OBJECTIVE To evaluate the efficacy， safety and cost-effectiveness of toripalimab （Tor） combined with chemotherapy （CT） in the treatment of locally advanced or metastatic non-small cell lung cancer （NSCLC）. METHODS PubMed， the Cochrane Library， Embase， Web of Science， CBM， CNKI， Wanfang Data， and Health Technology Assessment （HTA） related websites were searched to collect the HTA reports， systematic reviews/meta-analyses and pharmacoeconomic studies of Tor+CT in the treatment of locally advanced or metastatic NSCLC from database/website inception to March 31， 2025. After data extraction and quality evaluation， the results of the included studies were analyzed descriptively. RESULTS A total of eleven studies were included， involving five systematic reviews/meta-analyses， and six pharmacoeconomic studies. Among the five systematic reviews/ meta-analyses， two were of high quality， while there was one each of moderate， low， and very low quality. All six pharmacoeconomic studies were of good quality. In terms of efficacy， compared with CT， Tor+CT significantly improved patients’ progression-free survival （PFS） and overall survival （P＜0.05）. In addition， compared with ipilimumab+CT， durvalumab， durvalumab+tremelimumab and sugemalimab+CT， Tor+CT could also improve the PFS （P＜0.05）. In terms of safety， there was no significant difference in the incidence of grade≥3 adverse events between patients receiving Tor+CT and CT （P＞0.05）； while Tor+CT had a lower incidence of grade≥3 adverse E-mail： events， compared with camrelizumab+CT， pembrolizumab+ 3233255290@qq.com ipilimumab， nivolumab+CT and atezolizumab+CT （P＜0.05）.In terms of cost-effectiveness， Tor+CT treatment had certain cost-effectiveness advantages， compared with CT. CONCLUSIONS Compared with CT， other programmed death-1/programmed death-ligand 1 inhibitors alone， or their combination with CT， Tor+CT for the treatment of locally advanced or metastatic NSCLC has good efficacy， safety and cost-effectiveness.

Objective To explore the preventive effect and protective mechanism of electroacupuncture at Neiguan points on acute high altitude hypoxic brain injury by detecting the expression of EPO,p-PI3K,p-AKT and Bcl-2 proteins.Methods 48 male SD rats of SPF grade were randomly divided into control group,model group,western medicine group and Neiguan group.The acute high altitude hypoxic brain injury model was established using a hypobaric hypoxia chamber.The Western medication group received Citicoline Sodium via gastric gavage administration,while the Neiguan acupoint group was administered bilateral electroacupuncture stimulation at the Neiguan acupoints.The morphological changes of hippocampal tissues were observed by HE method,serum biochemical indexes were determined by ELISA method,neuronal apoptosis of rat hippocampal tissues was observed by TUNEL method and the positive rate was calculated,and the expression levels of EPO,p-PI3K,p-AKT and Bcl-2 proteins were detected in rat hippocampal tissues by Western-blot method.Results Compared with the control group,the model group exhibited extensive necrotic pyramidal cells with pyknotic and deeply stained nuclei,significantly elevated serum levels of GFAP,S100B,and UCH-L1(P<0.01),markedly increased hippocampal neuronal apoptosis(P<0.01),and upregulated protein levels of EPO,p-PI3K,p-AKT,and Bcl-2 in hippocampal tissue(P<0.01).Compared with the model group,both the western medication group and the electroacupuncture at Neiguan group exhibited a significant reduction in necrotic pyramidal cells in brain tissue,with occasional pyknotic and deeply stained nuclei.Serum levels of GFAP,S100B,and UCH-L1 were markedly decreased(P<0.01),hippocampal neuronal apoptosis was significantly reduced(P<0.01),and protein expression of EPO,p-PI3K,p-AKT,and Bcl-2 in hippocampal tissue was upregulated(P<0.01).No statistically significant differences were observed between the western medication group and the Neiguan electroacupuncture group(P>0.05).Conclusion Electroacupuncture at Neiguan may ameliorate acute high-altitude hypoxic brain injury,potentially through modulating EPO protein expression to activate the PI3K/AKT signaling pathway,thereby inhibiting hippocampal neuronal apoptosis.

