Analysis of the effect of the scorpion toxin AaH-II on action potential generation in the axon initial segment.

The toxin AaH-II, from the scorpion Androctonus australis Hector venom, is a 64 amino acid peptide that targets voltage-gated Na+ channels (VGNCs) and slows their inactivation. While at macroscopic cellular level AaH-II prolongs the action potential (AP), a functional analysis of the effect of the toxin in the axon initial segment (AIS), where VGNCs are highly expressed, was never performed so far. Here, we report an original analysis of the effect of AaH-II on the AP generation in the AIS of neocortical layer-5 pyramidal neurons from mouse brain slices. After determining that AaH-II does not discriminate between Nav1.2 and Nav1.6, i.e. between the two VGNC isoforms expressed in this neuron, we established that 7 nM was the smallest toxin concentration producing a minimal detectable deformation of the somatic AP after local delivery of the toxin. Using membrane potential imaging, we found that, at this minimal concentration, AaH-II substantially widened the AP in the AIS. Using ultrafast Na+ imaging, we found that local application of 7 nM AaH-II caused a large increase in the slower component of the Na+ influx in the AIS. Finally, using ultrafast Ca2+ imaging, we observed that 7 nM AaH-II produces a spurious slow Ca2+ influx via Ca2+-permeable VGNCs. Molecules targeting VGNCs, including peptides, are proposed as potential therapeutic tools. Thus, the present analysis in the AIS can be considered a general proof-of-principle on how high-resolution imaging techniques can disclose drug effects that cannot be observed when tested at the macroscopic level.

Immunomodulatory effects of epiphytic Loranthus micranthus leaf extracts collected from two host plants: Psidium guajava and Parkia biglobosa.

BACKGROUND: Immunological abnormalities are implicated in the pathogenesis of many chronic diseases. Due to the drug-related adverse effects of currently available orthodox immunomodulators, natural immunomodulators are being looked upon as potential agents to replace them in therapeutic regimens. This research aimed to investigate the immunomodulatory potential of L. micranthus extracts epiphytic on Psidium guajava (LMPGE) and Parkia biglobosa (LMPBE). METHODS: Phytochemical screening and acute toxicity testing were carried out to identify the phytoconstituents and safety profiles of the extracts. The extracts' innate and adaptive immunomodulatory potentials were determined in experimental animals using in vivo leucocyte mobilization, delayed-type hypersensitivity (DTH) response, hemagglutination antibody titre, and cyclophosphamide-induced myelosuppression models. Levamisole was used as the standard drug throughout the study. RESULTS: Compared to LMPBE, LMPGE contained significantly (p <  0.05) more tannins, cyanogenic glycosides, saponins, reducing sugars, glycosides, flavonoids, and alkaloids. Furthermore, the groups treated with the extracts had a significant (p <  0.05) increase in the total number of leucocytes, neutrophils, basophils, and antibody titers relative to the untreated control. In the same way, the treatment raised TLC in cyclophosphamide-intoxicated rats, with 250 mg/kg b. w. of LMPGE and LMPBE recording 9712.50 ± 178.00 and 8000.00 ± 105.00 ×  109 /L, respectively, compared to 3425.00 ± 2 5.00 × 109 /L in the untreated group. Overall, LMPGE was more effective. CONCLUSIONS: The findings from this study suggest that L. micranthus epiphytic in Psidium guajava and Parkia biglobosa has possible immune stimulating potential.

Electrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss.

T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss-apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.

Structure-function relationship of new peptides activating human Nav1.1.

Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.

Empagliflozin Protects against Haloperidol Experimentally-Induced Ovarian Toxicity.

