Liver as a new target organ in Alzheimer's disease: insight from cholesterol metabolism and its role in amyloid-beta clearance.

Alzheimer's disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer's disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer's disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease. In this review, we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

The association of cortisol, testosterone, and cortisol/testosterone ratio with stroke: A cross-sectional study.

AIMS: We aimed to investigate the association between serum cortisol, testosterone, and cortisol/testosterone (C/T) ratio and stroke. MATERIALS AND METHODS: A total of 6157 subjects were included in this study. The serum levels of cortisol and testosterone were determined by liquid chromatography-tandem mass spectrometry method. The relationships of serum cortisol, testosterone, and C/T ratio levels with the odds ratios (ORs) of stroke were calculated using logistic regression analysis. The dose-response associations between serum cortisol, testosterone, and C/T ratio levels with stroke estimated by restricted cubic splines. RESULTS: After adjusting for multiple variables, serum testosterone levels were negactively associated with stroke in males (per 1 unit, odds ratio (OR) = 0.83, 95 % confidence interval (CI): 0.70, 0.97). The serum C/T ratio is positively associated with stroke in both males and females (OR = 1.16, 95 % CI:1.04,1.34 in males and OR = 1.15, 95 % CI:1.02,1.31 in females). Restricted cubic splines showed a significant linear dose-response relationship between testosterone and C/T ratio and stroke in males (P for overall association <0.05, P for nonlinearity >0.05). CONCLUSION: Our study findings show that serum testosterone levels are negatively correlated with stroke in males; meanwhile, serum C/T ratio is positively correlated with stroke in both males and females.

Microalgal extracellular polymeric substances (EPS) and their roles in cultivation, biomass harvesting, and bioproducts extraction.

Microalgae extracellular polymeric substances (EPS) are complex high-molecular-weight polymers and the physicochemical properties of EPS strongly affect the core features of microalgae cultivation and resource utilization. Revealing the key roles of EPS in microalgae life-cycle processes in an interesting and novelty topic to achieve energy-efficient practical application of microalgae. This review found that EPS showed positive effect in non-gas uptake, extracellular electron transfer, toxicity resistance and heterotrophic symbiosis, but negative impact in gas transfer and light utilization during microalgae cultivation. For biomass harvesting, EPS favored biomass flocculation and large-size cell self-flocculation, but unfavored small size microalgae self-flocculation, membrane filtration, charge neutralization and biomass dewatering. During bioproducts extraction, EPS exhibited positive impact in extractant uptake, but the opposite effect in cellular membrane permeability and cell rupture. Future research on microalgal EPS were also identified, which offer suggestions for comprehensive understanding of microalgal EPS roles in various scenarios.

Ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features for automatic classification of ovarian masses according to O-RADS.

Background: Accurate and rapid discrimination between benign and malignant ovarian masses is crucial for optimal patient management. This study aimed to establish an ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features to automatically classify the ovarian masses into low risk and intermediate-high risk of malignancy lesions according to the Ovarian- Adnexal Reporting and Data System (O-RADS). Methods: The ultrasound images of 1,080 patients with 1,080 ovarian masses were included. The training cohort consisting of 683 patients was collected at the South China Hospital of Shenzhen University, and the test cohort consisting of 397 patients was collected at the Shenzhen University General Hospital. The workflow included image segmentation, feature extraction, feature selection, and model construction. Results: The pre-trained Resnet-101 model achieved the best performance. Among the different mono-modal features and fusion feature models, nomogram achieved the highest level of diagnostic performance (AUC: 0.930, accuracy: 84.9%, sensitivity: 93.5%, specificity: 81.7%, PPV: 65.4%, NPV: 97.1%, precision: 65.4%). The diagnostic indices of the nomogram were higher than those of junior radiologists, and the diagnostic indices of junior radiologists significantly improved with the assistance of the model. The calibration curves showed good agreement between the prediction of nomogram and actual classification of ovarian masses. The decision curve analysis showed that the nomogram was clinically useful. Conclusion: This model exhibited a satisfactory diagnostic performance compared to junior radiologists. It has the potential to improve the level of expertise of junior radiologists and provide a fast and effective method for ovarian cancer screening.

