Association of a cytosine-adenine repeat polymorphism in the estrogen receptor β gene with occurrence and severity of rheumatoid arthritis

We investigated the influence of the cytosine-adenine (CA) dinucleotide repeat polymorphism in intron 6 of estrogen receptor β (ERβ) gene on rheumatoid arthritis (RA) risk. One hundred and ninety-three RA patients and 77 control subjects with osteoarthritis (OA) were recruited. The CA repeat polymorphism was assayed by a dye-terminator cycle sequencing analysis. No statistically significant difference in the mean number of CA repeats between the RA and OA patients was observed (RA: 21.47, OA: 21.23, P = 0.324). The alleles were categorized according to the number of repeats: short (S, ≦21) and long (L, ≧22), in which the genotypes SS, SL, and LL were observed. No significant differences were observed for the allele and genotype distributions of this polymorphism in both patient groups. The RA patients were classified according to RA severity: mild (least erosive disease) and severe (more erosive and mutilating disease). Again, no significant difference in genotype frequency between these groups was observed, even after stratifying by sex. The present study indicates that additional studies are needed to clarify the roles of this polymorphism, estrogen, and ER in the development of autoimmune diseases.

17β-Estradiol Regulates Cultured Immature Boar Sertoli Cell Proliferation via the cAMP-ERK1/2 Pathway and the Estrogen Receptor β

Estrogen plays an important role in regulating Sertoli cell number in the testis. The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured, immature boar Sertoli cells via the estrogen receptor β （ERβ） and the cAMP-extracellular signal-regulated kinase （ERK1/2） pathway. Low levels （10-10-10-8 mol L-1） of 17β-estradiol increased cell number, but high levels （10-7-10-6 mol L-1） decreased it （P〈0.05）. Sertoli cell number began to recover for an additional 24 h in the medium without 17β-estradiol （10-6 mol L-l） （P〉0.05）. The effects of 17β-estradiol （10-9 mol L-1） peaked at the first 24 h （P〈0.05）. 17β-estradiol activated ERK1/2 from 5 min to 24 h, but the activiy of ERK1/2 began to decrease after 4 h. Both PD98059 and U0126, two ERK inhibitors, blocked cell division （P〈0.05）. 17β-estradiol （10-10-10-6 mol L-1） dose-dependently increased cAMP production （P 〈 0.05）, and both 17β-estradiol （10-9 mol L-1） and forskolin, which increases cAMP levels, induced cell proliferation and activated ERK1/2 （P〈 0.05）. Rp-cAMP, an antagonist of cAMP, blocked this 17β-estradiol activity （P〈 0.05）. Two estrogen receptor antagonists, ICI 182780 and ERβ antagonist （ERβAnt）, reduced Sertoli cell number, cAMP production and ERK1/2 activation （P〈 0.05）, but ERaAnt did not （P〉 0.05）. Therefore, 17β- estradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.

phytoestrogens/insoluble fibers and colonic estrogen receptor β: randomized, double-blind, placebo-controlled study

AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.

Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl4-induced liver cirrhosis

AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female Sprague-Dawley rats were ovariectomized(OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin(HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction(q RT-PCR). Collagengel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance(IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of Rho A and ROCK Ⅱ, and even suppressed ROCK Ⅱ activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase(e NOS) and phosphorylated e NOS, and promoted the activities of protein kinase G(PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK Ⅱ activity in activated HSCs. Finally, in vivo /in vitro experiments demonstrated that MLC activity was inhibited by DPN.CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver Rho A/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.

Association between estrogen receptor β gene Rsa1 polymorphism and depressive disorder in peri-menopausal and menopausal women

Objective: To investigate estrogen receptor β (ERβ) gene Rsa1 polymorphism and concentration of estrogen, FSH and LH in serum in peri-menopausal and menopausal women with depressive disorder. Methods: Seventy-four peri-menopausal and menopausal women with depressive disorder met ICD-10 and CCMD-3 assessment criteria for depressive disorder were recruited. ERβ gene Rsa1 polymorphism was analyzed with PCR-RFLP. Serum levels of estrogen, FSH and LH were measured by magnetism-ELISA. Results: The respective frequency of ERβ gene Rsa1 polymorphism was no significant difference between women with depressive disorder and the healthy women (χ 2=1.106,P>0.05). The serum level of estrogen was lower in women with depressive disorder than in the healthy women (P<0.05). No difference was found for FSH and LH between two groups. Conclusion: ERβ gene Rsa1 polymorphism may be not associated with depressive disorder in the peri-menopausal and menopausal women. The serum level of estrogen is associated with depressive disorder in the peri-menopausal and menopausal women.

