This study aims to investigate the pathogenesis of precancerous lesions of gastric cancer(PLGC) and explore the potential molecular mechanism of Weifuchun Capsules(WFC) in treating PLGC via the nuclear factor-κB(NF-κB)/NOD-like receptor protein 3(NLRP3) inflammasome signaling pathway. Ninety male SPF-grade Wistar rats were randomized into a normal feeding group and a modeling group. The normal feeding group received a regular diet, while the modeling group was subjected to the disease-syndrome combined modeling of PLGC. Specifically, the rats had free access to the water containing 120 μg·mL~(-1) N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) and received a diet containing 0.05% ranitidine in an irregular feeding pattern(alternations between fasting and overfeeding). After 15 weeks, the rats in the normal feeding group were randomized into control, control-NF-κB activator betulinic acid(C-BA), and control-NF-κB inhibitor pyrrolidine dithiocarbamaten(C-PDTC) groups. Meanwhile, the rats in the modeling group continuously underwent the modeling procedure and were randomized into model, WFC, model-NF-κB activator(M-BA), and model-NF-κB inhibitor(M-PDTC) groups. The model group and control group were given aseptic water by intragastric administration, once a day. WFC was given at a dose(432 mg·kg~(-1)) 6 times the equivalent dose for adults(body weight: 60 kg) by gavage, once a day. The rats in the C-BA and M-BA groups were administrated with BA by intraperitoneal injection at a dose of 10 mg·kg~(-1), twice a week. The rats in the C-PDTC and M-PDTC groups were administrated with PDTC by intraperitoneal injection at a dose of 50 mg·kg~(-1), twice a week. The interventions were carried out for 4 weeks. Histopathological changes of the gastric mucosa were observed and scored by hematoxylin-eosin(HE) and alcian blue-periodic acid Sthiff(AB-PAS) staining. The levels of inflammatory cytokines including interleukin(IL)-1β, IL-6, IL-18, tumor necrosis factor-alpha(TNF-α), and IL-10 in the gastric tissue were determined by enzyme-linked immunosorbent assay(ELISA). The expression levels of proteins associated with the NF-κB/NLRP3 inflammasome in the gastric mucosa were determined by Western blot. The positive expression areas of proteins related to NF-κB/NLRP3 inflammasome in the gastric mucosa were measured by immunohistochemistry. The results showed that compared with the control group, the model, C-BA, and M-BA groups showed significantly risen scores of mucosal inflammation, degree of inflammatory activity, gland atrophy, and intestinal metaplasia, and the model and M-BA groups showed significanly risen scores of dysplasia. Compared with the model group, the WFC group demonstrated significantly declined scores of mucosal inflammation and degree of inflammatory activity, as well as declined scores of intestinal metaplasia and dysplasia. Compared with the control group, the model and C-BA groups showed significantly elevated levels of IL-1β, IL-6, IL-18, and TNF-α in the gastric tissue, and the model group showed significantly elevated level of IL-10. In addition, the model and C-BA groups showed significantly up-regulated expression of NF-κB p65, NLRP3, cysteine-aspartic acid protease 1(caspase-1), and apoptosis-associated speck-like protein containing a CARD(ASC) in the gastric mucosa and increased positive expression areas of NF-κB p65, NLRP3, and ASC. Compared with the model group, the WFC group showed significantly decreased levels of IL-1β, IL-6, IL-18, TNF-α, and IL-10 in the gastric tissue, and the M-PDTC group showed significantly lowered levels of IL-1β, IL-18, and TNF-α in the gastric mucosa. Both WFC and M-PDTC groups demonstrated significantly down-regulated expression levels of NF-κB p65, phosphorylated NF-κB p65(p-NF-κB p65), NLRP3, and caspase-1 in the gastric mucosa, along with significant decreases in the positive expression areas of NF-κB p65, NLRP3, and ASC. In conclusion, the pathogenesis of PLGC is closely related to the activation of the NF-κB/NLRP3 inflammasome signaling pathway. WFC can alleviate mucosal inflammation, inhibit glandular atrophy, partially reverse intestinal metaplasia, and reduce dysplasia to delay the process of inflammation-cancer transformation, and meanwhile it can effectively lower the levels of inflammatory cytokines and down-regulate the expression of pathway-related proteins in the stomach. Therefore, WFC may treat PLGC by inhibiting the NF-κB/NLRP3 inflammasome signaling pathway.
Animals ; Male ; NF-kappa B/genetics* ; Rats ; Rats, Wistar ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Stomach Neoplasms/pathology* ; Inflammasomes/genetics* ; Humans ; Precancerous Conditions/metabolism* ; Capsules

