Peptide-based allosteric inhibitor targets TNFR1 conformationally active region and disables receptor-ligand signaling complex.

Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a pivotal role in mediating TNF induced downstream signaling and regulating inflammatory response. Recent studies have suggested that TNFR1 activation involves conformational rearrangements of preligand assembled receptor dimers and targeting receptor conformational dynamics is a viable strategy to modulate TNFR1 signaling. Here, we used a combination of biophysical, biochemical, and cellular assays, as well as molecular dynamics simulation to show that an anti-inflammatory peptide (FKCRRWQWRMKK), which we termed FKC, inhibits TNFR1 activation allosterically by altering the conformational states of the receptor dimer without blocking receptor-ligand interaction or disrupting receptor dimerization. We also demonstrated the efficacy of FKC by showing that the peptide inhibits TNFR1 signaling in HEK293 cells and attenuates inflammation in mice with intraperitoneal TNF injection. Mechanistically, we found that FKC binds to TNFR1 cysteine-rich domains (CRD2/3) and perturbs the conformational dynamics required for receptor activation. Importantly, FKC increases the frequency in the opening of both CRD2/3 and CRD4 in the receptor dimer, as well as induces a conformational opening in the cytosolic regions of the receptor. This results in an inhibitory conformational state that impedes the recruitment of downstream signaling molecules. Together, these data provide evidence on the feasibility of targeting TNFR1 conformationally active region and open new avenues for receptor-specific inhibition of TNFR1 signaling.

Short-term exposure to dexamethasone at environmentally relevant concentrations impairs embryonic development in Cyprinus carpio: Bioconcentration and alteration of oxidative stress-related gene expression patterns.

In recent years and as a result of the Covid-19 pandemic, the consumption of dexamethasone (DXE) has increased. This favors that this corticosteroid is highly released in aquatic environments, generating deleterious effects in aquatic organisms. The information on the toxic effects of DXE in the environment is still limited. Thus, the objective of this work was to determine whether DXE at short-term exposure can cause alterations to embryonic development and alteration of oxidative stress-related gene expression patterns in Cyprinus carpio. For this purpose, common carp embryos (2 hpf) were exposed to realistic concentrations of DXE until 96 hpf. Alterations to embryonic development were evaluated at 12, 24, 48, 72 and 96 hpf. In addition, oxidative stress in carp embryos at 72 and 96 hpf was evaluated by cellular oxidation biomarkers (lipoperoxidation level, hydroperoxide and carbonyl protein content) and antioxidant enzymes activities (superoxide dismutase and catalase). Oxidative stress-related gene expression (sod, cat and gpx1) was also evaluated. Our results showed that DXE concentrations above 35 ng/L are capable of producing alterations to embryonic development in 50 % of the embryo population. Furthermore, DXE was able to induce alterations such as scoliosis, hypopigmentation, craniofacial malformations, pericardial edema and growth retardation, leading to the death of half of the population at 50 ng/L of DXE. Concerning oxidative stress, the results demonstrated that DXE induce oxidative damage on the embryos of C. carpio. In conclusion, DXE is capable of altering embryonic development and generating oxidative stress in common carp C. carpio.

Integrative approach to elucidate the embryological effects of caffeine in Cyprinus carpio: Bioconcentration and alteration of oxidative stress-related gene expression patterns.

