Obesity usually exacerbates the immunosuppressive tumor microenvironment (ITME), hindering CD8⁺ T cell infiltration and function, which further represents a significant barrier to the efficacy of immunotherapy. Herein, a multifunctional liposomal system (CR-Lip) for encapsulating celastrol (CEL) was utilized to remodel obesity-related ITME and improve cancer immunotherapy, wherein Ginsenoside Rg3 (Rg3) was detected interspersed in the phospholipid bilayer and its glycosyl exposed on the surface of the liposome. CR-Lip had a relatively uniform size (116.5 nm), facilitating favorable tumor tissue accumulation through the interaction between Rg3 and glucose transporter 1 overexpressed in obese tumor cells. Upon reaching the tumor region, CR-Lip was found to induce the immunogenic cell death (ICD) of HFD tumor cells. Notably, the level of PHD3 in HFD tumor cells was effectively boosted by CR-Lip to effectively block metabolic reprogramming and increase the availability of major free fatty acids fuel sources. In vivo, experiments studies revealed that the easy-obtained nano platform stimulated enhanced the production of various cytokines in tumor tissues, DC maturation, CD8⁺ T-cell infiltration, and synergistic anticancer therapeutic potency with aPD-1 (tumor inhibition rate = 82.1%) towards obesity-related melanoma. Consequently, this study presented an efficacious approach to tumor immunotherapy in obese mice by encompassing tumor eradication, inducing ICD, and reprogramming metabolism. Furthermore, it offered a unique insight into a valuable attempt at the immunotherapy of obesity-associated related tumors.

Given the increasing concern regarding antibacterial resistance, the antimicrobial properties of naphthoquinones have recently attracted significant attention. While 1,4-naphthoquinone and its derivatives have been extensively studied, the antibacterial properties of 5,8-dihydroxy-1,4-naphthoquinone derivatives remain relatively unexplored. This study presents a comprehensive in vitro and in vivo analysis of the antibacterial activity of 35 naturally sourced and chemically synthesized derivatives of 5,8-dihydroxy-1,4-naphthoquinone. Kirby-Bauer antibiotic testing identified three compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA), with one compound (PNP-02) demonstrating activity comparable to vancomycin in minimum inhibitory concentration, minimum bactericidal concentration (MBC), and time-kill assays. Microscopic and biochemical analyses revealed that PNP-02 adversely affects the cell wall and cell membrane of MRSA. Mechanistic investigations, including proteomic sequencing analyses, Western blotting, and RT-qPCR assays, indicated that PNP-02 compromises cell membrane integrity by inhibiting arginine biosynthesis and pyrimidine metabolism pathways, thereby increasing membrane permeability and inducing bacterial death. In an in vivo mouse model of skin wound healing, PNP-02 exhibited antibacterial efficacy similar to vancomycin. The compound demonstrated low toxicity to cultured human cells and in hemolysis assays and remained stable during serum incubation. These findings suggest that PNP-02 possesses promising bioactivity against MRSA and represents a potential novel antibacterial agent.
Methicillin-Resistant Staphylococcus aureus/genetics* ; Anti-Bacterial Agents/chemistry* ; Naphthoquinones/administration & dosage* ; Animals ; Microbial Sensitivity Tests ; Mice ; Humans ; Staphylococcal Infections/microbiology* ; Molecular Structure

Occupational noise-induced hearing loss (NIHL) is an irreversible sensorineural hearing loss that severely endangers workers’ health, making early screening crucial. This article reviewed the research progress on early screening methods for occupational NIHL, introduced the testing mechanisms of three core screening methods—tympanometry, otoacoustic emissions, and extended high-frequency audiometry —and summarized their clinical application advantages and limitations. It is proposed that multimodal combined detection (e.g., the combination of tympanometry, otoacoustic emissions, and extended high-frequency audiometry) can significantly improve the accuracy and comprehensiveness of early screening. Meanwhile, future studies with prospective cohort design are encouraged to verify the long-term monitoring value of each method and to strengthen the joint development of screening technologies with cutting-edge approaches such as machine learning, in order to further improve screening efficiency and provide stronger protection for workers’ hearing health.