The present experiment aimed to identify the potential protective role of empagliflozin (EMPA) on haloperidol (HAL)-induced ovarian damage in female rats because of its anti-inflammatory, antioxidant, and antiapoptotic effects. EMPA was administered in the presence and absence of HAL. Thirty-two adult female albino rats were divided into four groups. Control group, EMPA group: received EMPA (10 mg/kg/day) p.o., HAL group: received HAL (2 mg/kg/day) p.o., HAL + EMPA group: HAL (2 mg/kg/day) combined with EMPA for 28 days. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-mullerian hormone (AMH) levels were measured. Ovarian oxidative stress parameters, besides inflammatory and apoptotic biomarkers, and ovarian Sirtuin-1 (Sirt-1) were evaluated. Ovarian histopathological examination and heat shock protein 70 (Hsp70) immunohistochemical study were performed. HAL significantly increased serum levels of FSH, LH, and ovarian inflammatory, apoptotic, and oxidative stress biomarkers and decreased serum AMH levels and Sirt-1 expression. Histopathological findings of ovarian damage and high Hsp70 immunoexpression were detected. EMPA significantly normalized the distributed hormonal levels, oxidative stress, inflammatory, and apoptotic biomarkers with a prompt improvement in the histopathological picture and a decrease in Hsp70 immunoexpression. Accordingly, EMPA protected against HAL-induced ovarian toxicity by modulating the Sirt-1/Hsp70/TNF-α/caspase-3 signaling pathway.

SARS-CoV-2 E and 3a Proteins Are Inducers of Pannexin Currents.

Controversial reports have suggested that SARS-CoV E and 3a proteins are plasma membrane viroporins. Here, we aimed at better characterizing the cellular responses induced by these proteins. First, we show that expression of SARS-CoV-2 E or 3a protein in CHO cells gives rise to cells with newly acquired round shapes that detach from the Petri dish. This suggests that cell death is induced upon expression of E or 3a protein. We confirmed this by using flow cytometry. In adhering cells expressing E or 3a protein, the whole-cell currents were not different from those of the control, suggesting that E and 3a proteins are not plasma membrane viroporins. In contrast, recording the currents on detached cells uncovered outwardly rectifying currents much larger than those observed in the control. We illustrate for the first time that carbenoxolone and probenecid block these outwardly rectifying currents; thus, these currents are most probably conducted by pannexin channels that are activated by cell morphology changes and also potentially by cell death. The truncation of C-terminal PDZ binding motifs reduces the proportion of dying cells but does not prevent these outwardly rectifying currents. This suggests distinct pathways for the induction of these cellular events by the two proteins. We conclude that SARS-CoV-2 E and 3a proteins are not viroporins expressed at the plasma membrane.

A Rat Model of Clinically Relevant Extracorporeal Circulation Develops Early Organ Dysfunctions.

In clinical practice, extracorporeal circulation (ECC) is associated with coagulopathy and inflammation, eventually leading to organ injuries without preventive systemic pharmacological treatment. Relevant models are needed to reproduce the pathophysiology observed in humans and preclinical tests. Rodent models are less expensive than large models but require adaptations and validated comparisons to clinics. This study aimed to develop a rat ECC model and to establish its clinical relevance. One hour of veno-arterial ECC or a sham procedure were achieved on mechanically ventilated rats after cannulations with a mean arterial pressure objective > 60 mmHg. Five hours post-surgery, the rats' behavior, plasmatic/blood biomarkers, and hemodynamics were measured. Blood biomarkers and transcriptomic changes were compared in 41 patients undergoing on-pump cardiac surgery. Five hours post-ECC, the rats presented hypotension, hyperlactatemia, and behavioral alterations. The same patterns of marker measurements (Lactate dehydrogenase, Creatinine kinase, ASAT, ALAT, and Troponin T) were observed in both rats and human patients. Transcriptome analyses showed similarity in both humans and rats in the biological processes involved in the ECC response. This new ECC rat model seems to resemble both ECC clinical procedures and the associated pathophysiology, but with early organ injury corresponding to a severe phenotype. Although the mechanisms at stake in the post-ECC pathophysiology of rats or humans need to be described, this new rat model appears to be a relevant and costless preclinical model of human ECC.

Long COVID and risk of erectile dysfunction in recovered patients from mild to moderate COVID-19.