Caffeine (CAF) is an alkaloid, which acts as a central nervous system (CNS) stimulant drug. In recent years, CAF has been recurrently detected in water bodies, generating deleterious effects in aquatic organisms. The information on the toxic effects of CAF in the environment is still limited. Thus, the objective of this work was to determine whether CAF at environmentally relevant concentrations (CAF concentrations were selected based on studies on the worldwide occurrence of this compound and on the toxicity of CAF in aquatic species) is capable of inducing alterations to embryonic development and alteration of oxidative stress-related gene expression patterns in Cyprinus carpio. For this purpose, common carp embryos (2 hpf) were exposed to realistic concentrations of CAF until 96 hpf. Alterations to embryonic development and teratogenic effects were evaluated at 12, 24, 48, 72 and 96 hpf. In addition, oxidative stress in carp embryos at 72 and 96 hpf was evaluated by cellular oxidation biomarkers (lipoperoxidation level, hydroperoxide content and carbonyl protein content) and antioxidant enzymes activities (superoxide dismutase and catalase). Oxidative stress-related gene expression (sod, cat and gpx1) was also evaluated. Our results showed that CAF concentrations above 500 ng/L are capable of producing teratogenic effects. Furthermore, CAF was able to induce alterations such cardiac malformations, somite alterations, pericardial edema and chorda malformations. Concerning oxidative stress, the results demonstrated that CAF induce oxidative damage on the embryos of C. carpio. Our outcomes also showed up-regulations in genes related to antioxidant activity sod, cat and gpx by CAF exposure. In conclusion CAF at environmentally relevant concentrations is able to alter the embryonic development of common carp by the oxidative stress pathway. Based on the above evidence, it can be inferred that acute exposure to CAF can lead to a toxic response that significantly harms fish's health, adversely affecting their essential organs' functioning.

Realistic concentrations of Bisphenol-A trigger a neurotoxic response in the brain of zebrafish: Oxidative stress, behavioral impairment, acetylcholinesterase inhibition, and gene expression disruption.

Bisphenol A (BPA) is a micro-pollutant found in various environmental matrices at concentrations as low as ng/L. Recent studies have shown that this compound can cause oxidative damage and neurotoxic effects in aquatic organisms. However, there is a lack of research investigating the effects of BPA at environmentally relevant concentrations. Therefore, this study aimed to assess the neurotoxic effects of acute BPA exposure (96 h) at environmentally relevant concentrations (220, 1180, and 1500 ng/L) in adult zebrafish (Danio rerio). The Novel Tank trial was used to evaluate fish swimming behavior, and our results indicate that exposure to 1500 ng/L of BPA reduced the total distance traveled and increased freezing time. Furthermore, the evaluation of biomarkers in the zebrafish brain revealed that BPA exposure led to the production of reactive oxygen species and increased acetylcholinesterase activity. Gene expression analysis also indicated the overexpression of mbp, α1-tubulin, and manf in the zebrafish brain. Based on our findings, we concluded that environmentally relevant concentrations of BPA can cause anxiety-like behavior and neurotoxic effects in adult zebrafish.

Functional and physicochemical properties of protein from giant squid (Dosidicus gigas) extracted using foam-aided pH-shift processing.

Jumbo squid (Dosidicus gigas) is a commercially valuable mollusk in Mexico; 80% of its body is edible. Despite the high protein content (∼18%) and low cholesterol content of this species, its high proteolytic activity (microbial and endogenous enzymes) induces protein degradation and consequent reduction in functional properties from a structural viewpoint. Gelation capacity (texture profile of the gels obtained), solubility, water holding capacity, foaming capacity, emulsification capacity, and emulsion stability were evaluated in protein concentrates obtained by foam-aided pH-shift processing: (A) myofibrillar protein extraction with distilled water and no pH-shifting; (B) alkaline solubilization and isoelectric precipitation; (C) acidic solubilization and isoelectric precipitation; and (D) process A and isoelectric precipitation. Process B showed superior gelation capacity, D had high emulsion stability across a wide range of pH values (4.0-8.0) and C lower plate counts of aerobic mesophilic. Therefore, all three alternative extraction processes showed techno-functional advantages. PRACTICAL APPLICATION: Jumbo squid is an abundant protein source in México, most of which is exported. Functional and physicochemical properties of muscle protein were improved by pH-shift processing. The recovered protein showed modifications of technological properties, using one of the methods described can lead to produce a protein extract with the most desirable attributes, such as foaming, emulsifying, or gelling capacities. The functional and physicochemical properties of protein from squid can be enhanced by selecting a certain pH-shift processing, depending on the desirable use. There is a broad perspective on the use of these protein extracts as ingredients or additives.

Women with preeclampsia exposed to air pollution during pregnancy: Relationship between oxidative stress and neonatal disease - Pilot study.

