Retrospective analysis of predictive factors for AVF dysfunction in patients undergoing MHD.

To construct an early clinical prediction model for AVF dysfunction in patients undergoing Maintenance Hemodialysis (MHD) and perform internal and external verifications. We retrospectively examined clinical data from 150 patients diagnosed with MHD at Hefei Third People's Hospital from January 2014 to June 2023. Depending on arteriovenous fistula (AVF) functionality, patients were categorized into dysfunctional (n = 62) and functional (n = 88) cohorts. Using the least absolute shrinkage and selection operator(LASSO) regression model, variables potentially influencing AVF functionality were filtered using selected variables that underwent multifactorial logistic regression analysis. The Nomogram model was constructed using the R software, and the Area Under Curve(AUC) value was calculated. The model's accuracy was appraised through the calibration curve and Hosmer-Lemeshow test, with the model undergoing internal validation using the bootstrap method. There were 11 factors exhibiting differences between the group of patients with AVF dysfunction and the group with normal AVF function, including age, sex, course of renal failure, diabetes, hyperlipidemia, Platelet count (PLT), Calcium (Ca), Phosphorus, D-dimer (D-D), Fibrinogen (Fib), and Anastomotic width. These identified factors are included as candidate predictive variables in the LASSO regression analysis. LASSO regression identified age, sex, diabetes, hyperlipidemia, anastomotic diameter, blood phosphorus, and serum D-D levels as 7 predictive factors. Unconditional binary logistic regression analysis revealed that advanced age (OR = 4.358, 95% CI: 1.454-13.062), diabetes (OR = 4.158, 95% CI: 1.243-13.907), hyperlipidemia (OR = 3.651, 95% CI: 1.066-12.499), D-D (OR = 1.311, 95% CI: 1.063-1.616), and hyperphosphatemia (OR = 4.986, 95% CI: 2.513-9.892) emerged as independent risk factors for AVF dysfunction in MHD patients. The AUC of the predictive model was 0.934 (95% CI: 0.897-0.971). The Hosmer-Lemeshow test showed high consistency between the model's predictive results and actual clinical observations (χ2 = 1.553, P = .092). Internal validation revealed an AUC of 0.911 (95% CI: 0.866-0.956), with the Calibration calibration curve nearing the ideal curve. Advanced age, coexisting diabetes, hyperlipidemia, blood D-D levels, and hyperphosphatemia are independent risk factors for AVF dysfunction in patients undergoing MHD.

Developmental pleiotropy of SDP1 from seedling to mature stages in B. napus.

Rapeseed, an important oil crop, relies on robust seedling emergence for optimal yields. Seedling emergence in the field is vulnerable to various factors, among which inadequate self-supply of energy is crucial to limiting seedling growth in early stage. SUGAR-DEPENDENT1 (SDP1) initiates triacylglycerol (TAG) degradation, yet its detailed function has not been determined in B. napus. Here, we focused on the effects of plant growth during whole growth stages and energy mobilization during seedling establishment by mutation in BnSDP1. Protein sequence alignment and haplotypic analysis revealed the conservation of SDP1 among species, with a favorable haplotype enhancing oil content. Investigation of agronomic traits indicated bnsdp1 had a minor impact on vegetative growth and no obvious developmental defects when compared with wild type (WT) across growth stages. The seed oil content was improved by 2.0-2.37% in bnsdp1 lines, with slight reductions in silique length and seed number per silique. Furthermore, bnsdp1 resulted in lower seedling emergence, characterized by a shrunken hypocotyl and poor photosynthetic capacity in the early stages. Additionally, impaired seedling growth, especially in yellow seedlings, was not fully rescued in medium supplemented with exogenous sucrose. The limited lipid turnover in bnsdp1 was accompanied by induced amino acid degradation and PPDK-dependent gluconeogenesis pathway. Analysis of the metabolites in cotyledons revealed active amino acid metabolism and suppressed lipid degradation, consistent with the RNA-seq results. Finally, we proposed strategies for applying BnSDP1 in molecular breeding. Our study provides theoretical guidance for understanding trade-off between oil accumulation and seedling energy mobilization in B. napus.

