Construction of glutathione-responsive paclitaxel prodrug nanoparticles for image-guided targeted delivery and breast cancer therapy.

Paclitaxel (PTX) remains an essential drug in the treatment of breast cancer. To improve metabolic stability and real-time monitoring of drug location, we develop a visualized nano-prodrug. Novel hyaluronic acid (HA)-coated glutathione (GSH)-sensitive chitosan (CS)-based nano-prodrug (HA/TPE-CS-SS-PTX NPs) with aggregation-induced emission effects (AIE) were accomplished. The prodrug NPs (drug loading 29.32%, particle size 105 nm, regular sphericity) exhibit excellent fluorescence stability. The prodrug NPs could target tumor cells with high expression of CD44 and decompose in the presence of high concentrations of glutathione. In vitro evaluations revealed that the prodrug NPs have significant cytotoxicity on 4T1 cells, and due to their excellent AIE characteristics, their position in cells can be tracked. Moreover, the prodrug NPs also shown superior anti-tumor effects in vivo experimental. Overall, the HA/TPE-CS-SS-PTX NPs we constructed have excellent bio-imaging capabilities and can be served as a potential nanomedicine for PTX delivery against breast cancer.

Exploring the role and mechanism of hyperoside against cardiomyocyte injury in mice with myocardial infarction based on JAK2/STAT3 signaling pathway.

BACKGROUND: Myocardial infarction (MI) is one of the most deadly diseases in the world. Hyperoside (Hyp) has been shown to have a protective effect on cardiovascular function through various signaling pathways, but whether it can protect myocardial infarction by regulating JAK2/STAT3 signaling pathway is unknown. AIM OF THE STUDY: To investigate whether Hyp could protect the heart against myocardial infarction injury in mice by modulating JAK2/STAT3 signaling pathway and its potential mechanism. METHODS: In vivo experiments, the myocardial infarction model was established by ligating the left anterior descending coronary artery (LAD) of male C57BL/6 mice permanently. The mice were divided into seven groups: sham group, MI group, MI+Hyp (9 mg/kg), MI+Hyp (18 mg/kg) group, MI+Hyp (36 mg/kg) group, MI+Captopril group (15 mg/kg) group and MI+Hyp (36 mg/kg)+AG490 (7.5 mg/kg) group. Each group of animals were given different concentrations of hyperoside, positive control drug or inhibitor of JAK2/STAT3 singaling. After 14 days of administration, the electrocardiogram (ECG), echocardiography and serum myocardial injury markers were examined; Slices of mouse myocardial tissue were assessed for histopathological changes by HE, Masson and Sirius Red staining. TTC and TUNEL staining were used to evaluate the myocardial infarction area and cardiomyocytes apoptosis respectively. The expression of JAK2/STAT3 signaling pathway, apoptosis and autophagy-related proteins were detected by western blot. In vitro experiments, rat H9c2 cardiomyocytes were deprived of oxygen and glucose (OGD) to stimulate myocardial ischemia. The experiment was divided into seven groups: Control group, OGD group, OGD+Hyp (20 µM) group, OGD+Hyp (40 µM) group, OGD+Hyp (80 µM), OGD+Captopril (10 µM) group and OGD+Hyp (80 µM)+AG490 (100 µM) group. Myocardial cell damage and redox index were measured 12 h after OGD treatment. ROS content in cardiomyocytes was detected by immunofluorescence. Cardiomyocytes apoptosis was detected by flow cytometry. The expressions of JAK2/STAT3 signaling pathway-related proteins, apoptosis and autophagy related proteins were detected by western blot. RESULTS: In vivo, hyperoside could ameolirate ECG abnormality, increase cardiac function, reduce myocardial infarction size and significantly reduce myocardial fibrosis level and oxidation level. The experimental results in vitro showed that Hyp could reduce the ROS content in cardiomyocytes, decrease the level of oxidative stress and counteract the apoptosis induced by OGD injury . Both in vivo and in vitro experiments showed that hyperoside could increase phosphorylated JAK2 and STAT3, indicating that hyperoside could play a cardioprotective role by activating JAK2/STAT3 signaling pathway. It was also shown that hyperoside could increase the autophagy level of cardiomyocytes in vivo and in vitro. However the cardiomyocyte-protective effect of Hyp was abolished in combination with JAK2/ STAT3 signaling pathway inhibitor AG490. These results indicated that the protective effect of Hyp on cardiomyocyte injury was at least partially achieved through the activation of the JAK2/STAT3 signaling pathway. CONCLUSION: Hyp can significantly improve cardiac function, ameliorate myocardial hypertrophy and myocardial remodeling in MI mice. The mechanism may be related to improving mitochondrial autophagy of cardiomyocytes to maintain the advantage of autophagy, and blocking apoptosis pathway through phagocytosis, thus suppressing apoptosis level of cardiomyocytes. These effects of Hyp are achieved, at least in part, by activating the JAK2/STAT3 signaling pathway.