Oxidative imbalance as a pathophysiological mechanism has been reported as an adverse outcome in pregnant women who develop preeclampsia and in their newborns. Furthermore, emerging evidence suggests the same mechanism by which air pollutants may exert their toxic effects. Therefore, the objective of the study was to evaluate the biomarkers of oxidative stress and their relationship with neonatal disease in premature newborns from mothers with preeclampsia exposed to air pollution during pregnancy. The data of air pollutants (PM2.5, PM10 and ozone) were collected at fixed monitoring stations. Oxidative and antioxidant status markers were obtained through special techniques in women with preeclampsia and in umbilical cord blood of their premature newborns. The oxidative stress markers were significantly higher in women with preeclampsia and their newborns who were exposed to higher levels of ambient air pollutants in the first and second trimester of pregnancy. Neonatal diseases are associated with preeclampsia in pregnancies, specifically intrauterine growth restriction (IUGR) and necrotizing enterocolitis (NEC). A significant correlation was identified in the levels of prooxidant agents and antioxidant enzyme activity in the presence of neonatal diseases associated with preeclampsia. There is increased oxidative damage in both the maternal and fetal circulation in women who develop preeclampsia exposed to air pollution during pregnancy. Therefore, these pregnancies complicated by preeclampsia have a greater adverse outcome as neonatal disease in the preterm infant.

Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer's disease.

Down syndrome (DS) arises from the triplication of human chromosome 21 and is considered the most common genetic cause of intellectual disability. Glial cells, specifically astroglia and microglia, display pathological alterations that might contribute to DS neuropathological alterations. Further, in middle adulthood, people with DS develop clinical symptoms associated with premature aging and Alzheimer's disease (AD). Overexpression of the amyloid precursor protein (APP) gene, encoded on chromosome 21, leads to increased amyloid-ß (Aß) levels and subsequent formation of Aß plaques in the brains of individuals with DS. Amyloid-ß deposition might contribute to astroglial and microglial reactivity, leading to neurotoxic effects and elevated secretion of inflammatory mediators. This review discusses evidence of astroglial and microglial alterations that might be associated with the AD continuum in DS.

Recent advances in the use of CRISPR/Cas for understanding the early development of molecular gaps in glial cells.

Glial cells are non-neuronal elements of the nervous system (NS) and play a central role in its development, maturation, and homeostasis. Glial cell interest has increased, leading to the discovery of novel study fields. The CRISPR/Cas system has been widely employed for NS understanding. Its use to study glial cells gives crucial information about their mechanisms and role in the central nervous system (CNS) and neurodegenerative disorders. Furthermore, the increasingly accelerated discovery of genes associated with the multiple implications of glial cells could be studied and complemented with the novel screening methods of high-content and single-cell screens at the genome-scale as Perturb-Seq, CRISP-seq, and CROPseq. Besides, the emerging methods, GESTALT, and LINNAEUS, employed to generate large-scale cell lineage maps have yielded invaluable information about processes involved in neurogenesis. These advances offer new therapeutic approaches to finding critical unanswered questions about glial cells and their fundamental role in the nervous system. Furthermore, they help to better understanding the significance of glial cells and their role in developmental biology.

G protein-coupled estrogen receptor (GPER/GPR30) levels in pelvic floor muscles and its association with estrogen status in female rabbits.

Objective: To assess the relative expression of the G-protein coupled estrogen receptor (GPER) in the bulbospongiosus (Bsm) and pubococcygeus (Pcm) muscles in control, ovariectomized (OVX), and OVX with estradiol benzoate supplementation (OVX + EB) rabbits.Methods: We used tissues from C, 1-month OVX, and OVX plus 15-day EB implanted (OVX + EB) groups. The GPER expression was evaluated by Western blot and immunohistochemistry for both Bsm and Pcm. Results: Both muscles showed a GPER immunoreactivity in blood vessels, inside myofibers next to myonuclei, and in polymorphonuclear cells. Four-week ovariectomy did not modify the GPER expression in the Bsm and Pcm, but two-week estradiol benzoate increased it in the latter muscle alone.Conclusions: We demonstrated that the Bsm and Pcm of female rabbits express GPER. High serum estradiol levels elevate GPER relative expression in the Pcm alone. The present study supports the remarkable estrogen sensitivity of the Pcm.

