Partial Discharge Fault Diagnosis in Power Transformers Based on SGMD Approximate Entropy and Optimized BILSTM.

Partial discharge (PD) fault diagnosis is of great importance for ensuring the safe and stable operation of power transformers. To address the issues of low accuracy in traditional PD fault diagnostic methods, this paper proposes a novel method for the power transformer PD fault diagnosis. It incorporates the approximate entropy (ApEn) of symplectic geometry mode decomposition (SGMD) into the optimized bidirectional long short-term memory (BILSTM) neural network. This method extracts dominant PD features employing SGMD and ApEn. Meanwhile, it improves the diagnostic accuracy with the optimized BILSTM by introducing the golden jackal optimization (GJO). Simulation studies evaluate the performance of FFT, EMD, VMD, and SGMD. The results show that SGMD-ApEn outperforms other methods in extracting dominant PD features. Experimental results verify the effectiveness and superiority of the proposed method by comparing different traditional methods. The proposed method improves PD fault recognition accuracy and provides a diagnostic rate of 98.6%, with lower noise sensitivity.

Emerging Nanotechnology in Preclinical Pancreatic Cancer Immunotherapy: Driving Towards Clinical Applications.

The high malignant degree and poor prognosis of pancreatic cancer (PC) pose severe challenges to the basic research and clinical translation of next-generation therapies. The rise of immunotherapy has improved the treatment of a variety of solid tumors, while the application in PC is highly restricted by the challenge of immunosuppressive tumor microenvironment. The latest progress of nanotechnology as drug delivery platform and immune adjuvant has improved drug delivery in a variety of disease backgrounds and enhanced tumor therapy based on immunotherapy. Based on the immune loop of PC and the status quo of clinical immunotherapy of tumors, this article discussed and critically analyzed the key transformation difficulties of immunotherapy adaptation to the treatment of PC, and then proposed the rational design strategies of new nanocarriers for drug delivery and immune regulation, especially the design of combined immunotherapy. This review also put forward prospective views on future research directions, so as to provide information for the new means of clinical treatment of PC combined with the next generation of nanotechnology and immunotherapy.

Inactivated cGAS-STING Signaling Facilitates Endocrine Resistance by Forming a Positive Feedback Loop with AKT Kinase in ER+HER2- Breast Cancer.

Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC.

Sex differences in the association between Body Mass Index and cognitive function in Parkinson disease: a cross-sectional study.

Objective: This study utilized a binary logistic regression model to explore the relationship between Body Mass Index (BMI) and cognitive function in Parkinson's disease (PD) patients. Methods: In this cross-sectional study, data were obtained from 1,005 Parkinson's patients enrolled in the Parkinson's Progression Markers Initiative (PPMI) from 2010 to 2023, including 378 females and 627 males. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) scale, and the correlation between BMI and cognitive function was determined using binary logistic regression. Results: The median age of enrollment was 63.6 (56.2, 69.6) years old, including 378 (37.6%) females and 627 (62.4%) males. In the final adjusted model, a significant positive correlation was found between BMI and the prevalence of cognitive impairment in females (OR = 1.06, 95% CI = 1.01 ~ 1.12, p = 0.022), while no correlation was found in males (OR = 1.03, 95% CI = 0.99 ~ 1.08, p = 0.165). The results after categorizing BMI indicate that, among females, the risk of cognitive impairment increases for both groups with BMI ≥ 30 kg/m2 and those with 25 ≤ BMI < 30 kg/m2 compared to the reference group with BMI < 25 kg/m2, with a p for trend <0.001 indicating a stable and strong association between BMI and cognitive impairment in females. In males, the results were not significant. The trend of linear fitting was consistent with the above results. Conclusion: In female Parkinson's patients, there is a positive correlation between BMI and cognitive impairment, while no correlation was found in male patients. This study provides new evidence of sex differences in the correlation between BMI and cognitive impairment among Parkinson's patients. The role of sex differences in the relationship between BMI and cognitive impairment should be considered in future research.

Motor dysfunction in Parkinson's patients: depression differences in a latent growth model.

