Rational design of CT-coupled J-aggregation platform based on Aza-BODIPY for highly efficient phototherapy.

Supramolecular engineering is exceptionally appealing in the design of functional materials, and J-aggregates resulting from noncovalent interactions offer intriguing features. However, building J-aggregation platforms remains a significant challenge. Herein, we report 3,5-dithienyl Aza-BODIPYs with a donor-acceptor-donor (D-A-D) architecture as the first charge transfer (CT)-coupled J-aggregation BODIPY-type platform. The core acceptor moieties in one molecule interact with donor units in neighboring molecules to generate slip-stacked packing motifs, resulting in CT-coupled J-aggregation with a redshifted wavelength up to 886 nm and an absorption tail over 1100 nm. The J-aggregates show significant photoacoustic signals and high photothermal conversion efficiency of 66%. The results obtained in vivo show that the J-aggregates have the potential to be used for tumor photothermal ablation and photoacoustic imaging. This study not only demonstrates Aza-BODIPY with D-A-D as a novel CT-coupled J-aggregation platform for NIR phototherapy materials but also motivates further study on the design of J-aggregation.

Mitochondria-targeted BODIPY dyes for small molecule recognition, bio-imaging and photodynamic therapy.

Mitochondria are essential for a diverse array of biological functions. There is increasing research focus on developing efficient tools for mitochondria-targeted detection and treatment. BODIPY dyes, known for their structural versatility and excellent spectroscopic properties, are being actively explored in this context. Numerous studies have focused on developing innovative BODIPYs that utilize optical signals for imaging mitochondria. This review presents a comprehensive overview of the progress made in this field, aiming to investigate mitochondria-related biological events. It covers key factors such as design strategies, spectroscopic properties, and cytotoxicity, as well as mechanism to facilitate their future application in organelle imaging and targeted therapy. This work is anticipated to provide valuable insights for guiding future development and facilitating further investigation into mitochondria-related biological sensing and phototherapy.

Effects of maize and soybean intercropping on soil phosphorus bioavailability and microbial community structure in rhizosphere.

To investigate the effect of maize/soybean intercropping on rhizosphere soil microbial communities and phosphorus (P) bioavailability, we examined the changes of soil bioavailable P fractions and microbial community characteristics in the monoculture and intercropping systems based on high-throughput sequencing. The results showed that maize/soybean intercropping increased the contents of rhizosphere soil organic matter (SOM), available phosphorus (AP), microbial biomass phosphorus (MBP), and aboveground biomass. The increase of AP was mainly related to the increasing enzyme extracted phosphorus (Enzyme-P) and hydrochloric acid extracted phosphorus (HCl-P) contents. The dominant bacterial phyla under each treatment were Proteobacteria, Actinobacteria, Acidobacteria and Chloroflexi, while the dominant bacterial genera were Nocardioides, Solirubacter, Sphingomonas and Arthrobacter, with Proteobacteria and Sphingomonas having the highest relative abundance. The relative abundance of Proteobacteria and Sphingomonas in intercropping maize rhizosphere soil was significantly higher than that in monoculture, and that of Proteobacteria in intercropping soybean rhizosphere soil was significantly higher than monoculture. Soil properties and P fractions were closely related to the rhizosphere soil microbial composition. In all, maize/soybean intercropping could affect the rhizosphere soil P bioavailability by altering the structure of rhizosphere microbial communities.

Effect of gut microbiome regulated Taohong Siwu Decoction metabolism on glioma cell phenotype.

