RESUMO
Anxiety and depression caused by inflammatory bowel disease (IBD) negatively affect the mental health of patients. Emerging studies have demonstrated that the gut-brain axis (GBA) mediates IBD-induced mood disorders, but the underlying mechanisms of these findings remain unknown. Therefore, it's vital to conduct comprehensive research on the GBA in IBD. Multi-omics studies can provide an understanding of the pathological mechanisms of the GBA in the development of IBD, helping to uncover the mechanisms underlying the onset and progression of the disease. Thus, we analyzed the prefrontal cortex (PFC) of Dextran Sulfate Sodium Salt (DSS)-induced IBD mice using transcriptomics and metabolomics. We observed increased mRNA related to acetylcholine synthesis and secretion, along with decreased phosphatidylcholine (PC) levels in the PFC of DSS group compared to the control group. Fecal metagenomics also revealed abnormalities in the microbiome and lipid metabolism in the DSS group. Since both acetylcholine and PC are choline metabolites, we posited that the DSS group may experience choline deficiency and choline metabolism disorders. Subsequently, when we supplemented CDP-choline, IBD mice exhibited improvements, including decreased anxiety-like behaviors, reduced PC degradation, and increased acetylcholine synthesis in the PFC. In addition, administration of CDP-choline can restore imbalances in the gut microbiome and disruptions in lipid metabolism caused by DSS treatment. This study provides compelling evidence to suggest that choline metabolism plays a crucial role in the development and treatment of mood disorders in IBD. Choline and its metabolites appear to have a significant role in maintaining the stability of the GBA.
Assuntos
Colite , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Colite/induzido quimicamente , Colite/patologia , Eixo Encéfalo-Intestino , Acetilcolina , Multiômica , Transtornos de Ansiedade , Colina , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung diseases, which mainly existed in middle-aged and elderly people. The accumulation of reactive oxygen species (ROS) is a common characteristic of IPF. Previous research also shown that lactate levels can be abnormally elevated in IPF patients. Emerging evidence suggested a relationship between lactate and ROS in IPF which needs further elucidation. In this article, we utilized a mouse model of BLM-induced pulmonary fibrosis to detect alterations in ROS levels and other indicators associated with fibrosis. Lactate could induce mitochondrial fragmentation by modulating expression and activity of DRP1 and ERK. Moreover, Increased ROS promoted P65 translocation into nucleus, leading to expression of lung fibrotic markers. Finally, Ulixertinib, Mdivi-1 and Mito-TEMPO, which were inhibitor activity of ERK, DRP1 and mtROS, respectively, could effectively prevented mitochondrial damage and production of ROS and eventually alleviate pulmonary fibrosis. Taken together, these findings suggested that lactate could promote lung fibrosis by increasing mitochondrial fission-derived ROS via ERK/DRP1 signaling, which may provide novel therapeutic solutions for IPF.
Assuntos
Dinaminas , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial , Espécies Reativas de Oxigênio , Animais , Espécies Reativas de Oxigênio/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Dinaminas/metabolismo , Bleomicina , Transdução de Sinais , Ácido Láctico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Mitocôndrias/metabolismo , Masculino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Camundongos , HumanosRESUMO
Executive function is an underlying mechanism linking family socioeconomic status (SES) and academic achievement. Previous studies mainly investigated either the mediating or moderating role of executive function within this relationship, which either overlook the individual differences that are independent of the environment or neglect the influence of the environment on shaping personal factors. To avoid a piecemeal approach to theory, the current study aimed to test the mediating and moderating roles of executive function in a single analytic model. Two hundred and thirty-six Chinese fifth graders (Mage = 10.70 years, SD = 0.49, range = 10.23-11.75 years, and 40.30% girls) were recruited. Their executive function performance was measured using eight different tasks, and their Chinese literacy skills and mathematics achievement were assessed by routine school evaluations. One year after the initial assessment, children's academic achievements were evaluated again. Results demonstrated that parental SES positively predicted children's academic achievement when controlling for prior academic achievement, and children's executive function mediated this relationship. Also, executive function moderated the association between SES and academic achievement in that, the negative predictive effect of low SES on academic achievement was only significant for children with lower levels of executive function, which is not shown in children with higher levels of executive function. By demonstrating the dual roles of executive function in the SES-achievement link, this work provides evidence for supporting the optimal development of children from diverse socioeconomic backgrounds and emphasizes the significance of developing individualized intervention strategies on executive function to mitigate the negative effect of low SES on children's academic achievement.
