OBJECTIVE: To observe the effect of heat-sensitive moxibustion at "Feishu" (BL13) on immunoinflammatory response in rats with allergic rhinitis (AR) based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, so as to explore its underlying mechanism. METHODS: Thirty-two male SD rats were randomly divided into a blank group (6 rats) and a modeling group (26 rats). In the modeling group, AR model was prepared using systemic and local attack sensitization method with ovalbumin. The successfully-modeled rats were randomized into a model group (6 rats), a medication group (6 rats) and a moxibustion group (14 rats). In the moxibustion group, the suspending moxibustion was operated at bilateral "Feishu" (BL13), 40 min each time, once daily, for 21 consecutive days; during which, the temperature of the body and tail was recorded. During intervention, if the temperature of the body and tail increased by >1 ℃, the heat-sensitive reaction at the point was determined in the rats of the moxibustion group, and these rats were collected in a heat-sensitive moxibustion group (8 rats involved and 6 rats of them were randomly collected to ensure the sample-size consistency); and those without heat-sensitive moxibustion reaction were assigned to a traditional moxibustion group (6 rats). In the medication group, fluticasone propionate nasal spray was applied, 8 μL on each side, once daily and for 21 days. The behavioral score for AR symptoms after modeling and intervention, and the content of serum immunoglobulin E (IgE) after modeling were observed. After intervention, the histological morphology of the nasal mucosa was observed using HE staining, the positive expression of thymic stromal lymphopoietin (TSLP) in the nasal mucosa was detected using immunohistochemistry, the levels of IgE, interleukin (IL)-4, IL-5, IL-13 and interferon-γ (IFN-γ) were detected by ELISA, and the protein expression of the member 4 of tumor necrosis factor receptor superfamily (OX40), phosphorylated protein kinase B (p-AKT), phosphorylated phosphatidylinositol 3-kinase (p-PI3K) in nasal mucosa was detected by Western blotting. RESULTS: After modeling, the behavioral score of AR symptoms and serum IgE level in the modeling group were higher than those of the blank group (P<0.01), suggesting the success of AR modeling. After intervention, compared with the blank group, the behavioral score of AR symptoms was increased (P<0.01)；the nasal mucosa structure was disordered, the inflammatory infiltration was severe; the positive expression of TSLP in the nasal mucosa increased (P<0.01), the levels of serum IgE, IL-4, IL-5, and IL-13 elevated (P<0.01), and the level of IFN-γ decreased (P<0.01); and the protein expression of OX40, p-AKT, and p-PI3K in the nasal mucosa increased (P<0.05) in the model group. Compared with the model group, the behavioral score of AR symptoms was reduced (P<0.01); the nasal mucosa structure, inflammatory infiltration, and vascular dilation were ameliorated to varying degrees; the positive expression of TSLP in the nasal mucosa decreased (P<0.01); the content of serum IgE, IL-4, IL-5, and IL-13 decreased (P<0.05), and that of IFN-γ increased (P<0.05) in the medication, traditional moxibustion, and heat-sensitive moxibustion groups. Compared with the model group, the protein expression of p-AKT was reduced in the medication and traditional moxibustion groups (P<0.05), the protein expression of OX40, p-AKT, and p-PI3K in the nasal mucosa decreased in the heat-sensitive moxibustion group (P<0.05). When compared with the medication group, the positive expression of TSLP in the nasal mucosa was reduced (P<0.05) in the heat-sensitive moxibustion group. In comparison with the traditional moxibustion group, the content of serum IL-13 was reduced and the content of IFN-γ elevated in the heat-sensitive moxibustion and the medication groups (P<0.05), the protein expression of p-PI3K reduced in the medication group (P<0.05), and the positive expression of TSLP and the protein expression of OX40 and p-PI3K in the nasal mucosa were reduced in the heat-sensitive moxibustion group (P<0.05). CONCLUSION Heat-sensitive moxibustion at "Feishu" (BL13) can alleviate the symptoms of AR rats, ameliorate the inflammatory infiltration and telangiectasia of nasal mucosa, and inhibit immunoinflammatory response, which may be obtained by regulating PI3K/AKT signal pathway.
Animals ; Moxibustion ; Male ; Rats ; Signal Transduction ; Rats, Sprague-Dawley ; Rhinitis, Allergic/genetics* ; Proto-Oncogene Proteins c-akt/immunology* ; Acupuncture Points ; Humans ; Phosphatidylinositol 3-Kinases/immunology* ; Phosphatidylinositol 3-Kinase/immunology*

