Apigenin Alleviates Autistic-like Stereotyped Repetitive Behaviors and Mitigates Brain Oxidative Stress in Mice.

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10-30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 mg/kg, i.p.). BTBR mice pretreated with APG (20 mg/kg) or ARP (1 mg/g, i.p.) displayed significant improvements in the marble-burying test (MBT), cotton-shredding test (CST), and self-grooming test (SGT) (all p < 0.05). However, a lower dose of APG (10 mg/kg, i.p.) failed to modulate behaviors in the MBT or SGT, but significantly attenuated the increased shredding behaviors in the CST of tested mice. Moreover, APG (10-30 mg/kg, i.p.) and ARP (1 mg/kg) moderated the disturbed levels of oxidative stress by mitigating the levels of catalase (CAT) and superoxide dismutase (SOD) in the hippocampus and cerebellum of treated BTBR mice. In patch clamp studies in hippocampal slices, the potency of choline (a selective agonist of α7-nAChRs) in activating fast inward currents was significantly potentiated following incubation with APG. Moreover, APG markedly potentiated the choline-induced enhancement of spontaneous inhibitory postsynaptic currents. The observed results propose the potential therapeutic use of APG in the management of ASD. However, further preclinical investigations in additional models and different rodent species are still needed to confirm the potential relevance of the therapeutic use of APG in ASD.

Additive Effects of Citrus Juice Flavonoid Naringenin and Statins on HERG Channels Expressed in Xenopus Oocytes.

OBJECTIVE: Naringenin, a major flavonoid found in citrus juice, has been shown to inhibit HERG channels and cause QT prolongation. Statins, the most commonly used class of cholesterol reducing drugs, have also been reported to inhibit HERG channels and prolong QT interval in patients using these drugs. However, the interaction between naringenin and statins on the function of HERG channels has not been studied. MATERIALS AND METHODS: In the present study, we expressed HERG channels in Xenopus oocytes and tested the effects of naringenin and statins separately and combined on HERG channels. RESULTS: When 30 µM naringenin was added to statins (1 µM rosuvastatin or 3 µM atorvastatin), significantly greater inhibition of HERG was demonstrated, compared to the inhibition caused by statins alone. CONCLUSIONS: The results indicate that an additive interaction occurs between naringenin and statins; this could pose an increased risk of arrhythmias by decreasing repolarization reserve.

α7 nicotinic acetylcholine receptor interaction with G proteins in breast cancer cell proliferation, motility, and calcium signaling.

Chronic smoking is a primary risk factor for breast cancer due to the presence of various toxins and carcinogens within tobacco products. Nicotine is the primary addictive component of tobacco products and has been shown to promote breast cancer cell proliferation and metastases. Nicotine activates nicotinic acetylcholine receptors (nAChRs) that are expressed in cancer cell lines. Here, we examine the role of the α7 nAChR in coupling to heterotrimeric G proteins within breast cancer MCF-7 cells. Pharmacological activation of the α7 nAChR using choline or nicotine was found to increase proliferation, motility, and calcium signaling in MCF-7 cells. This effect of α7 nAChR on cell proliferation was abolished by application of Gαi/o and Gαq protein blockers. Specifically, application of the Gαi/o inhibitor pertussis toxin was found to abolish choline-mediated cell proliferation and intracellular calcium transient response. These findings were corroborated by expression of a G protein binding dominant negative nAChR subunit (α7345-348A), which resulted in significantly attenuating calcium signaling and cellular proliferation in response to choline. Our study shows a new role for G protein signaling in the mechanism of α7 nAChR-associated breast cancer growth.

Transient receptor potential vanilloid 1 (TRPV1)-independent actions of capsaicin on cellular excitability and ion transport.