Multi-biomarker approach and IBR index to evaluate the effects of bisphenol A on embryonic stages of zebrafish (Danio rerio).

This study assessed the effects of Bisphenol A in embryonic stages of zebrafish, applying an IBR multi-biomarker approach that included alterations in growth and oxidative status and relates it with the expression of Nrf1, Nrf2, Wnt3a, Wnt8a, COX-2, Qdpra, and DKK1 genes. For this purpose, we exposed zebrafish embryos to eight environmentally relevant concentrations of BPA (220, 380, 540, 700, 860, 1180, 1340, and 1500 ng L-1) until 96 h post-fertilization. Our results show that BPA induces several malformations in embryos (developmental delay, hypopigmentation, tail malformations, and on), leading to their death. The LC50, EC50 of malformations, and teratogenic index (TI) were 1234.60 ng L-1, 987.77 ng L-1, and 1.25, respectively; thus, this emerging contaminant is teratogenic. Regarding oxidative stress and gene expression, we demonstrated BPA altered oxidative status and the gene expression in embryos of Danio rerio.

Antioxidant and Antimicrobial Peptides Derived from Food Proteins.

Recently, the demand for food proteins in the market has increased due to a rise in degenerative illnesses that are associated with the excessive production of free radicals and the unwanted side effects of various drugs, for which researchers have suggested diets rich in bioactive compounds. Some of the functional compounds present in foods are antioxidant and antimicrobial peptides, which are used to produce foods that promote health and to reduce the consumption of antibiotics. These peptides have been obtained from various sources of proteins, such as foods and agri-food by-products, via enzymatic hydrolysis and microbial fermentation. Peptides with antioxidant properties exert effective metal ion (Fe2+/Cu2+) chelating activity and lipid peroxidation inhibition, which may lead to notably beneficial effects in promoting human health and food processing. Antimicrobial peptides are small oligo-peptides generally containing from 10 to 100 amino acids, with a net positive charge and an amphipathic structure; they are the most important components of the antibacterial defense of organisms at almost all levels of life-bacteria, fungi, plants, amphibians, insects, birds and mammals-and have been suggested as natural compounds that neutralize the toxicity of reactive oxygen species generated by antibiotics and the stress generated by various exogenous sources. This review discusses what antioxidant and antimicrobial peptides are, their source, production, some bioinformatics tools used for their obtainment, emerging technologies, and health benefits.

Optimization of the Physical, Optical and Mechanical Properties of Composite Edible Films of Gelatin, Whey Protein and Chitosan.

The aim of this work was to evaluate the effect of the concentration of gelatin (G) (3-6 g), whey protein (W) (2.5-7.5 g) and chitosan (C) (0.5-2.5 g) on the physical, optical and mechanical properties of composite edible films (CEFs) using the response surface methodology (RSM), as well as optimizing the formulation for the packaging of foods. The results of the study were evaluated via first- and second-order multiple regression analysis to obtain the determination coefficient values with a good fit (R ˃ 0.90) for each of the response variables, except for the values of solubility and b*. The individual linear effect of the independent variables (the concentrations of gelatin, whey protein and chitosan) significantly affected (p ≤ 0.05) the water vapor permeability (WVP), strength and solubility of the edible films. The WVP of the edible films varied from 0.90 to 1.62 × 10-11 g.m/Pa.s.m2, the resistance to traction varied from 0.47 MPa to 3.03 MPa and the solubility varied from 51.06% to 87%. The optimized values indicated that the CEF prepared with a quantity of 4 g, 5 g and 3 g of gelatin, whey protein and chitosan, respectively, provided the CEF with a smooth, continuous and transparent surface, with L values that resulted in a light-yellow hue, a lower WVP, a maximum strength (resistance to traction) and a lower solubility. The results revealed that the optimized formulation of the CEF of G-W-C allowed a good validation of the prediction model and could be applied, in an effective manner, to the food packaging industry, which could help in mitigating the environmental issues associated with synthetic packaging materials.

