The dual role of sirtuins in cancer: biological functions and implications.

Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles-either as promoters or inhibitors-in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer.

The impact of female sex hormones on cardiovascular disease: from mechanisms to hormone therapy.

Cardiovascular disease remains the leading cause of mortality in women, yet it has not raised the awareness from the public. The pathogenesis of cardiovascular disease differs significantly between females and males concerning the effect of sex hormones. Estrogen and progestogen impact cardiovascular system through genomic and non-genomic effects. Before menopause, cardiovascular protective effects of estrogens have been well described. Progestogens were often used in combination with estrogens in hormone therapy. Fluctuations in sex hormone levels, particularly estrogen deficiency, were considered the specific risk factor in women's cardiovascular disease. However, considerable heterogeneity in the impact of hormone therapy was observed in clinical trials. The heterogeneity is likely closely associated with factors such as the initial time, administration route, dosage, and formulation of hormone therapy. This review will delve into the pathogenesis and hormone therapy, summarizing the effect of female sex hormones on hypertension, pre-eclampsia, coronary heart disease, heart failure with preserved ejection fraction, and cardiovascular risk factors specific to women.

Effectiveness of Cognitive-Based Interventions on Psychological Distress in Adolescents With Physical Disabilities: A Systematic Review and Meta-Analysis.

Adolescents with physical disabilities experience common psychological distress that interacts with impaired physical function. While cognitive-based interventions have been implemented for adolescents with physical disabilities, their effects on enhancing psychological health remain uncertain. This systematic review aimed to synthesise the effects of cognitive-based interventions on the psychological distress of this population and identify optimal components for evidence-based interventions. Following the PRISMA guideline, nine databases were searched to identify eligible randomised controlled trials examining the effects of cognitive-based interventions for adolescents with physical disabilities from inception to October 2023. Data syntheses were performed using the R software, employing random-effects models. Twelve trials involving 1201 participants were identified. The pooled results revealed that cognitive-based interventions did not yield noticeable effects in reducing anxiety (g = -0.43 for postintervention; -0.14 for medium term; -0.37 for long term), depression (g = -0.05 for postintervention; -0.02 for medium term; -0.15 for long term) and stress levels (g = -0.15) over time. The secondary outcome (physical function) improved significantly in the long term compared to the control groups (g = 0.31). Furthermore, this review identified variations in the effectiveness of CBIs among different recipients, durations and modes of delivery. Given the limited number and overall low quality of identified studies for each outcome, conducting high-quality randomised controlled trials is recommended to validate the effectiveness of cognitive-based interventions in reducing psychological distress among adolescents with physical disabilities.

Effects of CYP3A4 genetic polymorphisms on the pharmacokinetics and efficacy of perampanel in Chinese pediatric patients with epilepsy.

OBJECTIVE: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up. RESULTS: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ±â€¯328.1 ng/mL, in contrast to the CC phenotype at 334.0 ±â€¯161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625-900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy. CONCLUSION: The CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.

Targeting Neuronal GPR65 With Delayed BTB09089 Treatment Improves Neurorehabilitation Following Ischemic Stroke.

BACKGROUND: GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown. METHODS: Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65-/-) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65-/- and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting. RESULTS: BTB09089 significantly promoted motor outcomes in WT but not in GPR65-/- mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65-/- mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65-/- mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65-/- mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice. CONCLUSIONS: Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.

Research on ultrasound-based radiomics: a bibliometric analysis.

