Mast Cell's Role in Cytokine Release Syndrome and Related Manifestations of COVID-19 Disease.

In this narrative review, firstly, we describe the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathogenesis of its infection in humans. Later, the importance of mast cells in SARS-CoV-2 infection and their role in Coronavirus Disease 2019 (COVID-19) will be discussed. SARS-CoV-2 is a transmissible agent frequently detected in some mammalian species and also in humans. Literature data published in PubMed that covered mast cells' role in cytokine release syndrome and related manifestations of COVID-19 disease were reviewed by the authors independently and collectively. Recommendations for the management of cytokine release syndrome and related manifestations were made by the authors. Mast cells are concentrated in environments where they encounter viruses, bacteria, and toxins, especially in the skin, nasal mucosa, lungs, airways, gastrointestinal tract, and meninges, to prevent their entry into the human body. Once SARS-CoV-2 enters the host, it stimulates one of the mast cells, together with pre-existing innate immune cells that form a defensive barrier in the submucosa of the respiratory tract and nasal cavities against pathogenic microorganisms. The roles of mast cells in SARS-CoV-2-induced hyperinflammation and cytokine storms have recently been one of the hot topics in the literature. Physicians should keep in mind the mast cells' role in cytokine release syndrome and related manifestations of COVID-19 disease. Mast cell-targeting therapies (e.g., H1 and H2 receptor antagonists) can reduce the severity and course of the disease when used after complications associated with COVID-19 are suspected or seen.

Additive cell protective and oxidative stress reducing effects of combined treatment with cromolyn sodium and masitinib on MPTP-induced toxicity in SH-SY5Y neuroblastoma cells.

The suppression of oxidative-stress induced neurotoxicity by antioxidants serves as a potential preventive strategy for neurodegenerative diseases. In this study, we aimed to investigate the cell protective and antioxidant effects of masitinib and cromolyn sodium against toxin-induced neurodegeneration. First, human neuroblastoma SH-SY5Y cells were differentiated into neuron-like (d)-SH-SY5Y cells. The differentiated cells were confirmed by immuno-staining with anti-PGP9.5 antibody, a neuronal marker. Cell culture groups were formed, and a neurotoxin, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) was applied on cells followed by masitinib and/or cromolyn sodium treatments. Survival rate of cells were detected by MTT assay. Anti-inflammatory Transforming Growth Factor-ß1 (TGF-ß1) and nitric oxide (NO) levels and total oxidant and antioxidant capacities (TOC and TAC) in cell conditioned media (CM) were measured. Morphological analysis and apoptotic nuclear assessment of cells were also noted. When (d)-SH-SY5Y cells were exposed to neurotoxin, cell viability rates of these cells were found to be decreased in a concentration-dependent manner. CM of toxin applied group displayed higher levels of TOC/TAC ratios and NO levels compared to control (p < 0.01). Both masitinib and cromolyn sodium protected cells from toxin-induced cell death as revealed by ameliorated rates of viability, reversed toxin-induced elevation of TOC/TAC ratios, and decreased NO levels in their CM (p < 0.01). Combined treatment significantly reduced TOC/TAC ratios and NO levels more effectively compared to mono-treatments. Both drugs also increased TGF-ß1 levels significantly in cell CM. When these agents were tested for therapeutic effects against toxin-induced cell degeneration, better viability results were obtained by both masitinib and cromolyn sodium treatment, with significantly better amelioration provided by combined application of these drugs (p < 0.01). This study demonstrated new findings that combined treatment with cromolyn sodium, an FDA-approved drug of asthma, and masitinib, an orally administered drug with a low toxicity, exert neuroprotective and additive therapeutic effects. We propose that combination therapy of masitinib and cromolyn sodium may represent an innovative treatment in neurodegenerative diseases. Combination therapy may be more advantageous that it enables combined application of lower doses of both drugs, providing less side effects.

The protective effects of omega 3 fatty acids and sesame oil against cyclosporine A-induced nephrotoxicity.

Cyclosporine A (CsA) is a drug used in autoimmune disorders and organ transplantations. Omega 3 fatty acids (O-3) and sesame oil (SO) have antioxidant properties. We aimed to investigate and compare the protective effects of O-3 and SO against CsA-induced nephrotoxicity. Seven groups of male Wistar albino rats were included in the study. In group 1 (control), saline was administered, and in group 2, CsA (subcutaneously) was administered. In group 3, CsA+SO (orally; p.o.) was given; in group 4, CsA+O-3 (p.o.) was given; and in group 5, CsA+SO+O-3 was given. In group 6, SO was administered, and in group 7, O-3 was administered. After 15 days of treatment, kidneys were excised. Histopathological evaluation, apoptotic cell count, and renal/hepatic function tests were performed. In group 2, vacuolar degeneration and necrosis of tubular cells as well as hemorrhagic foci were observed; the apoptotic cell number was higher than in the control (P < 0.001). In groups 3, 4, and 5, tubular scores and apoptotic cell count were lower than in group 2 (P < 0.01 and P < 0.001, respectively). In groups 6 and 7, healthy renal histology and a few apoptotic cells were determined. In groups 2, 3, 4, and 5, blood urea nitrogen was higher and albumin was lower than in the control (P < 0.001). Liver enzymes were unchanged. O-3/SO showed similar protective effects against CsA-induced nephrotoxicity, as revealed by a remarkable decrease in histopathological changes and apoptotic cell count. However, impaired renal function tests were not improved with O-3/SO treatment. SO and O-3 can be used as chemoprotectants against CsA.