Objective: This study aims to utilize latent growth model (LGM) to explore the developmental trajectory of motor dysfunction in Parkinson's disease (PD) patients and investigate the relationship between depression and motor dysfunction. Methods: Four-year follow-up data from 389 PD patients were collected through the Parkinson's Progression Marker Initiative (PPMI). Firstly, a univariate LGM was employed to examine the developmental trajectory of motor dysfunction in PD patients. Subsequently, depression levels were introduced as covariates into the model, and depression was further treated as a parallel growth latent variable to study the longitudinal relationship between motor dysfunction and depression. Results: In the trajectory analysis of motor dysfunction, the fit indices for the quadratic growth LGM model were χ2 = 7.419, df = 6, CFI = 0.998, TLI = 0.997, SRMR = 0.019, and RMSEA = 0.025, indicating that the growth trend of motor dysfunction follows a quadratic curve rather than a simple linear pattern. Introducing depression symptoms as time-varying covariates to explore their effect on motor dysfunction revealed significant positive correlations (ß = 0.383, p = 0.026; ß = 0.675, p < 0.001; ß = 0.385, p = 0.019; ß = 0.415, p = 0.014; ß = 0.614, p = 0.003), suggesting that as depression levels increase, motor dysfunction scores also increase. Treating depression as a parallel developmental process in the LGM, the regression coefficients for depression intercept on motor dysfunction intercept, depression slope on motor dysfunction slope, and depression quadratic factor on motor dysfunction quadratic factor were 0.448 (p = 0.046), 1.316 (p = 0.003), and 1.496 (p = 0.038), respectively. These significant regression coefficients indicate a complex relationship between depression and motor dysfunction, involving not only initial level associations but also growth trends over time and possible quadratic effects. Conclusion: This study indicates a quadratic growth trajectory for motor dysfunction in PD, suggesting a continuous increase in severity with a gradual deceleration in growth rate. The relationship between depression and motor dysfunction is complex, involving initial associations, evolving trends over time, and potential quadratic effects. Exacerbation of depressive symptoms may coincide with motor function deterioration.

Sedentary Behavior and Risk of Depression in Older Adults: A Systematic Meta-Analysis.

Background: The elderly represents the population group with the highest rate of sedentary behavior. Sedentary behavior has an adverse impact on the elderly, which might be related to depression. Methods: We queried PubMed, EMBASE, Web of Science, and MEDLINE to collect literature data. The odds ratio (OR) and corresponding 95% confidence interval (CI) were adopted for the pooled measurements. Sub-group analyses were conducted through stratified meta-analyses based on study design, depression indicator, adjustment for physical activity, sedentary behavior indicator, and type. Sensitivity analyses were performed to test the robustness of the results, and publication bias was assessed through a funnel plot. Results: Seven cross-sectional studies and five cohort studies were included in our meta-analysis. The overall pooled OR was 1.38 (95%CI: 1.16-1.65; P < 0.01), which indicated that sedentary behavior was positively associated with depression in older adults. Sub-group analysis showed that different study designs, depression indicators, sedentary behavior indicators, adjustment for physical activity, sedentary behavior indicator, and type produced different results. In the cross-sectional studies (OR = 1.45, 95%CI: 1.15-1.84), CES-D scale (OR = 1.54, 95%CI: 1.13-2.10), self-reported (OR = 1.39, 95%CI: 1.04-1.87), watching TV (OR = 1.75, 95%CI: 1.02-3.02), and not adjusted for physical activity (OR = 1.37, 95%CI: 1.14-1.65) groups, there was a strong correlation between sedentary behavior and depression in the elderly. Conclusion: Sedentary behavior is associated with depression in the elderly. As a preventive strategy, we should consider reducing their sedentary time and appropriately increasing physical activity.

Cost-Effectiveness Analysis of 6 Tyrosine Kinase Inhibitors as First-Line Treatment for ALK-Positive NSCLC in China.

