Recent advances in the exploration of oxazolidinone scaffolds from compound development to antibacterial agents and other bioactivities.

Bacterial infections cause a variety of life-threatening diseases, and the continuous evolution of drug-resistant bacteria poses an increasing threat to current antimicrobial regimens. Gram-positive bacteria (GPB) have a wide range of genetic capabilities that allow them to adapt to and develop resistance to practically all existing antibiotics. Oxazolidinones, a class of potent bacterial protein synthesis inhibitors with a unique mechanism of action involving inhibition of bacterial ribosomal translation, has emerged as the antibiotics of choice for the treatment of drug-resistant GPB infections. In this review, we discussed the oxazolidinone antibiotics that are currently on the market and in clinical development, as well as an updated synopsis of current advances on their analogues, with an emphasis on innovative strategies for structural optimization of linezolid, structure-activity relationship (SAR), and safety properties. We also discussed recent efforts aimed at extending the activity of oxazolidinones to gram-negative bacteria (GNB), antitumor, and coagulation factor Xa. Oxazolidinone antibiotics can accumulate in GNB by a conjugation to siderophore-mediated ß-lactamase-triggered release, making them effective against GNB.

Engineered hsa-miR-455-3p-Abundant Extracellular Vesicles Derived from 3D-Cultured Adipose Mesenchymal Stem Cells for Tissue-Engineering Hyaline Cartilage Regeneration.

Efforts are made to enhance the inherent potential of extracellular vesicles (EVs) by utilizing 3D culture platforms and engineered strategies for functional cargo-loading. Three distinct types of adipose mesenchymal stem cells-derived EVs (ADSCs-EVs) are successfully isolated utilizing 3D culture platforms consisting of porous gelatin methacryloyl (PG), PG combined with sericin methacryloyl (PG/SerMA), or PG combined with chondroitin sulfate methacryloyl (PG/ChSMA). These correspond to PG-EVs, PG/SerMA-EVs, and PG/ChSMA-EVs, respectively. Unique microRNA (miRNA) profiles are observed in each type of ADSCs-EVs. Notably, PG-EVs encapsulate higher levels of hsa-miR-455-3p and deliver more hsa-miR-455-3p to chondrocytes, which results in the activation of the hsa-miR-455-3p/PAK2/Smad2/3 axis and the subsequent hyaline cartilage regeneration. Furthermore, the functionality of PG-EVs is optimized through engineered strategies, including agomir/lentivirus transfection, electroporation, and Exo-Fect transfection. These strategies, referred to as Agomir-EVs, Lentivirus-EVs, Electroporation-EVs, and Exo-Fect-EVs, respectively, are ranked based on their efficacy in encapsulating hsa-miR-455-3p, delivering hsa-miR-455-3p to chondrocytes, and promoting cartilage formation via the hsa-miR-455-3p/PAK2/Smad2/3 axis. Notably, Exo-Fect-EVs exhibit the highest efficiency. Collectively, the 3D culture conditions and engineered strategies have an impact on the miRNA profiles and cartilage regeneration capabilities of ADSCs-EVs. The findings provide valuable insights into the mechanisms underlying the promotion of cartilage regeneration by ADSCs-EVs.

High-performance prediction of epilepsy surgical outcomes based on the genetic neural networks and hybrid iEEG marker.

Accurately identification of the seizure onset zone (SOZ) is pivotal for successful surgery in patients with medically refractory epilepsy. The purpose of this study is to improve the performance of model predicting the epilepsy surgery outcomes using genetic neural network (GNN) model based on a hybrid intracranial electroencephalography (iEEG) marker. We extracted 21 SOZ related markers based on iEEG data from 79 epilepsy patients. The least absolute shrinkage and selection operator (LASSO) regression was employed to integrated seven markers, selected after testing in pairs with all 21 biomarkers and 7 machine learning models, into a hybrid marker. Based on the hybrid marker, we devised a GNN model and compared its predictive performance for surgical outcomes with six other mainstream machine-learning models. Compared to the mainstream models, underpinning the GNN with the hybrid iEEG marker resulted in a better prediction of surgical outcomes, showing a significant increase of the prediction accuracy from approximately 87% to 94.3% (P = 0.0412). This study suggests that the hybrid iEEG marker can improve the performance of model predicting the epilepsy surgical outcomes, and validates the effectiveness of the GNN in characterizing and analyzing complex relationships between clinical data variables.

Design, synthesis and antibacterial evaluation of low toxicity amphiphilic-cephalosporin derivatives.

Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 µg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of reactive oxygen species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC50 > 128 µg/mL. These findings suggest that 2d is a promising drug candidate for treating bacterial infections.

Time-Aware Dual LSTM Neural Network with Similarity Graph Learning for Remote Sensing Service Recommendation.

Technological progress has led to significant advancements in Earth observation and satellite systems. However, some services associated with remote sensing face issues related to timeliness and relevance, which affect the application of remote sensing resources in various fields and disciplines. The challenge now is to help end-users make precise decisions and recommendations for relevant resources that meet the demands of their specific domains from the vast array of remote sensing resources available. In this study, we propose a remote sensing resource service recommendation model that incorporates a time-aware dual LSTM neural network with similarity graph learning. We further use the stream push technology to enhance the model. We first construct interaction history behavior sequences based on users' resource search history. Then, we establish a category similarity relationship graph structure based on the cosine similarity matrix between remote sensing resource categories. Next, we use LSTM to represent historical sequences and Graph Convolutional Networks (GCN) to represent graph structures. We construct similarity relationship sequences by combining historical sequences to explore exact similarity relationships using LSTM. We embed user IDs to model users' unique characteristics. By implementing three modeling approaches, we can achieve precise recommendations for remote sensing services. Finally, we conduct experiments to evaluate our methods using three datasets, and the experimental results show that our method outperforms the state-of-the-art algorithms.

Soil fungal community is more sensitive than bacterial community to modified materials application in saline-alkali land of Hetao Plain.

Soil salinization has become a major challenge that severely threatens crop growth and influences the productivity of agriculture. It is urgent to develop effective management measures to improve saline-alkali soil. Thus, in this study, soil properties, microbial communities, and function under desulfurization gypsum (DE), soil amendment (SA), farm manure (FA), and co-application of desulfurization gypsum, soil amendment, and farm manure (TA) in a field experiment were examined by high-throughput sequencing. The results showed that the application of modified materials is an effective approach in improving saline-alkali soil, especially TA treatment significantly increased the content of available phosphorus (AP), available potassium (AK), soil organic matter (SOM), and alkaline hydrolysis nitrogen (AHN) and decreased pH, bulk density (BD), and electrical conductivity (EC). The application of modified materials resulted in notable enhancement in fungal diversity and altered the composition and structure of the fungal community. Conversely, the effect on the bacterial community was comparatively minor, with changes limited to the structure of the community. Regarding the fungal community composition, Ascomycota, Mortierellomycota, and Basidiomycota emerged as the dominant phyla across all treatments. At each taxonomic level, the community composition exhibited significant variations in response to different modified materials, resulting in divergent soil quality. The TA treatment led to a decrease in Mortierellomycota and an increase in Ascomycota, potentially enhancing the ability to decompose organic matter and facilitate soil nutrient cycling. Additionally, the sensitivity of fungal biomarkers to modified materials surpassed that of the bacterial community. The impact of modified materials on soil microbial communities primarily stemmed from alterations in soil EC, AP, AK, and SOM. FUNGuild analysis indicated that the saprotroph trophic mode group was the dominant component, and the application of modified materials notably increased the symbiotroph group. PICRUSt analysis revealed that metabolism was the most prevalent functional module observed at pathway level 1. Overall, the application of modified materials led to a decrease in soil EC and an increase in nutrient levels, resulting in more significant alterations in the soil fungal community, but it did not dramatically change the soil bacterial community. Our study provides new insights into the application of modified materials in increasing soil nutrients and altering soil microbial communities and functions and provides a better approach for improving saline-alkali soil of Hetao Plain.

Effective ciprofloxacin cationic antibacterial agent against persister bacteria with low hemolytic toxicity.

With the widespread use of antibiotics, bacterial resistance has developed rapidly. To make matters worse, infections caused by persistent bacteria and biofilms often cannot be completely eliminated, which brings great difficulties to clinical medication. In this work, three series of quinolone pyridinium quaternary ammonium small molecules were designed and synthesized. Most of the compounds showed good antibacterial activity against Gram-positive bacteria (S. aureus and E. faecalis) and Gram-negative bacteria (E. coli and S. maltophilia). The activity of the para-pyridine quaternary ammonium salt was better than that of the meta-pyridine. 3f was the optimal compound with good stability in body fluids and was unlikely to induce bacterial resistance. The hemolysis rate of erythrocytes at 1280 µg/mL for 3f was only 5.1%. Encouragingly, 3f rapidly killed bacteria within 4 h at 4 × MIC concentration and was effective in killing persistent bacteria in biofilms. The antibacterial mechanism experiments showed that 3f could cause disorder of bacterial membrane potential, increase bacterial membrane permeability, dissolve and destroy the membrane. Incomplete bacterial membranes lead to leakage of bacterial genetic material, concomitant production of ROS, and bacterial death due to these multiple effects.

Factors influencing willingness to participate in ophthalmic clinical trials and strategies for effective recruitment.

AIM: To explore the factors influencing individuals' willingness to participate in ophthalmic clinical trials. METHODS: A questionnaire survey was conducted from January to April 2021 among patients and their family members at Zhongshan Ophthalmic Center, Sun Yat-sen University, in Guangzhou, China. The survey gathered data on respondents' willingness, demographic and socioeconomic profiles, as well as their reasons and concerns regarding engagement in clinical trials. RESULTS: Of the 1078 residents surveyed (mean age 31.2±13.1y; 65.8% females) in Guangzhou, 749 (69.5%) expressed a willingness to participate in future ophthalmic clinical trials. Specific characteristics associated with greater willingness included a younger age, lower annual income, higher education, prior participation experience, previous ophthalmic treatment, and a better understanding of clinical trials. With the exception of age, these characteristics were significantly linked to a higher willingness. The primary barrier to participation, expressed by 64.8% of those willing and 54.4% of those unwilling, was "Uncertain efficacy". In terms of motivations, the willing group ranked "Better therapeutic benefits" (35.0%), "Professional monitoring" (34.3%), and "Trust in healthcare professionals" (33.1%) as their top three reasons, whereas the unwilling participants indicated "Full comprehension of the protocol" (46.2%) as the key facilitator. CONCLUSION: This study reveals a substantial willingness to participate in ophthalmic clinical trials and demonstrates the predictive role of demographic and socioeconomic factors. Variations in motivators and concerns between willing and unwilling participants highlight the significance of tailored recruitment strategies. Importantly, the need for and trust in healthcare professionals stand out as powerful motivations, underscoring the importance of enhancing physician-patient relationships, adopting patient-centered communication approaches, and addressing individualized needs to improve accrual rates.

Omega-3 supplementation improves depressive symptoms, cognitive function and niacin skin flushing response in adolescent depression: A randomized controlled clinical trial.

BACKGROUND: Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (ω3) polyunsaturated fatty acids are a promising adjuvant therapy in adult depression. The primary objective of this study was to investigate the efficacy of adjuvant ω3 treatment on depressive symptoms in adolescent depression. Secondarily, we explored the effects of ω3 on cognitive function and memory and niacin skin flushing response (NSFR), as their robust associations with adolescent depression. METHODS: A total of 71 adolescents with depression (aged 13-24; 59.2 % female) were randomly assigned to receive ω3 plus Paxil (n = 34) or Paxil alone (n = 37) for 12 weeks. Primary outcome was depression severity according to scores on Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes were cognitive function and memory, and NSFR. RESULTS: Significant improvements in depressive symptoms over time (p = 0.00027 at week 12) were observed in the ω3 + Paxil group compared with Paxil group. Additionally, in the ω3 + Paxil group, significant improvements in memory over time, and greater cognitive function and NSFR were also observed compared with the Paxil group; the NSFR was negatively correlated with MADRS scores at baseline. LIMITATIONS: The trial was open label; thus, the outcome measures should be viewed as preliminary since inherent bias in outcomes due to the potential of a placebo effect. CONCLUSIONS: Our results demonstrate that adjuvant ω3 treatment is effective for reducing depressive symptoms as well as improving cognitive function, memory and the NSFR; these results suggest ω3 is a promising adjuvant treatment for adolescent depression.

