A pH-Responsive Drug-Delivery System Based on Apatinib-Loaded Metal-Organic Frameworks for Ferroptosis-Targeted Synergistic Anti-Tumor Therapy.

Purpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.

METTL14 inhibits the proliferation, migration and invasion of prostate cancer cells by increasing m6A methylation of CDK4.

Background: Methyltransferase-like (METTL) plays an important role in various biological processes, but its role in prostate cancer (PCa) is still unclear. This study aimed to explore the mechanism by which methyltransferase-like 14 (METTL14) inhibits the physiological activity of PCa cells by increasing the N6-methyladenosine (m6A) modification of cyclin-dependent kinase 4 (CDK4). Methods: Clinical samples were collected for bioinformatics analysis. A PCa mouse model was constructed. Cell counting kit-8 (CCK-8), flow cytometry, colony formation assays, scratch assays, Transwell assays, real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and western blotting were used to detect the corresponding indicators. Results: METTL14 was found to be beneficial to inhibit the proliferation, invasion, and migration of PCa cells. When the m6A RNA increased, the half-life of CDK4 mRNA decreased after oe-METTL14 (overexpression of METTL14). Overexpression of CDK4 reversed the effect of oe-METTL14. Coimmunoprecipitation experiments revealed there were interactions between CDK4 and forkhead box M1 (FOXM1). Transfection of si-CDK4 was similar to transfection of oe-METTL14. After transfection with oe-FOXM1, the invasion and migration ability of cells increased, and cell apoptosis decreased. After transfection with si-FOXM1 alone, autophagy related 7 (ATG7) expression was significantly downregulated, and autophagy levels were reduced. The overexpression of ATG7 reversed the effect of si-FOXM1. The tumor volume and weight of the oe-METTL14 group mice were significantly reduced, and tumor proliferation was decreased in comparison to untreated tumor-bearing mice. Conclusions: METTL14 inhibits the invasion and migration of PCa cells and induces cell apoptosis by inhibiting CDK4 stability and FOXM1/ATG7-mediated autophagy.

Risk factor prediction and immune correlation analysis of cuproptosis-related gene in osteoarthritis.

Osteoarthritis (OA) is a widespread inflammatory joint disease with significant global disability burden. Cuproptosis, a newly identified mode of cell death, has emerged as a crucial factor in various pathological conditions, including OA. In this context, our study aims to investigate the intrinsic relationship between cuproptosis-related genes (CRGs) and OA, and assess their potential as biomarkers for OA diagnosis and treatment. Datasets from the GEO databases were analysed the differential expression of CRGs, leading to the identification of 10 key CRGs (CDKN2A, DLD, FDX1, GLS, LIAS, LIPT1, MTF1, PDHA1, DLAT and PDHB). A logistic regression analysis and calibration curves were used to show excellent diagnostic accuracy. Consensus clustering revealed two CRG patterns, with Cluster 1 indicating a closer association with OA progression. RT-PCR confirmed a significant increase in the expression levels of these nine key genes in IL-1ß-induced C28/i2 cells, and the expression of CDKN2A and FDX1 were also elevated in conditioned monocytes, while the expression of GLS and MTF1 were significantly decreased. In vitro experiments demonstrated that the expression levels of these 7/10 CRGs were significantly increased in chondrocytes induced by IL-1ß, and upon stimulation with cuproptosis inducers, chondrocyte apoptosis was exacerbated, accompanied by an increase in the expression of cuproptosis-related proteins. These further substantiated our research findings and indicated that the nine selected cuproptosis genes have high potential for application in the diagnosis of OA.

A rat model of cerebral small vascular disease induced by ultrasound and protoporphyrin.

