Activation Of Beta Research Articles

Exploring the role of macromolecular crowding and TNFR1 in cell volume control

The excessive cosolute densities in the intracellular fluid create a physicochemical condition called macromolecular crowding (MMC). Intracellular MMC entropically maintains the biochemical thermodynamic equilibria by favouring associative reactions while hindering transport processes. Rapid cell volume shrinkage during extracellular hypertonicity elevates the MMC and disrupts the equilibria, potentially ushering cell death. Consequently, cells actively counter the hypertonic stress through regulatory volume increase (RVI) and restore the MMC homeostasis. Here, we establish fluorescence anisotropy of EGFP as a reliable tool for studying cellular MMC and explore the spatiotemporal dynamics of MMC during cell volume instabilities under multiple conditions. Our studies reveal that the actin cytoskeleton enforces spatially varying MMC levels inside adhered cells. Within cell populations, MMC is uncorrelated with nuclear DNA content but anti-correlated with the cell spread area. Although different cell lines have statistically similar MMC distributions, their responses to extracellular hypertonicity vary. The intensity of the extracellular hypertonicity determines a cell's ability for RVI, which correlates with Nuclear Factor Kappa Beta (NFkB) activation. Pharmacological inhibition and knockdown experiments reveal that Tumour Necrosis Factor Receptor 1 (TNFR1) initiates the hypertonicity induced NFkB signalling and RVI. At severe hypertonicities, the elevated MMC amplifies cytoplasmic microviscosity and hinders Receptor Interacting Protein Kinase 1 (RIPK1) recruitment at the TNFR1 complex, incapacitating the TNFR1-NFkB signalling and consequently, RVI. Together, our studies unveil the involvement of TNFR1-NFkB signalling in modulating RVI and demonstrate the pivotal role of MMC in determining cellular osmoadaptability.

ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease.

Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer's disease (AD). Activation of estrogen receptor beta (ERβ) can be clinically relevant since it avoids the negative systemic effects of ERα activation. However, very few studies have explored ERβ-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ERβ in mediating sex-specific protection against AD pathology in the clinically relevant App NL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female App NL-G-F mice with the selective ERβ agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ERβ-knockout mice were used to assess ERβ's effect on microglial activation and phagocytosis. We find that ERβ activation protects against amyloid pathology and cognitive decline in male and female App NL-G-F mice. Ovariectomy increased soluble amyloid beta (Aβ) in cortex and insoluble Aβ in hippocampus, but had otherwise limited effects on pathology. We further identify that ERβ does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ERβ protects against AD pathology differently in males and females, warranting reassessment of ERβ in combating AD.

Pro-fibrotic effect of the susceptible gene PCSK5 in vascular fibrosis of Takayasu arteritis via TGF-β and SMAD3 signaling pathway activation

BackgroundVascular fibrosis directly causes vascular thickening in Takayasu arteritis (TAK), in which sustained transforming growth factor beta (TGF-β) activation is critical. Understanding TGF-β activation regulation and blocking it might yield a therapeutic effect in TAK. Proprotein convertase subtilisin/kexin type 5 (PCSK5) rs6560480 (T/C) is associated with TAK development. In this study, we assessed the association between the PCSK5 rs6560480 genotype and PCSK5 expression in TAK and explored its molecular role in TGF-β activation and vascular fibrosis development. MethodsIn TAK patients, PCSK5 and TGF-β expression in plasma and aortic tissue was examined by ELISA and immunohistochemical staining, and PCSK5 rs6560480 was genotyped. The correlation between PCSK5 and extracellular matrix (ECM) expression was examined by Western blotting (WB) and immunohistochemistry staining. Detection by co-immunoprecipitation was performed to detect the interaction between PCSK5 and TGF-β in adventitial fibroblasts (AAFs). Downstream signaling pathways were detected by WB and validated with appropriate inhibitors. Potential immunosuppressive agents to inhibit the effects of PCSK5 were explored in cell culture and TAK patients. ResultsPatients with PCSK5 rs6560480 TT patients had significantly higher PCSK5 levels and more thickened vascular lesions than patients with PCSK5 rs6560480 CT. PCSK5 expression was significantly increased in alpha smooth muscle actin (α-SMA)-positive myofibroblasts in TAK vascular lesions. Overexpressing PCSK5 facilitated TGF-β and downstream SMAD2/3 activation and ECM expression in AAFs and aorta in in-vitro culture. The mechanistic study supported that PCSK5 activated precursor TGF-β (pro-TGF-β) to the mature form by binding the pro-TGF-β cleavage site. Leflunomide inhibited PCSK5 and pro-TGF-β binding, decreasing TGF-β activation and ECM expression, which was also partially validated in leflunomide-treated patients. ConclusionThe findings revealed a novel pro-fibrotic mechanism of PCSK5 in TAK vascular fibrosis via TGF-β and downstream SMAD2/3 pathway activation. Leflunomide might be anti-fibrotic by disrupting PCSK5 and pro-TGF-β binding, presenting a new TAK treatment approach.

