Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

The medicinal materials of Bawei Chenxiang Pills(BCPs) were extracted via three methods: reflux extraction by water, reflux extraction by 70% ethanol, and extraction by pure water following reflux extraction by 70% ethanol, yielding three extracts of ST, CT, and CST. The efficacy of ST(760 mg·kg~(-1)), CT(620 mg·kg~(-1)), and CST(1 040 mg·kg~(-1)) were evaluated by acute myocardial ischemia(AMI) and p-chlorophenylalanine(PCPA)-induced insomnia in mice, respectively. Western blot was further utilized to investigate their hypnosis mechanisms. The main chemical components of different extracts were identified by the UPLC-Q-Exactive-MS technique. The results showed that CT and CST significantly increased the ejection fraction(EF) and fractional shortening(FS) of myocardial infarction mice, reduced left ventricular internal dimension at end-diastole(LVIDd) and left ventricular internal dimension at end-systole(LVIDs). In contrast, ST did not exhibit significant effects on these parameters. In the insomnia model, CT significantly reduced sleep latency and prolonged sleep duration, whereas ST only prolonged sleep duration without shortening sleep latency. CST showed no significant effects on either sleep latency or sleep duration. Additionally, both CT and ST upregulated glutamic acid decarboxylase 67(GAD67) protein expression in brain tissue. A total of 15 main chemical components were identified from CT, including 2-(2-phenylethyl) chromone and 6-methoxy-2-(2-phenylethyl) chromone. Six chemical components including chebulidic acid were identified from ST. The results suggested that chromones and terpenes were potential anti-myocardial ischemia drugs of BCPs, and tannin and phenolic acids were potential hypnosis drugs. This study enriches the pharmacological and chemical research of BCPs, providing a basis and reference for their secondary development, quality standard improvement, and clinical application.
Animals ; Drugs, Chinese Herbal/isolation & purification* ; Mice ; Male ; Sleep Initiation and Maintenance Disorders/physiopathology* ; Humans ; Myocardial Infarction/drug therapy* ; Myocardial Ischemia/drug therapy*

OBJECTIVES: To investigate the application value of thromboelastography (TEG) in assessing coagulation function in children with severe hemophilia A (HA) after emicizumab (EMI) therapy. METHODS: A retrospective analysis was performed on the activated partial thromboplastin time (APTT) and TEG testing results of 17 children with severe HA before and after EMI treatment at Shenzhen Children's Hospital from January 2023 to July 2024. Correlation analysis was conducted between coagulation factor VIII (FVIII) equivalent activity and reaction time (R value) measured by TEG. RESULTS: After EMI treatment, the mean bleeding rate for children with severe HA was 1.6 events per year, with 15 children (88%) without spontaneous bleeding or joint bleeding. The children with severe HA showed a significant reduction in APTT after EMI treatment (P<0.05), with a significantly shorter APTT than the normal control group (P<0.05). There was no correlation between APTT and FVIII equivalent activity after treatment (P>0.05). After EMI treatment, TEG parameters, including R value, kinetic time, alpha angle (α), maximum amplitude, clot strength, and coagulation index, shifted from a hypocoagulable state before treatment to a nearly normal state after treatment (P<0.05). The R value demonstrated a strong negative correlation with FVIII equivalent activity (r=-0.758, P<0.05). CONCLUSIONS The bleeding condition of children with severe HA can be effectively controlled after EMI treatment. Routine APTT testing cannot reflect true coagulation function, whereas TEG testing is clinically valuable in assessing the coagulation function of children with severe HA undergoing EMI treatment.
Humans ; Thrombelastography ; Hemophilia A/physiopathology* ; Male ; Child ; Antibodies, Bispecific/therapeutic use* ; Antibodies, Monoclonal, Humanized/therapeutic use* ; Blood Coagulation/drug effects* ; Child, Preschool ; Retrospective Studies ; Female ; Partial Thromboplastin Time ; Adolescent ; Infant