Background: A large number of studies related to ultrasound-based radiomics have been published in recent years; however, a systematic bibliometric analysis of this topic has not yet been conducted. In this study, we attempted to identify the hotspots and frontiers in ultrasound-based radiomics through bibliometrics and to systematically characterize the overall framework and characteristics of studies through mapping and visualization. Methods: A literature search was carried out in Web of Science Core Collection (WoSCC) database from January 2016 to December 2023 according to a predetermined search formula. Bibliometric analysis and visualization of the results were performed using CiteSpace, VOSviewer, R, and other platforms. Results: Ultimately, 466 eligible papers were included in the study. Publication trend analysis showed that the annual publication trend of journals in ultrasound-based radiomics could be divided into three phases: there were no more than five documents published in this field in any year before 2018, a small yearly increase in the number of annual publications occurred between 2018 and 2022, and a high, stable number of publications appeared after 2022. In the analysis of publication sources, China was found to be the main contributor, with a much higher number of publications than other countries, and was followed by the United States and Italy. Frontiers in Oncology was the journal with the highest number of papers in this field, publishing 60 articles. Among the academic institutions, Fudan University, Sun Yat-sen University, and the Chinese Academy of Sciences ranked as the top three in terms of the number of documents. In the analysis of authors and cocited authors, the author with the most publications was Yuanyuan Wang, who has published 19 articles in 8 years, while Philippe Lambin was the most cited author, with 233 citations. Visualization of the results from the cocitation analysis of the literature revealed a strong centrality of the subject terms papillary thyroid cancer, biological behavior, potential biomarkers, and comparative assessment, which may be the main focal points of research in this subject. Based on the findings of the keyword analysis and cluster analysis, the keywords can be categorized into two major groups: (I) technological innovations that enable the construction of radiomics models such as machine learning and deep learning and (II) applications of predictive models to support clinical decision-making in certain diseases, such as papillary thyroid cancer, hepatocellular carcinoma (HCC), and breast cancer. Conclusions: Ultrasound-based radiomics has received widespread attention in the medical field and has been gradually been applied in clinical research. Radiomics, a relatively late development in medical technology, has made substantial contributions to the diagnosis, prediction, and prognostic evaluation of diseases. Additionally, the coupling of artificial intelligence techniques with ultrasound imaging has yielded a number of promising tools that facilitate clinical decision-making and enable the practice of precision medicine. Finally, the development of ultrasound-based radiomics requires multidisciplinary cooperation and joint efforts from the field biomedicine, information technology, statistics, and clinical medicine.

Supplemented Gegen Qinlian Decoction Formula attenuates podocyte mitochondrial fission and renal fibrosis in diabetic kidney disease by inhibiting TNF-α-mediated necroptosis, compared with empagliflozin.

ETHNOPHARMACOLOGICAL RELEVANCE: Recently, podocyte mitochondrial dysfunction and necroptosis have been shown to play critical roles in renal fibrosis (RF) in diabetic kidney disease (DKD); however, these conditions lack effective treatment. In China, the supplemented Gegen Qinlian Decoction Formula (SGQDF), which originates from the classical prescription Gegen Qinlian Decoction, has been widely used to treat patients with DKD. However, it remains unclear whether SGQDF alleviates podocyte injury-associated RF in patients with DKD. AIM OF STUDY: This study aimed to clarify the therapeutic effects of SGQDF compared with those of empagliflozin (EMPA) on podocyte mitochondrial fission and RF in DKD and its necroptosis-related mechanisms. MATERIALS AND METHODS: Modified DKD rat models were developed through a combination of uninephrectomy, streptozotocin administration through intraperitoneal injection, and exposure to a high-fat diet. Following RF formation, the DKD rat models received either a high dose of SGQDF (H-SGQDF), a low dose of SGQDF (L-SGQDF), EMPA, or vehicle for 4 weeks. In our in vitro study, we subjected cultured murine podocytes to a high-glucose environment and various treatments including Mdivi-1, adalimumab, and necrostatin-1, with or without H-SGQDF or EMPA. SGQDF target prediction and molecular docking verification were performed. For the in vivo study, we focused on examining changes in the parameters associated with renal injury, RF, and oxidative stress (OS)-induced injuries in podocytes. Both in vivo and in vitro studies included an analysis of changes in podocyte mitochondrial fission, TNF-α-induced podocyte necroptosis, and the RIPK1/RIPK3/MLKL signaling pathway activation. RESULTS: SGQDF improved renal injury markers, including body weight, blood glucose, serum creatinine, blood urea nitrogen, and urinary albumin, in a dose-dependent manner. The beneficial effects of H-SGQDF in vivo were greater than those of L-SGQDF alone in vivo. Interestingly, similar to EMPA, H-SGQDF ameliorated RF and reduced OS-induced podocyte injury in diabetic kidneys. Furthermore, TNF-α signaling was shown to be important in the network construction of "the SGQDF-component-target." Based on this, we also showed that the beneficial effects in vivo and in vitro of H-SGQDF were closely related to the improvement in mitochondrial dysfunction and the inhibition of TNF-α-induced necroptosis in podocytes. CONCLUSION: In the present study, we showed that H-SGQDF, similar to EMPA, attenuates podocyte mitochondrial fission and RF, and that the underlying therapeutic mechanisms are closely related to inhibiting the activation of the RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. Our findings provide new pharmacological evidence for the application of H-SGQDF in the RF treatment of DKD.

