RESUMO

The incidence of germinal center B-cell-like type diffuse large B-cell lymphoma (GCB DLBCL) is steadily increasing, with a known hereditary component. Although some molecular mechanisms in GCB DLBCL have been elucidated, understanding remains incomplete, limiting the effectiveness of targeted therapies. In GCB DLBCL patients, abnormally high expression of zeste homologs 2 (EZH2) is noted, and the compensatory effect of EZH1 following EZH2 inhibition contributes to poor prognosis. This highlights the potential of dual targeting of EZH1/2 as a promising strategy. In this study, we developed a novel inhibitor, EZH-1-P2, targeting EZH1/2, and evaluated its anti-tumor effects on DLBCL cells. Mechanistically, inhibition of EZH1/2 affects the epigenetic regulation of gene expression related to p53, impacting cell cycle progression and GCB DLBCL cell growth. Additionally, while EZH1/2 inhibition impacts NOTCH signaling, the precise mechanism by which it affects M2-type tumor-associated macrophage (M2-TAM) polarization and germinal center expansion requires further investigation. Our research introduces EZH-1-P2 as a novel inhibitor with potential as a candidate for GCB DLBCL therapy, although further studies are needed to fully elucidate its mechanisms.

RESUMO

Metabotropic glutamate receptor 4 (mGluR4) is widely regarded as an umami receptor activated by L-glutamate to exert essential functions. Numerous studies have shown that umami receptors participate in food intake regulation. However, little is known about mGluR4's role in mediating food ingestion and its possible molecular mechanism. Mandarin fish, a typical carnivorous fish, is sensitive to umami substances and is a promising vertebrate model organism for studying the umami receptor. In this study, we identified the mGluR4 gene and conducted evolutionary analyses from diverse fish species with different feeding habits. mGluR4 of mandarin fish was cloned and functionally expressed to investigate the effects of L-glutamate on mGluR4. We further explored whether the signal pathway mGluR4-Ca2+-ERK1/2 participates in the process in mandarin fish brain cells. The results suggest that L-glutamate could regulate Neuropeptide Y (Npy) via the mGluR4-Ca2+-ERK1/2 signaling pathway in mandarin fish. Our findings unveil the role of mGluR4 in feeding decisions and its possible molecular mechanisms in carnivorous fishes.

Assuntos

Proteínas de Peixes , Ácido Glutâmico , Sistema de Sinalização das MAP Quinases , Neuropeptídeo Y , Receptores de Glutamato Metabotrópico , Animais , Sequência de Aminoácidos , Cálcio/metabolismo , Proteínas de Peixes/metabolismo , Proteínas de Peixes/genética , Peixes/metabolismo , Peixes/genética , Ácido Glutâmico/metabolismo , Neuropeptídeo Y/metabolismo , Neuropeptídeo Y/genética , Perciformes/metabolismo , Perciformes/genética , Filogenia , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/genética

RESUMO

Developing sustainable, efficient, and selective gold recovery technology is essential to implement the valorization of complementary alternative sources for this precious metal, such as spent e-waste, and to preserve the environment. The main challenge in recovering gold from liquors obtained from leached waste electronics is the low concentration of this precious metal compared to impurities. Here, we report the preparation of a novel multivariate biological metal-organic framework (MTV-BioMOF) as a potential material for the selective recovery of gold metal ions from water, even in the presence of other interfering metals. Moreover, MTV-BioMOF can be incorporated within single-walled carbon nanotube buckypapers (SWCNT-BP) to yield an MTV-BioMOF@HS-SWCNT-BP composite, which combines enhanced mechanical properties and high chemical stability. The thiol-functionalized SWCNT-BP surface and the presence of thioether groups evenly decorating the MTV-BioMOF channels shape a task-specific functional environment that boosts the interactions with gold metal ions. The efficiency of gold recovery reaches values up to 99.5% when MTV-BioMOF@SWCNT-BP is used as an adsorbent for treating Au(III) in very diluted solutions (initial concentration of 5 ppm). This high recovery efficiency, with values as high as 98.0%, is maintained even in the presence of competing metal cations, also demonstrating a noticeable selectivity. This composite material represents a promising paradigm for the selective extraction, enrichment, and purification of gold.

RESUMO

OBJECTIVE: To evaluate the effect of multiple single cannulation technique on the complications of arteriovenous fistula. METHODS: A comprehensive literature search was conducted to investigate the impact of multiple single cannulation technique on the complications of arteriovenous fistula. The search was performed in both Chinese and English databases including Wanfang Medicine, China National Knowledge Infrastructure, Vip, Pubmed, Embase, and The Cochrane Library, with a search period up to December 20, 2023. Following literature screening and data extraction, the quality of the included studies was assessed using the Cochrane Bias Assessment Tool for Randomized Controlled Trials. Statistical analysis was performed using Review Manager version 5.3. RESULTS: Thirteen papers, totaling 1299 patients, were included in the analysis. The experimental group consisted of 646 patients, while the control group had 595 patients. The meta-analysis revealed that the multiple single cannulation technique was more effective than rope ladder cannulation and buttonhole cannulation in reducing the incidence of angiomas (odds ratio [OR] = 0.19; 95% confidence interval [CI] = 0.10-0.35), stenosis (OR = 0.22; 95% CI 0.13-0.39), thrombosis (OR = 0.17; 95% CI = 0.07-0.39), and blood seepage (OR = 0.13; 95% CI = 0.08-0.21) of arteriovenous fistulas (P < .05). Additionally, it was found to increase the success rate of nurses' single cannulation (OR = 4.20; 95% CI = 1.78-9.95) of arteriovenous fistulas (P < .05). CONCLUSION: Multiple single cannulation technique could effectively reduce the incidence of complications of arteriovenous fistula, improve the success rate of cannulation, prolong the life span of arteriovenous fistula, and prolong the survival cycle of hemodialysis patients.

Assuntos

Derivação Arteriovenosa Cirúrgica , Cateterismo , Humanos , Derivação Arteriovenosa Cirúrgica/métodos , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Cateterismo/métodos , Cateterismo/efeitos adversos , Diálise Renal/métodos , Diálise Renal/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto

RESUMO

While online gaming has become a choice for relaxation and entertainment in today's digital age, Internet Gaming Disorder (IGD) has also become a widely concerning mental disorder. Nature connectedness has been found to effectively reduce addiction-related risks and alleviate symptoms of addictive behaviors. It is a relatively lacking but very important factor influencing psychological recovery and regulation in the digital society. This study aims to explore the relationship between nature connectedness and IGD, and the mediating roles of intolerance of uncertainty and desire thinking. A total of 571 young people voluntarily participated in the questionnaire survey. The results showed that: (1) nature connectedness was negatively correlated with IGD; (2) intolerance of uncertainty plays a mediating role between nature connectedness and IGD; and (3) intolerance of uncertainty and desire thinking plays a chain mediating role between nature connectedness and IGD. Analysis of the research results indicates that nature connectedness can effectively reduce IGD and reveal its mechanism of action. The findings provide new insights for the study and intervention of IGD in the digital age.

RESUMO

Triclosan (TCS) is an eminent antibacterial agent. However, extensive usage causes potential health risks like hepatotoxicity, intestinal damage, kidney injury, etc. Existing studies suggested that TCS would disrupt bile acid (BA) enterohepatic circulation, but its toxic mechanism remains unclear. Hence, the current study established an 8-week TCS exposure model to explore its potential toxic mechanism. The results discovered 8 weeks consecutive administration of TCS induced distinct programmed cell death, inflammatory cell activation and recruitment, and excessive BA accumulation in liver. Furthermore, the expression of BA synthesis and transport associated genes were significantly dysregulated upon TCS treatment. Additional mechanism exploration revealed that Fxr inhibition induced by TCS would be the leading cause for unusual BA biosynthesis and transport. Subsequent Fxr up-stream investigation uncovered TCS exposure caused pyroptosis and its associated IL-1ß would be the reason for Fxr reduction mediated by NF-κB. NF-κB blocking by dimethylaminoparthenolide ameliorated TCS induced BA disorder which confirmed the contribution of NF-κB in Fxr repression. To sum up, our findings conclud TCS-caused BA disorder is attributed to Fxr inhibition, which is regulated by the IL-1ß-NF-κB signaling pathway. Hence, we suggest Fxr would be a potential target for abnormal BA stimulated by TCS and its analogs.

Assuntos

Ácidos e Sais Biliares , Interleucina-1beta , NF-kappa B , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Triclosan , Triclosan/toxicidade , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Camundongos , Masculino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Anti-Infecciosos Locais/toxicidade

RESUMO

With the abuse of antibiotics, multidrug resistant strains continue to emerge and spread rapidly. Therefore, there is an urgent need to develop new antimicrobial drugs. As a highly conserved cell division protein in bacteria, filamenting temperature-sensitive mutant Z (FtsZ) has been identified as a potential antimicrobial target. This paper reviews the structure, function, and action mechanism of FtsZ and a variety of natural and synthetic compounds targeting FtsZ, including 3-MBA derivatives, taxane derivatives, cinnamaldehyde, curcumin, quinoline and quinazoline derivatives, aromatic compounds, purpurin, and totarol. From these studies, FtsZ has a clear supporting role in the field of antimicrobial drug discovery. The urgent need and interest of antibacterial drugs will contribute to the discovery of new clinical drugs targeting FtsZ.

RESUMO

This comprehensive meta-analysis aimed to assess the effectiveness of digital interventions in improving developmental skills for children and adolescents with autism spectrum disorder (ASD). We conducted a systematic literature search based on three databases. A pre-test adjusted between-group standardized effect size was computed for effect size synthesis. We utilized a robust variance estimation model to analyze overall treatment effect. Moderator analyses and publication bias were also addressed. Twenty-eight studies (150 effect sizes) using randomized control trials (RCT; n = 22) or quasi-experimental designs (QED; n = 6) were included. Most studies (n = 22) included social-emotional skills as primary outcomes. The meta-analysis revealed a medium to large overall effect size, with Hedges' g = 0.62, 95% CI [0.36, 0.88], p < 0.001. We found that digital interventions have a statistically significantly large effect on enhancing social-emotional skills compared with language and communication skills, cognitive skills, daily living skills, and physical skills. The results of moderator analyses indicated that computer-based interventions have larger effect sizes in comparison to tablet/smartphone-based interventions. No statistically significant differences were observed between studies utilizing RCT and those using QED. We recommended the integration of digital interventions as supplemental resources in behavioral and educational interventions. Further research needs to focus on more females, young children, and adolescents with ASD in digital intervention research.

RESUMO

Background: Limited epidemiological evidence suggests that exposure to trace elements adversely impacts the development of gastric precancerous lesions (GPL) and gastric cancer (GC). This study aimed to estimate the association of individual urinary exposure to multiple elements with GPL and GC. Methods: A case-control investigation was conducted in Anhui Province from March 2021 to December 2022. A total of 528 subjects (randomly sampled from 1,020 patients with GPL, 200 patients with GC, and 762 normal controls) were included in our study. Urinary levels of iron (Fe), copper (Cu), zinc (Zn), nickel (Ni), strontium (Sr), and Cesium (Cs) were measured using inductively coupled plasma mass spectrometry (ICP-MS). Four different statistical approaches were employed to explore the risk of GPL and GC with mixed exposure, including multivariate logistic regression, weighted quantile regression (WQS), quantile g-computation (Qgcomp), and the Bayesian kernel machine regression (BKMR) model. Results: The WQS model indicated that urinary exposure to a mixture of elements is positively correlated with both GPL and GC, with ORs for the mixture exposure of 1.34 (95% CI: 1.34-1.61) for GPL and 1.38 (95% CI: 1.27-1.50) for GC. The Qgcomp and BKMR models also demonstrated a statistically significant positive correlation between the mixture and both GPL and GC. Conclusion: Considering the limitations of case-control studies, future prospective studies are warranted to elucidate the combined effects and mechanisms of trace elements exposure on human health.

Assuntos

Lesões Pré-Cancerosas , Neoplasias Gástricas , Oligoelementos , Humanos , Neoplasias Gástricas/urina , Neoplasias Gástricas/epidemiologia , China/epidemiologia , Masculino , Oligoelementos/urina , Feminino , Estudos de Casos e Controles , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/urina , Idoso , Adulto

RESUMO

The corticostriatal connection plays a crucial role in cognitive, emotional, and motor control. However, the specific roles and synaptic transmissions of corticostriatal connection are less studied, especially the corticostriatal transmission from the anterior cingulate cortex (ACC). Here, a direct glutamatergic excitatory synaptic transmission in the corticostriatal projection from the ACC is found. Kainate receptors (KAR)-mediated synaptic transmission is increased in this corticostriatal connection both in vitro and in vivo seizure-like activities. GluK1 containing KARs and downstream calcium-stimulated adenylyl cyclase subtype 1 (AC1) are involved in the upregulation of KARs following seizure-like activities. Inhibiting the activities of ACC or its corticostriatal connection significantly attenuated pentylenetetrazole (PTZ)-induced seizure. Additionally, injection of GluK1 receptor antagonist UBP310 or the AC1 inhibitor NB001 both show antiepileptic effects. The studies provide direct evidence that KARs are involved in seizure activity in the corticostriatal connection and the KAR-AC1 signaling pathway is a potential novel antiepileptic strategy.

RESUMO

Acute kidney injury (AKI) presents as a condition marked by a sudden and rapid decrease in kidney function over a short timeframe, resulting from diverse causes. As a transcription factor, PR domain-containing 16 (PRDM16), has recently been implicated in brown fat biogenesis and heart diseases. Our recent works indicated that PRDM16 could suppress the occurrence of renal interstitial fibrosis in diabetic kidney disorder. Nonetheless, the effect and regulatory mechanism of PRDM16 in AKI remain elusive. Our study demonstrated that PRDM16 inhibited apoptosis induced by ischemic/reperfusion (I/R) in BUMPT (Boston University mouse kidney proximal tubular) cells and HK-2(Human Kidney-2) cells. Mechanistically, PRDM16 not only bound to the promoter region of S100 Calcium Binding Protein A6 (S100A6)and upregulated its expression but also interacted with its amino acids 945-949, 957-960, and 981-984 to suppress the p38MAPK and JNK axes via inhibition of PKC-η activity and mitochondrial reactive oxygen species (ROS) production. Furthermore, cisplatin- and I/R-stimulated AKI progression were ameliorated in PRDM16 proximal-tubule-specific knockin mice, whereas exacerbated in PRDM16 knockout proximal-tubule-specific mice). Moreover, we observed that formononetin ameliorated I/R- and cisplatin-triggered AKI progression in mice. Taken together, these findings reveal a novel self-protective mechanism in AKI, whereby PRDM16 regulates the S100A6/PKC-η/ROS/p38MAPK and JNK pathways to inhibit AKI progression.

RESUMO

Biomaterial-based solar-driven evaporation has great potential for wastewater treatment and seawater desalination with a high energy conversion and utilization efficiency. However, technology gaps still exist for effectively and directly applying multiscale structures and intrinsic water transport channels of natural materials to enhance high-efficiency photothermal evaporation. In this study, a high-performance biomass-derived photothermal evaporative material was obtained using Salvinia natans, a common aquatic floating plant, together with simple poly(m-phenylenediamine) oxidation modification, building a hybrid biomass evaporator. With advantageous natural features of adequate water transport, microscale-nanoscale hierarchical structures, effective water activation, and antisalt-fouling function, the hybrid biomass evaporator achieves a high evaporation rate of 2.24 kg m-2 h-1 under one sun radiation (1 kW m-2). In addition, modified Salvinia natans also demonstrate certain ability to remove heavy metals during the photothermal evaporation of wastewater. This work offers a new perspective on the synthesis of an environmentally friendly and cost-effective solar-driven evaporator material, which has the advantages of low cost, simple process, and high photothermal conversion efficiency, and can be widely applied to seawater desalination and the treatment of wastewater with high salt concentrations.

RESUMO

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was -59.13 (-64.103, -54.153) (Adjusted p<0.0001) and -60.43 (-65.450, -55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.

Assuntos

Anticorpos Monoclonais Humanizados , LDL-Colesterol , Hipercolesterolemia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/efeitos adversos , China , LDL-Colesterol/sangue , Método Duplo-Cego , População do Leste Asiático , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9 , Resultado do Tratamento

RESUMO

Exosomes play a crucial role in various biological processes, such as human development, immune responses, and disease occurrence. The membrane proteins on exosomes are pivotal factors for their biological functionality. Currently, numerous membrane proteins have been identified on exosome membranes, participating in intercellular communication, mediating target cell recognition, and regulating immune processes. Furthermore, membrane proteins from exosomes derived from cancer cells can serve as relevant biomarkers for early cancer diagnosis. This article provides a comprehensive review of the composition of exosome membrane proteins and their diverse functions in the organism's biological processes. Through in-depth exploration of exosome membrane proteins, it is expected to offer essential foundations for the future development of novel biomedical diagnostics and therapies.

Assuntos

Exossomos , Proteínas de Membrana , Exossomos/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Animais , Neoplasias/imunologia , Neoplasias/metabolismo , Comunicação Celular , Biomarcadores Tumorais/metabolismo , Biomarcadores

RESUMO

The Yak (Bos grunniens) is a special breed of livestock predominantly distributed in the Qinghai-Tibet Plateau of China. Intramuscular fat (IMF) content in beef cattle is a vital indicator of meat quality. In this study, RNA-Seq and Protein-Seq were respectively employed to sequence the transcriptome and proteome of the longissimus dorsi (LD) tissue from 4-year-old yaks with significant differences in IMF content under the same fattening conditions. Five overlapping genes (MYL3, ACADS, L2HGDH, IGFN1, and ENSBGRG00000000-926) were screened using combined analysis. Functional verification tests demonstrated that the key gene ACADS inhibited yak intramuscular preadipocyte (YIMA) differentiation and proliferation, promoted mitochondrial biogenesis gene expression, and increased the mitochondrial membrane potential (MMP). Furthermore, co-transfection experiments further demonstrated that interfering with ACADS reversed the effect of PPARα agonists in promoting lipid differentiation. In conclusion, ACADS potentially inhibits lipid deposition in YIAMs by regulating the PPARα signalling pathway. These findings offer insights into the molecular mechanisms underlying yak meat quality.

Assuntos

Músculo Esquelético , Animais , Bovinos , Músculo Esquelético/metabolismo , Adipócitos/metabolismo , Adipócitos/citologia , Transcriptoma , Diferenciação Celular , Tecido Adiposo/metabolismo , Metabolismo dos Lipídeos , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Proteoma/metabolismo , Multiômica

RESUMO

INTRODUCTION: Acute kidney injury (AKI) is associated with increased mortality. AKI-related mortality trends by U.S. urban and rural counties were assessed. METHODS: In the cross-sectional study, based on the Centers for Disease Control and Prevention WONDER (Wide-ranging ONline Data for Epidemiologic Research) Multiple Cause of Death data, age-standardized mortality with AKI as the multiple cause was obtained among adults aged ≥25 years from 2001-2020, by age, sex, race and ethnicity, stratified by urban-rural counties. Joinpoint regressions were used to assess trends from 2001-2019 in AKI-related mortality rate. Pairwise comparison was used to compare mean differences in mortality between urban and rural counties from 2001-2019. RESULTS: From 2001-2020, age-standardized AKI-related mortality was consistently higher in rural than urban counties. AKI-related mortality (per 100,000 population) increased from 18.95 in 2001 to 29.46 in 2020 in urban counties and from 20.10 in 2001 to 38.24 in 2020 in rural counties. In urban counties, AKI-related mortality increased annually by 4.6% during 2001-2009 and decreased annually by 1.8% until 2019 (p<0.001). In rural counties, AKI-related mortality increased annually by 5.0% during 2001-2011 and decreased by 1.2% until 2019 (p<0.01). The overall urban-rural difference in AKI-related mortality was greater after 2009-2011. AKI-related mortality was significantly higher among older adults, men, and non-Hispanic Black adults than their counterparts in both urban and rural counties. Higher mortality was concentrated in rural counties in the Southern United States. CONCLUSIONS: Multidisciplinary efforts are needed to increase AKI awareness and implement strategies to reduce AKI-related mortality in rural and high-risk populations.

RESUMO

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Assuntos

Inibidores de Checkpoint Imunológico , Proteínas de Membrana , Miocardite , Nucleotidiltransferases , Piroptose , Animais , Miocardite/imunologia , Miocardite/patologia , Miocardite/induzido quimicamente , Miocardite/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Camundongos , Masculino , Humanos , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Transdução de Sinais , Camundongos Endogâmicos C57BL , Camundongos Knockout , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Feminino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Gasderminas

RESUMO

ABSTRACT: Menopausal and postmenopausal women, characterized by a significant reduction in ovarian hormones, have a high prevalence of chronic pain with great pain intensity. However, the underlying mechanism of hyperalgesia induced by ovarian hormone withdrawal remains poorly understood. Here, we report that decreases in the activity and excitability of GABAergic neurons in the dorsal raphe nucleus (DRN) are associated with hyperalgesia induced by ovariectomy in mice. Supplementation with 17ß-estradiol, but not progesterone, is sufficient to increase the mechanical pain threshold in ovariectomized (OVX) mice and the excitability of DRN GABAergic (DRNGABA) neurons. Moreover, activation of the DRNGABA neurons projecting to the lateral parabrachial nucleus was critical for alleviating hyperalgesia in OVX mice. These findings show the essential role of DRNGABA neurons and their modulation by estrogen in regulating hyperalgesia induced by ovarian hormone withdrawal, providing therapeutic basis for the treatment of chronic pain in physiological or surgical menopausal women.