Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport GDP-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis (OC) and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 (Slc35c1 cKO) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T-cell, neutrophil and F4/80 macrophage infiltration, but did not affect the levels of serum and liver BA in mouse models of cholestasis. LC-MS/MS analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and PLC/PRF/5-ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

Comparison of cognitive performance in first-episode drug-naïve schizophrenia, bipolar II disorder, and major depressive disorder patients after treatment.

BACKGROUND: Cognitive impairment is a recognized fundamental deficit in individuals diagnosed with schizophrenia (SZ), bipolar II disorder (BD II), and major depressive disorder (MDD), among other psychiatric disorders. However, limited research has compared cognitive function among first-episode drug-naïve individuals with SZ, BD II, or MDD. METHODS: This study aimed to address this gap by assessing the cognitive performance of 235 participants (40 healthy controls, 58 SZ patients, 72 BD II patients, and 65 MDD patients) using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and after 12 weeks of treatment in SZ, BD II, and MDD patients. To clarify, the healthy controls only underwent RBANS testing at baseline, whereas the patient groups were assessed before and after treatment. The severity of symptoms in SZ patients was measured using the Positive and Negative Syndrome Scale (PANSS), and depression in BD II and MDD patients was assessed using the Hamilton Depression Scale-24 items (HAMD-24 items). RESULTS: Two hundred participants completed the 12-week treatment period, with 35 participants dropping out due to various reasons. This group included 49 SZ patients, 58 BD II patients, and 53 MDD patients. Among SZ patients, significant improvements in immediate and delayed memory were observed after 12 weeks of treatment compared to their initial scores. Similarly, BD II patients showed significant improvement in immediate and delayed memory following treatment. However, there were no significant differences in RBANS scores for MDD patients after 12 weeks of treatment. CONCLUSIONS: In conclusion, the findings of this study suggest that individuals with BD II and SZ may share similar deficits in cognitive domains. It is important to note that standardized clinical treatment may have varying degrees of effectiveness in improving cognitive function in patients with BD II and SZ, which could potentially alleviate cognitive dysfunction.

Differences in fractional amplitude of low-frequency fluctuations (fALFF) and cognitive function between untreated major depressive disorder and schizophrenia with depressive mood patients.

BACKGROUND: Distinguishing untreated major depressive disorder without medication (MDD) from schizophrenia with depressed mood (SZDM) poses a clinical challenge. This study aims to investigate differences in fractional amplitude of low-frequency fluctuations (fALFF) and cognition in untreated MDD and SZDM patients. METHODS: The study included 42 untreated MDD cases, 30 SZDM patients, and 46 healthy controls (HC). Cognitive assessment utilized the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Resting-state functional magnetic resonance imaging (rs-fMRI) scans were conducted, and data were processed using fALFF in slow-4 and slow-5 bands. RESULTS: Significant fALFF changes were observed in four brain regions across MDD, SZDM, and HC groups for both slow-4 and slow-5 fALFF. Compared to SZDM, the MDD group showed increased slow-5 fALFF in the right gyrus rectus (RGR). Relative to HC, SZDM exhibited decreased slow-5 fALFF in the left gyrus rectus (LGR) and increased slow-5 fALFF in the right putamen. Changes in slow-5 fALFF in both RGR and LGR were negatively correlated with RBANS scores. No significant correlations were found between remaining fALFF (slow-4 and slow-5 bands) and RBANS scores in MDD or SZDM groups. CONCLUSIONS: Alterations in slow-5 fALFF in RGR may serve as potential biomarkers for distinguishing MDD from SZDM, providing preliminary insights into the neural mechanisms of cognitive function in schizophrenia.

Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism.

