Dual-extraction modeling: A multi-modal deep-learning architecture for phenotypic prediction and functional gene mining of complex traits.

Despite considerable advances in extracting crucial insights from bio-omics data to unravel the intricate mechanisms underlying complex traits, the absence of a universal multi-modal computational tool with robust interpretability for accurate phenotype prediction and identification of trait-associated genes remains a challenge. This study introduces the dual-extraction modeling (DEM) approach, a multi-modal deep-learning architecture designed to extract representative features from heterogeneous omics datasets, enabling the prediction of complex trait phenotypes. Through comprehensive benchmarking experiments, we demonstrate the efficacy of DEM in classification and regression prediction of complex traits. DEM consistently exhibits superior accuracy, robustness, generalizability, and flexibility. Notably, we establish its effectiveness in predicting pleiotropic genes that influence both flowering time and rosette leaf number, underscoring its commendable interpretability. In addition, we have developed user-friendly software to facilitate seamless utilization of DEM's functions. In summary, this study presents a state-of-the-art approach with the ability to effectively predict qualitative and quantitative traits and identify functional genes, confirming its potential as a valuable tool for exploring the genetic basis of complex traits.

Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.

Novel CHCHD2 mutations causing C-terminal truncation and interrupted CHCHD2 protein stability in Parkinson's disease (PD) patients were previously found. However, there is limited understanding of the underlying mechanism and impact of subsequent CHCHD2 loss-of-function on PD pathogenesis. The current study further identified the crucial motif (aa125-133) responsible for diminished CHCHD2 expression and the molecular interplay within the C1QBP/CHCHD2/CHCHD10 complex to regulate mitochondrial functions. Specifically, CHCHD2 deficiency led to decreased neural cell viability and mitochondrial structural and functional impairments, paralleling the upregulation of autophagy under cellular stresses. Meanwhile, as a binding partner of CHCHD2, C1QBP was found to regulate the stability of CHCHD2 and CHCHD10 proteins to maintain the integrity of the C1QBP/CHCHD2/CHCHD10 complex. Moreover, C1QBP-silenced neural cells displayed severe cell death phenotype along with mitochondrial damage that initiated a significant mitophagy process. Taken together, the evidence obtained from our in vitro and in vivo studies emphasized the critical role of CHCHD2 in regulating mitochondria functions via coordination among CHCHD2, CHCHD10, and C1QBP, suggesting the potential mechanism by which CHCHD2 function loss takes part in the progression of neurodegenerative diseases.

Discovery and Exploration of Lipid-Modifying Drug Targets for ALS by Mendelian Randomization.

Observational studies have faced challenges in identifying replicable causes for amyotrophic lateral sclerosis (ALS). To address this, we employed an unbiased and data-driven approach to discover and explore potential causal exposures using two-sample Mendelian randomization (MR) analyses. In the phenotype discovery stage, we assessed 3948 environmental exposures from the UK Biobank and utilized ALS summary statistics (Europeans, 20,806 cases, 59,804 controls) as the outcome within a phenome-wide MR pipeline. Through a range of sensitivity analyses, two medication traits were identified to be protective for ALS. In the target exploration stage, we further conducted drug target MR analyses using the latest and trans-ethnic summary data on lipid-related traits and ALS (Europeans, 27,205 cases, 110,881 controls; East Asians, 1234 cases, 2850 controls). Our aim was to explore potential causal drug targets through six lipid-modifying effects. These comprehensive analyses revealed significant findings. Specifically, "cholesterol-lowering medication" and "atorvastatin" survived predefined criteria in the phenotype discovery stage and exhibited a protective effect on ALS. Further in the target exploration stage, we demonstrated that the therapeutic effect of APOB through LDL-lowering was associated with reduced ALS liability in Europeans (OR = 0.835, P = 5.61E - 5). Additionally, the therapeutic effect of APOA1 and LDLR through TC-lowering was associated with reduced ALS liability in East Asians (APOA1, OR = 0.859, P = 5.38E - 4; LDLR, OR = 0.910, P = 2.73E - 5). Overall, we propose potential protective effects of cholesterol-lowering drugs or statins on ALS risk from thousands of exposures. Our research also suggests APOB, APOA1, and LDLR as novel therapeutic targets for ALS and supports their potential protective mechanisms may be mediated by LDL-lowering or TC-lowering effects.

