Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1^CreERT2; R26^GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6^f/f; CX3CR1^CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
Animals ; Mice ; Macrophages/metabolism* ; Tumor Necrosis Factor-alpha/genetics* ; Tooth Movement Techniques/methods* ; Activating Transcription Factor 6/metabolism* ; Bone Remodeling ; Flow Cytometry ; Blotting, Western

Alopecia areata （AA） is a common hair loss disorder， and the core pathogenesis is the internal gene-ration of turbid toxin caused by qi movement disorder in the liver， spleen， and kidney. Turbid toxin serves as both a pivotal etiological trigger and a pathological driver of disease exacerbation. Clinically， AA can be classified into four principal patterns， including liver constraint with spleen deficiency， internal accumulation of damp-heat， liver-kidney depletion， and qi-blood depletion. Therapeutic strategies prioritize clearing and resolving turbid toxin while regulating the qi movement of the liver， spleen， and kidney. Accordingly， different formulas were applied. Self-formulated Shugan Jianpi Huazhuo Formula （疏肝健脾化浊方） is suggested to drain dampness， resolve turbidity， and unblock qi movement. Self-formulated Sanjiao Fenxiao Jiedu Formula （三焦分消解毒方） can be used to clear heat， drain dampness and resolve toxin. Self-formulated Zishen Yanggan Toudu Decoction （滋肾养肝透毒汤） can clear and vent latent toxins， while Self-formulated Guiqi Shengfa Didu Formula （归芪生发涤毒方） is employed to tonify qi and blood， purge toxins， and regenerate vitality. By differentiating and treating AA based on the functional patterns of the liver， spleen， and kidney， this approach expands the application scope of the turbid toxin theory and provides valuable insights for treatment of AA.

Interferon regulatory factor 1(IRF-1)is a member of the IRF family.It is the first transcription factor to be identified that could bind to the interferon-stimulated response element(ISRE)on the target gene and displays crucial roles in the interferon-induced signals and pathways.IRF-1,as an important medium,has all of the advantages of full cell cycle regulation,cell death signaling transduction,and reinforcing immune surveillance,which are well documented.Current studies indicate that IRF-1 is of vital importance to the occurrence and evolution of multifarious liver diseases,including but not limited to inhibiting the replication of the hepatitis virus(A/B/C/E),alleviating the progression of liver fibrosis,and aggravating hepatic ischemia-reperfusion injury(HIRI).The tumor suppression of IRF-1 is related to the clinical characteristics of liver cancer patients,which makes it a potential indicator for predicting the prognosis and recurrence of liver cancer;additionally,the latest studies have revealed other effects of IRF-1 such as protection against alcoholic/non-alcoholic fatty liver disease(AFLD/NAFLD),cholangiocarcinoma suppression,and uncommon traits in other liver diseases that had previously received little attention.Intriguingly,several compounds and drugs have featured a protective function in specific liver disease models in which there is significant involvement of the IRF-1 signal.In this paper,we hope to propose a prospective research basis upon which to help decipher translational medicine applications of IRF-1 in liver disease treatment.

Objective To investigate the influence of type 2 diabetes mellitus(T2DM)on cognitive function and the effective connectivity with in the default mode network(DMN)in the brain.Methods A total of 93 hospitalized patients diagnosed with T2DM were enrolled in this study as T2DM group from The First Affiliated Hospital of Guangzhou University of Chinese Medicine during September 2021 to December 2022.Simultaneously,108 healthy individuals were recruited from the community as normal control(NC)group.The cognitive functions were evaluated in the two groups.A random dynamic causal modeling approach was employed to analyze the effective connectivity within DMN in both groups.Additionally,Pearson correlation analysis was performed to examine the association between differential connectivity,clinical indicators,and cognitive scores in both groups.Results In comparison to the NC group,T2DM individuals exhibited statistically significant reductions in scores in the auditory verbal learning test(AVLT)for immediate recall and the digit symbol substitution test(DSST)(P＜0.05).Additionally,they displayed a notable decrease in effective connectivity from the left lateral parietal cortex(LLPC)to the posterior cingulate cortex(PCC),as well as from the LLPC to the right lateral parietal cortex(RLPC)within the DMN(P＜0.05).Pearson correlation analysis unveiled a negative association between HbA1c levels and the strength of effective connectivity from LLPC to PCC.Conversely,a positive correlation was observed between AVLT(immediate)scores and the strength of effective connectivity from LLPC to PCC and LLPC to RLPC.Additionally,DSST scores displayed a positive correlation with the strength of effective connectivity from LLPC to PCC(P＜0.05).Conclusion Patients with T2DM display compromised effective connectivity from LLPC to PCC and LLPC to RLPC within the DMN network,and this alteration may associated with cognitive impairment.