Immunogenicity of mucosal COVID-19 vaccine candidates based on the highly attenuated vesicular stomatitis virus vector (VSVMT) in golden syrian hamster.

COVID-19 is caused by coronavirus SARS-CoV-2. Current systemic vaccines generally provide limited protection against viral replication and shedding within the airway. Recombinant VSV (rVSV) is an effective vector which inducing potent and comprehensive immunities. Currently, there are two clinical trials investigating COVID-19 vaccines based on VSV vectors. These vaccines were developed with spike protein of WA1 which administrated intramuscularly. Although intranasal route is ideal for activating mucosal immunity with VSV vector, safety is of concern. Thus, a highly attenuated rVSV with three amino acids mutations in matrix protein (VSVMT) was developed to construct safe mucosal vaccines against multiple SARS-CoV-2 variants of concern. It demonstrated that spike protein mutant lacking 21 amino acids in its cytoplasmic domain could rescue rVSV efficiently. VSVMT indicated improved safeness compared with wild-type VSV as the vector encoding SARS-CoV-2 spike protein. With a single-dosed intranasal inoculation of rVSVΔGMT-SΔ21, potent SARS-CoV-2 specific neutralization antibodies could be stimulated in animals, particularly in term of mucosal and cellular immunity. Strikingly, the chimeric VSV encoding SΔ21 of Delta-variant can induce more potent immune responses compared with those encoding SΔ21 of Omicron- or WA1-strain. VSVMT is a promising platform to develop a mucosal vaccine for countering COVID-19.

Three new cadinene-type sesquiterpenoids from the aerial parts of Ageratina adenophora.

Three new cadinene sesquiterpenoids 1-3, were isolated from the aerial sections of Ageratina adenophora using various chromatographic techniques. Their structures were characterised by comprehensive spectroscopic investigations (including 1D, 2D-NMR and HRMS), and single crystal X-ray diffraction. The cytotoxic activity of new compounds 1-3 were evaluated by testing in vitro tumour growth inhibitory rate against five human tumour cell lines, HL-60, A-549, SMMC-7721, MDA-MB-231, and SW480.

The estimated glomerular filtration rate was U-shaped associated with abdominal aortic calcification in US adults: findings from NHANES 2013-2014.

Objectives: The high incidence of abdominal aortic calcification (AAC) is well-documented in individuals with severe renal function decline. However, there is limited research on the historical relationship between estimated glomerular filtration rate (eGFR) and the risk of AAC occurrence in the general population undergoing routine medical examinations. The main objective of this study was to investigate the historical relationship between eGFR and AAC in the general population of the United States. Methods: We performed a cross-sectional study using the National Health and Nutrition Examination Survey 2013-2014 database. Weighted multivariate linear regression models were used to estimate the associations of eGFR with AAC score. Smooth curve fitting and two-piecewise linear regression were employed to explore the potential non-linear relationship. Results: A total of 2,978 participant (48.22% were male) aged 40-80 years were included in this study. The fully-adjusted model demonstrated a negative correlation between eGFR and AAC score (ß = -0.015, 95% CI: -0.023 to -0.006). However, when applying the smooth curve fitting method, a U-shaped relationship was identified, and the inflection point was calculated at 76.43 ml/min/1.73 m2 using the two-piecewise linear regression model. Conclusions: There was a U-shaped association between eGFR and AAC score in general US adults, with an inflection point at about 76.43 ml/min/1.73 m2.

Comparative study on main compounds and hypoglycemic effects of dispensing granules of Coptidis Rhizoma and Scutellaria-Coptis herb couple with traditional decoction.