Efficacy of polyethylene glycol loxenatide for type 2 diabetes mellitus patients: a systematic review and meta-analysis.

Objective: Some studies have proved that polyethylene glycol loxenatide (PEG-Loxe) has significant effects on controlling blood glucose and body weight in patients with type 2 diabetes mellitus (T2DM), but there is still some controversy over the improvement of blood lipid profiles (BLP) and blood pressure (BP), and more evidences are needed to verify such effects. Therefore, this study was conducted to provide a comprehensive evaluation of the efficacy of PEG-Loxe in improving blood glucose (BG), BLP, BP, body mass index (BMI), and body weight (BW) in patients with T2DM for clinical reference. Methods: Randomized controlled trials (RCT) in which PEG-Loxe was applied to treat T2DM were retrieved by searching PubMed, Cochrane Library, Embase, Medline, Scopus, Web of Science, China National Knowledge Infrastructure, China Scientific Journal, Wanfang Data, and SinoMed databases. Outcome measures included BG, BLP, BP, BMI, and BW. RevMan 5.3 software was used to perform data analysis. Results: Eighteen trials were identified involving 2,166 patients. In experimental group 1,260 patients received PEG-Loxe alone or with other hypoglycemic agents, while in control group 906 patients received placebo or other hypoglycemic agents. In the overall analysis, PEG-Loxe significantly reduced the levels of glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-h postprandial blood glucose (2-h PBG), BMI, and BW compared with control group. However, it had no obvious effect on total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Conclusion: PEG-Loxe has better hypoglycemic effects compared with placebo in patients with T2DM, but could not significantly improved TG, LDL-C, HDL-C, SBP, and DBP. And the combination of conventional hypoglycemic drugs (CHD) and PEG-Loxe could more effectively improve the levels of HbA1c, FPG, 2-h PBG, TC, TG, BMI, and BW compared with CHD in T2DM patients. Systematic Review Registration: www.inplasy.com, identifier INPLASY202350106.

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling.

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 µM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

The fate of sulfonamides in microenvironments of rape and hot pepper rhizosphere soil system.

Sulfonamides (SAs) in agricultural soils can be degraded in rhizosphere, but can also be taken up by vegetables, which thereby poses human health and ecological risks. A glasshouse experiment was conducted using multi-interlayer rhizoboxes to investigate the fate of three SAs in rape and hot pepper rhizosphere soil systems to examine the relationship between the accumulation and their physicochemical processes. SAs mainly entered pepper shoots in which the accumulation ranged from 0.40 to 30.64 mg kg-1, while SAs were found at high levels in rape roots ranged from 3.01 to 16.62 mg kg-1. The BCFpepper shoot exhibited a strong positive linear relationship with log Dow, while such relationship was not observed between other bioconcentration factors (BCFs) and log Dow. Other than lipophilicity, the dissociation of SAs may also influence the uptake and translocation process. Larger TF and positive correlation with log Dow indicate preferential translocation of pepper SAs. There was a significant (p < 0.05) dissipation gradient of SAs observed away from the vegetable roots. In addition, pepper could uptake more SAs under solo exposure, while rape accumulated more SAs under combined exposure. When SAs applied in mixture, competition between SAs might occur to influence the translocation and dissipation patterns of SAs.