Grasp Posture Variability Leads to Greater Ipsilateral Sensorimotor Beta Activation During Simulated Prosthesis Use

Motor behaviour using upper-extremity prostheses of different levels is greatly variable, leading to challenges interpreting ideal rehabilitation strategies. Elucidating the underlying neural control mechanisms driving variability benefits our understanding of adaptation after limb loss. In this follow-up study, non-amputated participants completed simple and complex reach-to-grasp motor tasks using a body-powered transradial or partial-hand prosthesis simulator. We hypothesised that under complex task constraints, individuals employing variable grasp postures will show greater sensorimotor beta activation compared to individuals relying on uniform grasping, and activation will occur later in variable compared to uniform graspers. In the simple task, partial-hand variable and transradial users showed increased neural activation from the early to late phase of the reach, predominantly in the hemisphere ipsilateral to device use. In the complex task, only partial-hand variable graspers showed a significant increase in neural activation of the sensorimotor cortex from the early to the late phase of the reach. These results suggest that grasp variability may be a crucial component in the mechanism of neural adaptation to prosthesis use, and may be mediated by device level and task complexity, with implications for rehabilitation after amputation.

Binding requirements for latent transforming growth factor Beta2 activation

Although the mechanism for activation of latent TGFβ1 and TGFβ3 is understood to involve the binding of the TGFβ propeptide (LAP) to both an integrin and an insoluble substrate, the activation of latent TGFβ2 has been unclear because the TGFβ2 LAP does not have the classical integrin binding sequence found in the other two TGFβ isoform LAPs. To assess the potential requirement for covalent linkage with a matrix or cell surface protein for the activation of latent TGFβ2, we generated mice in which the TGFβ2 Cys residue predicted to be involved in binding was mutated to Ser (Tgfb2C24S). We reasoned that, if covalent interaction with a second molecule is required for latent TGFβ2 activation, mutant mice should display a Tgfb2 null (Tgfb2−/−)-like phenotype. Tgfb2C24S mice closely phenocopy Tgfb2−/− mice with death in utero between E18 and P1 and with congenital heart and kidney defects similar to those described for Tgfb2−/− mice. The mutant latent TGFβ2 is secreted at levels similar to WT, yet TGFβ signaling monitored as nuclear pSmad2 is suppressed. We conclude that, like latent TGFβ1, latent TGFβ2 activation requires binding to an immobilized matrix or plasma membrane molecule.