BACKGROUND:Both calorie restriction and time-restricted feeding,as two common dietary patterns,have been shown to improve health by regulating metabolism.However,the difference between these dietary patterns,metabolic indices,as well as the gut microbiota still requires further attention.OBJECTIVE:To explore the differences of calorie restriction and time-restricted feeding on the metabolic indices and gut microbiota of mice.METHODS:The C57BL/6J mice were randomly divided into three groups of ad libitum,calorie restriction,and time-restricted feeding(n=6 per group)for 28 weeks of dietary intervention.Various parameters such as body weight,food intake,glucose tolerance,serum fasting insulin,Homeostasis Model Assessment of Insulin Resistance,and leptin were measured.The impact of different interventions on the gut microbiota structure in mice was explored using 16S rRNA sequence analysis.Key operational taxonomic units responsive to dietary interventions were identified through LEfSe analysis.RESULTS AND CONCLUSION:(1)Compared with the ad libitum group,the body weight,food intake,area under the glucose tolerance curve of the calorie restriction and time-restricted feeding groups were decreased(P＜0.01),and the serum leptin was decreased(P＜0.05).The fasting insulin level and serum leptin level of the calorie restriction group were decreased(P＜0.05)and were significantly lower than those of the time-restricted feeding group(P＜0.05);homeostasis model assessment of insulin resistance decreased in the calorie restriction group(P＜0.01).(2)Compared with the ad libitum group,the αdiversity of gut microbiota in the calorie restriction group and the time-restricted feeding group was decreased(P＜0.05),but the diversity of the time-restricted feeding group was slightly lower than that in the calorie restriction group.(3)There were 15 key operational taxonomic units related to calorie restriction and the time-restricted feeding intervention,of which 8 were positively correlated with metabolic phenotypes and their abundance decreased,and 3 were negatively correlated with metabolic phenotypes and their abundance increased(P＜0.05).OTU819 Lachnospiraceae_UCG-006 was positively correlated with body weight,area under the glucose tolerance curve,homeostasis model assessment of insulin resistance,and fasting insulin,while OTU1397 Muribaculaceae was negatively correlated with these indicators.The results show that both calorie restriction and the time-restricted feeding intervention can improve the weight and glucose metabolism of mice,and both intervention modes caused the remodeling of the gut microbiota,which helped to improve the metabolic disorders.

BACKGROUND:Both calorie restriction and time-restricted feeding,as two common dietary patterns,have been shown to improve health by regulating metabolism.However,the difference between these dietary patterns,metabolic indices,as well as the gut microbiota still requires further attention.OBJECTIVE:To explore the differences of calorie restriction and time-restricted feeding on the metabolic indices and gut microbiota of mice.METHODS:The C57BL/6J mice were randomly divided into three groups of ad libitum,calorie restriction,and time-restricted feeding(n=6 per group)for 28 weeks of dietary intervention.Various parameters such as body weight,food intake,glucose tolerance,serum fasting insulin,Homeostasis Model Assessment of Insulin Resistance,and leptin were measured.The impact of different interventions on the gut microbiota structure in mice was explored using 16S rRNA sequence analysis.Key operational taxonomic units responsive to dietary interventions were identified through LEfSe analysis.RESULTS AND CONCLUSION:(1)Compared with the ad libitum group,the body weight,food intake,area under the glucose tolerance curve of the calorie restriction and time-restricted feeding groups were decreased(P＜0.01),and the serum leptin was decreased(P＜0.05).The fasting insulin level and serum leptin level of the calorie restriction group were decreased(P＜0.05)and were significantly lower than those of the time-restricted feeding group(P＜0.05);homeostasis model assessment of insulin resistance decreased in the calorie restriction group(P＜0.01).(2)Compared with the ad libitum group,the αdiversity of gut microbiota in the calorie restriction group and the time-restricted feeding group was decreased(P＜0.05),but the diversity of the time-restricted feeding group was slightly lower than that in the calorie restriction group.(3)There were 15 key operational taxonomic units related to calorie restriction and the time-restricted feeding intervention,of which 8 were positively correlated with metabolic phenotypes and their abundance decreased,and 3 were negatively correlated with metabolic phenotypes and their abundance increased(P＜0.05).OTU819 Lachnospiraceae_UCG-006 was positively correlated with body weight,area under the glucose tolerance curve,homeostasis model assessment of insulin resistance,and fasting insulin,while OTU1397 Muribaculaceae was negatively correlated with these indicators.The results show that both calorie restriction and the time-restricted feeding intervention can improve the weight and glucose metabolism of mice,and both intervention modes caused the remodeling of the gut microbiota,which helped to improve the metabolic disorders.