Introduction: To establish a new model for exploring the mechanism of the gut microbiome and drug metabolism, we explored whether Taohong Siwu Decoction acts after metabolism by intestinal flora under the premise of clarifying the interaction between intestinal flora and drug metabolism. Methods: Taohong Siwu Decoction (TSD) was fed to germ-free mice and conventional mice, respectively. The serum from both groups of mice was removed and co-cultured with glioma cells in vitro. The co-cultured glioma cells were compared separately for changes at the RNA level using RNA-seq technology. The genes of interest in the comparison results were selected for validation. Results: The differences in the phenotypic alterations of glioma cells between serum from TSD-fed germ-free mice and normal mice were statistically significant. In vitro experiments showed that Taohong Siwu Decoction-fed normal mouse serum-stimulated glioma cells, which inhibited proliferation and increased autophagy. RNA-seq analysis showed that TSD-fed normal mouse serum could regulate CDC6 pathway activity in glioma cells. The therapeutic effect of TSD is significantly influenced by intestinal flora. Conclusion: The treatment of tumors by TSD may be modulated by intestinal flora. We established a new method to quantify the relationship between intestinal flora and the regulation of TSD efficacy through this study.

Elemene induces cell apoptosis via inhibiting glutathione synthesis in lung adenocarcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma wenyujin Y.H. Chen & C. Ling, also known as Wen-E-Zhu, has been used for cancer treatment since ancient times, with roots dating back to the Song Dynasty. Elemene (EE), a sesquiterpene extract with potent anticancer properties, is extracted from Wen-E-Zhu, with ß-elemene (BE) being its main active compound, along with trace amounts of ß-caryophyllene (BC), γ-elemene and δ-elemene isomers. EE has demonstrated broad-spectrum anti-cancer effects and is commonly used in clinical treatments for various types of malignant cancers, including lung cancer. Studies have shown that EE can arrest the cell cycle, inhibit cancer cell proliferation, and induce apoptosis and autophagy. However, the exact mechanism of its anti-lung cancer activity remains unclear and requires further research and investigation. AIM OF THE STUDY: In this study, the possible mechanism of EE and its main active components, BE and BC, against lung adenocarcinoma was investigated by using A549 and PC9 cell lines. MATERIALS AND METHODS: The subcutaneous tumor model of nude mice was constructed to evaluate the efficacy of EE in vivo, then the in vitro half-inhibitory concentration (IC50) of EE and its main active components, BE and BC, on A549 and PC9 cells at different concentrations were determined by CCK-8. Flow cytometry was used to detect the apoptosis and cycle of A549 and PC9 cells treated with different concentrations of BE and BC for 24 h. Non-targeted metabolomics analysis was performed on A549 cells to explore potential target pathways, which were subsequently verified through kit detection and western blot analysis. RESULTS: Injection of EE in A549 tumor-bearing mice effectively suppressed cancer growth in vivo. The IC50 of EE and its main active components, BE and BC, was around 60 µg/mL. Flow cytometry analysis showed that BE and BC blocked the G2/M and S phases of lung adenocarcinoma cells and induced apoptosis, leading to a significant reduction in mitochondrial membrane potential (MMP). Results from non-targeted metabolomics analysis indicated that the glutathione metabolism pathway in A549 cells was altered after treatment with the active components. Kit detection revealed a decrease in glutathione (GSH) levels and an increase in the levels of oxidized glutathione (GSSG) and reactive oxygen (ROS). Supplementation of GSH reduced the inhibitory activity of the active components on lung cancer and also decreased the ROS content of cells. Analysis of glutathione synthesis-related proteins showed a decrease in the expression of glutaminase, cystine/glutamate reverse transporter (SLC7A11), and glutathione synthase (GS), while the expression of glutamate cysteine ligase modified subunit (GCLM) was increased. In the apoptosis-related pathway, Bax protein and cleaved caspase-9/caspase-9 ratio were up-regulated and Bcl-2 protein was down-regulated. CONCLUSIONS: EE, BE, and BC showed significant inhibitory effects on the growth of lung adenocarcinoma cells, and the mechanism of action was linked to the glutathione system. By down-regulating the expression of proteins related to GSH synthesis, EE and its main active components BE and BC disrupted the cellular redox system and thereby promoted cell apoptosis.

Deciphering the Mechanism of YuPingFeng Granules in Treating Pneumonia: A Network Pharmacology and Molecular Docking Study.