BACKGROUND: Immunosuppression is closely related to the pathogenesis of sepsis, but the underlying mechanisms have not yet been fully elucidated. In this study, we aimed to examine the role of the Sterile Alpha Motif, Src Homology 3 domain and nuclear localization signal 1 (SAMSN1) in sepsis and elucidate its potential molecular mechanism in sepsis induced immunosuppression. METHODS: RNA sequencing databases were used to validate SAMSN1 expression in sepsis. The impact of SAMSN1 on sepsis was verified using gene knockout mice. Flow cytometry was employed to delineate how SAMSN1 affects immunity in sepsis, focusing on immune cell types and T cell functions. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated gene editing in RAW264.7 macrophages enabled interrogation of SAMSN1 's regulatory effects on essential macrophage functions, including cell proliferation and phagocytic capacity. The mechanism of SAMSN1 in the interaction between macrophages and T cells was investigated using the RAW264.7 cell line and primary cell lines. RESULTS: SAMSN1 expression was significantly increased in patients with sepsis and was positively correlated with sepsis mortality. Genetic deletion of Samsn1 in murine sepsis model improved T cell survival, elevated T cell cytolytic activity, and activated T cell signaling transduction. Concurrently, Samsn1 knockout augmented macrophage proliferation capacity and phagocytic efficiency. In macrophage, SAMSN1 binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), causing nuclear factor erythroid 2-related factor 2 (NRF2) to dissociate from the KEAP1-NRF2 complex and translocate into the nucleus. This promotes the transcription of the coinhibitory molecules CD48/CD86/carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), which bind to their corresponding receptors natural killer cell receptor 2B4/CD152/T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on the surface of T cells, inducing T-cell exhaustion. CONCLUSIONS SAMSN1 deletion augmented adaptive T cell immunity and macrophage phagocytic-proliferative dual function. Furthermore, it mediates the KEAP1-NRF2 axis, which affects the expression of coinhibitory molecules on macrophages, leading to T-cell exhaustion. This novel immunosuppression mechanism potentially provides a candidate molecular target for sepsis immunotherapy.
Animals ; NF-E2-Related Factor 2/metabolism* ; Mice ; Macrophages/immunology* ; Sepsis/metabolism* ; Kelch-Like ECH-Associated Protein 1/genetics* ; T-Lymphocytes/immunology* ; Humans ; Signal Transduction/physiology* ; RAW 264.7 Cells ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Flow Cytometry ; T-Cell Exhaustion

