Medicinal Chemistry of Antisense Oligonucleotides for Therapeutic Use in SARS-CoV-2: Design Strategies and Challenges for Targeted Delivery.

BACKGROUND: The evolution of novel Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) strains with greater degrees of infectivity, resistance to vaccine-induced acquired immunity, and more severe morbidity have contributed to the recent spread of COVID-19. In light of this, novel therapeutic alternatives with improved effectiveness and fewer side effects have become a necessity. Despite many new or repurposed antiviral agents recommended for Coronavirus disease (COVID-19) therapy, this objective remains unfulfilled. Under these circumstances, the scientific community holds the significant responsibility to develop classes of novel therapeutic modalities to combat SARS-CoV-2 with the least harmful side effects. OBJECTIVE: Antisense Oligonucleotides (ASOs) are short single-stranded oligonucleotides that allow the specific targeting of RNA, leading to its degradation. They may also prevent cellular factors or machinery from binding to the target RNA. It is possible to improve the pharmacokinetics and pharmacodynamics of ASOs by chemical modification or bioconjugation, which may provide conditions for customization of a particular clinical target. This study aimed to outline the potential use of ASOs in the treatment of COVID-19 disease, along with the use of antisense stabilization and transfer methods, as well as future challenges and limitations. METHODS: We have reviewed the structure and properties of ASOs containing nucleobase, sugar, or backbone modifications, and provided an overview of the therapeutic potential, delivery challenges, and strategies of ASOs in the treatment of COVID-19. RESULTS: The first-line therapy for COVID-19-infected individuals, as well as the development of oligonucleotide-based drugs, warrants further investigation. Chemical changes in the oligonucleotide structure can affect the biological processes. These chemical alterations may lead to enhanced potency, while changing the pharmacokinetics and pharmacodynamics. CONCLUSION: ASOs can be designed to target both coding and non-coding regions of the viral genome to disrupt or completely degrade the genomic RNA and thereby eliminate SARS-CoV-2. They may be very effective in areas, where vaccine distribution is challenging, and they may be helpful for future coronavirus pandemics.

Issue 4 - Impact of air pollution on COVID-19 mortality and morbidity: An epidemiological and mechanistic review.

Air pollution is a major global environment and health concern. Recent studies have suggested an association between air pollution and COVID-19 mortality and morbidity. In this context, a close association between increased levels of air pollutants such as particulate matter ≤2.5 to 10 µM, ozone and nitrogen dioxide and SARS-CoV-2 infection, hospital admissions and mortality due to COVID 19 has been reported. Air pollutants can make individuals more susceptible to SARS-CoV-2 infection by inducing the expression of proteins such as angiotensin converting enzyme (ACE)2 and transmembrane protease, serine 2 (TMPRSS2) that are required for viral entry into the host cell, while causing impairment in the host defence system by damaging the epithelial barrier, muco-ciliary clearance, inhibiting the antiviral response and causing immune dysregulation. The aim of this review is to report the epidemiological evidence on impact of air pollutants on COVID 19 in an up-to-date manner, as well as to provide insights on in vivo and in vitro mechanisms.

Neuropeptides affecting social behavior in mammals: Oxytocin.

Oxytocin (OXT), a neuropeptide consisting of only nine amino acids, is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OXT is best known for its role in lactation and parturition, recent research has shown that it also has a significant impact on social behaviors in mammals. However, a comprehensive review of this topic is still lacking. In this paper, we systematically reviewed the effects of OXT on social behavior in mammals. These effects of OXT from the perspective of five key behavioral dimensions were summarized: parental behavior, anxiety, aggression, attachment, and empathy. To date, researchers have agreed that OXT plays a positive regulatory role in a wide range of social behaviors, but there have been controversially reported results. In this review, we have provided a detailed panorama of the role of OXT in social behavior and, for the first time, delved into the underlying regulatory mechanisms, which may help better understand the multifaceted role of OXT. Levels of OXT in previous human studies were also summarized to provide insights for diagnosis of mental disorders.

