Unveiling potential therapeutic targets for diabetes-induced frozen shoulder through Mendelian randomization analysis of the human plasma proteome.

INTRODUCTION: This study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms. RESEARCH DESIGN AND METHODS: We employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein-protein interaction network. RESULTS: Our MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p<3.03E-5). According to colocalization analysis, parathyroid hormone-related protein (PTHLH) was moderately correlated with the genetic variance of frozen shoulder (posterior probability=0.68), while secreted frizzled-related protein 4 was highly correlated with the genetic variance of frozen shoulder (posterior probability=0.97). Additionally, nine plasma proteins were activated during diabetes-associated pathologies. Subsequent MR analysis of nine diabetic target proteins with four frozen shoulder causal proteins indicated that insulin receptor subunit alpha, interleukin-6 receptor subunit alpha, interleukin-1 receptor accessory protein, glutathione peroxidase 7, and PTHLH might contribute to the onset and progression of frozen shoulder induced by diabetes. CONCLUSIONS: Our study identified a causal relationship between diabetes and frozen shoulder, highlighting the pathological pathways through which diabetes influences frozen shoulder.

[Clinical Efficacy of Modified Arthroscopic Revision Release of Gluteal Muscle Contracture With Residual Symptoms After Open Surgery]. / æ”¹è‰¯åŽçš„å ³èŠ‚é•œç¿»ä¿®æ¾è§£æœ¯å¯¹å¼€æ”¾æœ¯åŽæœ‰æ®‹ç•™ç—‡çŠ¶çš„è‡€è‚ŒæŒ›ç¼©ç—‡çš„ä¸´åºŠç–—æ•ˆ.

Objective: To investigate the clinical efficacy of modified arthroscopic revision release for patients who have gluteal muscle contracture and who have poor outcomes after traditional open surgery. Methods: The data of patients who underwent modified arthroscopic revision release for residual symptoms of gluteal muscle contracture after traditional open surgery were retrospectively collected and analyzed. All subjects underwent the procedure between December 2015 and December 2022. The surgical efficacy was assessed by evaluating improvements in specific symptoms, including bilateral lower extremity inequality, hip internal rotation and adduction mobility, squatting with both knees pressed together, and the ability to cross one's legs in supine position, as well as the preoperative and postoperative results for the gluteal muscle contracture functionality scale. Paired t-test was performed to examine whether the differences between preoperative and postoperative measurements were statistically significant. Results: A total of 36 patients were followed up systematically, with the mean follow-up period being (22.4±4.9) months. All patients had significantly higher scores for assessment with the gluteal muscle contracture functionality scale at the last follow-up than their preoperative assessment results, showing an increase from the preoperative scores of 40.2±5.5 to 78.4±4.9 (P<0.05). At the follow-up, all patients showed improvement in hip adduction and internal rotation mobility compared with their preoperative status and all patients were able to squat with both knees pressed together. Moreover, only 1 patient still had difficulty in crossing his legs. A total of 27 cases (75%) had preoperative leg length inequality, all of which improved to varying degrees at follow-up. Among all the patients (72 hips/cases), 8 cases had subcutaneous hematomas and incisional ecchymosis, which were resolved after conservative treatments such as hot compresses. 3 cases showed decreased hip abductor strength, but the muscle strength gradually recovered after postoperative exercise and rehabilitation. There were no complications such as subcutaneous exudate, neurovascular injury, or surgical site infection. Conclusion: Modified arthroscopic revision release of gluteus muscle contracture is suitable for cases with poor outcomes after conventional open surgery.

Investigating the anti-atherosclerotic effects and potential mechanism of Dalbergia odorifera in ApoE-deficient mice using network pharmacology combined with metabolomics.