Assuntos
Sucesso Acadêmico , Função Executiva , Classe Social , Humanos , Feminino , Masculino , Criança , ChinaRESUMO
Purpose: Through network pharmacology combined with molecular docking and in vivo validation, the study examines the unexplored molecular mechanisms of Tongxieyaofang (TXYF) in the treatment of irritable bowel syndrome (IBS). In particular, the potential pharmacological mechanism of TXYF alleviating IBS by regulating CHRM3 and intestinal barrier has not been studied. Patients and Methods: LC-MS technique and TCMSP database were used in combination to identify the potential effective components and target sites of TXYF. Potential targets for IBS were obtained from Genecards and OMIM databases. PPI and cytoHub analysis for targets. Molecular docking was used to validate the binding energy of effective components with related targets and for visualization. GO and KEGG analysis were employed to identify target functions and signaling pathways. In the in vivo validation, wrap restraint stress-induced IBS model was employed to verify the change for cytoHub genes and CHRM3 expression. Furthermore, inflammatory changes of colon were observed by HE staining. The changes of Ach were verified by ELISA. IHC and WB validated CHRM3 and GNAQ/PLC/MLCK channel variations. AB-PAS test and WB test confirmed the protection of TXYF on gut barrier. The NF-κB/MLCK pathway was also verified. Results: In TXYF decoction, LC-MS identified 559 chemical components, with 23 remaining effective components after screening in TCMSP. KEGG analysis indicated that calcium plays a crucial role in TXYF treated for IBS. Molecular docking validated the binding capacity of the effective components Naringenin and Nobiletin with cytoHub-gene and CHRM3. In vivo validation demonstrated that TXYF inhibits the activation of Ach and CHRM3 in IBS, and inhibits for the GNAQ/PLC/MLCK axis. Additionally, TXYF downregulates TNF-α, MMP9, and NF-κB/MLCK, while modulating goblet cell secretion to protect gut barrier. Conclusion: TXYF inhibits Ach and CHRM3 expression, regulating the relaxation of intestinal smooth muscle via GNAQ/PLC/MLCK. Additionally, TXYF inhibits NF-κB/MLCK activated and goblet cell secretion to protect gut barrier.
Assuntos
Medicamentos de Ervas Chinesas , Síndrome do Intestino Irritável , Simulação de Acoplamento Molecular , Receptor Muscarínico M3 , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Animais , Receptor Muscarínico M3/metabolismo , Receptor Muscarínico M3/antagonistas & inibidores , Humanos , Masculino , Ratos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Ratos Sprague-Dawley , Farmacologia em RedeRESUMO
Although previous studies have indicated that statin therapy can effectively prevent the development of CIN, this observation remains controversial, especially in high-risk patients. A meta-analysis was performed to evaluate the efficacy of statin pretreatment for preventing the development of CIN in patients with chronic kidney disease (CKD) and to determine its effectiveness in various subgroups. We searched the online databases PubMed, EMBASE, and the Cochrane Library. RCTs that involved the comparison of the short-term moderate or high-dose statin pretreatment with placebo for CIN prevention in CKD patients undergoing angiography were included. The primary outcome was CIN prevalence. Seven RCTs comprising 4256 participants were investigated in this analysis. The risk of developing CIN in patients pretreated with statins was significantly lower than that in patients pretreated with placebo (RR=0.57, 95%CI=0.43-0.76, p=0.000). The SCr values of the statin group, when analyzed 48h after angiography were lower than those of the placebo group ((SMD=-0.15, 95% CI=-0.27 to -0.04, p=0.011). In the subgroup analysis, statin pretreatment could decrease the risk of CIN in CKD patients with DM (RR=0.54, 95% CI=0.39-0.76, p=0.000), but not in CKD patients without DM (RR=0.84, 95% CI=0.44-1.60, p=0.606). The efficacy of atorvastatin for preventing CIN was consistent with that observed with the use of rosuvastatin. The risk ratios (RR) were 0.51 (95% CI=0.32-0.81, p=0.004) and 0.60 (95% CI=0.41-0.88, p=0.009), respectively. Our study demonstrated that statin pretreatment could prevent the development of CIN in CKD patients. However, subgroup analysis demonstrated that statin pretreatment, despite being effective in preventing CIN in patients with CKD and DM, was not helpful for CKD patients without DM. Rosuvastatin and atorvastatin exhibited similar preventive effects with respect to CIN.