bone marrow, blood and lung. By contrast, anti-Ly6G treatment in Aim2-/- mice with experimental COPD had no effect on neutrophils in bone marrow, partially reduced neutrophils in the blood and had no effect on neutrophils or neutrophil caspase-1 levels in the lungs. These findings identify that following cigarette smoke exposure, Aim2 is important for anti-Ly6G-mediated depletion of neutrophils, suppression of neutrophil recruitment and mediates activation of caspase-1 in neutrophils.

Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models.

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases.

Nuclear factor κB (NFκB) is a unique protein complex that plays a major role in lung inflammation and respiratory dysfunction. The NFκB signaling pathway, therefore becomes an avenue for the development of potential pharmacological interventions, especially in situations where chronic inflammation is often constitutively active and plays a key role in the pathogenesis and progression of the disease. NFκB decoy oligodeoxynucleotides (ODNs) are double-stranded and carry NFκB binding sequences. They prevent the formation of NFκB-mediated inflammatory cytokines and thus have been employed in the treatment of a variety of chronic inflammatory diseases. However, the systemic administration of naked decoy ODNs restricts their therapeutic effectiveness because of their poor pharmacokinetic profile, instability, degradation by cellular enzymes and their low cellular uptake. Both structural modification and nanotechnology have shown promising results in enhancing the pharmacokinetic profiles of potent therapeutic substances and have also shown great potential in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. In this review, we examine the contribution of NFκB activation in respiratory diseases and recent advancements in the therapeutic use of decoy ODNs. In addition, we also highlight the limitations and challenges in use of decoy ODNs as therapeutic molecules, cellular uptake of decoy ODNs, and the current need for novel delivery systems to provide efficient delivery of decoy ODNs. Furthermore, this review provides a common platform for discussion on the existence of decoy ODNs, as well as outlining perspectives on the latest generation of delivery systems that encapsulate decoy ODNs and target NFκB in respiratory diseases.

Role of Long Non-Coding RNAs in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a debilitating condition of the pulmonary circulatory system that occurs in patients of all ages and if untreated, eventually leads to right heart failure and death. Despite existing medical treatment options that improve survival and quality of life, the disease remains incurable. Thus, there is an urgent need to develop novel therapies to treat this disease. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in pulmonary vascular remodeling and PAH. LncRNAs are implicated in pulmonary arterial endothelial dysfunction by modulating endothelial cell proliferation, angiogenesis, endothelial mesenchymal transition, and metabolism. LncRNAs are also involved in inducing different pulmonary arterial vascular smooth muscle cell phenotypes, such as cell proliferation, apoptosis, migration, regulation of the phenotypic switching, and cell cycle. LncRNAs are essential regulators of gene expression that affect various diseases at the chromatin, transcriptional, post-translational, and even post-translational levels. Here, we focus on the role of LncRNAs and their molecular mechanisms in the pathogenesis of PAH. We also discuss the current research challenge and potential biomarker and therapeutic potentials of lncRNAs in PAH.

Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment.

Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.

Promising therapeutic approaches in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a debilitating multifactorial disease characterized by progressive pulmonary vascular remodeling, elevated pulmonary arterial pressure, and pulmonary vascular resistance, resulting in right ventricular failure and subsequent death. Current available therapies do not reverse the disease, resulting in a persistent high morbidity and mortality. Thus, there is an urgent unmet medical need for novel effective therapies to better treat patients with PAH. Over the past few years, enthusiastic attempts have been made to identify novel effective therapies that address the essential roots of PAH with targeting key signaling pathways in both preclinical models and patients with PAH. This review aims to discuss the most emerging and promising therapeutic interventions in PAH pathogenesis.

Improving Right Ventricular Function by Increasing BMP Signaling with FK506.

Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFß1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.