Background: Lung cancer ranks first in both cancer incidence and mortality in China. The emergence of novel treatments for ALK-positive NSCLC led to an improvement in survival and quality of life for patients with advanced ALK mutation-positive non-small cell lung cancer (NSCLC). This study sought to assess the cost-effectiveness of 6 tyrosine kinase inhibitors (TKIs)-crizotinib, alectinib, ceritinib, brigatinib, ensartinib, and lorlatinib-as first-line treatments for ALK-positive NSCLC from the perspective of the Chinese health care system. Methods: A Markov model was developed to estimate the cost-effectiveness of these 6 TKIs. In this model, ALK-positive NSCLC patients were initially simulated to receive 1 of the 6 TKIs as first-line therapy, followed by different TKIs as subsequent treatment and salvage chemotherapy as last-line treatment. Survival data were sourced from the latest published clinical trials. Costs were derived from recent national health insurance negotiations and hospital information systems of selected health care facilities. Utilities for healthy states and adverse events were obtained from the literature. One-way and probabilistic sensitivity analysis as well as scenario analysis was conducted to assess the robustness of the results. Results: Compared to ensartinib, crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib demonstrated incremental quality-adjusted life years (QALYs) of -1.13, 0.39, -0.58, -0.09, and 0.35, respectively. The corresponding incremental costs were $10 677, $33 501, -$6426, $2672, and $24 358. This resulted in ICERs of -$9449/QALY, $85 900/QALY, $11 079/QALY, $29 689/QALY and $69 594/QALY, respectively. Conclusion: Crizotinib was considered to be absolutely dominated by ensartinib. Under a willingness-to-pay threshold of $38 223/QALY, ceritinib and brigatinib were cost-effective compared with ensartinib, while lorlatinib and alectinib were not cost-effective when compared with ensartinib. Overall, brigatinib emerged as the most cost-effective treatment among all the options considered.

Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

The role of NCAPH in cancer treatment.

Many solid tumors frequently overexpress Non-SMC Condensin I Complex Subunit H (NCAPH), and new studies suggest that NCAPH may be a target gene for clinical cancer therapy. Numerous investigations have shown that a variety of transcription factors, including as MYBL2, FOXP3, GATA3, and OTC1, can stimulate the transcription of NCAPH. Additionally, NCAPH stimulates many oncogenic signaling pathways, such as ß-Catenin/PD-L1, PI3K/AKT/SGK3, MEK/ERK, AURKB/AKT/mTOR, PI3K/PDK1/AKT, and Chk1/Chk2. Tumor immune microenvironment modification and tumor growth, apoptosis, metastasis, stemness, and treatment resistance all depend on these signals. NCAPH has the ability to form complexes with other proteins that are involved in glycolysis, DNA damage repair, and chromatin remodeling. This review indicates that NCAPH expression in most malignant tumors is associated with poor prognosis and low recurrence-free survival.

Job burnout and its influencing factors among village doctors during the COVID-19 pandemic: a cross-sectional study.

Objective: The aim of this study is to understand the job burnout of village doctors during the COVID-19 epidemic and its influencing factors, and to provide a reference for effectively alleviating the job burnout of village doctors. Methods: A cross-sectional survey was conducted among village doctors in S province in December 2021. The survey included a general information questionnaire and the CMBI Burnout Scale. Epidata was used for dual input, and descriptive analysis, t-test, chi-square test, and binary Logistic regression for statistical analysis were used. Results: A total of 993 village doctors participated in the survey. Most of them were male village doctors (62.84%), with an average age of 46.57 (SD = 7.50). Village doctors believed that the impact of the epidemic on work was serious, with a score of 3.87 ± 0.91. The economic support was small, with a score of 2.31 ± 0.99. The development space was low, with a score of 2.62 ± 0.98. The overall incidence of burnout was 53.47%. In the burnout group, 54.05% were mild, 33.14% were moderate, and 12.81% were severe. The high degree of difficulty in using WeChat (OR = 1.436, 95%CI: 1.229-1.679), high work pressure (OR = 1.857, 95%CI: 1.409-2.449), high risk of practice (OR = 1.138, 95%CI: 1.004-1.289), less economic support (OR = 0.825, 95%CI: 0.684-0.995), less technical support (OR = 0.696, 95%CI: 0.565-0.858), and poor emotional support (OR = 0.632, 95%CI: 0.513-0.780) were more likely to have job burnout. Conclusion: Burnout is a common phenomenon among village doctors during the COVID-19 pandemic, which needs to be prevented and alleviated by various measures.