Cerebral small vascular disease (CSVD) has a high incidence worldwide, but its pathological mechanisms remain poorly understood due to the lack of proper animal models. The current animal models of CSVD have several limitations such as high mortality rates and large-sized lesions, and thus it is urgent to develop new animal models of CSVD. Ultrasound can activate protoporphyrin to produce reactive oxygen species in a liquid environment. Here we delivered protoporphyrin into cerebral small vessels of rat brain through polystyrene microspheres with a diameter of 15 µm, and then performed transcranial ultrasound stimulation (TUS) on the model rats. We found that TUS did not affect the large vessels or cause large infarctions in the brain of model rats. The mortality rates were also comparable between the sham and model rats. Strikingly, TUS induced several CSVD-like phenotypes such as cerebral microinfarction, white matter injuries and impaired integrity of endothelial cells in the model rats. Additionally, these effects could be alleviated by antioxidant treatment with N-acetylcysteine (NAC). As control experiments, TUS did not lead to cerebral microinfarction in the rat brain when injected with the polystyrene microspheres not conjugated with protoporphyrin. In sum, we generated a rat model of CSVD that may be useful for the mechanistic study and drug development for CSVD.

Roles and Mechanisms of Dopamine Receptor Signaling in Catecholamine Excess Induced Endothelial Dysfunctions.

Endothelial dysfunction may contribute to pathogenesis of Takotsubo cardiomyopathy, but mechanism underlying endothelial dysfunction in the setting of catecholamine excess has not been clarified. The study reports that D1/D5 dopamine receptor signaling and small conductance calcium-activated potassium channels contribute to high concentration catecholamine induced endothelial cell dysfunction. For mimicking catecholamine excess, 100 µM epinephrine (Epi) was used to treat human cardiac microvascular endothelial cells. Patch clamp, FACS, ELISA, PCR, western blot and immunostaining analyses were performed in the study. Epi enhanced small conductance calcium-activated potassium channel current (ISK1-3) without influencing the channel expression and the effect was attenuated by D1/D5 receptor blocker. D1/D5 agonists mimicked the Epi effect, suggesting involvement of D1/D5 receptors in Epi effects. The enhancement of ISK1-3 caused by D1/D5 activation involved roles of PKA, ROS and NADPH oxidases. Activation of D1/D5 and SK1-3 channels caused a hyperpolarization, reduced NO production and increased ROS production. The NO reduction was membrane potential independent, while ROS production was increased by the hyperpolarization. ROS (H2O2) suppressed NO production. The study demonstrates that high concentration catecholamine can activate D1/D5 and SK1-3 channels through NADPH-ROS and PKA signaling and reduce NO production, which may facilitate vasoconstriction in the setting of catecholamine excess.

External circuit loading mode regulates anode biofilm electrochemistry and pollutants removal in microbial fuel cells.

This study investigated the effects of different external circuit loading mode on pollutants removal and power generation in microbial fuel cells (MFC). The results indicated that MFC exhibited distinct characteristics of higher maximum power density (Pmax) (named MFC-HP) and lower Pmax (named MFC-LP). And the capacitive properties of bioanodes may affect anodic electrochemistry. Reducing external load to align with the internal resistance increased Pmax of MFC-LP by 54.47 %, without no obvious effect on MFC-HP. However, intermittent external resistance loading (IER) mitigated the biotoxic effects of sulfamethoxazole (SMX) (a persistent organic pollutant) on chemical oxygen demand (COD) and NH4+-N removal and maintained high Pmax (424.33 mW/m2) in MFC-HP. Meanwhile, IER mode enriched electrochemically active bacteria (EAB) and environmental adaptive bacteria Advenella, which may reduce antibiotic resistance genes (ARGs) accumulation. This study suggested that the external circuit control can be effective means to regulate electrochemical characteristics and pollutants removal performance of MFC.

Triple gene mutations boost amylose and resistant starch content in rice: insights from sbe2b/sbe1/OE-Wxa mutants.

Previous studies have modified rice's resistant starch (RS) content by mutating single and double genes. These mutations include knocking out or reducing the expression of sbe1 or sbe2b genes, as well as overexpressing Wxa . However, the impact of triple mutant sbe2b/sbe1/OE-Wxa on RS contents remained unknown. Here, we constructed a double mutant with sbe2b/RNAi-sbe1, based on IR36ae with sbe2b, and a triple mutant with sbe2b/RNAi-sbe1/OE-Wxa , based on the double mutant. The results showed that the amylose and RS contents gradually increased with an increase in the number of mutated genes. The triple mutant exhibited the highest amylose and RS contents, with 41.92% and 4.63%, respectively, which were 2- and 5-fold higher than those of the wild type, which had 22.19% and 0.86%, respectively. All three mutants altered chain length and starch composition compared to the wild type. However, there was minimal difference observed among the mutants. The Wxa gene contributed to the improvement of 1000-grain weight and seed-setting rate, in addition to the highest amylose and RS contents. Thus, our study offers valuable insight for breeding rice cultivars with a higher RS content and yields.