Placental expressions of estrogen receptor α,estrogen receptor β in intrahepatic cholestasis of pregnancy

Objective:To investigate the association of the expression of estrogen receptor α,estrogen receptor β in placenta with intrahepatic cholestasis of pregnancy(ICP) susceptibility.Methods:In 14 cases of mild ICP,14 cases of severe ICP and 14 cases of normal cases(control group) with corresponding age and gestation weeks,the expressions of ERα and ERβ were detected by means of immunohistochemical method S-P.Results:The mean grey numbers of ERα in each group mentioned above were 151.68±3.76,149.85±3.69,153.18±3.18,without significant difference(P>0.05).The mean grey numbers of ERβ in each group mentioned above were 146.51±3.81,139.43±9.97,149.87±4.17,with significant difference(P>0.05);the expression of ERβ of severe ICP group was significantly higher than that of the mild ICP group and the control group(P<0.05).The expression of ERβ in every group was higher than that of ERα(P<0.05).Conclusion:ERβ maybe play an important part in the etiology and development of ICP.

17β-Estradiol Regulates SKP2 Expression in Cultured Immature Boar Sertoli Cells Mainly via Estrogen Receptor β,cAMP-PKA and ERK1/2

Estrogen plays an important role in regulating testicular Sertoli cell number. Furthermore, S-phase kinase-associated protein 2 （SKP2） plays a central role in mammalian cell cycle progression. The objective of this study was to determine whether 17β-estradiol can regulate the expression of SKP2, and the Sertoli cell cycle, via estrogen receptor β （ERβ）, the cyclic adenosine monophosphate （cAMP）-protein kinase A （PKA） and extracellular signal-regulated kinase （ERK1/2） pathway. When cultured immature boar Sertoli cells were treated with 17β-estradiol, a time-dependent increase in SKP2 mRNA and protein level was observed by real-time PCR and Western blot, and 17β-estradiol activity peaked at 30 min. Treatment with ICI182780 and ERβ antagonist reduced 17β-estradiol-induced expression of SKP2 and proliferating cell nuclear antigen （PCNA）, while increasing the protein concentration of p27kip1. However, the effect of ERa antagonist on these parameters was lower than that of ICI 182780 and ERβ. Forskolin had a similar effect as 17β-estradiol on the expression of SKP2, PCNA and p27kip1, Rp-cAMP, H-89 and U0126 treatment reduced 17β-estradiol-induced changes, while H-89 also inhibited ERK1/2 activation. Therefore, 17β-estradiol mainly regulates SKP2 mRNA and protein expression via ERβ-cAMP-PKA and ERK1/2 activation. SKP2 and PCNA expression were positively correlated, while increased SKP2 expression likely resulted in p27kip1 degradation.

Estrogen Receptor β of Host Promotes the Progression of Lung Cancer Brain Metastasis of an Orthotopic Mouse Model

Estrogen receptors (ERα and ERβ) in the brain play critical roles in maintaining brain tissue homeostasis and in tissue repair after injury. Growth of cancer metastasis in the brain is a constant damaging process. The role of ERs of the host in the progression of cancer brain metastasis is unknown. To determine the role of ERβ of host in the progression of lung cancer brain metastasis, we used an isogenic murine lung cancer cell line, Lewis lung carcinoma cells (3LL), to produce orthotopic lung cancer brain metastases in wild type and ERβ knockout (ERβ-/-) mice. In the wild type mice, we found that ERα and ERβ appeared in the tumor associated reactive astrocytes at 24hr after injection of tumor cells, and ERβ remained thereafter while ERα disappeared after 1 week. The metastasis bearing ERβ-/- mice survived significantly longer than the wild type mice. To further test the role of ERβ of reactive astrocytes in the survival of cancer cells, we knocked down ERβ in cultured actrocytes using shRNA and performed 3D co-culture with 3LL cells in the presence/absence of chemotherapeutic agents, oxaliplatin and 5-fluorouracil. We found that loss of ERβ in astrocytes significantly reduced the survivability of 3LL cells co-cultured with astrocytes. It is concluded that ERβ of host, especially ERβ in reactive astrocytes, promotes the progression of lung cancer brain metastasis and ERβ might be a potential therapeutic target for lung cancer brain metastasis.

Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain malignancies.In contrast,ERβis more broadly expressed in metabolic tissues and the skin.Thus,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERαactivation.Here,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or genistein.Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in vitro.We further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound healing.Therefore,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

P2Y1 receptor in Alzheimer’s disease

Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.

Does local vaginal estrogen after tension-free transobturator vaginal tape reduce overactive bladder symptoms in postmenopausal women? A prospective randomized, controlled study

Objective:We aimed to evaluate the efficacy of topical estrogen after transvaginal tension-free vaginal tape-obturator(TVT-O)in the treatment of de novo overactive bladder symptoms that appear after surgery.Methods:This is a prospective randomized controlled study performed in the Urology and Gynecology Departments,Kasr Al Ainy Hospital,Cairo University,Cairo,Egypt.Two hundred and ten postmenopausal females presenting during the period between January 2017 and November 2020 with stress urinary incontinence were included in the study.Patients were divided into two groups,105 patients in Group A(treatment group)and 105 patients in Group B(control group).Patients in Group A underwent transvaginal TVT-O followed by local vaginal estrogen treatment for 6 months,while patients in Group B underwent transvaginal TVT-O only.The study included any postmenopausal female with urodynamic stress urinary incontinence.All patients had to fulfill a 3-day bladder diary,overactive bladder symptoms score,urine analysis,urodynamic study,and post-voiding residual urine measurement by abdominal ultrasound preoperatively and at 3-month and 6-month follow-ups.Results:At 6-month follow-up,daytime frequency was reduced to 8%in Group A(increased to 21%in Group B)with a statistically significant difference between both groups(p=0.009).At 6-month follow-up,nocturia was 8%in Group A(11%in Group B)with no statistically significant difference between both groups(p=0.469).There was a statistically significant difference between both groups as regards to urinary urgency at 6-month follow-up(p=0.024).There was a statistically significant difference in postoperative wound healing events as regards to cure,hyperemia,gapping,and wound infection 1 week after intervention between both groups(p=0.008).No local or systemic side-effects were reported from local estrogen use.Conclusion:Local vaginal estrogen treatment given to postmenopausal patients after midurethral sling procedures can reduce the symptoms of daytime frequency and urinary urgency.Long-term follow-up is needed.

Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

Melanocortin 3,5 receptors immunohistochemical expression in colonic mucosa of inflammatory bowel disease patients:A matter of disease activity?

BACKGROUND Melanocortin 3 and 5 receptors(i.e.,MC3R and MC5R)belong to the melanocortin family.However,data regarding their role in inflammatory bowel diseases(IBD)are currently unavailable.AIM This study aims to ascertain their expression profiles in the colonic mucosa of Crohn’s disease(CD)and ulcerative colitis(UC),aligning them with IBD disease endoscopic and histologic activity.METHODS Colonic mucosal biopsies from CD/UC patients were sampled,and immunohisto-chemical analyses were conducted to evaluate the expression of MC3R and MC5R.Colonic sampling was performed on both traits with endoscopic scores(Mayo endoscopic score and CD endoscopic index of severity)consistent with inflamed mucosa and not consistent with disease activity(i.e.,normal appearing mucosa).RESULTS In both CD and UC inflamed mucosa,MC3R(CD:+7.7 fold vs normal mucosa,P<0.01;UC:+12 fold vs normal mucosa,P<0.01)and MC5R(CD:+5.5 fold vs normal mucosa,P<0.01;UC:+8.1 fold vs normal mucosa,P<0.01)were significantly more expressed compared to normal mucosa.CONCLUSION MC3R and MC5R are expressed in the colon of IBD patients.Furthermore,expression may differ according to disease endoscopic activity,with a higher degree of expression in the traits affected by disease activity in both CD and UC,suggesting a potential use of these receptors in IBD pharmacology.

Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

Estrogen restores disordered lipid metabolism in visceral fat of prediabetic mice

BACKGROUND Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes.Estrogen[17β-estradiol(E2)]is known to offer protection against obesity via diverse me-chanisms,while its specific effects on visceral adipose tissue(VAT)remain to be fully elucidated.AIM To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes.METHODS Metabolic parameters were collected,encompassing body weight,weights of visceral and subcutaneous adipose tissues(VAT and SAT),random blood glucose levels,glucose tolerance,insulin tolerance,and overall body composition.The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software.Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses,respectively.RESULTS Feeding a high-fat diet(HFD)moderately increased the weights of both VAT and SAT,but this increase was mitigated by the protective effect of endogenous E2.Conversely,ovariectomy(OVX)led to a significant increase in VAT weight and the VAT/SAT weight ratio,and this increase was also reversed with E2 treatment.Notably,OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone,signaling a widespread reduction in lipid metabolic activity,which was completely counteracted by E2 adminis-tration.This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level.CONCLUSION In conclusion,the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat,leading to a universally decreased lipid metabolic status in E2 deficient mice.E2 treatment effectively reversed this condition,shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

Glucagon-like peptide 1 receptor activation:anti-inflammatory effects in the brain

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migraine.

Atropine can induce autophagy independent of the M3 muscarinic acetylcholine receptor

Background: No other effects of atropine other than as an antagonist of muscarinic acetylcholine receptor (mAChR) have been found. Methods: In this study, human kidneyepithelial cells were treated with different physiological regulators. Results: Subsequently, it was found that atropine could significantly induce autophagy as demonstrated by the appearance of autophagosome-like double- or single-membrane vesicles in the cytoplasm ofhost cells and the number of GFP-LC3 dots. In addition, increased conversion of the autophagy marker protein LC3-I and LC3-II and increased p62/SQSTM1 indicatedincomplete autophagy. In addition, atropine induced autophagosome levels in a dose-dependent manner within a certain concentration range in human kidney epithelial cells. In atropine-treated mouse skeletal muscle cells containing nicotinic acetylcholinereceptors and rat cardiac muscle cells containing mAchR, atropine induced autophagy in mouse skeletal muscle cells but not in rat cardiac muscle cells. Furthermore, atropine did not induce autophagy in tissue cells containing mAchR in vivo but did in tissue cells not containing mAchR. Conclusion: This study expands the application and understanding of atropine’s action mechanism in the field of medicine.

Role of bitter contributors and bitter taste receptors:a comprehensive review of their sources,functions and future development

Bitterness,one of the 5“basic tastes”,is usually undesired by humans.However,abundant literature reported that bitter fruits and vegetables have beneficial health effects due to their bitter contributors.This review provided an updated overview of the main bitter contributors of typical bitter fruits and vegetables and their health benefits.The main bitter contributors,including phenolics,terpenoids,alkaloids,amino acids,nucleosides and purines,were summarized.The bioactivities and wide range of beneficial effects of them on anti-cancers,anti-inflammations,anti-microbes,neuroprotection,inhibiting chronic and acute injury in organs,as well as regulating behavior performance and metabolism were reported.Furthermore,not only did the bitter taste receptors(taste receptor type 2 family,T2Rs)show taste effects,but extra-oral T2Rs could also be activated by binding with bitter components,regulating physiological activities via modulating hormone secretion,immunity,metabolism,and cell proliferation.This review provided a new perspective on exploring and explaining the nutrition of bitter foods,revealing the relationship between the functions of bitter contributors from food and T2Rs.Future trends may focus on revealing the possibility of T2Rs being targets for the treatment of diseases,exploring the mechanism of T2Rs mediating the bioactivities,and making bitter foods more acceptable without getting rid of bitter contributors.

Precision targeting in hepatocellular carcinoma:Exploring ligandreceptor mediated nanotherapy

Hepatocellular carcinoma(HCC)is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality.Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages,but it is often ineffective and suffers from problems such as multidrug resistance,rapid drug clearance,nonspecific targeting,high side effects,and low drug accumulation in tumor cells.In response to these limitations,recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC.This review focuses on recent advances in nanoparticle-based targeted drug delivery systems,with special attention to various receptors overexpressed on HCC cells.These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC.We comprehensively summarize the current understanding of these receptors,their role in nanoparticle targeting,and the impact of such targeted therapies on HCC.By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies,more effective and precise treatment of HCC can be achieved.