Castleman's disease is a rare polyclonal lymphoproliferative disorder.This article reports the diagnosis and treatment of a 45-year-old female patient with idiopathic multicentric Castleman's disease.The patient presented recurrent fever,enlarged lymph nodes,and elevated levels of inflammation markers.After multiple serological examinations and tissue biopsies,she was diagnosed with hyaline vascular-type Castleman's disease.Initially,the patient received siltuximab targeting interleukin-6,which significantly improved her condition.Considering the cost and convenience of long-term treatment,she subsequently switched the therapy to an oral treatment regimen of thalidomide,cyclophosphamide,and prednisone (TCP),which maintained disease control.This report aims to highlight the diagnostic complexity and diversity of treatment options for idiopathic multicentric Castleman's disease,demonstrating the potential of the TCP regimen as a cost-effective treatment choice.
Humans ; Castleman Disease/drug therapy* ; Female ; Middle Aged ; Thalidomide/therapeutic use* ; Prednisone/therapeutic use* ; Cyclophosphamide/therapeutic use* ; Antibodies, Monoclonal/administration & dosage*

Nodal marginal zone B-cell lymphoma(NMZL),the least common subtype of marginal zone lymphoma,represents a low-grade malignancy arising from the marginal zone of lymph node follicles,composed of small B-cells with an inert non-Hodgkin lymphoma nature.It accounts for 1.5% to 1.8% of all non-Hodgkin lymphomas and 10% of all marginal zone lymphomas.The low incidence and lack of typical clinical and pathological features pose a challenge to the diagnosis and clinical management of NMZL.In this article,we reported the diagnosis and treatment of a case of NMZL located in the parapharyngeal space of the left neck and reviewed the relevant literature from both domestic and international sources.We summarized the clinical manifestations,histopathological features,immunohistochemical characteristics,imaging features,diagnosis and treatment modalities,and prognosis of NMZL.
Humans ; Lymphoma, B-Cell, Marginal Zone/pathology* ; Lymph Nodes/pathology* ; Neck/pathology* ; Male

