Genistein as Potential Therapeutic Candidate for Menopausal Symptoms and Other Related Diseases.

Plant-derived compounds have recently attracted greater interest in the field of new therapeutic agent development. These compounds have been widely screened for their pharmacological effects. Polyphenols, such as soy-derived isoflavones, also called phytoestrogens, have been extensively studied due to their ability to inhibit carcinogenesis. These compounds are chemically similar to 17ß-estradiol, and mimic the binding of estrogens to its receptors, exerting estrogenic effects in target organs. Genistein is an isoflavone derived from soy-rich products and accounts for about 60% of total isoflavones found in soybeans. Genistein has been reported to exhibit several biological effects, such as anti-tumor activity (inhibition of cell proliferation, regulation of the cell cycle, induction of apoptosis), improvement of glucose metabolism, impairment of angiogenesis in both hormone-related and hormone-unrelated cancer cells, reduction of peri-menopausal and postmenopausal hot flashes, and modulation of antioxidant effects. Additionally, epidemiological and clinical studies have reported health benefits of genistein in many chronic diseases, such as cardiovascular disease, diabetes, and osteoporosis, and aid in the amelioration of typical menopausal symptoms, such as anxiety and depression. Although the biological effects are promising, certain limitations, such as low bioavailability, biological estrogenic activity, and effects on target organs, have limited the clinical applications of genistein to some extent. Moreover, studies report that modification of its molecular structure may eliminate the biological estrogenic activity and its effects on target organs. In this review, we summarize the potential benefits of genistein on menopause symptoms and menopause-related diseases like cardiovascular, osteoporosis, obesity, diabetes, anxiety, depression, and breast cancer.

Brown Seaweed Egregia menziesii's Cytotoxic Activity against Brain Cancer Cell Lines.

Brown seaweeds contain bioactive compounds that show anti-tumorigenic effects. These characteristics have been repeatedly observed in the Lessoniaceae family. Egregia menziesii, a member of this family, is distributed in the North Pacific and its properties have been barely studied. We evaluated herein the cytotoxic and anti-proliferative activity of extracts of this seaweed, through toxicity assay in Artemia salina and lymphocytes, and MTT proliferation assay, in Bergmann glia cells, 3T3-L1 and brain cancer cell lines. E. menziesii's extracts inhibited the spread of all the tested cell lines. The hexane extract showed the highest cytotoxic activity, while the methanol extract was moderately cytotoxic. Interestingly, seaweed extracts displayed a selective inhibition pattern. These results suggest that E. menziesii's extracts might be good candidates for cancer prevention and the development of novel chemotherapies due to its highest cytotoxicity in transformed cells compare to glia primary cultures.

Glutamate-Dependent BMAL1 Regulation in Cultured Bergmann Glia Cells.

Glutamate, the major excitatory amino acid, activates a wide variety of signal transduction cascades. This neurotransmitter is involved in photic entrainment of circadian rhythms, which regulate physiological and behavioral functions. The circadian clock in vertebrates is based on a transcription-translation feedback loop in which Brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) acts as transcriptional activator of others clock genes. This protein is expressed in nearly all suprachiasmatic nucleus neurons, as well as in the granular layer of the cerebellum. In this context, we decided to investigate the role of glutamate in the molecular mechanisms involved in the processes of transcription/translation of BMAL1 protein. To this end, primary cultures of chick cerebellar Bergmann glial cells were stimulated with glutamatergic ligands and we found that BMAL1 levels increased in a dose- and time dependent manner. Additionally, we studied the phosphorylation of serine residues in BMAL1 under glutamate stimulation and we were able to detect an increase in the phosphorylation of this protein. The increased expression of BMAL1 is most probably the result of a stabilization of the protein after it has been phosphorylated by the cyclic AMP-dependent protein kinase and/or the Ca(2+)/diacylglycerol dependent protein kinase. The present results strongly suggest that glutamate participates in regulating BMAL1 in glial cells and that these cells might prove to be important in the control of circadian rhythms in the cerebellum.

GLAST/EAAT1-induced glutamine release via SNAT3 in Bergmann glial cells: evidence of a functional and physical coupling.