Associations between genetic mutations in different SARS-CoV-2 strains and negative conversion time of viral RNA among imported cases in Hangzhou: A cross-sectional study.

PURPOSE: Previous studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on factors that influence the achievement of negative conversion of viral RNA. This study aimed to investigate the effects of the genetic mutations in different SARS-CoV-2 strains on the negative conversion time (NCT) among imported cases in Hangzhou, Zhejiang Province, China, in order to provide valuable insights for developing targeted epidemic prevention guidelines. METHODS: This retrospective study involved 146 imported SARS-CoV-2 cases in Hangzhou from 8 April 2021 to 11 June 2022. We compared the SARS-CoV-2-specific indicators, clinical indexes, and NCT among the wild-type (WT), Delta, and Omicron groups. Spearman correlation analysis was used to identify the correlations of NCT with mutation types/frequencies. RESULTS: The mean age of the imported cases was 35.3 (SD: 12.3) years, with 71.92 % males and 28.08 % females. The mean cycle threshold (Ct) values of open reading frame 1ab (ORF1ab) and nucleocapsid (N) RNA were 25.17 (SD: 6.44) and 23.4 (SD: 6.76), respectively. The mutations of SARS-CoV-2 strains were mainly located in N, membrane (M), spike (S), ORF1a, ORF1b, ORF3a, ORF6, and ORF9b genes among the WT, Delta, and Omicron groups. NCT was significantly prolonged in the WT and Delta groups compared to the Omicron group. T lymphocyte, white blood cell, eosinophil, and basophil counts were dramatically higher in the WT group than the Delta group. White blood cell, red blood cell, and basophil counts were significantly lower in the Delta group than the Omicron group. Spearman correlation analysis revealed a significant correlation between the NCT of viral RNA and mutation types of viral genes of WT and Omicron strains. Additionally, NCT was markedly negatively correlated with the frequencies of five mutations in Omicron strains (ORF1b:P1223L, ORF1b:R1315C, ORF1b:T2163I, ORF3a:T223I, and ORF6:D61L). CONCLUSIONS: This study indicates that five mutations in Omicron strains (ORF1b:P1223L/R1315C/T2163I, ORF3a:T223I and ORF6:D61L) shortened NCT in imported SARS-CoV-2 cases.

Differentiation and quantification of extracellular polymeric substances from microalgae and bacteria in the mixed culture.

Extracellular polymeric substances (EPS) play significant roles in the formation, function, and interactions of microalgal-bacteria consortia. Understanding the key roles of EPS depends on reliable extraction and quantification methods, but differentiating of EPS from microalgae versus bacteria is challenging. In this work, cation exchange resin (CER) and thermal treatments were applied for total EPS extraction from microalgal-bacteria mixed culture (MBMC), flow cytometry combined with SYTOX Green staining was applied to evaluate cell disruption during EPS extraction, and auto-fluorescence-based cell sorting (AFCS) was used to separate microalgae and bacteria in the MBMC. Thermal extraction achieved much higher EPS yield than CER, but higher temperature and longer time reduced cell activity and disrupted the cells. The highest EPS yield with minimal loss of cell activity and cell disruption was achieved using thermal extraction at 55℃ for 30 min, and this protocol gave good results for MBMC with different microalgae:bacteria (M:B) mass ratios. AFCS combined with thermal treatment achieved the most-efficient biomass differentiation and low EPS loss (<4.5 %) for the entire range of M:B ratios. EPS concentrations in bacteria were larger than in microalgae: 42.8 ± 0.4 mg COD/g TSS versus 9.19 ± 0.38 mg COD/g TSS. These findings document sensitive and accurate methods to extract and quantify EPS from microalgal-bacteria aggregates.

Ultrasound radiomics-based artificial intelligence model to assist in the differential diagnosis of ovarian endometrioma and ovarian dermoid cyst.