Dalbergia odorifera (DO) is a precious rosewood species in Southern Asia, and its heartwood is used in China as an official plant for invigorating blood circulation and eliminating stasis. This study aims to evaluate the efficacy of DO on atherosclerosis (AS), and further explore its active components and potential mechanisms. The apolipoprotein-E (ApoE)-deficient mice fed a high-fat diet were used as model animals, and the pathological changes in mice with or without DO treatment were compared to evaluate the pharmacodynamics of DO on AS. The mechanisms were preliminarily expounded by combining with metabolomics and network pharmacology. Moreover, the bioactive components and targets were assessed by cell experiments and molecular docking, respectively. Our findings suggested that DO significantly modulated blood lipid levels and alleviated intimal hyperplasia in atherosclerotic-lesioned mice, and the mechanisms may involve the regulation of 18 metabolites that changed during the progression of AS, thus affecting 3 major metabolic pathways and 3 major signaling pathways. Moreover, the interactions between 16 compounds with anti-proliferative effect and hub targets in the 3 signaling pathways were verified using molecular docking. Collectively, our findings preliminarily support the therapeutic effect of DO in atherosclerosis, meanwhile explore the active constituents and potential pharmacological mechanisms, which is conducive to its reasonable exploitation and utilization.

Causal relationship between lipid profile and muscle atrophy: A bi-directional Mendelian randomization study.

BACKGROUND: The aim of this study was to analyze the bi-directional causal relationship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization (MR) analysis. METHODS: The appendicular lean mass (ALM), whole body fat-free mass (WBFFM) and trunk fat-free mass (TFFM) were used as genome-wide association study (GWAS) data for evaluating muscle mass; the usual walking pace (UWP) and low grip strength (LGS) were used as GWAS data for evaluating muscle strength; and the triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), apolipoprotein A-1 (Apo A-1), and apolipoprotein B (Apo B) were used as GWAS data for evaluating lipid profile. For specific investigations, we mainly employed inverse variance weighting for causal estimation and MR-Egger for pleiotropy analysis. RESULTS: MR results showed that the lipid profile predicted by genetic variants was negatively correlated with muscle mass, positively correlated with UWP, and was not causally correlated with LGS. On the other hand, the muscle mass predicted by genetic variants was negatively correlated with lipid profile, the UWP predicted by genetic variants was mainly positively correlated with lipid profile, while the LGS predicted by genetic variants had no relevant causal relationship with lipid profile. CONCLUSIONS: Findings of this MR analysis suggest that hyperlipidemia may affect muscle mass and lead to muscle atrophy, but has no significant effect on muscle strength. On the other hand, increased muscle mass may reduce the incidence of dyslipidemia.

Intraoperative Diastolic Hypotension-Prolonged Postoperative Hospital Stay in Patients with Gastric Cancer: A Retrospective Cohort Study with Propensity Score Matching.

Purpose: In patients undergoing surgical resection for gastric cancer, perioperative hemodynamic fluctuations may affect organ perfusion, increase the incidence of postoperative complications, and prolong hospital stay. Patients and Methods: We retrospectively identified patients who underwent resection for gastric cancer at our institution from April 1, 2015 to October 30, 2018. Demographic information, perioperative data, and information on postoperative recovery were recorded. The primary outcome was length of postoperative hospital stay; the secondary outcome was incidence of postoperative complications. Propensity score matching was performed. The associations between perioperative factors and postoperative hospital stay were analyzed using multivariable logistic regression models in the full and matched cohorts. Results: In total, 933 patients were included; of these, 676 had diastolic hypotension (defined as diastolic blood pressure <60 mmHg for >10 min). In both cohorts, patients with diastolic hypotension had statistically significantly longer postoperative hospital stay (full: mean 14.5 ± standard deviation 10.2 vs 11.6 ± 6.5 days, P < 0.001; matched: 13.7 ± 9.9 vs 11.7 ± 6.6 days, P = 0.009) and a higher incidence of postoperative complications (full: 170 [25.1%] vs 27 [10.5%] cases, P < 0.001; matched: 60 [24.4%] vs 33 [13.4%] cases, P = 0.003), compared with patients without diastolic hypotension. After correction for confounding factors, intraoperative diastolic hypotension was associated with longer postoperative hospital stay in both the full and the matched cohort (full: HR, 1.535 [95% CI, 1.115-2.114], P = 0.009; matched: HR, 1.532 [95% CI, 1.032-2.273], P = 0.034). Conclusion: For patients with gastric cancer, intraoperative diastolic hypotension may increase the incidence of postoperative complications and prolong postoperative hospital stay.

Forkhead Box O Signaling Pathway in Skeletal Muscle Atrophy.

Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis because of disease, aging, and physical inactivity. Patients with skeletal muscle atrophy have decreased muscle mass and fiber cross-sectional area, and experience reduced survival quality and motor function. The forkhead box O (FOXO) signaling pathway plays an important role in the pathogenesis of skeletal muscle atrophy by regulating E3 ubiquitin ligases and some autophagy factors. However, the mechanism of FOXO signaling pathway leading to skeletal muscle atrophy is still unclear. The development of treatment strategies for skeletal muscle atrophy has been a thorny clinical problem. FOXO-targeted therapy to treat skeletal muscle atrophy is a promising approach, and an increasing number of relevant studies have been reported. This article reviews the mechanism and therapeutic targets of the FOXO signaling pathway mediating skeletal muscle atrophy, and provides ideas for the clinical treatment of this condition.

An integrated approach for identifying the efficacy and potential mechanisms of TCM against atherosclerosis-Wu-Zhu-Yu decoction as a case study.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) is a chronic disease that is associated with high morbidity. However, therapeutic approaches are limited. Wu-Zhu-Yu decoction (WZYD) is a well-known traditional Chinese medicine prescription that is traditionally used to treat headaches and vomiting. Modern studies have demonstrated the cardiotonic effects of WZYD. However, whether WZYD can alleviate AS and its underlying mechanisms remain unclear. AIM OF THE STUDY: This study aims to investigate the antiatherosclerotic efficacy of WZYD and illustrate its potential mechanisms using an integrated approach combining in vivo and in vitro assessments, including metabolomics, network pharmacology, cell experiments, and molecular docking analyses. MATERIALS AND METHODS: In this work, an atherosclerotic mouse model was established by administering a high-fat diet to apolipoprotein-E deficient (ApoE-/-) mice for twelve weeks. Meanwhile, the mice were intragastrically administered WZYD at different dosages. Efficacy evaluation was performed through biochemical and histopathological assessments. The potential active constituents, metabolites, and targets of WZYD in atherosclerosis were predicted by metabolomics combined with network pharmacology analysis, the constituents and targets were further assessed through cell experiments and molecular docking analysis. RESULTS: WZYD decreased the lipid levels in serum, reduced the areas of aortic lesions, and attenuated intimal thickening, which had antiatherosclerotic effects in ApoE-/- mice. Metabolomics and network pharmacology approach revealed that the ten constituents (6-shogaol, evodiamine, isorhamnetin, quercetin, beta-carotene, 8-gingerol, kaempferol, 6-paradol, 10-gingerol, and 6-gingerol) of WZYD affected 24 metabolites by acting on the candidate targets, thus resulting in changes in five metabolic pathways (sphingolipid metabolism; glycine, serine and threonine metabolism; arachidonic acid metabolism; tryptophan metabolism; and fatty acid biosynthesis pathway). Cell experiments indicated that the ten key compounds showed antiproliferative effects on the vascular smooth muscle cell. Moreover, the key compounds exhibited direct interactions with the key targets, as assessed by molecular docking analysis. CONCLUSION: This study revealed that WZYD exerted therapeutic effects on atherosclerosis, and the potential mechanisms were elucidated. Furthermore, it offered a powerful integrated strategy for studying the efficacy of traditional Chinese medicine and exploring its active components and possible mechanisms.

An enhanced analytical strategy integrating offline two-dimensional liquid chromatography with high-resolution accurate mass spectrometry and molecular networking: Comprehensive characterization of HuangLian JieDu Decoction as a case study.

Comprehensive ingredient research is of great significance for understanding the effective material basis of herbal medicines, but due to the diversity and complexity of their phytochemicals, such research is challenging. Here, a multifaceted strategy was proposed to analyze and identify the composition of HuangLian JieDu Decoction based on offline two-dimensional liquid chromatography combined with ultraviolet detection and high-resolution mass spectrometry. Multiple components were separated by two-dimensional liquid chromatography, which consisted of hydrophilic interaction chromatography and reversed-phase liquid chromatography, and then further characterized by high-resolution mass spectrometry with a full mass spectrometry/precursor ion list/data-dependent secondary scan data acquisition method. For data processing, database screening and molecular networking were used to identify the components in HuangLian JieDu Decoction. The offline two-dimensional liquid chromatography combined with ultraviolet detection and a high-resolution mass spectrometry system showed good orthogonality of 76.35% and a high peak capacity of 5175, effectively separating multiple components. Finally, 527 compounds, including 164 alkaloids, 133 terpenoids, 88 flavonoids, 60 phenylpropanoids, 38 organic acids, and 44 other compounds, were characterized. This integrated approach is suitable for the comprehensive characterization of herbal medicines and other complex chemical systems.

p38MAPK Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects.

Osteoarthritis (OA) is an aging-related joint disease, pathologically featured with degenerated articular cartilage and deformation of subchondral bone. OA has become the fourth major cause of disability in the world, imposing a huge economic burden. At present, the pathogenesis and pathophysiology of OA are still unclear. Complex regulating networks containing different biochemical signaling pathways are involved in OA pathogenesis and progression. The p38MAPK signaling pathway is a member of the MAPK signaling pathway family, which participates in the induction of cellular senescence, the differentiation of chondrocytes, the synthesis of matrix metalloproteinase (MMPs) and the production of pro-inflammatory factors. In recent years, studies on the regulating role of p38MAPK signaling pathway and the application of its inhibitors have attracted growing attention, with an increasing number of in vivo and in vitro studies. One interesting finding is that the inhibition of p38MAPK could suppress chondrocyte inflammation and ameliorate OA, indicating its therapeutic role in OA treatment. Based on this, we reviewed the mechanisms of p38MAPK signaling pathway in the pathogenesis of OA, hoping to provide new ideas for future research and OA treatment.

The effect of propofol on the proliferation and apoptosis of hepatocellular carcinoma cells through TGF-Β1/Smad2 signaling pathway.

Malignant tumors are a serious threat to human health. Surgical resection is the most effective treatment for liver cancer. However, liver cancer is mostly found at an advanced stage, is difficult to remove by surgery, and has a very high recurrence rate after surgery. The current liver cancer treatment drugs have serious side effects, and the treatment effect is not ideal, far from meeting the clinical needs. Based on this, this paper studies the effect of propofol on the proliferation and apoptosis of liver cancer cells through the TGF-B1/Smad2 signaling pathway, and explores the proliferation, adhesion and apoptosis of cancer cells in patients with propofol. This paper uses a comparative experiment. With medical imaging method, 80 rats with liver cancer in the same period were cultured. High-precision microscope and radiolocation method were used to observe and record the whole process of propofol regulating Smad2 signal pathway. The results show that propofol can effectively inhibit the proliferation of cancer cells in patients with liver cancer. Propofol can increase the activity and content of transforming growth factor-ß1 by 12% and 20%, respectively, and then inhibit the proliferation rate of liver cancer cells by 10% through the Smad2 signaling pathway, and exponentially increase the apoptotic number of liver cancer cells. This shows that propofol has a significant inhibitory effect on the cycle of liver cancer cells. Under the action of propofol, the life cycle of liver cancer cells is shortened, which provides a certain theoretical basis for the treatment of liver cancer.