Micro-Structure Engineering in Pd-InOx Catalysts and Mechanism Studies for CO2 Hydrogenation to Methanol.

Significant interest has emerged for the application of Pd-In2O3 catalysts as high-performance catalysts for CO2 hydrogenation to CH3OH. However, precise active site control in these catalysts and understanding their reaction mechanisms remain major challenges. In this investigation, a series of Pd-InOx catalysts were synthesized, revealing three distinct types of active sites: In-O, Pd-O(H)-In, and Pd2In3. Lower Pd loadings exhibited Pd-O(H)-In sites, while higher loadings resulted in Pd2In3 intermetallic compounds. These variations impacted catalytic performance, with Pd-O(H)-In catalysts showing heightened activity at lower temperatures due to the enhanced CO2 adsorption and H2 activation, and Pd2In3 catalysts performing better at elevated temperatures due to the further enhanced H2 activation. In situ DRIFTS studies revealed an alteration in key intermediates from *HCOO over In-O bonds to *COOH over Pd-O(H)-In and Pd2In3 sites, leading to a shift in the main reaction pathway transition and product distribution. Our findings underscore the importance of active site engineering for optimizing catalytic performance and offer valuable insights for the rational design of efficient CO2 conversion catalysts.

Alantolactone improves cognitive impairment in rats with Porphyromonas gingivalis infection by inhibiting neuroinflammation, oxidative stress, and reducing Aß levels.

Neuroinflammation caused by the chronic periodontal pathogen Porphyromonas gingivalis is growing regarded as as a key factor in the pathogenesis of Alzheimer's disease (AD). Alantolactone (AL), a sesquiterpene lactone isolated from the root of Inula racemosa Hook. f, has been proven to provide various neuroprotective effects. However, whether AL can improve cognitive impairment caused by P. gingivalis infection remains unclear. In this research, a rat model of P. gingivalis infection was used to examine the neuroprotective benefits of AL. The results revealed that 6 weeks of AL treatment (50 and 100 mg/kg) shortened escape latency and increased the number of crossings over the platform location and time spent in the target quadrant of P. gingivalis-infected rats in the Morris water maze experiment. By activating the Nrf2/HO-1 pathway, AL suppressed malondialdehyde (MDA) levels and simultaneously increased the activity of total superoxide dismutase (T-SOD). Furthermore, AL lowered the presence of IL-6, IL-1ß, and TNFα in the hippocampal and cortical tissues of P. gingivalis-infected rats by inhibiting astrocyte and microglial activation and NF-κB phosphorylation. AL also significantly reduced Aß levels in the cortical and hippocampus tissues of rats infected with P. gingivalis. In conclusion, AL improved cognitive impairment in P. gingivalis-infected rats by inhibiting neuroinflammation, reducing Aß1-42 level, and exerting antioxidative stress effects.

Insights into the microscopic heterogeneity of whey proteins between yak colostrum and mature milk based on 4D lable-free quantitative phosphoproteomics.

This study aimed to reveal the change patterns of the phosphorylation modification status of yak whey phosphoproteins during lactation and their physiological effects. Herein, we comprehensively characterized whey phosphoproteome in yak colostrum and mature milk using an ultra-high throughput phosphoproteomics approach incorporating trapped ion mobility technology. A total of 344 phosphorylation sites from 206 phosphoproteins were identified, with individual site modification predominating. Notably, 117 significantly different phosphorylation sites were distributed on 89 whey phosphoproteins. Gene ontology analysis indicated that these significantly different whey phosphoproteins (SDWPPs) were mainly annotated to carbohydrate metabolic process, membrane, extracellular region and calcium ion binding. Metabolic pathway enrichment analysis demonstrated that SDWPPs were critically involved in protein processing in endoplasmic reticulum, NOD-like receptor signaling pathway and N-glycan biosynthesis. Our results elucidate the phosphorylation profiles of yak whey phosphoproteins at different lactations and their adaptive regulatory role in meeting the nutritional requirements of yak calves during development.