The phloem and xylem structure of plants and the neutral and ionic partitioning of sulfonamides (SAs) influence the uptake and translocation of SAs.A significant (p < 0.05) dissipation gradient of SAs was observed away from the vegetable roots.Combined exposure could promote the correlation between log BCF and log D_ow.

The role of EndophilinA1 in chronic unpredicted mild stress-induced depression model mice.

BACKGROUND: Depression is a common mental disease, accompanied by anxiety and persistent depression. Endophilin A1 (EPA1) is a brain-specific protein enriched in synaptic terminals that is primarily expressed in the central nervous system. It has been reported that EPA1 is involved in neurotransmitter release, which indicates that the protein may be involved in depression. However, it is unclear whether EPA1 is implicated in the development of depression. METHODS: The mice depression model was established by chronic unpredicted mild stress (CUMS). Depression-like behaviors were detected by sucrose preference test (SPT), forced swim test (FST), tail-suspension test (TST) and open-field test (OFT). Neuronal histopathology was applied by hematoxylin and eosin stain (H&E), and Nissl stain. EPA1, NLRP1 inflammatory complexes, NADPH oxidase2 (NOX2), synaptic-related protein expression of the mice were tested by western blot. Immunofluorescence was applied to detect the expression of EPA1 and ROS in mice hippocampus. EPA1 knockdown was performed by an adeno-associated virus (AAV) vector containing EPA1-shRNA-EGFP infusion. RESULT: CUMS exposure induced depressive-like behaviors and increased the expression of EPA1 in the hippocampus. Knockdown hippocampal EPA1 ameliorated CUMS-induced depressive-like behaviors, decreased calcium (Ca2+) overload, decreased ROS generation and NOX2 expression, inhibited NLRP1 inflammasome-driven neuroinflammation, and restored the levels of BDNF, PSD95, GAP-43, SYN, and MAP-2 in the hippocampus. CONCLUSION: EPA1 contributes to CUMS induced depressive-like behaviors and the mechanism may be related to NLRP1 inflammasome-driven inflammatory response, regulating calcium ion homeostasis and ROS generation, and alleviating synaptic function damage. This indicated that EPA1 may participate in the occurrence and development of depression.

A novel self-assembled nanoplatform based on retrofitting poloxamer 188 for triple-negative breast cancer targeting treatment.

Poloxamer 188 is a widely used pharmaceutical excipient, which can be found in a variety of drug formulations. In this study, a novel self-assembled nanoplatform was developed for active targeting of folate receptor-overexpressing triple-negative breast cancer. This platform, FPP NPs, was prepared by the retrofitted poloxamer 188 derivatives, resulting in nanoparticles with an appropriate size (< 100 nm), good stability, and satisfactory biocompatibility. Cellular uptake and in vivo distribution studies showed that the FPP NPs had strong tumor cell uptake and active targeting capabilities. Furthermore, docetaxel (DTX) was loaded into FPP NPs in this research. The resulting DTX/FPP NPs exhibited high drug encapsulation efficiency and drug loading capacity, and could rapidly release DTX under slightly acidic conditions, significantly increasing the antitumor activity of the encapsulated drug both in vitro and in vivo. In addition, DTX/FPP NPs could significantly decrease the hepatotoxicity and nephrotoxicity of DTX. Therefore, this drug delivery nanoplatform, based on retrofitted poloxamer 188 with self-assembly properties in aqueous solution and active targeting capabilities to tumors, may provide a promising approach for targeted treatment of triple-negative breast cancer.

Identification of Zip8-correlated hub genes in pulmonary hypertension by informatic analysis.