[Effect of Preoperative Anxiety on Early Prognosis of Patients after Thoracoscopic Lung Cancer Resection].

BACKGROUND: Patients with lung cancer are often accompanied by anxiety, which affects postoperative recovery. The aim of this study is to explore the effects of preoperative anxiety on early prognosis in patients after thoracoscopic lung cancer resection. METHODS: A total of 100 patients undergoing thoracoscopic resection of lung cancer were divided into 2 groups by hospital anxiety and depression scale (HADS): 44 in anxiety group (anxiety score>8) and 56 in control group (anxiety score<8). The primary endpoint: length of postoperative hospital stay. The secondary endpoint: length of hospital stay, visual analogue scale (VAS), the incidence of nausea and vomiting as well as postoperative new arrhythmia and the consumption of postoperative analgesic and rescue antiemetic. RESULTS: Compared with the control group, the length of postoperative hospital stay and hospital stay in the anxiety group were both significantly longer [(5.1±2.5) d vs (4.0±1.3) d, P<0.01; (10.9±4.0) d vs (9.1±4.1) d, P<0.05)], the VAS score and the incidence of nausea as well as arrhythmia were significantly increased [(4.7±1.9) vs (2.6±1.8), P<0.001; 40.9% vs 16.1%, P<0.01; 36.4% vs 20.7%, P<0.05], and the consumption of postoperative analgesic and rescue antiemetic were also significantly increased [(72.5±8.9) mL vs (68.2±9.4) mL, P<0.05; (2.1±2.9) mg vs (0.9±1.9) mg, P<0.05]. CONCLUSIONS: Preoperative anxiety can affect the early prognosis of patients after thoracoscopic lung cancer resection, prolong hospitalization time, increase the postoperative pain score and the incidence of postoperative nausea and new arrhythmia as well as the consumption of postoperative analgesic and rescue antiemetic.

MiR-98 modulates macrophage polarization and suppresses the effects of tumor-associated macrophages on promoting invasion and epithelial-mesenchymal transition of hepatocellular carcinoma.

BACKGROUND: Tumor-associated macrophages (TAMs) are generally recognized as a promoter of tumor progression. miR-98 has been shown to suppress the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. Here, we aim to investigate the role of miR-98-mediated macrophage polarization in HCC progression. METHODS: Human blood monocytes were isolated from healthy male donors and incubated with culture medium collected from HepG2 cells for 7 days. The phenotype of the macrophages was detected. The protein expression was detected by Western blot. Levels of cytokines secreted in culture medium were measured using the specific enzyme-linked immunosorbent assay kits. To explore the role of miR-98 in HCC-conditioned TAMs, HCC cells HepG2 and SMMC7721 were cultured with conditioned medium from HCC-conditioned TAMs that had been transfected with miR-98 mimic/inhibitor. Cell proliferation, migration and invasion assays were performed. RESULTS: HCC-conditioned TAMs possessed M2-like phenotype, including increased protein expression of CD163 and TNF-αlow, IL-1ßlow, TGF-ßhigh and IL-10high phenotype. HCC-conditioned TAMs also promoted proliferation, migration, invasion and EMT of HepG2 and SMMC7721 cells. Furthermore, miR-98 modulated macrophage polarization from M2 to M1 in HCC-conditioned TAMs, as evidenced by the alteration of M1- or M2-related cytokines. Moreover, miR-98 mimic significantly suppressed the HCC-conditioned TAMs-mediated promotion of cell migration, invasion and EMT in HepG2 and SMMC7721 cells compared with negative control, whereas miR-98 inhibitor exerted reversed effects. CONCLUSIONS: miR-98 may play a vital role in regulating macrophage polarization, thereby suppressing the TAMs-mediated promotion of invasion and EMT in HCC.