This study aims to explore the mechanism of Jiaotai Pills in treating depression based on metabolomics and network pharmacology. The chemical constituents of Jiaotai Pills were identified by UHPLC-Orbitrap Exploris 480, and the targets of Jiaotai Pills and depression were retrieved from online databases. STRING and Cytoscape 3.7.2 were used to construct the protein-protein interaction network of core targets of Jiaotai Pills in treating depression and the "compound-target-pathway" network. DAVID was used for Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses of the core targets. The mouse model of depression was established with chronic unpredictable mild stress(CUMS) and treated with different doses of Jiaotai Pills. The behavioral changes and pathological changes in the hippocampus were observed. UHPLC-Orbitrap Exploris 120 was used for metabolic profiling of the serum, from which the differential metabolites and related metabolic pathways were screened. A "metabolite-reaction-enzyme-gene" network was constructed for the integrated analysis of metabolomics and network pharmacology. A total of 34 chemical components of Jiaotai Pills were identified, and 143 core targets of Jiaotai Pills in treating depression were predicted, which were mainly involved in the arginine and proline, sphingolipid, and neurotrophin metabolism signaling pathways. The results of animal experiments showed that Jiaotai Pills alleviated the depression behaviors and pathological changes in the hippocampus of the mouse model of CUMS-induced depression. In addition, Jiaotai Pills reversed the levels of 32 metabolites involved in various pathways such as arginine and proline metabolism, sphingolipid metabolism, and porphyrin metabolism in the serum of model mice. The integrated analysis showed that arginine and proline metabolism, cysteine and methionine metabolism, and porphyrin metabolism might be the key pathways in the treatment of depression with Jiaotai Pills. In conclusion, metabolomics combined with network pharmacology clarifies the antidepressant mechanism of Jiaotai Pills, which may provide a basis for the clinical application of Jiaotai Pills in treating depression.
Animals ; Drugs, Chinese Herbal/chemistry* ; Depression/genetics* ; Mice ; Network Pharmacology ; Metabolomics ; Male ; Disease Models, Animal ; Humans ; Protein Interaction Maps/drug effects* ; Antidepressive Agents

As the population is aging rapidly,the incidence of Alzheimer's disease(AD)is increasing year by year.The World Health Organization stresses that early prevention plays a key role in reducing the incidence of AD.Subjective cognitive decline(SCD)is an early window of AD development,and timely intervention can effectively slow down the progression of the disease or prevent it from developing into dementia,thus reducing the burden on the society.White matter hyperintensity(WMH)can effectively reflect white matter changes and provide strong evidence to identify SCD.In this paper,we review the recent research progress in WMH and SCD,reveal the problems in the current research on WMH,explain the correlation between WMH and SCD in terms of physiopathology and cognitive function,and put forward several suggestions for the future research.
Humans ; White Matter/pathology* ; Cognitive Dysfunction/pathology* ; Alzheimer Disease/pathology* ; Magnetic Resonance Imaging

Objective To investigate the clinical effect of apical microsurgery combined with guided bone regeneration(GBR)on refractory apical periodontitis and masticatory function.Methods A total of 82 patients with refractory apical periodontitis admitted to our hospital from June 2019 to September 2021 were selected as the study subjects,and they were divided into the control group and the com-bined group according to the random number table,with 41 cases in each group.The control group was treated with apical microsurgery,and the combined group was treated with apical microsurgery combined with GBR.The clinical efficacy,masticatory function and the levels of bone absorption markers[Wnt3a,osteoprotegerin(OPG),receptor activator of nuclear factor-κB ligand(RANKL)]of patients in the two groups were compared.Results The total effective rate of the combined group(100%)was higher than that of the control group(85.37%),the difference was statistically significant(P<0.05).The masticatory efficiency and bite force of patients in both groups increased gradually 3,6 and 12 months after operation(P<0.05),which were higher in the combined group compared with the control group(P<0.05).The tooth mobility of patients in both groups decreased gradually 3,6 and 12 months after operation,and the tooth mobility of patients 3 and 6 months after operation in the combined group were lower than those in the control group(P<0.05).The levels of Wnt3a and OPG of patients 1 week after operation in both groups increased,which were higher in the combined group compared with the control group(P<0.05).The RANKL level of gingival crevicular fluid of patients 1 week after operation in both groups decreased,and which was lower in the combined group compared with the control group(P<0.05).Conclusion The microapical surgery combined with GBR is effective for refractory apical periodontitis,which can effectively inhibit bone resorption,and improve masticatory function.

