Microvascular diseases （MVD） can affect multiple systems in the body and are important factors in the occurrence and development of cardiovascular， cerebrovascular， renal， and metabolic diseases， as well as the aging process. It is proposed that the key pathogenesis of MVD is "cold constraint in sanjiao （三焦）". Based on the theory of cold pathogen， and by integrating the common and local pathologies of sanjiao， a treatment principle of promoting blood circulation and warming is established. A basic prescription for promoting blood circulation and warming is formulated， with modifications based on the specific pathogenesis of the upper， middle， and lower jiao （焦）. For the upper jiao， cold constraint primarily involves the failure of the clear yang to rise and qi and blood stagnation， for which treatment should focus on diffusing and unblocking the heart and the lung， opening constraint and vibrating yang， commonly adding Shengxian Decoction （升陷汤） for warming and dispersing to assist in diffusion and dissipation， and using Guizhi Decoction （桂枝汤）-series formulas to harmonize ying-wei （营卫） and open the striae and interstices； both formulas can invigorate yang qi. For the middle jiao， cold constraint primarily involves the dysfunction of the central yang and internal accumulation of turbid pathogen， for which treatment should focus on harmonizing the spleen and stomach， warming and reinforcing yang； formulas such as Sini Powder （四逆散）， Zhishi Xiaopi Pill （枳实消痞丸）， and Banxia Xiexin Decoction （半夏泻心汤） can be used to restore qi flow， promote digestion， and balance cold and heat； Shengyang Yiwei Decoction （升阳益胃汤） can further enhance raising the clear and directing the turbid downward， expelling cold and removing dampness. For the lower jiao， cold constraint primarily involves damage to the original yang and dysfunction of qi transformation， for which the treatment should focus on tonifying original qi and reinforcing the foundation， as well as promoting diuresis and supporting yang； depending on the degree of deficiency and the presence of internal water accumulation， formulas like Jingui Shenqi Pill （金匮肾气丸）， Fuzi Decoction （附子汤）， and Zhenwu Decoction （真武汤） can be used. Based on the theory of cold constraint， the principle of promoting blood circulation and warming method runs through the differentiation and treatment of MVD. By further incorporating the pathological characteristics of sanjiao， flexible treatment strategies can be developed， which helps deepen the understanding of the disease's etiology and pathogenesis， while broadening clinical diagnostic and therapeutic approaches.

Objective To determine the optimal conditions for CXCR4 upregulation by comparing the expression levels of chemokine(C-X-C motif)receptor 4(CXCR4)in MSCs cultured with varying concentrations of oxygen and hydrogen peroxide(H2O2).Methods MSCs were cultured with 0.1％,1％,or 3％O2 and 50 μmol/L H2O2 for different lengths of time(3,6,12,and 24 h).The mRNA and protein expressions of CXCR4 in MSCs were measured by real-time quantitative PCR(qPCR),Western blotting,and immunofluorescence staining.The viability and chemotactic ability of MSCs were measured using CCK-8,wound-healing and Transwell migration assays.Results Both hypoxia and H2O2 treatment were found to upregulate MSC expressions of CXCR4 to some extent.The mRNA and protein levels of CXCR4 were higher after 6-12 h of culture of MSCs with 3％O2,and significantly higher when treated with H2O2 for 6 h.Cell viability was significantly increased after culture with 3％O2 compared with the control group and both 3％O2 and H2O2 pretreatment could enhance chemotactic migration in MSCs.Conclusion Culture with 3％O2 and H2O2 pretreatment can upregulate CXCR4 expressions in MSCs and enhance migration in cells,with superior effects observed with 3％O2.Therefore,treatment with 3％O2 represents the best choice for upregulating the chemotactic ability of MSCs.

OBJECTIVE To provide references for the safe use of lorlatinib in clinical practice. METHODS The reporting odds ratio （ROR） method， Medicines and Healthcare Products Regulatory Agency comprehensive standard method （referred to as “MHRA method”） and the Bayesian confidence propagation neural network （BCPNN） method were used to detect adverse drug events （ADEs） signals of lorlatinib in the FDA Adverse Event Reporting System from the first quarter of 2019 to the fourth quarter of 2022. RESULTS & CONCLUSIONS Totally 114 overlapping ADEs signals of lorlatinib were detected by the three methods， among which there were 73 new suspicious ADEs signals which were not covered in the instruction of lorlatinib. When using loratinib in clinical practice， special attention should be paid to ADEs with a high number of cases and signals， such as various neurological diseases， psychiatric diseases， respiratory system， thoracic and mediastinal diseases； clinical manifestations included cerebral edema， cerebral infarction， pulmonary hypertension， mutism， decreased sexual desire， pleural effusion. The signals of mobile thrombophlebitis， radiation necrosis， mutism， vesicoureteral reflux not mentioned in the instructions were all strong in BCPNN detection with high specificity， to which we should pay attention in clinical application.