Background: Pulmonary hypertension (PH) is a syndrome characterized by marked remodeling of the pulmonary vasculature and increased pulmonary vascular resistance, ultimately leading to right heart failure and even death. The localization of Zrt/Irt-like Protein 8 (ZIP8, a metal ion transporter, encoded by SLC39A8) was abundantly in microvasculature endothelium and its pivotal role in the lung has been demonstrated. However, the role of Zip8 in PH remains unclear. Methods: Bioinformatics analysis was employed to identify SLC39A8 expression patterns and differentially expressed genes (DEGs) between PH patients and normal controls (NC), based on four datasets (GSE24988, GSE113439, GSE117261, and GSE15197) from the Biotechnology Gene Expression Omnibus (NCBI GEO) database. Gene set enrichment analysis (GSEA) was performed to analyze signaling pathways enriched for DEGs. Hub genes were identified by cytoHubba analysis in Cytoscape. Reverse transcriptase-polymerase chain reaction was used to validate SLC39A8 and its correlated metabolic DEGs expression in PH (SU5416/Hypoxia) mice. Results: SLC39A8 expression was downregulated in PH patients, and this expression pattern was validated in PH (SU5416/Hypoxia) mouse lung tissue. SLC39A8-correlated genes were mainly enriched in the metabolic pathways. Within these SLC39A8-correlated genes, 202 SLC39A8-correlated metabolic genes were screened out, and seven genes were identified as SLC39A8-correlated metabolic hub genes. The expression patterns of hub genes were analyzed between PH patients and controls and further validated in PH mice. Finally, four genes (Fasn, Nsdhl, Acat2, and Acly) were downregulated in PH mice. However, there were no significant differences in the expression of the other three hub genes between PH mice and controls. Of the four genes, Fasn and Acly are key enzymes in fatty acids synthesis, Nsdhl is involved in cholesterol synthesis, and Acat2 is implicated in cholesterol metabolic transformation. Taken together, these results provide novel insight into the role of Zip8 in PH.

The Role of Endophilin A1 in Lipopolysaccharide-Induced Parkinson's Disease Model Mice.

BACKGROUND: Endophilin A1 (EPA1) is encoded by the SH3GL2 gene, and SH3GL2 was designated as a Parkinson's disease (PD) risk locus by genome-wide association analysis, suggesting that EPA1 may be involved in the occurrence and development of PD. OBJECTIVE: To investigate the role of EPA1 in lipopolysaccharide (LPS)-induced PD model mice. METHODS: The mice PD model was prepared by injecting LPS into the substantia nigra (SN), and the changes in the behavioral data of mice in each group were observed. The damage of dopaminergic neurons, activation of microglia, and reactive oxygen species (ROS) generation were detected by immunofluorescence method; calcium ion concentration was detected by calcium content detection kit; EPA1 and inflammation and its related indicators were detected by western blot method. EPA1 knockdown was performed by an adeno-associated virus vector containing EPA1-shRNA-eGFP infusion. RESULTS: LPS-induced PD model mice developed behavioral dysfunction, SN dopaminergic nerve damage, significantly increased calcium ion, calpain 1, and ROS production, activated NLRP1 inflammasome and promoted pro-inflammatory cell release, and SN EPA1 knockdown improves behavioral disorders, alleviates dopaminergic neuron damage, reduces calcium, calpain 1, ROS generation, and blocks NLRP1 inflammasome-driven inflammatory responses. CONCLUSION: The expression of EPA1 in the SN of LPS-induced PD model mice was increased, and it played a role in promoting the occurrence and development of PD. EPA1 knockdown inhibited the NLRP1 inflammasome activation, decreased the release of inflammatory factors and ROS generation, and alleviated dopaminergic neuron damage. This indicated that EPA1 may participating in the occurrence and development of PD.

An integrated analytical strategy to decipher the metabolic profile of alkaloids in Compound Kushen injection based on UHPLC-ESI-QTOF/MSE.