Recent symptomatic omicron infection reduced COVID-19 pneumonia risk during reinfection: A computed tomography-based cohort study.

OBJECTIVES: SARS-CoV-2 infection could cause persistent lung injury or indicate potential genetic susceptibilities. While infection-elicited hybrid immunity could protect against severe COVID-19, it remains unknown whether recent infection could reduce pneumonia risk during reinfection due to insufficient viral and chest CT screening. METHODS: 15,598 patients, 96% fully vaccinated and 52% boosted, from Xiangyang, China who had symptomatic COVID-19 and chest CT scans during the first omicron BF.7 wave in December 2022 to January 2023 were followed through the second omicron XBB.1.5 wave between May and August 2023. 17,968 second-wave COVID-19 patients with chest CT scans but without prior symptomatic COVID-19 history were enrolled as first-time infection controls. RESULTS: 19.6% (3,061/15,598) first-wave patients were diagnosed with pneumonia. Among second-wave reinfected patients, only 0.2% (4/2,202) developed pneumonia, which was lower than the 1.7% (311/17,968) pneumonia prevalence among second-wave first-time patients, with adjusted relative risk (RR) of 0.11 (95% CI: 0.04-0.29). 1.3% (40/3,039) first wave pneumonia survivors showed residual abnormal patterns in follow-up CT scans within 8 months after pneumonia diagnosis. CONCLUSIONS: In a highly vaccinated population, prior symptomatic omicron infection within 8 months reduced pneumonia risk during reinfection. Uninfected individuals might need up-to-date vaccination to reduce pneumonia risk.

Bacteroides fragilis alleviates necrotizing enterocolitis through restoring bile acid metabolism balance using bile salt hydrolase and inhibiting FXR-NLRP3 signaling pathway.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.

Development of a Prediction Model and Corresponding Scoring Table for Postherpetic Neuralgia Using Six Machine Learning Algorithms: A Retrospective Study.

