The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review.

BACKGROUND: Endometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium. EAC is the most common female malignancy following the menopause period. About 40% of patients with EAC are linked with obesity and interrelated with hypertension, diabetes mellitus, and high circulating estrogen levels. Proprotein convertase (PC) furin was involved in the progression of EAC. RECENT FINDINGS: Furin is a protease enzyme belonging to the subtilisin PC family called PC subtilisin/kexin type 3 that converts precursor proteins to biologically active forms and products. Aberrant activation of furin promotes abnormal cell proliferation and the development of cancer. Furin promotes angiogenesis, malignant cell proliferation, and tissue invasion by malignant cells through its pro-metastatic and oncogenic activities. Furin activity is correlated with the malignant proliferation of EAC. Higher expression of furin may increase the development of EAC through overexpression of pro-renin receptors and disintegrin and metalloprotease 17 (ADAM17). As well, inflammatory signaling in EAC promotes the expression of furin with further propagation of malignant transformation. CONCLUSION: Furin is associated with the development and progression of EAC through the induction of proliferation, invasion, and metastasis of malignant cells of EAC. Furin induces ontogenesis in EAC through activation expression of ADAM17, pro-renin receptor, CD109, and TGF-ß. As well, EAC-mediated inflammation promotes the expression of furin with further propagation of neoplastic growth and invasion.

New insights on the potential effect of progesterone in Covid-19: Anti-inflammatory and immunosuppressive effects.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and sex hormones have immune-modulator effects during different viral infections, including SARS-CoV-2 infection. One of the essential sex hormones is progesterone (P4). AIMS: This review aimed to reveal the association between P4 and Covid-19. RESULTS AND DISCUSSION: The possible role of P4 in COVID-19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti-inflammatory cytokines, and inhibition release of pro-inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti-inflammatory Th2 with activation release of anti-inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon-gamma production that increased during SARS-CoV-2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS-CoV-2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ-aminobutyric acid (GABAA ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID-19 patients. CONCLUSION: Taken together, the anti-inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID-19.

Hypoxia-Inducible Factor 1 and Preeclampsia: A New Perspective.

PURPOSE OF REVIEW: Preeclampsia (PE) is a serious and distinct type of pregnancy-induced hypertension, with an incidence of 2-8% worldwide. PE is defined as pregnancy-related hypertension with proteinuria and peripheral edema after 20 weeks of gestation. Hypoxic placenta triggers the release of inflammatory and humoral substances into maternal circulation, leading to induction of oxidative stress, lipid peroxidation, endothelial dysfunction, and peripheral vasoconstriction. The objective of the present narrative review was to find the association between PE and hypoxia-inducible factor 1 (HIF-1) in pregnant women from a new perspective. RECENT FINDINGS: HIF-1 is the key transcription factor that regulates cellular responses to hypoxia and low oxygen tension. HIF-1α is involved in the differentiation and growth of the placenta mainly in the first and second trimesters. During normal gestation, HIF-1α responds to the alterations in oxygen tension, cytokine, and angiogenic factors release. HIF-1α is considered a key biomarker of placental function and vascularization during pregnancy. HIF-1α plays a crucial role in the pathogenesis of PE through activation of anti-angiogenic and inhibition of proangiogenic factors. As well, HIF-1α increases the expression of the p38MAPK and NLRP3 inflammasomes, which promote placental inflammation and dysfunction. HIF-1α acts as a potential link between inflammatory signaling pathways and the development of PE.

An insight into the placental growth factor (PlGf)/angii axis in Covid-19: a detrimental intersection.

Coronavirus disease 2019 (Covid-19) is a recent and current infectious pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Covid-19 may lead to the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severe cases. Down-regulation of angiotensin-converting enzyme (ACE2) by the SARS-CoV-2 increases the production of angiotensin II (AngII), which increases the release of pro-inflammatory cytokines and placental growth factor (PlGF). PlGF is a critical molecule involved in vasculogenesis and angiogenesis. PlGF is stimulated by AngII in different inflammatory diseases through a variety of signaling pathways. PlGF and AngII are interacted in SARS-CoV-2 infection resulting in the production of pro-inflammatory cytokines and the development of Covid-19 complications. Both AngII and PlGF are interacted and are involved in the progression of inflammatory disorders; therefore, we aimed in this review to highlight the potential role of the PlGF/AngII axis in Covid-19.

Prostaglandins and non-steroidal anti-inflammatory drugs in Covid-19.

In response to different viral infections, including SARS-CoV-2 infection, pro-inflammatory, anti-inflammatory cytokines, and bioactive lipids are released from infected and immune cells. One of the most critical bioactive lipids is prostaglandins (PGs) which favor perseverance of inflammation leading to chronic inflammation as PGs act as cytokine amplifiers. PGs trigger the release of pro-inflammatory cytokines, activate Th cells, recruit immune cells, and increase the expression of pro-inflammatory genes. Therefore, PGs may induce acute and chronic inflammations in various inflammatory disorders and viral infections like SARS-CoV-2. PGs are mainly inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) by blocking cyclooxygenase enzymes (COXs), which involve PG synthesis. NSAIDs reduce inflammation by selective or non-selective blocking activity of COX2 or COX1/2, respectively. In the Covid-19 era, there is a tremendous controversy regarding the use of NSAIDs in the management of SARS-CoV-2 infection. As well, the possible role of PGs in the pathogenesis of SARS-CoV-2 infection is not well-defined. Thus, the objective of the present study is to review the potential role of PGs and NSAIDs in Covid-19 in a narrative review regarding the preponderance of assorted views.