Patients with coronavirus disease 2019 (COVID-19) were shown to have reduced serum testosterone levels compared to healthy individuals. Low testosterone levels are linked with the development of erectile dysfunction (ED). In this case-controlled study, 20 healthy controls and 39 patients with ED 3 months after recovering from mild-to-moderate COVID-19 pneumonia were studied. The patients ranged in age from 31 to 47 years. To identify early and late COVID-19 infections, real-time polymerase-chain reaction (RT-PCR) and COVID-19 antibody testing were done. The levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), free testosterone (FT), free androgenic index (FAI), and sex hormone-binding globulin (SHBG) were measured. The sexual health inventory for patients (SHIM) score was used to measure the erectile function of the patients and controls. When compared to the controls, the TT serum level in long COVID-19 (LC) patients with ED was low (p = 0.01). In contrast to controls, FT and FAI were both lower in LC patients with ED. (p = 0.001). FSH serum levels did not significantly differ (p = 0.07), but in ED patients, LH serum levels were elevated. SHIM scores were associated with low TT (p = 0.30), FT (p = 0.09), and high LH (p = 0.76) in LC patients with ED. Male patients with decreased serum levels of LH and testosterone may have hypothalamic-pituitary-gonadal axis dysfunction, which could lead to the development of LC-induced ED. Therefore, an in-depth research is necessary to confirm the causal link between COVID-19 and ED in LC patients.

A need for exhaustive and standardized characterization of ion channels activity. The case of KV11.1.

hERG, the pore-forming subunit of the rapid component of the delayed rectifier K+ current, plays a key role in ventricular repolarization. Mutations in the KCNH2 gene encoding hERG are associated with several cardiac rhythmic disorders, mainly the Long QT syndrome (LQTS) characterized by prolonged ventricular repolarization, leading to ventricular tachyarrhythmias, sometimes progressing to ventricular fibrillation and sudden death. Over the past few years, the emergence of next-generation sequencing has revealed an increasing number of genetic variants including KCNH2 variants. However, the potential pathogenicity of the majority of the variants remains unknown, thus classifying them as variants of uncertain significance or VUS. With diseases such as LQTS being associated with sudden death, identifying patients at risk by determining the variant pathogenicity, is crucial. The purpose of this review is to describe, on the basis of an exhaustive examination of the 1322 missense variants, the nature of the functional assays undertaken so far and their limitations. A detailed analysis of 38 hERG missense variants identified in Long QT French patients and studied in electrophysiology also underlies the incomplete characterization of the biophysical properties for each variant. These analyses lead to two conclusions: first, the function of many hERG variants has never been looked at and, second, the functional studies done so far are excessively heterogeneous regarding the stimulation protocols, cellular models, experimental temperatures, homozygous and/or the heterozygous condition under study, a context that may lead to conflicting conclusions. The state of the literature emphasizes how necessary and important it is to perform an exhaustive functional characterization of hERG variants and to standardize this effort for meaningful comparison among variants. The review ends with suggestions to create a unique homogeneous protocol that could be shared and adopted among scientists and that would facilitate cardiologists and geneticists in patient counseling and management.

Nav1.2 and BK channel interaction shapes the action potential in the axon initial segment.

In neocortical layer-5 pyramidal neurons, the action potential (AP) is generated in the axon initial segment (AIS) when the membrane potential (Vm ) reaches the threshold for activation of the voltage-gated Na+ channels (VGNCs) Nav 1.2 and Nav 1.6. Yet, whereas these VGNCs are known to differ in spatial distribution along the AIS and in biophysical properties, our understanding of the functional differences between the two channels remains elusive. Here, using ultrafast Na+ , Vm and Ca2+ imaging in combination with partial block of Nav 1.2 by the peptide G1 G4 -huwentoxin-IV, we demonstrate an exclusive role of Nav 1.2 in shaping the generating AP. Precisely, we show that selective block of ∼30% of Nav 1.2 widens the AP in the distal part of the AIS and we demonstrate that this effect is due to a loss of activation of BK Ca2+ -activated K+ channels (CAKCs). Indeed, Ca2+ influx via Nav 1.2 activates BK CAKCs, determining the amplitude and the early phase of repolarization of the AP in the AIS. By using control experiments using 4,9-anhydrotetrodotoxin, a moderately selective inhibitor of Nav 1.6, we concluded that the Ca2+ influx shaping the early phase of the AP is exclusive of Nav 1.2. Hence, we mimicked this result with a neuron model in which the role of the different ion channels tested reproduced the experimental evidence. The exclusive role of Nav 1.2 reported here is important for understanding the physiology and pathology of neuronal excitability. KEY POINTS: We optically analysed the action potential generated in the axon initial segment of mouse layer-5 neocortical pyramidal neurons and its associated Na+ and Ca2+ currents using ultrafast imaging techniques. We found that partial selective block of the voltage-gated Na+ channel Nav 1.2, produced by a recently developed peptide, widens the shape of the action potential in the distal part of the axon initial segment. We demonstrate that this effect is due to a reduction of the Ca2+ influx through Nav 1.2 that activates BK Ca2+ -activated K+ channels. To validate our conclusions, we generated a neuron model that reproduces the ensemble of our experimental results. The present results indicate a specific role of Nav 1.2 in the axon initial segment for shaping of the action potential during its generation.

