Female Reproductive Health in SARS-CoV-2 Pandemic Era.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic struck global health systems with overgrowing demands in many fields of health care; yet, reproductive care, particularly pregnancy care remains a special focus of interest. Pregnancy is a major physiologic change that alters temporarily normal function of many organs, and specifically the immune system. Therefore, pregnant women are more susceptible to respiratory pathogens compared to the others. The current pandemic may have serious consequences on pregnancy whether directly or indirectly. In the present review, direct and indirect possible adverse effects of SARS-CoV-2 infection on female reproductive system by focusing on pregnancy and delivery has been discussed in details. In addition, the pregnancy consequences and whether maternal infection can affect infants were deliberated. The adverse impact of luck down and related psychological complications and obesity on pregnant women were discussed as well. Finally, the effects of SARS-CoV-2 vaccination on maternal health and pregnancy outcome was analyzed.

Is There any Alternative Receptor for SARS-CoV-2?

Angiotensin-converting enzyme II (ACE2) in association with type II transmembrane serine protease (TMPRSS2) is considered the main receptor of SARS-CoV-2. However, considering the clinical complications of COVID-19 in different organs, there is no strong association between the abundance of ACE2/TMPRSS2 co-expression and clinical features of the disease and the severity of complications. Since SARS-CoV-2 affects certain organs that lack or have low expression of ACE2/TMPRSS2, it may be possible that the virus employs other receptors for colonization and entry. Based on recent studies, glucose-regulated protein 78 (GRP78) can be a potential alternative receptor for SARS-CoV-2 entry. In this letter, supporting evidence proposed GRP78 as an alternative receptor in SARS-CoV-2 infection.

Hypertension in COVID-19, A Risk Factor for Infection or A Late Consequence?

There are a lot of data about the correlation of SARS-CoV-2 infection and hypertension (HTN), but most of them are in the increased risk of morbidity and mortality in patients with HTN. SARS-CoV-2 can interfere with host cells through the renin-angiotensin system (RAS) via the angiotensin-converting enzyme 2 (ACE2) receptor. RAS activation is associated with pro-inflammatory effects through the ACE/Ang II/ Angiotensin II type 1 receptor (AT1R) pathway or anti-inflammatory effects through ACE2/Ang1-7/Mas axis. In the current paper, we discuss the pathophysiology of newly diagnosed HTN and its effect on morbidity in patients with coronavirus disease 2019 (COVID-19).

Athletes' Mesenchymal Stem Cells Could Be the Best Choice for Cell Therapy in Omicron-Infected Patients.

New severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Omicron, contains 32 mutations that have caused a high incidence of breakthrough infections or re-infections. These mutations have reduced vaccine protection against Omicron and other new emerging variants. This highlights the need to find effective treatment, which is suggested to be stem cell-based therapy. Stem cells could support respiratory epithelial cells and they could restore alveolar bioenergetics. In addition, they can increase the secretion of immunomodulatory cytokines. However, after transplantation, cell survival and growth rate are low because of an inappropriate microenvironment, and stem cells face ischemia, inflammation, and oxidative stress in the transplantation niche which reduces the cells' survival and growth. Exercise-training can upregulate antioxidant, anti-inflammatory, and anti-apoptotic defense mechanisms and increase growth signaling, thereby improving transplanted cells' survival and growth. Hence, using athletes' stem cells may increase stem-cell therapy outcomes in Omicron-affected patients.

Mini review ATF4 and GRP78 as novel molecular targets in ER-Stress modulation for critical COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in more than 4.4 million deaths worldwide as of August 24, 2021. Viral infections such as SARS-CoV2 are associated with endoplasmic reticulum (ER) stress and also increased the level of reactive oxygen species. Activating transcription factor 4 (ATF4) is preferentially translated under integrated stress conditions and controls the genes involved in protein homeostasis, amino acid transport and metabolism, and also protection from oxidative stress. The GRP78, regulated either directly or indirectly by ATF4, is an essential chaperone in the ER and overexpressed and appears on the surface of almost all cells during stress and function as a SARS-CoV2 receptor. In this mini-review article, we briefly discuss the effects of SARS-CoV2 infection on the ER stress, and then the stress modulator functions of ATF4 and GRP78 as novel therapeutic targets were highlighted. Finally, the effects of GRP78 inhibitory components as potential factors for targeted therapies for COVID-19 critical cases were discussed.

COVID-19 Vaccination Willingness and Acceptability in Multiple Sclerosis Patients: A Cross Sectional Study in Iran.