The heart primarily derives its energy through lipid oxidation. In cardiomyocytes, lipids are stored in lipid droplets (LDs) and are utilized in mitochondria, although the structural and functional connections between these two organelles remain largely unknown. In this study, visible evidence have presented indicating that a complex is formed at the mitochondria-LD membrane contact (MLC) site, involving mitochondrion-localized Mfn2 and LD-localized Hsc70. This complex serves to tether mitochondria to LDs, facilitating the transfer of fatty acids (FAs) from LDs to mitochondria for ß-oxidation. Reduction of Mfn2 induced by lipid overload inhibits MLC, hinders FA transfer, and results in lipid accumulation. Restoring Mfn2 reinstates MLC, alleviating myocardial lipotoxicity under lipid overload conditions both in-vivo and in-vitro. Additionally, prolonged lipid overload induces Mfn2 degradation through the ubiquitin-proteasome pathway, following Mfn2 acetylation at the K243 site. This leads to the transition from adaptive lipid utilization to maladaptive lipotoxicity. The experimental findings are supported by clinical data from patients with obesity and age-matched non-obese individuals. These translational results make a significant contribution to the molecular understanding of MLC in the heart, and offer new insights into its role in myocardial lipotoxicity.

Coverage with the First Dose of Human Papillomavirus Vaccination among Females Aged 9-50 Years in Shenzhen, China: A Surveillance Based on Administrative Health Records in 2023.

China started to offer human papillomavirus (HPV) vaccines to females aged 9-45 years in 2016. However, there was a lack of reports about HPV vaccination coverage in a representative sample of females in China. Therefore, this study aimed to examine the current HPV coverage and associated factors among females aged 9-50 years in Shenzhen, China, based on administrative health records kept by community health centers. A multistage random sampling approach was used. The research team randomly selected 18 community health centers in Shenzhen, and 3118 health records of females aged 9-50 years were then randomly selected from these health centers. Among all participants, 18.7% received at least one dose of HPV vaccination. The highest coverage was observed among females aged 18-26 years (23.4%), followed by those aged 27-35 years (22.0%) and 36-45 years (20.2%). Such coverage was very low among females aged 9-17 years (4.6%) and those aged 46-50 years (3.2%). Among females aged 18 years or above, higher education level, having a family doctor, and permanent residency in Shenzhen were associated with higher HPV vaccination coverage, while older age and being married/divorced were negatively associated with coverage. The HPV vaccination coverage in Shenzhen was 18.7% and there is a strong need for improvement.

Ulinastatin in combination with aprotinin improves systemic inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: To investigate the impact of ulinastatin combined with protease inhibitors on serum inflammatory factors in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: A retrospective analysis was conducted on 86 patients who underwent cardiac surgery with cardiopulmonary bypass at Xi'an Gaoxin Hospital from May 2019 to June 2021. Based on the administration of drugs by a micro-infusion pump after anesthesia induction and before skin incision, the patients were divided into an observation group (receiving ulinastatin at a dose of 12,000 U/kg and protease inhibitors at a dose of 4 million units) with 46 cases and a control group (receiving protease inhibitors at a dose of 2 million units) with 40 cases. Peripheral blood leukocyte count, neutrophil percentage, interleukin (IL)-6, tumor necrosis factor (TNF)-α, serum creatine kinase isoenzyme (CK-MB), and serum cardiac troponin I (cTnI) levels were measured and compared between the two groups before surgery, 1 hour after surgery, and 24 hours after surgery. The positive inotropic drug usage, duration of postoperative mechanical ventilation, and incidence of complications were also compared between the two groups. Finally, an analysis was conducted to identify independent risk factors affecting patient prognosis. RESULTS: The peripheral blood white blood cell (WBC) count, neutrophil percentage, serum inflammatory factor level, CK-MB, and cTnI of the two groups of patients at 1 h and 24 h after the operation were significantly higher than those before the operation. However, the observation group had significantly lower levels of peripheral blood WBC count, neutrophil percentage, serum inflammatory factors, CK-MB, and cTnI compared to the control group (all P<0.05). Additionally, the observation group had significantly lower dopamine dosage and a shorter duration of mechanical ventilation compared to the control group (all P<0.05). The incidence of complications was lower in the observation group compared to the control group (P<0.05). TNF-α, cTnI, and treatment regimen were identified as independent risk factors associated with adverse patient prognosis. CONCLUSION: The perioperative use of ulinastatin combined with protease inhibitors in patients undergoing cardiac surgery with cardiopulmonary bypass is beneficial in suppressing systemic inflammatory response, improving cardiopulmonary function, and reducing the incidence of complications. These findings suggest its clinical utility.

A Global and Local Feature fused CNN architecture for the sEMG-based hand gesture recognition.