The growth hormone gene polymorphism and its relationship to performance and carcass features in Egyptian Awassi lambs.

The main purpose of the existing experiment was to assess the allelic and genotypic polymorphisms of the Growth hormone (GH) gene and its correlation with growth indices, efficiency of consumed feed, some body indices and carcass traits of the Egyptian Awassi sheep. Forty Egyptian Awassi male lambs were selected for their growing indices (post-weaning daily gain, marketing weight, and weaning weight), feed efficiency (consumed feed and of consumed feed), body conformational indicators (skeletal muscle index, relative body index, body mass index, and body index), and carcass features (dressing %, hot carcass weight, fore-legs %, neck %, loin %, ribs %, abdominal fat %, Tail % and hind-legs %). The polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) tool was applied to detect the genotypic and allelic GH gene polymorphisms properties. The PCR-RFLP analysis identified three main genotypes (AA, AB and BB) and two main alleles (A and B). The GH genotype (AA or AB) exhibited moderate significant influence (P < 0.05) on marketing weight, Loin% and Tail%. Also, genotype (AB or BB) of expressed GH gene significantly (P < 0.01) influence on consumed feed, post-weaning daily gain, neck% and body mass index, whereas, it had no influence on the phenotypic values of the other characteristics investigated. The presence of the A allele in the genotype was markedly associated (P < 0.01) with consumed feed, body mass index and post-weaning daily growth; conversely, the presence of the B allele in the genotype was significantly related (P < 0.05) with marketing weight, loin %, and tail %. While, GH gene expression was revealed to be highly significant (P < 0.01) in relation to post-weaning daily growth, feed intake, and neck %. According to the findings, determining the associations between GH gene variation and growth, efficiency of consumed feed, body measurements, and carcass features of Egyptian Awassi sheep and applying marker assisted selection with the GH gene to improve these traits is warranted and will be of significant economic value to sheep production.

Papaverinol-N-Oxide: A Microbial Biotransformation Product of Papaverine with Potential Antidiabetic and Antiobesity Activity Unveiled with In Silico Screening.

Bioconversion of biosynthetic heterocyclic compounds has been utilized to produce new semisynthetic pharmaceuticals and study the metabolites of bioactive drugs used systemically. In this investigation, the biotransformation of natural heterocyclic alkaloid papaverine via filamentous fungi was explored. Molecular docking simulations, using protein tyrosine phosphatase 1B (PTP1B), α-glucosidase and pancreatic lipase (PL) as target enzymes, were performed to investigate the antidiabetic potential of papaverine and its metabolites in silico. The metabolites were isolated from biotransformation of papaverine with Cunninghamella elegans NRRL 2310, Rhodotorula rubra NRRL y1592, Penicillium chrysogeneum ATCC 10002 and Cunninghamella blackesleeana NRRL 1369 via reduction, demethylation, N-oxidation, oxidation and hydroxylation reactions. Seven metabolites were isolated: namely, 3,4-dihydropapaverine (metabolite 1), papaveroline (metabolite 2), 7-demethyl papaverine (metabolite 3), 6,4'-didemethyl papaverine (metabolite 4), papaverine-3-ol (metabolite 5), papaverinol (metabolite 6) and papaverinol N-oxide (metabolite 7). The structural elucidation of the metabolites was investigated with 1D and 2D NMR and mass spectroscopy (EI and ESI). The molecular docking studies showed that metabolite 7 exhibited better binding interactions with the target enzymes PTP1B, α-glucosidase and PL than did papaverine. Furthermore, papaverinol-N-oxide (7) also displayed inhibition of α-glucosidase and lipase enzymes comparable to that of their ligands (acarbose and orlistat, respectively), as unveiled with an in silico ADMET profile, molecular docking and molecular dynamics studies. In conclusion, this study provides evidence for enhanced inhibition of PTP1B, α-glucosidase and PL via some papaverine fungal transformation products and, therefore, potentially better antidiabetic and antiobesity effects than those of papaverine and other known therapeutic agents.

