Icariin improves oxidative stress injury during ischemic stroke via inhibiting mPTP opening.

BACKGROUND: Ischemic stroke presents a significant threat to human health due to its high disability rate and mortality. Currently, the clinical treatment drug, rt-PA, has a narrow therapeutic window and carries a high risk of bleeding. There is an urgent need to find new effective therapeutic drugs for ischemic stroke. Icariin (ICA), a key ingredient in the traditional Chinese medicine Epimedium, undergoes metabolism in vivo to produce Icaritin (ICT). While ICA has been reported to inhibit neuronal apoptosis after cerebral ischemia-reperfusion (I/R), yet its underlying mechanism remains unclear. METHODS: PC-12 cells were treated with 200 µM H2O2 for 8 h to establish a vitro model of oxidative damage. After administration of ICT, cell viability was detected by Thiazolyl blue tetrazolium Bromide (MTT) assay, reactive oxygen species (ROS) and apoptosis level, mPTP status and mitochondrial membrane potential (MMP) were detected by flow cytometry and immunofluorescence. Apoptosis and mitochondrial permeability transition pore (mPTP) related proteins were assessed by Western blotting. Middle cerebral artery occlusion (MCAO) model was used to establish I/R injury in vivo. After the treatment of ICA, the neurological function was scored by ZeaLonga socres; the infarct volume was observed by 2,3,5-Triphenyltetrazolium chloride (TTC) staining; HE and Nissl staining were used to detect the pathological state of the ischemic cortex; the expression changes of mPTP and apoptosis related proteins were detected by Western blotting. RESULTS: In vitro: ICT effectively improved H2O2-induced oxidative injury through decreasing the ROS level, inhibiting mPTP opening and apoptosis. In addition, the protective effects of ICT were not enhanced when it was co-treated with mPTP inhibitor Cyclosporin A (CsA), but reversed when combined with mPTP activator Lonidamine (LND). In vivo: Rats after MCAO shown cortical infarct volume of 32-40%, severe neurological impairment, while mPTP opening and apoptosis were obviously increased. Those damage caused was improved by the administration of ICA and CsA. CONCLUSIONS: ICA improves cerebral ischemia-reperfusion injury by inhibiting mPTP opening, making it a potential candidate drug for the treatment of ischemic stroke.

A multi-period optimal distribution model of emergency resources for responding to COVID-19 under uncertain conditions.

Ideally, optimal emergency resource allocation would have been vital for effective relief work during the COVID-19 outbreak. However, the suddenness of the epidemic and uncertainty of its spread added some difficulties to distributing emergency resources. First, this study introduces triangular fuzzy numbers to describe the uncertainty of supply and demand of emergency resources, and interval numbers to describe the time required for resource transportation under disaster conditions. To minimize the total delivery time and difference in the total satisfaction rate, this study constructs an optimal model for emergency resource distribution under uncertain conditions that considers both efficiency and equity. Subsequently, an improved genetic algorithm (IMGA) is proposed to obtain the optimal decision scheme. Finally, a case study on emergency resource distribution during the COVID-19 pandemic is conducted for model verification. The results demonstrate that the proposed model can improve the efficiency and effect of emergency resource distribution. The model allocates some emergency resources to each demand site during each emergency period, which can help avoid large losses caused by extreme shortages of resources at a certain demand point. The emergency resource allocation scheme considers the transportation time and degree of impact, which is beneficial for enhancing the flexibility of decision-making and practical applicability of distribution operations. A comparative analysis of the algorithms shows that the proposed IMGA is an effective method for managing emergency resource distribution optimization problems because it has higher solving efficiency, better convergence, and stronger stability. These findings can provide decision support for the optimal distribution of large-scale, multiperiod emergency resources during the COVID-19 pandemic.

RSAD2, a pyroptosis-related gene, predicts the prognosis and immunotherapy response for colorectal cancer.