Glutamate, the major excitatory transmitter in the vertebrate brain, is removed from the synaptic cleft by a family of sodium-dependent glutamate transporters profusely expressed in glial cells. Once internalized, it is metabolized by glutamine synthetase to glutamine and released to the synaptic space through sodium-dependent neutral amino acid carriers of the N System (SNAT3/slc38a3/SN1, SNAT5/slc38a5/SN2). Glutamine is then taken up by neurons completing the so-called glutamate/glutamine shuttle. Despite of the fact that this coupling was described decades ago, it is only recently that the biochemical framework of this shuttle has begun to be elucidated. Using the established model of cultured cerebellar Bergmann glia cells, we sought to characterize the functional and physical coupling of glutamate uptake and glutamine release. A time-dependent Na⁺-dependent glutamate/aspartate transporter/EAAT1-induced System N-mediated glutamine release could be demonstrated. Furthermore, D-aspartate, a specific glutamate transporter ligand, was capable of enhancing the co-immunoprecipitation of Na⁺-dependent glutamate/aspartate transporter and Na⁺-dependent neutral amino acid transporter 3, whereas glutamine tended to reduce this association. Our results suggest that glial cells surrounding glutamatergic synapses may act as sensors of neuron-derived glutamate through their contribution to the neurotransmitter turnover.

A low density microarray method for the identification of human papillomavirus type 18 variants.

We describe a novel microarray based-method for the screening of oncogenic human papillomavirus 18 (HPV-18) molecular variants. Due to the fact that sequencing methodology may underestimate samples containing more than one variant we designed a specific and sensitive stacking DNA hybridization assay. This technology can be used to discriminate between three possible phylogenetic branches of HPV-18. Probes were attached covalently on glass slides and hybridized with single-stranded DNA targets. Prior to hybridization with the probes, the target strands were pre-annealed with the three auxiliary contiguous oligonucleotides flanking the target sequences. Screening HPV-18 positive cell lines and cervical samples were used to evaluate the performance of this HPV DNA microarray. Our results demonstrate that the HPV-18's variants hybridized specifically to probes, with no detection of unspecific signals. Specific probes successfully reveal detectable point mutations in these variants. The present DNA oligoarray system can be used as a reliable, sensitive and specific method for HPV-18 variant screening. Furthermore, this simple assay allows the use of inexpensive equipment, making it accessible in resource-poor settings.

Juvenile Exposure to BPA Alters the Estrous Cycle and Differentially Increases Anxiety-like Behavior and Brain Gene Expression in Adult Male and Female Rats.

Perinatal exposure to bisphenol A (BPA) in murine models has been reported to affect social behavior and increase anxiety. However, there is little information about the effects of BPA exposure during puberty, a period in which sex hormones influence the maturation and differentiation of the brain. In this work, we evaluated the effect of BPA administration during the juvenile stage (PND 21-50) on anxiety in male and female rats. Newly weaned Wistar rats were treated with BPA (0, 50, or 500 µg/kg/day) for 30 days. To compare the intra- and inter-sex behavioral profiles, rats were evaluated using four different anxiety models: the Open field test (OFT), the Elevated plus maze (EPM), the Light-dark box test (LDBT), and the Defensive burying test (DBT). Males exhibited a clear-cut anxious profile at both doses in all four tests, while no clear behavioral effect of BPA exposure was observed in female rats. The latter showed an altered estrous cycle that initiated earlier in life and had a shorter duration, with the estrous phase predominating. Moreover, the expression of ESR1, ESR2, GABRA1, GRIN1, GR, MR, and AR genes increased in the hippocampus and hypothalamus of male rats treated with 50 µg/kg, but not in females. Our results indicate that BPA consistently induces a higher anxiety profile in male than in female rats, as evidenced predominantly by an increase in passive-coping behaviors and changes in brain gene expression, highlighting the importance of sex in peripubertal behavioral toxicology studies.

Effects on cardiometabolic risk factors after reduction of artificially sweetened beverage consumption in overweight subjects. A randomised controlled trial.

