Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Objectives: To elucidate the potential mechanisms of electroacupuncture (EA) in restoring detrusor-bladder neck dyssynergia (DBND) following suprasacral spinal cord injury (SSCI). Methods: A total of 52 specific pathogen-free (SPF) grade famale Sprague-Dawley (SD) rats (10 – 12 weeks, 250 – 280 g) were randomly assigned to either a sham group (n = 12) or a spinal cord injury model group (n = 40). In the model group, DBND was induced through Hassan Shaker spinal cord transection at T10 level, with 24 rats meeting inclusion criteria and subsequently randomized into DBND group (n = 12) and EA intervention group (DBND + EA group, n = 12). After spinal shock recovery (day 19 after modeling), DBND + EA group received EA treatment at Ciliao (BL32), Zhongji (RN3), and Sanyinjiao (SP6) acupoints for 20 min per session at 10/50 Hz frequencies, once daily for 10 d. Sham and DBND groups received anesthesia only without EA intervention. On day 29 post-modeling, all rats underwent urodynamic assessments, followed by hematoxylin and eosin (HE) staining, tandem mass tag (TMT) proteomics, and Western blot (WB) analysis of detrusor and bladder neck tissues. Differentially expressed proteins (DEPs) were defined as proteins with P < 0.05, unique peptides ≥ 2, and fold change > 1.2 or < 0.83. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using KOBAS 3.0 (P < 0.01), and protein-protein interaction (PPI) networks were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) 11.5 and Cytoscape 3.9.1. Results: Compared with sham group, DBND group showed significantly elevated leak point pressure (LPP) and maximum cystometric capacity (MCC) (both P < 0.01). EA treatment significantly reduced both LPP and MCC compared with DBND group (P < 0.01 and P < 0.05, respectively). HE staining revealed that EA reduced detrusor fibrosis and improved bladder neck inflammation. TMT proteomics identified 30 overlapping DEPs in detrusor and 59 overlapping DEPs in bladder neck when comparing DBND + EA/DBND groups with sham group. In detrusor tissue, KEGG analysis revealed 10 significantly enriched pathways (P < 0.01), including mitogen-activated protein kinase (MAPK) signaling pathway. PPI analysis showed 22 of 30 DEPs were interconnected. In bladder neck tissue, 14 pathways were significantly enriched (P < 0.01), including relaxin signaling pathway, with 51 of 59 DEPs showing interconnections. Both TMT and WB validations demonstrated that compared with sham controls, DBND rats exhibited upregulated collagen type IV alpha 2 chain (Col4a2) and downregulated guanine nucleotide-binding protein G(z) subunit alpha (Gnaz) in detrusor tissue, while EA treatment normalized both proteins (both P < 0.05). In bladder neck tissue, DBND rats showed decreased expression of smoothelin (Smtn) and calcium-activated potassium channel subunit beta-1 (Kcnmb1) compared with sham controls (both P < 0.01), which were both upregulated following EA treatment (P < 0.01 and P < 0.05, respectively). Conclusion EA restores detrusor-bladder neck coordination in DBND through dual-target mechanisms. In detrusor tissue, EA modulates contraction via extracellular matrix remodeling, cyclic adenosine monophosphate (cAMP) signaling pathway regulation, and enhanced adenosine triphosphate (ATP) biosynthesis mediated by neurotransmitters. In bladder neck tissue, EA promotes relaxation by maintaining contractile phenotypes, reducing fibrosis, suppressing smooth muscle excitation, and regulating presynaptic neurotransmitter release. These findings provide mechanistic insights into EA's therapeutic role in managing DBND.

