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Article ; Online: Role of inflammasome in severe, steroid-resistant asthma

Bariaa A. Khalil / Narjes Saheb Sharif-Askari / Rabih Halwani

Current Research in Immunology, Vol 4, Iss , Pp 100061- (2023)

2023

Abstract: Purpose of review: Asthma is a common heterogeneous group of chronic inflammatory diseases with different pathological phenotypes classified based on the various clinical, physiological and immunobiological profiles of patients. Despite similar clinical ... ...

Abstract	Purpose of review: Asthma is a common heterogeneous group of chronic inflammatory diseases with different pathological phenotypes classified based on the various clinical, physiological and immunobiological profiles of patients. Despite similar clinical symptoms, asthmatic patients may respond differently to treatment. Hence, asthma research is becoming more focused on deciphering the molecular and cellular pathways driving the different asthma endotypes. This review focuses on the role of inflammasome activation as one important mechanism reported in the pathogenesis of severe steroid resistant asthma (SSRA), a Th2-low asthma endotype. Although SSRA represents around 5–10% of asthmatic patients, it is responsible for the majority of asthma morbidity and more than 50% of asthma associated healthcare costs with clear unmet need. Therefore, deciphering the role of the inflammasome in SSRA pathogenesis, particularly in relation to neutrophil chemotaxis to the lungs, provides a novel target for therapy. Recent findings: The literature highlighted several activators of inflammasomes that are elevated during SSRA and result in the release of proinflammatory mediators, mainly IL-1β and IL-18, through different signaling pathways. Consequently, the expression of NLRP3 and IL-1β is shown to be positively correlated with neutrophil recruitment and negatively correlated with airflow obstruction. Furthermore, exaggerated NLRP3 inflammasome/IL-1β activation is reported to be associated with glucocorticoid resistance. Summary: In this review, we summarized the reported literature on the activators of the inflammasome during SSRA, the role of IL-1β and IL-18 in SSRA pathogenesis, and the pathways by which inflammasome activation contributes to steroid resistance. Finally, our review shed light on the different levels to target inflammasome involvement in an attempt to ameliorate the serious outcomes of SSRA.
Keywords	Severe steroid resistant asthma (SSRA) ; Inflammasome ; Pyroptosis ; Neutrophilic asthma ; IL-1β ; IL-18 ; Specialties of internal medicine ; RC581-951
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Unraveling the gut-Lung axis

Mariam Wed Eladham / Balachandar Selvakumar / Narjes Saheb Sharif-Askari / Fatemeh Saheb Sharif-Askari / Saleh Mohamed Ibrahim / Rabih Halwani

Heliyon, Vol 10, Iss 1, Pp e24032- (2024)

Exploring complex mechanisms in disease interplay

2024

Abstract: The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung ... ...

Abstract	The link between gut and lung starts as early as during organogenesis. Even though they are anatomically distinct, essential bidirectional crosstalk via complex mechanisms supports GLA. Emerging studies have demonstrated the association of gut and lung diseases via multifaceted mechanisms. Advancements in omics and metagenomics technologies revealed a potential link between gut and lung microbiota, adding further complexity to GLA. Despite substantial studies on GLA in various disease models, mechanisms beyond microbial dysbiosis regulating the interplay between gut and lung tissues during disease conditions are not thoroughly reviewed. This review outlines disease specific GLA mechanisms, emphasizing research gaps with a focus on gut-to-lung direction based on current GLA literature. Moreover, the review discusses potential gut microbiota and their products like metabolites, immune modulators, and non-bacterial contributions as a basis for developing treatment strategies for lung diseases. Advanced experimental methods, modern diagnostic tools, and technological advancements are also highlighted as crucial areas for improvement in developing novel therapeutic approaches for GLA-related diseases. In conclusion, this review underscores the importance of exploring additional mechanisms within the GLA to gain a deeper understanding that could aid in preventing and treating a wide spectrum of lung diseases.
Keywords	GLA ; Microbiota ; Gut ; Lung ; Dysbiosis ; Metabolites ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	610
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Profiling Levels of Serum microRNAs and Soluble ACE2 in COVID-19 Patients