Compound Kushen injection (CKI) is a kind of sterilised water-soluble traditional Chinese medicine preparation that has been used for the clinical treatment of a variety of cancers (hepatocellular carcinoma, lung cancer, etc.) for 19 years. However, to date, the metabolism-related study on CKI in vivo has not been conducted.An integrated analytical strategy was established to investigate the metabolic profile of alkaloids of CKI in rat plasma, urine, and faeces based on ultra-high performance liquid chromatography-electrospray quadrupole time-of-flight mass spectrometry in MSE mode (UHPLC-ESI-QTOF/MSE).Nineteen prototype alkaloids (including 12 matrine-type alkaloids, 2 cytisine-type alkaloids, 3 lupinine-type alkaloids, and 2 aloperine-type alkaloids) of CKI were identified in vivo. Furthermore, 71 metabolites of alkaloids (including 11 of lupanine-related metabolites, 14 of sophoridine-related metabolites, 14 of lamprolobine-related metabolites, and 32 of baptifoline-related metabolites) were tentatively characterised. Metabolic pathways involved in the metabolism of phase I (include oxidation, reduction, hydrolysis, and desaturation), phase II (mainly include glucuronidation, acetylcysteine or cysteine conjugation, methylation, acetylation, and sulphation), and associated combination reactions.The integrated analytical strategy was successfully used to characterise the prototype alkaloids and their metabolites of CKI in vivo, and the results laying a foundation for further study its pharmacodynamic substances.

Self-assembled mononuclear complexes: open metal sites and inverse dimension-dependent catalytic activity for the Knoevenagel condensation and CO2 cycloaddition.

To lessen the greenhouse effect, measures such as improving the recovery of crude oil and converting carbon dioxide (CO2) into valuable chemicals are necessary to create a sustainable low-carbon future. To this end, the development of efficient new oil-displacing agents and CO2 conversion has aroused great interest in both academia and industry. The Knoevenagel condensation and CO2 cycloaddition are the key reactions to solve the above problems. Four Cu- or Zn-based molecular complexes built from different ligands possessing hydrophilic-hydrophobic layers and different dimensionalities were chosen as solid catalysts for this study. Structural analysis revealed the presence of hydrophilic-hydrophobic layers and open metal sites in the low-dimensional complexes. To obtain deep insight into the reaction mechanism, first-principles density functional theory (DFT) calculations were carried out. These calculations confirmed that in the Knoevenagel condensation reaction, the final formation of benzylidenemalononitrile is the rate-determining step (an energy barrier (ΔE) value of 73.2 kJ mol-1). The zero-dimensional (0D) Cu molecular complex with unsaturated metal centers, hydrophilic and hydrophobic layers, exhibited higher catalytic activity (yield: 100%, temperature: room temperature, and time: 2 h) compared with one- and two-dimensional Cu complexes. In the presence of a 0D Zn complex co-catalyzed with Br- in the CO2 cycloaddition reaction, the ΔE value reduces to 35.5 kJ mol-1 for the ring opening of styrene oxide (SO), which is significantly lower than Br- catalyzed (80.9 kJ mol-1) reactions. The roles of unsaturated metal centers, hydrophilic-hydrophobic layers and dimensionality in the Knoevenagel condensation and CO2 cycloaddition were explained in the results of structure-activity relationships.

Exploration of the main active components and pharmacological mechanism of Yerba Mate based on network pharmacology.

INTRODUCTION: Yerba mate is widely consumed in South American countries and is gaining popularity around the world. Long-term consumption of yerba mate has been proven to have health-care functions and therapeutic effects on many diseases; however, its underlying mechanism has not been clearly elucidated. In this research, we explored the pharmacological mechanism of yerba mate through a network pharmacological approach. MATERIAL AND METHODS: The bioactive components of yerba mate were screened from published literature and the Traditional Chinese Medicine System Pharmacology Database (TCMSP), and the targets and related diseases were retrieved by TCMSP. Furthermore, the component-target-disease network an protein-protein interaction (PPI) network were constructed, and combined with gene ontology (GO) functional analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis to explore the pharmacological mechanism of yerba mate. RESULTS: As a result, 16 bioactive components of yerba mate were identified, which acted on 229 targets in total. Yerba mate can be used to treat 305 diseases, such as breast cancer, asthma, Alzheimer's disease, osteoarthritis, diabetes mellitus, atherosclerosis, and obesity. Protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), transcription factor AP-1 (JUN), cellular tumour antigen (p53) TP53, tumour necrosis factor (TNF), transcription factor p65 (RELA), interleukin-6 (IL6), amyloid-beta precursor protein (APP), and vascular endothelial growth factor A (VEGFA) were identified as the key targets of yerba mate playing pharmacological roles. The signalling pathways identified by KEGG pathway enrichment analysis that were most closely related to the effects of yerba mate included pathways in cancer, fluid shear stress and atherosclerosis, and human cytomegalovirus infection. CONCLUSION: the results of our study preliminarily verify the basic pharmacological action and possible mechanism of yerba mate and provide a reference for the further development of its medicinal value.