Incidence and Severity of SARS-CoV-2 Infection in HIV-Infected Individuals During the First Year of the Pandemic.

BACKGROUND: We aim to investigate the infection rate, the clinical characteristics and outcomes of COVID-19-disease in a cohort of people living with HIV in Madrid (Spain), during the first year of pandemics. SETTING: Observational single-center study, in which we included all HIV-infected patients (aged ≥ 18 years) with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as of February 28, 2021, at the Hospital Universitario 12 de Octubre. METHODS: Confirmed disease was defined as any patient with a positive antigen test, reverse transcriptase polymerase chain reaction, or serology for SARS-CoV-2. We compared the characteristics of patients with mild disease (asymptomatic included) with those with moderate or severe disease (requiring admission). RESULTS: Of 2344 HIV-infected patients, 158 (82.9% male; median age, 46.5 years) were diagnosed with SARS-CoV-2 (infection rate, 6.74%; 95% confidence interval, 5.79 to 7.83). Thirty-nine individuals (24.7%) had moderate or severe disease, 43.7% had mild disease, and 31.6% were asymptomatic. Hypertension (23.4%) and obesity (15.8%) were the most prevalent comorbidities; 12.7% had at least 2 comorbidities. One hundred forty-five patients (97.3%) had RNA-HIV viral load of <50 copies per milliliter, and only 3 had CD4 cell count of <200 cells per cubic millimeter before infection. Of those admitted to hospital, 59% required oxygen support and 15.4%, invasive mechanical ventilation. Five patients died. None of the patient taking tenofovir-disoproxil-fumarate required admission. In the multivariate analysis, age remained as the only independent factor for moderate-severe disease (odds ratio, 1.09; 95% confidence interval 1.04 to 1.14; P < 0.001). CONCLUSIONS: People living with HIV are at risk of severe SARS-CoV-2 infection. Age was the only variable with an independent association with moderate-severe disease, after adjusting by comorbidities and other factors.

Effects of oxidative stress induced by environmental relevant concentrations of fluoxetine on the embryonic development on Danio rerio.

Fluoxetine (FLX) is a psychoactive drug that acts as an antidepressant. FLX is one of the world's best-selling prescription antidepressants. FLX is widely used for the treatment of various psychiatric disorders. For these reasons, this drug may eventually end up in the aquatic environment via municipal, industrial, and hospital discharges. Even though the occurrence of FLX in aquatic environments has been reported as ubiquitous, the toxic effects that this drug may induce, especially at environmentally relevant concentrations, on essential biological processes of aquatic organisms require more attention. In the light of this information, this work aimed to investigate the influence that fluoxetine oxidative stress-induced got over the embryonic development of Danio rerio. For this purpose, D. rerio embryos (4 h post fertilization) were exposed to environmentally relevant concentrations (5, 10, 15, 20, 25, 30, 35, and 40 ng L-1) of fluoxetine, until 96 h post fecundation. Along the exposure, survival, alterations to embryonic development, and teratogenic effects were evaluated using a stereomicroscope. Furthermore, oxidative stress biomarkers (superoxide dismutase, catalase, glutathione peroxidase, lipid peroxidation, hydroperoxide, and carbonyl content) were evaluated at 72 and 96 h post fecundation. LC50, EC50m, and teratogenic index were 30 ng L-1, 16 ng L-1, and 1.9, respectively. The main teratogenic effects induced by fluoxetine were pericardial edema, hatching retardation, spine alterations and craniofacial malformations. Concerning oxidative stress, our integrated biomarkers (IBR) analysis demonstrated that as the concentration increased, oxidative damage biomarkers got more influence over the embryos than antioxidant enzymes. Thus, fluoxetine induces an important oxidative stress response on the embryos of D. rerio. Collectively, our results allow us to concluded that FLX is a dangerous drug in the early life stages of D. rerio due to its high teratogenic potential and that FLX-oxidative stress induced may be involved in this toxic process.