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Objective To investigate whether exposure pathways influence the distribution pattern and toxicity of polystyrene nanoplastics(PSNPs)in hepatic cells.Methods Male C57BL/6J wild-type healthy mice aged 6 to 8 weeks old and weighed 18 to 22 g were administered with PSNPs via gavage or tail vein injection.Then,we tracked PSNPs distribution in the major organs of mice via an in vivo imaging system(IVIS).After that,we analyzed the cellular accumulation patterns in hepatic cell subpopulations(hepatocytes and Kupffer cells)using immunofluorescence and transmission electron microscopy(TEM).300 nm PSNPs were administered via gastric gavage or tail vein injection,and 70 nm PSNPs were injected via the portal vein.The cellular localization of PSNPs in the liver was analyzed using immunofluorescence.Subsequently,using AML-12 cells,a normal mouse liver cell line,as the parenchymal hepatocyte model,the uptake of PSNPs in AML-12 cells was analyzed by confocal laser scanning microscope(CLSM).Flow cytometry was performed to observe and quantify PSNPs uptake,and to analyze the underlying endocytosis mechanisms.IVIS was used to analyze PSNPs uptake features in vivo.Finally,using mouse macrophage line RAW264.7 as a Kupffer cell model and AML-12 cells as a parenchymal hepatocyte model,the cell-type-specific toxic effects induced by 100 μg/ml PSNPs were examined through transcriptomics and metabolomics analyses.Results IVIS revealed predominant hepatic accumulation of PSNPs regardless of exposure pathways via intragastric gavage or tail vein injection.Immunofluorescence/TEM demonstrated exposure pathway-dependent cellular distribution:intragastric PSNPs were localized mainly in hepatocytes,while intravenous PSNPs were accumulated in Kupffer cells.Changes in particle size(300 nm vs.70 nm)did not alter the cellular distribution pattern,while 70 nm PSNPs injected via the portal vein accumulated in Kupffer cells,which suggested that the cell-type-specific distribution of PSNPs in the liver was independent of PSNPs size and might be related to the transport of PSNPs in the gastrointestinal tract.Flow cytometry showed that PSNPs uptake by AML-12 was time-dependent and that the underlying endocytosis mechanism involved pathways mediated by clathrin(P<0.000 1),macropinocytosis(P=0.002 6),and lipid rafts(P<0.000 1).Findings on PSNPs distribution in blood revealed that the uptake of PSNPs by hepatocytes exhibited a rate saturation phenomenon.Multi-omics analysis identified distinct toxicity patterns:PSNPs disrupted lipid metabolism and neurotransmitter homeostasis in AML-12 cells and induced inflammation and oxidative stress in Kupffer cells.Conclusion Exposure pathways mediate the hepatic cell-type-specific distribution of PSNPs,thereby altering the downstream toxicological consequences induced by exposure to PSNPs.

Humans ; Aged ; Lung Diseases ; Pneumonia/drug therapy* ; Adrenal Cortex Hormones/therapeutic use* ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Administration, Inhalation ; Community-Acquired Infections/drug therapy*

Background::Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV.Methods::Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses.Results::ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure ( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). Conclusions::Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.Trial registration::Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Breast cancer has become one of the most prevalent cancers among women worldwide,posing a significant burden on their health.Current standard therapies are often expensive and associated with the risk of drug resistance.Drug repurposing has gained increasing attention as a cost-effective and time-saving strategy in pharmaceutical research.Many drugs already in clinical use or undergoing clinical trials can be repurposed for the treatment of new clinical indications.Based on a comprehensive understanding of the mechanisms of action of these drugs and the pathophysiological processes of breast cancer,researchers can better identify drugs with potential anti-breast cancer properties and translate them into clinical practice.This paper provides a review of the current research on repurposing existing drugs for breast cancer treatment,summarizes the mechanisms of action of these drugs,and discusses the challenges associated with the strategy of drug repurposing.

Objective:To examine the satisfaction and teaching effectiveness of Health Statistics among students majoring in Public Utility Administration,and to provide valuable insights for optimizing current teaching practices and enhancing teaching effectiveness.Methods:A survey questionnaire,specifically designed for this study,was administered to 56 students of grade 2021 majoring in Public Utility Administration in our school.The questionnaire covered topics such as the difficulty of teaching content,learning satisfaction,and the Student Evaluation of Educational Quality(SEEQ)scale.Results:Non-parametric testing was considered the most difficult knowledge point,and male students found statistical inference of quantitative data was the most challenging,while female students found non-parametric testing was the most difficult.In terms of satisfaction,the highest score was obtained for pre-class review,while the lowest score was given to improving learning interest in Rain Classroom.The overall score for teaching effectiveness,as measured by SEEQ,was good across seven dimensions.Teaching enthusiasm received the highest score(4.40±0.43),while homework volume received the lowest score(3.23±0.37).With the exception of homework grading,satisfaction was positively correlated with most dimensions of teaching effectiveness evaluation.Conclusions:Despite perceiving the course as generally difficult,students expressed high satisfaction and overall positive evaluation of teaching effectiveness.Therefore,it is recommended to actively explore new teaching reforms to cultivate well-rounded applied talents for public utilities.

