A comprehensive evaluation of connectivity methods for L1000 data.

The methodologies for evaluating similarities between gene expression profiles of different perturbagens are the key to understanding mechanisms of actions (MoAs) of unknown compounds and finding new indications for existing drugs. L1000-based next-generation Connectivity Map (CMap) data is more than a thousand-fold scale-up of the CMap pilot dataset. Although several systematic evaluations have been performed individually to assess the accuracy of the methodologies for the CMap pilot study, the performance of these methodologies needs to be re-evaluated for the L1000 data. Here, using the drug-drug similarities from the Drug Repurposing Hub database as a benchmark standard, we evaluated six popular published methods for the prediction performance of drug-drug relationships based on the partial area under the receiver operating characteristic (ROC) curve at false positive rates of 0.001, 0.005 and 0.01 (AUC0.001, AUC0.005 and AUC0.01). The similarity evaluating algorithm called ZhangScore was generally superior to other methods and exhibited the highest accuracy at the gene signature sizes ranging from 10 to 200. Further, we tested these methods with an experimentally derived gene signature related to estrogen in breast cancer cells, and the results confirmed that ZhangScore was more accurate than other methods. Moreover, based on scoring results of ZhangScore for the gene signature of TOP2A knockdown, in addition to well-known TOP2A inhibitors, we identified a number of potential inhibitors and at least two of them were the subject of previous investigation. Our studies provide potential guidelines for researchers to choose the suitable connectivity method. The six connectivity methods used in this report have been implemented in R package (https://github.com/Jasonlinchina/RCSM).

Proliferatins suppress lipopolysaccharide-induced inflammation via inhibition of the NF-κB and MAPK signaling pathways.

Three previously undescribed polyketides [proliferatin A-C (1-3)] with anti-inflammatory activity were isolated from Fusarium proliferatum. 1-3 attenuated the production of inflammatory signal messengers including nitric oxide (NO), reactive oxygen species, proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß), as well as the related proteins nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Transcriptome analyses based on RNA-seq indicated the potential anti-inflammatory mechanism of 1-3 involved in the nuclear factor kappa-B (NF-κB) and mitogen activated protein kinases (MAPKs) signaling pathways. Experimental evaluation of the protein levels revealed that 1-3 can inhibit the phosphorylation of IκB kinase (IKK), the degradation of NF-κB Inhibitor-α (IκBα), the phosphorylation of nuclear factor-κB (NF-κB) and can reduce NF-κB transportation to the nucleus. Interestingly, 1-3 decreased the phosphorylation of MAPKs including p-p38, p-ERK, and p-JNK. Molecular docking models suggest that binding of 1-3 to TLR4-MD-2 complex may lead to inhibition of NF-κB and MAPK signaling pathways, which was confirmed in vitro by surface plasmon resonance (SPR) assays. 1-3 can thus constitute potential therapeutic candidates for the treatment of inflammation-associated diseases.

N-acetyldopamine dimer inhibits neuroinflammation through the TLR4/NF-κB and NLRP3/Caspase-1 pathways.

Neuroinflammation mediated by microglia is an important pathophysiological mechanism in neurodegenerative diseases. However, there is a lack of effective drugs to treat neuroinflammation. N-acetyldopamine dimer (NADD) is a natural compound from the traditional Chinese medicine Isaria cicada. In our previous study, we found that NADD can attenuate DSS-induced ulcerative colitis by suppressing the NF-κB and MAPK pathways. Does NADD inhibit neuroinflammation, and what is the target of NADD? To answer this question, lipopolysaccharide (LPS)-stimulated BV-2 microglia was used as a cell model to investigate the effect of NADD on neuroinflammation. Nitric oxide (NO) detection, reactive oxygen species (ROS) detection and enzyme-linked immunosorbent assay (ELISA) results show that NADD attenuates inflammatory signals and proinflammatory cytokines in LPS-stimulated BV-2 microglia, including NO, ROS, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and interleukin-6 (IL-6). Western blot analysis show that NADD inhibits the protein levels of Toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), ASC and cysteinyl aspartate specific proteinase (Caspase)-1, indicating that NADD may inhibit neuroinflammation through the TLR4/NF-κB and NLRP3/Caspase-1 signaling pathways. In addition, surface plasmon resonance assays and molecular docking demonstrate that NADD binds with TLR4 directly. Our study reveals a new role of NADD in inhibiting the TLR4/NF-κB and NLRP3/Caspase-1 pathways, and shows that TLR4-MD2 is the direct target of NADD, which may provide a potential therapeutic candidate for the treatment of neuroinflammation.

