Corrigendum: BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

[This corrects the article DOI: 10.3389/fphar.2023.1265230.].

Role of fenofibrate in multiple sclerosis.

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the central nervous system (CNS). The underlying pathophysiology of MS is the destruction of myelin sheath by immune cells. The formation of myelin plaques, inflammation, and injury of neuronal myelin sheath characterizes its neuropathology. MS plaques are multiple focal regions of demyelination disseminated in the brain's white matter, spinal cords, deep grey matter, and cerebral cortex. Fenofibrate is a peroxisome proliferative activated receptor alpha (PPAR-α) that attenuates the inflammatory reactions in MS. Fenofibrate inhibits differentiation of Th17 by inhibiting the expression of pro-inflammatory signaling. According to these findings, this review intended to illuminate the mechanistic immunoinflammatory role of fenofibrate in mitigating MS neuropathology. In conclusion, fenofibrate can attenuate MS neuropathology by modulating different pathways, including oxidative stress, autophagy, mitochondrial dysfunction, inflammatory-signaling pathways, and neuroinflammation.

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

PEPITEM Treatment Ameliorates EAE in Mice by Reducing CNS Inflammation, Leukocyte Infiltration, Demyelination, and Proinflammatory Cytokine Production.

To investigate the effect of the therapeutic treatment of the immunopeptide, peptide inhibitor of trans-endothelial migration (PEPITEM) on the severity of disease in a mouse model of experimental autoimmune encephalomyelitis (EAE) as a model for human multiple sclerosis (MS), a series of experiments were conducted. Using C57BL/6 female mice, we dosed the PEPITEM in the EAE model via IP after observing the first sign of inflammation. The disease was induced using MOG35-55 and complete Freund's adjuvants augmented with pertussis toxin. The EAE score was recorded daily until the end of the experiment (21 days). The histological and immunohistochemistry analysis was conducted on the spinal cord sections. A Western blot analysis was performed to measure the protein concentration of MBP, MAP-2, and N-Cadherin, and ELISA kits were used to measure IL-17 and FOXP3 in the serum and spinal cord lysate. The therapeutic treatment with PEPITEM reduced the CNS infiltration of T cells, and decreased levels of the protein concertations of MBP, MAP-2, and N-Cadherin were observed, in addition to reduced concertations of IL-17 and FOXP3. Using PEPITEM alleviated the severity of the symptoms in the EAE model. Our study revealed the potential of PEPITEM to control inflammation in MS patients and to reduce the harmful effects of synthetic drugs.

Breast Milk Mesenchymal Stem Cells and/or Derived Exosomes Mitigated Adenine-Induced Nephropathy via Modulating Renal Autophagy and Fibrotic Signaling Pathways and Their Epigenetic Regulations.

Chronic kidney disease (CKD), a global health concern, is highly prevalent among adults. Presently, there are limited therapeutic options to restore kidney function. This study aimed to investigate the therapeutic potential of breast milk mesenchymal stem cells (Br-MSCs) and their derived exosomes in CKD. Eighty adult male Sprague Dawley rats were randomly assigned to one of six groups, including control, nephropathy, nephropathy + conditioned media (CM), nephropathy + Br-MSCs, nephropathy + Br-MSCs derived exosomes (Br-MSCs-EXOs), and nephropathy + Br-MSCs + Br-MSCs-EXOs. Before administration, Br-MSCs and Br-MSCs-EXOs were isolated, identified, and labeled with PKH-26. SOX2, Nanog, and OCT3/4 expression levels in Br-MSCs and miR-29b, miR-181, and Let-7b in both Br-MSCs and Br-MSCs-EXOs were assayed. Twelve weeks after transplantation, renal function tests, oxidative stress, expression of the long non-coding RNA SNHG-7, autophagy, fibrosis, and expression of profibrotic miR-34a and antifibrotic miR-29b, miR-181, and Let-7b were measured in renal tissues. Immunohistochemical analysis for renal Beclin-1, LC3-II, and P62, Masson trichome staining, and histopathological examination of kidney tissues were also performed. The results showed that Br-MSCs expressed SOX2, Nanog, and OCT3/4, while both Br-MSCs and Br-MSCs-EXOs expressed antifibrotic miR-181, miR-29b, and Let-7b, with higher expression levels in exosomes than in Br-MSCs. Interestingly, the administration of Br-MSCs + EXOs, EXOs, and Br-MSCs improved renal function tests, reduced renal oxidative stress, upregulated the renal expression of SNHG-7, AMPK, ULK-1, Beclin-1, LC3, miR-29b, miR-181, Let-7b, and Smad-7, downregulated the renal expression of miR-34a, AKT, mTOR, P62, TGF-ß, Smad-3, and Coli-1, and ameliorated renal pathology. Thus, Br-MSCs and/or their derived exosomes appear to reduce adenine-induced renal damage by secreting antifibrotic microRNAs and potentiate renal autophagy by modulating SNHG-7 expression.