Noha Mousaad Elemam / Hind Hasswan / Hayat Aljaibeji / Narjes Saheb Sharif-Askari / Rabih Halwani / Jalal Taneera / Nabil Sulaiman

Life, Vol 12, Iss 575, p

2022 Volume 575

Abstract: Background: The main mechanism of viral entry in COVID-19 infection is through the angiotensin-converting enzyme 2 (ACE2) receptor present in the lungs. Numerous studies suggested a clinical significance of risk factors, such as gender, obesity, and ... ...

Abstract	Background: The main mechanism of viral entry in COVID-19 infection is through the angiotensin-converting enzyme 2 (ACE2) receptor present in the lungs. Numerous studies suggested a clinical significance of risk factors, such as gender, obesity, and diabetes on the soluble form of ACE2 (sACE2) and related miRNAs in COVID-19 infection. This study aims to investigate the serum level of sACE2 and 4 miRNAs (miR-421, miR-3909, miR-212-5p, and miR-4677-3p) in COVID-19 patients and assess their associations with clinicopathological parameters. Methods: Serum samples were collected from non-diabetic and diabetic COVID-19 patients and healthy controls. sACE2 levels were quantified using ELISA, and serum miRNA levels were measured using qPCR. In addition, laboratory blood tests were retrieved from the clinical records of COVID-19 patients. Results: sACE2 levels were upregulated in COVID-19 patients regardless of sex, diabetes status, or obesity. Furthermore, the four investigated miRNAs were upregulated in COVID-19 patients and were positively correlated with each other. Furthermore, miR-421, miR-3909, and miR-4677-3p were positively associated with sACE2, suggesting a strong link between these markers. Notably, miR-212-5p was selectively upregulated in moderate, male, and non-obese COVID-19 patients. Interestingly, miR-212-5p was correlated with D-dimer, while sACE2 was correlated with coagulation tests, such as aPTT and platelets, indicating their potential as markers of coagulopathy in COVID-19. Additionally, there was a positive correlation between sACE2 and C-reactive protein in diabetic COVID-19 patients, indicating a promising role of this marker in the inflammatory status of these patients. Conclusions: sACE2 and its regulatory miRNAs were upregulated and correlated with laboratory investigations of COVID-19 patients, thus indicating their clinical significance as biomarkers in COVID-19 infection.
Keywords	miRNAs ; sACE2 ; COVID-19 ; obesity ; diabetes ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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

Bushra Mdkhana / Narjes Saheb Sharif-Askari / Rakhee K Ramakrishnan / Baraa Khalid Al-Sheakly / Shirin Hafezi / Fatemeh Saheb Sharif-Askari / Khuloud Bajbouj / Qutayba Hamid / Rabih Halwani

PLoS ONE, Vol 18, Iss 7, p e

2023 Volume 0284061

Abstract: 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- ... ...

Abstract	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.
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early administration of remdesivir to COVID-19 patients associates with higher recovery rate and lower need for ICU admission

Hawra Ali Hussain Alsayed / Fatemeh Saheb Sharif-Askari / Narjes Saheb Sharif-Askari / Ali Al Sayed Hussain / Qutayba Hamid / Rabih Halwani

PLoS ONE, Vol 16, Iss

A retrospective cohort study

2021 Volume 10

Abstract: Objectives Remdesivir is one of the most widely recommended and used medications for COVID-19 treatment. However, different outcomes have been reported for hospitalized patients with COVID-19 treated with remdesivir. Specifically, the effect of the ... ...