OBJECTIVE To explore the effect and safety of dapagliflozin on cardiac function and renal function， blood glucose， and quality of life in patients with heart failure （HF） combined with chronic kidney disease （CKD）. METHODS A total of 156 patients with HF combined with CKD admitted to Shangqiu First People’s Hospital from January 1， 2021 to January 1， 2023 were included. According to the random number table， the patients were randomly divided into conventional treatment group （n＝80） and dapagliflozin group （n＝76）. Conventional treatment group was given conventional treatment； dapagliflozin group was additionally given Dapagliflozin tablets 10 mg orally， once a day， based on conventional treatment group. Both groups were treated for 6 months. Cardiac function [left ventricular ejection fraction （LVEF）， left ventricular end-systolic diameter （LVESD）， left ventricular end-diastolic diameter （LVEDD）， N-terminal pro-brain natriuretic peptide （NT-proBNP）]， renal function [blood creatinine， urea nitrogen， urinary albumin excretion rate （UAER）， glomerular filtration rate （GFR）， creatinine 806731979@qq.com clearance rate （CCR）]， glycosylated hemoglobin， and the quality of life were observed in 2 groups before and after treatment. The occurrence of ADR was recorded. RESULTS After treatment， LVESD， LVEDD， NT-proBNP， blood creatinine， urea nitrogen， UAER in 2 groups as well as the level of glycosylated hemoglobin in dapagliflozin group were significantly lower than before treatment； the dapagliflozin group was significantly lower than the conventional treatment group. LVEF， GFR， CCR and Kansas City Cardiomyopathy Questionnaire score were significantly higher than before treatment， and the dapagliflozin group was significantly higher than the conventional treatment group （P＜0.05）. There was no statistical significance in glycosylated hemoglobin of conventional treatment group before and after treatment （P＞ 0.05）. There was no statistically significant difference in the incidence of dizziness， rash， liver dysfunction， urinary system infection， new dialysis and hypotension between the two groups （P＞0.05）. CONCLUSIONS Dapagliflozin can improve the cardiac function and renal function of patients with HF complicated with CKD， improve patients’ quality of life and lower blood sugar levels without increasing the risk of adverse events.

To determine the main components of the fishy smell of the Eupolyphaga Steleophaga, and to provide a theoretical basis for deodorizing the Eupolyphaga Steleophaga. METHODS Head space-solid phase microextraction-gas chromatography-mass spectrometry was used to identify the components of 10 batches of Eupolyphaga Steleophaga, and area normalization method and chemometrics method were used to analyze the smelly gas of different batches. Odor activity value(OAV) was used to evaluate the contribution of odor components and identify key odor components. RESULTS A total of 87 volatile odor components were identified, the key fishy smell compounds(OAV≥1) were m-methylphenol, dimethyltrisulfide, 4-methylphenol, 2-methyliso-borneol, 2-etzol, 4-methylvaleric acid, iso-valeric acid, etc. Modified fishy gas composition(0.1