Calcium dobesilate efficiency in the treatment of diabetic kidney disease through suppressing MAPK and chemokine signaling pathways based on clinical evaluation and network pharmacology.

Aims: To evaluate the effectiveness and potential mechanism of calcium dobesilate (CaD) in diabetic kidney disease (DKD) patients. Methods: We searched for available randomized controlled studies on DKD patients' treatment with CaD through open databases. Continuous variables were expressed as standardized mean difference (SMD) with a 95% confidence interval (CI). The putative targets and possible pathways of CaD on DKD were analyzed by network pharmacology. Molecular docking was employed to verify the match between CaD and the target genes. Results: In the meta-analysis, 42 trials were included, involving 3,671 DKD patients, of which 1,839 received CaD treatment in addition to conventional treatment, while 1,832 received conventional treatment. Compared with routine therapy, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) significantly decreased in the CaD treatment (early stage of DKD, Scr: p < 0.00001; BUN: p < 0.0001; clinical stage of DKD, Scr: p < 0.00001; BUN: p < 0.00001; kidney failure stage, Scr: p = 0.001; BUN: p = 0.004). The levels of serum cystatin C (Cys-C), urine levels of molecules reflecting kidney function (urinary albumin excretion rate (UAER) and micro glycoprotein), and inflammatory factors [hypersensitive c-reactive protein (hs-CRP)] were reduced compared with control groups, while glomerular filtration rate (GFR) was increased in patients treated with CaD for 12 weeks. CaD also showed a better effect on improving endothelial function. Network pharmacology results showed that the interaction pathway between CaD and DKD was mainly enriched in MAPK and chemokine signaling pathways. AKT1, CASP3, IGF1, MAPK8, and CCL5 might be the key targets for CaD in treating DKD. Conclusion: Combination with CaD is effective and safe in patients with DKD. Inhibition of MAPK and chemokine signaling pathways might be vital in treating CaD in DKD patients.

Which Frailty Evaluation Method Can Better Improve the Predictive Ability of the SASA for Postoperative Complications of Patients Undergoing Elective Abdominal Surgery?

Purpose: To determine which frailty method can better improve the predictive ability of the Surgical Apgar Score combined with American Society of Anesthesiologists physical status classification (SASA). Patients and Methods: A prospective cohort study was conducted. A total of 194 elderly patients undergoing elective abdominal surgery were included. Preoperative frailty using FRAIL questionnaire, frailty index (FI), Clinical Frailty Scale (CFS) and SASA scores was assessed. Primary outcome was in-hospital Clavien-Dindo ≥grade II complications. Multiple logistic regression was used to examine the association between frailty and complications. Receiver operating characteristic curves were used to explore the predictive ability of frailty. Results: According to the FRAIL, FI and CFS criteria, the prevalence of frailty in the study population was 43.8%, 32.5%, and 36.6%, respectively. After adjusting for all covariates, frailty was significantly associated with postoperative complications in hospital by FRAIL [odds ratio: 5.11, 95% CI: 1.41-18.44, P = 0.013], by FI [OR: 4.25, 95% CI: 1.21-14.90, P = 0.024] and by CFS [OR: 5.10, 95% CI: 1.52-17.17, P = 0.008]. The area under the curve (AUC) for SASA was 0.768 (95% CI: 0.702-0.826). Addition of frailty assessment (FRAIL, FI and CFS) increased the AUC to 0.787 (95% CI: 0.722-0.842), 0.798 (95% CI: 0.734-0.852), and 0.815 (95% CI: 0.753-0.867), respectively. Compared to SASA, only addition of CFS had a significant difference (P = 0.0478). Conclusion: Frailty is an effective predictor of postoperative complications in elderly Chinese patients undergoing elective abdominal surgery. Frailty assessment of CFS can better improve the predictive ability of SASA.