INTRODUCTION: Postherpetic neuralgia (PHN), a complication of herpes zoster, significantly impacts the quality of life of affected patients. Research indicates that early intervention for pain can reduce the occurrence or severity of PHN. This study aims to develop a predictive model and scoring table to identify patients at risk of developing PHN following acute herpetic neuralgia, facilitating informed clinical decision-making. METHODS: We conducted a retrospective review of 524 hospitalized patients with herpes zoster at The First Affiliated Hospital of Zhejiang Chinese Medical University from December 2020 to December 2023 and classified them according to whether they had PHN, collecting a comprehensive set of 30 patient characteristics and disease-related indicators, 5 comorbidity indicators, 2 disease score values, and 10 serological indicators. Relevant features associated with PHN were identified using the least absolute shrinkage and selection operator (LASSO). Then, the patients were divided into a training set and a test set in a 4:1 ratio, with comparability tested using univariate analysis. Six models were established in the training set using machine learning methods: support vector machines, logistic regression, random forest, k-nearest neighbor, gradient boosting, and neural network. The performance of these models was evaluated in the test set, and a nomogram based on logistic regression was used to create a PHN prediction score table. RESULTS: Eight non-zero characteristic variables selected from the LASSO regression results were included in the model, including age [area under the curve (AUC) = 0.812, p < 0.001], Numerical Rating Scale (NRS) (AUC = 0.792, p < 0.001), receiving treatment time (AUC = 0.612, p < 0.001), rash recovery time (AUC = 0.680, p < 0.001), history of malignant tumor (AUC = 0.539, p < 0.001), history of diabetes (AUC = 0.638, p < 0.001), varicella-zoster virus immunoglobulin M (AUC = 0.620, p < 0.001), and serum nerve-specific enolase (AUC = 0.659, p < 0,001). The gradient boosting model outperformed other classifier models on the test set with an AUC of 0.931, 95% confidence interval (CI) (0.882-0.980), accuracy of 0.886 (95% CI 0.809-0.940). In the test set, our predictive scoring table achieved an AUC of 0.820 (95% CI 0.869-0.970) with accuracy of 0.790 (95% CI 0.700-0.864). CONCLUSION: This study presents a methodology for predicting the development of postherpetic neuralgia in shingles patients by analyzing historical case data, employing various machine learning techniques, and selecting the optimal model through comparative analysis. In addition, a logistic regression model has been used to create a scoring table for predicting the postherpetic neuralgia.

Deep learning reconstruction for lumbar spine MRI acceleration: a prospective study.

BACKGROUND: We compared magnetic resonance imaging (MRI) turbo spin-echo images reconstructed using a deep learning technique (TSE-DL) with standard turbo spin-echo (TSE-SD) images of the lumbar spine regarding image quality and detection performance of common degenerative pathologies. METHODS: This prospective, single-center study included 31 patients (15 males and 16 females; aged 51 ± 16 years (mean ± standard deviation)) who underwent lumbar spine exams with both TSE-SD and TSE-DL acquisitions for degenerative spine diseases. Images were analyzed by two radiologists and assessed for qualitative image quality using a 4-point Likert scale, quantitative signal-to-noise ratio (SNR) of anatomic landmarks, and detection of common pathologies. Paired-sample t, Wilcoxon, and McNemar tests, unweighted/linearly weighted Cohen κ statistics, and intraclass correlation coefficients were used. RESULTS: Scan time for TSE-DL and TSE-SD protocols was 2:55 and 5:17 min:s, respectively. The overall image quality was either significantly higher for TSE-DL or not significantly different between TSE-SD and TSE-DL. TSE-DL demonstrated higher SNR and subject noise scores than TSE-SD. For pathology detection, the interreader agreement was substantial to almost perfect for TSE-DL, with κ values ranging from 0.61 to 1.00; the interprotocol agreement was almost perfect for both readers, with κ values ranging from 0.84 to 1.00. There was no significant difference in the diagnostic confidence or detection rate of common pathologies between the two sequences (p ≥ 0.081). CONCLUSIONS: TSE-DL allowed for a 45% reduction in scan time over TSE-SD in lumbar spine MRI without compromising the overall image quality and showed comparable detection performance of common pathologies in the evaluation of degenerative lumbar spine changes. RELEVANCE STATEMENT: Deep learning-reconstructed lumbar spine MRI protocol enabled a 45% reduction in scan time compared with conventional reconstruction, with comparable image quality and detection performance of common degenerative pathologies. KEY POINTS: • Lumbar spine MRI with deep learning reconstruction has broad application prospects. • Deep learning reconstruction of lumbar spine MRI saved 45% scan time without compromising overall image quality. • When compared with standard sequences, deep learning reconstruction showed similar detection performance of common degenerative lumbar spine pathologies.

HIF1A overexpression caused by etomidate activates PGK1-induced oxidative stress in postoperative cognitive dysfunction.