Abstract	Objectives Remdesivir is one of the most widely recommended and used medications for COVID-19 treatment. However, different outcomes have been reported for hospitalized patients with COVID-19 treated with remdesivir. Specifically, the effect of the timing of remdesivir initiation (from patient’s symptom onset) on clinical outcomes in COVID-19 patients has not been investigated. Methods This is a retrospective cohort study of patients hospitalized with COVID-19 and treated with or without remdisivir. The primary outcome was patient’s recovery rate, defined as clinical improvement and patient’s discharge by day 14 of symptom onset. The secondary outcome was the need for intensive care unit (ICU) admission, mechanical ventilation, and mortality within 28 days of patient’s symptom onset. Results Out of 323 hospitalized adults with COVID-19, 107 (33.1%) received no remdesivir during their hospital stay, 107 (33.1%) received remdesivir early within 7 days of the symptom onset, and 109 (33.7%) received it at 8 days or later of symptom onset. At day 14 following symptom onset, higher proportion of patients recovered in the early remdesivir compared to the late remdesivir cohort, or patients who did not receive remdesivir (adjusted odds ratio, aOR, 2.65; 95% confidence interval [CI], 1.31 to 5.35). Moreover, early administration of remdesivir was associated with lower admission to intensive care unit (adjusted hazard ratio [aHR], 0.31; 95% CI, 0.15 to 0.64), less need for mechanical ventilation (aHR, 0.22; 95% CI, 0.10 to 0.51), and lower mortality at 28 days (aHR, 0.15; 95% CI, 0.04 to 0.53), as compared to the late remdesivir cohort or patients who did not receive remdesivir. Conclusion Early administration of remdesivir within 7 days of symptom onset is associated with less need for mechanical ventilation and lower 28-days mortality.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early administration of remdesivir to COVID-19 patients associates with higher recovery rate and lower need for ICU admission

Hawra Ali Hussain Alsayed / Fatemeh Saheb Sharif-Askari / Narjes Saheb Sharif-Askari / Ali Al Sayed Hussain / Qutayba Hamid / Rabih Halwani

PLoS ONE, Vol 16, Iss 10, p e

A retrospective cohort study.

2021 Volume 0258643

Abstract	Objectives Remdesivir is one of the most widely recommended and used medications for COVID-19 treatment. However, different outcomes have been reported for hospitalized patients with COVID-19 treated with remdesivir. Specifically, the effect of the timing of remdesivir initiation (from patient's symptom onset) on clinical outcomes in COVID-19 patients has not been investigated. Methods This is a retrospective cohort study of patients hospitalized with COVID-19 and treated with or without remdisivir. The primary outcome was patient's recovery rate, defined as clinical improvement and patient's discharge by day 14 of symptom onset. The secondary outcome was the need for intensive care unit (ICU) admission, mechanical ventilation, and mortality within 28 days of patient's symptom onset. Results Out of 323 hospitalized adults with COVID-19, 107 (33.1%) received no remdesivir during their hospital stay, 107 (33.1%) received remdesivir early within 7 days of the symptom onset, and 109 (33.7%) received it at 8 days or later of symptom onset. At day 14 following symptom onset, higher proportion of patients recovered in the early remdesivir compared to the late remdesivir cohort, or patients who did not receive remdesivir (adjusted odds ratio, aOR, 2.65; 95% confidence interval [CI], 1.31 to 5.35). Moreover, early administration of remdesivir was associated with lower admission to intensive care unit (adjusted hazard ratio [aHR], 0.31; 95% CI, 0.15 to 0.64), less need for mechanical ventilation (aHR, 0.22; 95% CI, 0.10 to 0.51), and lower mortality at 28 days (aHR, 0.15; 95% CI, 0.04 to 0.53), as compared to the late remdesivir cohort or patients who did not receive remdesivir. Conclusion Early administration of remdesivir within 7 days of symptom onset is associated with less need for mechanical ventilation and lower 28-days mortality.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Assessment of Knowledge, Perceptions, and Attitudes During the Global Mpox Outbreak in June 2022

Rouba Karen Zeidan / Ankita Shukla / Amal Hussein / Hamzah AlZubaidi / Mohamad-Hani Temsah / Mohamed S. AlHajjaj / Najlaa Al-Bluwi / Manal Awad / Hawra Ali Hussein Alsayed / Narjes Saheb Sharif-Askari / Zahraa AlHano / Razan Agha / Qutayba Hamid / Rabih Halwani / Basema Saddik

International Journal of Public Health, Vol

A Cross-Sectional Study From the United Arab Emirates

2023 Volume 68

Abstract: Objectives: To examine knowledge, worry, anxiety, and vaccine acceptance for mpox among UAE adults.Methods: An online survey, advertised on academic and social media platform in June 2022 collected data from 959 participants (aged 18 and above) on mpox ... ...

Abstract	Objectives: To examine knowledge, worry, anxiety, and vaccine acceptance for mpox among UAE adults.Methods: An online survey, advertised on academic and social media platform in June 2022 collected data from 959 participants (aged 18 and above) on mpox beliefs, risks, knowledge, worry, anxiety, COVID-19 infection, vaccination, and willingness to receive the mpox vaccine. Bivariate and logistic regression analysis identified associations and predictors between variables.Results: 56% had optimal knowledge of mpox transmission and symptoms. 54% were worried, and 27% experienced anxiety related to the outbreak. Knowledge scores were higher among women, healthcare workers, and those with reliable information sources. High perceived infection risk, changes in precautionary measures, and belief in difficult treatment predicted more worry and anxiety. Higher worry and two or more doses of the COVID-19 vaccine predicted higher likelihood of taking the mpox vaccine.Conclusion: The UAE population showed low knowledge and high worry and anxiety during the global mpox outbreak. Increasing public awareness through targeted educational campaigns is vital. Promoting better understanding of infectious diseases, addressing concerns, and encouraging vaccine uptake can prepare for future outbreaks.
Keywords	mpox ; outbreak ; perception ; attitude ; stigma ; Public aspects of medicine ; RA1-1270
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Airways tissue expression of type I interferons and their stimulated genes is higher in children than adults

Narjes Saheb Sharif-Askari / Fatemeh Saheb Sharif-Askari / Shirin Hafezi / Zaina Kalaji / Mohamed Temsah / Saleh Almuhsen / Habiba S. Alsafar / Qutayba Hamid / Rabih Halwani

Heliyon, Vol 8, Iss 11, Pp e11724- (2022)

2022

Abstract: There is emerging evidence that age-dependent differences in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with stronger innate immune response in the upper respiratory tract in children compared to adults. The ... ...

Abstract	There is emerging evidence that age-dependent differences in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with stronger innate immune response in the upper respiratory tract in children compared to adults. The efficient induction of interferon (IFN) alpha and beta (α and β) signaling, and interferon-stimulated genes (ISGs) is fundamental to the host antiviral response. In-silico transcriptomic analyses was conducted to determine the expression levels of IFN α/β pathway genes as well as 524 human ISGs in upper and lower airways of children and adults at baseline and post respiratory infections including coronavirus disease 2019 (COVID-19). To validate our in-silico analysis, we conducted qRT-PCR to measure ISGs levels in children and adult's nasal epithelial samples. At baseline, children had significantly higher levels of IFN α/β and ISGs genes compared to adults. More distinction was also seen in bronchial compared to nasal basal levels. Children nasal epithelial cells exhibited superior antiviral IFN α/β and associated ISGs response following ex-vivo poly (I:C) treatment model, and in clinical samples of SARS-CoV-2 infected patients. This was also confirmed in nasal epithelial samples using qRT-PCR validation. No gender-based difference in type I IFN levels across both age groups were observed. Understanding the biological basis for children resistance against severe COVID-19 is a challenge that has substantial clinical importance. More mechanistic studies are needed to carefully quantify how much of early IFN levels is needed to bypass the viral evasion mechanism and prevent its further replication and dissemination to lower airways and the rest of the body.
Keywords	SARS-CoV-2 ; IFN alpha ; IFN beta ; Type I interferon ; Interferon-stimulated genes (ISGs) ; COVID-19 ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	610
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Favipiravir Effectiveness and Safety in Hospitalized Moderate-Severe COVID-19 Patients

Saleh Al-Muhsen / Nouf S. Al-Numair / Narjes Saheb Sharif-Askari / Roaa Basamh / Banan Alyounes / Amjad Jabaan / Fatemeh Saheb Sharif-Askari / Mohammed F. Alosaimi / Fahad Alsohime / Rabih Halwani / Haya Al-Saud

Frontiers in Medicine, Vol

Observational Prospective Multicenter Investigation in Saudi Arabia

2022 Volume 9

Abstract: ObjectivesThere are limited data on the efficacy and safety of favipiravir antiviral in coronavirus disease 2019 (COVID-19), particularly in the more progressed disease phase. This study aims to evaluate the favipiravir effect on reducing the length of ... ...

Abstract	ObjectivesThere are limited data on the efficacy and safety of favipiravir antiviral in coronavirus disease 2019 (COVID-19), particularly in the more progressed disease phase. This study aims to evaluate the favipiravir effect on reducing the length of hospital stay and in-hospital mortality among moderate and severe hospitalized COVID-19 patients.MethodsA prospective, multicenter observational study was conducted that included moderate and severe hospitalized adult COVID-19 patients in four major regions (Riyadh (Riyadh), Eastern (Dammam), Al-Qassem (Buraydah), and Macca (Jeddah) of Saudi Arabia. For the primary outcome of all-cause mortality, a Cox proportional hazard analysis was performed. While the association between favipiravir use and length of hospital stay was determined using adjusted generalized linear model. This study was approved by the Central Institutional Review Board in The Saudi Ministry of Health (MoH) with the approval number IRB # 20-85-M.ResultsThis study included 598 moderate and severe COVID-19 patients, of whom 156 (26%) received favipiravir. Favipiravir treatment was associated with more extended hospital stays (14 vs. 10 median days, P = 0.034) and higher mortality rate (aHR 3.63; 95% CI 1.06–12.45) compared to no favipiravir regimen. Despite lack of effectiveness, favipiravir use was only associated with higher diarrhea adverse effects (12 vs. 5%, P = 0.002), but it did not affect the renal and liver profiles of patients.ConclusionFavipiravir was ineffective in reducing the length of hospital stay and in-hospital mortality in patients with moderate and severe COVID-19.
Keywords	COVID-19 ; SARS-CoV-2 ; favipiravir ; in-hospital mortality ; length of hospital stay ; Medicine (General) ; R5-920
Subject code	360
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD

Narjes Saheb Sharif-Askari / Fatemeh Saheb Sharif-Askari / Mashael Alabed / Mohamed-Hani Temsah / Saba Al Heialy / Qutayba Hamid / Rabih Halwani

Molecular Therapy: Methods & Clinical Development, Vol 18, Iss , Pp 1-

2020 Volume 6

Abstract: It has been reported that angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the main cell entry proteins for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and play a critical role in causing ... ...

Abstract	It has been reported that angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the main cell entry proteins for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and play a critical role in causing coronavirus disease 2019 (COVID-19). To investigate the expression level of these SARS-CoV-2 host cell entry genes in the lung airway, we used public gene expression datasets. We have found a differential expression of ACE2 and TMPRSS2 in nasal and bronchial airways relative to age and diseases status. Children were found to have significantly lower expression of COVID-19 receptors in the upper and lower airways (nasal and bronchial). Moreover, the lung airway expression of both ACE2 and TMPRSS2 was found to be significantly upregulated in smokers compared with non-smokers, and in patients with chronic obstructive pulmonary disease (COPD) compared with healthy subjects. No difference was observed in the blood expression levels of ACE2 and TMPRSS2 between children and adults, or in COPD or diabetic patients. However, a significant increase in blood expression levels of these genes was observed in patients with essential hypertension, whereas only ACE2 was upregulated in the blood of asthmatics. These results suggest that the observed difference in COVID-19 severity between children and adults could, in part, be attributed to the difference in ACE2 and TMPRSS2 airways tissue expression levels.
Keywords	ACE2 ; TMPRSS2 ; SARS-CoV-2 ; COVID-19 ; nasal epithelium ; COPD ; Genetics ; QH426-470 ; Cytology ; QH573-671 ; covid19
Subject code	610
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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