Deteriorating complementary feeding practices and dietary quality in Jordan: Trends and challenges.

Quality complementary feeding (CF) of infants and young children is key to their growth and development. But in Jordan, providing appropriate CF remains a challenge. This study assesses trends in infant and young child feeding (IYCF) practices, and consumption by infants and young children aged 6-23 months of breast milk substitutes (BMSs), sugar-sweetened beverages (SSBs), and micronutrient-rich foods in Jordan from 1990 to 2017. We combined dietary data on infants and young children from six Demographic and Health Surveys (DHS) (n = 14,880 children) to compute IYCF indicators. The latter included minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum acceptable diet (MAD), as well as intake of micronutrient-rich foods and food groups, specific SSBs, and infant formula. We conducted trend analyses using logistic regression models adjusted for child's age in month, child age squared, governorates, urban/rural residence, mother's educational attainment, and household wealth quintiles. We found that the proportion of consumption of micronutrient-rich food groups declined significantly between 1990 and 2017, with fewer infants and young children consuming eggs (OR = 0.39, p ≤ 0.001, 2002 reference), meat, poultry, and fish (OR = 0.25, p ≤ 0.001, 2002 reference), dairy (OR = 0.59, p ≤ 0.001, 2002 reference) and Vitamin A-rich fruits and vegetables (OR = 0.66, p ≤ 0.001, 2002 reference). Conversely, there was increased use of BMSs and sugar-sweetened juices that paralleled a decline in the share of infants and young children meeting appropriate CF practices and consuming micronutrient-rich foods and food groups. By 2017, children aged 6-23 months were significantly less likely to meet MDD, MMF, and subsequently MAD; the odds of consuming BMSs were almost three times the reference (OR = 3.8, p ≤ 0.001, 1990 reference), as were the odds of consuming sugar sweetened juices  (OR = 3.63, p ≤ 0.001, 1990 reference). Food insecurity and undernutrition are low in Jordan; however, overweight and obesity rates are increasing concurrently as are micronutrient deficiencies. This highlights the need for policymakers to address factors at individual and household levels (behaviours and practices) as well as environmental issues (increasing access to unhealthy and ultraprocessed foods).

Mollugin prevents CLP-induced sepsis in mice by inhibiting TAK1-NF-κB/MAPKs pathways and activating Keap1-Nrf2 pathway in macrophages.

Sepsis is a life-threatening organ dysfunction associated with macrophage overactivation. Targeted therapy against macrophages is considered a promising strategy for sepsis treatment. Mollugin (MLG), a compound extracted from traditional Chinese medicine Rubia cordifolia L., possesses anti-tumor and anti-inflammatory activities. This study aimed to investigate the anti-inflammatory effects and mechanisms of MLG in macrophages and its therapeutic role in CLP-induced sepsis in mice. The results demonstrated that MLG downregulated the inflammatory response induced by LPS or tumor necrosis factor α (TNF-α) in macrophages. Mechanistically, MLG suppressed the phosphorylation of TAK1, the upstream modulator of IKKα/ß and MAPKs, thereby inhibiting the pro-inflammatory signaling transduction of NF-κB and MAPKs. Additionally, MLG also activated the Nrf2 antioxidant pathway, reducing intracellular reactive oxygen species. CETSA and molecular docking analyses revealed that MLG could effectively bind to TAK1 and Keap1, which may be involved in the inhibition of TAK1- NF-κB/MAPKs and activation of Nrf2 mediated by MLG. Animal study demonstrated that MLG ameliorated inflammatory injury of lung and liver in CLP-induced sepsis mice probably by reducing the levels of pro-inflammatory cytokines. Therefore, our study suggests that bi-directional roles of MLG in improving sepsis via blocking the TAK1-NF-κB/MAPKs and activating Nrf2 pathways, indicating its potential as a promising candidate drug for sepsis treatment.

IPOP: An Integrative Plant Multi-omics Platform for Cross-species Comparison and Evolutionary Study.