Objective: YuPingFeng Granules (YPFGs) is an herbal formula clinically used in China for more than 100 years to treat pneumonia. Nevertheless, the mechanism of YPFG in pneumonia treatment has not been established. This network pharmacology-based strategy has been performed to elucidate active compounds as well as mechanisms of YPFG in pneumonia treatment. Methods: First, active compounds of YPFG were identified in the traditional Chinese medicine systems pharmacology (TCMSP) database, and then the targets related to the active compounds were obtained from TCMSP and Swiss Target Prediction databases. Next, using DisGeNET, DrugBank, and GeneCards databases, we got therapeutic targets of pneumonia and common targets between pneumonia targets and YPFG. After that, a protein-protein interaction (PPI) network of pneumonia composed of common targets was built to analyze the interactions among these targets, which focused on screening for hub targets by topology. Then, online software and the ClusterProfiler package were utilized for the enrichment analysis of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) data. Finally, the visualization software of Autodock was used for molecular docking among the hub target proteins. Results: 10 hub genes were selected by comparing the GO and KEGG functions of pneumonia targets with those of the common targets of YPFG and pneumonia. By using molecular docking technology, a total of 3 active ingredients have been verified as being able to combine closely with 6 hub targets and contribute to their therapeutic effects. Conclusion: This research explored the multigene pharmacological mechanism of action of YPFG against pneumonia through network pharmacology. The findings present new ideas for studying the mechanism of action of Chinese medicine against pneumonia caused by bacteria.

Hemiepiphytic figs kill their host trees: acquiring phosphorus is a driving factor.

Hemiepiphytic figs killing their host trees is an ecological process unique to the tropics. Yet the benefits and adaptive strategies of their special life history remain poorly understood. We compared leaf phosphorus (P) content data of figs and palms worldwide, and functional traits and substrate P content of hemiepiphytic figs (Ficus tinctoria), their host palm and nonhemiepiphytic conspecifics at different growth stages in a common garden. We found that leaf P content of hemiepiphytic figs and their host palms significantly decreased when they were competing for soil resources, but that of hemiepiphytic figs recovered after host death. P availability in the canopy humus and soil decreased significantly with the growth of hemiepiphytic figs. Functional trait trade-offs of hemiepiphytic figs enabled them to adapt to the P shortage while competing with their hosts. From the common garden to a global scale, the P competition caused by high P demand of figs may be a general phenomenon. Our results suggest that P competition is an important factor causing host death, except for mechanically damaging and shading hosts. Killing hosts benefits hemiepiphytic figs by reducing interspecific P competition and better acquiring P resources in the P-deficient tropics, thereby linking the life history strategy of hemiepiphytic figs to the widespread P shortage in tropical soils.

Socioeconomic status influences on bone mineral density in American men: findings from NHANES 2011-2020.

The association between socioeconomic status (SES) and bone mineral density (BMD) in men remains controversial. We showed that SES was positively associated with BMD in American men. Confounding factors like race/ethnicity and age could affect the association. INTRODUCTION: Based on the data from the National Health and Nutrition Examination Survey (NHANES), 2011-2020, this article aims to investigate the association of SES (poverty income ratio (PIR) and education level) with the BMD in American men. METHODS: We evaluated the association of SES with BMD in 4446 men aged ≥ 20 years (mean age, 41.0 ± 13.4 years) from the NHANES 2011-2020. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine. We used multivariate linear regression models to examine the relationship between SES and total spine BMD, adjusted for a large range of confounding factors. RESULTS: Compared with other PIR quarters, individuals in the highest quarter of PIR were more likely to be older and white and had fewer smoking or drinking behaviors. After adjusting for race/ethnicity, age, drinking and smoking behavior, body mass index (BMI), total protein, serum calcium, serum uric acid, cholesterol, serum phosphorus, and blood urea nitrogen, PIR was positively correlated with total spine BMD (ß = 0.004 95% CI: 0.001-0.007, P = 0.006). Individuals with the highest degree (college degree or above) had a 0.057 g/cm2 greater BMD than that of the lowest degree (less than 9th grade) (ß = 0.057 95% CI: 0.037-0.077, P < 0.001). CONCLUSIONS: Our study indicates that SES was positively associated with the lumbar BMD among American men. Clinicians, healthcare providers, and policymakers should consider the unequal SES of men when implementing osteoporosis prevention and treatment strategies.