Significance of platelet endothelial cell adhesion molecule-1 (PECAM-1) and intercellular adhesion molecule-1 (ICAM-1) expressions in preeclamptic placentae.

Although preeclampsia (PE) is one of the most important problems affecting pregnant women, etiologic factors in its development are still unclear. We aimed to investigate the expression levels of platelet endothelial cell adhesion molecule-1 (PECAM-1) and intercellular adhesion molecule-1 (ICAM-1) in preeclamptic and control healthy placentas. Placental tissue samples were obtained after delivery from patients diagnosed with PE, and from normal term pregnants and analyzed by immunohistochemistry for the expression levels of the two adhesion molecules PECAM-1 and ICAM-1. A strong expression of PECAM-1 in endothelial cells lining the vessel walls of placental villi in placentas of control group was found, but the intensity of PECAM-1 expression was highly reduced in placentas of PE group (p = 0.017). Conversely, a strong expression of ICAM-1 was observed in placental villi in PE, significantly higher than that of normal placentas (p = 0.005). The findings of a decrease of PECAM-1 expression and an increase of ICAM-1 expression in preeclamptic placenta suggest the existence of functional roles of these adhesion molecules in the pathophysiology of PE, probably by contributing to the reduced trophoblast invasion and the increased vascular damage, respectively. Inhibiting ICAM-1 (i.e., with ICAM-1 monoclonal antibody) and promoting PECAM-1 expression may be good therapeutic approaches to prevent PE symptoms in the future.

Expression levels of cyclooxygenase-2, tumor necrosis factor-α and inducible NO synthase in placental tissue of normal and preeclamptic pregnancies.

OBJECTIVE: Although preeclampsia (PE) is one of the most important problems affecting pregnant women, etiologic factors in its development are still unclear. We aimed to investigate the expression levels of cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and inducible NO synthase (iNOS) in preeclamptic and healthy control placentas. PATIENTS AND METHODS: Placental tissue samples were obtained after delivery from patients diagnosed with PE and from normal-term pregnants and analyzed for COX-2, TNF-α and iNOS expression by immunohistochemistry. RESULTS: A strong expression of COX-2 was observed in syncytiotrophoblast cells of preeclamptic placentas, which was significantly higher than that of normal placentas (p = 0.005). A mild expression of TNF-α in both normal and preeclamptic syncytiotrophoblasts was seen (p = 0.435). In addition, a strong expression of iNOS in normal syncytiotrophoblasts was found, but the intensity of the iNOS expression was highly reduced in preeclamptic placentas (p = 0.001). No correlation was detected between COX-2, TNF-α and iNOS expression levels. CONCLUSION: The findings of a decrease of iNOS expression and an increase of COX-2 expression in placenta suggest the existence of functional roles of iNOS and COX-2 in the pathophysiology of PE, probably by contributing to the reduced placental blood flow and increased resistance to flow in the fetomaternal circulation.

The role of mast cells and angiogenesis in benign and malignant neoplasms of the uterus.

In this study, we looked for a relationship between the extent of angiogenesis and mast cell density (MCD) in human leiomyomas and endometrial carcinomas (EC), and investigated the clinicopathological relevance of mast cells (MCs) in EC. Specimens of 15 control, 20 leiomyoma, and 23 EC patients were investigated immunohistochemically using anti-CD31 and anti-tryptase antibodies. In EC, both stromal and myometrial expressions of CD31 were significantly higher than in the controls (p<0.01 and p=0.013; respectively). Stromal tryptase expression was not significantly lower than that of leiomyoma. In addition, in the leiomyoma group, CD31 and tryptase expressions were not much different compared to the controls. Moreover, a correlation was detected between cancer histological grade and both stromal and myometrial expressions of CD31 (p=0.017 and p=0.005; respectively). The findings show that high grade EC has a higher degree of vascularization than EC of lower grade, but MCD does not increase in parallel with the histological grade. This study has demonstrated that MCD does not correlate with angiogenesis and progression of grade in EC. Moreover, MCD in EC was found to be lower than in benign lesions of the uterus. In conclusion, MCs may not account for the angiogenic process which facilitates tumor growth.

Growth failure, tardive dyskinesia, megacolon development, and hepatic damage in neonatal rats following exposure to trimethobenzamide in utero.

OBJECTIVE: Trimethobenzamide (TMB) has a pregnancy category C labeling. Tardive dyskinesia and gastrointestinal involvement in neonates were not described earlier. We aimed to investigate neurological, developmental, and hepatic effects of TMB. METHODS: Ten 10 pregnant rats were divided into two groups. During pregnancy, Group I (control) were injected with saline; Group II with TMB (5 mg/kg/day). After delivery, two experiments were planned: experiment 1 (neuro) and Experiment 2 (hepatic). Control groups contained offsprings delivered from Group I mothers: Group I-offsp-neuro (n = 15) and Group I-offsp-hepatic (n = 15). Thirty offsprings delivered from Group II mothers formed Group II-offsp-neuro (n = 15) and Group II-offsp-hepatic (n = 15). Neuro group offsprings were followed-up to observe neurological symptoms and assessed for normal growth. Hepatic group livers were excised for histological evaluation. RESULTS: The body weight between neuro groups showed significant differences (p < 0.05). In Group II-offsp-neuro low body weight, poor hair growth, tardive dyskinesia and megacolon were observed. Some alterations of liver histology were noticed in Group II-offsp-hepatic (p < 0.001). CONCLUSIONS: In utero TMB exposure may cause growth retardation, neurological damage in the developing brain and intestine, and hepatic damage. Despite recent publications reporting safety of TMB, we suggest that obstetricians and pediatricians should make a good risk-benefit assessment before prescribing TMB.