Objective To investigate the predictive value of new simplified insulin resistance(IR)assessment indexes in identifying subclinical left ventricular systolic function impairment in patients with type 2 diabetes mellitus(T2DM).Methods A total of 150 T2DM patients with preserved left ventricular ejection fraction(LVEF≥50%)who were admitted to Department of Endocrinology of the First Affiliated Hospital of Air Force Medical University from June 2021 to December 2021 were retrospectively analyzed.All patients underwent two-dimensional speckle tracking echocardiography to measure left ventricular global longitudinal strain(GLS).According to GLS value,the subjects were divided into the normal group(GLS≥18%group,n=80)and the impaired group(GLS<18%group,n=70).Some new simplified IR assessment indicators were calculated and compared between the two groups,including body mass index(BMI),TG/HDL-C ratio,triglyceride-glucose(TyG)index,TyG-BMI index,TyG-WHR and metabolic score for IR(METS-IR).Correlation between the GLS and the new simplified IR assessment indexes was analyzed.The receiver operating characteristic(ROC)curve was used to analyze the diagnostic efficacy of different simplified IR assessment indexes,with the area under the curve(AUC)calculated.Furthermore,according to whether the subjects were complicated with hypertension,binary logistics regression analysis was performed to explore the independent correlation between the simplified IR assessment index and GLS<18%.Results Total 150 were included with aged(54.5±13.7)years with 96(64.0%)men and 54(36.0%)women.Compared with the GLS≥18%group,the TG/HDL-C ratio,TyG index,TyG-BMI,and METS-IR of subjects in the GLS<18%group were significantly increased(P<0.05).Pearson correlation analysis showed that TG/HDL-C ratio,TyG index,TyG-BMI,TyG-WHR,and METS-IR were negatively correlated with GLS(P<0.05).ROC analysis showed that TyG index had a certain predictive value for the evaluation of GLS<18%(AUC=0.678,95%CI 0.591-0.765,P<0.001).Stratification based on hypertension and further adjusting for confounding factors,TyG index remains significantly associated with GLS<18%(OR=3.249,95%CI 1.045-10.103,P=0.042).Conclusions The novel simplified insulin resistance evaluation indexes are closely associated with left ventricular subclinical systolic dysfunction in T2DM patients with preserved ejection fraction.TyG index is an effective index to identify left ventricular subclinical dysfunction in these populations.

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

Objective To investigate the effects of 5'-N-ethylocarbo-xamidoad-enosine(NECA)on cerebral ischemia-reperfusion oxidative injury and the levels of miR-29b and miR-125b in rats.Methods SD rats were divided into sham-operation,model,experimental and positive control groups with 12 rats in each group.Cerebral ischemia-reperfusion model was established in all the other 3 groups except control group.7 days before modeling,sham-operation group and model group were intraperitoneally injected with the same amount of normal saline,and experimental group was injected with 1.5 mg·kg-1 NECA,and positive control group was injected with 2.0 mg·kg-1 nimodipine.The rats in 4 groups were given the drug once a day for 7 days.Cerebral ischemia-reperfusion model was established by middle cerebral artery embolization in all the other 3 groups except sham-operation group.After the modeling was successful,the serum oxidative stress indexes glutathione(GSH),superoxide dismutase(SOD),catalase(CAT),malondialdehyde(MDA)of rats were determined by enzyme-linked immunosorbent assay,and the levels of miR-29b and miR-125b in brain tissue were detected by real-time fluorescence quantitative polymerase chain reaction.Results The SOD levels of sham-operation,model,experimental and positive control groups were(57.82±6.87),(10.75±0.24),(32.24±3.42)and(29.45±4.11)U·mL-1;the levels of GSH were(20.62±3.12),(9.45±1.92),(16.78±1.85)and(15.39±2.02)U·mg-1;the levels of CAT were(3.25±0.42),(0.85±0.11),(2.18±0.34)and(1.98±0.32)U·L-1;the levels of MDA were(0.42±0.09),(1.35±0.42),(0.75±0.06)and(0.72±0.08)nmol·mg-1;the expression levels of miR-29b in brain tissue were 1.02±0.11,0.42±0.02,0.84±0.08 and 0.87±0.10;the expression levels of miR-125b in brain tissue were 1.00±0.11,0.48±0.05,0.75±0.08 and 0.74±0.07,respectively.There were statistically significant differences between sham-operation group and model group(all P＜0.05).Compared with experimental group and positive control group,there were statistically significant differences in the above indexes(all P＜0.05).Conclusion NECA can improve oxidative damage and increase the expression levels of miR-29b and miR-125b in cerebral ischemia-reperfusion rats.