Multiple sclerosis (MS) is a chronic, predominantly immune-mediated degenerative disease of the central nervous system. Due to prolonged use of immunomodulatory and immunosuppressive medications, vaccine hesitancy could be common among MS patients. Our main aim in the current study was to evaluate the willingness and acceptability of COVID-19 vaccination in patients with MS. In our multicenter cross-sectional questionnaire-based clinical study, 892 patients completed the questionnaire between May to June 2021. The questionnaire consisted of demographic data, MS disease-related factors, history of COVID-19 infection/vaccination, and any existing comorbidities. Statistical analysis was performed using SPSS software version 19. Overall, 68% of the participants expressed willingness to be vaccinated. Major causes of vaccine refusal in our patients were the fear of reducing the efficacy of disease modifying drugs (DMDs) upon vaccination as well as distrusting the vaccines and overestimation bias in the power of their innate immunity and potential COVID-19 resistance. Some demographic factors affected vaccination enthusiasm in our study. Our findings did not show significant correlation between the age and comorbidity and vaccine willingness. Only one-third of our patients received their vaccine information from healthcare providers. The majority of them received these data from official broadcasting channels and social media. However, despite several concerns, the willingness of COVD-19 vaccination in the Iranian MS patients is remarkable.

Application of Stem Cell-Derived Extracellular Vesicles as an Innovative Theranostics in Microbial Diseases.

Extracellular vesicles (EVs), as nano-/micro-scale vehicles, are membranous particles containing various cargoes including peptides, proteins, different types of RNAs and other nucleic acids, and lipids. These vesicles are produced by all cell types, in which stem cells are a potent source for them. Stem cell-derived EVs could be promising platforms for treatment of infectious diseases and early diagnosis. Infectious diseases are responsible for more than 11 million deaths annually. Highly transmissible nature of some microbes, such as newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), drives researcher's interest to set up different strategies to develop novel therapeutic strategies. Recently, EVs-based diagnostic and therapeutic approaches have been launched and gaining momentum very fast. The efficiency of stem cell-derived EVs on treatment of clinical complications of different viruses and bacteria, such as SARS-CoV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Staphylococcus aureus, Escherichia coli has been demonstrated. On the other hand, microbial pathogens are able to incorporate their components into their EVs. The microbe-derived EVs have different physiological and pathological impacts on the other organisms. In this review, we briefly discussed biogenesis and the fate of EVs. Then, EV-based therapy was described and recent developments in understanding the potential application of stem cell-derived EVs on pathogenic microorganisms were recapitulated. Furthermore, the mechanisms by which EVs were exploited to fight against infectious diseases were highlighted. Finally, the deriver challenges in translation of stem cell-derived EVs into the clinical arena were explored.

Organoid and microfluidics-based platforms for drug screening in COVID-19.

Proposing efficient prophylactic and therapeutic strategies for coronavirus 2019 (COVID-19) requires precise knowledge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. An array of platforms, including organoids and microfluidic devices, have provided a basis for studies of SARS-CoV-2. Here, we summarize available models as well as novel drug screening approaches, from simple to more advanced platforms. Notably, organoids and microfluidic devices offer promising perspectives for the clinical translation of basic science, such as screening therapeutics candidates. Overall, modifying these advanced micro and macro 3D platforms for disease modeling and combining them with recent advances in drug screening has significant potential for the discovery of novel potent drugs against COVID-19.

The nano-based theranostics for respiratory complications of COVID-19.

High morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made coronavirus disease 2019 (COVID-19) the leading challenge for health experts all over the world. Currently, there is no specific treatment for COVID-19; however, thanks to worldwide intense attempts, novel vaccines such as mRNA-1273 (Moderna TX, Inc.) and BNT162b2 (Biontech/Pfizer) were developed very fast and FDA approved them for emergency use. Nanomedicine-based drug delivery can be an advanced therapeutic strategy to deal with clinical complications of COVID-19. Given the fact that SARS-CoV-2 typically affects the respiratory tract, application of inhalable nanoparticles (NPs) for targeted drug delivery to the alveolar space appears to be an effective and promising therapeutic strategy. Loading the medicinal components into NPs enhances the stability, bioavailability, solubility and sustained release of them. This approach can circumvent major challenges in efficient drug delivery such as solubility and any adverse impact of medicinal components due to off-targeted delivery and resulting systemic complications. Inhalable NPs could be delivered through nasal sprays, inhalers, and nebulizers. NPs also could interfere in virus attachment to host cells and prevent infection. Moreover, nanomedicine-based technologies can facilitate accurate and rapid detection of virus compared to the conventional methods. In this review, the nano-based theranostics modalities for the management of respiratory complications of COVID-19 were discussed.

Cross-talk between immune system and microbiota in COVID-19.

INTRODUCTION: Human gut microbiota plays a crucial role in providing protective responses against pathogens, particularly by regulating immune system homeostasis. There is a reciprocal interaction between the gut and lung microbiota, called the gut-lung axis (GLA). Any alteration in the gut microbiota or their metabolites can cause immune dysregulation, which can impair the antiviral activity of the immune system against respiratory viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. AREAS COVERED: This narrative review mainly outlines emerging data on the mechanisms underlying the interactions between the immune system and intestinal microbial dysbiosis, which is caused by an imbalance in the levels of essential metabolites. The authors will also discuss the role of probiotics in restoring the balance of the gut microbiota and modulation of cytokine storm. EXPERT OPINION: Microbiota-derived signals regulate the immune system and protect different tissues during severe viral respiratory infections. The GLA's equilibration could help manage the mortality and morbidity rates associated with SARS-CoV-2 infection.