An immune-related gene signature for predicting survival and immunotherapy efficacy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks the fourth in terms of cancer-related mortality globally. Herein, in this research, we attempted to develop a novel immune-related gene signature that could predict survival and efficacy of immunotherapy for HCC patients. METHODS: The transcriptomic and clinical data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) and GSE14520 datasets, followed by acquiring immune-related genes from the ImmPort database. Afterwards, an immune-related gene-based prognostic index (IRGPI) was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. Kaplan-Meier survival curves as well as time-dependent receiver operating characteristic (ROC) curve were performed to evaluate its predictive capability. Besides, both univariate and multivariate analyses on overall survival for the IRGPI and multiple clinicopathologic factors were carried out, followed by the construction of a nomogram. Finally, we explored the possible correlation of IRGPI with immune cell infiltration or immunotherapy efficacy. RESULTS: Analysis of 365 HCC samples identified 11 differentially expressed immune-related genes, which were selected to establish the IRGPI. Notably, it can predict the survival of HCC patients more accurately than published biomarkers. Furthermore, IRGPI can predict the infiltration of immune cells in the tumor microenvironment of HCC, as well as the response of immunotherapy. CONCLUSION: Collectively, the currently established IRGPI can accurately predict survival, reflect the immune microenvironment, and predict the efficacy of immunotherapy among HCC patients.

Aureonitol Analogues and Orsellinic Acid Esters Isolated from Chaetomium elatum and Their Antineuroinflammatory Activity.

Overexpression of various pro-inflammatory factors in microglial cells tends to induce neurodegenerative diseases, for which there is no effective therapy available. Aureonitol (1) and seven analogues, including six previously undescribed [elatumenol A-F (2-4, 6-8, respectively)], along with two new orsellinic acid esters [elatumone A and B (9 and 10)], were isolated from Chaetomium elatum. The structures of the compounds were established through comprehensive analysis of spectroscopic data, including high-resolution mass spectra and one- and two-dimensional NMR, and absolute configurations determined by the Mosher method, dimolybdenum tetraacetate-induced circular dichroism, and theoretical calculations including electronic circular dichroism and NMR. Metabolites 3, 4, 7, and 8 exhibited antineuroinflammatory activity by attenuating the production of inflammatory mediators, such as nitric oxide, interleukin-6, interleukin-1ß, tumor necrosis factor-α, and reactive oxygen species. Western blot results indicated 8 decreases the level of inducible nitric oxide synthase and cyclooxygenase-2 and suppresses the expression of Toll-like receptor 4 and nuclear factor kappa-B (NF-κB) as well as the phosphorylation of the inhibitor of NF-κB and p38 mitogen-activated protein kinases in lipopolysaccharide-activated BV-2 microglial cells.

Population genomics identifies patterns of genetic diversity and selection in chicken.

BACKGROUND: There are hundreds of phenotypically distinguishable domestic chicken breeds or lines with highly specialized traits worldwide, which provide a unique opportunity to illustrate how selection shapes patterns of genetic variation. There are many local chicken breeds in China. RESULTS: Here, we provide a population genome landscape of genetic variations in 86 domestic chickens representing 10 phenotypically diverse breeds. Genome-wide analysis indicated that sex chromosomes have less genetic diversity and are under stronger selection than autosomes during domestication and local adaptation. We found an evidence of admixture between Tibetan chickens and other domestic population. We further identified strong signatures of selection affecting genomic regions that harbor genes underlying economic traits (typically related to feathers, skin color, growth, reproduction and aggressiveness) and local adaptation (to high altitude). By comparing the genomes of the Tibetan and lowland fowls, we identified genes associated with high-altitude adaptation in Tibetan chickens were mainly involved in energy metabolism, body size maintenance and available food sources. CONCLUSIONS: The work provides crucial insights into the distinct evolutionary scenarios occurring under artificial selection for agricultural production and under natural selection for success at high altitudes in chicken. Several genes were identified as candidates for chicken economic traits and other phenotypic traits.

The temporal expression patterns of brain transcriptome during chicken development and ageing.