Objective To explore the effects of dydrogesterone combined with granulocyte colony-stimulating factor(G-CSF)on blood flow parameters and sex hormone levels in patients with thin endometrial(TE)infertility.Methods TE infertility patients were randomly divided into control group and treatment group.All patients were treated with freezing-thawing embryo transfer.The control group was treated with desdrogesterone after ovulation monitoring by vaginal ultrasound,10 mg each time,bid,and stopped until the 14th day after ovulation.In treatment group,G-CSF was given on the basis of control group,and the endometrial thickness and hemodynamic parameters were monitored by vaginal ultrasound 3 days later,and then embryo transfer was performed.Blood flow parameters,ultrasound parameters,endometrial morphology,sex hormone levels[follicle stimulating hormone(FSH),luteinizing hormone(LH),estradiol(E2),progesterone(P)]and pregnancy status were compared between the two groups.Results There were 49 cases in treatment group and 49 cases in control group.After treatment,endometrial thickness in treatment group and control group were(9.59±1.35)and(7.89±1.14)mm;follicle diameter were(19.35±1.58)and(17.75±1.42)mm;uterine volume were(92.68±7.85)and(85.69±6.74)cm3;PI were 1.29±0.27 and 1.74±0.32;RI were 0.32±0.09 and 0.50±0.11;peak systolic/end-diastolic velocity(S/D)were 2.03±0.28 and 2.21±0.25;P were(45.98±5.75)and(39.15±5.78)nmol·L-1;E2 were(462.58±58.42)and(339.45±45.97)pg·mL-1;FSH were(12.18±2.58)and(9.42±1.42)U·L-1;LH were(29.42±4.18)and(22.25±3.40)U·L-1;there were statistically significant differences between the two groups(all P＜0.05).The clinical pregnancy rate(51.02％)and implantation rate(57.14％)in treatment group were higher than those in control group(30.61％and 36.73％),and the differences were statistically significant(all P＜0.05).Conclusion Dydrogesterone combined with G-CSF can improve blood flow parameters,endometrial thickness and sex hormone levels in TE infertility patients,and help to increase the embryo implantation rate.

Objective:To observe any effect of exercise preconditioning on the levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in the brain tissue of rats after induced cerebral ischemia and reperfusion, and how it might promote angiogenesis.Methods:Thirty-six male Sprague-Dawley rats were randomly divided into a sham-operation group, a model group and an exercise preconditioning group, each of 12. After adaptive running training for 3 days, the exercise preconditioning group ran daily for 30 minutes at 15m/min for 14 days, while the other two groups did not exercise. Middle cerebral artery occlusion and reperfusion were then induced in the model and exercise preconditioning groups using the modified Zea-Longa suture method. Rats in the sham-operation group were only cut open to expose the right carotid artery. Right after the modeling, and again 24 hours later neurological deficit was evaluated using the Zea-Longa score and modified neurological severity scoring (mNSS). Infarct sizes were measured using 2, 3, 5-triphenyl tetrazolium chloride staining. Any morphological changes were noted using hematoxylin and eosin (HE) staining, and the expression of CD31 protein, hypoxia-inducible factor-1α and vascular endothelial growth factor in the ischemic cerebral cortex were quantified immunohistochemically.Results:Right after the modelling, compared with the sham-operation group, the average Zea-Longa scores of the model and exercise groups had increased significantly, but were not significantly different from each other. Twenty-four hours later the average Zea-Longa score, mNSS score and relative cerebral infarction area of the model group had increased significantly compared with the sham-operation group, while the exercise preconditioning group′s averages had decreased significantly. The HE staining showed that compared with the sham-operation group, pathological changes such as loose tissue, reduced number of nerve cells, nucleolysis, and vacuolization of the cerebral cortex on the ischemic side were found in the model group. Compared with the model group, the pathological changes in the exercise preconditioning group were less serious. The levels of CD31 protein, HIF-1α and VEGF in the ischemic cerebral cortexes of the model group had by then increased significantly. But compared with the model group, those levels had increased more in the exercise preconditioning group.Conclusion:Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce chronic injury. That may be related to the activation of the HIF-1α and/or VEGF signaling pathways.

ObjectiveTo study the anti-inflammatory effects of Blumea balsamifera （L.） DC oil （BBO） based on nuclear factor kappa-B （NF-κB） nonclassical and arachidonic acid （AA） pathway. MethodsEffects of BBO on the production of slow reacting substance of anaphylaxis （SRS-A） were detected by the ileal smooth muscle method. The contents of prostaglandin E₂ （PGE₂） and leukotriene B₄ （LTB₄） in lipopolysaccharides （LPS） -induced macrophages were detected by ELISA kit. The expression of COX-2， 5-LOX， FLAP and RelB were detected by qRT-PCR. Western blot was performed to detect the effects of BBO on the level of NF-κB nonclassical pathway proteins TNF receptor associated factor 3 （TRAF3）， TNF receptor associated factor 2 （TRAF2）， NF-κB-inducing kinase （NIK）， p100 and RelB. ResultsThe contractile tension of guinea pig ileum was reduced （P<0.001）， and the SRS-A production inhibition rate reached 65.34% at 1mg·mL^-1 BBO concentration. Compared with LPS group， BBO reduced the concentrations of PGE₂ （P<0.05） and LTB₄ （P<0.05）_， and decreased the expressions of COX-2 （P<0.05）， 5-LOX （P<0.05） and FLAP （P<0.05） in AA pathway at concentrations of 40-80 μg·mL^-1. Moreover， 40-80 μg·mL^-1 BBO decreased the concentrations of TRAF3 （P<0.05）， TRAF2 （P<0.05）， and NIK （P<0.05）， and further inhibited the phosphorylation of p100 （P<0.05）， as well as the level of the transcription factor RelB in genes （P<0.05） and proteins （P<0.05） in nonclassical NF-κB pathway， whereas BBO did not cause such changes. ConclusionBBO may potentially exert its anti-inflammatory effects by suppressing the regulatory proteins TRAF3 and TRAF2 and the transcription factor RelB in NF-κB nonclassical pathway. The inhibitory action extending to the induction kinase function of NIK， further hindering the phosphorylation of p100 and its binding with the transcription factor RelB. Consequently， downstream elements in the AA pathway， including the pivotal rate-limiting enzymes COX-2， 5-LOX and FLAP， were altered. This modulation influences the levels of inflammatory mediators such as PGE₂ and LTB₄.