Phenolic Compounds in Honey and Their Relationship with Antioxidant Activity, Botanical Origin, and Color.

Honey has been employed since antiquity due to its sensory, nutritional, and therapeutic properties. These characteristics are related to its physical and chemical composition. For example, phenolic compounds are substances that can determine antioxidant activity, as well as sensory characteristics, and can be employed as biomarkers of floral and geographical origin. This has generated a growing interest in the study of phenolic compounds and their influence in the intrinsic properties of this beekeeping product. This review aims to summarize, analyze, and update the status of the research that demonstrates the role of phenolic compounds in antioxidant activity, botanical-geographical origin, and the sensory characteristics of honey. These phenolic compounds, according to various results reported, have great relevance in honey's biological and functional activity. This leads to research that will link phenolic compounds to their floral, geographical, productive, and territorial origin, as well as some sensory and functional characteristics.

Effects of Peppermint Extract and Chitosan-Based Edible Coating on Storage Quality of Common Carp (Cyprinus carpio) Fillets.

Edible coatings have recently been developed and applied to different food matrices, due to their numerous benefits, such as increasing the shelf life of foods, improving their appearance, being vehicles of different compounds, such as extracts or oils of various spices that have antioxidant and antimicrobial activity, as well as being friendly to the environment. The objective of this research was to develop a new edible coating based on chitosan enriched with peppermint extract and to evaluate its effectiveness to inhibit microbial development in vitro and improve both the quality and shelf life of common carp (Cyprinus carpio) during refrigerated storage (4 ± 1 °C). Three treatments were used: edible coating (C + EC), edible coating +, 5% chitosan (C + ECCh) and edible coating + 1.5% chitosan + 10% peppermint (C + ECChP). Prior the coating carp fillets; the antibacterial activity and antioxidant capacity were evaluated in the peppermint extract and coating solutions. After coating and during storage, the following were determined on the fillet samples: microbiological properties, observed for ECP, an inhibition halo of 14.3 mm for Staphylococcus aureus, not being the case for Gram-negative species, for ECCh, inhibition halos of 17.6 mm, 17.1 mm and 16.5 mm for S. aureus, Salmonella typhimurium and Escherichia coli, respectively; for the ECChP, inhibition halos for S. aureus, S. typhimurium and E. coli of 20 mm, 17 mm and 16.8 mm, respectively. For the physicochemical characteristics: an increase in solubility was observed for all treatments during storage, reaching 46.7 mg SN protein/mg total protein for the control, and values below 29.1 mg SN protein/mg total protein (p < 0.05), for fillets with EC (C + EC > C + ECCh > C + ECChP, respectively at the end of storage. For the pH, maximum values were obtained for the control of 6.4, while for the fillets with EC a maximum of 5.8. For TVB-N, the fillets with different CE treatments obtained values (p < 0.05) of 33.3; 27.2; 25.3 and 23.3 mg N/100 g (control > C + E C > C + ECCh > C + ECChP respectively). Total phenolic compounds in the aqueous peppermint extract were 505.55 mg GAE/100 g dried leaves, with 98.78% antioxidant capacity in the aqueous extract and 81.88% in the EC. Biomolecule oxidation (hydroperoxide content) had a significant increase (p < 0.05) in all treatments during storage, 1.7 mM CHP/mg protein in the control, to 1.4 in C + EC, 1.27 in C + ECCh and 1.16 in C + ECChP; TBARS assay values increased in the different treatments during refrigerated storage, with final values of 33.44, 31.88, 29.40 and 29.21 mM MDA/mg protein in the control; C + EC; C + ECCh and C + ECChP respectively. In SDS -PAGE a protective effect was observed in the myofibrillar proteins of fillets with ECChP). The results indicate that the C + ECCh and C + ECChP treatments extend the shelf life of 3-5 days with respect to microbiological properties and 4-5 days with respect to physicochemical characteristics. A reduction in lipid and protein oxidation products was also observed during refrigerated storage. With these findings, this is considered a promising method to increase the shelf life of fish fillets combined with refrigeration and we are able to recommend this technology for the fish processing industry.