Subtractive panning for the isolation of monoclonal PEPITEM peptide antibody by phage display.

Antibody phage display is a key tool for the development of monoclonal antibodies against various targets. However, the development of anti-peptide antibodies is a challenging process due to the small size of peptides for binding. This makes anchoring of peptides a preferred approach for panning experiments. A common approach is by using streptavidin as the anchor protein to present biotinylated peptides for panning. Here, we propose the use of recombinant expression of the target peptide and an immunogenic protein as a fusion for panning. The peptide inhibitor of trans-endothelial migration (PEPITEM) peptide sequence was fused to the Mycobacterium tuberculosis (Mtb) α-crystalline (AC) as an anchor protein. The panning process was carried out by subtractive selection of the antibody library against the AC protein first, followed by binding to the library to PEPITEM fused AC (PEPI-AC). A unique monoclonal scFv antibodies with good specificity were identified. In conclusion, the use of an alternative anchor protein to present the peptide sequence coupled with subtractive panning allows for the identification of unique monoclonal antibodies against a peptide target.

Clinical Characteristics and Risk Factors among Patients with Positive COVID-19 Test Admitted to ICU.

Background: Studies that show common characteristics among ICU-admitted patients due to COVID-19 are available on the net, but such studies in Saudi Arabia are limited. Methods: A descriptive cross-sectional study establishing common comorbidities and risk factors among critically ill patients who tested positive for COVID-19 at the National Guard Hospital from March 2, 2020, to March 20, 2021. The data were obtained from the BEST Care System of King Abdulaziz Medical City, computed, and analyzed using SPSS. Results: Three hundred eighty-five COVID-19 patients admitted to the intensive care unit (ICU) were included in this study. The mean age was 60.85 ± 20.46, 60.85% were males, and 39.2% were females. There was statistically significant positive relationship between severity of the symptoms and age (P = 0.002). The mean duration of hospital stay in the sample was 21.85 ± 28.47. More than one-third (37.4%) of cases admitted to the hospital died while about two-thirds of the cases were discharged after complete recovery. Two hundred ninety (75.3%) of the patients who were admitted to the National Guard Health Affairs (Riyadh, Saudi Arabia) had respiratory disease. Two hundred twelve patients (55.1%) had diabetes mellitus, while the number of hypertensive patients was 203 (52.7%). There was a significant positive relation among patients with gastrointestinal tract infection (GIT) risk factors and the severity of the symptoms of COVID-19 (P = 0.000). In addition, there was a strong significant relation between hypertension patients and the severity of the COVID-19 symptoms (P = 0.017). Conclusion: COVID-19 patients who have GIT and hypertension have been found to be at an increased risk of COVID-19 symptom severity. Old age was also found to have an increased risk for COVID-19 symptom severity.

Epstein-Barr Virus (EBV) and Multiple Sclerosis Disease: A Biomedical Diagnosis.