Capsaicin is a naturally occurring alkaloid derived from chili pepper that is responsible for its hot pungent taste. Capsaicin is known to exert multiple pharmacological actions, including analgesia, anticancer, anti-inflammatory, antiobesity, and antioxidant effects. The transient receptor potential vanilloid subfamily member 1 (TRPV1) is the main receptor mediating the majority of the capsaicin effects. However, numerous studies suggest that the TRPV1 receptor is not the only target for capsaicin. An increasing number of studies indicates that capsaicin, at low to mid µM ranges, not only indirectly through TRPV1-mediated Ca2+ increases, but also directly modulates the functions of voltage-gated Na+ , K+ , and Ca2+ channels, as well as ligand-gated ion channels and other ion transporters and enzymes involved in cellular excitability. These TRPV1-independent effects are mediated by alterations of the biophysical properties of the lipid membrane and subsequent modulation of the functional properties of ion channels and by direct binding of capsaicin to the channels. The present study, for the first time, systematically categorizes this diverse range of non-TRPV1 targets and discusses cellular and molecular mechanisms mediating TRPV1-independent effects of capsaicin in excitable, as well as nonexcitable cells.

Methylene Blue Inhibits Cromakalim-Activated K+ Currents in Follicle-Enclosed Oocytes.

The effects of methylene blue (MB) on cromakalim-induced K+ currents were investigated in follicle-enclosed Xenopus oocytes. In concentrations ranging from 3-300 µM, MB inhibited K+ currents (IC50: 22.4 µM) activated by cromakalim, which activates KATP channels. MB inhibited cromakalim-activated K+ currents in a noncompetitive and voltage-independent manner. The respective EC50 and slope values for cromakalim-activation of K+ currents were 194 ± 21 µM and 0.91 for controls, and 206 ± 24 µM and 0.87 in the presence of 30 µM MB. The inhibition of cromakalim-induced K+ currents by MB was not altered by pretreatment with the Ca2+ chelator BAPTA, which suggests that MB does not influence Ca2+-activated second messenger pathways. K+ currents mediated through a C-terminally deleted form of Kir6.2 (KirΔC26), which does not contain the sulfonylurea receptor, were still inhibited by MB, indicating direct interaction of MB with the channel-forming Kir6.2 subunit. The binding characteristics of the KATP ligand [3H]glibenclamide are not altered by MB in a concentration range between 1 µM-1 mM, as suggested by radioligand binding assay. The presence of a membrane permeable cGMP analogue (8-Br-cGMP, 100 µM) and a guanylate cyclase activator (BAY 58-2667, 3 µM) did not affect the inhibitory effects of MB, suggesting that MB does not inhibit cromakalim-activated K+ currents through guanylate cyclase. Collectively, these results suggest that MB directly inhibits cromakalim-activated K+ currents in follicular cells of Xenopus oocytes.

Probing the Ubiquitination-Mediated Function of Epithelial Sodium Channel in A549 Cells.

BACKGROUND: The activity of the amiloride-sensitive epithelial sodium channel (ENaC) in the tight epithelia of the lung is regulated by proteolytic activation and ubiquitination. Pathophysiology of lung diseases is directly related to changes in one or both of these mechanisms. METHODS: In this study, we investigated the impact of ubiquitination and cathepsin-mediated proteolytic activation mechanisms on the functional regulation of ENaC in lung cancer A549 cells using the patch-clamp technique. RESULTS: Our findings suggest that inhibiting the proteasome (polyubiquitination) with MG132 improves ENaC activity, whereas altering the pH of the lysosome (monoubiquitination inhibition) with NH4Cl has no effect on ENaC activity. In A549 cells, inhibition of cathepsin B (CSTB) decreased the ENaC current, open probabilities (NPo and Po), and the number of active channels. CONCLUSION: These findings delineate novel modes of ENaC degradation and proteolytic activation of functional channels in A549 cells. Our findings indicate that both proteolytic activation and ubiquitination of ENaC significantly affect channel function and add new insights into the endogenous ENaC processing which might help to further understand the pathophysiology of the lung disease.

Effects of cannabinoids on ligand-gated ion channels.

Phytocannabinoids such as Δ9-tetrahydrocannabinol and cannabidiol, endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and synthetic cannabinoids such as CP47,497 and JWH-018 constitute major groups of structurally diverse cannabinoids. Along with these cannabinoids, CB1 and CB2 cannabinoid receptors and enzymes involved in synthesis and degradation of endocannabinoids comprise the major components of the cannabinoid system. Although, cannabinoid receptors are known to be involved in anti-convulsant, anti-nociceptive, anti-psychotic, anti-emetic, and anti-oxidant effects of cannabinoids, in recent years, an increasing number of studies suggest that, at pharmacologically relevant concentrations, these compounds interact with several molecular targets including G-protein coupled receptors, ion channels, and enzymes in a cannabinoid-receptor independent manner. In this report, the direct actions of endo-, phyto-, and synthetic cannabinoids on the functional properties of ligand-gated ion channels and the plausible mechanisms mediating these effects were reviewed and discussed.