BACKGROUND: The transcriptional profiles of mammals during brain development and ageing have been characterized. However the global expression patterns of transcriptome in the chicken brain have not been explored. Here, we systematically investigated the temporal expression profiles of lncRNAs and mRNAs across 8 stages (including 3 embryonic stages, 2 growth stages and 3 adult stages) in the female chicken cerebrum. RESULTS: We identified 39,907 putative lncRNAs and 14,558 mRNAs, investigated the temporal expression patterns by tracking a set of age-dependent genes and predicted potential biological functions of lncRNAs based on co-expression network. The results showed that genes with functions in development, synapses and axons exhibited a progressive decay; genes related to immune response were up-regulated with age. CONCLUSIONS: These results may reflect changes in the regulation of transcriptional networks and provide non-coding RNA gene candidates for further studies and would contribute to a comprehensive understanding of the molecular mechanisms of chicken development and may provide insights or deeper understanding regarding the regulatory mechanisms of age-dependent protein coding and non-protein coding genes in chicken. In addition, as the chicken is an important model organism bridging the evolutionary gap between mammals and other vertebrates, these high resolution data may provide a novel evidence to improve our comprehensive understanding of the brain transcriptome during vertebrate evolution.

Association between expression of MMP-7 and MMP-9 and pelvic lymph node and para-aortic lymph node metastasis in early cervical cancer.

AIMS: To investigate the association of matrix metalloproteinase (MMP)-7 and MMP-9 with pelvic lymph node and para-aortic lymph node metastasis in early cervical cancer. METHODS: A total of 137 patients with early cervical cancer (Stage Ia2-IIa2) were recruited from the Department of Gynecology and Obstetrics, Tumor Hospital of Liaoning Province from January 2009 to May 2014. We evaluated the expression of MMP-7 and MMP-9 by immunohistochemistry and their association with the clinicopathological parameters such as pelvic, common iliac and para-aortic lymph node metastasis. Spearman correlation was performed to analyze the correlation between MMP-7 and MMP-9 in cervical cancer. Finally, the areas under the receiver operating characteristic curve (ROC) of MMP-7 and MMP-9 in pelvic lymph node metastasis were assessed. RESULTS: MMP-7 expression was significantly higher in patients with adenocarcinomas and adenosquamous carcinomas (P = 0.014), vascular cancer embolus (P = 0.041), pelvic lymph node metastasis (P = 0.000) and a higher level of Ki-67 (P = 0.000). MMP-9 expression was significantly associated with vascular cancer embolus (P = 0.003), depth of stromal invasion (P = 0.001), pelvic lymph node metastasis (P = 0.003), common iliac lymph node metastasis (P = 0.001) and para-aortic lymph nodes metastasis (P = 0.004). Coexpression of MMP-7 and MMP-9 was significantly associated with vascular cancer embolus (P < 0.001), higher expression of Ki-67 (P < 0.001) and pelvic lymph node metastasis (P < 0.001). Spearman correlation analysis indicated a positive correlation between MMP-7 and MMP-9 (r = 0.263, P = 0.002). Areas under the ROC of MMP-7 and MMP-9 were 0.707 and 0.646, respectively. CONCLUSION: MMP-7 and MMP-9 expressions were associated with lymph node metastasis in patients with early cervical cancers, suggesting a positive correlation of MMP-7 and MMP-9 with invasive potential in early cervical cancers.

Posterior tibial slope impacts intraoperatively measured mid-flexion anteroposterior kinematics during cruciate-retaining total knee arthroplasty.

PURPOSE: Posterior tibial slope (PTS) for cruciate-retaining (CR) total knee arthroplasty (TKA) is usually pre-determined by the surgeon. Limited information is available comparing different choices of PTS on the kinematics of the CR TKA, independent of the balancing of the extension gap. This study hypothesized that with the same balanced extension gap, the choice of PTS significantly impacts the intraoperatively measured kinematics of CR TKA. METHODS: Navigated CR TKAs were performed on seven fresh-frozen cadavers with healthy knees and intact posterior cruciate ligament (PCL). A custom designed tibial baseplate was implanted to allow in situ modification of the PTS, which altered the flexion gap but maintained the extension gap. Knee kinematics were measured by performing passive range of motion (ROM) tests from full extension to 120° of flexion on the intact knee and CR TKAs with four different PTSs (1°, 4°, 7°, and 10°). The measured kinematics were compared across test conditions to assess the impact of PTS. RESULTS: With a consistent extension gap, the change of PTS had significant impact on the anteroposterior (AP) kinematics of the CR TKA knees in mid-flexion range (45°-90°), but not so much for the high-flexion range (90°-120°). No considerable impacts were found on internal/external (I/E) rotation and hip-knee-ankle (HKA) angle. However, the findings on the individual basis suggested the impact of PTS on I/E rotation and HKA angle may be patient-specific. CONCLUSIONS: The data suggested that the choice of PTS had the greatest impact on the mid-flexion AP translation among the intraoperatively measured kinematics. This impact may be considered while making surgical decisions in the context of AP kinematics. When using a tibial component designed with "center" pivoting PTS, a surgeon may be able to fine tune the PTS to achieve proper mid-flexion AP stability.