BACKGROUND: The clinical applications of dispensing granules (DG) have increased dramatically. However, it is controversial whether the DG has the same quality and efficacy compared with traditional decoction (TD). In this study, the contents of main compounds, hypoglycemic effects, and potential mechanism of Coptidis Rhizoma (CR) and Scutellaria-coptis (SC), constituted of a 1:1 mixture of CR and Scutellariae Radix (SR), in the forms of TD and DG were compared. METHODS: The quantitative analysis was performed on an UPLC-PDA method. The 6-weeks-old male db/db mice were used as Type 2 Diabetes Mellitus (T2DM) mouse modle to investigate the antidiabetic effects of CR and SC in TD form (CR TD and SC TD), as well as CR and SC in DG form (CR DG and SC DG). RESULTS: The total content of five alkaloids in CR TD ranged from 71.00 to 78.62 mg, whereas in CR DG it ranged from 38.77 to 53.68 mg in CR DG per 1 g of decoction pieces. Compared to CR TD, CR DG exhibited a 36% reduction on average. For SC samples, the precipitation occurred in the processing of TD but not in the DG, and the relative ratio of alkaloids to flavonoids was determined to be 1:1 in TD and 1:2 in DG. Furthermore, the animal experiments showed that the CR DG (equivalent to 3 g decoction pieces/kg) had almost the same hypoglycemic effect as CR TD when they were administered for 6 weeks. Compared with SC DG (equivalent to 6 g decoction pieces/kg), SC TD showed a better trend in ameliorating T2DM via ameliorating pancreatic structure and function, and activating Akt/AMPK/GLUT4 signaling pathways. CONCLUSION: This study indicated that the contents of main compounds were generally higher in CR TD than CR DG originated from the same raw materials. Additionally, changes in the contents of the primary components validated that the compound interactions are exclusive to SC TD during co-decoction, rather than SC DG. The disparate prossing of SC DG and SC TD caused differences both in chemical composition and hypoglycemic effect, suggesting that the substitutability of DG and TD requires further research.

An Investigation of Pharmacokinetic Interaction of Vericiguat with Apigenin based on a Newly Developed Ultra-performance Liquid Chromatography-tandem Mass Spectrometry Assay.

BACKGROUND: Vericiguat, as a new stimulator of soluble guanylate cyclase (sGC), was recently approved as a first-in-class treatment for reducing risks in patients with ejection fraction less than 45 percent and heart failure (HF) in the USA. OBJECTIVE: The main aim of the present experiment was to establish an acceptable, sensitive assay based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for quantitatively analyzing the plasma concentration levels of vericiguat in rats, and to further evaluate the effect of apigenin on the metabolism of vericiguat in vivo. METHOD: In sample processes, acetonitrile was finally chosen for quickly precipitating protein. The levels of vericiguat in plasma were analyzed by a Xevo TQ-S triple quadrupole tandem mass spectrometry (Milford, MA, USA) in a positive ion mode. RESULTS: The scope of the calibration standard for vericiguat ranged from 0.5 to 1000 ng/mL, where a great linearity was acceptable. The lower limit of quantification (also called LLOQ) of vericiguat presented the sensitivity of this assay was evaluated as low as 0.5 ng/mL. Additionally, selectivity, accuracy and precision, extraction recovery, matrix effect, and stability were all verified. Subsequently, this approach also supported to assess the plasmatic concentrations of vericiguat from an interaction survey on herb-- drug, in which oral administration of apigenin (20 mg/kg) obviously increased the plasmatic levels of vericiguat and altered the pharmacokinetics of vericiguat in rats. CONCLUSION: These results would help us to further understand the pharmacokinetic properties of vericiguat when co-administration with apigenin, and to avoid unexpected clinical risks in the future.

Potential roles of tumor microenvironment in gefitinib-resistant non-small cell lung cancer: A narrative review.