Capsaicin Inhibits Multiple Voltage-Gated Ion Channels in Rabbit Ventricular Cardiomyocytes in TRPV1-Independent Manner.

Capsaicin is a naturally occurring alkaloid derived from chili pepper which is responsible for its hot, pungent taste. It exerts multiple pharmacological actions, including pain-relieving, anti-cancer, anti-inflammatory, anti-obesity, and antioxidant effects. Previous studies have shown that capsaicin significantly affects the contractility and automaticity of the heart and alters cardiovascular functions. In this study, the effects of capsaicin were investigated on voltage-gated ion currents in rabbit ventricular myocytes. Capsaicin inhibited rapidly activated (IKr) and slowly activated (IKs) K+ currents and transient outward (Ito) K+ current with IC50 values of 3.4 µM,14.7 µM, and 9.6 µM, respectively. In addition, capsaicin, at higher concentrations, suppressed voltage-gated Na+ and Ca2+ currents and inward rectifier IK1 current with IC50 values of 42.7 µM, 34.9 µM, and 38.8 µM, respectively. Capsaicin inhibitions of INa, IL-Ca, IKr, IKs, Ito, and IK1 were not reversed in the presence of capsazepine (3 µM), a TRPV1 antagonist. The inhibitory effects of capsaicin on these currents developed gradually, reaching steady-state levels within 3 to 6 min, and the recoveries were usually incomplete during washout. In concentration-inhibition curves, apparent Hill coefficients higher than unity suggested multiple interaction sites of capsaicin on these channels. Collectively, these findings indicate that capsaicin affects cardiac electrophysiology by acting on a diverse range of ion channels and suggest that caution should be exercised when capsaicin is administered to carriers of cardiac channelopathies or to individuals with arrhythmia-prone conditions, such as ischemic heart diseases.

Cannabidiol Inhibits Multiple Ion Channels in Rabbit Ventricular Cardiomyocytes.

Cannabidiol (CBD), a major non-psychotropic cannabinoid found in the Cannabis plant, has been shown to exert anti-nociceptive, anti-psychotic, and anti-convulsant effects and to also influence the cardiovascular system. In this study, the effects of CBD on major ion currents were investigated using the patch-clamp technique in rabbit ventricular myocytes. CBD inhibited voltage-gated Na+ and Ca2+ channels with IC50 values of 5.4 and 4.8 µM, respectively. In addition, CBD, at lower concentrations, suppressed ion currents mediated by rapidly and slowly activated delayed rectifier K+ channels with IC50 of 2.4 and 2.1 µM, respectively. CBD, up to 10 µM, did not have any significant effect on inward rectifier I K1 and transient outward I to currents. The effects of CBD on these currents developed gradually, reaching steady-state levels within 5-8 min, and recoveries were usually slow and partial. Hill coefficients higher than unity in concentration-inhibition curves suggested multiple CBD binding sites on these channels. These findings indicate that CBD affects cardiac electrophysiology by acting on a diverse range of ion channels and suggest that caution should be exercised when CBD is administered to carriers of cardiac channelopathies or to individuals using drugs known to affect the rhythm or the contractility of the heart.

The prognostic value of squamous differentiation in endometrioid type endometrial cancer: a matched analysis.