Protective effect of Xingnaojing injection on ferroptosis after cerebral ischemia injury in MCAO rats and SH-SY5Y cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Xingnaojing（XNJ）injection is a traditional Chinese medicine injection with neuroprotective effect, which has been widely used in the treatment of stroke for many years. AIM OF THE STUDY: This study aimed to explore the potential mechanism of XNJ in cerebral ischemia mediated by ferroptosis using proteomics and in vivo and in vitro experiments. MATERIALS AND METHODS: After the rat model of middle cerebral artery occlusion (MCAO) was successfully established, they were randomly divided into model, XNJ, and deferoxamine (DFO) group. Triphenyl tetrazolium chloride (TTC) staining, Hematoxylin and eosin (H&E), and Nissl staining were used to observe the infarct area, pathological changes and the degree of neuronal apoptosis of rat brain. Proteins extracted from rat brain tissues were analyzed by quantitative proteomics using tandem mass tags (TMT). Western blotting and immunohistochemical assessment were used to measure the expression of ferroptosis-related proteins. In vitro, the SH-SY5Y cells were subjected to hypoxia (37°C/5% CO2/1% O2) for 24 h to observe the survival rate, and detect the reactive oxygen species (ROS) content and ferroptosis-related proteins. RESULTS: In TTC and H&E experiments, we found that XNJ drug treatment reduced the infarct volume and brain tissue damage in MCAO rats. Nissl staining also showed that compared with MCAO group rats, the Nissl bodies of brain tissue after XNJ drug intervention were clear with a 3.54-fold increased times, suggesting that XNJ improved cerebral infraction, and neurological deficits in MCAO rats. Proteomics identified 101 intersected differentially expressed proteins (DEPs). According to the bioinformatics analysis, these DEPs were closely related to ferroptosis. Further research indicated that MCAO-induced cerebral ischemia was alleviated by upregulating recombinant glutathione peroxidase 4 (GPX4), ferroportin (FPN) expression, Heme oxygenase-1 (HO-1) expression, and downregulating cyclooxygenase-2 (COX-2), transferring receptor (TFR) and divalent metal transporter-1 (DMT1) expression after XNJ treatment. In addition, in vitro experiment indicated that XNJ improved the survival rate of hypoxia-damaged SH-SY5Y cells. XNJ increased the level of GPX4 and inhibited the protein expression of COX-2 and TFR after cell hypoxia. Moreover, different concentrations of XNJ (0.25%, 0.5%, 1%) reduced the ROS content of hypoxic cells, suggesting that XNJ could inhibit hypoxia-induced cell damage by regulating the expression of ferroptosis-related proteins and decreasing the production of ROS. CONCLUSIONS: XNJ could promote the recovery of neurological function in MCAO rats and hypoxia SH-SY5Y cells by regulating ferroptosis.

Two new C-benzylated chalcones and one new mimosin-type homoisoflavonoid from the twigs and leaves of Caesalpinia digyna.

Two new C-benzylated chalcones, 2',4'-dihydroxy-3'-(2-hydroxylbenzyl) chalcone (1) and 2',4'-dihydroxy-5'-(2-hydroxybenzyl) chalcone (2), one new and one known mimosin-type homoisoflavonoid, mimosol H (7) and mimosol G (8), together with four known chalcones (3-6) and four known sappanin-type homoisoflavonoids (9-12), were isolated from the twigs and leaves of Caesalpinia digyna. Their structures were characterized by comprehensive spectroscopic analyses (including NMR and HRESIMS). Compounds 1, 2 and 8 exhibited moderate cytotoxicity against SMMC-7721, A-549 and/or MDA-MB-231 cell lines with IC50 values ranging from 11.41 ± 0.88 to 30.01 ± 1.56 µM. Notably, C-benzyl chalcones (1 and 2) were isolated from species of the genus Caesalpinia for the first time. Homoisoflavonoids 7 and 8 are the first examples of mimosin-type homoisoflavonoids reported in Caesalpinia digyna.

Network Pharmacology and Bioinformatics Methods Reveal the Mechanism of Berberine in the Treatment of Ischaemic Stroke.