During the course of treating non-small cell lung cancer (NSCLC) with epithelial growth factor receptor (EGFR) mutant, gefitinib resistance (GR) is unavoidable. As the environment for tumor cells to grow and survive, tumor microenvironment (TME) can significantly affect therapeutic response and clinical outcomes, offering new opportunities for addressing GR. Dynamic changes within the TME were identified during the treatment of gefitinib, suggesting the close relationship between TME and GR. Various dynamic processes like angiogenesis, hypoxia-pathway activation, and immune evasion can be blocked so as to synergistically enhance the therapeutic effects of gefitinib or reverse GR. Besides, cellular components like macrophages can be reprogrammed for the same purpose. In this review, we summarized recently proposed therapeutic targets to provide an overview of the potential roles of TME in treating gefitinib-resistant NSCLC, and discussed the difficulty of applying these targets in cancer treatment.

[Spatial-temporal Variations and Pollution Assessment of Heavy Metals in Sediments of Qionghai Lake in Xichang City].

Based on the analysis of the total concentrations of 10 metals in the sediment core and total concentrations and chemical fractions of seven metals in the surface sediments of Qionghai Lake in Xichang City, Sichuan Province, the spatial-temporal characteristics of metal accumulation and pollution over the past century and the potential ecological risk of metals in surface sediments were studied. Before the 1970s, metal concentrations in the sediment core were stable. The total concentrations of Al, Fe, K, and Cr in the sediment core exhibited visible peaks in the 1970s, which were related to the enhanced input of fine-grained topsoil caused by increasing precipitation, lake reclamation, and deforestation. Since the 1990s, the total concentrations of Al, Fe, K, and Cr decreased with the reduced topsoil erosion, whereas the total concentrations of As, Cd, Cu, Pb, and Zn gradually increased or remained stable. The enrichment factor results showed that Cd, Pb, and Zn were the main contaminants, with Cd as the typical contaminant in the sediment core. The Cd contamination started in the 1960s and has remained at a moderate level since the 1990s. In the surface sediments, the total concentrations of Cd were higher in the northwest lake area, and no visible spatial concentration trends of the other metals were displayed. The bioavailable fractions of Cd, Pb, and Zn accounted for 95%, 63%, and 48% of the total metal concentrations on average. Among the bioavailable fractions, Cd was mainly in the acid-soluble fraction, and Pb and Zn were mainly in the reducible and oxidized fractions. The bioavailable fractions of the other metals were less than 27%. The results of total concentrations and bioavailable fractions of metals revealed that Pb and Zn in the surface sediments were slightly or moderately contaminated, and Cd was moderately contaminated on average. Cd contamination was at a severe level in the northwest lake area. The concentrations of anthropogenic Cd, Pb, and Zn in the surface sediments estimated from the total and bioavailable concentrations were comparable (P>0.05), indicating that anthropogenic metals primarily existed in bioavailable fractions in the sediment. Integrating the assessment results from sediment quality guidelines, potential ecological risk index, and chemical forms of metals, Cd in surface sediments may pose a high ecological risk, whereas the other metals has a low ecological risk.

Establishment of a sensitive UPLC-MS/MS method to quantify safinamide in rat plasma.

A fast, simple, and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established for the quantification of safinamide in rat plasma. Plasma samples were treated with acetonitrile for protein precipitation, and diazepam was used as an internal standard (IS). The analytes were separated on an Acquity UPLC C18 (2.1 mm × 50 mm, 1.7 µm) chromatographic column with gradient elution using a mobile phase (0.1% formic acid-acetonitrile). Then, the eluates were detected by electrospray ionization (ESI) in positive ion mode. The analytes were quantified by multiple reaction monitoring (MRM) using the transition m/z 303.3→215.0 of safinamide and m/z 285.0→154.0 of IS. Safinamide had good linearity in the concentration range of 1.0-2000 ng/mL, and the lower limit of quantitation (LLOQ) was 1.0 ng/mL. The intra- and inter-day precision and accuracy of safinamide were less than 7.63%, while the average recovery rate was 92.98%-100.29%. The method was validated to be stable and had low noise, short chromatographic run time, wide linear range, small sample volumes, low sample injection volumes, and high sensitivity. Therefore, it can be used in pharmacokinetics and preclinical and clinical studies.