The advent of high-throughput sequencing technologies has led to the production of a significant amount of omics data in plants, which serves as valuable assets for conducting cross-species multi-omics comparative analysis. Nevertheless, the current dearth of comprehensive platforms providing evolutionary annotation information and multi-species multi-omics data impedes users from systematically and efficiently performing evolutionary and functional analysis on specific genes. In order to establish an advanced plant multi-omics platform that provides timely, accurate, and high-caliber omics information, we collected 7 distinct types of omics data from 6 monocots, 6 dicots, and 1 moss, and reanalyzed these data using standardized pipelines. Additionally, we furnished homology information, duplication events, and phylostratigraphic stages of 13 species to facilitate evolutionary examination. Furthermore, the integrative plant omics platform (IPOP) is bundled with a variety of online analysis tools that aid users in conducting evolutionary and functional analysis. Specifically, the Multi-omics Integration Analysis tool is available to consolidate information from diverse omics sources, while the Transcriptome-wide Association Analysis tool facilitates the linkage of functional analysis with phenotype. To illustrate the application of IPOP, we conducted a case study on the YTH domain gene family, wherein we observed shared functionalities within orthologous groups and discerned variations in evolutionary patterns across these groups. To summarize, the IPOP platform offers valuable evolutionary insights and multi-omics data to the plant sciences community, effectively addressing the need for cross-species comparison and evolutionary research platforms. All data and modules within IPOP are freely accessible for academic purposes (http://omicstudio.cloud:4012/ipod/).

Multivariate joint order recurrence networks for characterization of multi-lead ECG time series from healthy and pathological heartbeat dynamics.

Analysis of nonlinear dynamic characteristics of cardiac systems has been a hot topic of clinical research, and the recurrence plots have earned much attention as an effective tool for it. In this paper, we propose a novel method of multivariate joint order recurrence networks (MJORNs) to evaluate the multi-lead electrocardiography (ECG) time series with healthy and psychological heart states. The similarity between time series is studied by quantifying the structure in a joint order pattern recurrence plot. We take the time series that corresponds to each of the 12-lead ECG signals as a node in the network and use the entropy of diagonal line length that describes the complex structure of joint order pattern recurrence plot as the weight to construct MJORN. The analysis of network topology reveals differences in nonlinear complexity for healthy and heart diseased heartbeat systems. Experimental outcomes show that the values of average weighted path length are reduced in MJORN constructed from crowds with heart diseases, compared to those from healthy individuals, and the results of the average weighted clustering coefficient are the opposite. Due to the impaired cardiac fractal-like structures, the similarity between different leads of ECG is reduced, leading to a decrease in the nonlinear complexity of the cardiac system. The topological changes of MJORN reflect, to some extent, modifications in the nonlinear dynamics of the cardiac system from healthy to diseased conditions. Compared to multivariate cross recurrence networks and multivariate joint recurrence networks, our results suggest that MJORN performs better in discriminating healthy and pathological heartbeat dynamics.

Epileptic detection in single and multi-lead EEG signals using persistent homology based on bi-directional weighted visibility graphs.

Epilepsy is a widespread neurological disorder, and its recurrence and suddenness are making automatic detection of seizure an urgent necessity. For this purpose, this paper performs topological data analysis (TDA) of electroencephalographic (EEG) signals by the medium of graphs to explore the potential brain activity information they contain. Through our innovative method, we first map the time series of epileptic EEGs into bi-directional weighted visibility graphs (BWVGs), which give more comprehensive reflections of the signals compared to previous existing structures. Traditional graph-theoretic measurements are generally partial and mainly consider differences or correlations in vertices or edges, whereas persistent homology (PH), the essential part of TDA, provides an alternative way of thinking by quantifying the topology structure of the graphs and analyzing the evolution of these topological properties with scale changes. Therefore, we analyze the PH for BWVGs and then obtain the two indicators of persistence and birth-death for homology groups to reflect the topology of the mapping graphs of EEG signals and reveal the discrepancies in brain dynamics. Furthermore, we adopt neural networks (NNs) for the automatic detection of epileptic signals and successfully achieve a classification accuracy of 99.67% when distinguishing among three different sets of EEG signals from seizure, seizure-free, and healthy subjects. In addition, to accommodate multi-leads, we propose a classifier that incorporates graph structure to distinguish seizure and seizure-free EEG signals. The classification accuracies of the two subjects used in the classifier are as high as 99.23% and 94.76%, respectively, indicating that our proposed model is useful for the analysis of EEG signals.