Impact of particulate air pollution on airway injury and epithelial plasticity; underlying mechanisms.

Air pollution plays an important role in the mortality and morbidity of chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Particulate matter (PM) is a significant fraction of air pollutants, and studies have demonstrated that it can cause airway inflammation and injury. The airway epithelium forms the first barrier of defense against inhaled toxicants, such as PM. Airway epithelial cells clear airways from inhaled irritants and orchestrate the inflammatory response of airways to these irritants by secreting various lipid mediators, growth factors, chemokines, and cytokines. Studies suggest that PM plays an important role in the pathogenesis of chronic airway diseases by impairing mucociliary function, deteriorating epithelial barrier integrity, and inducing the production of inflammatory mediators while modulating the proliferation and death of airway epithelial cells. Furthermore, PM can modulate epithelial plasticity and airway remodeling, which play central roles in asthma and COPD. This review focuses on the effects of PM on airway injury and epithelial plasticity, and the underlying mechanisms involving mucociliary activity, epithelial barrier function, airway inflammation, epithelial-mesenchymal transition, mesenchymal-epithelial transition, and airway remodeling.

Impact of Earthquakes on Lung Health.

Earthquakes are catastrophic natural disasters that cause extensive damage to infrastructure and disrupt the lives of millions worldwide. Beyond the immediate physical and psychological damage caused by earthquakes, these events can significantly impact respiratory health. The inhalation of dust, smoke, particulates, toxic gases, and asbestos exposure can lead to various respiratory health pathologies. These include respiratory infections, exacerbations of pre-existing respiratory diseases, chest traumas, and pulmonary and venous thromboembolism. Longitudinal studies are necessary to assess the long-term respiratory health effects in affected populations. By addressing these knowledge gaps, future mitigation strategies and preparedness measures can be developed to minimize the respiratory health impacts of earthquakes and improve the well-being of affected communities. Robust building infrastructure and comprehensive earthquake preparedness are emerging as the most important determinants for not only mitigating building collapse but also significantly reducing the potential health impacts that follow. This comprehensive review aims to provide a systematic overview of the lung health impacts of earthquakes. It highlights the need for further research to identify specific pollutants, air contaminants, and environmental factors contributing to respiratory health issues following earthquakes.

Detection of tongue edema caused by endotracheal intubation tube in ICU patients by ultrasonography: a prospective, observational, clinical study.

PURPOSE: We aimed to determine the tongue edema that may develop due to the pressure exerted by the endotracheal intubation (ETI) tube on the tongue during the follow-up period of mechanical ventilation in patients intubated in the intensive care unit (ICU) by submental ultrasonography (USG). Also, we aimed to investigate the effect of tongue edema on the oxygen saturation values (SpO2) measured two h after extubation. METHODS: One hundred patients aged 18-65 years, who were followed up with mechanical ventilation in the ICU from the 0th day of intubation, were included. Patients (n = 57) who were followed up on mechanical ventilation for four days or longer after ETI were included in the study group. Those who were followed up on mechanical ventilation for three days or less after endotracheal intubation and were extubated during this period were included in the control group (n = 43). The tongue cross-sectional areas (TSAs) of patients in both groups were measured twice with submental USG. The first measurement (TSA1) was performed on the 0th day of ETI in all patients in both groups. The second measurement (TSA2) was performed on the 4th day of ETI in the study group and just before extubation in the control group. The difference between TSA2 and TSA1 was defined as tongue edema. Also, the effect of tongue edema on the oxygen saturation levels measured at the 2nd h after extubation of the patients in the control group was investigated. RESULTS: The tongue edema was more prevalent in the study group (p < 0.01). A significant negative correlation was found between the SpO2 levels two hours after extubation and the increase in the mean TSA values indicating tongue edema (p < 0.01). The oxygen saturations of the patients with tongue edema were 4% lower than those without tongue edema. CONCLUSIONS: Tongue edema may develop due to the long-term application of pressure of the ETI tube on the tongue and may impair oxygenation after extubation. GOV IDENTIFIER: NCT05249738.

The effect of multiple outgrowths from bronchial tissue explants on progenitor/stem cell number in primary bronchial epithelial cell cultures from smokers and patients with COPD.

Background: Although studies suggest a deficiency in stem cell numbers in chronic airway diseases such as chronic obstructive pulmonary disease (COPD), the role of bronchial epithelial progenitor/stem (P/S) cells is not clear. The objectives of this study were to investigate expression of progenitor/stem (P/S) cell markers, cytokeratin (CK) 5, CK14 and p63 in bronchial epithelial explants and cell cultures obtained from smokers with and without COPD following multiple outgrowths, and to study this effect on bronchial epithelial cell (BEC) proliferation. Methods: Bronchial epithelial explants were dissected from lung explants and cultured on coverslips. Confluent cultures were obtained after 3-4 weeks' (transfer, Tr1), explants were then transferred and cultured for a second (Tr2) and third (Tr3) time, respectively. At each stage, expression of CK5, CK14 and p63 in explants and BEC were determined by immunostaining. In parallel experiments, outgrowing cells from explants were counted after 4wks, and explants subsequently transferred to obtain new cultures for a further 3 times. Results: As the transfer number advanced, CK5, CK14 and p63 expression was decreased in both explants and BEC from both smokers without COPD and patients with COPD, with a more pronounced decrease in BEC numbers in the COPD group. Total cell numbers cultured from explants were decreased with advancing outgrowth number in both groups. Smoking status and lung function parameters were correlated with reduced P/S marker expression and cell numbers. Conclusion: Our findings suggest that the number of P/S cells in airway epithelium may play a role in the pathogenesis of COPD, as well as a role in the proliferation of airway epithelial cells, in vitro.

Impact of desert dust storms, PM10 levels and daily temperature on mortality and emergency department visits due to stroke.

Objective: It is known that the inhalation of air pollutants adversely affects human health. These air pollutants originated from natural sources such as desert storms or human activities including traffic, power generating, domestic heating, etc. This study aimed to investigate the impacts of desert dust storms, particulate matter ≤10 µm (PM10) and daily maximum temperature (MT) on mortality and emergency department (ED) visits due to stroke in the city of Gaziantep, Southeast Turkey. Method: The data on mortality and ED visits due to stroke were retrospectively recruited from January 1, 2009, to March 31, 2014, in Gaziantep City Centre. Results: PM10 levels did not affect ED visits or mortality due to stroke; however, MT increased both ED visits [adjusted odds ratio (OR) = 1.002, 95% confidence interval (CI) = 1.001-1.003] and mortality (OR = 1.006, 95% CI = 0.997-1.014) due to stroke in women. The presence of desert storms increased ED visits due to stroke in the total population (OR = 1.219, 95% CI = 1.199-1.240), and all subgroups. It was observed that desert dust storms did not have an increasing effect on mortality. Conclusion: Our findings suggest that MT and desert dust storms can induce morbidity and mortality due to stroke.

The role of sound stimulation in production of plant secondary metabolites.

Sound vibration is one of natural stimuli trigging physiological changes in plants. Recent studies showed that sound waves stimulated production of a variety of plant secondary metabolites, including flavonoids, in order to enhance seed germination, flowering, growth or defense. In this review, we examine the potential role of sound stimulation on the biosynthesis of secondary metabolites and the followed cascade of physiological changes in plants, from the perspective of transcriptional regulation and epigenetic regulation for the first time. A systematic summary showed that a wide range of factors may regulate the production of secondary metabolites, including plant species, growth stage, sound types, sound frequency, sound intensity level and exposure time, etc. Biochemical and physiological changes due to sound stimulation were thoroughly summarized as well, for secondary metabolites can also act as a free radical scavenger, or a hormone signaling molecule. We also discussed the limits of previous studies, and the future application of sound waves in biosynthesis of plant secondary metabolites.

Impact of Global Climate Change on Pulmonary Health: Susceptible and Vulnerable Populations.

As fossil fuel combustion continues to power the global economy, the rate of climate change is accelerating, causing severe respiratory health impacts and large disparities in the degree of human suffering. Hotter and drier climates lead to longer and more severe wildland fire seasons, impairing air quality around the globe. Hotter temperatures lead to higher amounts of ozone and particles, causing the exacerbation of chronic respiratory diseases and premature mortality. Longer pollen seasons and higher pollen concentrations provoke allergic airway diseases. In arid regions, accelerated land degradation and desertification are promoting dust pollution and impairing food production and nutritional content that are essential to respiratory health. Extreme weather events and flooding impede healthcare delivery and can lead to poor indoor air quality due to mold overgrowth. Climate and human activities that harm the environment and ecosystem may also affect the emergence and spread of viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and associated morbidity and mortality exacerbated by air pollution. Children and elderly individuals are more susceptible to the adverse health effects of climate change. Geographical and socioeconomic circumstances, together with a decreased capacity to adapt, collectively increase vulnerability to the adverse effects of climate change. Successful mitigation of anthropogenic climate change is dependent on the commitment of energy-intensive nations to manage greenhouse gas emissions, as well as societal support and response to aggravating factors. In this review, we focus on the respiratory health impacts of global climate change, with an emphasis on susceptible and vulnerable populations and low- and middle-income countries.

Animal models and mechanisms of tobacco smoke-induced chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and its global health burden is increasing. COPD is characterized by emphysema, mucus hypersecretion, and persistent lung inflammation, and clinically by chronic airflow obstruction and symptoms of dyspnea, cough, and fatigue in patients. A cluster of pathologies including chronic bronchitis, emphysema, asthma, and cardiovascular disease in the form of hypertension and atherosclerosis variably coexist in COPD patients. Underlying causes for COPD include primarily tobacco use but may also be driven by exposure to air pollutants, biomass burning, and workplace related fumes and chemicals. While no single animal model might mimic all features of human COPD, a wide variety of published models have collectively helped to improve our understanding of disease processes involved in the genesis and persistence of COPD. In this review, the pathogenesis and associated risk factors of COPD are examined in different mammalian models of the disease. Each animal model included in this review is exclusively created by tobacco smoke (TS) exposure. As animal models continue to aid in defining the pathobiological mechanisms of and possible novel therapeutic interventions for COPD, the advantages and disadvantages of each animal model are discussed.

Forthcoming complications in recovered COVID-19 patients with COPD and asthma; possible therapeutic opportunities.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been growing swiftly worldwide. Patients with background chronic pulmonary inflammations such as asthma or chronic obstructive pulmonary diseases (COPD) are likely to be infected with this virus. Of note, there is an argument that COVID-19 can remain with serious complications like fibrosis or other pathological changes in the pulmonary tissue of patients with chronic diseases. Along with conventional medications, regenerative medicine, and cell-based therapy could be alternative approaches to compensate for organ loss or restore injured sites using different stem cell types. Owing to unique differentiation capacity and paracrine activity, these cells can accelerate the healing procedure. In this review article, we have tried to scrutinize different reports related to the harmful effects of SARS-CoV-2 on patients with asthma and COPD, as well as the possible therapeutic effects of stem cells in the alleviation of post-COVID-19 complications. Video abstract.

Capsaicin suppresses ciliary function, while inducing permeability in bronchial epithelial cell cultures of COPD patients.

Take Home Message: Capsaicin modified inflammatory response and caused toxicity in bronchial epithelial cultures from patients with COPD. More importantly, capsaicin decreased ciliary beat frequency and induced epithelial permeability and these effects were partially prevented by formoterol and roflumilast. Tear gas is widely used to halt mass demonstrations. Studies have reported its adverse effects on multiple organ systems; however, its effect on individuals with chronic respiratory diseases and the underlying mechanisms of these effects are unclear. For the first time in the literature, we investigated the effects of capsaicin, the active ingredient of tear gas, on bronchial epithelial cell (BEC) cultures obtained from well-characterized groups of nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). BEC cultures were incubated with 50-500 µM capsaicin in the absence and presence of formoterol (1µM) and roflumilast (0.1 µM) for 24 h. Ciliary beat frequency (CBF) and transepithelial electrical resistance (TEER) were assessed at T1/4, T1/2, T1, T2, T4, T6, and T24 h, whereas the release of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, and lactate dehydrogenase (LDH) was measured at T24 h. Capsaicin (250 µM) significantly decreased CBF of all BEC cultures from T1/4 h to T24 h (p<0.05). Formoterol significantly prevented decreases in CBF induced by capsaicin. Higher concentrations of capsaicin (250-500 µM) significantly reduced TEER of BECs from nonsmokers (T2-T24 h), smokers (T24 h) and COPD patients (T2 and T24 h), which was partially prevented by roflumilast. Capsaicin (500 µM) decreased release of IL-8 (p<0.0001) and GM-CSF (p<0.05) while inducing release of LDH in BECs (p<0.05), and this was more prominent in BEC from patients with COPD. In conclusion, our findings demonstrate that capsaicin can suppress ciliary activity and cytokine release from BECs, induce BEC culture permeability and cellular toxicity and that these effects can be partially prevented by formoterol and roflumilast.

Emerging role of exosomes in the pathology of chronic obstructive pulmonary diseases; destructive and therapeutic properties.

Chronic obstructive pulmonary disease (COPD) is known as the third leading cause of human death globally. Enhanced chronic inflammation and pathological remodeling are the main consequences of COPD, leading to decreased life span. Histological and molecular investigations revealed that prominent immune cell infiltration and release of several cytokines contribute to progressive chronic remodeling. Recent investigations have revealed that exosomes belonging to extracellular vesicles are involved in the pathogenesis of COPD. It has been elucidated that exosomes secreted from immune cells are eligible to carry numerous pro-inflammatory factors exacerbating the pathological conditions. Here, in this review article, we have summarized various and reliable information about the negative role of immune cell-derived exosomes in the remodeling of pulmonary tissue and airways destruction in COPD patients.

The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD.

Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated.

Comparison of the intubation success rate between the intubating catheter and videolaryngoscope in difficult airways: a prospective randomized trial.

BACKGROUND: Several devices and algorithms have already been examined and compared for difficult airway management. However, there is no existing study comparing the success of the Intubating Catheter (IC) and the Videolaryngoscope (VL) in patients who are difficult to intubate. We aimed to compare Frova IC and McGrath VL in terms of intubation success rates in patients with difficult intubation. METHODS: This prospective, randomized study was performed in an university hospital. Patients who underwent an operation under general anesthesia and whom airway management process was deemed difficult were included in this study. Patients were randomly divided into two groups by envelopes containing a number: the intubating catheter group (Group IC), intubated using the Frova IC, and the videolaryngoscope group (Group VL), intubated using the McGrath VL. Study data were collected by a technician who was blind to the study groups and the type of device used in the intubation procedure. RESULTS: A total of 49 patients with difficult airway were included in the study, including 25 patients in the Frova IC Group and 24 patients in the McGrath VL Group. The rate of successful intubation was determined to be 88% in Group IC and 66% in Group VL (p = 0.074). The mean duration of intubation attempt in Group VL was 44.62 seconds, whereas in Group IC, it was 51.12 seconds (p = 0.593). Group VL was found to have a significantly lower Cormack-Lehane grade compared to Group IC (p < 0.001). CONCLUSION: Frova IC is a candidate to be an indispensable instrument in terms of cost-effectiveness in clinics such as anesthesia and emergency medicine, where difficult intubation cases are frequently encountered. However, the combination of Frova IC and McGrath VL seems to be more successful in difficult intubation situations, so future studies should focus on using these two devices together.

KRAS signaling in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.