Comparative analysis of village doctors' relative deprivation: based on two cross-sectional surveys.

BACKGROUND: Village doctors are the main health service providers in China's rural areas. Compared with other rural groups, they will have a sense of relative deprivation, which has an impact on their practice mentality and job stability. This study aims to analyze the changes and causes of relative deprivation among village doctors, so as to improve the stability of them. METHODS: The data were collected from two surveys conducted in Shandong Province in 2015 and 2021. In 2015, 322 village doctors were surveyed and 307 questionnaires were collected, with a recovery rate of 95.3%. In 2021, 394 village doctors were surveyed and 366 questionnaires were collected, with a recovery rate of 92.9%. Descriptive and univariate analysis were used to compare the changes before and after the survey. RESULTS: The scores of vertical deprivation of village doctors increased from 2.77 ± 0.81 in 2015 to 3.04 ± 0.83 in 2021, with a statistically significant difference (P < 0.001). The reference group selected by village doctors changed from village teachers to ordinary villagers. Compared to village teachers, the horizontal deprivation score of village doctors increased from 3.47 ± 0.87 to 3.97 ± 0.77, with a statistically significant difference (P < 0.001). Compared to villagers, only the professional reputation deprivation score increased, from 2.38 ± 0.93 to 2.68 ± 0.76, with a statistically significant difference (P < 0.05). CONCLUSIONS: As time goes by, village doctors fail to reach the expected level in terms of economic income, social status, professional reputation and living standards, resulting in a sense of relative deprivation. This may have a negative impact on village doctors' work motivation and behavior, and will fail to guarantee the sustainability of the team. We should pay attention to this unbalanced mentality of village doctors.

CXCR5+TIM-3-PD-1+ stem-like cytotoxic CD8+ T cells: elevated in chronic rhinosinusitis and associated with disease severity.

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease with an autoimmune background. Altered expression levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3), C-X-C chemokine receptor type 5 (CXCR5), and programmed cell death protein 1 (PD-1) are implicated in the progression of inflammatory and autoimmune diseases. Moreover, CXCR5+TIM-3-PD-1+ stem-like cytotoxic T cells function as memory stem cells during chronic disease processes and retain cytotoxicity-related gene networks. Objectives: To explore the expressions of CXCR5, TIM-3, and PD-1 on T cells and their correlation with clinical parameters in CRS. Methods: Flow cytometry was used to assess the expressions and co-expressions of CXCR5, TIM-3, and PD-1 on T cells in the tissues of the paranasal sinus and peripheral blood of patients with CRS as well as healthy controls. Immunofluorescence was used to assess the co-localization of TIM-3, CXCR5, and PD-1 with T cells. The disease severity of our patients with CRS was evaluated using the Lund-Mackay score. A complete blood count was also performed for the patients with CRS. Results: Expression levels of CXCR5 and PD-1 on T cells were significantly increased in the nasal tissues of patients with CRS. Compared with those in healthy controls, patients with CRS had high percentages of CXCR5+TIM-3-PD-1+ CD8+ and CD4+ T cells in nasal tissues, while no significant difference was observed in peripheral blood levels. Patients with CRS had a higher density of nasal CXCR5+TIM-3-PD-1+ T cells than that in healthy controls. CXCR5+TIM-3-PD-1+ CD8+ T cell levels in the nasal polyps of patients with CRS were negatively correlated with the patients' Lund-Mackay scores. The levels of CXCR5+TIM-3-PD-1+ T cells in nasal tissues were also negatively associated with disease duration and positively associated with the chronic inflammatory state of CRS. Conclusions: The level of CXCR5+TIM-3-PD-1+ stem cell-like T cells, especially CXCR5+TIM-3-PD-1+ CD8+ T cells, is increased in CRS. Therefore, inducing CXCR5+TIM-3-PD-1+ T cell exhaustion may be an effective immunotherapy for CRS.