ObjectiveThrough the correlation analysis between intestinal absorption profile and inhibition of macrophage foaming， the pharmacodynamic components of Zhuriheng dripping pills（ZRH） were explored to provide a basis for establishing its quality standard. MethodIntestinal absorption fluids with 0， 5， 10， 15， 20 times clinical equivalent doses were prepared by a rat everted gut sac（EGS）， and the oxidized low density lipoprotein（ox-LDL）-induced RAW264.7 macrophage foaming model was used to investigate the effect of intestinal absorption fluid with different doses on the accumulation of lipids in RAW264.7 cells by oil red O staining and cholesterol content determination， and to screen for the optimal dose. Ultra performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry（UPLC-Q-Exactive Orbitrap MS） was used to analyze and identify intestinal absorption fractions of ZRH intestinal absorption fluids， and partial least squares-discriminant analysis（PLS-DA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） were performed on different doses of ZRH intestinal absorption fluids using SIMCA 13.0 with peak area as the independent variable and the pharmacodynamic indicators as the dependent variables to screen the compounds with variable importance in the projection（VIP） value>1.0 as contributing components， and Pearson correlation analysis was used to determine the spectral effect relationship， determined the compounds and positive correlation with pharmacodynamic were as active ingredients. Molecular docking was used to verify the binding energy of peroxisome proliferator-activated receptor α（PPARα）， PPARγ， PPARβ， human retinoid X receptor α（RXRA） and nuclear transcription factor-κB（NF-κB） with the active ingredients in ZRH intestinal absorption fluids. Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） was performed to detect the mRNA levels of PPARγ， scavenger receptor A1（SRA1） and adenosine triphosphate-binding cassette transporter A1（ABCA1） in RAW264.7 cells， Westen blot was used to detect the expression level of PPARγ protein in RAW264.7 cells， and enzyme-linked immunosorbent assay（ELISA） was used to detect the levels of interleukin（IL）-1β and NF-κB in RAW264.7 cells. ResultAccording to the results of oil red O staining and cholesterol content determination， the ZRH intestinal absorption fluids could significantly reduce macrophage foaming， and intestinal absorption fluids with 15， 20 times clinical equivalent doses had the best effect， the 15-fold ZRH intestinal absorption fluid was finally determined as the study subject. Spectral effect relationship showed that 52 corresponding peaks in the ZRH-containing intestinal fluid were positively correlated with the efficacy， including organic acids， phenylpropanoids， iridoids， flavonoids， bile acids， coumarins and chromones. Target validation results showed that 86.9%-96.2% of the total components processed good binding activities with the key targets of PPARα， PPARγ， PPARβ， RXRA and NF-κB， and the docking energy values were all less than -6.0 kcal·mol^-1（1 cal≈4.19 J）. The results of validation showed that， compared with the normal group， the model group showed a significant increase in the levels of SRA1 and PPARγ mRNA expression， a significant decrease in ABCA1 mRNA expression， a significant increase in the level of PPARγ protein expression， and a significant increase in the levels of IL-1β and NF-κB（P<0.01）， compared with the model group， the 15-fold intestinal absorption fluid group showed a significant decrease in the levels of SRA1 and PPARγ mRNA expression（P<0.05， P<0.01）， ABCA1 mRNA expression level was significantly up-regulated， the levels of IL-1β and NF-κB were significantly reduced（P<0.01）， and PPARγ protein expression level was significantly reduced（P<0.05）. ConclusionThis study identifies 52 components and their metabolites in ZRH intestinal absorption fluid that are positively correlated with the inhibition of macrophage foaming， which may be related to the regulation of the PPARs pathway in cells and the reduction of the levels of inflammatory factors， and can provide a reference for the quality control and clinical application of ZRH.