Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

Incremental value of amyloid PET in a tertiary memory clinic setting in China.

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.

Therapeutic efficacy of probiotics for symptoms of attention-deficit hyperactivity disorder in children and adolescents: meta-analysis.

BACKGROUND: The efficacy of probiotics as a therapeutic alternative for attention-deficit hyperactivity disorder (ADHD) remain unclear. AIMS: To investigate the effectiveness of probiotics for symptoms of ADHD and identify possible factors affecting their efficacy. METHOD: Randomised placebo-controlled trials were identified through searching major databases from inception to April 2023, using the main keywords 'probiotics' and 'ADHD' without limitation on languages or geographic locations. The outcome of interest included improvement in total symptoms of ADHD, symptoms of inattention and hyperactivity/impulsivity, and drop-out rate. Continuous and categorical data were expressed as effect sizes based on standardised mean differences (SMDs) and odds ratios, respectively, with 95% confidence intervals. RESULTS: Meta-analysis of seven trials involving 379 participants (mean age 10.37 years, range 4-18 years) showed no significant improvement in total symptoms of ADHD (SMD = 0.25; P = 0.12), symptoms of inattention (SMD = 0.14; P = 0.3) or hyperactivity/impulsivity (SMD = 0.08; P = 0.54) between the probiotic and placebo groups. Despite non-significance on subgroup analyses, there was a large difference in effect size between studies using probiotics as an adjunct to methylphenidate and those using probiotics as supplementation (SMD = 0.84 v. 0.07; P = 0.16), and a moderate difference in effect size between studies using multiple strains of probiotics and those using single-strain regimens (SMD = 0.45 v. 0.03; P = 0.19). CONCLUSIONS: Current evidence shows no significant difference in therapeutic efficacy between probiotics and placebos for treatment of ADHD symptoms. However, albeit statistically non-significant, higher therapeutic efficacies associated with multiple-strain probiotics or combining probiotics with methylphenidate may provide direction for further research.

Effects of probiotics on neurocognitive outcomes in infants and young children: a meta-analysis.

Background: Therapeutic efficacies of probiotics in improving neurocognitive functions in infants and young children remained unclear. This meta-analysis focused on different cognitive outcomes in this population. Methods: Major databases were searched electronically from inception to October 2023 to identify randomized controlled trials (RCTs) that investigated the therapeutic efficacy of probiotics in enhancing cognitive functions assessed by standardized tasks. The overall effect size was calculated as standardized mean difference (SMD) based on a random effects model. Results: Nine RCTs with 3,026 participants were identified. Both our primary and secondary results demonstrated no significant difference in neurocognitive outcomes between infants/children treated with probiotics and those receiving placebos. However, our subgroup analysis of studies that offered a probiotics treatment course of over six months demonstrated a significantly better neurocognitive outcome than placebos (SMD = 0.21, p = 0.03, two studies with 451 participants), but this finding was based on only two RCTs. Conclusion: Despite lack of significant therapeutic effects of probiotics on neurocognitive outcomes, our finding of a positive impact of probiotics on neurocognitive development in those undergoing treatment for over six months may provide an important direction for further investigations into the enhancement of therapeutic effects of probiotics on neurocognitive development in infants and young children. Systematic review registration: PROSPERO CRD42023463412.

The plant immune receptor SNC1 monitors helper NLRs targeted by a bacterial effector.

Plants deploy intracellular receptors to counteract pathogen effectors that suppress cell-surface-receptor-mediated immunity. To what extent pathogens manipulate intracellular receptor-mediated immunity, and how plants tackle such manipulation, remains unknown. Arabidopsis thaliana encodes three similar ADR1 class helper nucleotide-binding domain leucine-rich repeat receptors (ADR1, ADR1-L1, and ADR1-L2), which are crucial in plant immunity initiated by intracellular receptors. Here, we report that Pseudomonas syringae effector AvrPtoB suppresses ADR1-L1- and ADR1-L2-mediated cell death. ADR1, however, evades such suppression by diversifying into two ubiquitination sites targeted by AvrPtoB. The intracellular sensor SNC1 interacts with and guards the CCR domains of ADR1-L1/L2. Removal of ADR1-L1/L2 or delivery of AvrPtoB activates SNC1, which then signals through ADR1 to trigger immunity. Our work elucidates the long-sought-after function of SNC1 in defense, and also how plants can use dual strategies, sequence diversification, and a multi-layered guard-guardee system, to counteract pathogen's attack on core immunity functions.