We aimed to examine the effect of the squamous differentiation on survival outcomes of women with endometrioid adenocarcinoma. We retrospectively reviewed the patients with endometrioid adenocarcinoma who underwent primary surgical treatment in a tertiary referral hospital. Sixty-nine patients having squamous differentiation constituted the case group. Each woman in the case group was matched with two patients in the control group based on age, disease stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy. During the follow-up, the recurrence rates were similar between the case (5/69, 7.2%) and control (10/138, 7.2%) groups (p = 1.0). The 5-year disease-free survival rate was 90.2% for the case group and 88.6% for the control group (p = .51). The 5-year overall survival rate was 94.6% for the case group and 91.8% for the control group (p = .12). Squamous differentiation seems to have no impact on the prognosis of patients with endometrioid adenocarcinoma.IMPACT STATEMENTWhat is already known on this subject? A focus of squamous differentiation is recognised in 12.8-25% of women with endometrioid adenocarcinoma. The prognostic value of the squamous differentiation was evaluated in several previous studies. However, it could not be clarified due to the conflicting results of these studies.What do the results of this study add? The probable confounding effects of well-known prognostic factors including age at diagnosis, International Federation of Gynaecology and Obstetrics stage, tumour grade, lymphovascular space invasion, tumour size, myometrial invasion, type of surgery and adjuvant therapy were eliminated with the case-control study design in the current study. Our findings indicate that the presence of squamous differentiation does not have any prognostic effect in endometrioid type endometrial cancer.What are the implications of these findings for clinical practice and/or further research? The molecular prognosticators of endometrial cancer were extensively studied in recent years. It is likely that clinicopathological and molecular prognostic factors will be integrated for predicting prognosis as a part of routine clinical practice soon. In this context, the prognostic value of the squamous differentiation in endometrioid adenocarcinomas may further be clarified by larger and multicentric studies that utilise central pathology review.

The safety of major gynaecologic cancer surgery without routine preoperative COVID-19 testing in the COVID-19 era: a multicentre, retrospective, case-control study.

Our goal was to address the safety of major gynaecologic cancer surgery without routine preoperative COVID-19 testing in the COVID-19 era. The databases of seven gynaecologic cancer centres were searched in order to identify all consecutive gynaecologic cancer patients undergoing major surgery between March 11, 2020 and May 15, 2020 for this retrospective, case-control study. The case group consisted of patients with histopathologically confirmed gynaecologic cancers, and each case was matched with two counterparts who had undergone primary surgery before the COVID-19 pandemic. The case and the control groups were compared in terms of length of hospital stay, admission to the intensive care unit (ICU), intraoperative and postoperative complications.During the study period, 154 women with gynaecologic cancer undergoing major surgery were identified. Although the case group had more co-morbidities compared to the control group (103/154 vs. 178/308, respectively; p = .04), the median length of hospital stays, the rate of ICU admission, intraoperative complication rates and postoperative complication rates were similar in the two groups. Gynaecologic cancer surgery may be performed safely in the COVID-19 era with similar rates of ICU admission, intraoperative and postoperative complications compared to the patients operated before the COVID-19 pandemic.IMPACT STATEMENTWhat is already known on this subject? Many societies have announced their guidelines about the surgical management of gynaecologic cancer patients during the COVID-19 pandemic. However, most of them are not evidence-based and mostly on expert opinions.What do the results of this study add? The main findings of this retrospective, case-control study indicate that the short-term (30 day) outcomes of gynaecologic cancer patients undergoing major surgery in the COVID-19 era are similar to those who had been operated before the COVID-19 pandemic. The length of hospital stays, the rates of admission to the ICU, intraoperative and postoperative complications were comparable between women undergoing major gynaecologic cancer surgery in the COVID-19 era and the women who had been operated before the pandemic.What are the implications of these findings for clinical practice and/or further research? We can suggest that definitive surgery may be performed for gynaecologic cancer patients in the COVID-19 era if the resources permit and appropriate precautions such as social distancing, isolation and the use of personal protective equipment are taken.

Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice.