Dietary glutathione supplementation attenuates oxidative stress and improves intestinal barrier in diquat-treated weaned piglets.

The aim of this study was to investigate the protective effects of glutathione (GSH) against oxidative stress and intestinal barrier disruption caused by diquat (an oxidative stress inducer) in weaned piglets. Twenty-four piglets were randomly assigned to four treatments with six pigs per treatment for an 18-d trial. Treatments were basal diet, basal diet + diquat challenge, 50 mg/kg GSH diets + diquat challenge and 100 mg/kg GSH diets + diquat challenge. On day 15, piglets in basal diet group and diquat-challenged groups were intraperitoneally injected with sterile saline and diquat at 10 mg/kg body weight, respectively. The results showed that GSH supplementation improved growth performance of diquat-injected piglets from days 15 to 18 (p < 0.05), especially at a dose of 100 mg/kg GSH. Meanwhile, diquat also caused oxidative stress and intestinal barrier damage in piglets. However, GSH supplementation enhanced the antioxidant capacity of serum and jejunum, as evidenced by the increase in GSH content and total superoxide dismutase activities and the decrease in 8-hydroxy-2'-deoxyguanosine concentrations (p < 0.05). GSH also up-regulated the mRNA expressions of intestinal tight junction protein (zonula occludens 1, ZO1; occludin, OCLN; claudin-1, CLDN1) and mitochondrial biogenesis and function (peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, PGC1α; mitochondrial transcription factor A, TFAM; cytochrome c, CYCS), compared with diquat-challenged piglets in basal diet (p < 0.05). Thus, the study demonstrates that GSH protects piglets from oxidative stress caused by diquat and 100 mg/kg GSH has a better protective role.

Protective effect of antihypertensive drugs on the risk of Parkinson's disease lacks causal evidence from mendelian randomization.

Background: Evidence from observational studies concerning the causal role of blood pressure (BP) and antihypertensive medications (AHM) on Parkinson's disease (PD) remains inconclusive. A two-sample Mendelian randomization (MR) study was performed to evaluate the unconfounded association of genetic proxies for BP and first-line AHMs with PD. Methods: Instrumental variables (IV) from the genome-wide association study (GWAS) for BP traits were used to proxy systolic BP (SBP), diastolic BP, and pulse pressure. SBP-associated variants either located within encoding regions or associated with the expression of AHM targets were selected and then scaled to proxy therapeutic inhibition of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, and thiazides. Positive control analyses on coronary heart disease (CHD) and stroke were conducted to validate the IV selection. Summary data from GWAS for PD risk and PD age at onset (AAO) were used as outcomes. Results: In positive control analyses, genetically determined BP traits and AHMs closely mimicked the observed causal effect on CHD and stroke, confirming the validity of IV selection methodology. In primary analyses, although genetic proxies identified by "encoding region-based method" for ß-blockers were suggestively associated with a delayed PD AAO (Beta: 0.115; 95% CI: 0.021, 0.208; p = 1.63E-2; per 10-mmHg lower), sensitivity analyses failed to support this association. Additionally, MR analyses found little evidence that genetically predicted BP traits, overall AHM, or other AHMs affected PD risk or AAO. Conclusion: Our data suggest that BP and commonly prescribed AHMs may not have a prominent role in PD etiology.

HIV Tat-Conjugated Histone H3 Peptides Induce Tumor Cell Death Via Cellular Stress Responses.