Colorectal cancer (CRC) is among the most prevalent malignant tumors, known for its high heterogeneity. Although many treatments and medications are available, the long-term survival rate of CRC patients is far from satisfactory. Pyroptosis is closely related to tumor progression. This study aimed to identify pyroptosis-related genes (PRGs) and candidate biomarkers to predict the prognosis of CRC patients. Used bioinformatics, we identified PRGs and subsequently screened 288 co-expression genes between pyroptosis-related modules and differentially expressed genes in CRC. Among these hub genes, we selected the top 24 for further analysis and found that Radical S-Adenosyl Methionine Domain Containing 2 (RSAD2) was a novel biomarker associated with the progression of CRC. We developed a risk model for RSAD2, which proved to be an independent prognostic indicator. The receiver operator characteristic analysis showed that the model had an acceptable prognostic value for patients with CRC. In addition, RSAD2 also affects the tumor immune microenvironment and prognosis of CRC. We further validated RSAD2 expression in CRC patients using RT-qPCR and the role of RSAD2 in pyroptosis. Taken together, this study comprehensively assessed the expression and prognostic value of RSAD2 in patients with CRC. These findings may offer a new direction for early CRC screening and development of future immunotherapy strategies.

Prognostic and clinicopathological value of Ki-67 in patients with oesophageal squamous cell carcinoma: a systematic review and meta-analysis.

OBJECTIVES: The relationship between Ki-67 expression and the prognosis of patients with oesophageal squamous cell carcinoma (ESCC) has been extensively studied. However, their findings were inconsistent. Consequently, the present meta-analysis was performed to identify the precise value of Ki-67 in predicting the prognosis of ESCC. DESIGN: The current meta-analysis was carried out in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: Electronic databases of PubMed, Embase, Web of Science and Cochrane Library were systematically searched until 26 September 2023. STATISTICAL METHODS: Pooled HRs and corresponding 95% CIs were calculated to estimate the role of Ki-67 in predicting overall survival (OS) and disease-free survival (DFS) in ESCC. Between-study heterogeneity was evaluated using Cochrane's Q test and I2 statistics. Specifically, significant heterogeneities were identified based on p<0.10 on the Q statistic test or I2>50% so the random-effects model should be used; otherwise, the fixed-effects model should be used. The relationship between Ki-67 and clinicopathological characteristics of ESCC was evaluated by combining ORs with their corresponding 95% CIs. RESULTS: 11 articles with 1124 patients were included in the present meta-analysis. Based on our analysis, increased Ki-67 expression was markedly associated with poor OS (HR 1.62, 95% CI 1.15 to 2.28, p=0.006) and DFS (HR 1.72, 95% CI 1.22 to 2.43, p=0.002) in ESCC. Moreover, subgroup analysis revealed that Ki-67 upregulation significantly predicted OS and DFS when a Ki-67 threshold of >30% was used. Nonetheless, Ki-67 was not significantly associated with sex, T stage, N stage, TNM stage, tumour differentiation or tumour location. CONCLUSIONS: In the present meta-analysis, high Ki-67 expression significantly predicted OS and DFS in patients with ESCC, especially when Ki-67>30% was used as the threshold. These results suggest that Ki-67 could serve as an effective and reliable prognostic indicator for ESCC.

Unraveling verticillium wilt resistance: insight from the integration of transcriptome and metabolome in wild eggplant.

Verticillium wilt, caused by Verticillium dahliae, is a soil-borne disease affecting eggplant. Wild eggplant, recognized as an excellent disease-resistant resource against verticillium wilt, plays a pivotal role in grafting and breeding for disease resistance. However, the underlying resistance mechanisms of wild eggplant remain poorly understood. This study compared two wild eggplant varieties, LC-2 (high resistance) and LC-7 (sensitive) at the phenotypic, transcriptomic, and metabolomic levels to determine the molecular basis of their resistance to verticillium wilt. These two varieties exhibit substantial phenotypic differences in petal color, leaf spines, and fruit traits. Following inoculation with V. dahliae, LC-2 demonstrated significantly higher activities of polyphenol oxidase, superoxide dismutase, peroxidase, phenylalanine ammonia lyase, ß-1,3 glucanase, and chitinase than did LC-7. RNA sequencing revealed 4,017 differentially expressed genes (DEGs), with a significant portion implicated in processes associated with disease resistance and growth. These processes encompassed defense responses, cell wall biogenesis, developmental processes, and biosynthesis of spermidine, cinnamic acid, and cutin. A gene co-expression analysis identified 13 transcription factors as hub genes in modules related to plant defense response. Some genes exhibited distinct expression patterns between LC-2 and LC-7, suggesting their crucial roles in responding to infection. Further, metabolome analysis identified 549 differentially accumulated metabolites (DAMs) between LC-2 and LC-7, primarily consisting of compounds such as flavonoids, phenolic acids, lipids, and other metabolites. Integrated transcriptome and metabolome analyses revealed the association of 35 gene-metabolite pairs in modules related to the plant defense response, highlighting the interconnected processes underlying the plant defense response. These findings characterize the molecular basis of LC-2 resistance to verticillium wilt and thus have potential value for future breeding of wilt-resistant eggplant varieties.