Background: Accurately differentiating between ovarian endometrioma and ovarian dermoid cyst is of clinical significance. However, the ultrasound appearance of these two diseases is variable, occasionally causing confusion and overlap with each other. This study aimed to develop a diagnostic classification model based on ultrasound radiomics to intelligently distinguish and diagnose the two diseases. Methods: We collected ovarian ultrasound images from participants diagnosed as patients with ovarian endometrioma or ovarian dermoid cyst. Feature extraction and selection were performed using the Mann-Whitney U-test, Spearman correlation analysis, and the least absolute shrinkage and selection operator (LASSO) regression. We then input the final features into the machine learning classifiers for model construction. A nomogram was established by combining the radiomic signature and clinical signature. Results: A total of 407 participants with 407 lesions were included and categorized into the ovarian endometriomas group (n = 200) and the dermoid cyst group (n = 207). In the test cohort, Logistic Regression (LR) achieved the highest area under curve (AUC) value (0.981, 95% CI: 0.963-1.000), the highest accuracy (94.8%), and the highest sensitivity (95.5%), while LightGBM achieved the highest specificity (97.1%). A nomogram incorporating both clinical features and radiomic features achieved the highest level of performance (AUC: 0.987, 95% CI: 0.967-1.000, accuracy: 95.1%, sensitivity: 88.0%, specificity: 100.0%, PPV: 100.0%, NPV: 88.0%, precision: 93.6%). No statistical difference in diagnostic performance was observed between the radiomic model and the nomogram (P > 0.05). The diagnostic indexes of radiomic model were comparable to that of senior radiologists and superior to that of junior radiologist. The diagnostic performance of junior radiologists significantly improved with the assistance of the model. Conclusion: This ultrasound radiomics-based model demonstrated superior diagnostic performance compared to those of junior radiologists and comparable diagnostic performance to those of senior radiologists, and it has the potential to enhance the diagnostic performance of junior radiologists.

Chiral Supramolecular Nanofibers Regulated Tumor-Derived Exosomes Secretion for Constructing an Anti-Tumor Extracellular Microenvironment.

Tumor-derived exosomes (TDEs) induced extracellular microenvironment has recently been validated to be critical for tumor progression and metastasis, however, remodeling it for oncotherapy still remains a major challenge due to difficulty in regulation of TDEs secretion. Herein, the supramolecular chiral nanofibers, composed of L/D -phenylalanine derivates (L/D-Phe) and linear hyaluronic acid (HA), are successfully employed to construct TDEs induced anti-tumor extracellular microenvironment. The left-handed L-Phe @HA nanofibers significantly inhibit TDEs secretion into extracellular microenvironment, which results in suppression of tumor proliferation and metastasis in vitro and vivo. Biological assays and theoretical modeling reveal that these results are mainly attributed to strong adsorption of the key exosomes transporters (Ras-related protein Rab-27A and synaptosome-associated protein 23) on left-handed L-Phe @HA nanofibers via enhanced stereoselective interaction, leading to degradation and phosphorylated dropping of exosomes transporters. Subsequently, transfer function of exosomes transporters is limited, which causes remarkable inhibition of TDEs secretion. These findings provide a promising novel insight of chiral functional materials to establish an anti-tumor extracellular microenvironment via regulation of TDEs secretion.

Epidemiology and antimicrobial resistance of Salmonella serovars Typhimurium and 4,[5],12:i- recovered from hospitalized patients in China.

Global emergence of multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium is a continuing challenge for modern healthcare. However, the knowledge, regarding the epidemiology of salmonellosis caused by the monophasic variant S. 4,[5],12:i:- in hospitalized patients, is limited in China. To bridge this gap, we carried out a retrospective study to determine the antimicrobial resistance, trends, and risk factors of S. Typhimurium and S. 4,[5],12:i:- (n = 329) recovered from patients in Zhejiang province between 2011 and 2019. The results showed that 90.57% (298/329) of the isolates were MDR; among them, 48.94% (161/329) and 12.46% (41/329) were phenotypically resistant to cephalosporins and fluoroquinolones, respectively, which are the drugs of choice used to treat salmonellosis in clinics. Additionally, we observed a higher incidence of infections among the young population (<5 years old). Notably, the higher prevalence of ST34 (sequence type 34) isolates, especially after 2014, with MDR (57.05%, 170/298) phenotype, and incidence of ST34 isolates co-harbouring mcr-1 (mobile colistin resistance gene) and blaCTX-M-14 (ß-lactamase gene) suggest an association between STs and drug resistance. Together, the increasing prevalence of MDR ST34 calls for enhanced monitoring strategies to mitigate the spread and dissemination of MDR clones of S. Typhimurium and S. 4,[5],12:i-. Our study provides improved knowledge about non-typhoid Salmonella (NTS) infections, which could help in the effective recommendation of antimicrobials in hospitalized patients.