Brainwaves and Emotional Responses to Changes in Red Eye Shadow Brightness and Saturation

Purpose: Investigating how Munsell’s primary color (i.e., red eye shadow) influences human brain and emotional responses to establish foundational data for image formation. Methods: We analyzed the relative power differences in background brainwaves due to variations in five levels of brightness and saturation for each eye both in male and female individuals in their twenties. We used the coefficient of variation for brainwaves for our analysis. In addition, we assessed the preferences for altered red eye shadow and the emotional responses to determine the average preference index. We performed statistical analysis for brainwaves and emotional evaluations using repeated measure analysis of variance in SPSS, followed by post hoc testing with Tukey’s test at a 95% confidence level. Results: The brainwave and emotional responses obtained by presenting red eye shadow brightness and saturation modification-created stimuli revealed that both men and women exhibited beta and gamma wave activation and alpha wave inactivation upon low brightness and high saturation stimuli. Men were more sensitive to brightness stimuli, whereas women displayed higher-level variability in brainwave responses upon saturation changes. Both genders preferred red eye shadows with brightness and saturation levels of 8 and 2, respectively. The perceptual image responses indicated that stimuli with low or high brightness were perceived as modern and subtle or clear and cute, respectively. Medium or high saturation stimuli were perceived as clear and natural or associated with a modern image, respectively, by both genders. Conclusion: This study demonstrated the impact of various color stimuli on the human brain and emotions. We consider the obtained results as foundational data, which could be used in future image consulting or when crafting desired image presentations.

Tripolar concentric ring electrodes for capturing localised electroencephalography signals during sleep.

By design, tripolar concentric ring electrodes (TCRE) provide more focal brain activity signals than conventional electroencephalography (EEG) electrodes placed further apart. This study compared spectral characteristics and rates of data loss to noisy epochs with TCRE versus conventional EEG signals recorded during sleep. A total of 20 healthy sleepers (12 females; mean [standard deviation] age 27.8 [9.6] years) underwent a 9-h sleep study. Participants were set up for polysomnography recording with TCRE to assess brain activity from 18 sites and conventional electrodes for EEG, eyes, and muscle movement. A fast Fourier transform using multitaper-based estimation was applied in 5-s epochs to scored sleep. Odds ratios with Bonferroni-adjusted 95% confidence intervals were calculated to determine the proportional differences in the number of noisy epochs between electrode types. Relative power was compared in frequency bands throughout sleep. Linear mixed models showed significant main effects of signal type (p < 0.001) and sleep stage (p < 0.001) on relative spectral power in each power band, with lower relative spectral power across all stages in TCRE versus EEG in alpha, beta, sigma, and theta activity, and greater delta power in all stages. Scalp topography plots showed distinct beta activation in the right parietal lobe with TCRE versus EEG. EEG showed higher rates of noisy epochs compared to TCRE (1.3% versus 0.8%, p < 0.001). TCRE signals showed marked differences in brain activity compared to EEG, consistent with more focal measurements and region-specific differences during sleep. TCRE may be useful for evaluating regional differences in brain activity with reduced muscle artefact compared to conventional EEG.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in the pathogenesis and treatment for AD. We aimed to update the regulatory targets of the differentiation and maturation of OLs, and emphasized the key role of OLs in the occurrence and treatment of AD. This review first concluded the targets of OL differentiation and maturation with AD pathogenesis, and then advanced the key role of OLs in the pathogenesis of AD based on both clinic and basic experiments. Later, we extensively discussed the possible application of the current progress in the diagnosis and treatment of this complex disease. Molecules involving in OLs' differentiation or maturation, including various transcriptional factors, cholesterol homeostasis regulators, and microRNAs could also participate in the pathogenesis of AD. Clinical data point towards the impairment of OLs in AD patients. Basic research further supports the central role of OLs in the regulation of AD pathologies. Additionally, classic drugs, including donepezil, edaravone, fluoxetine, and clemastine demonstrate their potential in remedying OL impairment in AD models, and new therapeutics from the perspective of OLs is constantly being developed. We believe that OL dysfunction is one important pathogenesis of AD. Factors regulating OLs might be biomarkers for early diagnosis and agents stimulating OLs warrant the development of anti-AD drugs.