Development of a diagnostic nomogram for alpha-fetoprotein-negative hepatocellular carcinoma based on serological biomarkers.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Serum biomarkers play an important role in the early diagnosis and prognosis of HCC. Because a certain percentage of HCC patients are negative for alpha-fetoprotein (AFP), the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC. AIM: To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers. METHODS: A total of 180 HCC patients were enrolled in this study. The expression levels of GP73, des-γ-carboxyprothrombin (DCP), CK18-M65, and CK18-M30 were detected by a fully automated chemiluminescence analyser. The variables were selected by logistic regression analysis. Several models were constructed using stepwise backward logistic regression. The performance of the models was compared using the C statistic, integrated discrimination improvement, net reclassification improvement, and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA). RESULTS: The results showed that the expression levels of GP73, DCP, CK18-M65, and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls (P < 0.001). Multivariate logistic regression analysis revealed that GP73, DCP, and CK18-M65 were independent factors for diagnosing AFP-negative HCC. By comparing the diagnostic performance of multiple models, we included GP73 and CK18-M65 as the model variables, and the model had good discrimination ability (area under the curve = 0.946) and good goodness of fit. The DCA curves indicated the good clinical utility of the nomogram. CONCLUSION: Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC. The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC.

A meta-analysis of effectiveness of mobile health interventions on health-related outcomes in patients with heart failure.

AIMS: To systematically evaluate the effectiveness of mobile health (mHealth) interventions on medication adherence in patients with heart failure. METHODS: The literature search was conducted in PubMed, Web of Science, the Cochrane Library databases, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database and China Scientific Journal Database (VIP). The retrieval period was from the establishment of the database to May 2023. The included studies were trials to explore the effectiveness of mHealth interventions on medication adherence in patients with heart failure. Cochrane collaboration's tool was used for assessing risk of bias in randomized controlled trials. Stata 17.0 software was used to conduct data analysis. Continuous data were expressed as standard mean differences, and dichotomous data were expressed as relative risks with 95% confidence intervals (CIs). RESULTS: A total of 13 studies and 2534 participants were included. One study was rated as Grade A, and the other 12 studies were Grade B. The results of meta-analysis indicate that mHealth interventions are effective in improving medication adherence [relative risk (RR) = 1.26, 95% CI 1.10-1.44, P < 0.05 and standard mean difference = 0.80, 95% CI 0.44-1.15, P < 0.05], and reducing readmission rates (RR = 0.63, 95% CI 0.53-0.76, P < 0.05) and mortality (RR = 0.63, 95% CI 0.43-0.94, P < 0.05) of patients with heart failure. CONCLUSION: mHealth interventions are beneficial to improve medication adherence in patients with heart failure, and could effectively reduce the readmission rates and mortality of patients in the studies. There is a need to continuously improve the professional abilities of intervention personnel, carry out teamwork, and extend intervention and follow-up time. Convenient, fast and low-cost mobile medical devices should be adopted to reduce the cost of medical treatment. Scientific and reasonable intervention content will be formulated according to evidence-based guidelines and theoretical basis to enhance patients' ability at self-management and understanding of heart failure knowledge.

A bibliometric analysis of indocyanine green (ICG) in hepatobiliary surgery from 2008 to 2021.