BACKGROUND: The consumption of artificially sweetened beverages (ASBs) has been linked to metabolic alterations. The effect of reducing the regular consumption of these beverages on the metabolism is currently unknown. OBJECTIVE: To evaluate the effect of reducing consumption of ASBs on the metabolism in overweight young adults. DESIGN: A randomised, single-blind, controlled, 12-week, clinical trial was performed in overweight young adults who regularly consume ASBs. The 45 subjects who participated in the study were randomly divided into two groups: (1) control group (n=21) and (2) intervention group (no intake of ASBs, n=24). Body weight and composition, fasting plasma concentrations of glucose, triglycerides, insulin, cholesterol, low-density lipoproteins and high-density lipoproteins were measured at the beginning and end of the study. and the HOMA-IR was calculated. RESULTS: At the end of 12 weeks, the intervention group showed a significant decrease (as opposed to an increase in the control group) in the percentage of change in body weight (-1.22% vs 1.31%, p<0.004), body fat (-6.28% vs 6.15%, p<0.001) and insulin resistance index (-12.06 vs 38.21%, p<0.00002), as well as in levels of glucose (-4.26% vs 0.51%, p<0.05), triglycerides (-14.74% vs 19.90%, p<0.006), insulin (-8.02% vs 39.23%, p<0.00005), cholesterol (-8.71% vs 0.77%, p<0.01) and LDL (-9.46% vs 9.92%, p<0.004). CONCLUSION: A reduction in habitual consumption of ASBs in overweight young adults decreases biochemical measurements, body weight and composition, suggesting a participation in the metabolic processes.

Bariatric surgery and alcohol and substance abuse disorder: A systematic review.

INTRODUCTION: Bariatric surgery is a relatively safe surgical procedure with a high success rate. However, recent reports indicate a higher prevalence of alcohol or substance abuse disorder in this patient group. The purpose of this study was to review the related evidence to serve as a reference for multidisciplinary teams who treat these patients. METHODS: We searched the PubMed and CENTRAL databases. The odds ratios were extracted from the different articles, comparing the prevalence of the abuse of alcohol or other substances in the postoperative period versus preoperative levels. We also compared the prevalence of alcohol use disorder after different types of bariatric surgery. RESULTS: A total of 49 121 bariatric patients (80.8% female) were evaluated for alcohol use disorder. In general, bariatric surgery was found to be associated with an increase in the prevalence of alcohol abuse (4.58 ± 5.3 vs. 1.58 ± 10.7% in the preoperative period). We also found that the population of patients who underwent RYGB procedures had a higher prevalence of alcohol use disorder than patients who underwent another type of surgery (OR: 1.83; 95% CI: 1.51-2.21). The prevalence of substance abuse disorder (other than alcohol) after this procedure is less studied, although there appears to be an increased risk of abuse of certain substances. CONCLUSIONS: Bariatric surgery is the best treatment for obesity and its complications. The evidence reviewed suggests that it correlates with a modest but consistent increase in the prevalence of abuse of alcohol and other substances. Medical teams who treat bariatric patients must be informed about this eventuality for its timely prevention, diagnosis and treatment.

Elucidating Molecular Interactions of Ten Natural Compounds Targeting E6 HPV High Risk Oncoproteins Using Microsecond Molecular Dynamics Simulations.

BACKGROUND: Cervical cancer is a major public health issue worldwide, occurring in the vast majority of cases (85%) in low-income countries. Human papillomavirus (HPV) mainly infects the mucosal epithelium, and a small portion causes over 600,000 cases every year worldwide at various anatomical spots, mainly leading to anogenital and head and neck. INTRODUCTION: The E6 oncoprotein encoded by cancer-associated alpha HPV can transform epithelial cells into tumorigenic tissue. Therapy for this infection and blocking of the HPV E6 oncoprotein could be provided with cost-effective and abundant natural products which are an exponentially growing topic in the literature. Finding an active natural compound that readily blocks HPV E6 oncoprotein which could be available for developing countries without expensive extraction processes or costly synthetic pathways is of major interest. METHODS: Molecular dynamics simulation was performed using the most up-to-date AMBER protein force field ff14SB and a GPU enabled high performance computing cluster. RESULTS: In this research, we present a study of the binding properties between 10 selected natural compounds that are readily available with two variants of the E6 oncoprotein types (HPV-16 and HPV-18) using 10+ microsecond molecular dynamics simulations. CONCLUSION: Our results suggest that crocetin, ergosterol peroxide and κ-carrageenan natural products bind strongly to both HPV-16 and HPV-18 and could potentially serve as a scaffolding for further drug development.