Genetic diversity of the cultivated Salvia miltiorrhiza populations revealed by four intergenic spacers.

For better understanding the genetic diversity and phylogeny of the cultivated Salvia miltiorrhiza populations, four intergenic spacer sequences, ETS, psbA-trnH, trnL-trnF, and ycf1-rps15 of the 40 populations collected from China were Polymerase Chain Reaction (PCR) amplified, analyzed both individually and in combination. Haplotype diversity analysis showed that the cultivated S. miltiorrhiza populations had a very rich genetic diversity and an excellent capacity to resist environmental pressure. The best-fit nucleotide substitution models for ETS, psbA-trnH, trnL-trnF, ycf1-rps15, and their combined sequences were HKY+I, T92, T92, T92+G, and T92+G, respectively; the nucleotide conversion frequency in the combined sequences was lower than the transversion, and the relatively high nucleotide substitution frequencies suggests its high genetic variability. Neutral tests showed that the spacer sequences of the populations conform with the neutral evolution model, and there has been no current expansion events occurred. Phylogeny analyses based on both the individual and the combined sequences showed that the 40 populations were clustered in two clades with a very similar topological structure. The discrimination rate of the combined sequence marker is significantly increased to 52.5% (21 populations) over the highest 35% (13 populations) by the single marker of ETS, though still inadequate but a big step forward. Further exploration of more DNA markers is needed. This study for the first time revealed the rich genetic diversity and phylogeny of the currently cultivated S. miltiorrhiza populations in China and provides novel alternative molecular markers for the genetic identification and resources evaluation of the cultivated S. miltiorrhiza populations.

Unique BiFeO3/g-C3N4 mushroom heterojunction with photocatalytic antibacterial and wound therapeutic activity.

Bacterial infections have become a major problem threatening public health, and it is of great significance to treat wound infections in biological systems caused by bacteria. However, traditionally used bacteriostatic agents usually cause additional pollution. Herein a mushroom-shaped clean and Green BiFeO3/g-C3N4 composite is employed for the first time for photocatalytic antibacterial activity and for the further promotion of wound healing. The ratio between BiFeO3 and g-C3N4 was delicately regulated to control the generated amount of ˙OH and ˙O2- by catalyzing the decomposition of hydrogen peroxide (H2O2) under illumination. Results show that 10%BFO/CN demonstrates the best performance for ˙OH and ˙O2- production, resulting in the highest antibacterial ability against E. coli and S. aureus. In addition, the catalytic mechanism of BiFeO3/g-C3N4 towards antibacterial activity is disclosed by a combination of ESR monitoring and analysis of the Mott-Schottky diagram. Furthermore, in vivo experiments prove that 10%BFO/CN can effectively promote anti-infection and wound healing in nude mice. This work sheds deep scientific insight on the synergistic effect of photocatalysis and photo-Fenton degradation as well as their application in antibacterial and wound therapeutic activity.

Effect of dapagliflozin on diabetic patients with cardiovascular disease via MAPK signalling pathway.

Clinical studies have shown that dapagliflozin can reduce cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM), but the exact mechanism is unclear. In this study, we used the molecular docking and network pharmacology methods to explore the potential mechanism of dapagliflozin on T2DM complicated with cardiovascular diseases (CVD). Dapagliflozin's potential targets were predicted via the Swiss Target Prediction platform. The pathogenic targets of T2DM and CVD were screened by the Online Mendelian Inheritance in Man (OMIM) and Gene Cards databases. The common targets of dapagliflozin, T2DM and CVD were used to establish a protein-protein interaction (PPI) network; the potential protein functional modules in the PPI network were found out by MCODE. Metascape tool was used for Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis. A potential protein functional module with the best score was obtained from the PPI network and 9 targets in the protein functional module all showed good binding properties when docking with dapagliflozin. The results of KEGG pathway enrichment analysis showed that the underlying mechanism mainly involved AGE-RAGE signalling pathway in diabetic complications, TNF signalling pathway and MAPK signalling pathway. Significantly, the MAPK signalling pathway was considered as the key pathway. In conclusion, we speculated that dapagliflozin played a therapeutic role in T2DM complicated with CVD mainly through MAPK signalling pathway. This study preliminarily reveals the possible mechanism of dapagliflozin in the treatment of T2DM complicated with CVD and provides a theoretical basis for future clinical research.