Hundreds of scientific documents have reported on the application of indocyanine green (ICG) in hepatobiliary surgery in the past 13 years, but few bibliometric studies have been conducted. This study aimed to identify the situations of authors, countries/regions, institutions, journals, and hot topics in this field. The overall status and prospects of the current research in this field can be elucidated by bibliometric analysis. Publications from 2008 to 2021 were retrieved from the Web of Science (WoS) Core Collection. The search terms included "liver," "hepatic," "gallbladder," "bile duct," "surgery," "hepatectomy," "ICG," "indocyanine green," and related synonyms. The full records of the search results were exported in text, and the cooperation network and hot topics were evaluated and visualized using CiteSpace software. The number of publications increased between 2008 and 2021. A total of 1527 publications were included in the results, and the frequency of citations was 30,742. The largest proportion of the publications emanated from Japan, and the majority of the papers were published by Kokudo. Tian Jie contributed the largest number of papers in China. Research was relatively concentrated among one country/region. The latest hotspots, "preservation" and "resistance", frequently occurred. Cooperation between authors, countries, and institutions needs to be strengthened for high-quality research. Recent studies have focused on hepatectomy, bile duct resection, liver transplantation, and tumors in this field. Future research may focus on other aspects, such as liver preservation and resistance.

Role of membrane fouling layer in microbial fuel cell-membrane bioreactor (MFC-MBR) for controlling sulfamethoxazole and corresponding resistance genes.

Integrated MFC-MBR systems effectively remove antibiotics and control the release of antibiotic resistance genes (ARGs). However, the fouling layers on membranes can potentially act as reservoirs for ARGs. This study aims to elucidate the roles of membrane fouling layers and levels in influencing sulfamethoxazole (SMX) removal and ARGs control within an MFC-MBR system. Our findings demonstrate that low-intensity bioelectricity (400-500 mV) mitigates membrane fouling rates. The membrane fouling layer significantly contributes (39%-47%) to SMX removal compared to the cathode/anode zones. Higher extracellular polymeric substance (EPS) content and a lower protein/polysaccharide (PN/PS) ratio favor SMX removal by the membrane fouling layer. Across different levels of membrane fouling, the PN/PS ratio rather than EPS concentration plays a crucial role in SMX removal efficiency. The MFC-MBR with low fouling achieved superior SMX removal (69.1%) compared to medium (54.3%) and high fouling conditions (46.8%). The presence of ARGs in the membrane fouling layer increases with fouling formation, with intrinsic ARGs prevailing. Dense membrane fouling layers effectively retain ARGs, thereby reducing the risk of extracellular ARGs (eARGs) diffusion in effluents. These results provide insights into controlling ARGs in MFC-MBR systems and underscore the significant role of membrane fouling layers in antibiotics and ARGs removal.

Insights to the cooperation of double-working potential electroactive biofilm for performance of sulfamethoxazole removal: ARG fate and microorganism communities.

Bioelectrochemical systems (BESs) have shown great potential in enhancing sulfamethoxazole (SMX) removal. However, electroactive biofilms (EBs) constructed with single potentials struggle due to limited biocatalytic activity, hindering deep SMX degradation. Here, we constructed a double-working potential BES (BES-D) to investigate its ability to eliminate SMX and reduce the levels of corresponding antibiotic resistance genes (ARGs). The preferable electrochemical activity of EB in BES-D was confirmed by electrochemical characterization, EPS analysis, physical structure, viability of the biofilm, and cytochrome content. BES-D exhibited a notably greater SMX removal efficiency (94.2 %) than did the single-working potential BES (BES-S) and the open-circuit group (OC). Degradation pathway analysis revealed that the cooperative EB could accelerate the in-depth removal of SMX. Moreover, EB interaction in BES-D decreased the relative abundance of ARGs in biofilms compared to that in BES-S, although the absolute number of ARG copies increased in BES-D effluents. Compared to those in BES-S and OC, more complex cross-niche microbial associations in the EB of BES-D were observed by network analysis of the bacterial community and ARG hosts, enhancing the degradation efficiency of SMX. In conclusion, BES-D has significant potential for SMX removal and the enhancement of EB activity. Nonetheless, the risk of ARG dissemination in effluent remains a concern.

Development of a nomogram for predicting liver transplantation prognosis in hepatocellular carcinoma.