Bariatric surgery and alcohol and substance abuse disorder: A systematic review. / Cirugía bariátrica y trastorno por abuso de alcohol y otras sustancias: una revisión sistemática.

INTRODUCTION: Bariatric surgery is a relatively safe surgical procedure with a high success rate. However, recent reports indicate a higher prevalence of alcohol or substance abuse disorder in this patient group. The purpose of this study was to review the related evidence to serve as a reference for multidisciplinary teams who treat these patients. METHODS: We searched the PubMed and CENTRAL databases. The odds ratios were extracted from the different articles, comparing the prevalence of the abuse of alcohol or other substances in the postoperative period versus preoperative levels. We also compared the prevalence of alcohol use disorder after different types of bariatric surgery. RESULTS: A total of 49 121 bariatric patients (80.8% female) were evaluated for alcohol use disorder. In general, bariatric surgery was found to be associated with an increase in the prevalence of alcohol abuse (4.58±5.3 vs. 1.58±10.7% in the preoperative period). We also found that the population of patients who underwent RYGB procedures had a higher prevalence of alcohol use disorder than patients who underwent another type of surgery (OR: 1.83; 95% CI: 1.51-2.21). The prevalence of substance abuse disorder (other than alcohol) after this procedure is less studied, although there appears to be an increased risk of abuse of certain substances. CONCLUSIONS: Bariatric surgery is the best treatment for obesity and its complications. The evidence reviewed suggests that it correlates with a modest but consistent increase in the prevalence of abuse of alcohol and other substances. Medical teams who treat bariatric patients must be informed about this eventuality for its timely prevention, diagnosis and treatment.

Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis.

Hepatic encephalopathy (HE) is one of the most disabling metabolic diseases. It consists of a complication of liver disease through the action of neurotoxins, such as excessive production of ammonia from liver, resulting in impaired brain function. Its prevalence and incidence are not well known, although it has been established that up to 40% of cirrhotic patients may develop HE. Patients with HE episodes display a wide range of neurological disturbances, from subclinical alterations to coma. Recent evidence suggests that the resolution of hepatic encephalopathy does not fully restore cognitive functioning in cirrhotic patients. Therefore, the aim of this review was to evaluate the evidence supporting the presence of lingering cognitive deficits in patients with a history of HE compared to patients without HE history and how liver transplant affects such outcome in these patients. We performed two distinct meta-analysis of continuous outcomes. In both cases the results were pooled using random-effects models. Our results indicate that cirrhotic patients with a history of HE show clear cognitive deficits compared control cirrhotic patients (Std. Mean Difference (in SDs) = -0.72 [CI 95%: -0.94, -0.50]) and that these differences are not fully restored after liver transplant (Std. Mean Difference (in SDs) = -0.72 [CI 95%: -0.94, -0.50]).

Effects on cardiometabolic risk factors after reduction of artificially sweetened beverage consumption in overweight subjects. A randomised controlled trial.

BACKGROUND: The consumption of artificially sweetened beverages (ASBs) has been linked to metabolic alterations. The effect of reducing the regular consumption of these beverages on the metabolism is currently unknown. OBJECTIVE: To evaluate the effect of reducing consumption of ASBs on the metabolism in overweight young adults. DESIGN: A randomised, single-blind, controlled, 12-week, clinical trial was performed in overweight young adults who regularly consume ASBs. The 45 subjects who participated in the study were randomly divided into two groups: (1) control group (n=21) and (2) intervention group (no intake of ASBs, n=24). Body weight and composition, fasting plasma concentrations of glucose, triglycerides, insulin, cholesterol, low-density lipoproteins and high-density lipoproteins were measured at the beginning and end of the study. and the HOMA-IR was calculated. RESULTS: At the end of 12 weeks, the intervention group showed a significant decrease (as opposed to an increase in the control group) in the percentage of change in body weight (-1.22% vs 1.31%, p<0.004), body fat (-6.28% vs 6.15%, p<0.001) and insulin resistance index (-12.06 vs 38.21%, p<0.00002), as well as in levels of glucose (-4.26% vs 0.51%, p<0.05), triglycerides (-14.74% vs 19.90%, p<0.006), insulin (-8.02% vs 39.23%, p<0.00005), cholesterol (-8.71% vs 0.77%, p<0.01) and LDL (-9.46% vs 9.92%, p<0.004). CONCLUSION: A reduction in habitual consumption of ASBs in overweight young adults decreases biochemical measurements, body weight and composition, suggesting a participation in the metabolic processes.