Objective To analyze the application dose of ciprofol combined with fentanyl in patients undergoing gastroscopy.Method 99 gastroscopy patients from June 2021 to June 2023 were selected as the study objects,and divided into three groups with 33 cases each by random number table method.Group A was given 0.3 mg/kg ciprofol+1.5 μg/kg fentanyl anesthesia,group B was given 0.4 mg/kg ciprofol+1.5 μg/kg fentanyl anesthesia,group C was given 0.5 mg/kg ciprofol+1.5 μg/kg fentanyl anesthesia.Anesthesia,examination,electroencephalogram bispectral index(BIS),mean arterial pressure(MAP),heart rate(HR)and adverse reaction were compared among all groups.Results The success rate of the first anesthesia in Group A was lower than that in Group B and Group C,the gastroscopy examination time was longer than that in Group B and Group C,and the awakening time and hospital leave time were shorter than those in Group B and Group C,the awakening time and hospitalization time of Group B were shorter than those of Group C,the BIS of Group A at time points T2 to T5 was higher than that of Group B and Group C,the MAP and HR levels at time points T2 to T5 in Group A were lower than those in Group B and Group C,the incidence of body movement and coughing in Group A was higher than that in Group B and Group C,the incidence of hypotension and nausea and vomiting in Group C was higher than that in Group A and Group B,and the differences were statistically significant(P<0.05).One patient in Group A and one patient in Group C stopped gastroscopy due to hypoxemia,Group B did not experience hypoxemia,and the difference was not statistically significant(P>0.05).There were 4 cases in Group A,6 cases in Group B and 10 cases in Group C who received intervention with vasoactive drugs due to hypotension,and the difference was statistically significant(P<0.05).Conclusion Patients undergoing gastroscopy which should use 0.4 mg/kg ciprofol+1.5 μg/kg fentanyl anesthesia can achieve better anesthesia effect,shorten examination time and hospitalization time,stabilize vital signs,and reduce adverse reaction incidence rate.

Objective To investigate the effect of smoking on the semen quality in infertile men.Methods A total of 360 male infertility patients were enrolled and divided into the smoking group(n=190)and non-smoking group(n=170)based on whether they smoked or not.Furthermore,the smoking group was subdivided into group A(≤10 sticks/d,n=63),group B(11～20 sticks/d,n=80),and group C(>20 sticks/d group,n=47)according to the amount of smoking.Semen volume,liquefaction time,sperm concentration,motility,DNA fragmentation rate and normal morphological rate were observed and compared between and within the groups.Results There were significant differences in semen volume,liquefaction time,sperm motility,normal morphological rate and DNA fragmentation rate between the smoking group and the non-smoking group(P<0.05).The semen volume,sperm motility and normal morphological rate of the smoking group were lower than those in the non-smoking group,and the DNA fragmentation rate and semen liquefaction time were higher than those in the non-smoking group.And with the increase of smoking volume,sperm motility and normal morphological rate decreased,semen liquefaction time and DNA fragmentation rate increased,and there was no significant difference in the sperm concentration between the smoking group and non-smoking group(P>0.05).There was no significant difference in the semen volume between the three groups with different smoking amounts(P>0.05).Conclusion Smoking has a negative impact on the sperm quality parameters such as semen volume,sperm motility,normal morphological rate,sperm motility,liquefaction time and DNA fragmentation,and the effect of heavy smoking is particularly obvious.We should strengthen the comprehensive health education,promote the healthy lifestyles and reduce smoking.