The variations of endophilin A2-FoxO3a-autophagy signal in angiotensin II-induced dopaminergic neuron injury mouse model and by biochanin A.

Biochanin A (Bioch A) is a natural plant estrogen, with various biological activities such as anti-apoptosis, anti-oxidation, and suppression of inflammation. In this study, we investigated the protective effects of Bioch A on angiotensin II (AngII) - induced dopaminergic (DA) neuron damage in vivo and on molecular mechanisms. Spontaneous activity and motor ability of mice among groups was detected by open-field test and swim-test. The expression of TH, microtubule-associated proteins light chain 3B II (LC3BII)/LC3BI, beclin-1, P62, forkhead box class O3 (FoxO3), phosphorylated (p) FoxO3a/FoxO3a, FoxO3, and endophilin A2 were determined by Western blot and immunohistochemistry or immunofluorescence staining. Our results showed that AngII treatment significantly increased the behavioral dysfunction of mice and DA neuron damage. Meanwhile, AngII treatment increased the expression of LC3BII/LC3BI, beclin-1, P62, and FoxO3a and decreased the expression of endophilin A2 and p-FoxO3a/FoxO3a, however, Bioch A treatment alleviate these changes. In summary, these results suggest that Bioch A exerts protective effects on AngII-induced mouse model may be related to regulating endophilin A2, FoxO3a, and autophagy-related proteins; however, the specific mechanism is not yet clear and needs further study.

Cascade catalytic nanoplatform based on ions interference strategy for calcium overload therapy and ferroptosis.

Intracellular ions played prominent part in cell function and behavior. Disrupting intracellular ions homeostasis might switch ions signal from "regulating" to "destroying". Inspired by this, we introduced the ions interference strategy for tumor therapy. Herein, curcumin (CUR) and transferrin (Tf) co-loaded calcium peroxide nanoparticles (CaO2 NPs) were formulated. With tumor targeting ability, CaO2/Tf/CUR pinpointed tumor cells and then instantaneously decomposed in acidic lysosomes, concurrently accompanying with the release of Ca2+ and CUR, as well as the production of H2O2. Then H2O2 not only damaged structure of Tf to release Fe3+, but also was converted to hydroxyl radicals via ferric ions mediated Fenton reaction for ferroptosis. In addition, the released Ca2+ and CUR induced Ca2+ overload via exogenous and endogenous calcium ions accumulation, respectively, further activating mitochondria apoptosis signaling pathway for cell injury. Therefore, based on calcium and ferric ions interference strategy, the cascade catalytic CaO2/Tf/CUR offered synergistic combination of ferroptosis, Ca2+ overload therapy and chemotherapy, which held a great promise in cancer treatment.

A novel NIR fluorescence probe with cysteine-activated structure for specific detection of cysteine and its application in vitro and in vivo.

Cysteine (Cys) as a vital antioxidant molecule and an effective biomarker for illness, plays an essential role in physiological functions and pathological processes. Extensive work has been done to explore the physiological functions of Cys and develop probes for detection of biothiols. However, the challenge to differentiate Cys from glutathione and homocystine remains. In this work, we constructed a novel near-infrared (NIR) probe, termed TMN-Cys, using TMN-NH2 and thionoesters. The probe could selectively detect Cys over homocysteine and glutathione in solution. It displayed a large Stokes shift (210 nm) upon treatment with Cys, and its detection limit was as low as 79 nM. Moreover, this probe showed low toxicity and was successfully employed in monitoring endogenous Cys in living cells and mice.