Identification and expression profiling of SmGATA genes family involved in response to light and phytohormones in eggplant.

GATA proteins are transcription factors of zinc finger proteins, which play an important role in plant growth development and abiotic stress. However, there have been no identification or systematic studies of the GATA gene family in eggplant. In this study, 28 SmGATA genes were identified in the genome database of eggplant, which could be divided into four subgroups. Plant development, hormones, and stress-related cis-acting elements were identified in promoter regions of the SmGATA gene family. RT-qPCR indicated that 4 SmGATA genes displayed upregulated expressions during fruit developmental stage, whereas 2 SmGATA genes were down-regulated expression patterns. It was also demonstrated that SmGATA genes may be involved in light signals to regulate fruit anthocyanin biosynthesis. Furthermore, the expression patterns of SmGATA genes under ABA, GA and MeJA treatments showed that the SmGATAs were involved in the process of fruit ripening. Notably, SmGATA4 and SmGATA23 were highly correlated with the expression of anthocyanin biosynthesis genes, light-responsive genes, and genes that function in multiple hormone signaling pathways and the proteins they encoded were localized in the nucleus. All these results showed GATA genes likely play a major role in regulating fruit anthocyanin biosynthesis by integrating the light, ABA, GA and MeJA signaling pathways and provided references for further research on fruit quality in eggplant.

Probabilistic risk assessment of dietary exposure to lead in residents of Guangzhou, China.

Lead and its compounds can have cumulative harmful effects on the nervous, cardiovascular, and other systems, and especially affect the brain development of children. We collected 4918 samples from 15 food categories in 11 districts of Guangzhou, China, from 2017 to 2022, to investigate the extent of lead contamination in commercial foods and assess the health risk from dietary lead intake of the residents. Lead was measured in the samples using inductively coupled plasma mass spectrometry. Dietary exposure to lead was calculated based on the food consumption survey of Guangzhou residents in 2011, and the health risk of the population was evaluated using the margin of exposure (MOE) method. Lead was detected in 76.5% of the overall samples, with an average lead content of 29.4 µg kg-1. The highest lead level was found in bivalves. The mean daily dietary lead intakes were as follows: 0.44, 0.34, 0.25, and 0.28 µg kg-1 body weight (bw) day-1 for groups aged 3-6, 7-17, 18-59, and ≥ 60 years, respectively. Rice and rice products, leafy vegetables, and wheat flour and wheat products were identified as the primary sources of dietary lead exposure, accounting for 73.1%. The MOE values demonstrated the following tendency: younger age groups had lower MOEs, and 95% confidence ranges for the groups aged 3-6 and 7-17 began at 0.6 and 0.7, respectively, indicating the potential health risk of children, while those for other age groups were all above 1.0. Continued efforts are needed to reduce dietary lead exposure in Guangzhou.

Retrospective Analysis of Pyrotinib-Based Therapy for Metastatic Breast Cancer: Promising Efficacy in Combination with Trastuzumab.

Purpose: To evaluate the efficacy and safety of a pyrotinib-based therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in the real world. Methods: Clinical data of 218 patients with HER2-positive MBC who received a pyrotinib-based therapy from January 2020 to March 2023 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. Results: Finally, 195 patients were included in the efficacy cohort. The median progression-free survival (PFS) in the total population is 12.4 months (95% CI, 9.8-15.0 months). More than half of the patients in the efficacy cohort received pyrotinib mono-targeted therapy (103 cases, 52.8%). Among the remaining patients, 74 (37.9%) patients chose a combined trastuzumab-targeted therapy and 17 (8.7%) chose to combine inetetamab. Median PFS in the pyrotinib group vs pyrotinib plus trastuzumab group was 10.5 months vs 20.1 months (P<0.001). The median PFS of primary trastuzumab resistance population reached to 20.1 months in pyrotinib plus trastuzumab group. Double-targets' advantage was also observed in the brain metastases subgroup (17.9 months vs 10.0 months, P=0.386). The patients who received pyrotinib plus inetetamab as second and higher-line treatment reached a median PFS of 7.9 months (95% CI, 4.0-11.8 months). Forty-one (19.8%) of 207 patients included in the safety cohort experienced grade 3 or higher diarrhea, the most common adverse event in safety analysis, and no adverse event-related deaths. Conclusion: The combination of pyrotinib and trastuzumab demonstrated promising efficacy in the treatment of HER2-positive metastatic breast cancer, including those who had primary resistance to trastuzumab and brain metastases. Pyrotinib plus trastuzumab is expected to be a potent option in the first-line. Additionally, the concurrent administration of pyrotinib and inetetamab could be an alternative to consider in the second and higher-line treatment for metastatic breast cancer. The adverse reactions of pyrotinib were tolerable in general.