Plasminogen activator inhibitor 1 and gestational diabetes: the causal relationship.

Plasminogen activator inhibitor 1 (PAI-1) also known as serpin E1 or endothelial plasminogen activator inhibitor, is produced from endothelial cells and adipose tissue. PAI-1 inhibits tissue plasminogen activator (tPA) and urokinase (uPA) preventing activation of plasminogen and fibrinolysis. Gestational diabetes mellitus (GDM) is defined as glucose intolerance and hyperglycemia during pregnancy. The underlying mechanism of GDM is due to the reduction of insulin secretion or the development of insulin resistance (IR). Normal PAI-1 is a crucial mediator for maintaining pregnancy, though aberrantly high PAI-1 promotes inflammation and thrombosis with increased risk of pregnancy loss. Increasing PAI-1 level had been shown to be an early feature of cardio-metabolic derangement in women with GDM. As well, GDM is regarded as an independent predictor for increasing PAI-1 levels compared to normal pregnancy. Taken together, GDM seems to be the causal factor in the increase of PAI-1 via induction of IR, hyperglycemia and hypertriglyceridemia. In conclusion, GDM triggers expression and release of PAI-1 which linked with GDM severity due to exaggerated pro-inflammatory and inflammatory cytokines with the development of IR. High PAI-1 levels in GDM may induce hypofibrinolysis and thrombotic complications.

5-HT/CGRP pathway and Sumatriptan role in Covid-19.

Coronavirus disease 2019 (Covid-19) is a pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In Covid-19, there is uncontrolled activation of immune cells with a massive release of pro-inflammatory cytokines and the development of cytokine storm. These inflammatory changes induce impairment of different organ functions, including the central nervous system (CNS), leading to acute brain injury and substantial changes in the neurotransmitters, including serotonin (5-HT) and calcitonin gene-related peptide (CGRP), which have immunomodulatory properties through modulation of central and peripheral immune responses. In Covid-19, 5-HT neurotransmitters and CGRP could contribute to abnormal and atypical vascular reactivity. Sumatriptan is a pre-synaptic 5-HT (5-HT1D and 5-HT1B) agonist and inhibits the release of CGRP. Both 5-HT and CGRP seem to be augmented in Covid-19 due to underlying activation of inflammatory signaling pathways and hyperinflammation. In virtue of its anti-inflammatory and antioxidant properties with inhibition release of 5-HT and CGRP, Sumatriptan may reduce Covid-19 hyperinflammation. Therefore, Sumatriptan might be a novel potential therapeutic strategy in managing Covid-19. In conclusion, Sumatriptan could be an effective therapeutic strategy in managing Covid-19 through modulation of 5-HT neurotransmitters and inhibiting CGRP.

Maternal Transmission of SARS-CoV-2: Safety of Breastfeeding in Infants Born to Infected Mothers.

Coronavirus disease 2019 (COVID-19) is a recent epidemic disease caused by severe acute respiratory syndrome virus type 2 (SARS-CoV-2). In pregnancy, SARS-Cov-2 infection creates additional alarm due to concerns regarding the potential for transmission from the mother to the baby during both the antenatal and postpartum times. In general, breastfeeding is seldom disallowed because of infection of the mother. However, there are few exceptions with regards to certain infectious organisms with established transmission evidence from mother to infant and the link of infection of a newborn with significant morbidity and mortality. It is confirmed that pregnant women can become infected with SARS-CoV-2, although the debate on the possible vertical transmission of SARS-CoV-2 infection during pregnancy is still open. In this regard, the literature is still poor. On the contrary, the information on the safety of breastfeeding even during infections seems reassuring when the mother takes the necessary precautions. However, there are still answered questions regarding the precautions to be taken during breastfeeding by COVID-19 patients. This paper reviews the existing answers to these and many other questions. This review therefore presents a summary of the present-day understanding of infection with SARS-CoV-2 and discusses the answers around the maternal transmission of COVID-19 and the potential threat of breastfeeding to babies born to infected pregnant mothers. In conclusion, intrauterine transmission of SARS-CoV-2 infection is less likely to occur during pregnancy. Most studies suggest that COVID-19 is not transmitted through breast milk. Correspondingly, COVID-19-infected neonates might acquire the infection via the respiratory route because of the postnatal contact with the mother rather than during the prenatal period. International organizations encourage breastfeeding regardless of the COVID-19 status of the mother or child as long as proper hygienic and safety measures are adhered to so as to minimize the chance of infant infection by droplets and direct contact with the infected mother. Pasteurized donor human milk or infant formula as supplemental feeding can be quite beneficial in the case of mother-infant separation till breastfeeding is safe.