Tumor-specific activation of folate receptor beta enables reprogramming of immune cells in the tumor microenvironment.

Folate receptors can perform folate transport, cell adhesion, and/or transcription factor functions. The beta isoform of the folate receptor (FRβ) has attracted considerable attention as a biomarker for immunosuppressive macrophages and myeloid-derived suppressor cells, however, its role in immunosuppression remains uncharacterized. We demonstrate here that FRβ cannot bind folate on healthy tissue macrophages, but does bind folate after macrophage incubation in anti-inflammatory cytokines or cancer cell-conditioned media. We further show that FRβ becomes functionally active following macrophage infiltration into solid tumors, and we exploit this tumor-induced activation to target a toll-like receptor 7 agonist specifically to immunosuppressive myeloid cells in solid tumors without altering myeloid cells in healthy tissues. We then use single-cell RNA-seq to characterize the changes in gene expression induced by the targeted repolarization of tumor-associated macrophages and finally show that their repolarization not only changes their own phenotype, but also induces a proinflammatory shift in all other immune cells of the same tumor mass, leading to potent suppression of tumor growth. Because this selective reprogramming of tumor myeloid cells is accompanied by no systemic toxicity, we propose that it should constitute a safe method to reprogram the tumor microenvironment.

FOXS1 is increased in liver fibrosis and regulates TGFβ responsiveness and proliferation pathways in human hepatic stellate cells

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFβ) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFβ induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFβ to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFβ-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFβ-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFβ-activation. To validate the RNA-seq findings, we used our state-of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFβ responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.

NFkB and MMP-13 expression in condylar cartilage of temporomandibular joint with occlusal disharmony in vivo

Background: Temporomandibular disorder (TMD) is a collection of symptoms that causes pain and disturbs a person's life quality. One of the trigger factors is mechanical overloading. Mechanical overloading in occlusal disharmony conditions will lead to an inflammatory reaction in the temporomandibular joint (TMJ). This condition will induce nuclear factor Kappa Beta (NFkB) activation to transcribe proinflammatory cytokines and matrix metalloproteinase-13 (MMP13) and will also degrade condylar cartilage as a major factor in strengthening the TMJ. Purpose: The aim of this study was to analyze the expression of NFkB and MMP13 in the condylar cartilage of TMJ with occlusal disharmony. Methods: This research was an experimental study with post-test-only control group design. Twenty Rats (Rattus norvegicus) were divided into four groups: One control group without any intervention and three experimental groups. Occlusal-reducing intervention was due on the right molar of the experimental groups, which were divided into the 7th, 14th, and 21st days. Immunohistochemical staining was performed to determine the expression of NFkB and MMP13 in the condylar cartilage. The data were analyzed by using the Welch test and independent t-test. Results: There were significant differences in NFkB and MMP13 expression between the control and experiment experimental groups (p&lt;0.05). NFkB expression increased on the 7th, 14th, and 21st days of observation. The MMP13 expression showed a significant difference between the control and experimental groups (p&lt;0.05). Conclusion: Occlusal disharmony increases NFkB and MMP13 expression and could affect TMJ integrity and induce TMD. These findings are important for describing the mechanism of TMJ damage and developing potential alternative therapies to prevent further TMD.

Benzo[a]pyrene exposure affects colorectal cancer susceptibility by regulating ERβ-mediated LINC02977 transcription

Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERβ) regulated by PAHs in CRC as well as the underlying mechanisms of ERβ-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC–MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERβ expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E2) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E2 had the opposite effects. Additionally, this study mapped ERβ genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERβ binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERβ by PAHs and endogenous E2 may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERβ and its downstream targets for CRC prevention and treatment.

Cytosolic nucleic acid sensors and interferon beta-1 activation drive radiation-induced anti-tumour immune effects in human pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines. Human PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIG-I/MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genome-wide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-κB for radiation-induced IFNB1 activation. We demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF-κB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF-κB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiation-induced immune effects when exposed to single-dose protons or photons. Our findings provide a rationale for combinatorial radiation-immunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy.