Antitumor activities of biscoumarin and dihydropyran derivatives.

Rising worldwide cancer incidence and resistance to current anti-cancer drugs necessitate the need for new pharmaceutical compounds and drug delivery system. Two novel series of biscoumarin (1-4) and dihydropyran (5-16) derivatives were synthesized via a one-pot multicomponent condensation reaction and evaluated for their antitumor activity in vitro. The X-ray crystal structure analysis of four representative compounds 2, 7, 10 and 13 confirmed the structures of these compounds. Compounds 1-4 showed the most potent antitumor activity among the total 16 derivatives. More interestingly, preliminary mechanism studies revealed that the most potent compound 4 induced apoptosis and arrested the cell cycle at the S phase in HUTU80 cells. Additionally, the increased accumulation of HUTU80 cells in the sub G1 peak further pointed to the occurence of the cell apoptosis. The selectivity index analysis demonstrated that all the biscoumarin compounds (SI=3.1-7.5) possess higher selectivity towards intestinal epithelial adenocarcinoma cell line (HuTu80) than positive control drug carboplatin (SI=1.6-1.8). The biscoumarin compounds also showed no obvious acute toxicity on mice.

Incorporating population-level variability in orthopedic biomechanical analysis: a review.

Effectively addressing population-level variability within orthopedic analyses requires robust data sets that span the target population and can be greatly facilitated by statistical methods for incorporating such data into functional biomechanical models. Data sets continue to be disseminated that include not just anatomical information but also key mechanical data including tissue or joint stiffness, gait patterns, and other inputs relevant to analysis of joint function across a range of anatomies and physiologies. Statistical modeling can be used to establish correlations between a variety of structural and functional biometrics rooted in these data and to quantify how these correlations change from health to disease and, finally, to joint reconstruction or other clinical intervention. Principal component analysis provides a basis for effectively and efficiently integrating variability in anatomy, tissue properties, joint kinetics, and kinematics into mechanistic models of joint function. With such models, bioengineers are able to study the effects of variability on biomechanical performance, not just on a patient-specific basis but in a way that may be predictive of a larger patient population. The goal of this paper is to demonstrate the broad use of statistical modeling within orthopedics and to discuss ways to continue to leverage these techniques to improve biomechanical understanding of orthopedic systems across populations.

Increased shape and size offerings of femoral components improve fit during total knee arthroplasty.

PURPOSE: Contemporary total knee arthroplasty femoral component designs offer various degrees of fit amongst the global population. The purpose of this study was to assess component fit of contemporary femoral component design families against multiple ethnicities. METHODS: Using a multi-ethnic dataset including Caucasian, Indian, and Korean subjects, this study investigated component fit in six contemporary femoral component design families (A: Persona™, B: NexGen (®), C: Sigma (®), D: GENESIS™ II, E: Triathlon (®), F: Vanguard (®)). Component overhang/underhang was measured between the resected distal femur and its corresponding component size and compared across design families and ethnicities. The severity of overhang/underhang and propensity of downsizing due to clinically significant overhang were quantified for the overall dataset and each ethnicity. RESULTS: In all the overhang cases, Designs A and B had significantly lower component overhang than the other designs (p < 0.02). In all the underhang cases, Designs C and E had significantly greater underhang than the other designs (p < 0.01). Component design influenced the occurrence (% bones) of component downsizing due to clinically significant overhang (>3 mm), with the highest incidence observed in Designs D (20.5%) and F (17.7%), and the lowest incidence observed in Designs A (0%) and B (0.4%). Variation in component fit was significantly impacted by designs (p < 0.01) but not ethnicities (n.s.). CONCLUSIONS: The inclusion of multiple ML/AP shape offerings and the increased number of available sizes in Design A, as compared to other contemporary femoral component design families studied, result in improved femoral component fit across various ethnicities.

