Cellular stress responses and dysfunctional Mitochondrial–cellular senescence, and therapeutics in chronic respiratory diseases

Manevski, Marko; Muthumalage, Thivanka; Devadoss, Dinesh; Sundar, Isaac K.; Wang, Qixin; Singh, K. R. P.; Unwalla, Hoshang; Chand, Hitendra S.; Rahman, Irfan

doi:10.1016/j.redox.2020.101443

Cited by 48 publications

(36 citation statements)

References 213 publications

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“…The UPR is comprised of a series of transcriptional, translational, and post-translational processes that can lower the rate of protein synthesis and increase the protein folding capacity of the ER machinery. This results in an increase of misfolded protein elimination, and escalating the size of the ER compartment thereby reducing the ER stress [ 98 ]. Usually, transient ER stress can be overcome by UPR, but if the damaging stimulus persists, inflammatory response genes are activated [ 131 ].…”

Section: Mitochondrial Pathways Altered In Nmdmentioning

confidence: 99%

“…When ER senses ROS, ER redox status can change, and might induce ER stress [ 97 ]. To defend against ER stress and overcome potential protein misfolding, cells can activate an adaptive unfolded protein response (UPR), which increases the size and capacity of ER to reduce ER stress and increase the removal of misfolded proteins by autophagy [ 98 ].…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

2020

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Neuromuscular diseases (NMDs) are a heterogeneous group of acquired or inherited rare disorders caused by injury or dysfunction of the anterior horn cells of the spinal cord (lower motor neurons), peripheral nerves, neuromuscular junctions, or skeletal muscles leading to muscle weakness and waste. Unfortunately, most of them entail serious or even fatal consequences. The prevalence rates among NMDs range between 1 and 10 per 100,000 population, but their rarity and diversity pose difficulties for healthcare and research. Some molecular hallmarks are being explored to elucidate the mechanisms triggering disease, to set the path for further advances. In fact, in the present review we outline the metabolic alterations of NMDs, mainly focusing on the role of mitochondria. The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria. Briefly, increased levels of inflammation have been linked to reactive oxygen species (ROS) accumulation, which is key in mitochondrial genomic instability and mitochondrial respiratory chain (MRC) dysfunction. ROS burst, impaired autophagy, and increased inflammation are observed in many NMDs. Increasing knowledge of the etiology of NMDs will help to develop better diagnosis and treatments, eventually reducing the health and economic burden of NMDs for patients and healthcare systems.

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Section: Mitochondrial Pathways Altered In Nmdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

2020

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“…To our surprise, signi cantly lower counts of Mt-tRNA and small nucleolar RNA were observed in CS, WP, E-cig and DS (P<0.05) in comparison to NS (Fig. 3 A, B (60,61). The Mt-tRNA gene mutations were reported in idiopathic pulmonary brosis, lung cancer and hypertension (62)(63)(64).…”

Section: Cs (29)mentioning

confidence: 76%

Exosomal microRNAs are novel circulating biomarkers in cigarette,waterpipe smokers, E-cigarette users and dual smokers

Singh

Maremanda

et al. 2020

Preprint

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Background: Electronic cigarettes (e-cigs) produce aerosolized substances by heating a liquid, which contains large number of chemicals. The aerosol generated by E-cig may produce adverse health effects. Cigarette smoke exposure causes various diseases including COPD, atherosclerosis, and lung cancer. Waterpipe tobacco smoking also causes various acute and chronic health effects including cardiopulmonary diseases. microRNAs are present in higher concentration in exosomes that play a major role in various physiological and pathological functions. We hypothesized that the non-coding RNAs transcript may serve as susceptibility to disease biomarkers by smoking and vaping. Results: Our data show the enrichment of various non-coding RNAs that include microRNAs, tRNAs, piRNAs, snoRNAs, snRNAs, Mt-tRNAs, and other biotypes in exosomes. A comprehensive differential expression analysis of microRNAs, tRNAs and piRNAs showed significant changes across different pairwise comparisons. The seven microRNAs that were common and differentially expressed of when all the smoking and vaping groups were compared with non-smokers (NS) are hsa-let-7a-5p, hsa-miR-21-5p, hsa-miR-29b-3p, hsa-let-7f-5p, hsa-miR-143-3p, hsa-miR-30a-5p and hsa-let-7i-5p. The e-cig vs. NS group has differentially expressed 5 microRNAs (hsa-miR-224-5p, hsa-miR-193b-3p, hsa-miR-30e-5p, hsa-miR-423-3p, hsa-miR-365a-3p, and hsa-miR-365b-3p) that is specific for this group and are not expressed in other three groups. Gene set enrichment analysis of microRNAs showed significant changes in the top six enriched functions that consisted of biological pathway, biological process, molecular function, cellular component, site of expression and transcription factor in all the groups. Further, the pairwise comparison of tRNAs and piRNA in all these groups revealed significant changes in their expressions. Conclusions: Plasma exosomes of cigarette smokers, waterpipe smokers, e-cig users and dual smokers have common differential expression of microRNAs which may serve to distinguish smoking and vaping subjects from NS. Among them has-let-7a-5p has high sensitivity and specificity to distinguish NS with the rest of the users, using ROC curve analysis. This study will pave the way for the utilizing the potential of exosomes/miRNAs as a novel theranostic agents in understanding the lung injury caused by tobacco smoking and vaping.