Aim: To elucidate the mechanism of action of berberine on ischaemic stroke based on network pharmacology, bioinformatics, and experimental verification. Methods: Berberine-related long noncoding RNAs (lncRNAs) were screened from public databases. Differentially expressed lncRNAs in ischaemic stroke were retrieved from the Gene Expression Omnibus (GEO) database. GSE102541 was comprehensively analysed using GEO2R. The correlation between lncRNAs and ischaemic stroke was evaluated by the mammalian noncoding RNA-disease repository (MNDR) database. The component-target-disease network and protein-protein interaction (PPI) network of berberine in the treatment of ischaemic stroke were constructed by using network pharmacology. We then performed gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses. Finally, according to the molecular docking analysis and the binding probability between the lncRNA and key proteins, the effectiveness of the results was further verified by in vitro experiments. Results: After matching stroke-related lncRNAs with berberine-related lncRNAs, four genes were selected as potential targets of berberine in the treatment of ischaemic stroke. Subsequently, lncRNA H19 was identified as the potential crucial regulatory lncRNA of berberine. Here, 52 target proteins of berberine in the treatment of ischaemic stroke were identified through database mining. Through topological analysis, 20 key targets were identified which were enriched in inflammation, apoptosis, and immunity. Molecular docking results showed that MAPK8, JUN, and EGFR were central genes. Finally, in vitro experiments demonstrated that lncRNA H19, p-JNK1/JNK1, p-c-Jun/c-Jun, and EGFR expressions were significantly increased in hypoxia-treated SH-SY5Y cells and were restored by berberine treatment. Conclusion: The potential targets and biological effects of berberine in the treatment of ischaemic stroke were predicted in this study. The lncRNA H19/EGFR/JNK1/c-Jun signalling pathway may be a key mechanism of berberine-induced neuroprotection in ischaemic stroke.

Topic modeling to characterize the natural history of ANCA-Associated vasculitis from clinical notes: A proof of concept study.

OBJECTIVES: Clinical notes from electronic health records (EHR) are important to characterize the natural history, comorbidities, and complications of ANCA-associated vasculitis (AAV) because these details may not be captured by claims and structured data. However, labor-intensive chart review is often required to extract information from notes. We hypothesized that machine learning can automatically discover clinically-relevant themes across longitudinal notes to study AAV. METHODS: This retrospective study included prevalent PR3- or MPO-ANCA+ AAV cases managed within the Mass General Brigham integrated health care system with providers' notes available between March 1, 1990 and August 23, 2018. We generated clinically-relevant topics mentioned in notes using latent Dirichlet allocation-based topic modeling and conducted trend analyses of those topics over the 2 years prior to and 5 years after the initiation of AAV-specific treatment. RESULTS: The study cohort included 660 patients with AAV. We generated 90 topics using 113,048 available notes. Topics were related to the AAV diagnosis, treatment, symptoms and manifestations (e.g., glomerulonephritis), and complications (e.g., end-stage renal disease, infection). AAV-related symptoms and psychiatric symptoms were mentioned months before treatment initiation. Topics related to pulmonary and renal diseases, diabetes, and infections were common during the disease course but followed distinct temporal patterns. CONCLUSIONS: Automated topic modeling can be used to discover clinically-relevant themes and temporal patterns related to the diagnosis, treatment, comorbidities, and complications of AAV from EHR notes. Future research might compare the temporal patterns in a non-AAV cohort and leverage clinical notes to identify possible AAV cases prospectively.

IL-6 promotes collagen-induced arthritis by activating the NLRP3 inflammasome through the cathepsin B/S100A9-mediated pathway.

Rheumatoid arthritis (RA) is an inflammatory disease with symmetric polyarthritis. IL-6 and NLRP3 inflammasome in macrophages contribute to the pathogenesis of RA. This study aimed to investigate the relationship between IL-6 and the NLRP3 inflammasome in RA. Here, we found that IL-6 inhibition reduced NLRP3 inflammasome activation in mice with collage-induced arthritis (CIA). In vitro studies showed that IL-6 directly induced NLRP3 inflammasome activation via cathepsin B (CTSB) in the presence of ATP. In addition, S100A9 induced by ATP stimulation promoted the interaction of CTSB and NLRP3 to activate the NLRP3 inflammasome. Our findings show a novel mechanism of NLRP3 inflammasome activation by IL-6 that may lead to a potential therapy for RA by interrupting the interaction between IL-6 and the NLRP3 inflammasome.

Effectiveness of warm needling acupuncture for pain relief in patients with diabetic peripheral neuropathy: A protocol of systematic review.

BACKGROUND: Warm needling acupuncture (WNA) has been widely utilized for pain management in patients with diabetic peripheral neuropathy (DPN). However, its results are still inconsistent, and no systematic review has specifically addressed this issue. Thus, this systematic review will comprehensively and systematically investigate the effectiveness and safety of WNA for pain relief in DPN. METHODS: A comprehensive literature search of MEDLINE, EMBASE, Cochrane Library, Web of Science, Scopus, Allied and Complementary Medicine Database, CBM database, and China National Knowledge Infrastructure will be performed for randomized controlled trials that report WNA for pain relief in patients with DPN. All electronic databases will be searched from initial to the present without limitations of language and publication status. Two investigators will independently screen papers, collect data, and assess study quality. Cochrane risk of bias tool will be used for study quality assessment, and evidence quality will be evaluated using Grading of Recommendations Assessment, Development and Evaluations approach. RevMan 5.3 software will be applied for running statistical analysis. RESULTS: This study will summarize the evidence for the effectiveness and safety of WNA for the management of pain in patients with DPN. CONCLUSIONS: The findings of this study may provide helpful evidence to judge whether WNA for pain relief in DPN is effective or not.

Acupuncture for diabetic neuropathic pain: A protocol for systematic review and meta analysis.

BACKGROUND: Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus, it severely affects the quality of life of Diabetic patients. Acupuncture is proofed to have favorable effects in treating DNP, however, evidence needs to be gathered and interpreted. We will make a comprehensive review of clinical trials concerning acupuncture in treating DNP and do meta-analysis if possible. METHOD: The following databases will be searched from the inception to September 2020: PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Wan-Fang Database, and Chinese Scientific Journal Database. RCTs that evaluated acupuncture for patients with DNP will be included. The primary outcome will be patient-reported pain intensity using validated scales or verbal reporting. The secondary outcomes including the Toronto clinical scoring system, Sensory Nerve Conduction Velocity, Motor Nerve Conduction Velocity, and quality of life. The study selection, data extraction, and study quality evaluation will be performed independently by 2 researchers. A meta-analysis will be performed using RevMan V5.3 statistical software if possible; otherwise, descriptive analysis or subgroup analysis will be conducted. The quality of evidence for outcomes will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: This study will evaluate the effect and safety of acupuncture in treating DNP. CONCLUSIONS: The evidence we generated from the present study will provide more options for DNP management in clinical practice. SYSTEMATIC REVIEW REGISTRATION: INPLASY202090043.

Anti-inflammatory and immunomodulatory effects of baicalin in cerebrovascular and neurological disorders.

Inflammatory responses play an extraordinary role in the pathogenesis of cerebrovascular and neurological disorders. Baicalin is one of the important flavonoids, which is extracted from Scutellaria baicalensis Georgi. Recently, numerous in vivo and in vitro studies have shown that baicalin has salutary effects for anti-inflammatory and immunomodulatory and has been demonstrated to exert beneficial therapeutic properties in cerebrovascular and neurological diseases. In this review, we aim to discuss that baicalin exerts anti-inflammatory effects through multiple pathways and targets, thus affecting the production of a variety of inflammatory cytokines and neuroprotective process of neurological diseases; furthermore, the related targets of the anti-inflammatory effects of baicalin were analyzed via using the tools of network pharmacology, to provide theoretical basis and innovative ideas for the future clinical application of baicalin.

Alkaloids from the stem barks of Erythrina stricta.

Four previously undescribed erythrinan alkaloids, 8α-acetonylerythristemine, 8α-acetonylerysotrine, 10ß-hydroxy-11ß-methoxyerysotramidine and 3-epierysotrine, one undescribed pyrrolidine derivative, S-1-(4-hydroxy-3-methoxyphenethyl)-5-hydroxy pyrrolidin-2-one, and one undescribed amide, N-(3-hydroxy-4-methoxyphenethyl)-4-hydroxylbutanamide, along with thirteen known alkaloids were isolated from the stem barks of Erythrina strica Roxb. (Leguminosae). Their structures were identified by extensive analysis of physical, spectroscopic and spectrometric data. It's very interesting that the coexistence of 3-methoxytyramine, erythrinarbine, S-1-(4-hydroxy-3-methoxyphenethyl)-5-hydroxy pyrrolidin-2-one and N-(3-hydroxy-4-methoxyphenethyl)-4-hydroxylbutanamide that may be closely related in biosynthesis, supports the hypothetical biogenetic pathway of pyrrolo [2,1-a]isoquinoline alkaloids.

Transport properties of paeoniflorin and amygdalin across caco-2 cell monolayer model and their modulation of cytochrome p450 metabolism.

Paeoniflorin and amygdalin are two major active saponins constituents in some Chinese herbal formulas used for cardio-cerebrovascular diseases. However, their intestinal absorption property and metabolic characteristics have not been clarified. The aim of this work was to study the absorption property of Paeoniflorin and Amygdalin across Caco-2 cell monolayer and their metabolic characteristics on the activity of cytochrome P450 (CYP450) enzyme. The results showed that the transport amount of Paeoniflorin and Amygdalin was positively correlated with the time and concentrations, and the transport amount from AP side to BL side was higher than that from BL to AP. The absorptions of Paeoniflorin and Amygdalin were reduced by P-glycoprotein, which provided the pharmacokinetic basis for their clinical application. Furthermore, we demonstrated that Paeoniflorin and Amygdalin had obvious inhibiting effects on CYP2C9 and CYP2E1. The transports of Paeoniflorin and Amygdalin across Caco-2 cell monolayer model were deduced as the passive transport, which indicated that the present bioassay system was appropriate and reliable for the evaluation of the transport characteristics and metabolic characteristics of active ingredient groups in Bu-yang-huan-wu decoction. Moreover, this research method may also be suitable for the appropriate bioactivity and metabolic characteristics analysis of other plant extracts.

Development and Validation of a Deep Learning Algorithm for Mortality Prediction in Selecting Patients With Dementia for Earlier Palliative Care Interventions.

Importance: Early palliative care interventions drive high-value care but currently are underused. Health care professionals face challenges in identifying patients who may benefit from palliative care. Objective: To develop a deep learning algorithm using longitudinal electronic health records to predict mortality risk as a proxy indicator for identifying patients with dementia who may benefit from palliative care. Design, Setting, and Participants: In this retrospective cohort study, 6-month, 1-year, and 2-year mortality prediction models with recurrent neural networks used patient demographic information and topics generated from clinical notes within Partners HealthCare System, an integrated health care delivery system in Boston, Massachusetts. This study included 26 921 adult patients with dementia who visited the health care system from January 1, 2011, through December 31, 2017. The models were trained using a data set of 24 229 patients and validated using another data set of 2692 patients. Data were analyzed from September 18, 2018, to May 15, 2019. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUC) for 6-month and 1- and 2-year mortality prediction models and the factors contributing to the predictions. Results: The study cohort included 26 921 patients (16 263 women [60.4%]; mean [SD] age, 74.6 [13.5] years). For the 24 229 patients in the training data set, mean (SD) age was 74.8 (13.2) years and 14 632 (60.4%) were women. For the 2692 patients in the validation data set, mean (SD) age was 75.0 (12.6) years and 1631 (60.6%) were women. The 6-month model reached an AUC of 0.978 (95% CI, 0.977-0.978); the 1-year model, 0.956 (95% CI, 0.955-0.956); and the 2-year model, 0.943 (95% CI, 0.942-0.944). The top-ranked latent topics associated with 6-month and 1- and 2-year mortality in patients with dementia include palliative and end-of-life care, cognitive function, delirium, testing of cholesterol levels, cancer, pain, use of health care services, arthritis, nutritional status, skin care, family meeting, shock, respiratory failure, and swallowing function. Conclusions and Relevance: A deep learning algorithm based on patient demographic information and longitudinal clinical notes appeared to show promising results in predicting mortality among patients with dementia in different time frames. Further research is necessary to determine the feasibility of applying this algorithm in clinical settings for identifying unmet palliative care needs earlier.

Expanding vocabularies for complementary and alternative medicine therapies.

OBJECTIVE: There is a significant consumer demand for complementary and alternative medicine (CAM) therapies as possible alternatives to drugs in the treatment and prevention of chronic diseases. Expanding controlled vocabularies to include CAM treatment relations could help meet those needs by facilitating information retrieval from the published literature. The purpose of this study is to design and evaluate two methods to semi-automatically extract CAM treatment-related semantic predications (subject-predicate-object triplets) from the biomedical literature using the Semantic Medline database (SemMedDB). METHODS: Predications were retrieved from SemMedDB, a database of semantic predications extracted from article abstracts available in Medline. Predications were retrieved for 20 biologically-based and 3 mind-body CAM therapies. The first method (allMedline) retrieved predications from any Medline citation, while the second method (soundStudies) only retrieved predications from scientifically sound clinical studies. Filtering criteria were applied to identify the predications focusing on the treatment and prevention of medical disorders using various CAM modalities. The disorders were extracted for each CAM therapy and ranked by occurrence. A reference vocabulary, composed of 20 biologically-based and 3 mind-body CAM therapies, was developed to evaluate the performance of each method according to precision and recall of the top 100 ranked concepts as well as average precision and recall. RESULTS: The difference between allMedline and soundStudies in terms of median precision for the top 100 concepts ranked by occurrence was significant (21.0% versus 27.0%, p < .001). The soundStudies method had significantly higher precision (7.0% vs 11.5%, p < .001) and the allMedline had significantly higher recall (37.1% vs 25.6%, p < .001). CONCLUSION: The soundStudies method may be useful for extracting treatment-related predications from the biomedical literature for the highest ranked concepts. Additional work is needed to improve the algorithm as well as identify and report shortcomings for future enhancements of the tools used to populate SemMedDB.

A retrospective study of Yiqibushenhuoxue decoction for the treatment of chronic obstructive pulmonary disease.

This retrospective study aimed to investigate the effect and safety of Yiqibushenhuoxue decoction (YQBSHXD) for the treatment of chronic obstructive pulmonary disease (COPD).This study involved 120 cases of patients with COPD. These cases were assigned to an intervention group and a control group equally, 60 subjects each group. Patients in both groups underwent Salmeterol. In addition, the cases in the intervention group also received YQBSHXD. All cases received a total of 12 weeks treatment. The primary outcome of lung function was measured by forced expiratory volume in 1 second (FEV1), and FEV1/forced vital capacity (FVC). The secondary outcomes included severity of dyspnea on exertion, evaluated by 6-minute walk test (6MWT) with measurement of 6-minute walk distance (6MWD); and quality of life, assessed by the St. George's Respiratory Questionnaire (SGRQ). In addition, adverse events (AEs) were also recorded in this study. All outcome measurements were assessed before and after 12-week treatment.After 12-week treatment, cases in the intervention group underwent YQBSHXD did not show better outcome in lung function improvement, measured by the FEV1 (P = .11), and FEV1/FVC (P = .15), compared with those in the control group. However, YQBSHXD may help to alleviate the severity of dyspnea on exertion, as measured by 6MWD (P = .03), and to improve the quality of life, as assessed by the SGRQ (P < .01). Additionally, no significant differences in AEs were detected between the 2 groups.The results of this study showed that YQBSHXD may help to manage COPD after 12-week treatment, although the lung function has not been improved.

Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer.

BACKGROUND & AIMS: Treatment of liver cancer remains challenging because of a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but it only provides limited survival benefit. In this study we aimed to identify potential combination therapies to improve the clinical response to sorafenib. METHODS: To investigate the cause of the limited therapeutic effect of sorafenib, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergizes with sorafenib. Synergistic effects of sorafenib and selumetinib on cell apoptosis and phospho-ERK (p-ERK) were analyzed by caspase-3/7 apoptosis assay and western blot, respectively. p-ERK was measured by immunochemical analysis using a tissue microarray containing 78 liver cancer specimens. The in vivo effects of the combination were also measured in two xenograft models. RESULT: We found that suppression of ERK2 (MAPK1) sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK (MEK1/2 [MAP2K1/2]) or ERK (ERK1/2 [MAPK1/3]) kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active p-ERK, through synergistic inhibition of ERK kinase activity. CONCLUSION: Our data provide a combination strategy for treating liver cancer and suggest that tumors with high basal p-ERK levels, which are seen in approximately 30% of liver cancers, are most likely to benefit from such combinatorial treatment. LAY SUMMARY: Sorafenib is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but only provides limited survival benefit. Herein, we found that inhibition of the kinase ERK2 increases the response to sorafenib in liver cancer. Our data indicate that a combination of sorafenib and a MEK inhibitor is most likely to be effective in tumors with high basal phospho-ERK levels.

Protective effects of baicalin on rabbit articular chondrocytes in vitro.

Drug therapy is one of the typical treatments for post-injury inflammation of cartilage. Traditional Chinese herbs have potential as treatments, as their long history of clinical application has demonstrated they are effective and induce minimal side effects. Baicalin is a traditional Chinese medicine that has been used to treat inflammation, fever, ulcers and cancer for hundreds of years. Previous studies have demonstrated that baicalin may decrease levels of interleukin-1ß and suppress the expression of type-I collagen, thus attenuating cartilage degeneration. In the present study, the effect of baicalin on chondrocytes was assessed by examining the morphology, proliferation, extracellular matrix (ECM) synthesis and cartilage-specific gene expression of chondrocytes. The results indicated that baicalin may promote the proliferation of articular chondrocytes, secretion of cartilage ECM and collagen type II, aggrecan and SRY box (Sox) 9 gene upregulation. The expression of collagen I, a marker of chondrocyte dedifferentiation, was downregulated by baicalin; therefore, baicalin may maintain the phenotype of chondrocytes. Within the recommended concentrations of baicalin ranging from 0.625-6.25 µmol/l cell proliferation was increased and a 1.25 µmol/l dose of baicalin exerted the most positive effect on articular chondrocytes. The results of the present study may therefore indicate that baicalin may be used as a novel agent promoting the repair of articular cartilage damage.

Glycyrrhetinic acid protects H9c2 cells from oxygen glucose deprivation-induced injury through the PI3K/AKt signaling pathway.

Glycyrrhetinic acid (GA) is an ingredient of triterpene saponins found in Gancao (Radix Glycyrrhizae). Here, we investigated the protective effects of GA in H9c2 cells, and explored its possible mechanism of action. Different concentrations of GA were used to treat H9c2 cells under oxygen glucose deprivation. We analyzed cell necrosis and apoptosis using optical microscopy, Hoechst 33342 staining, FITC-annexin V/PI double-staining and lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and interleukin (IL)-1ß assays. Changes in related pro-apoptosis and anti-apoptosis proteins were detected by Western blot. Optical microscopy showed that GA improved cell morphology, including cell shrinkage, cauliflower-like membrane blebbing, and even some cell debris. Meanwhile, GA also ameliorated cell nuclei characteristics such as nucleus size, chromatin condensation and bright staining from Hoechst 33342 staining. GA also lowered the apoptotic rate and the levels of LDH, CK-MB and IL-1ß in a dose-dependent manner. Furthermore, GA treatment increased Bcl-2 protein expression and decreased caspase-8 and Bax protein expression, while elevating the Bcl-2/Bax ratio. GA preconditioning increased p-AKt protein expression; however, after adding LY 294002, the p-AKt expression decreased obviously. Our results demonstrated that GA could protect H9c2 cells from apoptosis in a dose-dependent manner, and the potential mechanism might be related to the PI3K/AKt signaling pathway.

Caesalpinone A, a new type of gorgonane sesquiterpenoid containing an unprecedented 1,15-bridge, from the pods of Caesalpinia spinosa Kuntze.

Caesalpinone A (1), a new type of gorgonane sesquiterpenoid containing an unprecedented 1,15-bridge, along with ten known sesquiterpenoids (2-11) were isolated from the pods of Caesalpinia spinosa Kuntze (Tara). The structure of caesalpinone A was elucidated based on its 1D and 2D NMR spectra. The absolute configuration of 1 was assigned by the comparison of the experimental and calculated electronic circular dichroism spectra. Compound 1 was evaluated for the inhibitory activities against five human tumor cell lines. The sesquiterpenoids of isodaucane skeleton and caryolane skeleton were isolated from Caesalpinia genus for the first time. Compounds 5-9 were firstly reported from Tara.

Effects of Active Components of Fuzi and Gancao Compatibility on Bax, Bcl-2, and Caspase-3 in Chronic Heart Failure Rats.

Hypaconitine (HA) and glycyrrhetinic acid (GA) are active components of Fuzi (Aconitum carmichaelii) and Gancao (Glycyrrhiza uralensis Fisch); they have been used in compatibility for chronic heart failure (CHF) from ancient times. The purpose of the present research was to explore whether apoptosis pathways were related with the protective effects of HA + GA against CHF rats or not. The rats were progressed with transverse-aortic constriction (TAC) operation for 4 weeks to build the CHF state, and then the Digoxin (1 mg/kg), HA (2.07 mg/kg), GA (25 mg/kg), and HA (2.07 mg/kg) + GA (25 mg/kg) were orally administrated to rats for 1 week. The levels of BNP and cTnI in the plasma were decreased in the HA + GA group, and the heart/body weight ratio (H/B) and left ventricular (LV) parameters of transthoracic echocardiography were also declined; moreover, the expressions of Bax, Bcl-2, and caspase-3 were all improved in the HA + GA group than other groups in the immunohistochemistry and western blot methods. In general, the data suggested that Fuzi and Gancao compatibility could protect the CHF rats from apoptosis, which provided a strong evidence for further searching for mechanisms of them.