A meta-analysis on the therapeutic efficacy of repetitive transcranial magnetic stimulation for cognitive functions in attention-deficit/hyperactivity disorders.

BACKGROUND: Therapeutic efficacies of repetitive transcranial magnetic stimulation (rTMS) for improving cognitive functions in patients with deficit/hyperactivity disorder (ADHD) remained unclear. The aim of this meta-analysis was to investigate the therapeutic efficacy of rTMS focusing on different cognitive performances. METHODS: Major databases were searched electronically from inception to February 2023 by using keywords mainly "rTMS" and "ADHD" to identify randomized controlled trials (RCTs) that investigated the therapeutic efficacy of rTMS for improving cognitive functions assessed by standardized tasks in patients with ADHD. The overall effect size (ES) was calculated as standardized mean difference (SMD) based on a random effects model. RESULTS: Meta-analysis of five RCTs with 189 participants (mean age of 32.78 and 8.53 years in adult and child/adolescent populations, respectively) demonstrated that rTMS was more effective for improving sustained attention in patients with ADHD compared with the control groups (SMD = 0.54, p = 0.001).Our secondary analysis also showed that rTMS was more effective for improving processing speed than the control groups (SMD = 0.59, p = 0.002) but not for enhancing memory or executive function. CONCLUSIONS: Our results supported the therapeutic efficacy of rTMS for improving sustained attention and processing speed. However, the limitation of available data warrants further studies to verify these findings.

Bulk T-cell receptor sequencing confirms clonality in pediatric eosinophilic esophagitis and identifies a food-specific repertoire.

BACKGROUND: Eosinophilic esophagitis (EoE) involves a chronic immune-mediated response to dietary antigens. Recent work identifies T-cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food-specific T-cell repertoire. We sought to confirm T-cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers. METHODS: Bulk TCR sequencing was performed on mRNA isolated from esophageal biopsies obtained from adults and children with EoE (n = 15) who had food triggers confirmed by endoscopic evaluation. Non-EoE adult and pediatric controls (n = 10) were included. Differences in TCR clonality by disease and treatment status were assessed. Shared and similar V-J-CDR3s were assessed based on specific food triggers. RESULTS: Active EoE biopsies from children but not adults displayed decreased unique TCRα/ß clonotypes and increased relative abundance of TCRs comprising >1% of the total compared to non-EoE controls and paired inactive EoE samples. Among patients in which baseline, post diet elimination, and food trigger reintroduction samples (n = 6) were obtained, we observed ~1% of TCRs were shared only between pre-diet elimination and trigger reintroduction. Patients with a shared EoE trigger (milk) had a greater degree of shared and similar TCRs compared to patients with differing triggers (seafood, wheat, egg, soy). CONCLUSION: We confirmed relative clonality in children but not adults with active EoE and identified potential food-specific TCRs, particularly for milk-triggered EoE. Further studies are needed to better identify the broad TCR repertoire relevant to food triggers.

Efficacy of electrical cranial stimulation for treatment of psychiatric symptoms in patients with anxiety: A systematic review and meta-analysis.

Background: Therapeutic effects of electrical cranial stimulation (CES) in patients suffering from anxiety remained unclear. This meta-analysis aimed at investigating acceptability and therapeutic efficacy of CES against anxiety, depression, and insomnia for patients who experienced symptoms of anxiety. Methods: Major electronic databases were searched from inception until December 10, 2022 for randomized controlled trials (RCT) focusing on therapeutic effectiveness of CES in patients whose primary complaints included anxiety. Effect sizes (ES) for different treatment outcomes were estimated by using generic inverse variance method. Results: Eight RCTs were identified including a total of 337 participants. The therapeutic effectiveness of CES was significantly better than that in the control groups for anxiety (ES=-0.96, p <0.00001, eight trials, 337 patients), depression (ES=-0.69, p=0.003, five trials), and insomnia (ES=-1.02, p = 0.0006, three trials) in those who presented with symptoms of anxiety. Subgroup analyses found that CES was equally effective regardless of comorbid presentation of depressive symptoms (ES=-0.94 in patients with anxiety only vs. ES=-1.06 in those with depression and anxiety) and whether CES was used as monotherapy or add-on therapy to medications (ES = -0.88 vs. ES = -1.12, respectively). Moreover, subgroup analysis of RCTs using the same device "Alpha-Stim" for CES was more effective in alleviating anxiety than sham controls (ES = -0.88, p < 0.00001, four trials, 230 patients). Regarding acceptability, the use of CES did not increase the risk of treatment-related dropout compared to the control group (RR = 1.26, p = 0.57, I2 = 0%, four trials, 324 patients). Conclusion: Our study supported the use of CES for symptoms of anxiety, depression, and insomnia in those suffering from anxiety with fair acceptability and demonstrated the efficacy of "Alpha-Stim", the most commonly used device for CES, in this patient population. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022382619.