Anatomic tibial component design can increase tibial coverage and rotational alignment accuracy: a comparison of six contemporary designs.

PURPOSE: The aim of this study was to comprehensively evaluate contemporary tibial component designs against global tibial anatomy. We hypothesized that anatomically designed tibial components offer increased morphological fit to the resected proximal tibia with increased alignment accuracy compared to symmetric and asymmetric designs. METHODS: Using a multi-ethnic bone dataset, six contemporary tibial component designs were investigated, including anatomic, asymmetric, and symmetric design types. Investigations included (1) measurement of component conformity to the resected tibia using a comprehensive set of size and shape metrics; (2) assessment of component coverage on the resected tibia while ensuring clinically acceptable levels of rotation and overhang; and (3) evaluation of the incidence and severity of component downsizing due to adherence to rotational alignment and overhang requirements, and the associated compromise in tibial coverage. Differences in coverage were statistically compared across designs and ethnicities, as well as between placements with or without enforcement of proper rotational alignment. RESULTS: Compared to non-anatomic designs investigated, the anatomic design exhibited better conformity to resected tibial morphology in size and shape, higher tibial coverage (92% compared to 85-87%), more cortical support (posteromedial region), lower incidence of downsizing (3% compared to 39-60%), and less compromise of tibial coverage (0.5% compared to 4-6%) when enforcing proper rotational alignment. CONCLUSIONS: The anatomic design demonstrated meaningful increase in tibial coverage with accurate rotational alignment compared to symmetric and asymmetric designs, suggesting its potential for less intra-operative compromises and improved performance. LEVEL OF EVIDENCE: III.

MYST family histone acetyltransferases regulate reproductive diapause initiation.

Histone acetylation, a crucial epigenetic mechanism, has been suggested to play a role in diapause regulation, but this has not been confirmed through gene loss-of-function studies. In this work, we investigated the involvement of MYST family genes, which are key writers of histone acetylation, in initiating reproductive diapause using the cabbage beetle Colaphellus bowringi as a model. We identified C. bowringi orthologs of MYST, including Tip60, KAT6A, KAT7, and KAT8, from previous transcriptomes. Analyses of phylogenetic trees and protein domains indicated that these MYST proteins are structurally conserved across animal species. Expression of these MYST genes was found to be enriched in heads and ovaries of C. bowringi. Under reproductive photoperiod conditions, RNAi targeting MYST genes, especially KAT8, suppressed ovarian growth and yolk deposition, resembling the characteristics of diapausing ovaries. Additionally, KAT8 knockdown led to the upregulation of diapause-related genes, such as heat shock proteins and diapause protein 1, and the emergence of diapause-like guts. Moreover, KAT8 knockdown reduced the expression of a crucial enzyme involved in juvenile hormone (JH) biosynthesis, likely due to decreased H4K16ac levels. Consequently, our findings suggest that MYST family genes, specifically KAT8, influence the JH signal, thereby regulating the initiation of reproductive diapause.

Development and experimental verification of a prognosis model for disulfidptosis-associated genes in HNSCC.

Disulfidptosis is a newly discovered cell death pattern that has been less studied in head and neck squamous carcinoma (HNSCC). Exploring the molecular features of different subtypes of HNSCC based on disulfidptosis-associated genes (DAGs) is important for HNSCC. In addition, immunotherapy plays a pivotal role in the treatment of HNSCC. Exploring the sensitivity of immunotherapies and developing predictive models is essential for HNSCC. We analyzed the expression and mutational status of DAGs in 790 HNSCC patients and correlated the dates with clinical prognosis. HNSCC patients were divided into 2 groups based on their DAG expression. The relationship between DAGs, risk genes, and the immune microenvironment was analyzed using the CIBERSORT algorithm. A disulfidptosis risk model was constructed based on 5 risk genes using the LASSO COX method. To facilitate the clinical applicability of the proposed risk model, we constructed column line plots and performed stem cell correlation analysis and antitumor drug sensitivity analysis. Two different disulfidptosis-associated clusters were identified using consistent unsupervised clustering analysis. Correlations between multilayer DAG alterations and clinical characteristics and prognosis were observed. Then, a well-performing disulfidptosis-associated risk model (DAG score) was developed to predict the prognosis of HNSCC patients. We divided patients into high-risk and low-risk groups based on the DAG score and found that patients in the low-risk group were more likely to survive than those in the high-risk group (P < .05). A high DAG score implies higher immune cell infiltration and increased mutational burden. Also, univariate and multivariate Cox regression analyses revealed that the DAG score was an independent prognostic predictor for patients with HNSCC. Subsequently, a highly accurate predictive model was developed to facilitate the clinical application of DAG scores, showing good predictive and calibration power. Overall, we present a comprehensive overview of the DAG profile in HNSCC and develop a new risk model for the therapeutic status and prognosis of patients with HNSCC. Our findings highlight the potential clinical significance of DAG and suggest that disulfidptosis may be a potential therapeutic target for patients with HNSCC.