Local anesthesia, epidural anesthesia and general anesthesia comparison in lumbar disc herniation: a network meta-analysis.

There were 3 major anesthesia methods for discectomy: local, epidural and general. A lot of studies has been established to compare these three methods in different aspects, however, the result is still controversial. We conducted this network meta-analysis to evaluate these methods. Electronic databases including PubMed, EMBASE, Cochrane Library, were searched to identify clinical trials that reported the effects of local anesthesia general anesthesia and epidural anesthesia in lumbar disc herniation. Three indicators were included for evaluation: post-operative VAS score, complication, operation duration. In total, 12 studies and 2287 patients were included for this study. For complication, epidural anesthesia shows significantly lower rate compare to general anesthesia (OR: 0.45, 95% CI [0.24, 0.45], P=0.015), but local anesthesia didn't show significant result, no significant heterogeneity was observed between designs. For VAS score, epidural anesthesia showed a better effect (MD: -1.61, 95%CI [-2.24, -0.98]) compare to general anesthesia, and local anesthesia has a similar effect (MD: -0.91, 95%CI [-1.54, -0.27]). However this result showed a very high heterogeneity (I2=95%). For operation duration, local anesthesia showed a significant lesser time compare to general anesthesia (MD: -46.31(minutes), 95%CI [-73.73, -19.19]) but epidural anesthesia didn't have one, this result also showed a very high heterogeneity (I2=98%). Epidural anesthesia showed lesser post- operative complication compare to general anesthesia in lumbar disc herniation surgery.

Site-Specific Conjugation of a Selenopolypeptide to Alpha-1-antitrypsin Enhances Oxidation Resistance and Pharmacological Properties.

Human alpha-1-antitrypsin (A1AT), a native serine-protease inhibitor that protects tissue damage from excessive protease activities, is used as an augmentation therapy to treat A1AT-deficienct patients. However, A1AT is sensitive to oxidation-mediated deactivation and has a short circulating half-life. Currently, there is no method that can effectively protect therapeutic proteins from oxidative damage in vivo. Here we developed a novel biocompatible selenopolypeptide and site-specifically conjugated it with A1AT. The conjugated A1AT fully retained its inhibitory activity on neutrophil elastase, enhanced oxidation resistance, extended the serum half-life, and afforded long-lasting protective efficacy in a mouse model of acute lung injury. These results demonstrated that conjugating A1AT with the designed selenopolymer is a viable strategy to improve its pharmacological properties, which could potentially further be applied to a variety of oxidation sensitive biotherapeutics.

Bioactivity-guided discovery of quality control markers in rhizomes of Curcuma wenyujin based on spectrum-effect relationship against human lung cancer cells.