Histone H3 is a nucleosome scaffold protein that is involved in a variety of intracellular processes. Aberrant modification of H3 is important in carcinogenesis. In contrast, free histones in cells can act as stimuli to trigger cellular immune responses and cell death. In this study, we linked cell-penetrating peptide HIV Tat to a histone H3 fragment to achieve intracellular delivery in tumor cells. We found that Tat-conjugated histone polypeptides localized to nuclei of lung and breast cancer cells and caused cell death. A trans-configured Tat sequence displayed dramatically improved peptide half-life and cytotoxicity. Mechanistic studies demonstrated that treatment with the peptides significantly elevated mitogen-activated protein kinase (MAPK) signaling, reactive oxygen species (ROS) production, as well as levels of stress-inducible transcription factor ATF3 (activating transcription factor 3) and AP-1 (activating protein-1). Cytotoxicity of the peptide was significantly reduced by inhibition of AP-1 activity and ROS production. These results suggest the potential of Tat-conjugated H3 peptides as antitumor agents to induce cell death via increased cellular stress response by activating p38-MAPK signaling and intracellular ROS production.

JAC1 targets YY1 mediated JWA/p38 MAPK signaling to inhibit proliferation and induce apoptosis in TNBC.

Triple negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, and has no ideal therapeutic target and ideal medicine. Downregulation of JWA is closely related to the poor overall survival in many cancers including TNBC. In this study, we reported at the first time that JWA gene activating compound 1 (JAC1) inhibited the proliferation of TNBC in vitro and in vivo experimental models. JAC1 specifically bound to YY1 and eliminated its transcriptional inhibition of JWA gene. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. JAC1 also promoted ubiquitination and degradation of YY1. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC through p-Akt signaling pathway. In conclusion, JAC1 suppressed the proliferation of TNBC through the JWA/P38 MAPK signaling and YY1/HSF1/p-Akt signaling. JAC1 maybe a potential therapeutic agent for TNBC.

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway.

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1ß and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

Berberine Alleviates Insulin Resistance and Inflammation via Inhibiting the LTB4-BLT1 Axis.

Background: Chronic low-grade inflammation is recognized as a key pathophysiological mechanism of insulin resistance. Leukotriene B4 (LTB4), a molecule derived from arachidonic acid, is a potent neutrophil chemoattractant. The excessive amount of LTB4 that is combined with its receptor BLT1 can cause chronic low-grade inflammation, aggravating insulin resistance. Berberine (BBR) has been shown to relieve insulin resistance due to its anti-inflammatory properties. However, it is not clear whether BBR could have any effects on the LTB4-BLT1 axis. Methods: Using LTB4 to induce Raw264.7 and HepG2 cells, we investigated the effect of BBR on the LTB4-BLT1 axis in the progression of inflammation and insulin resistance. Results: Upon exposure to LTB4, intracellular insulin resistance and inflammation increased in HepG2 cells, and chemotaxis and inflammation response increased in RAW264.7 cells. Interestingly, pretreatment with BBR partially blocked these changes. Our preliminary data show that BBR might act on BLT1, modulating the LTB4-BLT1 axis to alleviate insulin resistance and inflammation. Conclusions: Our study demonstrated that BBR treatment could reduce intracellular insulin resistance and inflammation of hepatic cells, as well as chemotaxis of macrophages induced by LTB4. BBR might interact with BLT1 and alter the LTB4-BLT1 signaling pathway. This mechanism might be a novel anti-inflammatory and anti-diabetic function of BBR.

JWA suppresses proliferation in trastuzumab-resistant breast cancer by downregulating CDK12.

Breast cancer is the most common cancer worldwide. JWA is a microtubule-associated protein that has been identified as a tumor suppressor, and its downregulation in tumors is an independent adverse prognostic factor. The objective of this study was to explore the expression, regulation, and mechanism of JWA in trastuzumab-resistant breast cancers. In this study, we found that JWA expression was lower in trastuzumab-resistant breast cancers than that in trastuzumab-sensitive breast cancers. Furthermore, it was confirmed that overexpression of JWA inhibited proliferation and promoted apoptosis in trastuzumab-resistant breast cancers both in vitro and in vivo. In addition, the low expression of JWA in trastuzumab-resistant breast cancers is associated with a poor prognosis. Combining RNA-sequence datasets and next-generation sequencing, it was found that JWA negatively regulated CDK12, and was involved in the G1-to-S transition of the cell cycle. It has been reported that CDK12 drives breast cancer initiation and induces trastuzumab resistance. Taken together, high expression of JWA could inhibit the growth of trastuzumab-resistant breast cancer, and JWA is a potential predictive marker for trastuzumab resistance. In addition, targeted therapy with JWA may be a novel therapeutic strategy to improve the survival rate of trastuzumab-resistant breast cancer.

JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling.

The overexpression of HER2 is associated with a malignant proliferation of breast cancer. In this study, we developed a non-cytotoxic JWA gene activating compound 1 (JAC1) to inhibit the proliferation of HER2-positive breast cancer cells in vitro and in vivo experimental models. JAC1 increased the ubiquitination of HER2 at the K716 site through the E3 ubiquitin ligase SMURF1 which was due to the decreased expression of NEDD4, the E3 ubiquitin ligase of SMURF1. In conclusion, JAC1 suppresses the proliferation of HER2-positive breast cancer cells through the JWA triggered HER2 ubiquitination signaling. JAC1 may serve as a potential therapeutic agent for HER2-positive breast cancer.

Real-world data of chronic myelomonocytic leukemia: A chinese single-center retrospective study.

Chronic myelomonocytic leukemia (CMML) is a rare disease of elderly people characterized by the presence of sustained peripheral blood monocytosis, overlapping features of myeloproliferation, and myelodysplasia. We present a large retrospective study of 156 CMML patients in China. Mean age at diagnosis was 68 years old (range 23-91). According to the CMML-specific prognostic scoring system (CPSS), 10 patients (8.3%) were low risk, 27 patients (22.5%) were intermediate-1 risk, 72 patients (60%) were intermediate-2 risk, and 11 patients (9.2%) were high risk. A total of 90 patients (57.7%) received hypomethylating agents (HMAs) treatment, 19 patients (12.2%) received chemotherapy and 47 patients (30.1%) received the best supportive care. Seventeen patients (10.9%) underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) after HMAs treatment or chemotherapy. With a median follow-up of 35.3 months, overall response rate (ORR) was 69.5% in the HMAs ± chemotherapy group, 79.5% in the HMAs monotherapy group, 60.0% in the HMAs + chemotherapy group, and 37.5% in the chemotherapy group. HMAs monotherapy group had prolonged OS compared with the chemotherapy group (23.57 months vs. 11.73 months; p = 0.035). Patients who achieved ORR had prolonged OS (25.83 months vs. 8.00 months; p < 0.001) and LFS (20.53 months vs. 6.80 months; p < 0.001) compared with those not achieved ORR in the HMA ± chemotherapy group. By univariate analysis, only higher hemoglobulin (≥80 g/L) and lower serum LDH levels (<300 U/L) predicted for better OS and LFS. By multivariate analysis, only Hb ≥ 80 g/L predicted for prolonged OS, Hb ≥ 80 g/L, and monocytes < 3 × 109/L predicted for prolonged LFS. In summary, our study highlights the benefit of HMAs therapy in CMML, but we still need to develop novel therapeutics to achieve better outcomes.

JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis.

BACKGROUND: Gastric cancer (GC) is the most prevalent gastrointestinal tumor with an unfavorable clinical prognosis. GC patients are largely threatened owing to metastasis and drug resistance. Tumor angiogenesis plays an important role in the development of gastric cancer and is a challenge in the treatment of gastric cancer. METHODS: Mouse xenograft models were used for screening of therapeutic peptides on GC growth and metastasis. Routine laboratory experimental methods including conditional cell culture, tube formation assay, qRT-PCR, Western blotting, immunohistochemistry (IHC), ubiquitination assay, and immunofluorescence (IF) were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3/SP1 and TRIM25/MEK1/2. RESULTS: We identified an MMP2-targeted peptide JP3 that plays inhibiting roles in modulating growth and metastasis of GC in vivo and has no observable toxic side effects. JP3 reduced tumor microvessel density (MVD) in vivo and human umbilical vein endothelial cells (HUVECs) tube formation in vitro. Mechanistic studies revealed that JP3 reduces polyubiquitination-mediated degradation of TRIM25 by increasing the stability of TRIM25 through phosphorylating it at Ser12. TRIM25, as an E3 ubiquitin ligase, promoted the ubiquitin of SP1 at K610, further suppressed expression of MMP2 and inhibited angiogenesis in GC. Importantly, the inversely association between TRIM25 and SP1 protein level was further verified in human GC tissues. Decreased TRIM25 expression and increased SP1 expression in tumor tissues were positively correlated with poor prognosis of GC patients. CONCLUSIONS: MMP2-targeted peptide JP3 plays a therapeutic role in GC through anti-angiogenesis by modulating TRIM25/SP1/MMP2.