Possible Male Reproduction Complications after Coronavirus Pandemic.

Coronavirus disease 2019 (COVID-19), as a severe respiratory disease, affects various tissues and organs. The specific SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), is highly expressed in male gonads. Thus, male reproductive tissues could be a potential target for virus colonization. We performed a comprehensive search in PubMed and Google Scholar to retrieve relevant articles published till 15 April 2021. The keywords used were: male fertility, male reproductive health, semen parameters, sex hormones, SARS-CoV-2, and COVID-19. Validated evidence about the adverse effects of the SARS-CoV-2 infection on the male reproductive system is limited and few studies have reported semen analysis results or presence of viral RNA in semen samples of infected men. Nevertheless, alterations in reproductive hormones such as decreased level of testosterone (T) with raised luteinizing hormone (LH) have been reported in some patients. Although the impact of SARS-CoV-2 infection on the male reproduction health remains unclear, evidence suggests that male gonads may be potentially vulnerable to SARS-CoV-2 infection. In this article, we discussed the possible impacts of COVID-19 on male gonads, sex hormones, and semen quality and suggested preventive solutions.

Organoids in modelling infectious diseases.

Approaches based on animal and two-dimensional (2D) cell culture models cannot ensure reliable results in modeling novel pathogens or in drug testing in the short term; therefore, there is rising interest in platforms such as organoids. To develop a toolbox that can be used successfully to overcome current issues in modeling various infections, it is essential to provide a framework of recent achievements in applying organoids. Organoids have been used to study viruses, bacteria, and protists that cause, for example, respiratory, gastrointestinal, and liver diseases. Their future as models of infection will be associated with improvements in system complexity, including abilities to model tissue structure, a dynamic microenvironment, and coinfection. Teaser. Organoids are a flexible tool for modelling viral, bacterial and protist infections. They can provide fast and reliable information on the biology of pathogens and in drug screening, and thus have become essential in combatting emerging infectious diseases.

Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. METHODS: A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). FINDINGS: There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24-48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48-96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2-7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5-19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. INTERPRETATION: We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

Therapeutic modalities and novel approaches in regenerative medicine for COVID-19.

The recent coronavirus disease 2019 outbreak around the world has had an enormous impact on the global health burden, threatening the lives of many individuals, and has had severe socio-economic consequences. Many pharmaceutical and biotechnology companies have commenced intensive research on different therapeutic strategies, from repurposed antiviral drugs to vaccines and monoclonal antibodies to prevent the spread of the disease and treat infected patients. Among the various strategies, advanced therapeutic approaches including cell- and gene-editing-based therapeutics are also being investigated, and initial results in in-vitro and early phase I studies have been promising. However, further assessments are required. This article reviews the underlying mechanisms for the pathogenesis of severe acute respiratory syndrome coronavirus-2, and discusses available therapeutic candidates and advanced modalities that are being evaluated in in-vitro/in-vivo models and are of note in clinical trials.

Engineering a Model to Study Viral Infections: Bioprinting, Microfluidics, and Organoids to Defeat Coronavirus Disease 2019 (COVID-19).

While the number of studies related to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is constantly growing, it is essential to provide a framework of modeling viral infections. Therefore, this review aims to describe the background presented by earlier used models for viral studies and an approach to design an "ideal" tissue model for SARS-CoV-2 infection. Due to the previous successful achievements in antiviral research and tissue engineering, combining the emerging techniques such as bioprinting, microfluidics, and organoid formation are considered to be one of the best approaches to form in vitro tissue models. The fabrication of an integrated multi-tissue bioprinted platform tailored for SARS-CoV-2 infection can be a great breakthrough that can help defeat coronavirus disease in 2019.

IBD Patients Could Be Silent Carriers for Novel Coronavirus and Less Prone to its Severe Adverse Events: True or False?

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract. The goal of IBD treatment is to reduce the inflammation period and induce long-term remission. Use of anti-inflammatory drugs including corticosteroids, immunosuppressants and biologicals, is often the first step in the treatment of IBD. Therefore, IBD patients in pandemic of infectious diseases are considered a high-risk group. The public believes that IBD patients are at a higher risk in the current coronavirus 2 pandemic. Nevertheless, these patients may experience mild or moderate complications compared to healthy people. This might be because of particular anti-TNF-α treatment or any immunosuppressant that IBD patients receive. Moreover, these patients might be silent carrier for the virus.

Novel therapeutic approaches for treatment of COVID-19.

To date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndrome are still unsolved issues causing the severity of this disease. Therefore, immune response modulation and inflammation management can be considered as an essential step. There is no doubt that more studies are required to clarify immunopathogenesis and immune response; however, new therapeutic approaches including mesenchymal stromal cell and immune cell therapy showed inspiring results.