Multiple sclerosis (MS) is a degenerative disease that affects 2.8 million people worldwide. It is a central nervous system disease (CNS), in which the myelin sheath covering the brain and spinal cord neurons is attacked. If the myelin sheath is damaged, a person can suffer permanent damage to the nerves. There are a number of factors that can increase a person's risk of developing MS, such as obesity, smoking, vitamin D deficiency, certain tissue types (HLADRB1∗15 : 01) and infection with the Epstein-Barr virus (EBV). The latter virus can cause infectious mononucleosis, which can, in turn, result in lifelong infection in the host. To establish the relationship between MS and EBV, the author conducted a study on 1176 MS patients admitted to Saudi Arabia King Abdulaziz City centers. The researcher determined that MS occurred twice as much in females as it did in males, and also that EBV was much more widespread in MS female patients than MS male patients (27 : 1). Age was not a factor in the occurrence of EBV. There were limitations on data completeness and availability. Other trials using larger cohorts of patients are needed.

Mesenchymal stem cell therapy: A review of clinical trials for multiple sclerosis.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is the result of the body's own immune cells being auto-reactive to the myelin regions of the body as if these regions were foreign antigens. This demyelination process is damaging to the electrical conductivity of neurons. The current medicines are only capable of fighting off the symptoms of the disease, but not the disease itself. Specialized stem cells, known as mesenchymal stem cells (MSCs), seem to be the candidate therapy to get rid of MS. MSCs can be isolated from multiple sources of the person's body, and even from the umbilical cord (UC) and placenta of a donor. These cells have anti-inflammatory effects so they can target the overactivity and self-antigen attacks by T cells and macrophages; this immune system overactivity is characteristic of MS. MSCs show the ability to locate into brain lesions when injected and thus can compensate for the loss of the brain function by differentiating into neuronal precursor cells and glial cells. The author has listed tables of clinical trials that have utilized MSCs from different sources, along with the years and the phase of study completed for each trial. The consensus is that these cells work on inhibiting CD4+ and CD8+ T cell activation, T regulatory cells (Tregs), and macrophage switch into the auto-immune phenotype. The best source of MSCs seems to be the UC due to the easiness of extraction, the noninvasive method of collection, their higher expansion ability and more powerful immune-modulating properties compared to other locations in the body. Studies showed there was a significant decline of mRNA expression of several cytokines after the administration of MSCs derived from the UC (UCMSCs). Other researchers were able to repair the defects of Tregs in MS patients by co-culturing Tregs from these patients with UCMSCs, which decreased the production of the pro-inflammatory cytokine IFN γ , and also suggested a strong link between Tregs lack of functionality in MS patients with the pathogenesis of the disease.

Awareness of Medical Students toward Circadian Rhythm and Sleep Disorder Based on Biomedical Diagnosis.

Background: Sleep disorders affect an individual's mental and physical health and vice versa. Sleep medicine is underrecognized as a specialty; therefore, many sleep disorders go undiagnosed. This study is aimed at assessing the knowledge of medical students toward circadian neuroscience and sleep disorder based on biomedical diagnosis. Methods: This cross-sectional study was conducted in both male and female medical colleges from the third to the sixth year. A self-administered structured questionnaire consisting of sociodemographic data and the Assessment of Sleep Knowledge in Medical Education (ASKME) survey assessed the students' general knowledge and attitude towards sleep disorder and sleep medicine. Chi-square/Fisher exact tests were used to analyse the participants' knowledge level toward specific sociodemographic data. Also, for two-level continuous variables, the Wilcoxon two-sample test was used. Results: The total number of participants was 296, with 154 female and 142 male participants. The prevalence of inadequate knowledge was considerable with 96.62% of students, compared to adequate knowledge with only 3.38%. The students' attitude to sleep medicine was negative 14.53% and positive among 85.47%. We found that gender was significantly associated with attitude with a p value = 0.0057. The specific interest in sleep medicine had a significant association with knowledge and attitude, p value of 0.0522 and 0.0059, respectively. Conclusion: This study concluded that medical students possess inadequate knowledge regarding sleep medicine, yet they have a positive attitude towards it.