Global research trends in tongue cancer from 2000 to 2022: bibliometric and visualized analysis.

OBJECTIVES: This study conducts a systematic bibliometric analysis of tongue cancer publications to identify key topics, hotspots, and research distribution. METHODS: We analyzed tongue cancer publications in the Web of Science core collection database, assessing their quantity and quality. We investigated contributors, including countries, affiliations, journals, authors, and categories, within collaborative networks. Additionally, we synthesized key research findings using various analytical techniques, such as alluvial flow, burstness analysis, cluster analysis, co-occurrence network of associations, and network layer overlay. RESULTS: From 2000 to 2022, this bibliometric study covers 2205 articles and reviews across 617 journals, involving 72 countries, 2233 institutions, and 11,266 authors. It shows consistent growth, particularly in 2016. Key contributors include China (499 publications), Karolinska Institute (84 publications), Oral Oncology (144 publications), and Tuula Salo (47 publications). Other notable contributors are the USA (16,747 citations), the National Cancer Institute (NCI) (2597 citations), and the Memorial Sloan-Kettering Cancer Center (MSK) (2231 citations). Additionally, there are significant teams led by Tuula Salo and Dalianis. We have identified six primary clusters: #0 apoptosis, #1 depth of invasion, #2 radiotherapy, #3 hpv, #4 tongue cancer, #5 oral cancer. The top ten highly cited documents primarily pertain to epidemiology, prognostic indicators in early-stage oral tongue cancer, and HPV. Additionally, we observed 16 reference clusters, with depth of invasion (#3), young patients (#4), and tumor budding (#6) gaining prominence since 2012, indicating sustained research interests. CONCLUSIONS: This analysis emphasizes the increasing scholarly interest in tongue cancer research. The bibliometric evaluation highlights pivotal recent research themes such as HPV, depth of invasion, tumor budding, and surgical margins. CLINICAL RELEVANCE: The bibliometric analysis highlights the key topics and studies which have shaped the understanding and management of tongue cancer.

Effects of Hydrophobic Biochar-Modified Landfill Soil Cover on Methane Oxidation.

Landfill cover soils play an important role in mitigating landfill methane (CH4) emissions. Incorporating biochar into the soil has proven effective in reducing CH4 emissions. However, the role of hydrophobic biochar in this context remains underexplored. This study investigated the CH4 removal efficiency of a biochar-modified landfill soil cover column (RB) and hydrophobic biochar-modified landfill soil cover column (RH) under varying CH4 influx gas concentrations (25 and 35%), simulated CH4 inflow rates (10, 15, and 20 ml/min), and temperatures (20, 25, 30, 35, and 40 °C). RH consistently outperformed RB in terms of CH4 removal efficiency under these experimental conditions. The optimal conditions for CH4 degradation by both RB and RH were observed at a CH4 influx gas concentration of 35%, a simulated CH4 inflow rate of 10 ml/min, and a temperature of ~30 °C. RH achieved a CH4 removal rate of up to 99.96%. In summary, the addition of hydrophobic biochar enhanced the air permeability and hydrophobicity of landfill cover soils, providing a promising alternative to conventional cover soils for reducing CH4 emissions from landfills.

Chiral Supramolecular Hydrogel Enhanced Transdermal Delivery of Sodium Aescinate to Modulate M1 Macrophage Polarization Against Lymphedema.

Sodium aescinate (SA) shows great potential for treating lymphedema since it can regulate the expression of cytokines in M1 macrophages, however, it is commonly administered intravenously in clinical practice and often accompanied by severe toxic side effects and short metabolic cycles. Herein, SA-loaded chiral supramolecular hydrogels are prepared to prove the curative effects of SA on lymphedema and enhance its safety and transdermal transmission efficiency. In vitro studies demonstrate that SA- loaded chiral supramolecular hydrogels can modulate local immune responses by inhibiting M1 macrophage polarization. Typically, these chiral hydrogels can significantly increase the permeability of SA with good biocompatibility due to the high enantioselectivity between chiral gelators and stratum corneum and L-type hydrogels are found to have preferable drug penetration over D-type hydrogels. In vivo studies show that topical delivery of SA via chiral hydrogels results in dramatic therapeutic effects on lymphedema. Specifically, it can downregulate the level of inflammatory cytokines, reduce the development of fibrosis, and promote the regeneration of lymphatic vessels. This study initiates the use of SA for lymphedema treatment and for the creation of an effective chiral biological platform for improved topical administration.