Haplotype-resolved gapless genome and chromosome segment substitution lines facilitate gene identification in wild rice.

The abundant genetic variation harbored by wild rice (Oryza rufipogon) has provided a reservoir of useful genes for rice breeding. However, the genome of wild rice has not yet been comprehensively assessed. Here, we report the haplotype-resolved gapless genome assembly and annotation of wild rice Y476. In addition, we develop two sets of chromosome segment substitution lines (CSSLs) using Y476 as the donor parent and cultivated rice as the recurrent parents. By analyzing the gapless reference genome and CSSL population, we identify 254 QTLs associated with agronomic traits, biotic and abiotic stresses. We clone a receptor-like kinase gene associated with rice blast resistance and confirm its wild rice allele improves rice blast resistance. Collectively, our study provides a haplotype-resolved gapless reference genome and demonstrates a highly efficient platform for gene identification from wild rice.

Real-time sports injury monitoring system based on the deep learning algorithm.

In response to the low real-time performance and accuracy of traditional sports injury monitoring, this article conducts research on a real-time injury monitoring system using the SVM model as an example. Video detection is performed to capture human movements, followed by human joint detection. Polynomial fitting analysis is used to extract joint motion patterns, and the average of training data is calculated as a reference point. The raw data is then normalized to adjust position and direction, and dimensionality reduction is achieved through singular value decomposition to enhance processing efficiency and model training speed. A support vector machine classifier is used to classify and identify the processed data. The experimental section monitors sports injuries and investigates the accuracy of the system's monitoring. Compared to mainstream models such as Random Forest and Naive Bayes, the SVM utilized demonstrates good performance in accuracy, sensitivity, and specificity, reaching 94.2%, 92.5%, and 96.0% respectively.

Advances in Engineered Nanoparticles for the Treatment of Ischemic Stroke by Enhancing Angiogenesis.

Angiogenesis, or the formation of new blood vessels, is a natural defensive mechanism that aids in the restoration of oxygen and nutrition delivery to injured brain tissue after an ischemic stroke. Angiogenesis, by increasing vessel development, may maintain brain perfusion, enabling neuronal survival, brain plasticity, and neurologic recovery. Induction of angiogenesis and the formation of new vessels aid in neurorepair processes such as neurogenesis and synaptogenesis. Advanced nano drug delivery systems hold promise for treatment stroke by facilitating efficient transportation across the the blood-brain barrier and maintaining optimal drug concentrations. Nanoparticle has recently been shown to greatly boost angiogenesis and decrease vascular permeability, as well as improve neuroplasticity and neurological recovery after ischemic stroke. We describe current breakthroughs in the development of nanoparticle-based treatments for better angiogenesis therapy for ischemic stroke employing polymeric nanoparticles, liposomes, inorganic nanoparticles, and biomimetic nanoparticles in this study. We outline new nanoparticles in detail, review the hurdles and strategies for conveying nanoparticle to lesions, and demonstrate the most recent advances in nanoparticle in angiogenesis for stroke treatment.

Safety and Efficacy of Bone Marrow Mesenchymal Stem Cells in the Treatment of Ischemic Stroke: A Meta-Analysis.