Estrogens influence differentially on the pelvic floor muscles activation at somatovisceral reflexes involved in micturition of rabbits.

OBJECTIVE: To determine the estrogen-dependency of the bladder and urethral function and the coordinated activation of pelvic floor muscles (PFM) during micturition. METHODS: We allocated age-matched female rabbits to control, 1-month ovariectomized (OVX), and OVX plus 2-week estradiol benzoate (EB) groups to record cystometry, urethral pressure, and electromyograms of bulbospongiosus (Bsm), and pubococcygeus muscles (Pcm) simultaneously. We also measured serum estradiol levels and myofiber cross-sectional area. We assessed urodynamic and urethral variables, categorized the Bsm-Pcm activation patterns at storage and voiding phases, and obtained the power spectrum density of muscle activation around the voiding phase. We investigated the influence of ovarian hormones, in general, and the contribution of estrogen, particularly on the functions of the bladder, urethra, and PFM. Statistical significance was set at P < 0.05. RESULTS: Ovarian hormones influence the bladder, urethral, and PFM functions. The urodynamics analyses indicated estrogens contribute to voiding duration and, to a lesser extent, to the time between bladder contractions. Urethral pressure at closure (maximal pressure-to-maximal urethral pressure ratio) improved partially (8%, P < 0.05) in the OVX plus 2-week estradiol benzoate compared with OVX, but urethral resistance increased (∼1.9-fold, P < 0.05) compared with control rabbits. Our findings support that Pcm activity at voiding is estrogen-sensitive, albeit EB administration reduced it at storage resume, which relates to high urethral resistance. CONCLUSIONS: Ovariectomy impairs bladder and urethral pressures and Bsm and Pcm activation at micturition in anesthetized rabbits. Estrogen administration partially reverts some of these effects and influences Pcm activation.

Glycogen Synthase Kinase 3ß Modulates the Inflammatory Response Activated by Bacteria, Viruses, and Parasites.

Knowledge of glycogen synthase kinase 3ß (GSK3ß) activity and the molecules identified that regulate its function in infections caused by pathogenic microorganisms is crucial to understanding how the intensity of the inflammatory response can be controlled in the course of infections. In recent years many reports have described small molecular weight synthetic and natural compounds, proteins, and interference RNA with the potential to regulate the GSK3ß activity and reduce the deleterious effects of the inflammatory response. Our goal in this review is to summarize the most recent advances on the role of GSK3ß in the inflammatory response caused by bacteria, bacterial virulence factors (i.e. LPS and others), viruses, and parasites and how the regulation of its activity, mainly its inhibition by different type of molecules, modulates the inflammation.

Differential estrogen-related responses in myofiber cross-sectional area of pelvic floor muscles in female rats.

OBJECTIVE: To determine the role of estrogens in myofiber cross-sectional area (CSA) of the pubococcyegeus (Pcm) and iliococcygeus muscles (Icm). METHODS: In Experiment 1, we excised the Pcm and Icm during the metestrus and proestrus stages of the estrous cycle to measure the myofiber CSA. In Experiment 2, we allocated other rats into the following groups: sham (Sh), ovariectomized (OVX), OVX plus 1,4,6-androstatriene-3,17-dione (ATD; OVX + ATD), an aromatase inhibitor, and OVX plus estradiol benzoate (OVX + EB). We carried out appropriate statistical tests to determine significant differences (p ≤ 0.05) in variables measured for both Experiments. RESULTS: The Pcm myofiber CSA at proestrus was higher than at metestrus, while the Icm myofiber CSA did not change. Ovariectomy increased the Pcm myofiber CSA, which was exacerbated with the ATD administration. The EB supplementation successfully reversed the ovariectomy-induced enlargement of the CSA. No significant changes were detected for the Icm myofiber CSA. CONCLUSIONS: Fluctuating ovarian steroid levels at the estrus cycle significantly influence the CSA myofiber of the Pcm but not that of the Icm. Estrogen actions, having a gonadal or extragonadal origin, influence importantly the CSA of the Pcm.

GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer.

The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3ß, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer's disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3ß kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α.