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This study aimed to evaluate the effects of a media literacy education intervention on adolescents' responses to digital marketing of weight-control products, focusing on media literacy, persuasion resistance efficacy, and purchase intention. Using a quasi-experimental design, the study involved 326 11th-grade students from a municipal high school in Kaohsiung City, Taiwan, with 189 students in the intervention group and 137 in the comparison group. Conducted in 2023, the intervention group participated in baseline and follow-up assessments and attended four 50 min media literacy sessions, while the comparison group completed only baseline and follow-up assessments with standard instruction. The results indicated that the media literacy intervention had positive effects on adolescents' conceptual, attitudinal, and critical media literacy, as well as their persuasion resistance efficacy in relation to digital marketing of weight-control products. However, no significant effect was observed on purchase intention. In conclusion, media literacy interventions can effectively enhance adolescents' media literacy and their ability to resist persuasion.

Background: Sarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co-chaperone protein, plays a crucial role in skeletal muscle development. GMI, an immunomodulatory protein, promotes myogenic differentiation through DNAJA3 activation. This study aims to elucidate the physiological effects of muscular Dnaja3 haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both in vitro and in vivo., Methods: We generated mouse strain with Dnaja3 heterozygosity (HSA-Dnaja3 f/+ ) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and HSA-Dnaja3 f/+ mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and HSA-Dnaja3 f/+ mice, at young or old age, were utilized to study the molecular mechanisms, mitochondrial respiration and ROS level, mitochondrial proteomes, and serological analyses, respectively. To evaluate the therapeutic efficacy of GMI, both short-term and long-term GMI treatment were administrated intraperitoneally to the HSA-Dnaja3 f/+ young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively., Results: Muscular Dnaja3 heterozygosity resulted in impaired locomotor activity (P < 0.05), reduced muscular cross-sectional area (P < 0.0001), and up-regulation of lipogenesis (ACC2) and pro-inflammation (STAT3) in skeletal muscles (P < 0.05). Primary myoblasts from the HSA-Dnaja3 f/+ mice displayed impaired mitochondrial respiration (P < 0.01) and imbalanced mitochondrial ROS levels. A systemic proteomic analysis of the purified mitochondria from the primary myoblasts was conducted to show the abnormalities in mitochondrial function and fatty acid metabolism (P < 0.0001). At age of 13 to 14 months, the HSA-Dnaja3 f/+ mice displayed increased body fat mass (P < 0.001), reduced fat-free mass (P < 0.01), and impaired glucose and insulin tolerance (P < 0.01). The short-term GMI treatment improved locomotor activity (P < 0.01) and down-regulated the protein levels of STAT3 (P < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (P < 0.01) via DNAJA3 activation. The long-term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (P < 0.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (P < 0.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (P < 0.01) through DNAJA3 activation (P < 0.05) in vitro., Conclusions: Muscular Dnaja3 haploinsufficiency dysregulates mitochondrial function and lipid metabolism then leads to sarcopenic obesity. GMI emerges as a therapeutic regimen for sarcopenic obesity treatment through DNAJA3 activation., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Objective: This study aimed to identify the incidence, risk factors, and outcomes of permanent pacemaker (PPM) implantation after transcatheter aortic valve implantation (TAVI) procedures., Methods: A retrospective analysis was conducted on 70 patients who underwent TAVI at the Department of Cardiology, Fujian Provincial Hospital, from January 2018 to March 2022. Based on whether a new PPM was implanted after TAVI, all patients were divided into two groups: NEW PPM and NO PPM. Baseline characteristics and clinical data were compared between the two groups. Univariate analysis was used to analyze different variables between the two groups. A binary logistic regression analysis was used to evaluate independent correlates for PPM implantation after TAVI., Results: The mean age of the 70 patients was 73.1 ± 8.8 years. The incidence of PPM implantation was 17.1%. Patients with diabetes and chronic kidney disease were more likely to require PPM (50% vs. 20.7%, p = 0.042, 25% vs. 5.2%, p = 0.042). Our study did not identify any significant differences in the incidence of electrocardiographic conduction disturbances except for the previous right bundle branch block (RBBB) (NO PPM 6.9% vs. NEW PPM 33.3%, p < 0.05). We found that prosthesis size, implantation depth, procedural duration, and length of hospital and intensive care unit (ICU) stays were comparable between the two groups. The leading independent predictors of PPM implantation were previous RBBB (odds ratio 10.129, p = 0.034)., Conclusion: The previous RBBB was the leading independent predictor of PPM implantation. New PPM was not associated with significantly new-onset left BBB, extended post-procedure hospitalization, ICU stay, or procedural duration., (© 2024. The Author(s).)

Background: This study aimed to evaluate the efficacy and reliability of three-dimensional (3D) fusion guidance in roadmapping for fluoroscopic navigation during trans-arterial embolization for refractory musculoskeletal pain (TAE-MSK pain) in the extremities., Methods: The included research patients were divided into two groups: group A-TAE-MSK pain performed without the use of 3D fusion guidance; group B-TAE-MSK pain performed with the use of 3D fusion guidance for fluoroscopic navigation. We compared the procedure time, radiation dose, visual analogue scale for pain scores, and adverse effects (before and 3 months after TAE-MSK pain) among the two groups. In the group B, we determined the reliability of ideal branch angle for pre-operative non-contrast 3D magnetic resonance angiography (MRA) and intra-operative 3D cone beam computed tomography (CBCT) angiography., Results: We recruited 65 patients, including 23 males and 42 females (average age 58.20±12.58 years), with 38 and 27 patients in groups A and B. A total of 247 vessels were defined as target branch vessels. Significant changes were observed in the fluoroscopy time which was 32.31±12.39 and 14.33±3.06 minutes, in group A and group B (P<0.001), respectively; procedure time, which was 46.45±17.06 in group A and 24.67±9.78 in group B (P<0.001); and radiation exposure dose, determined as 0.71±0.64 and 0.34±0.29 mSv (P<0.01) in group A and group B, respectively. Furthermore, the number of target branch vessels, that underwent successful catheterization were 107 (97%) in group B as compared to 96 (70%) in group A, which was also significant (P<0.001). The study also showed that the ideal branch-angle has a similarly high consistency in pre-operative and intra-operative angiography based on the intra-class correlation coefficient (ICC) (0.994; 0.990, respectively)., Conclusions: 3D fusion guidance for fluoroscopic navigation not only is a reliable process, but also effectively reduces the operation time and radiation dose of TAE-MSK pain., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-490/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

In this study, we examined the relationships between the use of online dating applications (apps), online victimization, and psychosocial distress among adolescents. This study was conducted in 2020. A sample of 2595 seventh-grade students from 30 Taiwanese middle schools was surveyed. We conducted a self-administered survey. Overall, 15% of the adolescents reported using online dating apps in the past year, while 78% reported having seen dating app advertisements on the internet in the past year. Multivariate analysis results indicated that adolescents' exposure to the marketing of dating apps and poor academic performance were both associated with the use of online dating apps. Adolescents who used dating apps were more likely to experience online privacy victimization, cyberbullying victimization, and online sexual harassment. The use of dating apps by adolescents, online privacy victimization, cyberbullying victimization, and online sexual harassment were associated with higher levels of depression, anxiety, and stress. In conclusion, adolescent use of dating apps is related to online victimization and psychological distress.