BACKGROUND:In recent years,the incidence of hyperuricemia caused by purine metabolism disorders has been increasing,which can induce inflammatory responses and lead to renal injury. OBJECTIVE:To explore the role and mechanism of solute carrier family 2 member 12(SLC2A12)in hyperuricemia-related renal injury. METHODS:Renal tubular cells(HK2 cells)were divided into five groups:HK2 group,HK2+uric acid group,HK2+uric acid+NC group,HK2+uric acid+siSLC2A12 group,and HK2+uric acid+siSLC2A12+MK-2206 group.HK2 cells were treated with uric acid and transfected with siRNA SLC2A12,followed by MK-2206 treatment to inhibit AKT expression.Cell proliferation was detected by CCK-8 assay.Apoptosis was detected by TUNEL assay.qRT-PCR and western blot assay were used to detect fibrogenic factors as well as activation of the AKT/FOXO3a pathway.The concentrations of inflammatory cytokines were measured by enzyme-linked immunosorbent assay. RESULTS AND CONCLUSION:(1)Uric acid treatment inhibited cell proliferation and promoted cell apoptosis in the HK2+uric acid group compared with the HK2 group.The proliferative ability of cells in the HK2+uric acid+siSLC2A12 group was further decreased and apoptotic cells were further increased compared with the HK2 group.Compared with the HK2+uric acid+siSLC2A12 group,the HK2+uric acid+siSLC2A12+MK-2206 group showed an increase in cell proliferation and a decrease in apoptotic cells.(2)Compared with the HK2 group,the connective tissue growth factor(CTGF),α-smooth muscle actin(α-SMA)and transforming growth factor beta(TGF-β)expressions increased in the HK2+uric acid group;CTGF,α-SMA and TGF-β expression further increased in the HK2+uric acid+siSLC2A12 group.Compared with the HK2+uric acid+siSLC2A12 group,the CTGF,α-SMA and TGF-β expressions decreased.(3)Compared with the HK2 group,the expression of p-AKT,FOXO3a,and p-FOXO3a elevated in the HK2+uric acid group;the expression of p-AKT further increased,while the expression of FOXO3a and p-FOXO3a decreased in the HK2+uric acid+siSLC2A12 group.Compared with the HK2+uric acid+siSLC2A12 group,p-AKT expression decreased;FOXO3a and p-FOXO3a expression increased in the HK2+uric acid+siSLC2A12+MK-2206 group.(4)Compared with the HK2 group,interleukin-6,interleukin-1 β,and tumor necrosis factor α levels increased in the HK2+uric acid group;interleukin-6,interleukin-1 β,and tumor necrosis factor α levels further increased in the HK2+uric acid+siSLC2A12 group.Compared with the HK2+uric acid+siSLC2A12 group,interleukin-6,interleukin-1 β,and tumor necrosis factor α levels diminished in the HK2+uric acid+siSLC2A12+MK-2206 group.(5)These findings indicate that SLC2A12 may protect against hyperuricemia-induced renal injury by counteracting uric acid-induced tubular fibrosis and inflammation through activation of the FOXO3a pathway.

Objective To explore the effect of multiparameter electroencephalogram(EEG)-guided anesthesia management on EEG burst suppression(BS)and postoperative delirium(POD)in elderly patients undergoing lower abdominal laparoscopic surgery.Methods A total of 100 elderly patients,48 males and 52 females,aged 65-85 years,BMI 18.5-28.0 kg/m2,and ASA physical status Ⅱ or Ⅲ,were enrolled for lower abdominal surgery under general anesthesia.Patients were randomly divided into two groups:multiparameter group and single parameter group,50 patients in each group.In multiparameter group,multiparameter EEG monitoring with patient statu index(PSI),spectral edge frequency(SEF),burst suppression ratio(BSR)and density spectral array(DSA)were used to guide the depth management of anesthesia.In single parameter group,single parameter PSI was used to guide the depth management of anesthesia.The total area under the hypotensive threshold of MAP(AUTMAP)was calculated,and the amount of anesthetic used during the operation and the use of vasoactive drugs,duration of anesthesia,extu-bation time,duration of PACU stay,and postoperative hospitalisation days were recorded.HR,MAP,PSI,and SEF were recorded before the induction of anesthesia,5 minutes after induction of anesthesia,5,30,and 60 minutes after incision,and at the end of surgery.The incidence,duration,and maximum BSR of in-traoperative BS,as well as the incidence of POD 1,2,and 3 days after surgery were recorded.Results There was no significant difference in AUTMAP values between the two groups.Compared with single parame-ter group,intraoperative propofol and remifentanil dosage were significantly decreased(P＜0.05),awak-ening time,PACU stay,and postoperative hospitalization time were significantly shorter in multiparameter group(P＜0.05),the PSI was significantly increased 5,30,and 60 minutes after incision and at the end of surgery,and the SEF was significantly increased 5 minutes after induction of anesthesia,5,30,and 60 minutes after induction and the end of surgery(P＜0.05).Compared with single parameter group,inci-dence of intraoperative BS was significantly decreased,duration of BS was significantly shorter,smaller maximum BSR was significantly decreased,and incidence of POD on 1 day after surgery in multiparameter group(P＜0.05).Conclusion Anesthesia management guided by multiparameter EEG can inhibit the oc-currence of BS,mitigate the degree of BS,and reduce the incidence of POD in elderly patients undergoing abdominal surgery.