Asiaticoside exerts neuroprotection through targeting NLRP3 inflammasome activation.

BACKGROUND: Parkinson's disease (PD), a neurodegenerative disorder, is characterized by motor symptoms due to the progressive loss of dopaminergic neurons in the substantia nigra (SN) and striatum (STR), alongside neuroinflammation. Asiaticoside (AS), a primary active component with anti-inflammatory and neuroprotective properties, is derived from Centella asiatica. However, the precise mechanisms through which AS influences PD associated with inflammation are not yet fully understood. PURPOSE: This study aimed to explore the protective mechanism of AS in PD. METHODS: Targets associated with AS and PD were identified from the Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards database. A protein-protein interaction (PPI) network was constructed to identify potential therapeutic targets. Concurrently, GO and KEGG analyses were performed to predict potential signaling pathways. To validate these mechanisms, the effects of AS on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice were investigated. Furthermore, neuroinflammation and the activation of the NLRP3 inflammasome were assessed to confirm the anti-inflammatory properties of AS. In vitro experiments in BV2 cells were then performed to investigate the mechanisms of AS in PD. Moreover, CETSA, molecular docking, and molecular dynamics simulations (MDs) were performed for further validation. RESULTS: Network pharmacology analysis identified 17 potential targets affected by AS in PD. GO and KEGG analyses suggested the biological roles of these targets, demonstrating that AS interacts with 149 pathways in PD. Notably, the NOD-like receptor signaling pathway was identified as a key pathway mediating AS's effect on PD. In vivo studies demonstrated that AS alleviated motor dysfunction and reduced the loss of dopaminergic neurons in MPTP-induced PD mice. In vitro experiments demonstrated that AS substantially decreased IL-1ß release in BV2 cells, attributing this to the modulation of the NLRP3 signaling pathway. CETSA and molecular docking studies indicated that AS forms a stable complex with NLRP3. MDs suggested that ARG578 played an important role in the formation of the complex. CONCLUSION: In this study, we first predicted that the potential target and pathway of AS's effect on PD could be NLRP3 protein and NOD-like receptor signaling pathway by network pharmacology analysis. Further, we demonstrated that AS could alleviate symptoms of PD induced by MPTP through its interaction with the NLRP3 protein for the first time by in vivo and in vitro experiments. By binding to NLRP3, AS effectively inhibits the assembly and activation of the inflammasome. These findings suggest that AS is a promising inhibitor for PD driven by NLRP3 overactivation.

Bioengineered Hydrogels Recapitulate Fibroblast Heterogeneity in Cancer.

Recently mapped transcriptomic landscapes reveal the extent of heterogeneity in cancer-associated fibroblasts (CAFs) beyond previously established single-gene markers. Functional analyses of individual CAF subsets within the tumor microenvironment are critical to develop more accurate CAF-targeting therapeutic strategies. However, there is a lack of robust preclinical models that reflect this heterogeneity in vitro. In this study, single-cell RNA sequencing datasets acquired from head and neck squamous cell carcinoma tissues to predict microenvironmental and cellular features governing individual CAF subsets are leveraged. Some of these features are then incorporated into a tunable hyaluronan-based hydrogel system to culture patient-derived CAFs. Control over hydrogel degradability and integrin adhesiveness enabled derivation of the predominant myofibroblastic and inflammatory CAF subsets, as shown through changes in cell morphology and transcriptomic profiles. Last, using these hydrogel-cultured CAFs, microtubule dynamics are identified, but not actomyosin contractility, as a key mediator of CAF plasticity. The recapitulation of CAF heterogeneity in vitro using defined hydrogels presents unique opportunities for advancing the understanding of CAF biology and evaluation of CAF-targeting therapeutics.