Mass Flow and Metabolic Pathway of Nonaeration Greywater Treatment in an Oxygenic Microalgal-Bacterial Biofilm.

A symbiotic microalgal-bacterial biofilm can enable efficient carbon (C) and nitrogen (N) removal during aeration-free wastewater treatment. However, the contributions of microalgae and bacteria to C and N removal remain unexplored. Here, we developed a baffled oxygenic microalgal-bacterial biofilm reactor (MBBfR) for the nonaerated treatment of greywater. A hydraulic retention time (HRT) of 6 h gave the highest biomass concentration and biofilm thickness as well as the maximum removal of chemical oxygen demand (94.8%), linear alkylbenzenesulfonates (LAS, 99.7%), and total nitrogen (97.4%). An HRT of 4 h caused a decline in all of the performance metrics due to LAS biotoxicity. Most of C (92.6%) and N (95.7%) removals were ultimately associated with newly synthesized biomass, with only minor fractions transformed into CO2 (2.2%) and N2 (1.7%) on the function of multifarious-related enzymes in the symbiotic biofilm. Specifically, microalgae photosynthesis contributed to the removal of C and N at 75.3 and 79.0%, respectively, which accounted for 17.3% (C) and 16.7% (N) by bacteria assimilation. Oxygen produced by microalgae favored the efficient organics mineralization and CO2 supply by bacteria. The symbiotic biofilm system achieved stable and efficient removal of C and N during greywater treatment, thus providing a novel technology to achieve low-energy-input wastewater treatment, reuse, and resource recovery.

Prussian blue analogues of Ni-Co-MoS2 nanozymes with high peroxidase like activity for sensitive detection of glyphosate and copper.

The rational development of efficient nanozymes for the colorimetric detection of targets is still challenging. Herein, Prussian blue analogues of Ni-Co-MoS2 nano boxes were fabricated for colorimetric detection of glyphosate and copper ions owing to its peroxidase like activity. At the sensing system, the Ni-Co-MoS2 nano boxes display high peroxidase activity, which could catalytically oxidize the colourless TMB to blue colour oxTMB. In presence of glyphosate in this sensing system the blue colour is diminished, ascribed to the inhibit the catalytic activity of Ni-Co-MoS2 nano boxes. Concurrently, the addition of copper ion, which result in blue colour was reappear due to the generation of glyphosate-copper complex formation. The Ni-Co-MoS2 nano boxes based colorimetric sensing platform was developed to sensitive detection of glyphosate and copper ions with low detection limit of 3 nM for glyphosate and 3.8 nM for copper. This method also displays satisfactory outcomes from real samples analysis and its good accuracy. Therefore, this work provides a great potential for rapid detection of the targets from the environments.

Poly-adenine-mediated tetrahedral DNA nanostructure with multiple target-recognition sites for ultrasensitive and rapid electrochemical detection of Aflatoxin B1.

Tetrahedral DNA nanostructures (TDNs) are widely used in the development of electrochemical biosensors due to their structural stability, programmability, and strong interfacial orderliness. However, the complex modifications on the electrode and the single vertex target recognition of the TDNs limit their applications in electrochemical biosensing. Herein, we developed a universal detection system based on a novel polyadenine-based tetrahedral DNA nanostructure (ATDN) using Aflatoxin B1 (AFB1) as the model target for analysis. In the absence of target AFB1, the signal probes (SP) modified with ferrocene would be anchored by five aptamers on ATDN. The target capture by aptamers led to a release of SP from the electrode surface, resulting in a significant reduction of the electrochemical signal. This new nanostructure was not only dispensed with multi-step electrode modifications and strong mechanical rigidity but also had five modification sites which enhanced the detection sensitivity for the target. As a result, this biosensor shows good analytical performance in the linear range of 1 fg mL-1 to 1 ng mL-1, exhibiting a low detection limit of 0.33 fg mL-1. Satisfactory accuracy has also been demonstrated through good recoveries (95.2%-98.9%). The proposed new tetrahedral DNA nanostructure can provide a more rapid and sensitive alternative to previous electrochemical sensors based on the conventional TDN. Since DNA sequences can be designed flexibly, the sensing platform in this strategy can be extended to detect various targets in different fields.