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“…Any alteration in the level of Mt-tRNA may have impact on mitochondrial function. The mitochondrial dysfunction has been associated with several lung diseases, such as asbestos-related lung fibrosis and COPD [70,71]. The Mt-tRNA gene mutations were reported in idiopathic pulmonary fibrosis, lung cancer and hypertension [72][73][74].…”

Section: Discussionmentioning

confidence: 99%

Exosomal microRNAs are novel circulating biomarkers in cigarette, waterpipe smokers, E-cigarette users and dual smokers

Singh

Maremanda

et al. 2020

BMC Med Genomics

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Background Electronic cigarettes (e-cigs) vaping, cigarette smoke, and waterpipe tobacco smoking are associated with various cardiopulmonary diseases. microRNAs are present in higher concentration in exosomes that play an important role in various physiological and pathological functions. We hypothesized that the non-coding RNAs transcript may serve as susceptibility to disease biomarkers by smoking and vaping. Methods Plasma exosomes/EVs from cigarette smokers, waterpipe smokers and dual smokers (cigarette and waterpipe) were characterized for their size, morphology and TEM, Nanosight and immunoblot analysis. Exosomal RNA was used for small RNA library preparation and the library was quantified using the High Sensitivity DNA Analysis on the Agilent 2100 Bioanalyzer system and sequenced using the Illumina NextSeq 500 and were converted to fastq format for mapping genes. Results Enrichment of various non-coding RNAs that include microRNAs, tRNAs, piRNAs, snoRNAs, snRNAs, Mt-tRNAs, and other biotypes are shown in exosomes. A comprehensive differential expression analysis of miRNAs, tRNAs and piRNAs showed significant changes across different pairwise comparisons. The seven microRNAs that were common and differentially expressed of when all the smoking and vaping groups were compared with non-smokers (NS) are hsa-let-7a-5p, hsa-miR-21-5p, hsa-miR-29b-3p, hsa-let-7f-5p, hsa-miR-143-3p, hsa-miR-30a-5p and hsa-let-7i-5p. The e-cig vs. NS group has differentially expressed 5 microRNAs (hsa-miR-224-5p, hsa-miR-193b-3p, hsa-miR-30e-5p, hsa-miR-423-3p, hsa-miR-365a-3p, and hsa-miR-365b-3p), which are not expressed in other three groups. Gene set enrichment analysis of microRNAs showed significant changes in the top six enriched functions that consisted of biological pathway, biological process, molecular function, cellular component, site of expression and transcription factor in all the groups. Further, the pairwise comparison of tRNAs and piRNA in all these groups revealed significant changes in their expressions. Conclusions Plasma exosomes of cigarette smokers, waterpipe smokers, e-cig users and dual smokers have common differential expression of microRNAs which may serve to distinguish smoking and vaping subjects from NS. Among them has-let-7a-5p has high sensitivity and specificity to distinguish NS with the rest of the users, using ROC curve analysis. These findings will pave the way for the utilizing the potential of exosomes/miRNAs as a novel theranostic agents in lung injury and disease caused by tobacco smoking and vaping.

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Cellular stress responses and dysfunctional Mitochondrial–cellular senescence, and therapeutics in chronic respiratory diseases

Cited by 48 publications

References 213 publications

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

Exosomal microRNAs are novel circulating biomarkers in cigarette,waterpipe smokers, E-cigarette users and dual smokers

Exosomal microRNAs are novel circulating biomarkers in cigarette, waterpipe smokers, E-cigarette users and dual smokers

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