SIRT1-dependent deacetylation of Txnip H3K9ac is critical for exenatide-improved diabetic kidney disease.

Glucagon-like peptide 1 receptor agonist exenatide (exendin-4) has potential protective capabilities against diabetic kidney disease (DKD). However, the underlying mechanism has not been fully elucidated. The expression of thioredoxin-interacting protein (Txnip) is upregulated during DKD progression by histone acetylation. Sirtuin 1 (SIRT1) is a deacetylase and is decreased in DKD, which indicates that it may regulate Txnip in this disease. Here, we used whole-body heterozygous Sirt1 knockout (Sirt1+/-) and kidney-specific Sirt1 knockout (KSK) mice to investigate whether SIRT1 regulates Txnip via histone deacetylation in DKD and exenatide-alleviated DKD. Exenatide substantially improved renal pathological damage, decreased the albumin-to-creatinine ratio (ACR), upregulated SIRT1 expression, and downregulated Txnip expression in kidneys of high-fat diet-treated C57BL/6J mice. However, these effects diminished in Sirt1+/- and KSK mice under exenatide treatment. The downregulation of Txnip expression by exendin-4 in high-glucose-treated SV40 MES13 cells was hampered during Sirt1 knockdown. These results demonstrate that kidney SIRT1 is indispensable in exenatide-improved DKD and downregulation of Txnip expression. Exendin-4 mechanistically downregulated Txnip histone 3 lysine 9 acetylation (H3K9ac) in a SIRT1-dependent manner and decreased spliced X-box binding protein 1 (XBP1s) recruitment to the Txnip promoter. These findings provide epigenetic evidence elucidating the specific mechanism for exenatide-mediated DKD alleviation and highlight the importance of Txnip as a promising therapeutic target for DKD.

Identifying circulating biomarkers for major depressive disorder.

Objective: To date, the current diagnosis of major depressive disorder (MDD) still depends on clinical symptomatologic criteria, misdiagnosis and ineffective treatment are common. The study aimed to explore circulating biomarkers for MDD diagnosis. Methods: A high-throughput antibody array technology was utilized to detect 440 circulating cytokines in eight MDD patients and eight age-and gender-matched healthy controls. LASSO regression was conducted for MDD-related characteristic proteins selection. Enzyme-linked immunosorbent assay (ELISA) was used to validate the characteristic proteins in 40 MDD patients and 40 healthy controls. Receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic values of characteristic proteins for discriminating MDD patients from healthy controls. Correlations between the levels of characteristic proteins and depression severity (HAMD-17 scores) were evaluated using linear regression. Results: The levels of 59 proteins were found aberrant in MDD patients compared with healthy controls. LASSO regression found six MDD-related characteristic proteins including insulin, CD40L, CD155, Lipocalin-2, HGF and LIGHT. ROC curve analysis showed that the area under curve (AUC) values of six characteristic proteins were more than 0.85 in discriminating patients with MDD from healthy controls. Furthermore, significant relationship was found between the levels of insulin, CD155, Lipocalin-2, HGF, LIGHT and HAMD-17 scores in MDD group. Conclusion: These results suggested that six characteristic proteins screened from 59 proteins differential in MDD may hold promise as diagnostic biomarkers in discriminating patients with MDD. Among six characteristic proteins, insulin, CD155, Lipocalin-2, HGF and LIGHT might be useful to estimate the severity of depressive symptoms.

Antidepressant polyprenylated acylphloroglucinols from Hypericum ascyron.

Phytochemical investigation on the 90% EtOH extract of the air-dried aerial parts of Hypericum ascyron resulted in the isolation of three new polycyclic polyprenylated derivatives ascyronines A-C (1-3). Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. All the polycyclic polyprenylated acylphloroglucinols were evaluated for their antidepressant activity by inhibiting the reuptake of tritiated serotonin ([3H]-5-HT) and noradrenalinet ([3H]-NE) in rat brain synaptosomes. Compounds 2 and 3 exhibited weak antidepressant activities in the [3H]-5-HT mode.