Deep learning methods have been widely used for the classification of hand gestures using sEMG signals. Existing deep learning architectures only captures local spatial information and has limitations in extracting global temporal dependency to enhance the model's performance. In this paper, we propose a Global and Local Feature fused CNN (GLF-CNN) model that extracts features both globally and locally from sEMG signals to enhance the performance of hand gestures classification. The model contains two independent branches extracting local and global features each and fuses them to learn more diversified features and effectively improve the stability of gesture recognition. Besides, it also exhibits lower computational cost compared to the present approaches. We conduct experiments on five benchmark databases, including the NinaPro DB4, NinaPro DB5, BioPatRec DB1-DB3, and the Mendeley Data. The proposed model achieved the highest average accuracy of 88.34% on these databases, with a 9.96% average accuracy improvement and a 50% reduction in variance compared to the models with the same number of parameters. Moreover, the classification accuracies for the BioPatRec DB1, BioPatRec DB3 and Mendeley Data are 91.4%, 91.0% and 88.6% respectively, corresponding to an improvement of 13.2%, 41.5% and 12.2% over the respective state-of-the-art models. The experimental results demonstrate that the proposed model effectively enhances robustness, with improved gesture recognition performance and generalization ability. It contributes a new way for prosthetic control and human-machine interaction.

Cyclosporine A-Encapsulated pH/ROS Dual-Responsive Nanoformulations for the Targeted Treatment of Colitis in Mice.

Inflammatory bowel disease (IBD) is a frequently occurring disease that seriously influences the patient's quality of life. To decrease adverse effects and improve efficacy of therapeutics, nanomedicines have been widely used to treat IBD. However, how to thoroughly release payloads under an inflammatory microenvironment and synergistic therapy of IBD need to be further investigated. To address this issue, cyclosporine A (CsA)-loaded, folic acid (FA)-modified, pH and reactive oxygen species (ROS) dual-responsive nanoparticles (FA-CsA NPs) were fabricated using pH/ROS-responsive material as carrier. The prepared FA-CsA NPs had spherical shape and uniform size distribution and could smartly release their payloads under acid and/or ROS microenvironment. In vitro experiments demonstrated that FA-CsA NPs can be effectively internalized by activated macrophages, and the internalized NPs could down-regulate the expression of proinflammatory cytokines compared to free drug or nontargeted NPs. In vivo experiments verified that FA-CsA NPs significantly accumulated at inflammatory colon tissues and the accumulated NPs obviously improved the symptoms of colitis in mice without obvious adverse effects. In conclusion, our results provided a candidate for the targeted treatment of IBD.

Anti-breast cancer-induced cardiomyopathy: Mechanisms and future directions.

With the progression of tumor treatment, the 5-year survival rate of breast cancer is close to 90%. Cardiovascular toxicity caused by chemotherapy has become a vital factor affecting the survival of patients with breast cancer. Anthracyclines, such as doxorubicin, are still some of the most effective chemotherapeutic agents, but their resulting cardiotoxicity is generally considered to be progressive and irreversible. In addition to anthracyclines, platinum- and alkyl-based antitumor drugs also demonstrate certain cardiotoxic effects. Targeted drugs have always been considered a relatively safe option. However, in recent years, some random clinical trials have observed the occurrence of subclinical cardiotoxicity in targeted antitumor drug users, which may be related to the effects of targeted drugs on the angiotensin converting enzyme, angiotensin receptor and ß receptor. The use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers may prevent clinical cardiotoxicity. This article reviews the toxicity and mechanisms of current clinical anti-breast cancer drugs and proposes strategies for preventing cardiovascular toxicity to provide recommendations for the clinical prevention and treatment of chemotherapy-related cardiomyopathy.

Simulating the effect of climate change on soil microbial community in an Abies georgei var. smithii forest.

Qinghai-Tibet Plateau is considered a region vulnerable to the effects of climate change. Studying the effects of climate change on the structure and function of soil microbial communities will provide insight into the carbon cycle under climate change. However, to date, changes in the successional dynamics and stability of microbial communities under the combined effects of climate change (warming or cooling) remain unknown, which limits our ability to predict the consequences of future climate change. In this study, in situ soil columns of an Abies georgei var. smithii forest at 4,300 and 3,500 m elevation in the Sygera Mountains were incubated in pairs for 1 year using the PVC tube method to simulate climate warming and cooling, corresponding to a temperature change of ±4.7°C. Illumina HiSeq sequencing was applied to study alterations in soil bacterial and fungal communities of different soil layers. Results showed that warming did not significantly affect the fungal and bacterial diversity of the 0-10 cm soil layer, but the fungal and bacterial diversity of the 20-30 cm soil layer increased significantly after warming. Warming changed the structure of fungal and bacterial communities in all soil layers (0-10 cm, 10-20 cm, and 20-30 cm), and the effect increased with the increase of soil layers. Cooling had almost no significant effect on fungal and bacterial diversity in all soil layers. Cooling changed the structure of fungal communities in all soil layers, but it showed no significant effect on the structure of bacterial communities in all soil layers because fungi are more adapted than bacteria to environments with high soil water content (SWC) and low temperatures. Redundancy analysis (RDA) and hierarchical analysis showed that changes in soil bacterial community structure were primarily related to soil physical and chemical properties, whereas changes in soil fungal community structure primarily affected SWC and soil temperature (Soil Temp). The specialization ratio of fungi and bacteria increased with soil depth, and fungi were significantly higher than bacteria, indicating that climate change has a greater impact on microorganisms in deeper soil layers, and fungi are more sensitive to climate change. Furthermore, a warmer climate could create more ecological niches for microbial species to coexist and increase the strength of microbial interactions, whereas a cooler climate could have the opposite effect. However, we found differences in the intensity of microbial interactions in response to climate change in different soil layers. This study provides new insights to understand and predict future effects of climate change on soil microbes in alpine forest ecosystems.

Differences and correlations of biochemical index levels in patients with bipolar disorder and major depressive disorder during a stable period.

The differences and correlation of biochemical indexes between bipolar disorder (BPD) and major depressive disorder (MDD) in stable stage were analyzed and discussed. Patients diagnosed with BPD and MDD in the Third People's Hospital of Foshan from January 2019 to December 2021 were selected as the research subjects, with 200 cases in each. Fasting serum was collected from patients and then detected regarding TC, TG, high-density lipoprotein, low-density lipoprotein (LDL), aspartate aminotransferase, lactic dehydrogenase, creatine kinase, creatine kinase-MB, urea, creatinine, uric acid, alanine aminotransferase, glucose (GLU), hemoglobin A1c, prolactin, high-sensitivity C-reactive protein, homocysteine. The results showed that the mean age and serum LDL, GLU, and HbAc1 levels of the MDD group were significantly higher than those of the BPD group (P < .05), while there was no significant difference in other indexes (P > .05). The prevalence of BPD was significantly negatively correlated with patient age (r = -0.164, P = .020), LDL (r = -0.150, P = .034), GLU (r = -0.140, P = .048), and HbAc1 (r = -0.215, P = .002) (P < .05). There were no significant differences in serum Hcy and high-sensitivity C-reactive protein levels between the BPD and MDD groups. The age, fasting blood glucose, glycosylated hemoglobin, and LDL of BPD patients were negatively correlated with their incidence.

Abnormal blood lipid and electrocardiogram characteristics in common mental disorders.

BACKGROUND: At present, there is not enough evidence to prove the relationship between blood lipid and electrocardiogram (ECG) abnormalities in common mental disorders (CMD). This study aimed to explore the relationship between them, to detect and prevent arrhythmia or sudden death. METHODS: We collected 272 CMD patients (maintained a fixed drug dose pattern for 1 year or more), including 95 schizophrenias (SC), 90 bipolar disorders (BD) and 87 major depressive disorders (MDD), and 78 healthy controls (HC) from the Third People's Hospital of Foshan, China. We analyzed and compared their blood lipid and ECG indicators, to clarify the relationship between them. RESULTS: 350 participants were included. There were no significant differences in age, gender, total cholesterol (TC), low density lipoprotein (LDL) and QTc (p > 0.05) among subjects. And there were significant differences in body mass index (BMI), triglyceride (TG), high density lipoprotein (HDL), heart rate, PR interval and QRS width (p < 0.05). Person correlation analysis showed that QRS width was positively correlated with BMI and TG. And negatively correlated with HDL. Meanwhile, QTc was positively correlated with BMI. Multiple linear regional analysis further proved that TG (B = 3.849, p = 0.007) and LDL (B = 11.764, p = 0.018) were the risk factors, and HDL (B = -9.935, p = 0.025) was the protective factor for QRS width increase. CONCLUSION: Long term medication of CMD patients should strengthen weight management, and conduct regular blood lipid and ECG examinations to achieve early detection and intervention in order to promote their health.

Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans.

BACKGROUND & AIMS: OATP1B3/SLCO1B3 is a human liver-specific transporter for the clearance of endogenous compounds (eg, bile acid [BA]) and xenobiotics. The functional role of OATP1B3 in humans has not been characterized, as SLCO1B3 is poorly conserved among species without mouse orthologs. METHODS: Slc10a1-knockout (Slc10a1-/-), Slc10a1hSLCO1B3 (endogenous mouse Slc10a1 promoter-driven human-SLCO1B3 expression in Slc10a1-/- mice), and human SLCO1B3 liver-specific transgenic (hSLCO1B3-LTG) mice were generated and challenged with 0.1% ursodeoxycholic-acid (UDCA), 1% cholic-acid (CA) diet, or bile duct ligation (BDL) for functional studies. Primary hepatocytes and hepatoma-PLC/RPF/5 cells were used for mechanistic studies. RESULTS: Serum BA levels in Slc10a1-/- mice were substantially increased with or without 0.1% UDCA feeding compared with wild-type (WT) mice. This increase was attenuated in Slc10a1hSLCO1B3-mice, indicating that OATP1B3 functions as a significant hepatic BA uptake transporter. In vitro assay using primary hepatocytes from WT, Slc10a1-/-, and Slc10a1hSLCO1B3-mice indicated that OATP1B3 has a similar capacity in taking up taurocholate/TCA as Ntcp. Furthermore, TCA-induced bile flow was significantly impaired in Slc10a1-/- mice but partially recovered in Slc10a1hSLC01B3-mice, indicating that OATP1B3 can partially compensate the NTCP function in vivo. Liver-specific overexpression of OATP1B3 markedly increased the level of hepatic conjugated BA and cholestatic liver injury in 1% CA-fed and BDL mice. Mechanistic studies revealed that conjugated BAs stimulated Ccl2 and Cxcl2 in hepatocytes to increase hepatic neutrophil infiltration and proinflammatory cytokine production (eg, IL-6), which activated STAT3 to repress OATP1B3 expression by binding to its promoter. CONCLUSIONS: Human OATP1B3 is a significant BA uptake transporter and can partially compensate Ntcp for conjugated BA uptake in mice. Its downregulation in cholestasis is an adaptive protective response.

Metafeature Selection via Multivariate Sparse-Group Lasso Learning for Automatic Hyperparameter Configuration Recommendation.

The performance of classification algorithms is mainly governed by the hyperparameter settings deployed in applications, and the search for desirable hyperparameter configurations usually is quite challenging due to the complexity of datasets. Metafeatures are a group of measures that characterize the underlying dataset from various aspects, and the corresponding recommendation algorithm fully relies on the appropriate selection of metafeatures. Metalearning (MtL), aiming to improve the learning algorithm itself, requires development in integrating features, models, and algorithm learning to accomplish its goal. In this article, we develop a multivariate sparse-group Lasso (SGLasso) model embedded with MtL capacity in recommending suitable configurations via learning. The main idea is to select the principal metafeatures by removing those redundant or irregular ones, promoting both efficiency and performance in the hyperparameter configuration recommendation. To be specific, we first extract the metafeatures and classification performance of a set of configurations from the collection of historical datasets, and then, a metaregression task is established through SGLasso to capture the main characteristics of the underlying relationship between metafeatures and historical performance. For a new dataset, the classification performance of configurations can be estimated through the selected metafeatures so that the configuration with the highest predictive performance in terms of the new dataset can be generated. Furthermore, a general MtL architecture combined with our model is developed. Extensive experiments are conducted on 136 UCI datasets, demonstrating the effectiveness of the proposed approach. The empirical results on the well-known SVM show that our model can effectively recommend suitable configurations and outperform the existing MtL-based methods and the well-known search-based algorithms, such as random search, Bayesian optimization, and Hyperband.