The epithelial-mesenchymal transition (EMT) is closely associated with Crohn's disease (CD) related intestinal fibrosis, a condition whose prevalence is increasing annually among children. Recently, the CD marker gene microarray screening revealed an upregulation of circ&#95;0001666 in the colon tissues of CD patients, but its underlying mechanisms remain unclear. In this study, we explored the molecular mechanism of circ&#95;0001666 in regulating EMT-mediated fibrosis in CD in vitro. The levels of circ&#95;0001666 and EMT-associated proteins were assessed in CD clinical samples, and a CD cell model was established using TGF-β1 to induce human intestinal epithelial cells (HIECs). Additionally, the expression levels of genes and proteins related to EMT and fibrosis were analyzed by quantitative real-time PCR and western blot, cell migration, and invasion were assessed via wound healing assay and transwell, respectively, and RNA pull-down and RNA immunoprecipitation assays were performed to verify the relationship between SRSF1 and BMP7 or circ&#95;0001666. Circ&#95;0001666 was overexpressed in the intestinal mucosal tissues of CD patients and was positively correlated with EMT. Silencing circ&#95;0001666 inhibited the migration, invasion, EMT, and fibrosis of HIECs induced by TGF-β1. Mechanistically, circ&#95;0001666 regulated BMP7 expression by interacting with SRSF1. Furthermore, the effects of inhibiting circ&#95;0001666 on HIECs could be partially reversed by overexpressing SRSF1 or silencing BMP7. Collectively, circ&#95;0001666 regulates TGF-β1-induced HIEC migration, invasion, EMT, and fibrosis. Circ&#95;0001666 also promoted EMT-mediated fibrosis by interacting with SRSF1 to accelerate BMP7 mRNA decay. These findings provide new insights into the pathogenesis of CD and suggest that circ&#95;0001666 might be a potential therapeutic target for CD., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

In this study, we examined influencer marketing and consumption of non-alcoholic beer by adolescents to determine how these factors could affect the intentions of adolescents to purchase and drink alcohol. A total of 3121 high-school students recruited from 36 schools in Taiwan completed a self-administered questionnaire during the COVID-19 pandemic in 2022. The results indicate that 19% of these adolescents consumed non-alcoholic beer and 28% consumed alcohol in the past year. Multivariate analysis positively associated adolescents' exposure to influencer marketing with their purchase and consumption of non-alcoholic beer. Adolescents' exposure to influencer marketing of non-alcoholic beer combined with lower levels of parental restrictive mediation was associated with increased odds of the purchase and consumption of alcohol. For individuals who did not purchase alcohol in the past year, both the exposure to influencer marketing and the consumption of non-alcoholic beer were associated with intending to purchase alcohol in the future. Similarly, individuals who previously abstained from the consumption of alcohol, both the exposure to influencer marketing and the consumption of non-alcoholic beer were associated with intending to consume alcohol. In conclusion, when adolescents were exposed to influencer marketing of non-alcoholic beer they were more likely to consume it, which resulted in an increased likelihood that they would then purchase and consume alcohol.

Cardiopulmonary resuscitation (CPR) education for the public may improve bystander intention to perform CPR on cardiac arrest patients. Studies have shown that different CPR education intervention methods can improve learning performance, with key indicators including attitude toward to CPR, intention to perform CPR, and degree of CPR knowledge and skills. The present study compared the traditional face-to-face method to hybrid and virtual reality (VR) methods to observe difference in learning performance and length of performance retention. This study adopted randomized controlled trial to compare CPR learning performance between traditional face-to-face, hybrid, and VR methods. Participants from each intervention group completed a pretest and 2 posttests. The measurement tools included an attitude and intention questionnaire, knowledge examination, and skill examination with a RESUSCI ANNE QCPR ® manikin. The performance among all participants in pretest showed no significant difference between the intervention groups, indicating no difference in their background attitude, knowledge, and skill level. Significant differences were observed in the average degree of intention to perform CPR between the hybrid and traditional groups in 1st and 2nd posttest. Compared to the pretest results, the posttests revealed significantly higher attitude toward CPR, intention to perform CPR, knowledge examination results, accuracy of overall chest compression, accuracy of CPR procedure, accuracy of AED usage, accuracy of chest compression rate, and accuracy of chest compression depth. The average time to reattending CPR learning and practice session was 11-12 weeks reported by participants. The hybrid and VR methods to CPR education resulted in the same level of improvement in learning performance as traditional face-to-face teaching. The suggested frequency for renewing CPR knowledge and skills is 12 weeks which may be considered in new strategies aimed at promoting CPR education and exposure to the public., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Photocatalytic water splitting is attracting considerable interest because it enables the conversion of solar energy into hydrogen for use as a zero-emission fuel or chemical feedstock. Herein, we present a universal approach for inserting hydrophilic non-conjugated segments into the main-chain of conjugated polymers to produce a series of discontinuously conjugated polymer photocatalysts. Water can effectively be brought into the interior through these hydrophilic non-conjugated segments, resulting in effective water/polymer interfaces inside the bulk discontinuously conjugated polymers in both thin-film and solution. Discontinuously conjugated polymer with 10 mol% hexaethylene glycol-based hydrophilic segments achieves an apparent quantum yield of 17.82% under 460 nm monochromatic light irradiation in solution and a hydrogen evolution rate of 16.8 mmol m -2 h -1 in thin-film. Molecular dynamics simulations show a trend similar to that in experiments, corroborating that main-chain engineering increases the possibility of a water/polymer interaction. By introducing non-conjugated hydrophilic segments, the effective conjugation length is not altered, allowing discontinuously conjugated polymers to remain efficient photocatalysis., (© 2022. The Author(s).)

Prostate cancer is a major cause of cancer-related mortality in men in developed countries. The compound, 4-acetylantroquinonol B (4AAQB), is isolated from Antrodia cinnamomea (commonly known as Niu-Chang-Chih), which has been shown to inhibit cancer growth. However, the anticancer activity of 4AAQB has not previously been examined in prostate cancer. This study aimed to investigate the effect of 4AAQB on cancer and angiogenesis, as well as to explore its mechanism of action. Human prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) were used in cell viability, cell migration, and cell cycle functional assays to evaluate the anticancer and antiangiogenic efficacy of 4AAQB in vitro. The effects of 4AAQB in vivo were determined using xenograft and angiogenesis models. The signaling events downstream of 4AAQB were also examined. The 4AAQB compound inhibited PC3 cell growth and migration, and reduced in vivo cancer growth, as shown in a subcutaneous xenograft model. Furthermore, 4AAQB inhibited HUVEC migration, tube formation, and aortic ring sprouting; it also reduced neovascularization in a Matrigel implant angiogenesis assay in vivo. The 4AAQB compound also decreased metastasis in the PC3 prostate cancer model in vivo. Serum or vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/Ak strain transforming (Akt), and extracellular signal-regulated kinase ½ (ERK ½) phosphorylation were attenuated by 4AAQB in both PC3 and HUVEC. In conclusion, 4AAQB is a potential candidate for prostate cancer therapy.

Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE -/- ) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation., (© 2022. The Author(s).)

Background: The aim of the study was to conduct a systematic review and meta-analysis to compare the functional outcomes and reoperation rates of cemented and cementless hip arthroplasty for treating displaced femoral neck fractures in elderly patients., Methods: Systematic searches were conducted of literature up to December 2018 on PubMed, Embase, Cochrane, and Web of Science for randomized controlled trials (RCTs) concerning current-generation stem designs only. Two reviewers independently determined eligibility, extracted the outcome data and assessed the risk of bias of eligible studies. The follow-up data and complication rates were pooled by using random-effects models and fixed-effects models, with mean differences and risk ratios for continuous and dichotomous variables, respectively., Results: Eight RCTs involving 1361 patients (1361 hips) were included in the meta-analysis. Cemented stems were associated with fewer implant-related complications (odds ratio [OR] = 0.303; 95% confidence interval [CI], 0.185%-0.496%; p < 0.001) and reoperations (OR = 0.492; 95% CI, 0.247%-0.977%; p = 0.043). There were no statistically significant differences between groups in functional outcomes, including those assessed by the EuroQol(EQ)-5D and Harris Hip Score, mortality rates, major systemic complications, minor local complications, operation times, intraoperative blood losses, and lengths of hospital stays., Conclusion: In treating displaced femoral neck fracture in elderly patients with hip arthroplasty with current-generation stems, cemented stems were found to have fewer implant-related complications and reoperations than those of cementless stems. Functional outcomes and mortality rates were similar between the groups., Competing Interests: Conflict of interest: Dr. Wei-Ming Chen, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

The new series ElatostemasectionWeddellia series Xingyiensia L.D. Duan & D.H. Yin (Urticaceae) is described. In addition, its new species Elatostemaxingyiense L.D. Duan & D.H. Yin, endemic to Guizhou Province, is also described and illustrated with photographs. The new series is morphologically similar to series Melanocarpa W.T. Wang and series Sublinearia W.T. Wang. The new species is most similar to E.melanocarpum , E.sublineare , E.obscurinerve , E.langicuspe and E.youyangense in morphology, but can be visibly distinguished by a combination of characters, including leaf vein, male inflorescences, female inflorescences and persistent tepals., (Dan-Hong Yin, Teng-Fei Huang, Zhen Lu, Lin-Dong Duan.)

Background: The optimal postoperative analgesia after open rotator cuff repair surgery remains unclear. This study compared the use of a multimodal pain regimen including periarticular injection (PAI), with a control condition. We hypothesized that PAI leads to decreased opioid consumption and lower pain scores., Methods: The perioperative analgesic regimen was standardized and implemented from January 1, 2017 to December 31, 2017. The PAI was administered from July 1, 2017 to December 31, 2017. The historical control group was enrolled from January 1, 2017 to June 30, 2017. The evaluation items included assessments of pain using a 10-point visual analog scale (VAS) before and after the mini-open rotator cuff repair and on postoperative days 1, 2, and 3. The dose of ketorolac suppository and its side effects were also evaluated., Results: The VAS score on the day of the operation was significantly low in the PAI group and less incidence of night pain. The time point of the rescue drug was longer in the PAI group than the control group (12.7 hours vs. 0.62 hours; p < 0.01). No cardiac or central nervous system toxicity was observed., Discussion: In our study, PAI in the shoulder after mini-open rotator cuff repair showed effective pain control on the day of the surgery, postponed the time of the first dosage of intravenous pain medication, and reduced the total dosage of the intravenous pain medication., Competing Interests: Conflicts of interest: Dr.Wei-Ming Chen, an editorial board member at the Journal of the Chinese Medical Association, had no role in the peer-review process of the decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Ageing and chronic diseases lead to muscle loss and impair the regeneration of skeletal muscle. Thus, it's crucial to seek for effective intervention to improve the muscle regeneration. Tid1, a mitochondrial co-chaperone, is important to maintain mitochondrial membrane potential and ATP synthesis. Previously, we demonstrated that mice with skeletal muscular specific Tid1 deficiency displayed muscular dystrophy and postnatal lethality. Tid1 can interact with STAT3 protein, which also plays an important role during myogenesis. In this study, we used GMI, immunomodulatory protein of Ganoderma microsporum, as an inducer in C2C12 myoblast differentiation. We observed that GMI pretreatment promoted the myogenic differentiation of C2C12 myoblasts. We also showed that the upregulation of mitochondria protein Tid1 with the GMI pre-treatment promoted myogenic differentiation ability of C2C12 cells. Strikingly, we observed the concomitant elevation of STAT3 acetylation (Ac-STAT3) during C2C12 myogenesis. Our study suggests that GMI promotes the myogenic differentiation through the activation of Tid1 and Ac-STAT3., Competing Interests: The authors have declared that no competing interests exist.

Patients with Idiopathic Parkinson's Disease (PD) have an increased risk for fractures. Currently, many studies have reported inferior outcomes in PD patients after orthopedic procedures. However, there are very few studies assessing the outcome of upper extremity fractures (UEF) in PD patients. In this study, we reviewed 40 patients with PD that received surgical intervention for an UEF. We retrospectively reviewed patients with PD that received surgical fixation for an UEF at a tertiary trauma center. The primary objective was to determine the treatment failure rate after surgical fixation. The secondary outcomes include mode of failure, time to treatment failure, length of hospital stay, readmission rate, reoperation rate, and postoperative complications. A total of 40 patients with PD (42 fractures) underwent surgery. The most common fracture type was radius fracture (n = 19), followed by humerus fracture (n = 15), metacarpal/phalangeal fracture (n = 5), clavicle fracture (n = 2) and olecranon fracture (n = 1). The overall treatment failure rate was 40.5% (n = 17). The time to treatment failure was 1.24 ± 3.1 months and length of hospital stay was 6 ± 3.9 days, the readmission rate within 30 days was 14% (n = 6), and reoperation rate was 14% (n = 6). The complication rate was 16.6% (n = 7) and patients with humeral fractures appeared to have the longest hospital stays (6.6 days) and increased complication rates (13%, n = 2). Patients with PD have high treatment failure rates despite surgical fixation of an UEF. These patients often have a frail status with multiple comorbidities which may complicate their postoperative course.Level of evidence level 4 case series.

Background: Traumatic hip dislocation with or without acetabular fractures can lead to various outcomes of the hip. Long-term follow-up studies on traumatic hip dislocation are few. We conducted a retrospective study of the treatment and long-term outcomes in patients with hip dislocation to determine prognostic factors., Methods: From 2001 to 2016, we enrolled 38 patients in our study. All the patients had been diagnosed through radiography or computed tomography. Emergent closed reduction was performed initially. We hypothesized that poor outcomes, including osteonecrosis and traumatic osteoarthritis, are related to specific factors., Results: All the patients had posterior dislocation initially. Closed reduction or open reduction due to irreducible after closed reduction was performed within 6 hours of dislocation in most patients. In total, nine patients had poor outcomes of the hip, including osteonecrosis and traumatic osteoarthritis and total hip arthroplasty. Specific factors that lead to poor outcomes were patient age and timing of reduction., Conclusion: Although end results in severe traumatic hip dislocation are disappointing, conservatism in applying the secondary reconstructive procedure is desirable. In our series, crucial factors for long-term prognosis were patient age and timing of hip reduction.

Polymer polyethylene glycol (PEG), or PEGylation of polypeptides improves protein drug stability by decrease degradation and reduces renal clearance. To produce a pharmaceutical disintegrin derivative, the N-terminal PEGylation technique was used to modify the disintegrin derivative [KGDRR]trimucrin for favorable safety and pharmacokinetic profiles and antithrombotic efficacy. We compared intact [KGDRR]trimucrin (RR) and PEGylated KGDRR (PEG-RR) by in vitro and in vivo systems for their antithrombotic activities. The activity of platelet aggregation inhibition and the bleeding tendency side effect were also investigated. PEG-RR exhibited optimal potency in inhibiting platelet aggregation of human/mouse platelet-rich plasma activated by collagen or ADP with a lower IC 50 than the intact derivative RR. In the illumination-induced mesenteric venous thrombosis model, RR and PEG-RR efficaciously prevented occlusive thrombosis in a dose-dependent manner. In rotational thromboelastometry assay, there was no effect of PEG-RR in human whole blood coagulation even given at a higher concentration (30 μg/mL), while RR slightly prolonged clotting time. However, RR and PEG-RR were not associated with severe thrombocytopenia or bleeding in FcγRIIa-transgenic mice at equally efficacious antithrombotic dosages. We also found the in vivo half-life of PEGylation was longer than RR (RR: 15.65 h vs. PEG-RR: 20.45 h). In conclusion, injectable PEG-RR with prolonged half-life and decreased bleeding risk is a safer anti-thrombotic agent for long-acting treatment of thrombus diseases., Competing Interests: The authors declare no conflict of interest.

Head and neck squamous cell carcinoma (HNSCC) is a highly lethal disease with high-level of epidemic both in the world and Taiwan. Previous studies support that head and neck cancer-initiating cells (HN-CICs), a subpopulation of cancer cells with enhanced stemness properties, contribute to therapy resistance and tumor recurrence. Arsenic trioxide (As 2 O 3 ; ATO) has shown to be an effective anti-cancer drug targeting acute promyelocytic leukemia (APL). Combinatorial treatment with high dose of ATO and cisplatin (CDDP) exert synergistic apoptotic effects in cancer cell lines of various solid tumors, however, it may cause of significant side effect to the patients. Nevertheless, none has reported the anti-cancerous effect of ATO/CDDP targeting HN-CICs. In this study, we aim to evaluate the low dose combination of ATO with conventional chemo-drugs CDDP treatment on targeting HN-CICs. We first analyzed the inhibitory tumorigenicity of co-treatment with ATO and chemo-drugs on HN-CICs which are enriched from HNSCC cells. We observed that ATO/CDDP therapeutic regimen successfully synergized the cell death on HN-CICs with a Combination Index (CI) <1 by Chou-Talalay's analysis in vitro . Interestingly, the ATO/CDDP regimen also induced exaggerated autophagy on HN-CICs. Additionally, this drug combination strategy also empowered both preventive and therapeutic effect by in vivo xenograft assays. Finally, we provide the underlying molecular mechanisms of ATO-based therapeutic regimen on HN-CICs. Together, low dose of combinatorial ATO/CDDP regimen induced cell death as well as exacerbated autophagy via AMPK-STAT3 mediated pathway in HN-CICs., (Copyright © 2020 Hu, Teo, Huang, Lee and Lo.)

Introduction: Idiopathic Parkinson's disease (PD) is a progressive neurologic disorder causing postural instability and unsteady gait. These patients are at increased risk for fractures and have inferior outcomes after treatment. Several studies have evaluated the incidence and outcome of PD patients after hip fractures. However, there are limited studies assessing the outcome of upper extremity fractures in these patients. In this study, we evaluated the outcome of PD patients that received surgical intervention for distal radial fractures (DRF). We hypothesize that these patients have an inferior outcome after surgery in comparison with non-PD patients., Methods: Between May 2005 and May 2017, we retrospectively reviewed all of the patients with DRF and subsequently underwent open reduction and internal fixation (ORIF) at a level 1 trauma center. All of the surgeries were performed by fellowship-trained orthopedic surgeons. The inclusion criteria include patients with a definitive diagnosis of PD, non-pathological DRF, and a minimum follow-up of 1 year or up until the time of treatment failure was noted. Each PD patient was matched for age and gender to 3 non-PD patients. The primary objective was to determine the failure rate after surgical fixation for DRF. The secondary outcomes include time to treatment failure, reoperation rate, readmission rate, length of hospital stay, and postoperative complications., Results: A total of 88 patients were included in this study (23 PD, 65 non-PD patients). All underwent ORIF and received standard postoperative follow-ups. The overall treatment failure rate in PD was 39.1% vs. 4.6% in the non-PD group (p < 0.05). The time to treatment failure were 9.11 ± 3.86 weeks and 14.67 ± 5.8 weeks for PD and non-PD, respectively (p < 0.05). PD patients had a significantly higher rate of failure when k-wires and ESF were used (p < 0.05%), while loss of reduction was the most common mode of failure in PD (44.4%). The length of hospital stay for PD was 5.3 ± 4.69 days compared with 3.78 ± 0.96 days for non-PD (p = 0.01). There were 3 PD patients readmitted within 30 days after surgery, and 1 patient had pneumonia after the surgery., Conclusion: This study revealed that patients with PD have a high treatment failure rate despite surgical intervention for DRF. PD patients had a longer hospital stay and had a shorter time to treatment failure. In treating PD patients complicated with DRF, the surgeon must take into consideration the complex disease course of PD and the associated comorbidities such as osteoporosis, frail status, and frequent falls. Rehabilitation and disposition plans should be discussed in advance and longer hospital stays should be expected. Level of evidenceLevel IV, retrospective cohort study.

Background: Pretreatment of lignocellulosic biomass generates different types of inhibitors (e.g., furfural and acetic acid), which could remarkably inhibit subsequent ethanol fermentation. Here, biochar as an additive in the fermentation broth was first applied to enhance ethanol production by Z. mobilis wild-type strain ZM4 in the presence of typical inhibitors., Results: This study showed that the biochar-mediated tolerance to furfural and acetic acid for the strain Z. mobilis  ZM4 was the highest reported level, resulting in much higher ethanol productivity under stress conditions than that in non-treated conditions. Further analysis showed that adsorptive detoxification was not the controlling factor for enhanced ethanol production under stress conditions, attributed to its low removal of furfural (< 20%) and incapability of acetic acid removal. When biochar was filtered from the biochar-treated inhibitor-containing broth, it still showed enhanced ethanol production. Furthermore, Z. mobilis immobilized on biochar was also observed. Thus, biochar extracts in the fermentation broth and cell immobilization on biochar might be the controlling factors for enhanced ethanol production under stress conditions., Conclusions: These results indicate that biochar-mediated enhanced ethanol fermentation (BMEEF) might be a promising strategy for ethanol production from lignocellulosic biomass., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Life-threatening thrombocytopenia and bleeding, common side effects of clinically available α IIb β 3 antagonists, are associated with the induction of ligand-induced integrin conformational changes and exposure of ligand-induced binding sites (LIBSs). To address this issue, we examined intrinsic mechanisms and structure-activity relationships of purified disintegrins, from Protobothrops flavoviridis venom (i.e., Trimeresurus flavoviridis ), TFV-1 and TFV-3 with distinctly different pro-hemorrhagic tendencies. TFV-1 with a different α IIb β 3 binding epitope from that of TFV-3 and chimeric 7 × 10 3 Fab, i.e., Abciximab, decelerates α IIb β 3 ligation without causing a conformational change in α IIb β 3 , as determined with the LIBS antibody, AP5, and the mimetic, drug-dependent antibody (DDAb), AP2, an inhibitory monoclonal antibody raised against α IIb β 3 . Consistent with their different binding epitopes, a combination of TFV-1 and AP2 did not induce FcγRIIa-mediated activation of the ITAM-Syk-PLCγ2 pathway and platelet aggregation, in contrast to the clinical antithrombotics, abciximab, eptifibatide, and disintegrin TFV-3. Furthermore, TFV-1 selectively inhibits Gα 13 -mediated platelet aggregation without affecting talin-driven clot firmness, which is responsible for physiological hemostatic processes. At equally efficacious antithrombotic dosages, TFV-1 caused neither severe thrombocytopenia nor bleeding in FcγRIIa-transgenic mice. Likewise, it did not induce hypocoagulation in human whole blood in the rotational thromboelastometry (ROTEM) assay used in perioperative situations. In contrast, TFV-3 and eptifibatide exhibited all of these hemostatic effects. Thus, the α IIb β 3 antagonist, TFV-1, efficaciously prevents arterial thrombosis without adversely affecting hemostasis.

Background and Purpose: Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad-spectrum pharmacological properties including anti-microbial, anti-diabetic and anti-tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti-angiogenic mechanisms of a novel 2-aminobenzimidazole-based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor., Experimental Approach: Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF-A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti-angiogenic effects of Jzu 17., Key Results: Jzu 17 inhibited VEGF-A-induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF-A-induced microvessel sprouting ex vivo and attenuated VEGF-A- or tumour cell-induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR-2 and its downstream signalling molecules in VEGF-A-stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR-2 with high affinity., Conclusions and Implications: Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF-A-VEGFR-2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis-related diseases., (© 2019 The British Pharmacological Society.)

Objective: To share our experience of transition from multiport to single-site robotic surgery for benign gynecological conditions as well as to assess the selection criteria of candidates for robotic single-site supracervical hysterectomy (RSSH)., Materials and Methods: A retrospective review was conducted on patients undergoing robotic supracervical hysterectomy by a single surgeon in a single institute between June 2014 and December 2017. Patients who underwent additional procedures along with supracervical hysterectomy and who had unexpectant corpus malignancy proved pathologically were excluded from comparisons between patients undergoing RSSH and robotic multiport supracervical hysterectomy (RMSH)., Results: Between June 2014 and December 2017, we accomplished 26 RSSH and 57 RMSH. There were no conversions, intraoperative complications, and readmissions within 30 days after surgery. In the RSSH group, the mean uterine weight was 264.6 ± 140.9 g with mean docking time of 15.8 ± 5.5 min, mean console time of 61.1 ± 35.6 min and mean operative time of 140.3 ± 34.4 min. In comparison to the RMSH group, the percentage of overweight/obese patients was lower (p = 0.018) and the uterine size was smaller (p < 0.001) with adenomyosis diagnosed more frequently (p = 0.002) in the RSSH group. While the operative time in the RSSH group was significantly shorter (p = 0.002), the RSSH group took longer time in docking (p < 0.001) and comparable time in console (p = 0.254). In view of chronological change, docking time and console time in the RMSH group remained steady, whereas steep decreases were observed in the RSSH group. The intraoperative blood loss and hemoglobin drop were comparable. The length of hospital stay was significantly shorter in the RSSH group (p = 0.005)., Conclusion: Transition from multiport to single-site surgery can be smooth for a surgical team experienced in the conventional multiport robotic system. RSSH is safe and feasible in properly selected patients., (Copyright © 2019. Published by Elsevier B.V.)

Snake venoms affect blood coagulation and platelet function in diverse ways. Some venom components inhibit platelet function, while other components induce platelet aggregation. Among the platelet aggregation inhibitors, disintegrins have been recognized as unique and potentially valuable tools for examining cell-matrix and cell-cell interactions and for the development of antithrombotic and antiangiogenic agents according to their anti-adhesive and anti-migration effect on tumor cells and antiangiogenesis activities. Disintegrins represent a family of low molecular weight, cysteine-rich, Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing polypeptides, which inhibit fibrinogen binding to integrin αIIbβ3 (i.e., platelet glycoprotein IIb/IIIa), as well as ligand binding to integrins αvβ3, and α5β1 expressed on cells (i.e., fibroblasts, tumor cells, and endothelial cells). This review focuses on the current efforts attained from studies using disintegrins as a tool in the field of arterial thrombosis, angiogenesis, inflammation, and tumor metastasis, and briefly describes their potential therapeutic applications and side effects in integrin-related diseases. Additionally, novel R(K)GD-containing disintegrin TMV-7 mutants are being designed as safer antithrombotics without causing thrombocytopenia and bleeding.

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to  stat1 -/- mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.

Background: Few studies have investigated the longitudinal association between cervical spondylosis (CS) and migraine by using a nationwide population-based database. Methods: We conducted a retrospective cohort study from 2000 to 2011 identifying 27,930 cases of cervical spondylosis and 111,720 control subjects (those without cervical spondylosis) from a single database. The subjects were frequency-matched on the basis of sex, age, and diagnosis date. The non- cervical spondylosis cohort was four times the size of the cervical spondylosis cohort. To quantify the effects of cervical spondylosis on the risk of migraine, univariate and multivariate Cox proportional hazard regression analyses were used to calculate the hazard ratio (HR), and 95% confidence interval (CI). Results: After a 10-year follow-up controlling for potential confounding factors, overall migraine incidence was higher in the cervical spondylosis cohort than in the non-cervical spondylosis cohort (5.16 and 2.09 per 1000 people per year, respectively; crude hazard ratio = 2.48, 95% confidence interval = 2.28-2.69), with an adjusted hazard ratio of 2.03 (95% confidence interval = 1.86-2.22) after accounting for sex, age, comorbidities, and medication. Individuals with myelopathy in the cervical spondylosis cohort had a 2.19 times (95% confidence interval = 1.80-2.66) higher incidence of migraine when compared than did those in the non- cervical spondylosis cohort. Conclusions: Individuals with cervical spondylosis exhibited a higher risk of migraine than those without cervical spondylosis. The migraine incidence rate was even higher among individuals with cervical spondylotic myelopathy., Competing Interests: The authors declare no conflict of interest.

Ultrasound-guided interscalene brachial plexus blockade (IBPB) has a relatively high success rate in shoulder surgery; however, whether multiple injections are superior to a single injection (SI) is currently unknown. In the present study, ultrasound-guided SI and triple-injection (TI) IBPBs were compared in a prospective randomized trial. A total of 111 patients undergoing arthroscopic shoulder surgery and presenting with an American Society of Anesthesiologists physical status grading of I-II were randomly allocated to receive IBPB with 15 ml of 1% ropivacaine as a SI or TI. Performance time, procedure-related pain scores, success rate and prevalence of complications were recorded. The distribution of sensory and motor block onset in the radial, median, ulnar and axillary nerves were assessed every 5 min until 30 min post-local anesthetic injection. The duration of sensory and motor blocks were also assessed. A significantly longer performance time was recorded in the TI group (P<0.001). No significant difference was observed in success rate (91% in TI vs. 88% in SI) 30 min post-injection, and the prevalence of complications and procedure-related pain were similar between the two groups. Sensory and motor blocks of the ulnar nerve in the TI group were significantly faster and more successful compared with the SI group at all time points (P<0.041). It was also observed that sensory and motor blocks in the TI group were prolonged compared with the SI group (P<0.041). In conclusion, the TI method exhibited a faster time of onset and resulted in a more successful blockade of the ulnar nerve. TI method may be a more effective approach for IBPB in a clinical setting.