Study protocol for a three-arm randomized controlled trial investigating the effectiveness, cost-utility, and physiological effects of a fully self-guided digital Acceptance and Commitment Therapy for Spanish patients with fibromyalgia.

Objective: Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA®) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. Methods: A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. Conclusions: This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Hernia uterine inguinale associated with Mayer-Rokitansky-Küster-Hauser syndrome: Three case reports and literature review.

RATIONALE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome) present with genital inguinal hernia was rare and probably under reported, on account of lack in typical gynecological symptom. It should be regarded with care.Here 3 cases diagnosed at our institution with detailed clinical information were present, and the literature was reviewed to paint a comprehensive profile of hernia uterine inguinale associated with MRKH syndrome. PATIENT CONCERNS: Case no. 1 was a 36-year-old female with recurrent dragalgia for 5 years. Left rudimentary uterus at the left groin area was revealed by sonography scan and confirmed by diagnostic laparoscopy.Case no. 2 was a 27-year-old woman diagnosed with MRKH syndrome and her MRI examination suggested a suspicious swelling measuring 2.0cm×2.0cm in left groin. The left nonfunctionally rudimentary uterus and adnexa were incarcerated in the left inguinal hernial sac, which was revealed by laparoscopy.Case no. 3 was a 29-year-old woman, admitted with right abdominal pain with a provisional diagnosis of appendicitis. After appendicectomy, pelvic exploration showed a part of left rudimentary uterus and elongated oviduct herniated through the left internal inguinal ring. DIAGNOSES: Hernia uterine inguinale associated with MRKH syndrome. INTERVENTIONS AND OUTCOMES: Case no.1: When the rudimentary uterus was pulled out from the hernia sac, it appearance dark ocher. Then the left rudimentary uterus was removed and the indirect defect of inguinal duct was closed.The patient was followed up for 18 months with no recurrence of abdominal pain.Case no.2 and 3:The left rudimentary uterus were replaced from the hernia sac, and the indirect defect was fixed with sutures.The patients recovered smoothly without complications for 12-month follow-up. LESSONS: Left involvement of rudimentary uterus was frequently observed in patients with MRKH syndrome, along with ipsilateral ovary and/or fallopian tube horned in the hernia. Abdominal pain or inguinale mass could be the chief complaints while some individuals were asymptomatic. Either surgical removal or replacement of rudimentary uterus was an effectively optional treatment strategy for hernia uterine inguinale.When a patient with MRKH syndrome presented with abdominal pain of unknown cause or inguinal mass, rudimentary uterine inguinal hernia should be suspected.

Yupingfeng San exhibits anticancer effect in hepatocellular carcinoma cells via the MAPK pathway revealed by HTS2 technology.