C-Reactive Protein: The Most Familiar Stranger.

C-reactive protein (CRP) is a highly conserved pentraxin with pattern recognition receptor-like activities. However, despite being used widely as a clinical marker of inflammation, the in vivo functions of CRP and its roles in health and disease remain largely unestablished. This is, to certain extent, due to the drastically different expression patterns of CRP in mice and rats, raising concerns about whether the functions of CRP are essential and conserved across species and how these model animals should be manipulated to examine the in vivo actions of human CRP. In this review, we discuss recent advances highlighting the essential and conserved functions of CRP across species, and propose that appropriately designed animal models can be used to understand the origin-, conformation-, and localization-dependent actions of human CRP in vivo. The improved model design will contribute to establishing the pathophysiological roles of CRP and facilitate the development of novel CRP-targeting strategies.

Efficacy and tolerability of psychostimulants for symptoms of attention-deficit hyperactivity disorder in preschool children: A systematic review and meta-analysis.

BACKGROUND: There was no previous meta-analysis investigating the efficacy/tolerability of psychostimulants for symptoms of attention-deficit hyperactivity disorder (ADHD) in preschool children. METHODS: Databases including PubMed, the Cochrane Library, EMBASE, ScienceDirect, and ClinicalTrials.gov were searched from inception to March 2022 for randomized controlled trials (RCTs) on therapeutic efficacy of psychostimulants against ADHD symptoms in preschool children (age ≤6 years) compared with placebos. Primary outcomes were (a) changes in ADHD symptoms evaluated by validated rating scales from parents'/teacher's observation, or (b) post-intervention improvements in neuropsychological performance. Secondary outcomes were risks of adverse events. RESULTS: Meta-analysis of nine eligible trials including 544 preschool children (mean age=4.86 years, female=11.98%, median treatment duration=4.33 weeks) supported the efficacy of psychostimulants against global symptoms from observations of parents (Hedges' g=0.6152, p<0.0001) and teachers (Hedges' g=0.6563, p=0.0039). Efficacy of psychostimulants was also noted against symptoms of inattention and hyperactivity/impulsivity, especially the latter (i.e., main symptoms in preschool children). Moreover, male gender, older age, and longer treatment duration were associated with better efficacy. Regarding adverse events, only the risk of poor appetite was higher in the psychostimulant group (odds ratio [OR]=2.39). However, the qualities of evidence were low to very low, indicating potential discrepancy between the true and estimated effect. CONCLUSIONS: Our results showed that psychostimulants might be beneficial for preschool children with ADHD, especially hyperactivity/impulsivity from teachers' observation, with tolerable side effects. Nevertheless, the true magnitude of the effect needs to be confirmed with more research due to low to very low certainty of the evidence.

Salidroside ameliorates pathological cardiac hypertrophy via TLR4-TAK1-dependent signaling.

Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1  day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.

The effectiveness of child-centered play therapy for executive functions in children with attention-deficit/hyperactivity disorder.

INTRODUCTION: Child-centered play therapy (CCPT) is a practical and recommended non-medication intervention for children with Attention-deficit/hyperactivity disorder (ADHD) but the mechanism in between is unclear. AIM: This study proposed to examine the effectiveness of CCPT on neuropsychological deficits and behavioral symptoms in ADHD. METHODS: Participants with ADHD diagnosis were referred from senior child and adolescent psychiatrists, and typical developmental children (TD) were recruited from community as a control group. All participants' executive functions were evaluated using Cambridge Neuropsychological Test Automated Battery. First of all, the participants were evaluated using Child Behavior Checklist (CBCL) by their parents. The ADHD participants were assigned into CCPT (ADHDc) and waitlist (ADHDw) group; and the ADHDc group then received CCPT weekly for 12 sessions, while the ADHDw continuously received their regular treatment (i.e., medication treatment or other alternative treatments) as usual. RESULTS: Total 52 participants were recruited (17 with ADHD and 35 typically developed children, TD). The results showed that overall the ADHD groups had worse neuropsychological performance and more behavioural disturbance than did the TD (ps < .05). After receiving the CCPT, the results showed that the ADHDc group had significant improvement in the cognitive flexibility (p < .05); while the ADHDw group had no changes.