BACKGROUND: At present, liver transplantation (LT) is one of the best treatments for hepatocellular carcinoma (HCC). Accurately predicting the survival status after LT can significantly improve the survival rate after LT, and ensure the best way to make rational use of liver organs. AIM: To develop a model for predicting prognosis after LT in patients with HCC. METHODS: Clinical data and follow-up information of 160 patients with HCC who underwent LT were collected and evaluated. The expression levels of alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, Golgi protein 73, cytokeratin-18 epitopes M30 and M65 were measured using a fully automated chemiluminescence analyzer. The best cutoff value of biomarkers was determined using the Youden index. Cox regression analysis was used to identify the independent risk factors. A forest model was constructed using the random forest method. We evaluated the accuracy of the nomogram using the area under the curve, using the calibration curve to assess consistency. A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomograms. RESULTS: The total tumor diameter (TTD), vascular invasion (VI), AFP, and cytokeratin-18 epitopes M30 (CK18-M30) were identified as important risk factors for outcome after LT. The nomogram had a higher predictive accuracy than the Milan, University of California, San Francisco, and Hangzhou criteria. The calibration curve analyses indicated a good fit. The survival and recurrence-free survival (RFS) of high-risk groups were significantly lower than those of low- and middle-risk groups (P < 0.001). The DCA shows that the model has better clinical practicability. CONCLUSION: The study developed a predictive nomogram based on TTD, VI, AFP, and CK18-M30 that could accurately predict overall survival and RFS after LT. It can screen for patients with better postoperative prognosis, and improve long-term survival for LT patients.

Small conductance calcium-activated potassium channel contributes to stress induced endothelial dysfunctions.

Patients with Takotsubo syndrome displayed endothelial dysfunction, but underlying mechanisms have not been fully clarified. This study aimed to explore molecular signalling responsible for catecholamine excess induced endothelial dysfunction. Human cardiac microvascular endothelial cells were challenged by epinephrine to mimic catecholamine excess. Patch clamp, FACS, ELISA, PCR, and immunostaining were employed for the study. Epinephrine (Epi) enhanced small conductance calcium-activated potassium channel current (ISK1-3) through activating α1 adrenoceptor. Phenylephrine enhanced edothelin-1 (ET-1) and reactive oxygen species (ROS) production, and the effects involved contribution of ISK1-3. H2O2 enhanced ISK1-3 and ET-1 production. Enhancing ISK1-3 caused a hyperpolarization, which increases ROS and ET-1 production. BAPTA partially reduced phenylephrine-induced enhancement of ET-1 and ROS, suggesting that α1 receptor activation can enhance ROS/ET-1 generation in both calcium-dependent and calcium-independent ways. The study demonstrates that high concentration catecholamine can activate SK1-3 channels through α1 receptor-ROS signalling and increase ET-1 production, facilitating vasoconstriction.

Complexity decline of hippocampal CA1 circuit model due to cholinergic deficiency associated with Alzheimer's disease.

A hallmark of Alzheimer's disease (AD) is cholinergic system dysfunction, directly affecting the hippocampal neurons. Previous experiments have demonstrated that reduced complexity is one significant effect of AD on electroencephalography (EEG). Motivated by these, this study explores reduced EEG complexity of cholinergic deficiency in AD by neurocomputation. We first construct a new hippocampal CA1 circuit model with cholinergic action. M-current IM and calcium-activated potassium current IAHP are newly introduced in the model to describe cholinergic input from the medial septum. Then, by enhancing IM and IAHP to mimic cholinergic deficiency, how cholinergic deficiency influences the model complexity is investigated by sample entropy (SampEn) and approximate entropy (ApEn). Numerical results show a more severe cholinergic deficit with lower model complexity. Furthermore, we conclude that the decline of SampEn and ApEn is due to the greatly diminished excitability of model neurons. These suggest that decreased neuronal excitability due to cholinergic impairment may contribute to reduced EEG complexity in AD. Subsequently, statistical analysis between simulated AD patients and normal control (NC) groups demonstrates that SampEn and auto-mutual-information (AMI) decrease rates significantly differ. Compared to NC, AD patients have a lower SampEn and a less negative AMI decline rate. These imply a low rate of new-generation information in AD brains with cholinergic deficits. Interestingly, the statistical correlation between SampEn and AMI is analyzed, and they have a large negative Pearson correlation coefficient. Thus, AMI reduction rates may be a complementary tool for complex analysis. Our modeling and complex analysis are expected to provide a deeper understanding of the reduced EEG complexity resulting from cholinergic deficiency.