ETHNOPHARMACOLOGICAL RELEVANCE: Yupingfeng San (YPFS) is a classic rousing prescription in Chinese medicine, with widly clinical application and remarkably curative effect. It consists of three herbs named Astragalus mongholicus Bunge (Huangqi), Atractylodes rubra Dekker (Baizhu) and Saposhnikovia divaricata (Turcz.) Schischk. (Fangfeng), and has a variety of pharmacological activities including immune regulation, antioxidant, anti-tumor, regulation of cytokines, etc. AIM OF THE STUDY: It has been proved that YPFS exerts its anti-tumor effect through enhancing the systemic and local immune responses in tumor patients, moreover, it has the direct tumor-suppressing effect and can reduce the adverse reactions caused by radiotherapy and chemotherapy drugs. Therefore, in this study, we explored the potential anti-HCC mechanism of YPFS based on HTS2 technology and systems pharmacology, aiming to provide a scientific basis for the clinical application of YPFS and a new strategy for Chinese medicine research. MATERIALS AND METHODS: In this study, systems pharmacology plus high throughput sequencing-based high throughput screening (HTS2) technology, and experimental validation were used to investigate the therapeutic mechanisms and the chemical basis of YPFS in HCC treatment. Firstly, the potential therapeutic targets and signaling pathways of YPFS in the treatment of HCC were obtained through systems pharmacology. Subsequently, HTS2 technology combined with PPI network analysis were used to reveal potential therapeutic targets. Finally, the anti-HCC effects and underlying mechanisms of YPFS were further verified in vitro in human hepatocellular carcinoma cell lines. Moreover, the possible chemical basis was explored by drug target verification and molecular docking technology. RESULTS: In total, 183 active ingredients were predicted by YPFS screening and 49 anti-HCC targets were further identified. Most of these targets were enriched into the "MAPK pathway", and the expression of 37 genes was significantly changed after herb treatment. Among them, 5 key targets, including VEGFA, GRB2, JUN, PDGFRB and CDC42, were predicted by protein-protein interaction (PPI) network analysis. According to our results, YPFS inhibited the proliferation, induced the apoptosis and caused cell cycle arrest of HCC cells. In addition, YPFS significantly reduced P38 gene expression. Fangfeng, one of the three herbs in YPFS, significantly down-regulated the expression of more target genes than that of the other two herbs. Lastly, as revealed by molecular docking analysis, 4'-O-glucosyl-5-O-methylvisamminol, an active ingredient identified in Fangfeng, showed a high affinity for P38. CONCLUSION: Taken together, this study shows that YPFS possesses the activities of anti-proliferation and pro-apoptosis in treating HCC, which are achieved by inhibiting the MAPK signaling pathway. P38 is one of the critical targets of YPFS in treating HCC, which may be directly bound and inhibited by 4'-O-glucosyl-5-O-methylvisamminol, a compound derived from YPFS.

p53 contributes to cardiovascular diseases via mitochondria dysfunction: A new paradigm.

Cardiovascular diseases (CVDs) are leading causes of global mortality; however, their underlying mechanisms remain unclear. The tumor suppressor factor p53 has been extensively studied for its role in cancer and is also known to play an important role in regulating CVDs. Abnormal p53 expression levels and modifications contribute to the occurrence and development of CVDs. Additionally, mounting evidence underscores the critical involvement of mitochondrial dysfunction in CVDs. Notably, studies indicate that p53 abnormalities directly correlate with mitochondrial dysfunction and may even interact with each other. Encouragingly, small molecule inhibitors targeting p53 have exhibited remarkable effects in animal models of CVDs. Moreover, therapeutic strategies aimed at mitochondrial-related molecules and mitochondrial replacement therapy have demonstrated their advantageous potential. Therefore, targeting p53 or mitochondria holds immense promise as a pioneering therapeutic approach for combating CVDs. In this comprehensive review, we delve into the mechanisms how p53 influences mitochondrial dysfunction, including energy metabolism, mitochondrial oxidative stress, mitochondria-induced apoptosis, mitochondrial autophagy, and mitochondrial dynamics, in various CVDs. Furthermore, we summarize and discuss the potential significance of targeting p53 or mitochondria in the treatment of CVDs.

Assembly of an iron-based complex into a metal-organic framework: a space confinement strategy for isolation of mono-iron complexes to protect from dimerization.

Non-heme mononuclear iron complexes, especially when supported by tripodal tetradentate ligands, show promising C-H bond activation efficiency in catalytic reactions. Nevertheless, they intrinsically decay readily to their dinuclear form, and the dimerization process is inevitable in homogenous solution, which dramatically hinders their further application. Hence, we demonstrate that the mononuclear iron complex [(TPA)FeII-2L]2+ (L = labile ligands, mainly solvent molecules) was successfully encapsulated in a highly robust metal-organic framework UiO-66 via a two-step "ship-in-a-bottle" strategy. The nearly perfect size matching of the octahedral cages of the host UiO-66 provides ideal space confinement for the guest complex to protect from dimerization and dramatically increases the mono-nuclear complex stability compared to its un-confined state. The successful encapsulation of [(TPA)FeII-2L]2+ in UiO-66 was verified thoroughly by spectroscopy, microscopy, N2 adsorption, and electrochemistry characterization techniques. This work shows that encapsulating an unstable molecular complex in MOFs via a two-step "ship-in-a-bottle" strategy highlights opportunities for extending the heterogenization of homogeneous complexes.