Nicotine addiction is a concern worldwide. Most mechanistic investigations are on nicotine substance dependence properties based on its pharmacological effects. However, no effective therapeutic treatment has been established. Nicotine addiction is reinforced by environments or habits. We demonstrate the neurobiological basis of the behavioural aspect of nicotine addiction. We utilized the conditioned place preference to establish nicotine-associated behavioural preferences (NABP) in rats. Brain-wide neuroimaging analysis revealed that the medial prefrontal cortex (mPFC) was activated and contributed to NABP. Chemogenetic manipulation of µ-opioid receptor positive (MOR⁺) neurons in the mPFC or the excitatory outflow to the nucleus accumbens shell (NAcShell) modulated the NABP. Electrophysiological recording confirmed that the MOR⁺ neurons directly regulate the mPFC-NAcShell circuit via GABA_A receptors. Thus, the MOR⁺ neurons in the mPFC modulate the formation of behavioural aspects of nicotine addiction via direct excitatory innervation to the NAcShell, which may provide new insight for the development of effective therapeutic strategies.
Animals ; Nucleus Accumbens/drug effects* ; Prefrontal Cortex/drug effects* ; Nicotine/pharmacology* ; Receptors, Opioid, mu/metabolism* ; Male ; Rats ; Rats, Sprague-Dawley ; Tobacco Use Disorder/metabolism* ; Neurons/drug effects* ; Neural Pathways/drug effects*

Objective To evaluate the roles of telomerase,interferon-γ(IFN-γ),adenosine deaminase(ADA)and T cell spot test(T-SPOT.TB)in the diagnosis of tuberculous and malignant pleural effusion.Methods Forty patients with early tuberculous pleurisy(tuberculosis group)and 40 patients with malignant pleural effusion(tumor group)were enrolled.Pleural effusion and fasting blood were extracted before treatment.The activity of telomerase and the concentration of IFN-γ were detected by enzyme-linked immunosorbent assay.The activity of ADA was detected by colorimetric analysis.The positive rate of T-SPOT.TB was detected by Elispot spot counting.Results Telomerase activity in the tuberculosis group was significantly lower than that in the tumor group([1.46±0.73]×10-3 nmol/L vs.[3.34±1.72]×10-3 nmol/L,P<0.01).The concentration of IFN-γ was(137.44±38.93)U/L and(27.94±8.46)U/L in the tuberculosis group and tumor group,respectively;ADA content was(68.42±9.58)U/L and(15.39±4.43)U/L.There were significant differences in IFN-γ and ADA between the 2 group(P<0.01).IFN-γ concentration,ADA activity and the positive rate of T-SPOT.TB in the tuberculosis group were significantly higher than those in the tumor group(P<0.01).The sensitivity and specificity of combined detection of telomerase,IFN-γ,ADA and T-SPOT.TB in differentiating tuberculous and malignant pleural effusion were 0.974 and 0.974,respectively.Conclusion The combined detection of telomerase,IFN-γ,ADA and T-SPOT.TB has important value in differential diagnosis of tuberculosis and malignant pleural effusion.

Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium(EF)and possess excellent therapeutic effects on various diseases.Encouragingly,in 2022,icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma(HCC)by National Medical Products Administration(NMPA)of China.Moreover,recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects.Nonetheless,both production effi-ciency and clinical applications of epimedium flavonoids have been restrained because of their low content,poor bioavailability,and unfavorable in vivo delivery efficiency.Recently,various strategies,including enzyme engineering and nanotechnology,have been developed to increase productivity and activity,improve delivery efficiency,and enhance therapeutic effects of epimedium flavonoids.In this review,the structure-activity relationship of epimedium flavonoids is described.Then,enzymatic en-gineering strategies for increasing the productivity of highly active baohuoside I and icaritin are dis-cussed.The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized.Finally,the challenges and an outlook on clinical translation of epi-medium flavonoids are proposed.