Akkermansia muciniphila isolated from forest musk deer ameliorates diarrhea in mice via modification of gut microbiota.

BACKGROUND: The forest musk deer, a rare fauna species found in China, is famous for its musk secretion which is used in selected Traditional Chinese medicines. However, over-hunting has led to musk deer becoming an endangered species, and their survival is also greatly challenged by various high incidence and high mortality respiratory and intestinal diseases such as septic pneumonia and enteritis. Accumulating evidence has demonstrated that Akkermannia muciniphila (AKK) is a promising probiotic, and we wondered whether AKK could be used as a food additive in animal breeding programmes to help prevent intestinal diseases. METHODS: We isolated one AKK strain from musk deer feces (AKK-D) using an improved enrichment medium combined with real-time PCR. After confirmation by 16S rRNA gene sequencing, a series of in vitro tests was conducted to evaluate the probiotic effects of AKK-D by assessing its reproductive capability, simulated gastrointestinal fluid tolerance, acid and bile salt resistance, self-aggregation ability, hydrophobicity, antibiotic sensitivity, hemolysis, harmful metabolite production, biofilm formation ability, and bacterial adhesion to gastrointestinal mucosa. RESULTS: The AKK-D strain has a probiotic function similar to that of the standard strain in humans (AKK-H). An in vivo study found that AKK-D significantly ameliorated symptoms in the enterotoxigenic Escherichia coli (ETEC)-induced murine diarrhea model. AKK-D improved organ damage, inhibited inflammatory responses, and improved intestinal barrier permeability. Additionally, AKK-D promoted the reconstitution and maintenance of the homeostasis of gut microflora, as indicated by the fact that AKK-D-treated mice showed a decrease in Bacteroidetes and an increase in the proportion of other beneficial bacteria like Muribaculaceae, Muribaculum, and unclassified f_Lachnospiaceae compared with the diarrhea model mice. CONCLUSION: Taken together, our data show that this novel AKK-D strain might be a potential probiotic for use in musk deer breeding, although further extensive systematic research is still needed.

Cholecystohepatic shunt pathway reduces secondary bile acid accumulation to enhance natural killer T cell-mediated anti-hepatocellular carcinoma immunity.

BACKGROUND AND AIM: The impact of cholecystectomy, which blocks the cholecystohepatic shunt pathway (CHSP), on the prognosis of patients with hepatocellular carcinoma (HCC) is unclear. Hepatic secondary bile acids (BAs) inhibit natural killer T (NKT) cell-mediated immunity against HCC, and the regulation of homeostasis of hepatic secondary BAs is controlled by the CHSP. However, the influence of CHSP on NKT cell-mediated immunity against HCC remains unclear. METHODS: The clinical data of hospitalized patients undergoing HCC resection were collected. Meanwhile, an in situ HCC mouse model was established, and the CHSP was augmented using oleanolic acid (OA). RESULTS: After 1:1 propensity score matching, Cox regression analysis revealed that cholecystectomy was an independent risk factor for HCC recurrence after hepatectomy (P = 0.027, hazard ratio: 1.599, 95% confidence interval: 1.055-2.422). Experimentally, when OA enhanced CHSP, a significant decrease was observed in the accumulation of secondary BAs in the livers of mice. Additionally, a significant increase was observed in the levels of C-X-C ligand 16 and interferon γ in the serum and tumor tissues. Further, the percentage of C-X-C receptor 6 (+) NKT cells in the tumor tissues increased significantly, and the growth of liver tumors was inhibited. CONCLUSIONS: This clinical study revealed that cholecystectomy promoted the recurrence after radical hepatectomy in patients with HCC. Preserving the normal-functioning gallbladder as much as possible during surgery may be beneficial to the patient's prognosis. Further investigation into the mechanism revealed that CHSP enhanced NKT cell-mediated immunity against HCC by reducing the hepatic accumulation of secondary BAs.