BACKGROUND: Due to the diversity of the ingredients, the complexity of the mechanism of action, the uncertainty of the effective ingredients, coupled with the multiple species and multiple growing areas, the quality control (QC) of Traditional Chinese Medicines (TCMs) is challenging. Discovering and identifying effective compounds from the complex extracts of TCMs and then establishing a scientific QC method is the key to the holistic QC of TCMs. PURPOSE: To develop an anti-lung-cancer-guided spectrum-effect relationship approach for the discovery of QC markers of the rhizome of Curcuma wenyujin (WEZ) and establish a bioactive compounds-based holistic QC method. METHODS: The chemical profiling of the volatile oil (WVO) from 42 batches of WEZ collected from different growing areas was performed by GC-MS. The anti-lung cancer activity of different WVO samples was determined by CCK-8 assay against human lung cancer cells (A549). The apoptosis and cell cycle analysis under different concentrations of WVO were detected by flow cytometry. SIMCA-P software was used to perform multivariate statistical analysis on the chemical composition of different WVO samples and to find the different components. Active compounds were screened using a PLSR model of the spectrum-effect relationship. Bioactive compounds-based fingerprint and quantification of the leading bioactive compounds were developed by GC-MS and GC-FID, respectively. RESULTS: Seventy-eight compounds were detected in WVO and 54 were successfully identified. The multivariate statistical analysis uncovered that WVO components and the anti-A549 activity of WVO at the concentration of 60 nl/ml differ greatly according to the origin of the plant. The WVO at the concentration of 60 nl/ml (IC50) increased A549 cells apoptosis significantly with late and early apoptosis of 15.61% and 7.80%, and the number of cells in the G2/M phase were also increased significantly under this concentration. The spectrum-effect relationship analysis revealed that 44 compounds were positively correlated with their activities, and the result was verified by A549 cell viability assay. Sixteen positively correlated compounds were further selected as QC markers according to their relative amount > 0.5% and anticancer activity. Finally, the 16 QC markers-based GC-MS fingerprint was established to holistically control the quality of WEZ, and a GC-FID method was developed for the quantification of leading bioactive compounds, ß-elemene and ß-caryophyllene. CONCLUSION: Based on an anti-lung-cancer-guided spectrum-effect relationship approach, the bioactive compounds-based holistic QC method was successfully developed for WEZ, which could provide a valuable reference for the QC of TCMs.

Zichong granules promote differentiation of ovarian granulosa-like cells from human embryonic stem cells in vitro.

OBJECTIVE: To investigate whether Zichong granules (, ZCKL), a very effective herbal formula for treating infertility, have an impact on the differentiation of ovarian granulosa cells from human embryonic stem cells (hESCs) in vitro, and to explore the cellular mechanisms of its clinical effects. METHODS: Serum from ZCKL-medicated rats was prepared and used to treat mesoderm cells derived from hESCs for 6 d. Normal rat serum and a set of growth factors were used as negative and positive controls, respectively. RESULTS: ZCKL-medicated rat serum, but not normal rat serum, induced hESCs-derived mesoderm cells to differentiate into functional ovarian granulosa-like cells (OGLCs) in a similar manner to defined growth factors. The induced OGLCs resembled the morphology of native human granulosa cells, expressed granulosa cell-specific markers at both the mRNA and protein levels, produced high levels of estradiol and strongly responded to follicle-stimulating hormone stimulation. Furthermore, mRNA levels of follistatin, mothers against decapentaplegic homolog 8 and bone morphogenetic protein 6 were dynamically changed during the process. CONCLUSION: In the ZCKL treatment of infertility, one mechanism by which ZCKL may act is by influencing ovarian granulosa cell differentiation and development, possibly through the follistatin and BMP/SMAD signaling pathways.

Early therapeutic interventions of traditional Chinese medicine in COVID-19 patients: A retrospective cohort study.