Isolation and Molecular Characterization of Corynebacterium pseudotuberculosis: Association with Proinflammatory Cytokines in Caseous Lymphadenitis Pyogranulomas.

Corynebacterium pseudotuberculosis (C. pseudotuberculosis) is a causative agent of numerous chronic diseases, including caseous lymphadenitis (CLA) in sheep and goats, which has a zoonotic potential in humans in addition to a poor therapeutic response. In this study, out of 120 collected samples, only 12 (10%) were positive for C. pseudotuberculosis by PCR and by intraperitoneal injection of male Guinea pigs and then characterized for antimicrobial susceptibility and its genetic-relatedness by enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR), which showed 2-4 bands ranging from 100 to 3000 bp that can be clustered into four clusters (C1-C4). Despite the serotype biovar 1 only infecting sheep and goats, ERIC-PCR reveals intra-subtyping variation. Examination of affected LNs and organs revealed marked enlargement with either thick creamy green pus or multiple abscesses of variable sizes with a central caseated core surrounded by dense fibrous capsule. A histopathological examination revealed a central necrotic core surrounded by a peripheral mantle of mononuclear cells and a fibrous capsule. Positive immune expression of nuclear factor kappa B (NF-κB/p65) and interleukin-1ß (IL-1ß) and negative expression of tumor necrosis factor (TNF) in CLA is the first report to our knowledge. Conclusion: In CLA pyogranulomas, IL1ß is a more crucial proinflammatory cytokine than TNF in the regulation of C. pseudotuberculosis infection, which is accompanied by marked NF-κB immunoexpression. Therefore, the NF-κB/p65 signaling pathway is involved in the activation of IL1ß, and additional immunohistochemical studies are required to determine the various roles of NF-κB/p65 in the inflammatory response within CLA pyogranulomas to control this pathogen.

Attenuation of hyperglycemia-associated dyslipidemic, oxidative, cognitive, and inflammatory crises via modulation of neuronal ChEs/NF-κB/COX-2/NOx, and hepatorenal functional deficits by the Tridax procumbens extract.

Tridax procumbens (cotton buttons) is a flowering plant with a medicinal reputation for treating infections, wounds, diabetes, and liver and kidney diseases. The present research was conducted to evaluate the possible protective effects of the T. procumbens methanolic extract (TPME) on an experimentally induced type 2 diabetes rat model. Wistar rats with streptozotocin (STZ)-induced diabetes were randomly allocated into five groups of five animals each, viz., a normal glycemic group (I), diabetic rats receiving distilled water group (II), diabetic rats with 150 (III) and 300 mg/kg of TPME (IV) groups, and diabetic rats with 100 mg/kg metformin group (V). All treatments were administered for 21 consecutive days through oral gavage. Results: Administration of the T. procumbens extract to diabetic rats significantly restored alterations in levels of fasting blood glucose (FBG), body weight loss, serum and pancreatic insulin levels, and pancreatic histology. Furthermore, T. procumbens significantly attenuated the dyslipidemia (increased cholesterol, low-density lipoprotein-cholesterol (LDL-C), triglycerides, and high-density lipoprotein (HDL) in diabetic rats), serum biochemical alterations (alanine transaminase (ALT), aspartate transaminase (AST), alanine phosphatase (ALP), blood urea nitrogen (BUN), creatinine, uric acid, and urea) and full blood count distortion in rats with STZ-induced diabetes. The TPME also improved the antioxidant status as evidenced by increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and decreased malondialdehyde (MDA); and decreased levels of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)), and proinflammatory mediators including nuclear factor (NF)-κB, cyclooxygenase (COX)- 2, and nitrogen oxide (NOx) in the brain of rats with STZ-induced diabetes compared to rats with STZ-induced diabetes that received distilled water. However, TPME treatment failed to attenuate the elevated monoamine oxidases and decreased dopamine levels in the brain of rats with STZ-induced diabetes. Extract characterization by liquid chromatography mass spectrometry (LC-MS) identified isorhamnetin (retention time (RT)= 3.69 min, 8.8%), bixin (RT: 25.06 min, 4.72%), and lupeol (RT: 25.25 min, 2.88%) as the three most abundant bioactive compounds that could be responsible for the bioactivity of the plant. In conclusion, the TPME can be considered a promising alternative therapeutic option for managing diabetic complications owing to its antidiabetic, antihyperlipidemic, antioxidant, and anti-inflammatory effects in rats with STZ-prompted diabetes.