Etomidate (ETO), a hypnotic agent used for anesthesia induction, has been shown to induce long-lasting cognitive deficits. In the present study, we investigated whether ETO could activate the HIF1A/PGK1 pathway to antagonize oxidative damage in mice with postoperative cognitive dysfunction (POCD). A mouse model of ETO-mediated POCD was established, and pathological changes, apoptosis, and inflammatory factors in mouse hippocampal tissues were analyzed by HE staining, TUNEL assay, and ELISA. ETO was revealed to cause cognitive dysfunction in mice. Integrated database mining was conducted to screen out transcription factors that are both related to ETO and POCD. Hypoxia-inducible factor 1-alpha (HIF1A) was overexpressed in mice with POCD, and downregulation of HIF1A alleviated cognitive dysfunction in mice. HIF1A downregulation inhibited the transcription of phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 abated the alleviating effects of HIF1A knockdown on oxidative stress in mice with POCD. In addition, HIF1A activation of PGK1 induced oxidative stress and apoptosis in HT-22 cells while inhibiting cell viability. Taken together, we demonstrated that HIF1A activation of PGK1 induced oxidative stress in ETO-mediated POCD.

E3 ubiquitin ligase TRIM31 alleviates dopaminergic neurodegeneration by promoting proteasomal degradation of VDAC1 in Parkinson's Disease model.

Mitochondrial dysfunction plays a pivotal role in the pathogenesis of Parkinson's disease (PD). As a mitochondrial governor, voltage-dependent anion channel 1 (VDAC1) is critical for cell survival and death signals and implicated in neurodegenerative diseases. However, the mechanisms of VDAC1 regulation are poorly understood and the role of tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase which is enriched in mitochondria, in PD remains unclear. In this study, we found that TRIM31-/- mice developed age associated motor defects and dopaminergic (DA) neurodegeneration spontaneously. In addition, TRIM31 was markedly reduced both in nigrostriatal region of PD mice induced by MPTP and in SH-SY5Y cells stimulated by MPP+. TRIM31 deficiency significantly aggravated DA neurotoxicity induced by MPTP. Mechanistically, TRIM31 interacted with VDAC1 and catalyzed the K48-linked polyubiquitination to degrade it through its E3 ubiquitin ligase activity. In conclusion, we demonstrated for the first time that TRIM31 served as an important regulator in DA neuronal homeostasis by facilitating VDAC1 degradation through the ubiquitin-proteasome pathway. Our study identified TRIM31 as a novel potential therapeutic target and pharmaceutical intervention to the interaction between TRIM31 and VDAC1 may provide a promising strategy for PD.

The effect of systematic couple group therapy on families with depressed juveniles: a pilot trial.

Background: Depression is a primary cause of illness and disability among teenagers, and the incidence of depression and the number of untreated young people have increased in recent years. Effective intervention for those youths could decrease the disease burden and suicide or self-harm risk during preadolescence and adolescence. Objective: To verify the short efficacy of the systemic couple group therapy (SCGT) on youths' depression changes and families with depressed adolescents. Methods: The study was a self-control trial; only within-group changes were evaluated. Participants were couples with a depressed child who was resistant to psychotherapy; they were recruited non-randomly through convenient sampling. The paired-sample t-test and Wilcoxon signed-rank test were used to compare differences before and after interventions. The effect sizes were also estimated using Cohen's d. Spearman's correlation analysis was used to examine associations between changes. Results: A downward trend was seen in depressive symptoms after treatment, and Cohen's d was 0.33 (p = 0.258). The adolescents perceived fewer interparental conflicts, and the effect sizes were medium for perceived conflict frequency (0.66, p = 0.043), conflict intensity (0.73, p = 0.028), conflict solutions (0.75, p = 0.025), coping efficacy (0.68, p = 0.038), and perceived threat (0.57, p = 0.072). For parents, global communication quality, constructive communication patterns, and subjective marital satisfaction significantly improved after interventions, with large effect sizes (1.11, 0.85, and 1.03, respectively; all p < 0.001). Other destructive communication patterns such as demand/withdraw (p = 0.003) and mutual avoidance (p = 0.018) and communication strategies like verbal aggression (p = 0.012), stonewalling (p = 0.002), avoidance-capitulation (p = 0.036), and child involvement (p = 0.001) also reduced, with medium effect sizes (0.69, 0.52, 0.55, 0.71, 0.46, and 0.79, respectively). Meanwhile, the associations between depression changes and changes in interparental conflicts (p < 0.001) and marital satisfaction (p = 0.001) were significant. Conclusions and clinical relevance: The SCGT offers the possibility for the treatment of families with depressed children who are unwilling to seek treatment. Helping parents improve communication and marital quality may have benefits on children's depressive symptoms.