Prevalence and Correlation of Metabolic Syndrome in Patients with Bipolar Disorder in NGHA, Riyadh.

Background: Metabolic syndrome is considered dangerous, especially to patients that are diagnosed with a mental condition such as bipolar disorder, since these types of patients can be difficult to deal with. Metabolic syndrome can lead to multiple cardiovascular diseases, strokes, and diabetes. A careful approach is important when it comes to facing a complex condition such as this. This research will contribute to giving more information about the prevalence and statistics of metabolic syndrome in bipolar disorder patients at NGHA, Riyadh. No published study in literature has investigated the prevalence of metabolic syndrome in patients with bipolar disorder in NGHA, Riyadh. Methods: The study was conducted among 191 adult male (66) and female (125) patients at NGHA, Riyadh. The medical records were used for the assessment of metabolic syndrome and referrals by using a chart review for individuals. The main variables are metabolic syndrome and bipolar disorder. It was conducted on both males and females. Data was collected on data collection form and further analysis on relations was made by using SAS (Version 9.4). Chi-squared test and the Wilcoxon Two-sample test for two-level continuous variables. P ≤ 0.05 was determined to be the significance level. Results: Out of 191 patients, 130 were obese, 85 had diabetes, and 89 were hypertensive. Additionally, 50 (40%) females and 29 (43.9%) males had metabolic syndrome, a total of 79 (41.4%) out of 191. Conclusion: The findings of this study indicate that there is an elevated prevalence of metabolic syndrome in bipolar disorder patients in NGHA, Riyadh. Highlighting the potential danger that people may not be aware of.

Assessment of the Knowledge Level of First Aid among Medical Students in Work Environment.

First aid is one of the most important life-saving skills a health provider specifically or anybody generally must have. It can be defined as the first treatment one provides at the site of the accident to the injured person until full medical treatment is available. In some emergency situations, simple first aid can make a life-or-death difference. Aim. This study is designed to evaluate the knowledge of first aid among medical students at KSAU-HS in Riyadh, Saudi Arabia. Methods. The cross-sectional study is conducted in KSAU-HS, Riyadh, about the knowledge of first aid among medical students. A self-administered structured questionnaire is used for the purpose of data collection. The main variables are as follows: to compare the knowledge of first aid between male and female medical students, among different years of study, and identify the percentage that have knowledge of first aid. Results. Out of 326 students, 10 students (3.1%) scored excellent, 99 (30.4%) good, 136 (41.7%) average, 75 (23%) poor, and 6 (1.8%) very poor. Conclusion. The level of knowledge improved with the advancement in years, but this was not sufficient, and more training should be given to all medical students on first aid.

COVID-19 and the role of stem cells.

There is currently an ongoing coronavirus respiratory disease (COVID-19) pandemic that is caused by SARS-CoV-2 virus, which emerged out of Wuhan, China. In severe cases, the disease can progress to respiratory distress, hypoxia, and multi-organ failure, all of which are associated with high mortality. Mesenchymal stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. MSCs have demonstrated their impressive ability to inhibit lung damage, reduce inflammation, attenuate the immune response, and aid with alveolar fluid clearance. Studies that investigated the use of MSCs and exosome cells derived from MSCs in treating COVD-19 patients have encouraging results. The conclusion of the results of four clinical studies, as presented in this review article, is reduced patient mortality in more than half of the subjects who were administered MSCs or exosomes derived from MSCs, intravenously, positioning these cells as a possible therapeutic solution for COVID-19. While the studies do have limitations, they do provide a stepping stone based on different approaches in the search for treatment to save patients.

Exposure to cell phones reduces heart rate variability in both normal-weight and obese normotensive medical students.