The Looming Effects of Estrogen in Covid-19: A Rocky Rollout.

In the face of the Covid-19 pandemic, an intensive number of studies have been performed to understand in a deeper way the mechanisms behind better or worse clinical outcomes. Epidemiologically, men subjects are more prone to severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infections than women, with a similar scenario being also stated to the previous coronavirus diseases, namely, SARS-CoV in 2003 and Middle East Respiratory Syndrome coronavirus diseases (MERS-CoV) in 2012. In addition, and despite that aging is regarded as an independent risk factor for the severe form of the disease, even so, women protection is evident. In this way, it has been expected that sex hormones are the main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, attracting more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect.

Role of dyslipidemia in the development of early-onset preeclampsia.

Preeclampsia (PE) is a gestational-related disease presented with hypertension, peripheral edema, and proteinuria after 20 weeks of gestation. In PE, there are various metabolic changes like dyslipidemia. In addition, both PE and dyslipidemia are associated with changes of platelet indices. Thus, objective of the current study was to illustrate the potential role of dyslipidemia and platelet changes in pregnant women with PE. This case-control study involved 37 preeclamptic pregnant women as compared to 24 healthy pregnant women as controls. Blood pressure profile, lipid profile, proteinuria, and platelet indices were measured. Blood pressure profile was higher in preeclamptic pregnant women as compared to the controls (P < 0.01). There was a significant dyslipidemic status in preeclamptic pregnant women compared with the controls (P < 0.01). Platetetcrit (PCT) and platelet count (PC) were lower in preeclamptic pregnant women compared with the controls (P = 0.001). On the other hand, platelet distribution width (PDW), mean platelet volume (MPV), and platelet-large cell ratio (P-LCR) were higher in the pregnant women with PE as compared with the controls (P = 0.001). PCT and PC were insignificantly linked, while P-LCR, MPV and PDW were significantly correlated with total cholesterol, triglyceride, low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio, systolic blood pressure, DBP, and MAP in preeclamptic patients compared with women of normal pregnancy. Both dyslipidemia and alterations in the platelet indices are correlated with blood pressure profile in PE. High MPV and PDW in association with high LDL/HDL ratio in pregnant women herald risk of PE.

Differential effect of metformin and/or glyburide on apelin serum levels in patients with type 2 diabetes mellitus: Concepts and clinical practice.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with abundant adipocytokine changes which may play an important role in the progression of insulin resistance and micro- and macro-vascular complications. Therefore, the objective of this study was to assess the differential effect of metformin alone or in combination with glyburide on apelin serum levels in patients with T2DM. In this case-control study, fifty patients with T2DM in the age range of 45-65 years and twenty-five healthy controls matched for age and body weight were recruited from single endocrinology center, subdivided according to the diabetic pharmacotherapy into: Group I: healthy controls (n = 25), Group II: T2DM patients on metformin (n = 15), Group III: T2DM patients on glyburide (n = 17), and Group IV: T2DM patients on metformin plus glyburide (n = 28). Biochemical and anthropometric variables in relation to apelin serum levels were estimated. Apelin serum levels were low in normal healthy controls compared to T2DM patients (P < 0.01). The differential effect of diabetic pharmacotherapy on apelin serum level was statistically significant (P < 0.01) compared to the controls, but insignificant when compared among used drugs (P > 0.05). Apelin level was high in T2DM compared to the controls; both metformin and glyburide might play a role in this elevation.

Concept and connotation of oxidative stress in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a systemic pregnancy-related disorder characterized by hypertension, proteinuria, and edema. Free radicals seem to play an important role in the induction of endothelial dysfunction in PE. AIM: The aim of the present study was to investigate serum levels of nitric oxide (NO), peroxynitrite (ONOO-), paraoxonase (PON-1), malondialdehyde (MDA), and lipid profile in preeclamptic patients compared to the women with normal pregnancy. MATERIALS AND METHODS: A total of 68 pregnant women were recruited. They were divided into two groups - Group A, 40 women were a newly diagnosed with PE and Group B, 28 women with normal pregnancy. Anthropometric measurements including body mass index and blood pressure in accordance with biochemical measurements including NO, ONOO-, PON-1, MDA, and lipid profile were done for preeclamptic pregnant women compared to the controls. RESULTS: Pregnant women with pre-eclampsia illustrated insignificant differences in the age (31.22±2.87) compared to the age of control P > 0.05. There were significant changes in the body mass index (BMI), type of delivery and smoking status of pregnant women with pre-eclampsia compared to the control P < 0.05. Both systolic and diastolic blood pressures were high in pregnant women with pre-eclampsia compared to the control P < 0.01. PON-1 and NO serum levels were significantly decreased (P < 0.01) while ONOO- and MDA serum levels were significantly increased in PE compared to the women with normal pregnancy. CONCLUSIONS: This study concluded that PE is associated with the augmentation of oxidative stress and reduction of endogenous antioxidant capacity regarding PON-1.