A Potential Link Between Visceral Obesity and Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aß) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aß. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aß formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aß formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.

A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

The Potential Role of MUC16 (CA125) Biomarker in Lung Cancer: A Magic Biomarker but with Adversity.

Lung cancer is the second most commonly diagnosed cancer in the world. In terms of the diagnosis of lung cancer, combination carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) detection had higher sensitivity, specificity, and diagnostic odds ratios than CEA detection alone. Most individuals with elevated serum CA125 levels had lung cancer that was either in stage 3 or stage 4. Serum CA125 levels were similarly elevated in lung cancer patients who also had pleural effusions or ascites. Furthermore, there is strong evidence that human lung cancer produces CA125 in vitro, which suggests that other clinical illnesses outside of ovarian cancer could also be responsible for the rise of CA125. MUC16 (CA125) is a natural killer cell inhibitor. As a screening test for lung and ovarian cancer diagnosis and prognosis in the early stages, CA125 has been widely used as a marker in three different clinical settings. MUC16 mRNA levels in lung cancer are increased regardless of gender. As well, increased expression of mutated MUC16 enhances lung cancer cells proliferation and growth. Additionally, the CA125 serum level is thought to be a key indicator for lung cancer metastasis to the liver. Further, CA125 could be a useful biomarker in other cancer types diagnoses like ovarian, breast, and pancreatic cancers. One of the important limitations of CA125 as a first step in such a screening technique is that up to 20% of ovarian tumors lack antigen expression. Each of the 10 possible serum markers was expressed in 29-100% of ovarian tumors with minimal or no CA125 expression. Therefore, there is a controversy regarding CA125 in the diagnosis and prognosis of lung cancer and other cancer types. In this state, preclinical and clinical studies are warranted to elucidate the clinical benefit of CA125 in the diagnosis and prognosis of lung cancer.

Development and validation of a predictive scoring system for in-hospital mortality in COVID-19 Egyptian patients: a retrospective study.

SARS-CoV-2 virus has rapidly spread worldwide since December 2019, causing COVID-19 disease. In-hospital mortality is a common indicator for evaluating treatment outcomes. Therefore, the developing and validating a simple score system from observational data could assist in modulating the management procedures. A retrospective cohort study included all data records of patients with positive PCR for SARS-CoV-2. The factors that associated with mortality were analyzed, then allocation of potential predictors of mortality was executed using different logistic regression modeling, subsequently scoring system was developed from the most weighted predictors. The mortality rate of patients with COVID-19 pneumonia was 28.5% and 28.74%, respectively. The most significant factors that affected in-hospital mortality were old age (> 60 years), delay in hospital admission (> 4 days), high neutrophil/lymphocyte ratio "NLR" (> 3); higher computed tomography severity score; and CT-SS (> 20), in addition to using remdesivir and tocilizumab in the treatment protocol (P < 0.001 for all). The validity of the newly performed score was significant; the AUC was 85%, P < 0.001, and its prognostic utility was good; the AUC was 75%, P < 0.001. The prognostic utility of newly developed score system (EGY.Score) was excellent and could be used to adjust the treatment strategy of highly at-risk patients with COVID-19 pneumonia.