AIM To prepare fisetin-loaded nanostructured lipid carriers,and to evaluate their in vivo pharmacokinetics.METHODS Ethanol injection method was applied to preparing the nanostructured lipid carriers.With monostearin-phospholipid ratio,monostearin-triacetin ratio and D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)concentration as influencing factors,encapsulation efficiency as an evaluation index,the formulation was optimized by Box-Behnken response surface method.The crystal form was analyzed by X-ray powder diffraction,after which the morphology was observed by transmission electron microscopy,infrared spectroscopy analysis was performed,the drug relaese was investigated by dialysis bag method,and the stability was determined.Eighteen rats were randomly assigned into 3 groups and given intragastric administration of the 0.5％CMC-Na suspensions of fisetin and its phospholipid complex,nanostructured lipid carriers(150 mg/kg),respectively,after which blood collection was made at0.25,0.5,1,1.5,2,3,4,6,8,12 h,UPLC-MS/MS was adopted in the plasma concentration determination of fisetin,and main pharmacokinetic parameters were calculated.RESULTS The optimal formulation was determined to be 1.56∶1 for monostearin-phospholipid ratio,3.05∶1 for monostearin-triacetin ratio,and 0.2 mg/mL for TPGS concentration.The nearly round fisetin-loaded nanostructured lipid carriers demonstrated the average encapsulation efficiency,drug loading,particle size and Zeta potential of(86.14±1.28)％,(8.96±0.26)％,(212.35±9.04)nm and-(31.13±1.16)mV,respectively.Raw medicine existed in the nanostructured lipid carriers in an amorphous state,preparation process did not affect the hydrogen bonding between raw medicine and phospholipids.The nanostructured lipid carriers displayed the accumulative release rate of 46.12％within 3 h in simulated gastric juice,and that of about 50％within 18 h in simulated intestinal fluid,whose freeze-dried powder exhibited good stability after being placed for 6 months.Compared with raw medicine and phospholipids complex,the nanostructured lipid carriers displayed prolonged tmax,t1/2(P＜0.01)and increased Cmax,AUC0-t,AUC0-∞(P＜0.01),whose relative bioavailability was enhanced to 7.07 times.CONCLUSION Nanostructured lipid carriers can improve the oral bioavailability of fisetin.

Objective:To investigate the protective effect of moxibustion on joints and its influence on the expression levels of S100 calcium binding protein A8(S100A8),S100 calcium binding protein A9(S100A9),serum amyloid A1(SAA1),and related inflammatory factors in rats with adjuvant arthritis(AA).Methods:Forty Wistar rats were randomly divided into a normal group,a model group,a moxibustion group,and a medication group,with 10 rats in each group.Except for the normal group,AA models were established in the other three groups by exposing rats to wind-cold-dampness environmental conditions combined with complete Freund's adjuvant.After successful modeling,the moxibustion group received moxibustion intervention,while the medication group was administered tripterygium glycosides tablets via oral gavage.The normal and model groups underwent similar handling and fixation without additional interventions.After 15 d of intervention,hematoxylin-eosin staining was used to assess pathological changes in the knee joint synovial membrane.Western blotting was performed to detect the protein expression of S100A8,S100A9,and SAA1 in the synovial tissue.Enzyme-linked immunosorbent assay was used to measure the serum levels of interferon(IFN)-γ,interleukin(IL)-6,and IL-23.Results:Compared to the normal group,the model group exhibited significantly increased protein expression of S100A8,S100A9,and SAA1 in the knee joint synovial tissue,as well as elevated serum levels of IFN-γ,IL-6,and IL-23(P<0.01).Histopathological analysis revealed marked synovial hyperplasia and extensive infiltration of inflammatory cells in the model group.Compared to the model group,both the moxibustion and medication groups showed significant reductions in the protein expression of S100A8,S100A9,and SAA1 in the synovial tissue,as well as decreased serum levels of IFN-γ,IL-6,and IL-23(P<0.01).Additionally,synovial tissue in these two groups displayed minimal hyperplasia and only mild inflammatory cell infiltration.Notably,compared to the moxibustion group,the medication group exhibited significantly higher protein expression of S100A9 in the synovial tissue(P<0.05),while no significant differences were observed in the expression of S100A8,SAA1,or serum levels of IFN-γ,IL-6,and IL-23(P>0.05).Both intervention groups showed comparable degrees of synovial inflammation,clear tissue structure,and no obvious hyperplasia.Conclusion:Moxibustion can alleviate joint swelling and reduce inflammatory responses in AA rats.Its mechanism may involve regulating the protein expression of S100A8,S100A9,and SAA1 in the knee joint synovial tissue.

AIM To prepare fisetin-loaded nanostructured lipid carriers,and to evaluate their in vivo pharmacokinetics.METHODS Ethanol injection method was applied to preparing the nanostructured lipid carriers.With monostearin-phospholipid ratio,monostearin-triacetin ratio and D-α-tocopheryl polyethylene glycol 1000 succinate(TPGS)concentration as influencing factors,encapsulation efficiency as an evaluation index,the formulation was optimized by Box-Behnken response surface method.The crystal form was analyzed by X-ray powder diffraction,after which the morphology was observed by transmission electron microscopy,infrared spectroscopy analysis was performed,the drug relaese was investigated by dialysis bag method,and the stability was determined.Eighteen rats were randomly assigned into 3 groups and given intragastric administration of the 0.5％CMC-Na suspensions of fisetin and its phospholipid complex,nanostructured lipid carriers(150 mg/kg),respectively,after which blood collection was made at0.25,0.5,1,1.5,2,3,4,6,8,12 h,UPLC-MS/MS was adopted in the plasma concentration determination of fisetin,and main pharmacokinetic parameters were calculated.RESULTS The optimal formulation was determined to be 1.56∶1 for monostearin-phospholipid ratio,3.05∶1 for monostearin-triacetin ratio,and 0.2 mg/mL for TPGS concentration.The nearly round fisetin-loaded nanostructured lipid carriers demonstrated the average encapsulation efficiency,drug loading,particle size and Zeta potential of(86.14±1.28)％,(8.96±0.26)％,(212.35±9.04)nm and-(31.13±1.16)mV,respectively.Raw medicine existed in the nanostructured lipid carriers in an amorphous state,preparation process did not affect the hydrogen bonding between raw medicine and phospholipids.The nanostructured lipid carriers displayed the accumulative release rate of 46.12％within 3 h in simulated gastric juice,and that of about 50％within 18 h in simulated intestinal fluid,whose freeze-dried powder exhibited good stability after being placed for 6 months.Compared with raw medicine and phospholipids complex,the nanostructured lipid carriers displayed prolonged tmax,t1/2(P＜0.01)and increased Cmax,AUC0-t,AUC0-∞(P＜0.01),whose relative bioavailability was enhanced to 7.07 times.CONCLUSION Nanostructured lipid carriers can improve the oral bioavailability of fisetin.

Objective:To investigate the protective effect of moxibustion on joints and its influence on the expression levels of S100 calcium binding protein A8(S100A8),S100 calcium binding protein A9(S100A9),serum amyloid A1(SAA1),and related inflammatory factors in rats with adjuvant arthritis(AA).Methods:Forty Wistar rats were randomly divided into a normal group,a model group,a moxibustion group,and a medication group,with 10 rats in each group.Except for the normal group,AA models were established in the other three groups by exposing rats to wind-cold-dampness environmental conditions combined with complete Freund's adjuvant.After successful modeling,the moxibustion group received moxibustion intervention,while the medication group was administered tripterygium glycosides tablets via oral gavage.The normal and model groups underwent similar handling and fixation without additional interventions.After 15 d of intervention,hematoxylin-eosin staining was used to assess pathological changes in the knee joint synovial membrane.Western blotting was performed to detect the protein expression of S100A8,S100A9,and SAA1 in the synovial tissue.Enzyme-linked immunosorbent assay was used to measure the serum levels of interferon(IFN)-γ,interleukin(IL)-6,and IL-23.Results:Compared to the normal group,the model group exhibited significantly increased protein expression of S100A8,S100A9,and SAA1 in the knee joint synovial tissue,as well as elevated serum levels of IFN-γ,IL-6,and IL-23(P<0.01).Histopathological analysis revealed marked synovial hyperplasia and extensive infiltration of inflammatory cells in the model group.Compared to the model group,both the moxibustion and medication groups showed significant reductions in the protein expression of S100A8,S100A9,and SAA1 in the synovial tissue,as well as decreased serum levels of IFN-γ,IL-6,and IL-23(P<0.01).Additionally,synovial tissue in these two groups displayed minimal hyperplasia and only mild inflammatory cell infiltration.Notably,compared to the moxibustion group,the medication group exhibited significantly higher protein expression of S100A9 in the synovial tissue(P<0.05),while no significant differences were observed in the expression of S100A8,SAA1,or serum levels of IFN-γ,IL-6,and IL-23(P>0.05).Both intervention groups showed comparable degrees of synovial inflammation,clear tissue structure,and no obvious hyperplasia.Conclusion:Moxibustion can alleviate joint swelling and reduce inflammatory responses in AA rats.Its mechanism may involve regulating the protein expression of S100A8,S100A9,and SAA1 in the knee joint synovial tissue.

Purpose::Cerebral edema (CE) is the main secondary injury following traumatic brain injury (TBI) caused by road traffic accidents (RTAs). It is challenging to be predicted timely. In this study, we aimed to develop a prediction model for CE by identifying its risk factors and comparing the timing of edema occurrence in TBI patients with varying levels of injuries.Methods::This case-control study included 218 patients with TBI caused by RTAs. The cohort was divided into CE and non-CE groups, according to CT results within 7 days. Demographic data, imaging data, and clinical data were collected and analyzed. Quantitative variables that follow normal distribution were presented as mean ± standard deviation, those that do not follow normal distribution were presented as median (Q 1, Q 3). Categorical variables were expressed as percentages. The Chi-square test and logistic regression analysis were used to identify risk factors for CE. Logistic curve fitting was performed to predict the time to secondary CE in TBI patients with different levels of injuries. The efficacy of the model was evaluated using the receiver operator characteristic curve. Results::According to the study, almost half (47.3%) of the patients were found to have CE. The risk factors associated with CE were bilateral frontal lobe contusion, unilateral frontal lobe contusion, cerebral contusion, subarachnoid hemorrhage, and abbreviated injury scale (AIS). The odds ratio values for these factors were 7.27 (95% confidence interval ( CI): 2.08 -25.42, p = 0.002), 2.85 (95% CI: 1.11 -7.31, p = 0.030), 2.62 (95% CI: 1.12 -6.13, p = 0.027), 2.44 (95% CI: 1.25 -4.76, p = 0.009), and 1.5 (95% CI: 1.10 -2.04, p = 0.009), respectively. We also observed that patients with mild/moderate TBI (AIS ≤ 3) had a 50% probability of developing CE 19.7 h after injury (χ 2= 13.82, adjusted R2 = 0.51), while patients with severe TBI (AIS > 3) developed CE after 12.5 h (χ 2= 18.48, adjusted R2 = 0.54). Finally, we conducted a receiver operator characteristic curve analysis of CE time, which showed an area under the curve of 0.744 and 0.672 for severe and mild/moderate TBI, respectively. Conclusion::Our study found that the onset of CE in individuals with TBI resulting from RTAs was correlated with the severity of the injury. Specifically, those with more severe injuries experienced an earlier onset of CE. These findings suggest that there is a critical time window for clinical intervention in cases of CE secondary to TBI.