BACKGROUND: We investigated and compared the effect of the radiofrequency electromagnetic field (RF-EM) emitted by a cell phone on the electrocardiogram and heart rate variability (HRV) of normotensive normal-weight and obese medical students. METHOD: Twenty medical student volunteers, normal weight (age = 23 ± 2, BMI = 23.05 ± 1.72) or obese (age = 24 ± 2, BMI = 32.39 ± 4.78), were exposed to a cell phone (1) close to the heart in silent mode, no ringing or vibrating; (2) close to the heart in ring and vibration mode; (3) next to the ear (brain) while listening; and (4) next to the ear while listening and speaking. RESULTS: The average basal HR of obese students significantly increased, while the PR interval; time domains, including standard deviation (SD) of all normal R-R intervals (SDNN), mean of the SD of all normal R-R intervals (SDNNi), SD of the average of normal R-R intervals (SDANN), and percentage of R-R intervals at least 50 ms different from the previous interval (pNN50); and high-power frequency (HF) decreased. The LF/HF ratio also significantly increased. The SDNN, SDNNi, SDANN, pNN50, and HF levels significantly decreased and the LF/HF significantly increased in normal-weight and obese individuals only when the phone was near the apex of the heart in ring and vibration mode. All changes were more profound in obese students. CONCLUSION: Keeping the phone in a chest pocket reduced the HRV of normal-weight and obese medical students and exaggerated the effect of obesity on sympathetic activation.

Comparative adhesive and migratory properties of mesenchymal stem cells from different tissues.

BACKGROUND: Mesenchymal stem cells (MSC) are used in therapy, often by injection into the blood. OBJECTIVE: We aimed to compare the adhesive and migratory properties of MSC from umbilical cords (UCMSC), bone marrow (BMMSC) or trabecular bone (TBMSC), which might influence delivery to injured tissue. METHODS: MSC were perfused through glass capillaries coated with matrix proteins, collagen or fibronectin, or albumin. Adherent cells were counted microscopically and their spreading analysed over time. MSC migration through 8 µm pore filters coated with the same proteins was analysed. RESULTS: The number of MSC adhering to collagen was greater than fibronectin, decreased as wall shear rate increased from 17 to 70 s-1, and was in the order UCMSC>BMMSC>TBMSC. Conversely, spreading was more effective on fibronectin and was in the order BMMSC>TBMSC≥UCMSC. Migration was promoted by coating the lower surface of filters with either matrix protein, with UCMSC migrating more efficiently than BMMSC. CONCLUSIONS: MSC show origin-dependent variations in their efficiency of capture from flow and subsequent spreading or ability to migrate on matrix proteins. UCMSC showed most efficient capture from flow, which was followed by less spreading, but more rapid migration. These responses might be associated with more effective delivery from the circulation into damaged tissue.

Origin-Specific Adhesive Interactions of Mesenchymal Stem Cells with Platelets Influence Their Behavior After Infusion.

We investigated the adhesive behavior of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow MSC (BMMSC) or umbilical cord MSC (UCMSC) adhered efficiently from flow to the matrix proteins, collagen, or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer. UCMSC induced platelet aggregation in platelet rich plasma, and caused a marked drop in platelet count when mixed with whole human or mouse blood in vitro, or when infused into mice. In contrast, BMMSC did not activate platelets or induce changes in platelet count. Interestingly, isolated UCMSC and BMMSC both adhered to predeposited platelets. The differences in behavior in blood were attributable to expression of podoplanin (an activating ligand for the platelet receptor CLEC-2), which was detected on UCMSC, but not BMMSC. Thus, platelets were activated when bound to UCMSC, but not BMMSC. Platelet aggregation by UCMSC was inhibited by recombinant soluble CLEC-2, and UCMSC did not cause a reduction in platelet count when mixed with blood from mice deficient in CLEC-2. We predict that both MSC would carry platelets in the blood, but their interaction with vascular endothelium would depend on podoplanin-induced activation of the bound platelets. Such interactions with platelets might target MSC to damaged tissue, but could also be thrombotic. Stem Cells 2018;36:1062-1074.