The aim of the present study was to investigate the effects of preconditioning of physiological cyclic stretch (CS) on the overexpression of early pro-inflammatory cytokines [including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8] during the inflammatory response induced by pathologically mechanical stretch in lung epithelial cells, and to determine its molecular mechanism of action. Cells were subjected to 5% CS for various durations (0, 15, 30, 60 and 120 min) prior to 6 h treatment with pathological 20% CS. In a separate experiment, cells were preconditioned with physiological 5% CS or incubated with a nuclear factor (NF)-κB inhibitor, pyrroldine dithiocarbamate (PDTC). The expression levels of inflammatory mediators were measured using reverse transcription-quantitative polymerase chain reaction. NF-κB was quantified using western blot analysis. Preconditioning with physiological 5% CS for 30, 60 and 120 min was demonstrated to significantly attenuate the release of pathologically mechanical stretch-induced early pro-inflammatory cytokines (TNF-α, IL-1β and IL-8) in alveolar epithelial cells (P<0.05) and significantly reduce the expression of NF-κB (P<0.05). Peak suppression was observed in cells preconditioned for 60 min. In the second set of experiments, it was demonstrated that mechanical stretch-induced release of TNF-α, IL-1β and IL-8 was significantly inhibited by both PDTC pretreatment and 5% CS pretreatment alone (all P<0.05). Furthermore, significant inhibition was also observed when both 5% CS pretreatment and PDTC pretreatment was used on mechanical stretch-induced cells (P<0.05), which was markedly greater than the inhibition induced by either pretreatment alone. The present findings suggest that preconditioning with physiological 5% CS is able to inhibit the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells. These anti-inflammatory effects are induced, at least in part, by suppressing the NF-κB signaling pathway.

Essentials FcγRIIa-mediated thrombocytopenia is associated with drug-dependent antibodies (DDAbs). We investigated the correlation between α IIb β 3 binding epitopes and induction of DDAbs. An FcγRIIa-transgenic mouse model was used to evaluate thrombocytopenia among anti-thrombotics. An antithrombotic with binding motif toward α IIb β-propeller domain has less bleeding tendency., Summary: Background Thrombocytopenia, a common side effect of Arg-Gly-Asp-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin α IIb β 3 . Objective To explore the correlation between α IIb β 3 binding epitopes and induction of DDAb binding to conformation-altered α IIb β 3 , we examined whether two purified disintegrins, TMV-2 and TMV-7, with distinct binding motifs have different effects on induction of α IIb β 3 conformational change and platelet aggregation in the presence of AP2, an IgG 1 inhibitory mAb raised against α IIb β 3 . Methods We investigated the possible mechanisms of intrinsic platelet activation of TMV-2 and TMV-7 in the presence of AP2 by examining the signal cascade, tail bleeding time and immune thrombocytopenia in Fc receptor γ-chain IIa (FcγRIIa) transgenic mice. Results TMV-7 has a binding motif that recognizes the α IIb β-propeller domain of α IIb β 3 , unlike that of TMV-2. TMV-7 neither primed the platelets to bind ligand, nor caused a conformational change of α IIb β 3 as identified with the ligand-induced binding site mAb AP5. In contrast to eptifibatide and TMV-2, cotreatment of TMV-7 with AP2 did not induce FcγRIIa-mediated platelet aggregation and the downstream activation cascade. Both TMV-2 and TMV-7 efficaciously prevented occlusive thrombosis in vivo. Notably, both eptifibatide and TMV-2 caused severe thrombocytopenia mediated by FcγRIIa, prolonged tail bleeding time in vivo, and repressed human whole blood coagulation indexes, whereas TMV-7 did not impair hemostatic capacity. Conclusions TMV-7 shows antiplatelet and antithrombotic activities resulting from a mechanism different from that of all other tested α IIb β 3 antagonists, and may offer advantages as a therapeutic agent with a better safety profile., (© 2017 International Society on Thrombosis and Haemostasis.)

Adductor canal block (ACB) is an effective analgesic alternative to femoral nerve block after total knee arthroplasty (TKA). The aim of the present study was to investigate whether addition of dexamethasone to ropivacaine for ACB is able to prolong analgesia and reduce pain. Study participants were randomized into groups receiving ACB with either 0.5% ropivacaine + normal saline (control group; n=93) or 0.5% ropivacaine + 8 mg dexamethasone (dexamethasone group; n=93). All patients were subjected to identical peri-operative management. Patients were assessed for the duration of analgesia by the return of pinprick sensation. A numerical rating scale, ranging from 0 to 10, was used to assess post-operative pain at 6, 12, 18, 24 and 48 h. Opioid use was recorded. Serum C-reactive protein and interleukin-6 levels were measured at 3, 6, 12, 24 and 48 h after surgery. The results revealed that the duration of sensory block was significantly longer in the dexamethasone group (23.42±3.35 vs. 14.67±2.96 h in control group, P<0.05). The dexamethasone group also had significantly lower pain scores at 6, 12, 18 and 24 h after surgery (all P<0.001), and at 48 h, pain was comparable in the two groups. Reduction in post-operative pain was associated with a decrease in serum C-reactive protein. Morphine use in the first 24 h after surgery was also lower in the dexamethasone group (4.23±1.80 vs. 8.42±2.44 mg in control group, P<0.05). In conclusion, addition of dexamethasone to ropivacaine for ACB was able to prolong the duration of analgesia and decreased early post-operative pain following TKA.

Essentials ARHGEF10 single-nucleotide polymorphism provides risk of ischemic and atherothrombotic stroke. The role of ARHGEF10 in platelet function was examined using ARHGEF10 knockout mice. ARHGEF10 deficiency inhibits platelet function and arterial thrombus formation. ARHGEF10 knockout protects mice from stroke-induced infarction., Summary: Background ARHGEF10, a member of the Rho guanine nucleotide exchange factor (GEF) family, stimulates Rho GTPases. Rho GTPases have been reported to regulate a variety of cellular behaviors, such as cell polarity, cytoskeletal organization, and gene transcription. ARHGEF10 single-nucleotide polymorphisms are linked to the risk of ischemic stroke. However, the role of ARHGEF10 in platelet function remains unknown. Objective To examine the role of ARHGEF10 in platelet function. Methods ARHGEF10 -/- were generated. We examined the in vitro and in vivo effects of ARHGEF10 knockout on platelet function and arterial thrombosis formation. Results ARHGEF10 -/- mice had normal platelet counts, but showed altered aggregation in response to thrombin, collagen, ADP, protease-activated receptor-4 peptide, and U46619 stimulation. ARHGEF10 knockout influenced platelet spreading on fibrinogen-coated surfaces, and caused the platelets to show less lamellipodia-like extension than wild-type platelets. ARHGEF10 knockout also inhibited platelet clot retraction induced by thrombin stimulation. ARHGEF10 knockout resulted in prolonged tail bleeding time and inhibited the stable thrombus formation induced by FeCl 3 in the carotid artery. Conclusions ARHGEF10 serves as an important regulator in platelet shape change, spreading, and aggregation. Moreover, ARHGEF10 also plays an important role in arterial thrombosis formation., (© 2017 International Society on Thrombosis and Haemostasis.)

Objective: Currently prescribed antiplatelet drugs have 1 common side effect-an increased risk of hemorrhage and thrombocytopenia. On the contrary, bleeding defects associated with glycoprotein VI (GPVI) expression deficiency are usually slightly prolonged bleeding times. However, GPVI antagonists are lacking in clinic., Approach and Results: Using reverse-phase high-performance liquid chromatography and sequencing, we revealed the partial sequence of trowaglerix α subunit, a potent specific GPVI-targeting snaclec (snake venom C-type lectin protein). Hexapeptide (Troα6 [trowaglerix a chain hexapeptide, CKWMNV]) and decapeptide (Troα10) derived from trowaglerix specifically inhibited collagen-induced platelet aggregation through blocking platelet GPVI receptor. Computational peptide design helped to design a series of Troα6/Troα10 peptides. Protein docking studies on these decapeptides and GPVI suggest that Troα10 was bound at the lower surface of D1 domain and outer surface of D2 domain, which was at the different place of the collagen-binding site and the scFv (single-chain variable fragment) D2-binding site. The newly discovered site was confirmed by inhibitory effects of polyclonal antibodies on collagen-induced platelet aggregation. This indicates that D2 domain of GPVI is a novel and important binding epitope on GPVI-mediated platelet aggregation. Troα6/Troα10 displayed prominent inhibitory effect of thrombus formation in fluorescein sodium-induced platelet thrombus formation of mesenteric venules and ferric chloride-induced carotid artery injury thrombosis model without prolonging the in vivo bleeding time., Conclusions: We develop a novel antithrombotic peptides derived from trowaglerix that acts through GPVI antagonism with greater safety-no severe bleeding. The binding epitope of polypeptides on GPVI is novel and important. These hexa/decapeptides have therapeutic potential for developing ideal small-mass GPVI antagonists for arterial thrombogenic diseases., (© 2017 American Heart Association, Inc.)

VEGF and VEGFR antibodies have been used as a therapeutic strategy to inhibit angiogenesis in many diseases; however, frequent and repeated administration of these antibodies to patients induces immunogenicity. In previous studies, we demonstrated that aggretin, a heterodimeric snake venom C-type lectin, exhibits pro-angiogenic activities via integrin α2β1 ligation. We hypothesised that small-mass aggretin fragments may bind integrin α2β1 and act as antagonists of angiogenesis. In this study, the anti-angiogenic efficacy of a synthesised aggretin α-chain C-terminus (AACT, residue 106-136) was evaluated in both in vitro and in vivo angiogenesis models. The AACT demonstrated inhibitory effects on collagen-induced platelet aggregation and HUVEC adhesion to immobilised collagen. These results indicated that AACT may block integrin α2β1-collagen interaction. AACT also inhibited HUVEC migration and tube formation. Aortic ring sprouting and Matrigel implant models demonstrated that AACT markedly inhibited VEGF-induced neovascularisation. In addition, induction of FAK/PI3K/ERK1/2 tyrosine phosphorylation and talin 1/2 associated with integrin β1 which are induced by VEGF were blocked by AACT. Similarly, tyrosine phosphorylation of VEFGR2 and ERK1/2 induced by VEGF was diminished in integrin α2-silenced endothelial cells. Our results demonstrate that AACT is a potential therapeutic candidate for angiogenesis related-diseases via integrin α2β1 blockade.

Background: Four-corner fusion is an effective procedure to treat advanced degenerative osteoarthritis of scaphoid nonunion advanced collapse or scapho-lunate advanced collapse wrists. However, lunocapitate fusion, an alternative procedure, shows benefits including less dissection of the soft tissue and also a shorter operation time. We reviewed 10 cases to reveal the complication rates and clinical outcomes of this procedure., Methods: We retrospectively reviewed 10 patients with symptomatic scaphoid nonunion advanced collapse or scapho-lunate advanced collapse wrists who had received lunocapitate fusion with scaphoid excision. The average follow-up period was 44.5 months (range, 22-68 months). Clinical evaluations were conducted and determined by radiographs, range of motion (flexion-extension), visual analog scale, and Mayo wrist scores. Complications including nonunion and implant migration were recorded., Results: Among these patients, eight developed solid radiographic union while the remaining two patients showed bone resorption and implant migration and needed revision surgeries. The visual analog scale was decreased from 5.0 to 1.1, and the flexion-extension arc was increased from 61° to 72.5°. The average Mayo Wrist Score was 70 points. The results showed outcomes similar to those of previous studies., Conclusion: Through our investigation and findings, we conclude that lunocapitate fusion can restore a functional and almost pain-free wrist. Moreover, these results were maintained at follow-up sessions, with complication rates being similar to those of previous studies. These results conclude a satisfactory therapeutic alternative to four-corner fusion for advanced degenerative osteoarthritis of wrists., (Copyright © 2016. Published by Elsevier Taiwan LLC.)

Hydroxypropyl methylcellulose (HPMC) is a biopolymer that is biodegradable, environmentally friendly, and bio-friendly. Owing to its unique chemical structure, HPMC can reduce the coefficient of friction (COF) and frictional wear and thus possesses excellent lubrication properties. HPMC has good dissolvability in specific solvents. The present research focuses on the reversible dissolution reaction subsequent to the film formation of HPMC, with a view to the healing and lubrication properties of thin films. Raman spectroscopy was used to test the film-forming properties of HPMC and the dissolution characteristics of various solvents. In this study, the solvents were water, methanol, ethanol, and acetone. The results showed that the HPMC film had the highest dissolvability in water. The ball-on-disk wear test was used to analyze the lubrication properties of HPMC, and the results showed that HPMC had the same COF and lubrication properties as the original film after being subjected to the water healing treatment. The HPMC film can be reused, recycled, and refilled, making it an ideal lubricant for next-generation ecotribology.

Background: Tid1 is a mitochondrial co-chaperone protein and its transcript is abundantly expressed in skeletal muscle tissues. However, the physiological function of Tid1 during skeletal myogenesis remains unclear., Methods: In vitro induced differentiation assay of mouse myoblast C2C12 cells was applied to examine the physiological role of Tid1 during skeletal myogenesis. In addition, transgenic mice with muscle specific (HSA-Cre) Tid1 deletion were established and examined to determine the physiological function of Tid1 during skeletal muscle development in vivo., Results: Expression of Tid1 protein was upregulated in the differentiated C2C12 cells, and the HSA-Tid1 f/f mice displayed muscular dystrophic phenotype. The expression of myosin heavy chain (MyHC), the protein served as the muscular development marker, was reduced in HSA-Tid1 f/f mice at postnatal day (P)5 and P8. The protein levels of ATP sensor (p-AMPK) and mitochondrial biogenesis protein (PGC-1α) were also significantly reduced in HSA-Tid1 f/f mice. Moreover, Tid1 deficiency induced apoptotic marker Caspase-3 in muscle tissues of HSA-Tid1 f/f mice. Consistent with the in vivo finding, we observed that downregulation of Tid1 not only reduced the ATP production but also abolished the differentiation ability of C2C12 cells by impairing the mitochondrial activity., Conclusion: Together, our results suggest that Tid1 deficiency reduces ATP production and abolishes mitochondrial activity, resulting in energy imbalance and promoting apoptosis of muscle cells during myogenesis. It will be of importance to understand the function of Tid1 during human muscular dystrophy in the future.

S100A4 is a calcium-binding protein capable of promoting epithelial-mesenchymal transition. Previously, we have demonstrated that S100A4 is required to sustain the head and neck cancer-initiating cells (HN-CICs) subpopulation. In this study, to further investigate the molecular mechanism, we established the head and neck squamous cell carcinoma (HNSCC) cell lines stably expressing mutant S100A4 proteins with defective calcium-binding sites on either N-terminal (NM) or C-terminal (CM), or a deletion of the last 15 amino-acid residues (CD). We showed that the NM, CM and CD harboring sphere cells that were enriched with HN-CICs population exhibited impaired stemness and malignant properties in vitro, as well as reduced tumor growth ability in vivo. Mechanistically, we demonstrated that mutant S100A4 proteins decreased the promoter activity of Nanog, likely through inhibition of p53. Moreover, the biophysical analyses of purified recombinant mutant S100A4 proteins suggest that both NM and CM mutant S100A4 were very similar to the WT S100A4 with subtle difference on the secondary structure, and that the CD mutant protein displayed the unexpected monomeric form in the solution phase.Taken together, our results suggest that both the calcium-binding ability and the C-terminal region of S100A4 are important for HN-CICs to sustain its stemness property and malignancy, and that the mechanism could be mediated by repressing p53 and subsequently activating the Nanog expression.