Characterizing the influence of various antimicrobials used for metaphylaxis against bovine respiratory disease on host transcriptome responses.

Currently, control against bovine respiratory disease (BRD) primarily consists of mass administration of an antimicrobial upon arrival to facility, termed "metaphylaxis." The objective of this study was to determine the influence of six different antimicrobials used as metaphylaxis on the whole blood host transcriptome in healthy steers upon and following arrival to the feedlot. One hundred and five steers were stratified by arrival body weight (BW = 247 ± 28 kg) and randomly and equally allocated to one of seven treatments: negative control (NC), ceftiofur (CEFT), enrofloxacin (ENRO), florfenicol (FLOR), oxytetracycline (OXYT), tildipirosin (TILD), or tulathromycin (TULA). On day 0, whole blood samples and BW were collected prior to a one-time administration of the assigned antimicrobial. Blood samples were collected again on days 3, 7, 14, 21, and 56. A subset of cattle (n = 6) per treatment group were selected randomly for RNA sequencing across all time points. Isolated RNA was sequenced (NovaSeq 6,000; ~35 M paired-end reads/sample), where sequenced reads were processed with ARS-UCD1.3 reference-guided assembly (HISAT2/StringTie2). Differential expression analysis comparing treatment groups to NC was performed with glmmSeq (FDR ≤ 0.05) and edgeR (FDR ≤ 0.1). Functional enrichment was performed with KOBAS-i (FDR ≤ 0.05). When compared only to NC, unique differentially expressed genes (DEGs) found within both edgeR and glmmSeq were identified for CEFT (n = 526), ENRO (n = 340), FLOR (n = 56), OXYT (n = 111), TILD (n = 3,001), and TULA (n = 87). At day 3, CEFT, TILD, and OXYT shared multiple functional enrichment pathways related to T-cell receptor signaling and FcεRI-mediated NF-kappa beta (kB) activation. On day 7, Class I major histocompatibility complex (MHC)-mediated antigen presentation pathways were enriched in ENRO and CEFT groups, and CEFT and FLOR had DEGs that affected IL-17 signaling pathways. There were no shared pathways or Gene Ontology (GO) terms among treatments at day 14, but TULA had 19 pathways and eight GO terms enriched related to NF- κβ activation, and interleukin/interferon signaling. Pathways related to cytokine signaling were enriched by TILD on day 21. Our research demonstrates immunomodulation and potential secondary therapeutic mechanisms induced by antimicrobials commonly used for metaphylaxis, providing insight into the beneficial anti-inflammatory properties antimicrobials possess.