Corrigendum: Cognitive Impairment After Resolution of Hepatic Encephalopathy: A Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.3389/fnins.2021.579263.].

Ergosterol Peroxide Isolated from Oyster Medicinal Mushroom, Pleurotus ostreatus (Agaricomycetes), Potentially Induces Radiosensitivity in Cervical Cancer.

Every year, more than 500,000 new cases of cervical cancer are reported, making it the fourth leading cause of cancer globally. Although human papillomavirus (HPV) vaccines show promise as a protective measure, HPV-related cancers remain a public health problem since the vaccines, which are only specific to certain viral types, are unavailable for mass distribution. Furthermore, the effects of toxicity following ionizing radiation therapy have reoriented views toward the search for radiosensitizers that can reduce toxicity as a consequence of decreased radiation doses. Here, we isolated ergosterol peroxide (EP) from Pleurotus ostreatus and purified it to test its potential effects in vitro. We thus observed that a gradual increase in EP dose correlates with a loss of viability in HeLa and CaSki cervical cell lines. Dose/response curves were constructed using cervical cancer cell lines, as well as normal human peripheral blood mononuclear cells. The selectivity of EP in human lymphocytes and cervical cancer cell lines was tested, and no toxicity was found in normal cells. A combination of treatments revealed a radiosensitizer effect in HeLa cells, when measuring the exposure to EP followed by irradiation with 137Cs. Our findings suggest that EP may be effective as a radiosensitizer in treating cervical cancer.

Glutamate-dependent transcriptional control in Bergmann glia: Sox10 as a repressor.

UNLABELLED: Glutamate (Glu) is the major excitatory transmitter in the vertebrate brain. Ligand-gated and G protein-coupled Glu receptors present in glial cells are presumably involved in neuronal function. Activation of Bergmann glial Glu receptors triggers a membrane to nuclei signaling cascade that regulates gene expression at the transcriptional and translational levels. Sry-related high-mobility group box (Sox10), a member of the conserved high-mobility group box transcription factor family is expressed in neural crest stem cells and in a subset of neural crest-derived lineages that include glial, but not neuronal cells. To gain insight into the role of Sox10 in Bergmann glial cells, we explored its expression and regulation. We demonstrate herein that Sox10 is expressed in Bergmann glial cells and that its DNA binding activity, mRNA, and protein levels as well as its transcriptional behavior augments upon the activation of metabotropic Glu receptors. Increase in Sox10-DNA complexes and Sox10 mRNA and protein levels were found upon exposure to Glu. Over-expression of Sox10 leads to transcriptional repression in reporter gene assays and in one of its target genes: the chick kainate binding protein gene. These findings add a new perspective into glial glutamatergic signaling and suggest the participation of Sox10 in cerebellar glutamatergic transactions. KEYWORDS: Bergmann glial cells, glutamate, metabotropic glutamate receptors, signaling, Sox10, transcriptional control.

Seaweeds-derived compounds modulating effects on signal transduction pathways: A systematic review.