Autistic spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impaired social interaction and cognitive deficit, restricted repetitive behaviors, altered immune responses, and imbalanced oxidative stress status. In recent years, there has been a growing interest in studying the role of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in the CNS. Influence of agonists for α7-nAChRs on the cognitive behavior, learning, and memory formation has been demonstrated in neuro-pathological condition such as ASD and attention-deficit hyperactivity disorder (ADHD). Curcumin (CUR), the active compound of the spice turmeric, has been shown to act as a positive allosteric modulator of α7-nAChRs. Here we hypothesize that CUR, acting through α7-nAChRs, influences the neuropathology of ASD. In patch clamp studies, fast inward currents activated by choline, a selective agonist of α7-nAChRs, were significantly potentiated by CUR. Moreover, choline induced enhancement of spontaneous inhibitory postsynaptic currents was markedly increased in the presence of CUR. Furthermore, CUR (25, 50, and 100 mg/kg, i.p.) ameliorated dose-dependent social deficits without affecting locomotor activity or anxiety-like behaviors of tested male Black and Tan BRachyury (BTBR) mice. In addition, CUR (50 and 100 mg/kg, i.p.) mitigated oxidative stress status by restoring the decreased levels of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus and the cerebellum of treated mice. Collectively, the observed results indicate that CUR potentiates α7-nAChRs in native central nervous system neurons, mitigates disturbed oxidative stress, and alleviates ASD-like features in BTBR mice used as an idiopathic rodent model of ASD, and may represent a promising novel pharmacological strategy for ASD treatment.

Apigenin and Structurally Related Flavonoids Allosterically Potentiate the Function of Human α7-Nicotinic Acetylcholine Receptors Expressed in SH-EP1 Cells.

Phytochemicals, such as monoterpenes, polyphenols, curcuminoids, and flavonoids, are known to have anti-inflammatory, antioxidant, neuroprotective, and procognitive effects. In this study, the effects of several polyhydroxy flavonoids, as derivatives of differently substituted 5,7-dihydroxy-4H-chromen-4-one including apigenin, genistein, luteolin, kaempferol, quercetin, gossypetin, and phloretin with different lipophilicities (cLogP), as well as topological polar surface area (TPSA), were tested for induction of Ca2+ transients by α7 human nicotinic acetylcholine (α7 nACh) receptors expressed in SH-EP1 cells. Apigenin (10 µM) caused a significant potentiation of ACh (30 µM)-induced Ca2+ transients, but did not affect Ca2+ transients induced by high K+ (60 mM) containing solutions. Co-application of apigenin with ACh was equally effective as apigenin preincubation. However, the effect of apigenin significantly diminished by increasing ACh concentrations. The flavonoids tested also potentiated α7 nACh mediated Ca2+ transients with descending potency (highest to lowest) by genistein, gossypetin, kaempferol, luteolin, phloretin, quercetin, and apigenin. The specific binding of α7 nACh receptor antagonist [125I]-bungarotoxin remained unchanged in the presence of any of the tested polyhydroxy flavonoids, suggesting that these compounds act as positive allosteric modulators of the α7-nACh receptor in SH-EP1 cells. These findings suggest a clinical potential for these phytochemicals in the treatment of various human diseases from pain to inflammation and neural disease.

CRISPR/Cas9 Mediated Knock Down of δ-ENaC Blunted the TNF-Induced Activation of ENaC in A549 Cells.

Tumor necrosis factor (TNF) is known to activate the epithelial Na+ channel (ENaC) in A549 cells. A549 cells are widely used model for ENaC research. The role of δ-ENaC subunit in TNF-induced activation has not been studied. In this study we hypothesized that δ-ENaC plays a major role in TNF-induced activation of ENaC channel in A549 cells which are widely used model for ENaC research. We used CRISPR/Cas 9 approach to knock down (KD) the δ-ENaC in A549 cells. Western blot and immunofluorescence assays were performed to analyze efficacy of δ-ENaC protein KD. Whole-cell patch clamp technique was used to analyze the TNF-induced activation of ENaC. Overexpression of wild type δ-ENaC in the δ-ENaC KD of A549 cells restored the TNF-induced activation of whole-cell Na+ current. Neither N-linked glycosylation sites nor carboxyl terminus domain of δ-ENaC was necessary for the TNF-induced activation of whole-cell Na+ current in δ-ENaC KD of A549 cells. Our data demonstrated that in A549 cells the δ-ENaC plays a major role in TNF-induced activation of ENaC.

Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors.

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4ß2 nAChRs, MLA and DhßE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4ß2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.

Is the extent of lymphadenectomy a prognostic factor in International Federation of Gynecology and Obstetrics stage II endometrioid endometrial cancer?