Autophagy is mediated by multiple molecules and pathways. In cardiovascular diseases， autophagy can play a role through key signaling pathways such as phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR）， adenosine monophosphate-activated protein kinase （AMPK）/mTOR， mitogen-activated protein kinases （MAPK）， p53， Wnt/β-catenin， etc. Traditional Chinese medicine （TCM） monomers for promoting blood circulation and removing blood stasis such as hydroxysafflor yellow A， ginsenoside Rb1， salidroside， ligustrin， curcumin， etc.， and TCM prescription and preparations such as Huangqi baoxin decoction， Taohong siwu decoction， Tongxinluo capsule， Shuangshen ningxin capsule， Suxiao jiuxin pills， etc. can regulate autophagy through the above-mentioned key signaling pathways， thereby alleviating the progression of cardiovascular diseases.

Microneedles can penetrate the skin barrier to deliver drugs without touching the nociceptive nerves， to effectively increase the efficiency of transdermal drug delivery and improve patient compliance. Exosomes have multiple physiological functions and good biocompatibility， and are natural nanoscale drug carriers. This paper reviews the pathways and advantages of exosomes combined with microneedles for the treatment of diseases， and describes the current research status of exosome microneedle drug delivery system in various diseases. Exosome microneedles can be divided into two categories： （1） exosomes as therapeutic agents， their unique physiological origin can effectively avoid the toxicity and immunogenicity of conventional drugs and other problems； combined with microneedles directly in the specific medication site can greatly improve the metabolic consumption of oral drug delivery and patient compliance of injection drug delivery. （2） Exosomes as drug carriers， their natural vesicle structure and endogenous characteristics can protect the metabolism of foreign drugs in the body and enhance the targeting； combined with microneedles can effectively solve the problem of transdermal delivery of drugs with high efficacy but poor stability. Exosome microneedle drug delivery system is still in the laboratory stage， but it has shown great development prospects in repairing spinal cord injury， promoting diabetic ulcer wound healing， germinating， intervening myocardial infraction， relieving chronic pain and other diseases.

Exosome is a kind of vesicle secreted by a variety of cells with lipid bilayer membrane structure， which has good biocompatibility， high targeting and high stability， and is a natural nanoscale drug carrier with great development potential in drug delivery system. In this paper， exosomes and their properties， exosome drug delivery pathways and methods， the design strategy of engineered exosome drug delivery systems for targeted disease therapy， and the application of exosome drug delivery systems in the treatment of a variety of diseases were reviewed. Exosome drug delivery pathways could be divided into two categories： exogenous and endogenous. Common exosome drug delivery methods included electroporation， co-incubation， and ultrasound. Engineered exosome drug delivery system can further improve drug loading and enhance drug targeting. The main way of engineering is to modify exosome surface through genetic engineering technology， physical modification， chemical modification， etc. Exosome drug delivery system provides a new idea for targeted therapy of arthritis， tumor， brain and other diseases.