Objective:To screen interleukin(IL)-1β secretion-related membrane transporters by macrophage experiment in vitro and conventional knockout mice.Methods:THP-1 cell line was differentiated to obtain human THP-1-derived macrophages,and the primary macrophages were obtained from human peripheral blood.FVB wild-type mice with the same sex and age were used as the controls of MRP1 knockout mice.The macrophages in abdominal cavity and bone marrow of mice were cultivated.The cells were treated with ABCC1/MRP1,ABCG2/BCRP,ABCB1/P-gp,OATP1B1,and MATE transporter inhibitors,then stimulated by lipopolysaccharide and adenosine triphosphate.The secretion level of IL-iβ was detected by ELISA,Western blot,and immunofluorescence.Results:After inhibiting ABCC1/MRP1 transporter,the secretion of IL-1β decreased significantly,while inhibition of the other 4 transporters had no effect.In animal experiment,the level of IL-1 β secreted by macrophages in bone marrow of MRP1 knockout mice was significantly lower than control group(P＜0.05).Conclusion:ABCC1/MRP1 transporter is a newly discovered IL-1β secretion pathway,which is expected to become a new target for solving clinical problems such as cytokine release syndrome.

Objective To investigate the value of 18F labeled prostate-specific membrane antigen(18F-PSMA)-1007 developing agent PET/CT(18F-PSMA-1007PET/CT)examination in the diagnostic evaluation and therapeutic decision of the newly diagnosed prostate cancer(PCa)and follow up after radical prostatecto-my(RP).Methods This study adopted the retrospective observational study method.A total of 68 patients receiving 18 F-PSMA-1007 PET/CT examination in this hospital from September 2022 to October 2023 were analyzed,including 36 cases of newly diagnosed PCa and 32 cases of biochemistry follow up failure after RP.A total of 30 items of clinical data were collected,including 8 items of basic clinical characteristics,7 items of pa-thology-related characteristics and 15 items of imaging characteristics.The patients clinical characteristics in the newly diagnosed PCa and biochemical failure after RP conducted the descriptive analysis.The Fisher exact probability method was used to analyze the differentiation of the SUVmax of primary lesions in different clini-cal subgroups[different tPSA levels at diagnosis,different mi-T stages,different Gleason scores at postopera-tive pathological puncture and different pathological types]in the newly diagnosed PCa group and the differ-entiation of recurrent lesion detection rates in different clinical subgroups(different tPSA in 18F-PSMA-1007 PET/CT examination,different pathological T stages,different lymph node invasion and different pathological Gleason scores in the biochemical failure after RP group.The Spearman correlation was adopted to test and analyze the correlation between the imaging features of positive lesions and tPSA.Results In the newly diag-nosed PCa group,there were 1 case of prostatic hyperplasia and 35 cases of PCa.SUVmax had no statistical differences among the primary lesions with different tPSA levels(P=0.81),different mi-T stages(P=0.70),different puncture Glleasonscores(P=0.20)and different pathological types(P=0.71).Moreover the tPSA value at diagnosis was positively correlated with the number of metastatic lesions(r=0.410,P=0.01).The clinical treatment decisions in 11 cases(31.43％)were changed according to the examination re-sults.In 9 cases of RP combined with lymph node dissection,the accuracy rate and concordance rate of 18F-PS-MA-1007 PET/CT and MRI in the lymph node detection rate all were 100％.I n the biochemical failure after RP group,the overall recurrent lesion detection rate was 71.88％(23/32),the operative area in situ recurrence(11 cases,34.38％)and bone metastasis(11 cases,34.38％)were most common.The differences of 18F-PS-MA-1007 PET/CT recurrent lesions detection rates had no statistical differences among the patients with dif-ferent tPSA levels(P=0.08),different pathological T stages(P=0.10),different postoperative pathological lymph node invasions(P=0.68)and different pathologic Gleason score in the 18F-PSMA-1007 PET/CT ex-amination.In the 18 F-PSMA-1007 PET/CT examination in the biochemical failure after RP,the tPSA value in the recurrent lesion was positively correlated with the number of recurrent lesions(r=0.48,P=0.01),SUVmax value in the recurrent lesion(r=0.46,P=0.01)and the SUVmean value(r=0.38,P=0.03).The clinical treatment decision in 18 cases(56.25％)was changed according to the examination results.Conclusion 18 F-PSMA-1007 PET/CT has good diagnostic value and efficiency for primary lesion and metastasis lesion of new-ly diagnosed PCa and recurrent foci of biochemical failure after RP.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*