OBJECTIVE To mine and analyze severe cutaneous adverse reaction signals of 5 commonly used immune checkpoint inhibitors （ICIs）， and to provide reference for clinically safe use of drugs. METHODS Based on the FDA adverse events reporting system （FAERS） database，adverse drug events （ADEs） reports about severe cutaneous adverse reactions related to ipilimumab， nivolumab， pembrolizumab， atezolizumab and durvalumab were collected from listing in the United States to the fourth quarter of 2022. The ADE signals were mined and analyzed with reporting odds ratio （ROR） and Bayesian confidence propagation neural network （BCPNN）. RESULTS A total of 5 726 reports of severe cutaneous adverse reactions were collected， including 3 037 reports for nivolumab，1 465 reports for pembrolizumab， 130 reports for durvalumab， 429 reports for atezolizumab and 665 reports for ipilimumab. All 5 kinds of ICIs caused positive signals， the correlation degree of which was as follows： pembrolizumab＞atezolizumab＞nivolumab＞ipilimumab＞durvalumab. Stevens-Johnson syndrome（SJS） and toxic epidermal necrolysis （TEN） have been reported for all 5 ICIs， and the association was the strongest with pembrolizumab. CONCLUSIONS All 5 kinds of ICIs are associated with the risk of severe skin adverse reactions， and close attention should be paid to their clinical use， especially being cautious when using pembrolizumab. The combination of ICIs should be avoided as much as possible.

Mucosal vaccines can effectively induce an immune response at the mucosal site and form the first line of defense against microbial invasion. The induced mucosal immunity includes the proliferation of effector T cells and the production of IgG and IgA antibodies, thereby effectively blocking microbial infection and transmission. However, after a long period of development, the transformation of mucosal vaccines into clinical use is still relatively slow. To date, fewer than ten mucosal vaccines have been approved. Only seven mucosal vaccines against coronavirus disease 2019 (COVID-19) are under investigation in clinical trials. A representative vaccine is the adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV) developed by Chen and coworkers, which is currently in phase III clinical trials. The reason for the limited progress of mucosal vaccines may be the complicated mucosal barriers. Therefore, this review summarizes the characteristics of mucosal barriers and highlights strategies to overcome these barriers for effective mucosal vaccine delivery.

Qi-Yu-San-Long decoction(QYSLD)is a traditional Chinese medicine that has been clinically used in the treatment of non-small-cell lung cancer(NSCLC)for more than 20 years.However,to date,metabolic-related studies on QYSLD have not been performed.In this study,a post-targeted screening strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight full infor-mation tandem mass spectrometry(UPLC-QTOF-MSE)was developed to identify QYSLD-related xeno-biotics in rat urine.The chemical compound database of QYSLD constituents was established from previous research,and metabolites related to these compounds were predicted in combination with their possible metabolic pathways.The metabolites were identified by extracted ion chromatograms using predicted m/z values as well as retention time,excimer ions,and fragmentation behavior.Overall,85 QYSLD-related xenobiotics(20 prototype compounds and 65 metabolites)were characterized from rat urine.The main metabolic reactions and elimination features of QYSLD included oxidation,reduction,decarboxylation,hydrolysis,demethylation,glucuronidation,sulfation,methylation,deglycosylation,acetylation,and associated combination reactions.Of the identified molecules,14 prototype compounds and 58 metabolites were slowly eliminated,thus accumulating in vivo over an extended period,while five prototypes and two metabolites were present in vivo for a short duration.Furthermore,one pro-totype and five metabolites underwent the process of"appearing-disappearing-reappearing"in vivo.Overall,the metabolic profile and characteristics of QYSLD in rat urine were determined,which is useful in elucidating the active components of the decoction in vivo,thus providing the basis for studying its mechanism of action.