OBJECTIVE: To observe the early interventions of traditional Chinese Medicine (TCM) on the conversion time of nucleic acid in patients with coronavirus disease 2019 (COVID-19), and find possible underlying mechanisms of action. METHODS: A retrospective cohort study was conducted on 300 confirmed COVID-19 patients who were treated with TCM, at a designated hospital in China. The patients were categorized into three groups: TCM1, TCM2 and TCM3, who respectively received TCM interventions within 7, 8-14, and greater than 15 days of hospitalization. Different indicators such as the conversion time of pharyngeal swab nucleic acid, the conversion time of fecal nucleic acid, length of hospital stay, and inflammatory markers (leukocyte count, and lymphocyte count and percentage) were analyzed to observe the impact of early TCM interventions on these groups. RESULTS: The median conversion times of pharyngeal swab nucleic acid in the three groups were 5.5, 7 and 16 d (P < 0.001), with TCM1 and TCM2 being statistically different from TCM3 (P < 0.01). TCM1 (P < 0.05) and TCM3 (P < 0.01) were statistically different from TCM2. The median conversion times of fecal nucleic acid in the three groups were 7, 9 and 17 d (P < 0.001). Conversion times of fecal nucleic acid in TCM1 were statistically different from TCM3 and TCM2 (P < 0.01). The median lengths of hospital stay in the three groups were 13, 16 and 21 d (P < 0.001). TCM1 and TCM2 were statistically different from TCM3 (P < 0.01); TCM1 and TCM3 were statistically different from TCM2 (P < 0.01). Both leucocyte and lymphocyte counts increased gradually with an increase in the length of hospital stay in TCM1 group patients, with a statistically significant difference observed at each time point in the group (P < 0.001). Statistically significant differences in lymphocyte count and percentage in TCM2 (P < 0.001), and in leucocyte count (P = 0.043) and lymphocyte count (P = 0.038) in TCM3 were observed. The comparison among the three groups showed a statistically significant difference in lymphocyte percentage on the third day of admission (P = 0.044). CONCLUSION: In this study, it was observed that in COVID-19 patients treated with a combination of Chinese and Western medicines, TCM intervention earlier in the hospital stay correlated with faster conversion time of pharyngeal swab and fecal nucleic acid, as well as shorter length of hospital stay, thus helping promote faster recovery of the patient. The underlying mechanism of action may be related to improving inflammation in patients with COVID-19.

Effect of Kangfuxin Liquid enema combined with mesalazine on gestational outcomes and quality of life in child-bearing female with active ulcerative colitis: A protocol for randomized, double-blind, controlled trial.

BACKGROUND: In recent years, the incidence of ulcerative colitis (UC) is on the rise, and most of them are young adults. As the peak of the disease overlaps with the childbearing age, it has a great impact on the fertility of female patients. We, therefore, conduct a randomized and controlled trial to evaluate the efficacy and safety of mesalazine enteric-coated tablets combined with Kangfuxin Liquid (KFX) enema for the child-bearing period female with active UC. METHODS: In this randomized controlled study, a total of 236 eligible patients will be assigned to the experimental group (n = 118) or the control group (n = 118) in a 1:1 ratio. The control group will be taken mesalazine enteric-coated tablets combined with placebo enema and the experimental group will be taken mesalazine enteric-coated tablets combined with KFX enema. Participants will receive 8 weeks of intervention treatment and 3 months of maintenance treatment before pregnancy. The primary assessment is the Mayo score. Secondary outcomes include mucosal healing, faecal calprotectin (FC), Inflammatory Bowel Disease Quality (IBDQ), and pregnancy outcome. DISCUSSION: This study will provide evidence regarding the efficacy and safety of KFX enema used before pregnancy on halting active UC, reducing the relapse rate during pregnancy, improving pregnancy outcome, and the quality of life. TRIAL REGISTRATION: Chinese Clinical Trials Register identifier, ChiCTR2000039161, registered on October 20, 2020.

Ancient DNA and multimethod dating confirm the late arrival of anatomically modern humans in southern China.

The expansion of anatomically modern humans (AMHs) from Africa around 65,000 to 45,000 y ago (ca. 65 to 45 ka) led to the establishment of present-day non-African populations. Some paleoanthropologists have argued that fossil discoveries from Huanglong, Zhiren, Luna, and Fuyan caves in southern China indicate one or more prior dispersals, perhaps as early as ca. 120 ka. We investigated the age of the human remains from three of these localities and two additional early AMH sites (Yangjiapo and Sanyou caves, Hubei) by combining ancient DNA (aDNA) analysis with a multimethod geological dating strategy. Although U-Th dating of capping flowstones suggested they lie within the range ca. 168 to 70 ka, analyses of aDNA and direct AMS 14C dating on human teeth from Fuyan and Yangjiapo caves showed they derive from the Holocene. OSL dating of sediments and AMS 14C analysis of mammal teeth and charcoal also demonstrated major discrepancies from the flowstone ages; the difference between them being an order of magnitude or more at most of these localities. Our work highlights the surprisingly complex depositional history recorded at these subtropical caves which involved one or more episodes of erosion and redeposition or intrusion as recently as the late Holocene. In light of our findings, the first appearance datum for AMHs in southern China should probably lie within the timeframe set by molecular data of ca. 50 to 45 ka.

Effectiveness of electroacupuncture for thin endometrium in infertile women: study protocol for a single-blind, randomized controlled trial.

BACKGROUND: Thin endometrium negatively impacts the reproductive function. Current treatments for thin endometrium do not always improve endometrial receptivity. Preliminary evidence suggests that electroacupuncture could have potential therapy for thin endometrium in infertile women. Thus, this randomized controlled trial was designed to test whether electroacupuncture can improve endometrial receptivity in infertile women with thin endometrium. METHODS: This study is a randomized, single-blinded, controlled, clinical trial. A total of 142 eligible patients will be recruited and randomly assigned to the electroacupuncture (EA) group or the sham electroacupuncture (SEA) group in a 1:1 ratio. Participants will receive 36 sessions over three menstrual cycles (12 weeks in total), with the same acupoint prescription. The primary outcome of this trial is endometrial thickness in the midluteal phase. The secondary outcomes include endometrial pattern, resistance index (RI) and pulsatility index (PI) of bilateral uterine artery and endometrium blood flow, serum estradiol (E2) and progesterone (P), and pregnancy rate. The pregnancy rate will be evaluated during a 6-month follow-up after completion of the trial. All other outcomes will be evaluated before treatment, during the treatment of 1st, 2nd, and 3rd menstrual cycle, and 6 months after treatment. DISCUSSION: If the outcome confirms the effectiveness of electroacupuncture for thin endometrium in infertile women, this treatment will be proposed for application in clinical practice. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR2 000029983. Registered on 18 February 2020.

Utility of Normalized TdP Score System in Drug Proarrhythmic Potential Assessment: A Blinded in vitro Study of CiPA Drugs.

Drugs that prolong QT may cause torsade de pointes (TdP). However, translation of nonclinical assessment of QT prolongation or hERG channel, targeted by QT-prolonging drugs, into clinical TdP risk has been insufficient to date. In this blinded study, we confirmed the utility of a Normalized TdP Score System in predicting drug-induced TdP risks among 34 drugs, including 28 with low, intermediate, and high TdP risks under the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative plus six compounds with names blinded to the investigators, using the rabbit ventricular wedge assay. Concentration-dependent TdP scores were determined by drug-induced changes in QT, Tp-e , and proarrhythmias. Disclosure of the names and testing concentrations was made after completion of the experiments and report to the sponsors. Drugs' normalized TdP scores were calculated thereafter based on their respective free clinical maximum concentration (Cmax ). Drugs' normalized TdP scores were calculated and ranked for 33 drugs, excluding 1 investigational drug, and the TdP risks of the 28 CiPA drugs were correctly distinguished according to their respective categories of low, intermediate, and high TdP risks under the CiPA initiative. Accordingly, we are able to propose the cutoff values of the normalized TdP scores at 1 × Cmax : ≤ 0, > 0 to < 0.65 and ≥ 0.65, respectively, for low, intermediate, and high risk. This blinded study supports utility of our Normalized TdP Score System in predicting drug-induced TdP risks in 33 drugs, including 28 used for characterization of other assays under the CiPA initiative. However, these results need to be replicated in other laboratories.

Icariin-induced inhibition of SIRT6/NF-κB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer.