Cat’s Claw Nutrients for Medical Treatments

Uncaria tomentosa (Willd. ex Schult.) DC is commonly known as cat’s claw that is derived from the Spanish word Uña de Gato that identifies the small, curved-back thorns on the stem at the leaf junction. It is a tropical medicinal vine of the Rubiaceae family that is widely distributed in the Amazon rainforest and other areas of South and Central America. Cat's claw, which is scientifically known as Uncaria tomentosa, has been historically used to treat and prevent inflammatory disorders, particularly osteoarthritis. Traditionally, it has been used to treat chronic viral infections, bacterial infections, numerous inflammatory and immunological disorders, asthma, dysentery, cancers, arthritis, and as a birth control agent. Nutraceuticals, including food or products containing cat’s claw, can be used to prevent and modify symptoms in osteoarthritis patients. So, cat’s claw is possibly effective in reducing the pain in patient’s joints. U. tomentosa is a potent complimentary herb for treating most parasites. Various chemical constituents are reported from the extracts of U. tomentosa along with their biological activities. It is worth noting that more than 50 phytochemical molecules have been identified and isolated from U. tomentosa, some of them are considered new to that species. It also was used for the treatment of various ailments including abscesses, urinary tract infections, contraception, rheumatism, and weakness. Additionally, it was used as a treatment option for mental disorders (anxiety). The preclinical assessment revealed that the cat’s claw defends towards various oxidative stresses, involving peroxynitrite that has been included in arthritis and other chronic inflammatory diseases along with inhibiting acute or chronic gastritis caused by high doses of nonsteroidal anti-inflammatory drugs (NSAIDs). U. tomentosa aqueous extract was used to protect against oxidative stress in human erythrocytes and relieve chronic intestinal inflammation. Cat’s claw has antitumor and immunostimulatory effects because of its oxindole alkaloids content. Anti proliferative effect of U. tomentosa against several cancer cell lines, namely cervical carcinoma, osteosarcoma, and breast cancer were documented. U. tomentosa hot water extract prevents inflammatory responses as well as tumor cell proliferation by inhibiting the transcriptional regulator nuclear factor kappa beta (NF-B) activation without interfering with interleukin-2 (IL-2) production or IL-2 receptor signaling. Medical technologists documented the ant proliferative effect of cat’s claw extracts against several cell lines, including glioma, premyelocytic leukemia, MCF7 breast cancer, acute lymphoblastic leukaemia, and neuroblastoma.

Self-Awareness of Goals Task (SAGT) and Planning Skills: The Neuroscience of Decision Making.

A goal's self-awareness and the planning to achieve it drive decision makers. Through a neuroscientific approach, this study explores the self-awareness of goals by analyzing the explicit and implicit processes linked to the ability to self-represent goals and sort them via an implicit dominant key. Thirty-five professionals performed a novel and ecological decision-making task, the Self-Awareness of Goals Task (SAGT), aimed at exploring the (i) self-representation of the decision-making goals of a typical working day; (ii) self-representation of how these goals were performed in order of priority; (iii) temporal sequence; and (iv) in terms of their efficacy. Electrophysiological (i.e., alpha, beta, and gamma band), autonomic, behavioral, and self-report data (General Decision Making Style and Big Five Inventory) are collected. Higher self-awareness of goals by time as well as efficacy and the greater activation of alpha, beta, and gamma bands in the temporoparietal brain area were found. Correlations reported positive associations between the self-awareness of goals via a time and dependent decision-making style and a conscientious personality, but also between the self-awareness of goals via an efficacy and rational decision-making style. The results obtained in this study suggest that the SAGT could activate recursive thinking in the examinee and grasp individual differences in self-representation and aware identification of decision-making goals.

Current status of cacanakinumab therapy for cardiovascular disease

Cardiovascular disease(CVD)is an important cause of death in the worldIn recent years, due to a large number of experimental results, people gradually abandon the previous view the CVD is caused by hyperlipidemia, and the CVD is caused by a chronic, low-intensity inflammatory response in blood vessels. in which inflammation is thought to be a key facilitator.However, there are limits to the study of drugs that use CVD for excessive inflammation.The Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, conducted in 2017, successfully demonstrated that inflammation plays an important role in atherosclerotic disease. Canakinumab is an antibody that can effectively inhibit the activation of IL-1 beta. The results of the Cantos trial ushered in a new era of new treatments aimed at treating cardiovascular diseases.Although the targeted anti-AS effect of CANTOS is prominent, its efficacy does not significantly improve the mortality and infection rate of patients with cardiovascular disease.To this end, we collected relevant data of Carnaro umab in recent years. This paper will focus on its clinical application and analyze its advantages and disadvantages, and give the possible improvement and development direction.