Objective: We aimed to systematically evaluate the efficacy and safety of bone marrow mesenchymal stem cells (BMMSCs) in the treatment of ischemic stroke. Methods: Six Chinese and English databases were searched for related randomized controlled trials from the establishment of the databases to 28 February 2023. Two investigators performed screening and a comprehensive analysis and evaluated the quality of the studies. They extracted information from the included studies, and managed and analzsed the data using RevMan 5.4.1 software (The First College of Clinical Medical Science, China Three Gorges University). Finally, they performed meta and heterogeneity analyses and created a risk-of-bias map. Results: A total of 13 high-quality articles were included. The National Institute of Health Stroke Scale (NIHSS) scores of the experimental group differed significantly from those of the control group at 3 months (I2 <50%, mean difference [MD] = -2.88, P < 0.001) after treatment. The Fugl-Meyer assessment (FMA) scores of the experimental group varied significantly from that of the control group at 1 month (I2 >50%, MD = 15.94, P < 0.001), 3 months (I2 >50%, MD = 12.71, P < 0.001), and 6 months (I2 >50%, MD = 13.76, P < 0.001) after treatment, and the overall difference (I2 >50%, MD = 14.38, P ≤ 0.001) was significant. The functional independence measure (FIM) scores were significantly different from that of the control group at 1 month (I2 >50%, MD = 20.04, P = 0.02), 3 months (I2 >50%, MD = 15.51, P < 0.001), and 6 months (I2 >50%, MD = 13.46, P = 0.03). There was no significant increase in adverse events compared with the traditional treatment regimen. Conclusion: To some extent, BMMSC transplantation can improve the neurological deficit, motor function, and daily living ability of patients with ischemic stroke.

Preoperative CECT-Based Multitask Model Predicts Peritoneal Recurrence and Disease-Free Survival in Advanced Ovarian Cancer: A Multicenter Study.

RATIONALE AND OBJECTIVES: Peritoneal recurrence is the predominant pattern of recurrence in advanced ovarian cancer (AOC) and portends a dismal prognosis. Accurate prediction of peritoneal recurrence and disease-free survival (DFS) is crucial to identify patients who might benefit from intensive treatment. We aimed to develop a predictive model for peritoneal recurrence and prognosis in AOC. METHODS: In this retrospective multi-institution study of 515 patients, an end-to-end multi-task convolutional neural network (MCNN) comprising a segmentation convolutional neural network (CNN) and a classification CNN was developed and tested using preoperative CT images, and MCNN-score was generated to indicate the peritoneal recurrence and DFS status in patients with AOC. We evaluated the accuracy of the model for automatic segmentation and predict prognosis. RESULTS: The MCNN achieved promising segmentation performances with a mean Dice coefficient of 84.3% (range: 78.8%-87.0%). The MCNN was able to predict peritoneal recurrence in the training (AUC 0.87; 95% CI 0.82-0.90), internal test (0.88; 0.85-0.92), and external test set (0.82; 0.78-0.86). Similarly, MCNN demonstrated consistently high accuracy in predicting recurrence, with an AUC of 0.85; 95% CI 0.82-0.88, 0.83; 95% CI 0.80-0.86, and 0.85; 95% CI 0.83-0.88. For patients with a high MCNN-score of recurrence, it was associated with poorer DFS with P < 0.0001 and hazard ratios of 0.1964 (95% CI: 0.1439-0.2680), 0.3249 (95% CI: 0.1896-0.5565), and 0.3458 (95% CI: 0.2582-0.4632). CONCLUSION: The MCNN approach demonstrated high performance in predicting peritoneal recurrence and DFS in patients with AOC.

Peripheral inflammation and trajectories of depressive symptomology after ischemic stroke: A prospective cohort study.

BACKGROUND: Understanding the association of peripheral inflammation and post-stroke depressive symptomology (PSDS) might provide further insights into the complex etiological mechanism of organic depression. However, studies focusing on the longitudinal patterns of PSDS were limited and it remained unclear whether peripheral inflammation influences the occurrence and development of PSDS. METHODS: A total of 427 prospectively enrolled and followed ischemic stroke patients were included in the analytical sample. Depressive symptomology was assessed on four occasions during 1 year after ischemic stroke. Peripheral inflammatory proteins on admission and repeated measures of peripheral immune markers in three stages were collected. Latent class growth analysis (LCGA) was employed to delineate group-based trajectories of peripheral immune markers and PSDS. Multinomial regression was performed to investigate the association of peripheral inflammation with PSDS trajectories. RESULTS: Four distinct trajectories of PSDS were identified: stable-low (n = 237, 55.5 %), high-remitting (n = 120, 28.1 %), late-onset (n = 44, 10.3 %), and high-persistent (n = 26, 6.1 %) PSDS trajectories. The elevation of peripheral fibrinogen on admission increased the risk of high-persistent PSDS in patients with early high PSDS. Additionally, chronic elevation of innate immune levels might not only increase the risk of high-persistent PSDS in patients with early high PSDS but also increase the risk of late-onset PSDS in patients without early high PSDS. The elevation of adaptive immune levels in the convalescence of ischemic stroke may contribute to the remission of early high PSDS. CONCLUSIONS: Peripheral immunity could influence the development of PSDS, and this influence might have temporal heterogeneity. These results might provide vital clues for the inflammation hypothesis of PSD.

Catalase-templated nanozyme-loaded microneedles integrated with polymyxin B for immunoregulation and antibacterial activity in diabetic wounds.

Diabetic wounds are characterized by chronic trauma, with long-term non-healing attributed to persistent inflammation and recurrent bacterial infections. Exacerbation of the inflammatory response is largely due to increased levels of reactive oxygen species (ROS). In this study, catalase (CAT) was used as a biological template to synthesize nanozyme-supported natural enzymes (CAT-Mn(SH)x) using a biomimetic mineralization method. Subsequently, polymyxin B (CAT-Mn(SH)x@PMB) was immobilized on its surface through electrostatic assembly. CAT-Mn(SH)x@PMB demonstrates the ability for slow and sustained release of hydrogen sulfide (H2S). Finally, CAT-Mn(SH)x@PMB loaded microneedles (MNs) substrate were synthesized using polyvinyl alcohol (PVA) and hydroxyethyl methacrylate (HEMA), and named CAT-(MnSH)x@PMB-MNs. It exhibited enhanced enzyme and antioxidant activities, along with effective antibacterial properties. Validation findings indicate that it can up-regulate the level of M2 macrophages and reduce the level of pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Additionally, it promotes angiogenesis and rapid nerve regeneration, thereby facilitating wound healing through its dual anti-inflammatory and antibacterial effects. Hence,this study introduces a time-space tissue-penetrating and soluble microneedle patch with dual anti-inflammatory and antibacterial effects for the treatment of diabetic wounds.

General Model for Predicting Response of Gas-Sensitive Materials to Target Gas Based on Machine Learning.

Gas sensors play a crucial role in various industries and applications. In recent years, there has been an increasing demand for gas sensors in society. However, the current method for screening gas-sensitive materials is time-, energy-, and cost-consuming. Consequently, an imperative exists to enhance the screening efficiency. In this study, we proposed a collaborative screening strategy through integration of density functional theory and machine learning. Taking zinc oxide (ZnO) as an example, the responsiveness of ZnO to the target gas was determined quickly on the basis of the changes in the electronic state and structure before and after gas adsorption. In this work, the adsorption energy and electronic and structural characteristics of ZnO after adsorbing 24 kinds of gases were calculated. These computed features served as the basis for training a machine learning model. Subsequently, various machine learning and evaluation algorithms were utilized to train the fast screening model. The importance of feature values was evaluated by the AdaBoost, Random Forest, and Extra Trees models. Specifically, charge transfer was assigned importance values of 0.160, 0.127, and 0.122, respectively, ranking as the highest among the 11 features. Following closely was the d-band center, which was presumed to exert influence on electrical conductivity and, consequently, adsorption properties. With 5-fold cross-validation using the Extra Tree accuracy, the 24-sample data set achieved an accuracy of 88%. The 72-sample data set achieved an accuracy of 78% using multilayer perceptron after 5-fold cross-validation, with both data sets exhibiting low standard deviations. This verified the accuracy and reliability of the strategy, showcasing its potential for rapidly screening a material's responsiveness to the target gas.

Combined untargeted metabolomics and network pharmacology approaches to reveal the therapeutic role of withanolide B in psoriasis.

Psoriasis is a refractory inflammatory skin disorder in which keratinocyte hyperproliferation is a crucial pathogenic factor. Up to now, it is commonly acknowledged that psoriasis has a tight connection with metabolic disorders. Withanolides from Datura metel L. (DML) have been proved to possess anti-inflammatory and anti-proliferative properties in multiple diseases including psoriasis. Withanolide B (WB) is one of the abundant molecular components in DML. However, existing experimental studies regarding the potential effects and mechanisms of WB on psoriasis still remain lacking. Present study aimed to integrate network pharmacology and untargeted metabolomics strategies to investigate the therapeutic effects and mechanisms of WB on metabolic disorders in psoriasis. In our study, we observed that WB might effectively improve the symptoms of psoriasis and alleviate the epidermal hyperplasia in imiquimod (IMQ)-induced psoriasis-like mice. Both network pharmacology and untargeted metabolomics results suggested that arachidonic acid metabolism and arginine and proline metabolism pathways were linked to the treatment of psoriasis with WB. Meanwhile, we also found that WB may affect the expression of regulated enzymes 5-lipoxygenase (5-LOX), 12-LOX, ornithine decarboxylase 1 (ODC1) and arginase 1 (ARG1) in the arachidonic acid metabolism and arginine and proline metabolism pathways. In summary, this paper showed the potential metabolic mechanisms of WB against psoriasis and suggested that WB would have greater potential in psoriasis treatment.