An integrated nationwide genomics study reveals transmission modes of typhoid fever in China.

IMPORTANCE: Typhoid fever is a life-threatening disease caused by Salmonella enterica serovar Typhi, resulting in a significant disease burden across developing countries. Historically, China was very much close to the global epicenter of typhoid, but the role of typhoid transmission within China and among epicenter remains overlooked in previous investigations. By using newly produced genomics on a national scale, we clarify the complex local and global transmission history of such a notorious disease agent in China spanning the most recent five decades, which largely undermines the global public health network.

Biofilm bioactivity affects nitrogen metabolism in a push-flow microalgae-bacteria biofilm reactor during aeration-free greywater treatment.

Non-aeration microalgae-bacteria biofilm has attracted increasing interest for its application in low cost wastewater treatment. However, it is unclear the quantified biofilm characteristics dynamics and how biofilm bioactivity affects performance and nitrogen metabolisms during wastewater treatment. In this work, a push-flow microalgae-bacteria biofilm reactor (PF-MBBfR) was developed for aeration-free greywater treatment. Comparatively, organic loading at 1.27 ± 0.10 kg COD/(m3⋅d) gave the highest biofilm concentration, density, specific oxygen generation (SOGR) and consumption rates (SOCR), and pollutants removal rates. Contributed to low residual linear alkylbenzene sulfonates and bioactivity, reactor downstream showed low bacteria and protein concentrations and SOCR (12.8 mg O2/g TSS·h), but high microalgae, carbohydrate, biofilm density, SOGR (49.4 mg O2/g TSS·h) and pollutants removal rates. Dissolved organic nitrogen (DON) showed higher molecular weight, CHONS and fraction with 4 atoms of N in reactor upstream. Most of nitrogen was fixed to newly synthesized biomass during assimilation process by related functional enzymes, minor contributed to denitrification due to low N2 emission. High nitrogen assimilation by microalgae showed high SOGR, which favored efficient multiple pollutants removal and reduced DON emission. Our findings favor the practical application of PF-MBBfR based on biofilm bioactivity, enhancing efficiency and reducing DON emission for low- energy-input wastewater treatment.

Endophyte inoculation enhanced microbial metabolic function in the rhizosphere benefiting cadmium phytoremediation by Phytolaccaacinosa.

Microbial metabolic activities in rhizosphere soil play a critical role in plant nutrient utilization and metal availability. However, its specific characteristics and influence on endophyte assisted phytoremediation remains unclear. In this study, an endophyte strain Bacillus paramycoides (B. paramycoides) was inoculated in the rhizosphere of Phytolacca acinosa (P. acinosa), and microbial metabolic characteristics of rhizosphere soils were analyzed using Biolog system to investigate how they influence phytoremediation performance of different types of cadmium contaminated soil. The results indicated that endophyte B. paramycoides inoculation enhanced bioavailable Cd percentage by 9-32%, resulting in the increased Cd uptake (32-40%) by P. acinosa. With endophyte inoculation, the utilization of carbon sources was significantly promoted by 4-43% and the microbial metabolic functional diversity increased by 0.4-36.8%. Especially, B. paramycoides enhanced the utilization of recalcitrant substrates carboxyl acids, phenolic compounds and polymers by 48.3-225.6%, 42.4-65.8% and 15.6-25.1%, respectively. Further, the microbial metabolic activities were significant correlated with rhizosphere soil microecology properties and impact phytoremediation performance. This study provided new insight into the microbial processes during endophyte assisted phytoremediation.

Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.

Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.

Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology.

BACKGROUND: Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP). METHODS: The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment. RESULTS: Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe. Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia. Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD. CONCLUSION: These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder.