BACKGROUND:Studies have testified that nano-ultrasound contrast agents have a strong permeability, making it possible to image the targeted tissues outside blood vessels and overcome the limitation that micron contrast agents are only available for the blood pool imaging. OBJECTIVE:To construct the folate-modified nanoparticles targeting breast cancer as ultrasound contrast agents, as wel as to observe their ability to specifical y bind to cel s and imaging effect in vitro. METHODS:Both contrast agents, pegylated lactic acid-glycolic acid copolymer wrapping liquid fluorocarbon formed nanoparticles (mPP/PFOB) and folate modified pegylated lactic acid-glycolic acid wrapping liquid fluorocarbon formed nanoparticles (mPPF/PFOB), were constructed by phacoemulsification-evaporation method. (1)Biocompatibility detection:HFF-1 and MCF-7 cel s in the logarithmic phase were cultivated with various concentrations (0, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2 and 1 g/L) of mPP/PFOB or mPPF/PFOB for 24 hours respectively, and then the cel viability was measured. (2)Targeting ability detection in vitro:HFF-1 and MCF-7 cel s in the logarithmic phase were divided into three groups. Cy5-labled mPP/PFOB and mPPF/PFOB were added into groups A and B, respectively;the cel s in group C were pretreated with folate for 2 hours, and sequential y Cy5-labled mPPF/PFOB was added into group C. Fluorescence intensity was detected by flow cytometry after 0.5 hours of culture. The distribution of contrast agents in cel s was observed using confocal microscopy after 20 minutes of culture. (3)Ultrasound imaging in vitro:there were three groups:saline was as group A;the suspension of saline and mPPF/PFOB nanoparticles was prepared as group B;MCF-7 cel s were resuspended with the mixture of saline and mPPF/PFOB nanoparticles to prepare the suspension of nanoparticles and cel s as group C. In each group, the suspension was added into latex gloves, that were then tightened and immersed in water. Final y, the ultrasound was use to detect the ultrasound imaging effect in vitro. RESULTS AND CONCLUSION:Neither nanoparticles were with significant cytotoxicity. The flow cytometry showed that the mean fluorescence intensity in MCF-7 cel s of group B was significantly higher than that of groups A and C. But there were no significant differences in the mean fluorescence intensity in HFF-1 cel s among the three groups. It was observed that mPPF/PFOB mainly gathered around the MCF-7 cel membrane, while mPP/PFOB randomly distributed in the cytoplasm. After mPPF/PFOB binding to MCF-7 cel s, they could enhance ultrasound echo in vitro. These findings indicate that the targeted nanoparticles mPPF/PFOB have good biocompatibility and can specifical y bind to breast cancer MCF-7 cel s in vitro and enhance the imaging capability.

Objective: To explore the correlation between menopausal hormone therapy（MHT）and breast lesions in perimenopausal women,and to provide evidence for safe use of MHT. Methods: The 40-60 year-old women who visited Hangzhou Women's Hospital and met the diagnostic criteria for perimenopausal syndrome were recruited. The intervention group received MHT and was divided into three subgroups according to the MHT regimen：estrogen-progesterone cycle therapy（A）,estrogen-progesterone continuous therapy（B）,estrogen therapy（C）. The control group did not receive MHT. All the patients received regular mammography to quantify and evaluate breast lesions. The generalized estimating equation was used to analyze the changes of breast lesions between different groups. Results: There were 80 cases in the intervention group,with 49 in group A,26 in group B,5 in group C,and 80 cases in the control group. After two years of follow-up,there was no statistically significant differences of time,group and interaction in breast density,volume of breast fibrous tissue and the volume of breast between three intervention groups and the control group（P>0.05）; there was no statistically significant differences of group and interaction in positive rate of calcification and breast mass between the intervention group and the control group（P>0.05）. Conclusion Receiving MHT intervention for two years did not increase the risk of breast lesions.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood, which seriously affects physical and mental health in children.Its etiology and pathogenesis are complex and have not been fully elucidated.Currently, the theory of Dopamine (DA) deficits has been widely recognized and studied in the international academic community.The DA system is considered as the key to the pathogenesis of ADHD.The causes of DA deficits are complex.In addition to the well-established reuptake disorder caused by abnormal DA transporter function, DA deficits are also associated with the activation of DA vesicle cycle enzymatic inactivation, vesicle transport dysfunction, and receptor dysfunction, which are of great significance in analyzing disease pathogenesis and drug development.This article reviews the research on the causes of DA deficits proposed in recent years based on the theory of DA deficits, aiming to provide ideas and references for the research on the pathogenesis of ADHD in China.

AIM:To study the regulation of endoplasmic reticulum stress(ERS)using the glucose regulated protein 78(GRP78)/CCAAT/enhancer binding protein homologous protein(CHOP)pathway and explore the related mech-anism of Wenyang-Shengji ointment in facilitating the repair of diabetic refractory wounds.METHODS:To establish a rat model of diabetic refractory wound repair,Sprague-Dawley(SD)rats were fed a high-fat diet and intraperitoneally in-jected with streptozotocin.Subsequently,full-thickness skin defects were induced in the dorsal region of the rats.The ex-periment included 4 groups:normal,model(diabetic refractory wounds),Wenyang-Shengji ointment,and Beifuxin(re-combinant bovine basic fibroblast growth factor gel)groups.The normal and model groups were treated with normal saline after disinfection.In the Wenyang-Shengji ointment and Beifuxin groups,the wounds were topically treated with the re-spective ointments once daily.After 14 d of treatment,wound healing was assessed and quantified using the wound healing rate.Hematoxylin-eosin(HE)staining was employed to examine the micromorphology of the wound tissue.Western blot analysis was performed to measure GRP78,CHOP and caspase-12 levels in the wound tissue.Immunohistochemical analy-sis was used to detect the expression and distribution patterns of GRP78,CHOP and caspase-12 in the wounds.Transmis-sion electron microscopy was used to observe reticulum numbers and swelling.Enzyme-linked immunosorbent assay was used to determine interleukin-1β(IL-1β)level as a pro-inflammatory factor within the wound.RESULTS:Indexes of each group were assessed 14 d after the corresponding intervention.Compared with normal group,the rats in model group exhibited a significant decrease in the wound healing rate(P＜0.01),accompanied by increased inflammatory exudation and poor granulation tissue growth.Additionally,there were increases in the expression levels of GRP78,CHOP and cas-pase-12 proteins(P＜0.01),as well as a significant elevation in the content of inflammatory factor IL-1β(P＜0.01).In contrast,compared with model group,treatment with Wenyang-Shengji ointment resulted in a significant improvement in wound healing rate(P＜0.01),reduction in inflammatory exudation,and enhanced granulation tissue growth(P＜0.01).Furthermore,there was a notable decrease in the protein expression of GRP78/CHOP/caspase-12 within the wound tissue following treatment with Wenyang-Shengji ointment(P＜0.01).The levels of inflammatory factor IL-1β also showed a sig-nificant decrease(P＜0.01).CONCLUSION:Wenyang-Shengji promotes the healing of diabetic refractory wounds,which may be associated with the downregulation of the GRP78/CHOP pathway,inhibition of excessive ERS,and reduc-tion in the level of wound cell apoptosis.

Objective To compare the differences in lower limb joint kinematics and muscle activation between Asian squat (AS) and Western squat (WS). Methods Eleven healthy adults were recruited to complete the biomechanical test of AS and WS. The 3D motion analysis system, force plates and surface electromyography (EMG) were used to collect kinematics, kinetics and muscle activation data of the subjects during two squats, and muscle force of the lower limb was also calculated by OpenSim. Results AS showed pelvis forward flexion, while WS showed pelvis backward extension at the time of peak knee flexion angle. Compared with the AS, a significant smaller hip flexion, larger knee flexion, larger hip abduction and hip rotation angles were found in WS at the time of peak knee flexion angle. Compared with AS, a significant greater peak force of soleus was found in WS during descent and ascent phases of squat. Additionally, a smaller peak force of anterior tibia was found in WS than that in AS during descent and ascent phases of the squat. No significant differences were found in other muscle peak force and the time of peak force between AS and WS. Conclusions The combined tibialis anterior activation and proximal joint flexion might be beneficial to stabilization during AS. The soleus muscle activation was significant in WS with heel lifting. The muscle activation pattern of proximal joint was similar between AS and WS. This study provides theoretical guidance for the design of clinical squat rehabilitation programs or the selection of squat training.

The concept of "virus sovereignty" proposed by Indonesia in 2007 challenges the international tradition of virus sharing. In the context of the global outbreak of coronavirus disease 2019, the issue of virus sharing has become an important topic in the reform of the global health governance mechanisms. Virus sharing is an important guarantee of dealing with major global infectious diseases. However, the emergence of the concept of "virus sovereignty" shows that there are defects in the operation of virus sharing mechanism in the international community. The "virus sovereignty" problem is an ethical issue essentially, involving asymmetric interests hindering unity and cooperation, intellectual property rights expansion challenging the principle of solidarity, and excessive self-defense amplifying utility risks. "Community of common health for mankind" provides a constructive and feasible option to solve the dilemma of "virus sovereignty".

Vaccine cooperation is an important means to deal with global infectious diseases. However, the cooperation cannot be achieved overnight. Ethical dilemma is one of the obstacles that hinders vaccine cooperation. Reviewing the history, the most successful vaccine collaboration to date has been the global smallpox eradication program. In the process of eradicating smallpox, there were also many ethical dilemmas, including the international pattern of the US-Soviet hegemony, which impacted the mutual help between countries, the ethical disputes of the vaccine itself hindering solidarity and cooperation among actors, and the vaccine coercion adopted to overcome vaccine hesitancy undermining the principle of proportionality among the freedom, equality and efficacy. The ethical dilemmas of vaccine cooperation were resolved by shaping professional and scientific consensus among medical professional groups, reaching consensus on cooperation between leading countries and developing countries, and integrating local culture to improve vaccination methods. Finally, in 1980, the world successfully eradicated smallpox. The case of smallpox eradication provides us lessons for vaccine cooperation against COVID-19 and the construction of a community of common health for mankind today.

Vaccine cooperation is an important means to deal with global infectious diseases. However, the cooperation cannot be achieved overnight. Ethical dilemma is one of the obstacles that hinders vaccine cooperation. Reviewing the history, the most successful vaccine collaboration to date has been the global smallpox eradication program. In the process of eradicating smallpox, there were also many ethical dilemmas, including the international pattern of the US-Soviet hegemony, which impacted the mutual help between countries, the ethical disputes of the vaccine itself hindering solidarity and cooperation among actors, and the vaccine coercion adopted to overcome vaccine hesitancy undermining the principle of proportionality among the freedom, equality and efficacy. The ethical dilemmas of vaccine cooperation were resolved by shaping professional and scientific consensus among medical professional groups, reaching consensus on cooperation between leading countries and developing countries, and integrating local culture to improve vaccination methods. Finally, in 1980, the world successfully eradicated smallpox. The case of smallpox eradication provides us lessons for vaccine cooperation against COVID-19 and the construction of a community of common health for mankind today.

ObjectiveTo establish a rat model of diabetic wound by feeding on a high-fat and high-sugar diet combined with intraperitoneal injection of streptozotocin （STZ） and surgical preparation of full-thickness skin defects， observe the effect of cinnamaldehyde on the wound healing of diabetes rats， and explore the therapeutic mechanism of cinnamaldehyde in improving wound healing of diabetes rats based on the PTEN-induced putative kinase （PINK1）/Parkin pathway-mediated mitochondrial autophagy. MethodForty-eight male SD rats were randomly divided into blank group （n=12） and diabetes group （n=36）. The diabetes group was further randomly divided into model group， cinnamaldehyde group， and Beifuxin group， with 12 rats in each group. The blank group and the model group received routine disinfection with physiological saline after creating the wounds， while the cinnamaldehyde group received topical application of polyethylene glycol 400 （PEG 400） gel containing 4 μmol·L^-1 cinnamaldehyde， and the Beifuxin group received topical application of Beifuxin gel. Dressings were changed once daily. The wound healing rate of each group was observed. On the 7th and 14th days after intervention， the wound tissues of the rats were collected. Hematoxylin and eosin （HE） staining was performed to observe the pathological changes in the local tissues. Immunohistochemistry （IHC） was used to detect the expression of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， vascular endothelial growth factor （VEGF）， and collagen fibers. Immunofluorescence （IF） and Real-time polymerase chain reaction （Real-time PCR） were used to detect the protein， and mRNA expression of PINK1， Parkin， microtubule-associated protein 1 light chain 3 Ⅱ （LC3 Ⅱ）. ResultAfter intraperitoneal injection of STZ， compared with the blank group， the random blood glucose values of rats in the diabetic group increased significantly （P<0.01）， all higher than 16.7 mmol·L^-1， and persistently hyperglycemic for some time after modeling. Compared with the blank group， the model group showed poor growth and healing of granulation tissue in the wounds， and the wound healing rate decreased （P<0.01）. On the 7^th day after intervention， the blank group had squamous epithelial coverage on the wounds. Compared with the blank group， the model group only had a small amount of scab at the wound edges， with a large number of infiltrating inflammatory cells in the wounds. The protein expression levels of IL-6 and TNF-α in the tissues increased （P<0.01）， and the protein and mRNA levels of PINK1， Parkin， and LC3Ⅱ decreased （P<0.01）. On the 14^th day after the intervention， the granulation tissue in the wounds of the blank group was mature and well-healed. Compared with the blank group， the model group still had infiltrating inflammatory cells and red blood cell exudation. The protein expression levels of VEGF and collagen fibers in the tissues decreased （P<0.01）， and the protein and mRNA expression levels of PINK1， Parkin， and LC3Ⅱ increased （P<0.01）. Compared with the model group， the cinnamaldehyde group and the Beifuxin group showed better wound healing， with increased wound healing rates （P<0.01）. On the 7th day after intervention， the protein expression levels of IL-6 and TNF-α in the tissues decreased （P<0.01）， and the protein and mRNA expression levels of PINK1， Parkin， and LC3Ⅱ increased （P<0.01）. On the 14th day after intervention， the protein expression levels of VEGF and collagen fibers in the tissues increased （P<0.01）， and the protein and mRNA expression levels of PINK1， Parkin， and LC3Ⅱ decreased （P<0.01）. ConclusionCinnamaldehyde can promote the wound healing of diabetes rats by increasing the wound healing rate， reducing the levels of inflammatory factors IL-6 and TNF-α， and increasing the levels of VEGF and collagen fibers. Its mechanism may be related to the regulation of the PINK1/Parkin signaling pathway， activation of mitochondrial autophagy， inhibition of inflammatory responses， and promotion of angiogenesis and collagen synthesis， thereby promoting the wound healing of diabetes rats.

Objective : To explore the mechanism of Wenyang Shengji Ointment (温阳生肌膏, WYSJO) in the treatment of diabetic wounds from the perspective of network pharmacology, and to verify it by animal experiments. Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and related literature were used to screen active compounds in WYSJO and their corresponding targets. GeneCards, Online Mendelian Inheritance in Man (OMIM), DrugBank, PharmGkb, and Therapeutic Target Database (TTD) databases were employed to identify the targets associated with diabetic wounds. Cytoscape 3.9.0 was used to map the active ingredients in WYSJO, which was the diabetic wound target network. Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) platform was utilized to construct protein-protein interaction (PPI) network. Kyoto Encyclopedia of Genes and Genomes (KEGG) andGene Ontology (GO) enrichment analyses were performed to identify signaling pathways between WYSJO and diabetic wounds. AutoDock 1.5.6 was used for molecular docking of core components in WYSJO to their targets. Eighteen rats were randomly divided into control, model, and WYSJO groups (n = 6). The model and WYSJO groups were used to prepare the model of refractory wounds in diabetes rats. The wound healing was observed on day 0, 5, 9, and 14 after treatment, and the wound tissue morphology was observed by hematoxylin-eosin(HE) staining. The expression levels of core genes were detected by quantitative real-timepolymerase chain reaction (qPCR). Result: A total of 76 active compounds in WYSJO, 206 WYSJO drug targets, 3 797 diabetic wound targets, and 167 diabetic wound associated WYSJO targets were screened out through network pharmacology. With the use of WYSJO-diabetic wound target network, core targets of seven active compounds encompassing quercetin, daidzein, kaempferol, rhamnetin, rhamnocitrin, strictosamide, and diisobutyl phthalate (DIBP) in WYSJO were found. GO enrichment analysis showed that the treatment of diabetes wounds with WYSJO may involve lipopolysaccharide, bacteria-derived molecules, metal ions, foreign stimuli, chemical stress, nutrient level, hypoxia, and oxidative stress in the biological processes. KEGG enrichment analysis showed that the treatment of diabetes wounds with WYSJO may involve advanced glycation end products (AGE-RAGE), p53, interleukin (IL)-17, tumor necrosis factor (TNF),hypoxia inducible factor-1 (HIF-1), apoptosis, lipid, atherosclerosis, etc. The results of animal experiments showed that WYSJO could significantly accelerate the healing process of diabetic wounds (P < 0.05), alleviate inflammatory response, promote the growth of granulation tissues, and down-regulate the expression levels of eight core genes [histone crotonyltransferase p300 (EP300), protoc gene-oncogene c-Jun (JUN), myelocytomatosis (MYC), hypoxia inducible factor 1A (HIF1A), mitogen-activated protein kinase 14 (MAPK14), specificity protein 1 (SP1), tumor protein p53 (TP53), and estrogen receptor 1 (ESR1)] predicted by the network pharmacology (P < 0.05). Conclusion The mechanism of WYSJO in treating diabetes wounds may be closely related to AGE-RAGE, p53, HIF-1, and other pathways. This study can provide new ideas for the pharmacological research of WYSJO, and provide a basis for its further transformation and application.