BACKGROUND: Recently, the study of marine natural products has gained interest due to their relevant biological activities. Specially, seaweeds produce bioactive compounds that could act as modulators of cell signaling pathways involved in a plethora of diseases. Thereby, the description of the molecular mechanisms by which seaweeds elicit its biological functions will certainly pave the way to the pharmacological development of drugs. AIM: This review describes the molecular mechanisms by which seaweeds act and its possible utilization in the design of new drugs. METHODS: This review was conducted according to the PRISMA-P guidelines for systematic reviews. Two independent authors searched into four different databases using combinations of keywords. Two more authors selected the articles following the eligibility criteria. Information extraction was conducted by two separated authors and entered into spreadsheets. Methodological quality and risk of bias were determined applying a 12-question Risk of Bias criteria tool. RESULTS AND DISCUSSION: We found 2360 articles (SCOPUS: 998; PubMed: 678; Wiley: 645 and EBSCO: 39) using the established keywords, of which 113 articles fit the inclusion criteria and were included in the review. This work comprises studies in cell lines, and animal models, any clinical trial was excluded. The articles were published from 2005 up to March 31st 2018. The biggest amount of articles was published in 2017. Furthermore, the seaweeds tested in the studies were collected in 15 countries, mainly in Eastern countries. We found that the main modulated signaling pathways by seaweeds-derivate extracts and compounds were: L-Arginine/NO, TNF-α, MAPKs, PI3K/AKT/GSK, mTOR, NF-κB, extrinsic and intrinsic apoptosis, cell cycle, MMPs and Nrf2. Finally, the articles we analyzed showed moderate risk of bias in almost all the parameters evaluated. However, the studies fail to describe the place and characteristics of sample collection, the sample size, and the blindness of the experimental design. CONCLUSION: In this review we identified and summarized relevant information related to seaweed-isolated compounds and extracts having biological activity; their role in different signal pathways to better understand their potential to further development of cures for cancer, diabetes, and inflammation-related diseases.

Anticancer activity of seaweeds.

Cancer is a major health problem worldwide and still lacks fully effective treatments. Therefore, alternative therapies, using natural products, have been proposed. Marine algae are an important component of the marine environment, with high biodiversity, and contain a huge number of functional compounds, including terpenes, polyphenols, phlorotannins, and polysaccharides, among others. These compounds have complex structures that have shown several biological activities, including anticancer activity, using in vitro and in vivo models. Moreover, seaweed-derived compounds target important molecules that regulate cancer processes. Here, we review our current understanding of the anticancer activity of seaweeds.

Signal transducers and activators of transcription 1 and 3 in prostate: effect of sexual activity.

The signal transducers and activators of transcription (Stat) are effector molecules downstream of cytokine receptors. Ligand occupancy of these receptors results in the tyrosine phosphorylation, dimerization and nuclear translocation of the Stat family of transcription factors and by these means regulate gene expression. Prolactin receptors as members of the cytokine-hematopoietin receptor superfamily, are linked to Stat activation. Sexual stimulation leads to an increase in prolactin secretion that might be involved in long-term changes in the protein repertoire associated to prostate hyperplasia. In order to gain insight into this phenomenon, we analyzed the tyrosine phosphorylation and DNA binding activity of two members of the Stat family in the prostate of sexual experienced rats after different number of ejaculations. A significant increase in Stat-1 and Stat-3 tyrosine phosphorylation was found after three ejaculations. Concomitantly an increase in Stat-1 and Stat-3 DNA-binding activity is detected after two and three ejaculation series. These results, favor the notion that ejaculation-induced prolactin secretion activates its prostate receptors resulting in Stat-1 and Stat-3 nuclear translocation, event likely to be associated to the so-called benign prostate hyperplasia.

Brain-derived neurotrophic factor and its receptors in Bergmann glia cells.

Brain-derived neurotrophic factor is an abundant and widely distributed neurotrophin expressed in the Central Nervous System. It is critically involved in neuronal differentiation and survival. The expression of brain-derived neurotrophic factor and that of its catalytic active cognate receptor (TrkB) has been extensively studied in neuronal cells but their expression and function in glial cells is still controversial. Despite of this fact, brain-derived neurotrophic factor is released from astrocytes upon glutamate stimulation. A suitable model to study glia/neuronal interactions, in the context of glutamatergic synapses, is the well-characterized culture of chick cerebellar Bergmann glia cells. Using, this system, we show here that BDNF and its functional receptor are present in Bergmann glia and that BDNF stimulation is linked to the activation of the phosphatidyl-inositol 3 kinase/protein kinase C/mitogen-activated protein kinase/Activator Protein-1 signaling pathway. Accordingly, reverse transcription-polymerase chain reaction (RT-PCR) experiments predicted the expression of full-length and truncated TrkB isoforms. Our results suggest that Bergmann glia cells are able to express and respond to BDNF stimulation favoring the notion of their pivotal role in neuroprotection.