OBJECTIVE To evaluate the mechanisms underlying the antidepressant effect of ZBH2012001,a novel serotonin and norepinephrine reuptake inhibitor(SNRI),in general and its ability to enhance monoaminergic transmission and suppress neuroinflammation in particular.METHODS① Male ICR mice were divided into vehicle(distilled water),duloxetine(DLX,10 or 20 mg·kg-1)and ZBH2012001(5,10 and 20 mg·kg-1)groups.One hour following ig administration,the antidepressant effect of ZBH2012001 was evaluated using the tail suspension test(TST)and forced swimming test(FST).② Radioligand binding assay was conducted to evaluate the affinity of ZBH2012001 for human serotonin transporters(hSERTs)and human norepinephrine transporters(hNETs).③ Mice were divided into vehicle(distilled water),DLX(10 or 20 mg·kg-1)and ZBH2012001(5,10 and 20 mg·kg-1)groups.One hour following drug administration,the 5-hydroxytryptophan(5-HTP)-induced head-twitch test or yohimbine-induced lethality test were performed to evaluate the effect of ZBH2012001 on the function of the 5-hydroxytryptamine(5-HT)and norepinephrine(NE)systems.④ Mice were divided into vehicle(distilled water+0.1%acetic acid),reserpine model(distilled water+reserpine 5 mg·kg-1),DLX(DLX 20 mg·kg-1+reserpine 5 mg·kg-1)and ZBH2012001(ZBH2012001 5,10 and 20 mg·kg-1+reserpine 5 mg·kg-1)groups.One hour following drug administration,reserpine was injected intraperitoneally to establish a monoamine-depletion model.The ptosis,akinesia,and hypothermia assays were performed to evaluate the effect of ZBH2012001 on the down-regulation of the reserpine-induced monoamine system.The TST in mice was used to evaluate the effect of ZBH2012001 on reserpine-induced depressive-like behavior while high-performance liquid chromatography with electrochemical detection(HPLC-ECD)was used to measure the levels of monoamines and their metabolites in the hippocampal tissue of reserpine-induced monoamine-depletion mice.ELISA was employed to detect the contents of tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6)in the hippocampal tissue of reserpine-induced monoamine-depletion mice.Western blotting was used to assess the expressions of ionized calcium-binding adapter molecule-1(Iba-1)and nuclear factor-kappa B(NF-κB)in the hippocampal tissue of reserpine-induced monoamine-depletion mice.RESULTS ① Compared with the vehicle group,ZBH2012001(5,10 and 20 mg·kg-1)significantly reduced the immobility time both in the TST in mice(P<0.01,respectively),and ZBH2012001(20 mg·kg-1)and in the FST in mice(P<0.05).② ZBH2012001 competitively inhibited the binding of[3H]-imipramine to hSERTs and[3H]-nisoxetine to hNETs,with the half maximal inhibitory concentration(IC50)values of 84.95 and 712.90 nmol·L-1,respectively.③Com-pared with the vehicle group,ZBH2012001(10 and 20 mg·kg-1)significantly increased the head twitches induced by 5-HTP in mice(P<0.01,respectively)and increased the mortality rate in mice induced by yohimbine(P<0.05,P<0.01).④ In the reserpine-induced monoamine-depletion model in mice,compared with the vehicle group,mice in the reserpine model group exhibited ptosis,akinesia and hypothermia feature(P<0.01,respectively),significantly prolonged immobility time in the TST(P<0.01),significantly decreased the levels of NE,5-HT and dopamine(DA)(P<0.05,P<0.01),significantly increased the metabolic conversion rate of 5-HT and DA(P<0.01,respectively),significantly elevated levels of TNF-α and IL-6(P<0.05,respectively),and significantly increased expressions of Iba-1 and NF-κB(P<0.05,respectively)in the hippocampus.Compared with the model group,ZBH2012001(5,10 and 20 mg·kg-1)significantly antagonized ptosis and hypothermia behaviors induced by reserpine(P<0.01,respectively),ZBH2012001(10 and 20 mg·kg-1)significantly shortened the immobility time in reserpine-treated mice(P<0.05,P<0.01),ZBH2012001(20 mg·kg-1)significantly increased the levels of NE and 5-HT in the hippocampus of reserpine-treated mice(P<0.05,respectively),decreased the metabolic conversion rate of 5-HT(P<0.05),significantly reduced the contents of TNF-α and IL-6 in the hippocampus of reserpine-treated mice(P<0.05,respectively),ZBH2012001(5,10 and 20 mg·kg-1)significantly reduced the expression of Iba-1 protein in the hippocampus of reserpine-treated mice(P<0.01,respec-tively),and ZBH2012001(20 mg·kg-1)significantly reduced the expression of NF-κB protein in the hippocampus of reserpine-treated mice(P<0.05).CONCLUSION ZBH2012001 exerts its antidepres-sant effect through a dual mechanism involving monoamine enhancement and inflammation suppres-sion.