A wild rice CSSL population facilitated identification of salt tolerance genes and rice germplasm innovation.

Salt stress is one of the major factors that limits rice production. Therefore, identification of salt-tolerant alleles from wild rice is important for rice breeding. In this study, we constructed a set of chromosome segment substitution lines (CSSLs) using wild rice as the donor parent and cultivated rice Nipponbare (Nip) as the recurrent parent. Salt tolerance germinability (STG) was evaluated, and its association with genotypes was determined using this CSSL population. We identified 17 QTLs related to STG. By integrating the transcriptome and genome data, four candidate genes were identified, including the previously reported AGO2 and WRKY53. Compared with Nip, wild rice AGO2 has a structure variation in its promoter region and the expression levels were upregulated under salt treatments; wild rice WRKY53 also has natural variation in its promoter region, and the expression levels were downregulated under salt treatments. Wild rice AGO2 and WRKY53 alleles have combined effects for improving salt tolerance at the germination stage. One CSSL line, CSSL118 that harbors these two alleles was selected. Compared with the background parent Nip, CSSL118 showed comprehensive salt tolerance and higher yield, with improved transcript levels of reactive oxygen species scavenging genes. Our results provided promising genes and germplasm resources for future rice salt tolerance breeding.

Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification.

BACKGROUND: Diabetic kidney disease (DKD) is one of the serious complications of diabetes mellitus, and the existing treatments cannot meet the needs of today's patients. Traditional Chinese medicine has been validated for its efficacy in DKD after many years of clinical application. However, the specific mechanism by which it works is still unclear. Elucidating the molecular mechanism of the Nardostachyos Radix et Rhizoma-rhubarb drug pair (NRDP) for the treatment of DKD will provide a new way of thinking for the research and development of new drugs. AIM: To investigate the mechanism of the NRDP in DKD by network pharmacology combined with molecular docking, and then verify the initial findings by in vitro experiments. METHODS: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to screen active ingredient targets of NRDP. Targets for DKD were obtained based on the Genecards, OMIM, and TTD databases. The VENNY 2.1 database was used to obtain DKD and NRDP intersection targets and their Venn diagram, and Cytoscape 3.9.0 was used to build a "drug-component-target-disease" network. The String database was used to construct protein interaction networks. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Ontology analysis were performed based on the DAVID database. After selecting the targets and the active ingredients, Autodock software was used to perform molecular docking. In experimental validation using renal tubular epithelial cells (TCMK-1), we used the Cell Counting Kit-8 assay to detect the effect of NRDP on cell viability, with glucose solution used to mimic a hyperglycemic environment. Flow cytometry was used to detect the cell cycle progression and apoptosis. Western blot was used to detect the protein expression of STAT3, p-STAT3, BAX, BCL-2, Caspase9, and Caspase3. RESULTS: A total of 10 active ingredients and 85 targets with 111 disease-related signaling pathways were obtained for NRDP. Enrichment analysis of KEGG pathways was performed to determine advanced glycation end products (AGEs)-receptor for AGEs (RAGE) signaling as the core pathway. Molecular docking showed good binding between each active ingredient and its core targets. In vitro experiments showed that NRDP inhibited the viability of TCMK-1 cells, blocked cell cycle progression in the G0/G1 phase, and reduced apoptosis in a concentration-dependent manner. Based on the results of Western blot analysis, NRDP differentially downregulated p-STAT3, BAX, Caspase3, and Caspase9 protein levels (P < 0.01 or P < 0.05). In addition, BAX/BCL-2 and p-STAT3/STAT3 ratios were reduced, while BCL-2 and STAT3 protein expression was upregulated (P < 0.01). CONCLUSION: NRDP may upregulate BCL-2 and STAT3 protein expression, and downregulate BAX, Caspase3, and Caspase9 protein expression, thus activating the AGE-RAGE signaling pathway, inhibiting the vitality of TCMK-1 cells, reducing their apoptosis. and arresting them in the G0/G1 phase to protect them from damage by high glucose.