Objective To analyze the distribution characteristics and drug resistance of pathogens in infected donors from organ donation after citizen's death. Methods Clinical data of 465 potential donors from organ donation after citizen's death were retrospectively analyzed. The airway secretion, urine and blood samples of all donors were cultured. The infection rate of the donors, the source and composition ratio of pathogens were summarized. The drug resistance of main Gram-negative and Gram-positive pathogens was analyzed. Results Among 465 donors, 330 cases were infected and the infection rate was 71.0%. Among the positive culture samples of all donors, lower respiratory tract samples accounted for 63.8%(292/458), 18.6%(85/458) for blood samples and 17.7%(81/458) for urine samples. A total of 512 pathogens were isolated, including 75.0%(384/512) of Gram-negative pathogens, 18.2%(93/512) of Gram-positive pathogens followed by 6.8%(35/512) of fungi. Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii were the most common Gram-negative pathogens. Klebsiella pneumoniae was sensitive to quinolones, compound preparations containing β-lactamase inhibitor (piperacillin-tazobactam, cefoperazone sodium-sulbactam sodium) and carbapenem antibiotics, whereas less sensitive to cephalosporins. Pseudomonas aeruginosa was sensitive to β-lactams, quinolones and aminoglycosides. Acinetobacter baumannii was sensitive to polymyxin, tigecycline and amikacin, whereas resistant to the other antibiotics. No Gram-positive pathogens was resistant to vancomycin, linezolid and teicoplanin. Staphylococcus aureus and coagulase-negative staphylococci were the most commonly isolated Gram-positive pathogens, which yielded resistance rates of 36% and 87% to oxacillin sodium, and were generally resistant to penicillin and erythromycin. The resistance rate of Enterococcus faecalis to quinolones and erythromycin exceeded 90%, and 55% for high-concentration gentamicin. Conclusions The infection rate of organ donors from organ donation after citizen's death is relatively high, and the main infection site is lung. Gram-negative pathogens are the most commonly isolated strains, and certain strains tend to exhibit multiple drug resistance.

Objective:To explore the effect of intensive insulin therapy on hemodynamics and cardiac function in organ donors.Methods:A total of 60 organ donors were randomly divided into two groups of intensive insulin therapy(IIT)and control(30cases each group). Blood glucose was adjusted at 6.2~10.0 mmol/L in control group and 4.4~6.1 mmol/L in IIT group.Blood glucose and insulin dosage during maintenance were recorded.Cardiac function values as well as serum inflammatory factor concentrations at admission and during donation were compared between two groups.Results:During maintenance, blood glucose was significantly lower in IIT group than that in control group [(5.1±0.6)vs(8.2±1.5)mmol/L, P<0.05] and insulin dosage was higher than that in control group [(9.5±3.2)vs(5.8±1.5)U/h, P<0.05]. As compared with control group, cardiac cycle efficiency(CCE), maximal rate of elevated pressure(DP/DT max)and left ventricular ejection fraction(LVEF)in were significantly higher in IIT group than those of control group.And serum cardiac troponin I(cTnI), N-terminal B-type natriuretic peptide(NT-Pro-BNP), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α)and high mobility group box-1 protein(HMGB1)as well as vasoactive-inotropic score(VIS)were significantly lower than those in control group( P<0.05). As compared with control group, cardiac donation rate of IIT group was significantly higher(30% vs 16.7%, P<0.05). Conclusions:Intensive insulin therapy and blood glucose control may blunt inflammatory response in organ donors, lessen myocardial injury and myocardial depression, stabilize hemodynamics and boost the rate of cardiac donation.

Objective:To systematically summarize and assess risk prediction models for occurrence of cervical cancer and to provide evidence for selecting the most reliable model for practice, and guide cervical cancer screening.Methods:Two groups of keywords related to cervical cancer and risk prediction model were searched on Chinese databases (CNKI, and Wanfang) and English databases (PubMed, Embase, and Cochrane Library). Original articles that developed or validated risk prediction models and published before November 21, 2019, were selected. Information form was created based on the CHARMS checklist. The PROBAST was used to assess the risk of bias.Results:12 eligible articles were identified, describing 15 prediction models, of which five were established in China. The predicted outcomes included multiple stages from cervical precancerous lesions to cancer occurrence, i.e., abnormal Pap smear (1), occurrence or recurrence of CIN (9), and occurrence of cervical cancer (5), etc. The most frequently used predictors were HPV infection (12), age (7), smoking (5), and education (5). There were two models using machine learning to develop models. In terms of model performance, the discrimination ranged from 0.53 to 0.87, while only two models assessed the calibration correctly. Only two models were externally validated in Taiwan of China, using people in different periods. All of the models were at high risk of bias, especially in the analysis domain. The problems were concentrated in the improper handling of missing data (13), preliminary evaluation of model performance (13), improper use of internal validation (12), and insufficient sample size (11). In addition, the problems of inconsistency measurements of predictors and outcomes (8) and the flawed report of the use of blindness for outcome measures (8) were also severe. Compared with the other models, the Rothberg (2018) model had relatively high quality. Conclusions:There are a certain number of cervical cancer risk prediction models, but the quality is poor. It is urgent to improve the measurement of predictors and outcomes, the statistical analysis details such as handling missing data and evaluation of model performance and externally validate existing models to better guide screening.