To investigate the mechanism by which Cangxi Tongbi Capsules promote chondrocyte autophagy to inhibit knee osteoarthritis(KOA) progression by regulating the circRNA＿0008365/miR-1271/p38 mitogen-activated protein kinase(MAPK) pathway. The cell and animal models of KOA were established and intervened with Cangxi Tongbi Capsules, si-circRNA＿0008365, si-NC, and Cangxi Tongbi Capsules combined with si-circRNA＿0008365. Flow cytometry and transmission electron microscopy were employed to determine the level of apoptosis and observe autophagosomes, respectively. Western blot was employed to reveal the changes in the protein levels of microtubule-associated protein light chain 3(LC3)Ⅱ/Ⅰ, Beclin-1, selective autophagy junction protein p62/sequestosome 1, collagen Ⅱ, a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS-5), and p38 MAPK. The mRNA levels of circRNA＿0008365, miR-1271, collagen Ⅱ, and ADAMTS-5 were determined by qRT-PCR. Hematoxylin-eosin staining was employed to reveal the pathological changes of the cartilage tissue of the knee, and enzyme-linked immunosorbent assay to measure the levels of interleukin-1β(IL-1β) and tumor necrosis factor-alpha(TNF-α). The chondrocytes treated with IL-1β showed down-regulated expression of circRNA＿0008365, up-regulated expression of miR-1271 and p38 MAPK, lowered autophagy level, increased apoptosis rate, and accelerated catabolism of extracellular matrix. The intervention with Cangxi Tongbi Capsules up-regulated the expression of circRNA＿0008365, down-regulated the expression of miR-1271 and p38 MAPK, increased the autophagy level, decreased the apoptosis rate, and weakened the catabolism of extracellular matrix. However, the effect of Cangxi Tongbi Capsules was suppressed after interfering with circRNA＿0008365. The in vivo experiments showed that Cangxi Tongbi Capsules dose-dependently inhibited the p38 MAPK pathway, enhanced chondrocyte autophagy, and mitigated articular cartilage damage and inflammatory response, thereby inhibiting the progression of KOA in rats. This study indicated that Cangxi Tongbi Capsules promoted chondrocyte autophagy by regulating the circRNA＿0008365/miR-1271/p38 MAPK pathway to inhibit the development of KOA.
Rats ; Animals ; Chondrocytes ; Osteoarthritis, Knee/pathology* ; RNA, Circular/pharmacology* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; MicroRNAs/metabolism* ; Apoptosis ; Autophagy/genetics* ; Collagen/metabolism*

Hypertension, a primary cause of cardiovascular and cerebrovascular events, has become a major global public health problem and caused a heavy burden of health economics on the society. In "the 20 Most Important and Most Preventable Health Problems" released by the Chinese Academy of Engineering, hypertension was ranked the second. Due to the disease complexity, many hypertension patients need to take antihypertensive drugs for life. Although significant progress has been achieved in blood pressure lowering by western medicines, the problems including adverse reactions, poor compliance due to long-term medication, and ineffective mitigation in clinical symptoms related to hypertension remain to be addressed. In the last decade, the research on traditional Chinese medicine(TCM) treatment of hypertension has received much attention and achieved remarkable progress. The TCM treatment of hypertension is the most active area of research with integrated Chinese and western medicine in China. In addition to lowering blood pressure smoothly, TCM can alleviate clinical symptoms, reverse risk factors, improve the quality of life, and protect target organs from the damage caused by hypertension. This article systematically reviews the research progress of TCM in treating hypertension in the last decade from the following four aspects: consensus on guideline, clinical trial, experimental study, and systematic review/Meta-analysis. It summarized the evidence of TCM in reducing blood pressure and clarified the mechanism of TCM in reducing blood pressure, aiming to provide a reference for the TCM diagnosis and treatment of hypertension and the development of new drugs.