Snake venoms affect blood coagulation and platelet function in a complex manner. However, two classes of venom proteins, snaclecs and disintegrins have been shown to specifically target receptors including GPIb, α2β1, GPVI, CLEC-2 and integrins αIIbβ3, αvβ3, α5β1 expressed on platelets, endothelial cells, phagocytes, tumor cells, thus affecting cell-matrices and cell-cell interactions. Here, we focus on disintegrins, a class of low molecular mass Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing, cysteine-rich polypeptide derived from various viper snake venoms. This review describes the potential applications of disintegrins in field of integrin-related diseases, especially arterial thrombosis, angiogenesis, tumor progression and septic inflammation. In addition, a novel RGD-containing disintegrin TMV-7 is being developed as a safer antithrombotic agent with minimal side effects, such as thrombocytopenia and bleeding.

As angiogenesis is required for tumor growth and metastasis, suppressing angiogenesis is a promising strategy in limiting tumor progression. Vascular endothelial growth factor (VEGF)-A, a critical pro-angiogenic factor, has thus become an attractive target for therapeutic interventions in cancer. In this study, we explored the underlying mechanisms of a novel anthraquinone derivative DDA in suppressing angiogenesis. DDA inhibited VEGF-A-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs). DDA also reduced VEGF-A-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization in vivo. VEGF-A-induced VEGFR1, VEGFR2, FAK, Akt, ERK1/2 or STAT3 phosphorylation was reduced in the presence of DDA. In addition, NRP-1 siRNA reduced VEGF-A's enhancing effects in VEGFR2, FAK and Akt phosphorylation and cell proliferation in HUVECs. DDA disrupted VEGF-A-induced complex formation between NRP-1 and VEGFR2. Furthermore, systemic administration of DDA was shown to suppress tumor angiogenesis and growth in in vivo mouse xenograft models. Taken together, we demonstrated in this study that DDA exhibits anti-angiogenic properties through suppressing VEGF-A signaling. These observations also suggest that DDA might be a potential drug candidate for developing anti-angiogenic agent in the field of cancer and angiogenesis-related diseases.

The aim of the current study was to investigate Fas and FasL expression and myocardial cell apoptosis in viral myocarditis patients. Human heart specimens were selected from patients who were autopsied between February 2012 and February 2015; of these, 25 patients were diagnosed with viral myocarditis. Another 15 cases with no diagnosis of myocarditis were selected for the control group. All tissue specimens were divided into two parts, one for reverse transcription-polymerase chain reaction analysis and the other for immunohistochemical and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. In situ detection of apoptosis was performed by the TUNEL method, which revealed that myocardial cells from the viral myocarditis group exhibited significant apoptosis, whereas no apoptotic cells were observed in the control group. The number of cells staining positive for Fas and FasL protein in the viral myocarditis group was significantly higher than that in the control group (P < 0.05). There was also a correlation between Fas and FasL protein expression levels and scores (r = 0.92, P < 0.05). The mRNA expression of Fas and FasL was significantly higher in the viral myocarditis group than in the control group (P < 0.05). In conclusion, the Fas-FasL system may be involved in the pathogenesis of viral myocarditis. Furthermore, cytotoxic T lymphocytes may mediate cardiac muscle cells apoptosis via Fas-FasL signaling, and thus participate in the pathogenesis of viral myocarditis.

Bacterial infection-induced sepsis is the leading cause of septic inflammatory disease. Rhodostomin (Rn), a snake venom disintegrin, was previously reported to interact with the αVβ3 integrin and the TLR4 on phagocyte in attenuating LPS-induced endotoxemia. In this report, we further evaluated the effects of Rn on TLR2-activated monocytes and its in vivo efficacy. Rn effectively suppressed the adhesion, migration, and cytokine release of Pam3CSK4-activated THP-1 cells. Rn specifically bound to integrin αVβ3 of TLR2-activated THP-1. Integrin αV and Akt siRNA transfection both restrained Pam3CSK4-elicited cytokine release. Rn decreased the Pam3CSK4-induced phosporylation of MAPKs, degradation of IκB and activation of FAK, Akt, c-Src and Syk. The Pam3CSK4-induced translocation of MyD88, a central adaptor of TLR2, to the cell membrane was also inhibited by Rn treatment. In the polymicrobial inflammatory caecal ligation and puncture model, Rn significantly reduced pro-inflammatory cytokine and chemokine release, alleviated tissue injury and elevated survival rate in vivo. Taken together, in addition to inhibiting the activation of TLR4, Rn exhibits anti-inflammatory activity through antagonizing the activation of phagocytes and interrupting the crosstalk between αVβ3 and TLR2-dependent signaling pathways.

Podoplanin (PDPN) enhances tumor metastases by eliciting tumor cell-induced platelet aggregation (TCIPA) through activation of platelet C-type lectin-like receptor 2 (CLEC-2). A novel and non-cytotoxic 5-nitrobenzoate compound 2CP was synthesized that specifically inhibited the PDPN/CLEC-2 interaction and TCIPA with no effect on platelet aggregation stimulated by other platelet agonists. 2CP possessed anti-cancer metastatic activity in vivo and augmented the therapeutic efficacy of cisplatin in the experimental animal model without causing a bleeding risk. Analysis of the molecular action of 2CP further revealed that Akt1/PDK1 and PKCμ were two alternative CLEC-2 signaling pathways mediating PDPN-induced platelet activation. 2CP directly bound to CLEC-2 and, by competing with the same binding pocket of PDPN in CLEC-2, inhibited PDPN-mediated platelet activation. This study provides evidence that 2CP is the first defined platelet antagonist with CLEC-2 binding activity. The augmentation in the therapeutic efficacy of cisplatin by 2CP suggests that a combination of a chemotherapeutic agent and a drug with anti-TCIPA activity such as 2CP may prove clinically effective.

A novel method for preparing eco-biodegradable lubricant based on hydroxypropyl methylcellulose (HPMC) via hydration process is demonstrated. The smooth and homogeneous HPMC coating has a uniform thickness (~35 μm). It has been demonstrated that the preparation parameters play a critical role in controlling the lubricating behavior of the coating; in addition, excess HPMC and water concentration suppress the tribology properties. Nevertheless, a remarkable friction-reduction and anti-wear performance has been obtained. Impressively, the preparation parameter of 5% HPMC + 30 mL water significantly improves lubricant performance and durability. A simple approach for the water-degradability evaluation of HPMC is proposed.

Background and Purpose: Angiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF-A and its receptors (VEGFRs) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd26, and explored its anti-angiogenic mechanisms., Experimental Approach: The effects of PPemd26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models., Key Results: PPemd26 significantly inhibited VEGF-A-induced proliferation, migration, invasion and tube formation of HUVECs. PPemd26 also attenuated VEGF-A-induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo. In addition, PPemd26 inhibited VEGF-A-induced phosphorylation of VEGFR2 and its downstream protein kinases including Akt, focal adhesion kinase, ERK and Src. Furthermore, systemic administration of PPemd26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo. Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD31 and proliferation marker Ki-67., Conclusions and Implications: This study provides evidence that PPemd26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd26 is a potential drug candidate for developing anti-angiogenic agents for the treatment of cancer and angiogenesis-related diseases., (© 2014 The British Pharmacological Society.)