Retinoic acid protects against lipopolysaccharide-induced ferroptotic liver injury and iron disorders by regulating Nrf2/HO-1 and RARβ signaling

Acute liver injury (ALI) can progress to severe liver diseases, making its prevention and treatment a focus of research. Retinoic acid (RA) has been shown to have anti-oxidative and iron-regulatory effects on organs. In this study, we investigated the effect of RA on lipopolysaccharide (LPS)-induced ALI in both in vivo and in vitro experiments. We found that RA significantly reduced LPS-induced serum iron and red blood cell-associated disorders, as well as decreased serum ALT and AST levels. RA also reversed the accumulation of non-heme iron and labile iron in LPS-induced mice and hepatocytes by increasing the expression of FTL/H and Fpn. Furthermore, RA inhibited tissue reactive oxygen species (ROS) and malondialdehyde (MDA) production and improved the expression of Nrf2/HO-1/GPX4 in mice and Nrf2 signaling in hepatocytes. In vitro experiments employing RAR agonists and antagonists have revealed that retinoic acid (RA) can effectively inhibit cell ferroptosis induced by lipopolysaccharide (LPS), erastin, and RSL3. The mechanism underlying this inhibition may involve the activation of retinoic acid receptors beta (RARβ) and gamma (RARγ). Knocking down the RARβ gene in Hepatocytes cells significantly diminished the RA's protective effect, indicating that the anti-ferroptotic role of RA was partially mediated by RARβ signaling. Overall, our study demonstrated that RA inhibited ferroptosis-induced liver damage by regulating Nrf2/HO-1/GPX4 and RARβ signaling.

Ligand-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations of New β-Estrogen Receptor Activators with Potential for Pharmacological Obesity Treatment.

Obesity is a pandemic and a serious health problem in developed and undeveloped countries. Activation of estrogen receptor beta (ERβ) has been shown to promote weight loss without modifying caloric intake, making it an attractive target for developing new drugs against obesity. This work aimed to predict new small molecules as potential ERβ activators. A ligand-based virtual screening of the ZINC15, PubChem, and Molport databases by substructure and similarity was carried out using the three-dimensional organization of known ligands as a reference. A molecular docking screening of FDA-approved drugs was also conducted as a repositioning strategy. Finally, selected compounds were evaluated by molecular dynamic simulations. Compounds 1 (-24.27 ± 0.34 kcal/mol), 2 (-23.33 ± 0.3 kcal/mol), and 6 (-29.55 ± 0.51 kcal/mol) showed the best stability on the active site in complex with ERβ with an RMSD < 3.3 Å. RMSF analysis showed that these compounds do not affect the fluctuation of the Cα of ERβ nor the compactness according to the radius of gyration. Finally, an in silico evaluation of ADMET showed they are safe molecules. These results suggest that new ERβ ligands could be promising molecules for obesity control.

Estrogen Receptor Beta Mediates the Dipsogenic Effect of Estradiol in Ovariectomized Female Rats

Introduction: Although the fluid inhibitory effects of estradiol are well characterized, a dipsogenic role of the hormone was recently identified. In ovariectomized (OVX) rats, unstimulated water intake, in the absence of food, was increased after estradiol treatment. Methods: The goals for these experiments were to further characterize the fluid enhancing effects of estradiol by determining the estrogen receptor subtype mediating the dipsogenic effect, examining saline intake, and testing for a dipsogenic effect of estradiol in male rats. Results: Pharmacological activation of estrogen receptor beta (ERβ) increased water intake, in the absence of food, and was associated with changes in postingestive feedback signals. Surprisingly, activation of ERα reduced water intake even in the absence of food. A follow-up study demonstrated that when food was available, co-activation of ERα and ERβ reduced water intake, but when food was not available water intake was increased. In addition, in OVX rats, estradiol increased saline intake through changes in postingestive and orosensory feedback signals. Finally, although estradiol decreased water intake in male rats with access to food, estradiol had no effect on water intake in the absence of food. Conclusions: These results demonstrate that the dipsogenic effect is mediated by ERβ, the fluid enhancing effects of estradiol generalize to saline, and is limited to females, which implies that a feminized brain is necessary for estradiol to increase water intake. These findings will aid in guiding future studies focused on elucidating the neuronal mechanisms that allow estradiol to both increase and decrease fluid intake.