Humans ; Antihypertensive Agents/therapeutic use* ; Drugs, Chinese Herbal/therapeutic use* ; Hypertension/drug therapy* ; Medicine, Chinese Traditional

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Objective:To analyze the clinical characteristics of adult Chinese patients with syncope.Methods:This is a cross-sectional survey study. Patients with preliminary diagnosis of syncope in the Emergency Department, Geriatrics and Cardiology Outpatient Department, or Syncope Unit of 37 hospitals in 19 provinces, autonomous regions and the Hong Kong Special Administrative Region from June 2018 to March 2021 were included in this study. The clinical features of these patients with syncope were analyzed.Results:A total of 4 950 consecutive patients with syncope were included in this study. The age was (56.3±16.8)years, and 2 604 cases (52.6%) were male. The most common type of syncope was neurally mediated syncope (2 345 (47.4%)), followed by cardiac syncope (1 085 (21.9%)), orthostatic hypotensive syncope (311 (6.3%)), and unexplained syncope accounted for nearly one third (1 155 (23.3%)). Predisposing syncope was more common in patients under 65 years of age(2 066(72.4%) vs. 786(27.6%),χ 2=136.5, P<0.001). Presyncope was more common in patients with neurally mediated syncope (1 972(79.0%) vs.1 908(73.9%), χ 2=17.756, P<0.001). Premonitory symptoms were more common in women(1 837(80.0%) vs. 1 863(73.0%),χ 2=33.432, P<0.001). Presyncope syndrome was more common in patients under 65 years of age (2 482(77.8%) vs. 1 218(73.4%),χ 2=17.523, P=0.001). Cyanosis was more common in ≥65 years old patients (271(18.2%) vs. 369(12.7%), χ 2=23.235, P<0.001). Urinary incontinence was more common in old patients aged ≥65 years(252(15.2%) vs. 345(10.8%), χ 2=19.313, P<0.001). Family history was more common in patients with cardiogenic syncope compared with other types of syncope (264(24.3%) vs. 754(19.5%), χ 2=11.899, P=0.001). Hypertention(1 480(30.5%)), coronary heart disease(1 057(21.4%)), atrial flutter and atrial fibrillation(359(7.2%)), second degree atrioventricular block(236(4.8%)) were common complications of syncope. The proportion of patients with coronary heart disease was significantly higher in cardiac syncope than that of other types of syncope(417(38.4%) vs. 640(16.6%), χ 2=241.376, P<0.001). Other common complications included cerebrovascular diseases (551 (11.1%)) and diabetes mellitus (632(12.8%)). Conclusions:Neurally mediated syncope is the most common syncope in adult Chinese population. Patients with predisposing conditions and premonitory conditions are younger. Presyncope is more common in women. The proportion of family history and coronary heart disease is higher in patients with cardiogenic syncope.

This article is a summary of the Second China Breast Milk Science Conference, which was held in Beijing from August 5 to 7, 2022, with the theme of "Data sharing, method sharing and science sharing". The purpose of the conference is to summarize the latest progress in breast milk research, identify the unresolved issues, and jointly discuss the direction of future breast milk research. Firstly, we summarize the contents and purpose of breast milk scientific research and prospect of breast milk science. The second part focuses on the research status of breast milk composition and its health effects, and puts forward the future research direction. The third section focuses on the health effects of breastfeeding and scientific support and key aspects of breastfeeding promotion actions. The fourth part elaborates the specific methods of current scientific research of breast milk and emphasize the importance of method standardization and the idea of future methodological research. The fifth part consists of the strategy of feeding infants with medical conditions and ways to better promote the growth and development of these infants. The last part introduces the innovation, deficiencies, and future research directions of infant formula production technology in China. This conference demonstrate the importance of multidisciplinary communication, discussions and collaborations in clinical medicine, nutrition, perinatal health, food science, and policy-making in the scientific research of breast milk, and provides guidance for future multidisciplinary research on the physiology of lactation, the composition of breast milk, breastfeeding, and infants and young children nutrition.