BACKGROUND:Clinical treatment for colon cancer mainly includes fluorouracil,irinotecan and oxaliplatin-based therapy.Studies have shown that membrane transport proteins such as ATP-binding cassette transport protein of G2(ABCG2)mediate the transport of these drugs.However,when patients develop resistance to these chemotherapeutic drugs,the high expression of ABCG2 leads to a significant decrease in the therapeutic effect and raises the problem of drug resistance in colon cancer.New drugs and treatments are urgently needed to improve the efficacy.Lycium barbarum polysaccharide has a wide range of biological activities.It can be used as anti-tumor drug to overcome the damage to normal cells in the process of chemotherapy and radiotherapy in tumor patients. OBJECTIVE:To explore the reversal effect of Lycium barbarum polysaccharide in combination with oxaliplatin on colon cancer drug-resistant cells through in vitro experiments to investigate the possible molecular mechanism of Lycium barbarum polysaccharide reversal on colon cancer drug-resistant cells. METHODS:Colon cancer cell line HCT116 and oxaliplatin-resistant cell line HCT116-OXR were selected for in vitro experiments.The optimal intervention concentration and intervention time of Lycium barbarum polysaccharide and oxaliplatin were determined by CCK8 assay of cell proliferation.Samples were further divided into the HCT116 control group,HCT116-OXR blank treatment group,Lycium barbarum polysaccharide group(2.5 mg/mL Lycium barbarum polysaccharide),and oxaliplatin group(10 μmol/L oxaliplatin),and Lycium barbarum polysaccharide + oxaliplatin group(2.5 mg/mL Lycium barbarum polysaccharide +10 μmol/L oxaliplatin).Cell apoptosis was detected by flow cytometry.The protein expression levels of phosphomannose isomerase(PMI)and ABCG2 were detected by immunofluorescence and western blot assay.Phosphatidylinositol3-kinase(PI3K),protein kinase B(AKT),B-cell lymphoma 2(Bcl-2)and BCL2-Associated X(Bax)were detected by western blot assay. RESULTS AND CONCLUSION:(1)HCT116-OXR was more sensitive to Lycium barbarum polysaccharide compared to HCT116(P<0.05).(2)Compared with the HCT116-OXR blank group,Lycium barbarum polysaccharide + oxaliplatin could promote apoptosis of HCT116-OXR cells(P<0.05).The protein expression of Bcl-2 was significantly down-regulated(P<0.05);the protein expression of Bax was significantly up-regulated(P<0.05);the protein expression of ABCG2,PMI,PI3K and AKT was significantly down-regulated(P<0.05).(3)These results indicate that Lycium barbarum polysaccharide reverses drug resistance in colon cancer by inhibiting PMI/PI3K/AKT signaling pathway,which lays the foundation for studying the molecular mechanism of Lycium barbarum polysaccharide's sensitizing chemotherapeutic effects.

Objective: To explore the neuroprotective effects of the Shaoyao Gancao decoction (SGD) against excitatory damage in PC12 cells and the role of the Src-NR2-nNOS pathway mediation by SGD in regulating γ-aminobutyric acid (GABA)-glutamate (Glu) homeostasis. Methods: N-Methyl-d-aspartic acid (NMDA) was used to establish a PC12 cell excitability injury model. To investigate the neuroprotective effect of SGD, a cell counting kit-8 (CCK-8) assay was used to determine PC12 cell viability, Annexin V/Propidium Iodide (Annexin V/PI) double staining was used to determine PC12 cell apoptosis, and Ca2+ concentration was observed using laser confocal microscopy. GABA receptor agonists and antagonists were used to analyze the neuroprotective interactions between γ-aminobutyric acid (GABA) and NMDA receptors. Additionally, molecular biology techniques were used to determine mRNA and protein expression in the Src-NR2-nNOS pathway. We analyzed the correlations between the regulatory sites of GABA and NMDA interactions, excitatory neurotoxicity, and brain damage at the molecular level. Results: NMDA excitotoxic injury manifested as a significant decrease in cell activity, increased apoptosis and caspase-3 protein expression, and a significant increase in intracellular Ca2+ concentration. Administration of SGD, a GABAA receptor agonist (muscimol), or a GABAB receptor agonist (baclofen) decreased intracellular Ca2+ concentrations, attenuated apoptosis, and reversed NMDA-induced upregulation of caspase-3, Src, NMDAR2A, NMDAR2B, and nNOS. Unexpectedly, a GABAA receptor antagonist (bicuculline) and a GABAB receptor antagonist (saclofen) failed to significantly increase excitatory neurotoxicity. Conclusions Taken together, these results not only provide an experimental basis for SGD administration in the clinical treatment of central nervous system injury diseases, but also suggest that the Src-NR2A-nNOS pathway may be a valuable target in excitotoxicity treatment.