The Prediction of Clinical Mastitis in Dairy Cows Based on Milk Yield, Rumination Time, and Milk Electrical Conductivity Using Machine Learning Algorithms.

In commercial dairy farms, mastitis is associated with increased antimicrobial use and associated resistance, which may affect milk production. This study aimed to develop sensor-based prediction models for naturally occurring clinical bovine mastitis using nine machine learning algorithms with data from 447 mastitic and 2146 healthy cows obtained from five commercial farms in Northeast China. The variables were related to daily activity, rumination time, and daily milk yield of cows, as well as milk electrical conductivity. Both Z-standardized and non-standardized datasets pertaining to four specific stages of lactation were used to train and test prediction models. For all four subgroups, the Z-standardized dataset yielded better results than those of the non-standardized one, with the multilayer artificial neural net algorithm showing the best performance. Variables of importance had a similar rank in this algorithm, indicating the consistency of these variables as predictors for bovine mastitis in commercial farms with similar automatic systems. Moreover, the peak milk yield (PMY) of mastitic cows was significantly higher than that of healthy cows (p < 0.005), indicating that high-yielding cattle are more prone to mastitis. Our results show that machine learning algorithms are effective tools for predicting mastitis in dairy cows for immediate intervention and management in commercial farms.

The relationship between Internet use and loneliness of middle-aged and older adult people: the moderating effect of residence.

Objectives: The proportion of middle-aged and older adult people exposed to the Internet continues to grow. Internet use may have an impact on the mental health of the older adult, especially loneliness. This study analyzed the relationship between Internet use and presence of loneliness. Methods: A total of 550 person aged 45 years and above were randomly selected from a province in eastern China at the end of 2022. The outcome variable was presence of loneliness, as measured by self-report. Descriptive analysis, chi-square test and binary logistic analysis were used to analyze the data. Results: 58.3% of respondents use the Internet. Internet use could reduce the possible of reported loneliness in middle-aged and older adult people (OR = 0.652, 95%CI: 0.465, 0.940), and residence played a moderating role in the relationship between them. Middle-aged and older adults who used the Internet for 1-3 h (OR = 0.464, 95%CI: 0.275, 0.784) and 3-5 h (OR = 0.484, 95%CI: 0.247, 0.946) were less likely to felt lonely than those who used the Internet for less than 1 h per day. In addition, middle-aged and older adult people using the Internet to contact relatives and friends (OR = 0.488, 95%CI:0.292, 0.818), read the news (OR = 0.485, 95%CI:0.277, 0.848), assets management (OR = 0.297, 95%CI:0.109, 0.818) were less likely to report loneliness, while those who made online payment (OR = 3.101, 95%CI:1.413, 6.807) were more likely to report loneliness. Conclusion: There is a significant negative correlation between Internet use and presence of loneliness, but different Internet duration and content have different effects on loneliness in middle-aged and older adult people. We should pay attention to the impact of Internet use on loneliness in middle-aged and older adult people.

Identifying potential Q-markers for quality evaluation of Zhenyuan capsule by integrating chemical analysis, network pharmacology, molecular docking, and molecular dynamics simulations.

Quality markers (Q-markers) are of great significance for quality evaluation of herbal medicines. Zhenyuan Capsule (ZYC) is a kind of Chinese patent medicine used to treat cardiovascular diseases. However, reliable and effective Q-markers for ZYC are still lacking. Herein, a UHPLC-Q/Orbitrap-MS/MS was performed to characterise the preliminary chemical profile of ZYC. A total of 86 components were characterised among which 20 constituents were unambiguously identified by reference compounds. Based on network pharmacology, seven major ginsenosides with great importance in the network were identified as Q-markers among which ginsenoside Re with the highest betweenness was screened to inhibit the development of coronary heart disease (CHD) by binding with vascular endothelial growth factor A (VEGFA). Docking and molecular dynamics simulation studies suggested that ginsenoside Re stably bound to VEGFA. Quantitative determination and chemical fingerprinting analysis were performed using HPLC-DAD. The results showed that ginsenosides screened might function as potential Q-markers for ZYC.

Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy.

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2-mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.