OBJECTIVE: To explore the mechanisms of large-conductance calcium-activated potassium channel (BKCa) involved in inflammatory response in sepsis. METHODS: The serum levels of BKCa were measured by enzyme-linked immunosorbent assay (ELISA) in patients with sepsis (28 cases), patients with common infection (25 cases) and healthy people (25 cases). The relationship between levels of BKCa and acute physiology and chronic health evaluation II (APACHE II) were analyzed. Cultured RAW 264.7 cells were stimulated by lipopolysaccharide (LPS). In some experiments, a cell model of sepsis was constructed using Nigericin as the second stimulus signal. The mRNA and protein expressions of BKCa in RAW 264.7 cells stimulated with LPS (0, 50, 100, 1 000 μg/L) were measured by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blotting. RAW 264.7 cells were transfected with small interfering RNA of BKCa (siRNA-BKCa), and the levels of caspase-1 precursor (pro-caspase-1), interleukin-1β precursor (pro-IL-1β) in cell, and the levels of caspase-1 p20, IL-1β p17 of cell culture medium, and NOD-like receptor protein 3 (NLRP3), nuclear factor-κB (NF-κB) were measured by Western blotting. The apoptosis were detected by staining with propidium iodide (PI), the release rate of lactate dehydrogenase (LDH) were measured, and the expression of apoptotic protein Gasdermin D (GSDMD) was measured by Western blotting to evaluate the effect of silencing BKCa on cell pyrosis. RESULTS: The level of serum BKCa in patients with sepsis was significantly higher than that in patients with common infection and health peoples (ng/L: 165.2±25.9 vs. 102.5±25.9, 98.8±20.0, both P < 0.05). In addition, the level of serum BKCa in patients with sepsis was significantly positively correlated with APACHE II score (r = 0.453, P = 0.013). LPS could construct a sepsis cell model by which LPS could promote BKCa expression in mRNA and protein with a concentration-dependent manner. The mRNA and protein expressions of BKCa in the cells stimulated by 1 000 μg/L LPS were significantly higher than that in the blank group (0 μg/L) [BKCa mRNA (2^-ΔΔCt): 3.00±0.36 vs. 1.00±0.16, BKCa/β-actin: 1.30±0.16 vs. 0.37±0.09, both P < 0.05]. Compared with the control group, the ratios of caspase-1 p20/pro-caspase-1 and IL-1β p17/pro-IL-1β in the model group were significantly increased (caspase-1 p20/pro-caspase-1: 0.83±0.12 vs. 0.27±0.05, IL-1β p17/pro-IL-1β: 0.77±0.12 vs. 0.23±0.12, both P < 0.05), however, transfection of siRNA-BKCa induced the decrease both of them (caspase-1 p20/pro-capase-1: 0.23±0.12 vs. 0.83±0.12, IL-1β p17/pro-IL-1β: 0.13±0.05 vs. 0.77±0.12, both P < 0.05). Compared with the control group, the number of apoptotic cells, LDH release rate and GSDMD expression in the model group were significantly increased [LDH release rate: (30.60±8.40)% vs. (15.20±7.10)%, GSDMD-N/GSDMD-FL: 2.10±0.16 vs. 1.00±0.16, both P < 0.05], however, transfection of siRNA-BKCa induced the decrease both of them [LDH release rate: (15.60±7.30)% vs. (30.60±8.40)%, GSDMD-N/GSDMD-FL: 1.13±0.17 vs. 2.10±0.16, both P < 0.05]. The mRNA and protein expressions of NLRP3 in sepsis cells were significantly higher than those in the control group [NLRP3 mRNA (2^-ΔΔCt): 2.06±0.17 vs. 1.00±0.24, NLRP3/GAPDH: 0.46±0.05 vs. 0.15±0.04, both P < 0.05]. However, the expression of NLRP3 after siRNA-BKCa transfection was significantly lower than that in model group [NLRP3 mRNA (2^-ΔΔCt): 1.57±0.09 vs. 2.06±0.17, NLRP3/GAPDH: 0.19±0.02 vs. 0.46±0.05, both P < 0.05]. Compared with the control group, the NF-κB p65 nuclear transfer of sepsis cell were significantly increased (NF-κB p65/Histone: 0.73±0.12 vs. 0.23±0.09, P < 0.05). However, the NF-κB p65 expression in the nucleus were decreased after siRNA-BKCa transfection (NF-κB p65/Histone: 0.20±0.03 vs. 0.73±0.12, P < 0.05). CONCLUSIONS BKCa is involved in the pathogenesis of sepsis, and its possible mechanism is to activate NF-κB/NLRP3/caspase-1 signaling pathway to induce inflammatory factor production and cell death.
Humans ; Histones ; Caspase 1 ; Large-Conductance Calcium-Activated Potassium Channels ; Lipopolysaccharides ; NF-kappa B ; NLR Family, Pyrin Domain-Containing 3 Protein ; L-Lactate Dehydrogenase ; Sepsis ; RNA, Small Interfering ; Caspases