IgD/FcδR is involved in T-cell acute lymphoblastic leukemia and regulated by IgD-Fc-Ig fusion protein.

T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Excessive IgD may play a role in T cell activation via IgD Fc receptor (FcδR). Here we aimed to investigate the effects of IgD in T-ALL and demonstrated the potential benefit by targeting IgD/FcδR in T-ALL patients with IgD-Fc-Ig fusion protein. In T-ALL patients' blood samples and cell lines, the level of IgD, the percentage of FcδR expressing cells and the binding affinity were determined by flow cytometry. T cell viability, proliferation and apoptosis were analyzed. A mouse xenograft model was used to evaluate the in vivo effect of IgD-Fc-Ig, an IgD-FcδR blocker. The levels of serum IgD and FcδR were abnormally increased in part of T-ALL patients and IgD could induce over-proliferation and inhibit apoptosis of T-ALL cells in vitro. FcδR was constitutively expressed on T-ALL cells. IgD-Fc-Ig showed similar binding affinity to FcδR and selectively blocked the stimulation effect of IgD on T-ALL cells in vitro. In vivo study exhibited that IgD-Fc-Ig may also have therapeutic benefit. IgD-Fc-Ig administration inhibited human T-ALL growth and extended survival in xenograft T-ALL mice. In conclusion, this work supports the idea of targeting IgD/FcδR in T-ALL patients with excessive IgD. IgD-Fc-Ig fusion protein might be a potential biological drug with high selectivity for T-ALL treatment.

The Efficacy and Safety of a Qiliqiangxin Capsule Combined with Sacubitril/Valsartan in the Treatment of Chronic Heart Failure: A Systematic Review and Meta-Analysis.

Background: Qiliqiangxin (QLQX) capsules are a commonly used proprietary Chinese medicine for the adjuvant treatment of chronic heart failure (CHF) in China. In recent years, several randomized controlled trials (RCTs) have reported on the efficacy and safety of QLQX combined with sacubitril/valsartan for CHF. Objective: The purpose of this study was to systematically analyze the clinical efficacy and safety of QLQX combined with sacubitril/valsartan in the management of CHF and to provide clinicians as well as scientists with optimal evidence-based medical evidence. Methods: We searched RCTs to evaluate the efficacy and safety of QLQX combined with sacubitril/valsartan in the treatment of CHF in the Wanfang Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, PubMed, Embase, and Cochrane Library databases from their inception until January 8, 2022. RCTs on QLQX in combination with sacubitril/valsartan for CHF were included. The outcome measures considered were total effective rate, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), 6-minute walking distance (6-MWD), and adverse events. The quality of the included RCTs was assessed thereafter using the Cochrane risk of bias tool. RevMan 5.3 software was used to conduct the meta-analysis. Results: The meta-analysis included 17 trials involving 1427 CHF patients. The results indicated that with sacubitril/valsartan administration combined with QLQX treatment, the total effective rate (relative risk (RR) = 1.24; 95% confidence interval (CI) (1.17, 1.31); p < 0.01), LVEF (mean difference (MD) = 6.20; 95% CI (5.36, 7.05; p < 0.01)), and 6-MWD (MD = 55.87; 95% CI (40.66, 71.09); p < 0.01) of CHF patients were significantly increased, and the LVEDD value of CHF patients was noted to be significantly reduced (MD = -3.98; 95% CI (-4.47, -3.48); p < 0.01). Moreover, there was no increase in the number of adverse events during treatment (RR = 0.67; 95% CI (0.33, 1.34); p < 0.01). Conclusions: This study indicated that in CHF patients, on the basis of sacubitril/valsartan treatment, combination with QLQX can potentially enhance the total effective rate, improve LVEF and 6-MWD, and reduce LVEDD values, with good safety. However, considering the poor quality of the included studies, a multicenter, randomized, double-blind controlled study is needed for further confirmation.

Gut Microbiota Deficiency Exacerbates Liver Injury in Bile Duct Ligated Mice via Inflammation and Lipid Metabolism.

Bile components play a critical role in maintaining gut microbiota homeostasis. In cholestasis, bile secretion is impaired, leading to liver injury. However, it remains to be elucidated whether gut microbiota plays a role in cholestatic liver injury. Here, we performed a sham operation and bile duct ligation (BDL) in antibiotic-induced microbiome depleted (AIMD) mice and assessed liver injury and fecal microbiota composition in these mice. Significant reductions in gut microbiota richness and diversity were found in AIMD-sham mice when compared to sham controls. Three-day BDL leads to great elevation of plasma ALT, ALP, total bile acids, and bilirubin where reduced diversity of the gut microbiota was also found. AIMD further aggravated cholestatic liver injury evidenced by significantly higher levels of plasma ALT and ALP, associated with further reduced diversity and increased Gram-negative bacteria in gut microbiota. Further analyses revealed increased levels of LPS in the plasma of AIMD-BDL mice where elevated expression of inflammatory genes and decreased expression of hepatic detoxification enzymes were also found in liver when compared to the BDL group. These findings indicate that gut microbiota plays a critical role in cholestatic liver injury. Maintaining its homeostasis may alleviate liver injury in patients with cholestasis.

HCN-induced embryo arrest: passion fruit as an ecological trap for fruit flies.

BACKGROUND: Fruit flies are important economic pests of fruits, vegetables, and nuts all over the world. In this study, a permanent ecological trap, which was created by the ovicidal effect of phytogenic hydrogen cyanide (HCN) liberated from passion fruits due to oviposition by fruit flies and can be used in the pest management, were determined. RESULTS: Observation of fruit fly eggs in Passiflora within the passion fruit cultivation region in southern China, from Aug 2019 to Oct 2020 showed that the exotic Passiflora attracted the native fruit flies to oviposit, but the eggs could not hatch. Using classical staging to categorize embryonic development and fumigation assays, we show that oviposition by fruit fly on passion fruits, release HCN from the cyanogenic mesocarp. Exposure of the eggs to HCN causes arrest of embryonic development and finally the death of eggs. CONCLUSION: Our results reveal that the life cycle of fruit fly in Passiflora is interrupted at the egg stage. Consequently, we predict that this ecological trap may be permanent. Extensive cultivation of the Passiflora vine as a dead-end trap crop may be an effective avenue to reduce populations of fruit fly pests. © 2023 Society of Chemical Industry.

The mRNA-binding protein DDX3 mediates TGF-ß1 upregulation of translation and promotes pulmonary fibrosis.

Pulmonary fibrosis is potentiated by a positive feedback loop involving the extracellular sialidase enzyme neuraminidase 3 (NEU3) causing release of active TGF-ß1 and TGF-ß1 upregulating NEU3 by increasing translation without affecting mRNA levels. In this report, we elucidate the TGF-ß1 upregulation of the translation mechanism. In human lung fibroblasts, TGF-ß1 increased levels of proteins, including NEU3, by increasing translation of the encoding mRNAs without significantly affecting levels of these mRNAs. A total of 180 of these mRNAs shared a common 20-nucleotide motif. Deletion of this motif from NEU3 mRNA eliminated the TGF-ß1 upregulation of NEU3 translation, while insertion of this motif in 2 mRNAs insensitive to TGF-ß1 caused TGF-ß1 to upregulate their translation. RNA-binding proteins including DEAD box helicase 3, X-linked (DDX3), bind the RNA motif, and TGF-ß1 regulates their protein levels and/or binding to the motif. We found that DDX3 was upregulated in the fibrotic lesions in patients with pulmonary fibrosis, and inhibiting DDX3 in fibroblasts reduced TGF-ß1 upregulation of NEU3 levels. In the mouse bleomycin model of pulmonary fibrosis, injections of the DDX3 inhibitor RK-33 potentiated survival and reduced lung inflammation, fibrosis, and tissue levels of DDX3, TGF-ß1, and NEU3. These results suggest that inhibiting an mRNA-binding protein that mediates TGF-ß1 upregulation of translation can reduce pulmonary fibrosis.

TRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage.

Intracellular Ca2+ dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca2+ regulatory modules cannot successfully abolish this symptom. Here we show that the knockout of transient receptor potential canonical (TRPC) channel isoforms TRPC1 and TRPC6 can ameliorate LPS-challenged heart failure and prolong survival in mice. The LPS-triggered Ca2+ release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC's molecular partner - calmodulin - is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4's Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide insight into the pathogenesis of endotoxemic cardiac dysfunction and suggest a novel approach for its treatment.