Jiao-tai-wan inhibits inflammation of the gut-brain-axis and attenuates cognitive impairment in insomnic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-tai-wan is a well-known traditional Chinese herbal medicine formula that is used to treat insomnia and systemic inflammation. Studies indicate chronic insomnia might contribute to the prevalence of cognitive impairment. The role of systemic inflammation and intestinal permeability in the progression of neurodegenerative diseases attracts much attention. AIM OF THE STUDY: This study aimed to investigate if Jiao-tai-wan plays a role in promoting the repair of the intestinal epithelial barrier to suppress systemic inflammation and cognitive impairment in sleep-deprived (SD) rats. MATERIALS AND METHODS: Male obesity-resistant SD rats were partially sleep-deprived for 16 weeks. During the last 8 weeks, they were treated with Jiao-tai-wan. A Morris water maze was used to analyze their cognitive ability. Aß42 and proinflammation cytokines in the cerebrospinal fluid, tissue, or serum were determined using enzyme-linked immunosorbent assay or polymerase chain reaction. Intestinal permeability was detected using the fluorescein isothiocyanate-dextran perfusion assay method. Plasma lipopolysaccharide (LPS) levels were detected with Tachypleus Amebocyte Lysate. Western bolt was used in the signaling pathway analysis. RESULTS: Sleep deprivation deteriorated the performance of rats in the Morris water maze and increased the Aß42, caspase3, IL-6, and TNF-α levels in their brains. The intestinal TLR4/NF-κB pathway was activated with an increase in the expression of IL-6 and TNF-α. The expression of tight junction proteins was also decreased in the intestinal tissue. This increased the intestinal permeability and circulation of LPS, LPS binding protein, IL-6, and TNF-α. Treatment with Jiao-tai-wan could partly reverse these changes. CONCLUSION: Jiao-tai-wan has the potential to attenuate systemic inflammation and cognitive impairment in partially sleep-deprived rats. The possible underlying mechanism is by preventing an inflammation trigger being transferred through the gut-brain-axis.

Activated toll-like receptor 4 is involved in oridonin-induced phagocytosis via promotion of migration and autophagy-lysosome pathway in RAW264.7 macrophages.

In our previous study, we demonstrated that oridonin enhances phagocytosis of apoptotic bodies by macrophage-like cells by inducing autophagy. However, the direct sensor of autophagy and the key event controlling phagocytosis remains unknown. Herein, we showed that Toll-like receptor 4 (TLR4), known to mediate immune responses, was activated by oridonin. Activated TLR4 contributes to phagocytosis of apoptotic cells by RAW264.7 macrophages. Indeed, inhibition or small interfering RNA (siRNA) silencing of TLR4 significantly attenuated oridonin-induced phagocytosis. Inhibition of TLR4 also decreased the level of autophagy and its associated proteins, Beclin-1 and light chain 3 (LC3), suggesting that activated TLR4 is involved in activation of autophagy. LPS-induced activation of TLR4 promoted phagocytosis and autophagy progression. Activation of TLR4 accompany increase in activities of lysosome acid phosphatase and cathepsin B as well as in up-regulation of lysosomal-associated membrane protein (LAMP 1 and 2) levels. Furthermore, TLR4 in association with translocation to cytoplasm leads to macrophage motility or migration through increased plasticity of skeleton and/or membrane structure. These results suggest that oridonin-induced phagocytosis of apoptotic bodies by macrophages is TLR4 signal pathway-mediated, via activation of the autophagy-lysosome pathway as well as increase of cell migration.