Surface electroencephalographic neurofeedback improves sustained attention in ADHD: a meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of surface electroencephalographic neurofeedback (EEG-NF) for improving attentional performance assessed by laboratory measures in patients with attention-deficit/hyperactivity disorder (ADHD) remains unclear. METHODS: Following the PRISMA guidelines, the PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ScienceDirect, Web of Science, and ClinicalTrials.gov databases were systematically searched for randomized controlled trials on the efficacy of surface EEG-NF against ADHD focusing on attentional performance evaluated by laboratory measures from inception to January 2022. RESULTS: Fourteen eligible studies were analyzed. Of the 718 participants involved, 429 diagnosed with ADHD received EEG-NF treatment. Significant improvement in attentional performance in ADHD subjects receiving EEG-NF was noted compared to their comparators (p < 0.01). Besides, there was a significant EEG-NF-associated beneficial effect on sustained attention (Hedges' g = 0.32, p < 0.01), whereas the impact on selective attention (p = 0.57) and working memory (p = 0.59) was limited. Moreover, protocol including beta wave enhancement was superior to that only focusing on reducing theta/beta ratio or modulation of slow cortical potential. Subgroup analyses showed that three sessions per week of EEG-NF produced the best effect, while the efficacy of surface EEG-NF was much poorer (Hedges' g = 0.05) when only studies that blinded their participants from knowledge of treatment allocation were included. No significant difference was noted in the improvement of attentional performance 6-12 months after EEG-NF intervention (n = 3, p = 0.42). CONCLUSIONS: Our results demonstrated the satisfactory effectiveness of surface EEG-NF for improving sustained attention, especially when beta wave enhancement was included, despite its failure to sustain a long-term effect. Further large-scale trials are warranted to support our findings.

Additive effects of EEG neurofeedback on medications for ADHD: a systematic review and meta-analysis.

To elucidate possible additive effects of electroencephalogram-based neurofeedback (EEG-NF) on medications against the core symptoms of attention-deficit/hyperactivity disorder (ADHD), randomized controlled trials (RCTs) were retrieved from electronic databases including PubMed, EMBASE, ClinicalKey, Cochrane CENTRAL, ScienceDirect, and ClinicalTrials.gov from inception to March 2022. The primary outcomes were changes in ADHD symptoms (i.e., global, inattention, hyperactivity/impulsivity) assessed with validated rating scales, while secondary outcome was all-cause discontinuation rate. Meta-analysis of five RCTs involving 305 participants [Median age = 9.285 years (range 8.6-11.05)] with a median follow-up of 12 weeks showed additive effects of EEG-NF on medications from parents' observations against ADHD global symptoms (Hedges' g = 0.2898, 95%CI [0.0238; 0.5557]) and inattention symptoms (Hedges' g = 0.3274, 95%CI [0.0493; 0.6055]). However, additive effects failed to sustain six months after EEG-NF intervention. Besides, there was no difference in improvement of hyperactivity/impulsivity from parents' observation, attentional performance, and all-cause discontinuation rate between the two groups. Our results supported additional benefits of combining EEG-NF with medications compared to medication alone in treating global symptoms and symptoms of inattention in ADHD patients. Nevertheless, given a lack of evidence showing a correlation between underlying physiological changes and small effect sizes in our preliminary results, further studies are warranted to support our findings.

SENP1 Protects Against Pressure Overload-Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling.

Background SENP1 (sentrin/small ubiquitin-like modifier-specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload-induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac-specific SENP1 knockdown markedly exacerbated transverse aortic constriction-induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus-mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1-JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte-specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy-promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post-transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload-induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein.

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.

Bone morphogenetic protein 10 alleviates doxorubicin-induced cardiac injury via signal transducer and activator of transcription 3 signaling pathway.

Doxorubicin (DOX) has limited antitumor applications owing to its association with life-threatening cardiac injury. Oxidative damage and cardiac apoptosis are crucial in DOX-induced cardiac injury. Bone morphogenetic protein 10 (BMP10) is predominantly distributed in the heart and acts as a cardioprotective factor that preserves cardiac function. However, the role of BMP10 in DOX-induced cardiac injury has not yet been explored. The current study aimed to examine the function and mechanism of action of BMP10 in DOX-induced cardiac injury. An adeno-associated viral system was used for the overexpression or silencing of cardiac-specific BMP10, and subsequently, a single dose of DOX was intraperitoneally injected to induce cardiac injury. Results showed that DOX exposure decreased BMP10 expression in the heart. Cardiac-specific overexpression of BMP10 alleviated the oxidative stress and apoptosis and improved cardiac function. Conversely, cardiac-specific silencing of BMP10 aggravated the redox disorder and apoptosis and worsened the cardiac dysfunction caused by DOX. Exogenous BMP10 supplementation amelioratesd the DOX-induced cardiac contractile dysfunction. Mechanistically, we found that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is reduced in DOX-induced cardiotoxicity, and, BMP10 activated impaired STAT3 via a non-canonical pathway. BMP10 lost its cardioprotective function in cardiomyocyte-specific STAT3 knockout (STAT3-cKO) mice. Based on our findings, we suggested that BMP10 is a potential therapeutic agent against DOX-induced cardiac injury and that the cardioprotective effects of BMP10 are dependent on the activation of STAT3.

Effects of Yi-Gan-san on the psychiatric behavior of children and adolescents with Tourette's Syndrome: A randomized, double-blind, controlled preliminary study.

ETHNOPHARMACOLOGICAL RELEVANCE: Gilles de la Tourette's Syndrome (TS) is a childhood-onset disease with clinical features of motor and phonic tics. Yi-Gan-san (YGS) is a traditional Chinese medicine formula that can reduce aggressiveness and agitation and inhibit dopamine function. This study investigated the effects of YGS on the psychiatric behavior of children and adolescents with TS. METHODS: A double-blind, randomized, controlled preliminary study was conducted. A total of 38 patients with TS were assigned to the control group (CG, 19 patients) who received the oral administration of YGS placebo (90% starch and 10% YGS; 2.5 g thrice daily) or to a treatment group (TG, 19 patients) who received YGS for 4 weeks. The primary outcome measure was the change in Yale Global Tic Severity Scale (YGTSS) overall and subscale scores. RESULTS: The intensity score for phonic tics before oral administration of YGS, and after 2 weeks, 3 weeks and 4 weeks was not significantly different between CG and TG groups (2.94 ± 1.14 vs 2.79 ± 1.08, p = .686; 2.29 ± 1.21 vs 1.95 ± 1.08, p = .370; 2.41 ± 1.18 vs 2.05 ± 1.51, p = .435; and 2.29 ± 1.26 vs 1.84 ± 1.42, p = .323, respectively), while the intensity score for phonic tics after 1-week oral administration of YGS in the TG was 1.89 ± 1.10 lower than 3.06 ± 1.39 in the CG (p = .008). CONCLUSION: Oral administration of YGS for 1 week only reduced the intensity of phonic tics compared with oral administration of YGS placebo, suggesting that YGS can reduce their intensity for a short period, and the compliance of oral administration of YGS for 4 weeks can be accepted in children and adolescents with Tourette's Syndrome. However, because this study was preliminary, the selection of an appropriate placebo and dosage and long-term observations are crucial areas for future studies.

The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants.

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.

Laparoscopic Revision for Gastric Clipping: a Single Center Experience and Taiwan Database Review.

PURPOSE: Laparoscopic gastric clipping (LGC) is a relatively novel restrictive bariatric surgery wherein a horizontal metallic clip is applied to the gastric fundus. Its intraoperative complications or the difficulties associated with the applied gastric clip (GC) during revisional procedures have seldom been mentioned. Herein, the experience of revisional procedures after initial gastric clipping is reported. MATERIALS AND METHODS: A retrospective cohort review of LGC based on the Taiwan Bariatric Registry of Taiwan Society Metabolic and Bariatric Surgery was performed. Six patients with severe obesity presented for revisional surgery after initial LGC by other surgeons. Patients' characteristics, indications, and details of revisional surgery were recorded. RESULTS: Between 2012 and 2019, 39 patients who underwent pure LGC and six patients with previous LGC history were referred for revisional surgery. Their mean age and the mean body mass index were 34.7 ± 9.5 years and 38.4 ± 10.5 kg/m2, respectively. Three, two, and one patient underwent revisional surgery for insufficient weight loss, weight recidivism, and intractable belching, respectively. The mean interval between initial LGC and revisional surgery was 40.5 ± 22.4 months. Laparoscopic removal of the GC with concomitant revisional surgeries were collected, including a revision to sleeve gastrectomy (n = 5) and revision to Roux-en-Y gastric bypass (n = 1). Moreover, the mean operative time was 286.8 ± 78.2 min. All patients had uneventful recovery postoperatively but experienced significant adhesion around the GC and the left liver. CONCLUSION: Laparoscopic revisional surgery with concomitant GC removal for patients with severe obesity after gastric clipping could be feasibly conducted by experienced bariatric surgeons.