Objective To investigate the effects of amylin,also known as islet amyloid polypeptide(IAPP),on learning and memory abilities and the phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt)signaling pathway in APP/PS1 mice.Methods A total of 20 APP/PS1 mice were randomly divided into Alzheimer's disease(AD)group and IAPP group,with 10 mice in each group.The mice in the latter group were given an intraperitoneal injection of 0.5 μmol/L IAPP,and those of the former group received same dose of PBS.Both interventions were given once per day,for 10 weeks.Morris water maze test was used to measure the learning and memory abilities;HE staining was employed to observe the pathological changes in the hippocampus;Transmission electron microscopy was utilized to observe the ultrastructure of hippocampal neurons;Biochemical assay were conducted to detect the contents of glutathione peroxidase(GSH-Px),malondialdehyde(MDA)and superoxide dismutase(SOD)in hippocampal tissues;ELISA was applied to measure the levels of inflammatory factors such as IL-1β,IL-6,and TNF-α as well as content of Aβ42 in hippocampal tissues;And Western blotting was conducted to detect the expression of PI3K/Akt proteins.Results Compared with the AD group,significantly shorter platform latency(P＜0.01),increased number of traversing the platform and longer time to explore the hidden platform(P＜0.01)were observed in the IAPP group,but no such difference was seen in the swimming speed of the mice.HE staining displayed that the IAPP group had more and well-arranged nerve cells in the hippocampal tissue when compared with the AD group(P＜0.05).Lower Aβ protein expression(P＜0.01),reduced oxidative stress and decreased contents of inflammatory factors(P＜0.01)in hippocampal tissue were observed in the IAPP group than the AD group.The IAPP group showed clearer structure of neuronal mitochondria,reduced vacuolization,and better arranged microtubules and microfilaments,and elevated expression of p-PI3K/PI3K and p-Akt/Akt proteins when compared with the AD group(P＜0.01).Conclusion Amylin can reduce oxidative stress and inflammatory responses,improve learning and memory abilities in AD mice,and promote the activity of PI3K/Akt signaling pathway.

Objective:To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) .Methods:A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results:Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P=0.02, OR=0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P=0.02, OR=0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P=0.036, HR=0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P=0.024, HR=2.14, 95% CI 1.10-4.15) , leukemia transformation ( P<0.001, HR=2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P=0.012, HR=2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion:Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Objective:To construct a nomogram model for predicting frailty in elderly hypertensive patients, and to evaluate the discrimination and consistency of the model.Methods:A total of 317 patients with essential hypertension who were admitted to Hebei Eighth People′s Hospital from February 2021 to June 2022 were taken, they were divided into modeling group (190 cases) and verification group (127 cases) according to the proportion of 6∶4, the patients in the modeling group were divided into the asthenic group (45 cases) and the non asthenic group (145 cases) according to whether the patients in the modeling group had asthenia. The nomograph model was constructed based on the results of Logistic analysis.Results:The age, obesity or overweight ratio, diabetes ratio and systolic blood pressure in the frail group were significantly higher than those in the non-frail group: (76.25 ± 3.64)years vs.(70.44 ± 3.82) years, 51.11%(23/45) vs. 24.83%(36/145), 46.67%(21/45) vs. 17.24%(25/145), (156.46 ± 18.64) mmHg (1 mmHg = 0.133 kPa) vs. (143.25 ± 12.38) mmHg, and the mini-nutrition assessment summary form (MNA-SF) score was significantly lower than that in the non-frail group: (11.45 ± 2.06) scores vs. (13.12 ± 1.22) scores, there were statistical differences ( P<0.05). Logistic results showed that age, body mass index, diabetes, and systolic blood pressure were the risk factors for frailty ( P<0.05). The receiver operating characteristic (ROC) curve evaluation showed that the area under the curve (AUC) in the modeling group was 0.998, and AUC in the validation group was 0.954. The Hosmer-Lemeshow goodness of fit test showed: modeling group χ2 = 6.18, P = 0.627; validation group χ2 = 6.58, P = 0.582. Conclusions:The nomogram prediction model of frailty risk in elderly hypertensive patients has good consistency and differentiation