MiR-98 suppresses the effects of tumor-associated macrophages on promoting migration and invasion of hepatocellular carcinoma cells by regulating IL-10.

We aim to investigate the role of miR-98-mediated macrophage polarization in hepatocellular carcinoma (HCC) progression and to explore the underlying mechanism. A total of 25 paired HCC and matched adjacent normal tissues (ANTs) were collected. We incubated human blood monocytes isolated from healthy male donors with culture medium collected from HepG2 cells for 7 days. The mRNA and protein expression was detected by qRT-PCR and Western blot, respectively. Levels of cytokines secreted in culture medium were measured using the specific ELISA kits. The miR-98 mimic/inhibitor was transfected to explore the role of miR-98 in HCC-conditioned tumor-associated macrophages (TAMs). HepG2 cells were then cultured with condition medium from HCC-conditioned TAMs pretreated with miR-98 mimic/inhibitor, and cell migration and invasion assays were performed. Luciferase reporter assay was performed to analyze the interaction between miR-98 and interleukin (IL)-10. Our results showed that miR-98 was downregulated and IL-10 was upregulated in HCC tissues and HCC-conditioned TAMs. Further studies identified that IL-10 was a direct target gene of miR-98 in HCC-conditioned TAMs. Moreover, miR-98 regulated the levels of inflammatory cytokines in HCC-conditioned TAMs. HCC-conditioned TAMs pretreated with miR-98 regulated migration and invasion of HepG2 cells in vitro, and the effects were significantly reversed by IL-10. In conclusion, miR-98 not only regulated expression of inflammatory cytokines in HCC-conditioned TAMs, but also modulated the capacity of HCC-conditioned TAMs to regulate HepG2 cell migration and invasion, at least in part, by targeting IL-10. As a result, miR-98 may suppress the progress of HCC.

Efficacy and possible mechanisms of Botulinum Toxin type A on hypertrophic scarring.

BACKGROUND: Clinical observations indicate that Botulinum toxin type A (BTXA) can inhibit the growth and improve the eventual appearance of hypertrophic scarring. However, the molecular mechanism remains unclear. OBJECTIVE: We used human keloid fibroblasts to investigate the molecular mechanism of BTXA on hypertrophic scarring. METHODS: Different concentrations of BTXA (0.01, 0.1, 1, and 10 U/L) were used to treat keloid fibroblasts. Changes in cellular morphology, viability, proliferation, cell cycle, and apoptosis were observed by immunofluorescence, MTT assay, and flow cytometry. In addition, real-time qPCR and Western blotting were used to explore the potential molecular mechanisms. RESULTS: Keloid fibroblast viability decreased with increasing BTXA dose. After BTXA treatment, the volume of keloid fibroblasts cells increased, but the nucleus of cells shrunk. Long thin dendrites were formed as the concentration of BTXA increased. Furthermore, the proliferation and S phase of keloid fibroblasts were inhibited by BTXA. Matrix metalloproteinase (, MMP)-1 and -2 RNA and protein showed high expression, but TGF-ß1 and MMP-9 showed low expression than the control. CONCLUSION: Botulinum toxin type A may promote the healing of scars by inhibiting the proliferation of keloid fibroblasts and regulating the expression of TGF-ß1, which could affect the expression of MMP-1 and MMP-2. This study provides theoretical support for the clinical application of BTXA to control hypertrophic scarring.

Risk in daily newspaper coverage of red tide blooms in Southwest Florida.

This study investigated newspaper coverage of Florida red tide blooms in four metropolitan areas of Southwest Florida during a 25-year period, 1987-2012. We focused on how journalists framed red tide stories with respect to environmental risk, health risk, and economic risk. We determined risk to be a key factor in this news coverage, being an aspect of coverage of red tide itself in terms of environmental risk, tourism risk, and public health risk. The study found that red tide news coverage is most often framed as an environmental story.