Objective To observe the therapeutic effect and mechanism of acupuncture at Zusanli-Zhongwan combined matching points on rats with exercise-induced stress gastric ulcer.Methods Forty male SD rats were randomly divided into blank group,model group,acupuncture group and Omeprazole group,with 10 rats in each group.Except for the blank group,the rats in the other groups were used to construct the model of exercise stress gastric ulcer by daily exhaustive swimming.After successful modeling,the acupuncture group was intervened by acupuncture at Zusanli(ST36)and Zhongwan(RN12),once a day,10 minutes each time.Rats in the Omeprazole group were given Omeprazole Enteric-Coated Tablets distilled water suspension by gavage two hours before daily swimming.After continuous 7-day intervention,the overall state and behavior of rats were observed,the gastric mucosal injury index was calculated by Guth method,the pathological morphology of gastric mucosa was observed by hematoxylin-eosin(HE)staining,the contents of superoxide dismutase(SOD),glutathione peroxidase(GSH-PX)and malondialdehyde(MDA)in serum were correspondingly determined by WST-1 method,colorimetry and TBA method,respectively,enzyme-linked immunosorbent assay(ELISA)was used to detect the contents of gastrin(GAS),somatostatin(SS),tumor necrosis factor-α(TNF-α),interleukin-1 β(IL-1β),interleukin-6(IL-6)and interleukin-10(IL-10)in serum,the expression levels of epidermal growth factor receptor(EGFR),matrix metalloproteinase 3(MMP3),nuclear factor erythroid-related factor 2(NRF2),heme oxygenase 1(HO-1)and mitochondrial SOD2,TNF-α,IL-1β,IL-6 and IL-10 mRNA in gastric mucosa were detected by real-time fluorescence quantitative polymerase chain reaction(qPCR).Results Compared with the blank group,the body mass of rats in the model group was increased slowly,the activity distance and activity in the open field test were decreased,the gastric mucosal ulcer index was increased significantly,the gastric mucosal function indexes involving GAS level was increased and SS level was decreased in serum,the mRNA expression level of EGFR in gastric mucosa was decreased and the mRNA expression level of MMP3 in gastric mucosa was increased.The serum levels of antioxidant substances SOD and GSH-PX were decreased significantly,and the serum level of oxidation product MDA was increased significantly.The mRNA expression levels of antioxidant genes NRF2,HO-1 and SOD2 in gastric mucosa were significantly decreased.The serum contents and the gastric mucosa mRNA levels of inflammatory factors TNF-α,IL-1α,IL-6 were significantly increased,while the serum content and the gastric mucosa mRNA level of IL-10 were significantly decreased.The differences were statistically significant(P＜0.05 or P＜0.01 or P＜0.001).HE staining showed obvious gastric mucosal injury.Compared with the model group,the above indexes in the acupuncture group and the Omeprazole group were significantly improved(P＜0.05 or P＜0.01 or P＜0.001).HE staining showed that the gastric mucosal injury was significantly reduced.Conclusion Acupuncture at Zusanli-Zhongwan combined matching points can reduce the local oxidative stress and inflammatory response in rats with exercise-induced stress gastric ulcer,reduce gastric mucosal injury,improve the emotional state of rats,and maintain the overall vitality of rats.

Objective To establish the diagnostic criteria for psoriasis vulgaris of spleen deficiency with dampness accumulation syndrome by using the methods of literature research,subjective experts'experience evaluation and mathematical statistical analysis together.Methods An alternative item pool of symptoms and signs related to psoriasis vulgaris of spleen deficiency with dampness accumulation syndrome was constructed on the basis of the results of literature research.A four-round questionnaire survey was carried out among 32 experts nationwide using the Delphi method,and then the concentration and coordination of the experts'opinions on each of the alternative items were analyzed.In the third round of the survey,all of diagnostic indicators were classified into primary or secondary symptoms according to the weighting coefficients of each item,and then the judgment condition options for the diagnostic criteria of the symptoms were formed.Through the fourth-round of expert survey,the diagnostic mode and diagnostic conditions of spleen deficiency with dampness accumulation syndrome were clarified.Results The alternative diagnostic indicators were screened according to the concentration degree and the variation coefficient of experts'opinions,and 24 diagnostic indicators were obtained after merging the similar indicators,of which there were three primary symptoms(poor appetite and anorexia,loose stool,and pale and swollen tongue with tooth marks)and 21 secondary symptoms(abdominal distension,tastelessness in the mouth without thirst,obesity,drowsiness,fatigue and lack of strength,thready and smooth pulse,soft pulse,undigested food in the stool,and light-red skin lesions,etc.).The fourth-round expert survey confirmed that the necessary conditions for the diagnosis of psoriasis vulgaris of spleen deficiency with dampness accumulation syndrome were"the disease-location of the spleen","the disease-nature of qi deficiency"and"the disease-nature of dampness";the diagnostic criteria for psoriasis of spleen deficiency with dampness accumulation syndrome were as follows:(1)with three primary symptoms;(2)with two primary symptoms and any two of the secondary symptoms.Conclusion The diagnostic criteria for psoriasis vulgaris of spleen deficiency with dampness accumulation syndrome constructed in this study include both primary and secondary symptoms,with clarified conditions and being easy to be practiced clinically,and have good clinical credibility.