Abnormal activation of the nuclear factor-kappa B (NF-κB) signaling pathway is closely implicated in triple-negative breast cancer growth, metastasis, and tumor immune escape. In this study, the anti-cancer effects of icariin, a natural flavonol glycoside, toward breast cancer cells and the underlying mechanisms were investigated. This investigation showed that icariin selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration- and time-dependent manner, but exhibited little cytotoxicity in normal breast cells. Moreover, icariin induced cell apoptosis via a mitochondria-mediated pathway, as indicated by the upregulated ratio of Bax/Bcl-2 and reactive oxygen species induction. Importantly, icariin impaired the activation of the NF-κB/EMT pathway, as evidenced by upregulation of SIRT6, resulting in inhibition of migration and invasion of breast cancer cells. Additionally, oss-128167, an inhibitor of SIRT6, dramatically attenuated anti-migration and anti-invasion effects of icariin. Transcriptomic analysis verified that impairment of NF-κB led to the selective function of icariin in breast cancer cells. Notably, icariin exhibited a significant tumor growth inhibition and anti-pulmonary metastasis effect in a tumor mouse model of MDA-MB-231 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Together, these results showed that icariin could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the SIRT6/NF-κB signaling pathway, suggesting that icariin might serve as a potential candidate drug for the treatment of breast cancer.

Comparison of surgical outcomes of lumbar disc herniation using local anesthesia and epidural anesthesia: A meta-analysis.

We performed this meta-analysis to evaluate the effects of epidural anesthesia and local anesthesia on the surgical outcomes of lumbar disc herniation (DH).Electronic databases including PubMed, EMBASE, Cochrane Library, and the Chinese Academic Journal Full-text Database were searched to identify randomized controlled trials (RCTs) that reported on the effects of local anesthesia and epidural anesthesia in lumbar DH surgical management. Evaluation indicators included: onset time of anesthesia, patient satisfaction, and the rate of adverse effects. There were 6 RCTs with a total of 606 patients in this meta-analysis: 274 cases in the local anesthesia group and 332 in the epidural anesthesia group.This meta-analysis demonstrated that the epidural anesthesia group had a better analgesic effect, a lower adverse effect rate (mean difference [MD] = 0.21, 95% confidence interval [CI] [0.08, 0.54], P = .001) and a better satisfaction rate: (MD = 6.54, 95% CI [2.77, 15.45], P < .0001). The duration of anesthesia was not statistically significant.Epidural anesthesia is a better choice for lumbar DH surgery compared to local anesthesia.

Pharmacokinetics after Periocular Methylprednisolone Sodium Succinate Injection in Rabbit Eyes.

The present study aimed to determine the pharmacokinetics and distribution of methylprednisolone sodium succinate (MPSS) and its metabolic product methylprednisolone (MP) in plasma and ocular tissues after periocular injection of MPSS in rabbit eyes. Forty-eight healthy New Zealand white rabbits were randomly divided into 12 groups, including the control group and 11 MPSS-treated groups sampling at different time points. Rabbits in the MPSS-treated groups underwent left eye periocular injection of MPSS (10 mg). The pharmacokinetics of MPSS and MP in plasma and ocular tissues (including aqueous humor, vitreous, iris, lens, sclera, optic nerve, and choroid and retina) were investigated by liquid chromatography tandem mass spectrometry (LC-MS/MS). After periocular injection, the time of maximum concentration (T max) of MPSS ranged from 0.25 h to 1 h in ocular tissues and was 0.25 h in plasma. T max of MP in ocular tissues ranged from 0.5 h to 6 h, and T max of MP in plasma was 0.5 h. The maximum concentration (C max) of MPSS and MP and the area under the curve (AUC0-t ) in ocular tissues from high to low was sclera, optic nerve, choroid and retina, iris, and lens. Especially, the concentrations of MPSS and MP in the lens were much lower when compared with the other ocular tissues. After periocular administration, MPSS could be rapidly metabolized to its active constituent MP in the ocular tissues. Also, the MPSS can be delivered effectively into the posterior segment of the eye (choroid and retina), while not easily be absorbed by the lens.