Selective degradation of hyperphosphorylated tau by proteolysis-targeting chimeras ameliorates cognitive function in Alzheimer's disease model mice.

Alzheimer's disease (AD) is one of the most common chronic neurodegenerative diseases. Hyperphosphorylated tau plays an indispensable role in neuronal dysfunction and synaptic damage in AD. Proteolysis-targeting chimeras (PROTACs) are a novel type of chimeric molecule that can degrade target proteins by inducing their polyubiquitination. This approach has shown promise for reducing tau protein levels, which is a potential therapeutic target for AD. Compared with traditional drug therapies, the use of PROTACs to reduce tau levels may offer a more specific and efficient strategy for treating AD, with fewer side effects. In the present study, we designed and synthesized a series of small-molecule PROTACs to knock down tau protein. Of these, compound C8 was able to lower both total and phosphorylated tau levels in HEK293 cells with stable expression of wild-type full-length human tau (termed HEK293-htau) and htau-overexpressed mice. Western blot findings indicated that C8 degraded tau protein through the ubiquitin-proteasome system in a time-dependent manner. In htau-overexpressed mice, the results of both the novel object recognition and Morris water maze tests revealed that C8 markedly improved cognitive function. Together, our findings suggest that the use of the small-molecule PROTAC C8 to degrade phosphorylated tau may be a promising therapeutic strategy for AD.

Chirality Interplay between the Interior and Exterior of Metal-Organic Cages.

A series of metal-organic cages featuring two stereogenic elements, in terms of the twisting of amide moieties within the ligand backbones and the rotation of diazaanthracene segments along the ligand ridges, were exploited. These two chiral components are correlative and serve as relays for transmitting chirality information between the internal and external cages. The chirality information induced by a chiral guest inside the cage cavity can pass through the cage framework and influence the orientation of the diazaanthracene segments on the periphery of the cage. In turn, the chirality of a stereogenic center within the diazaanthracene segments can transfer back into the cavity, enabling discrimination of enantiomeric guests.

Study on the Mechanism of the Combination of Methotrexate and Leflunomide in the Treatment of Rheumatoid Arthritis Based on Network Pharmacology, Molecular Docking, and in vitro Experimental Verification.

BACKGROUND: To date, disease-modifying antirheumatic drugs (DMARDs) are widely used as the primary first-line treatment option for patients with rheumatoid arthritis (RA), and the curative effect of methotrexate (MTX) and leflunomide (LEF; MTX + LEF) is greater than that of single-agent MTX therapy, but the synergistic mechanism of MTX + LEF is unclear. METHODS: First, we explored the mechanism of action of MTX + LEF in RA through network pharmacology and molecular docking. Venn diagram analysis revealed 97 overlapping gene targets of MTX + LEF-RA and STRING, along with Cytoscape plug-in MOCDE and cytoHubba; and GO enrichment analysis revealed that the functions of 97 synergistic targets were related to 123 molecular functions (MF), 63 cell components (CC), and 1,068 biological processes (BP). The Cytoscape plug-in ClueGO demonstrated that these targets were enriched in KEGG pathways of 52 terms, whereas 9 pivotal genes were mainly involved in the signaling pathways of estrogen, Ras, Rap1, PI3K-Akt, relaxin, TNF, AMPK, FoxO, prolactin, IL-17, and adherens junction. Finally, CETSA and DARTS validated the direct binding of MTX or LEF to the selected target proteins EGFR, PPARG, MMP9, and SRC in RAW264.7 cells. RESULTS: We identified 292 MTX targets and 247 LEF targets from 7 databases. Furthermore, 2,814 potential targets of RA were identified by merging 1,925 targets from 7 databases and 999 differentially expressed genes (DEGs) between normal controls and patients with RA extracted from 5 GEO databases. Nine pivotal genes, ESR1, ALB, CASP3, EGFR, HSP90AA1, SRC, MMP9, PPARG, and IGF1, were identified. Molecular docking verified that both MTX and LEF strongly bind to most of the 9 pivotal proteins except ESR1 and IGF1. CONCLUSION: These results contribute to our understanding of the enhancement mechanism of MTX combined with LEF and provide a targeted basis for the clinical treatment of RA.

Dan-Lou tablets reduce inflammatory response by inhibiting the activation of NLRP3 inflammasome for coronary heart disease.

BACKGROUND: The activation of the NLRP3 inflammasome has recently been revealed as a novel pathological mechanism of coronary heart disease (CHD). The Dan-Lou tablets (DLT) is widely used in the clinical treatment of CHD and prescription characterized by multi-component and multi-target regulation. However, the anti-inflammatory mechanism of DLT in the treatment of CHD remains unclear. PURPOSE: This study aimed to evaluate the effect of DLT in the treatment of CHD on the priming and activation of the NLRP3 inflammasome and to investigate the underlying anti-inflammatory mechanisms. METHODS: First, CHD rats model were established by a high-fat diet combined with left anterior coronary artery ligation (LADCA) followed by DLT intervention. The therapeutic effect of DLT was evaluated according to cardiac function, lipid level, and cardiac histopathology. Next, data-independent acquisition (DIA) proteomics was used to identify the key differential proteins of DLT intervention in CHD rats, and bioinformatics analysis was performed. Finally, the differentially expressed proteins in the NOD-like signaling pathway were verified based on bioinformatics results, and the priming and activation steps of the NLRP3 inflammasome were detected. RESULTS: In this study, a high-fat diet combined with LADCA was utilized to generate a CHD model, and DLT alleviated myocardial ischemia injury by inhibiting lipid deposition and inflammatory response. Proteomic studies observed that the RNF31, TXN2, and GBP2 of the NOD-like receptor signaling pathway were verified as the key targets of DLT in inhibiting myocardial injury in CHD rats. Furthermore, DLT in the treatment of CHD rats may function through the downregulation of P2X7R expression, thereby interfering with the priming (TLR4/MyD88/NF-κB) and activation (NLRP3/ASC/Caspase-1) of the NLRP3 inflammasome regulated by HSP90, and may then reduce the release of the IL-1ß and IL-18 inflammatory factors to play an anti-myocardial injury effect. CONCLUSION: Our findings elucidate a novel mechanism of DLT and provide some new drug evaluation targets and therapeutic strategies for CHD. This study innovatively proposed that DLT further exerts an anti-myocardial injury effect by inhibiting P2X7R expression, thereby interfering with the priming (TLR4/MyD88/NF-κB) and activation (NLRP3/ASC/Caspase-1) of the NLRP3 inflammasome regulated by HSP90, and then downregulates the release of the IL-1ß and IL-18 inflammatory factors.

Raddeanin A Protects the BRB Through Inhibiting Inflammation and Apoptosis in the Retina of Alzheimer's Disease.

Neuroinflammation and endothelial cell apoptosis are prominent features of blood-brain barrier (BBB) disruption, which have been described in Alzheimer's disease (AD) and can predict cognitive decline. Recent reports revealed vascular ß-amyloid (Aß) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer's disease by targeting ß-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aß-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/ß-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.