AIM: This study aimed to evaluate the prognostic significance of adequate lymph node dissection (LND) (≥10 pelvic lymph nodes (LNs) and ≥ 5 paraaortic LNs removed) in patients with International Federation of Gynecology and Obstetrics (FIGO) stage II endometrioid endometrial cancer (EEC). METHODS: A multicenter department database review was performed to identify patients who had been operated and diagnosed with stage II EEC at seven centers in Turkey retrospectively. Demographic, clinicopathological, and survival data were collected and analyzed. RESULTS: We identified 284 women with stage II EEC. There were 170 (59.9%) patients in the adequate lymph node dissection (LND) group and 114 (40.1%) in the inadequate LND group. The 5-year overall survival (OS) rate of the inadequate LND group was significantly lower than that of the adequate LND group (84.1% vs. 89.1%, respectively; p = 0.028). In multivariate analysis, presence of lymphovascular space invasion (LVSI) (hazard ratio [HR]: 2.39, 95% confidence interval [CI]: 1.23-4.63; p = 0.009), age ≥ 60 (HR: 3.30, 95% CI: 1.65-6.57; p = 0.001], and absence of adjuvant therapy (HR: 2.74, 95% CI: 1.40-5.35; p = 0.003) remained as independent risk factors for decreased 5-year disease-free survival (DFS). Inadequate LND (HR: 2.34, 95% CI: 1.18-4.63; p < 0.001), age ≥ 60 (HR: 2.67, 95% CI: 1.25-5.72; p = 0.011), and absence of adjuvant therapy (HR: 4.95, 95% CI: 2.28-10.73; p < 0.001) were independent prognostic factors for decreased 5-year OS in multivariate analysis. CONCLUSION: Adequate LND and adjuvant therapy were significant for the improvement of outcomes in FIGO stage II EEC patients. Furthermore, LVSI was associated with worse 5-year DFS rate in stage II EEC.

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury.

The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-ß, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.

Low-grade endometrial stromal sarcoma: A Turkish uterine sarcoma group study analyzing prognostic factors and disease outcomes.

OBJECTIVE: To investigate factors associated with refractory disease, recurrence, or death as well as disease-free survival (DFS) and overall survival (OS) in low-grade endometrial sarcoma (LGESS). METHODS: A multi-institutional, retrospective study was conducted in a total of 124 patients, who received a curative-intent surgery. The exclusion criteria were as follows: i) history of any other invasive disease; ii) neoadjuvant therapy; iii) fertility sparing surgery; iv) a different diagnosis after review of the slides. RESULTS: All patients underwent hysterectomy, 96% had bilateral salpingo-oophorectomy, and 65% had lymphadenectomy. Twelve (14.8%) of 81 patients undergoing lymphadenectomy had lymph node (LN) metastasis. Of those, 8 (9.8%) had pelvic LN metastasis whereas 4 (5.6%) had isolated paraaortic LN metastasis. Six of 8 (75%) patients with positive pelvic LNs had concurrent paraaortic LN metastasis. Among 124 patients, 3 patients (2.4%) had refractory disease following primary therapy. During a median follow-up of 45.5 months, 27 (22.3%) of 121 patients who achieved complete remission after primary therapy developed recurrence, and 10 patients (8.1%) died of disease. The 3-year DFS and OS were 76.9% and 93.8%, respectively. Stage was the sole independent prognostic factor in the whole cohort. When analyzing factors within subgroups of stage I and stage ≥II, there was no significant prognostic factor for stage I; however, lymphadenectomy and adjuvant chemotherapy were significantly associated with disease outcomes for stage ≥II. While lymphadenectomy was related with improved DFS, chemotherapy was associated with poor DFS and OS. CONCLUSION: The risk of LN metastasis at pelvic as well as paraaortic lymphatic basins is not negligible to omit lymphadenectomy in stage ≥II LGESS. Moreover, lymphadenectomy provides significant DFS advantage in patients with extrauterine disease.

Para-aortic lymphadenectomy: step by step surgical education video

Para-aortic lymph nodes are exclusively important for the staging of gynecologic malignancies. This surgical education video describes the step-by-step technique for para-aortic lymphadenectomy with anatomic landmarks in a cadaver.

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor.

The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.