ObjectiveTo investigate the effect of nicotinamide adenine dinucleotide on vascular endothelial injury in hypertension and its molecular mechanism. MethodsC57BL/6J mice were randomly divided into saline group （Saline） and hypertension group （Ang Ⅱ， which were infused with Ang Ⅱ via subcutaneously implanted osmotic pumps）， and supplemented daily with nicotinamide mononucleotide （300 mg/kg）， a precursor of NAD⁺. Blood pressure， endothelial relaxation function and pulse wave velocity were measured after 4 weeks. Wound healing assay and adhesion assay were used to evaluate the function of endothelial cells in vitro. mtROS levels were detected by immunofluorescence staining. RT-PCR was used to detect the mRNA expression of mtDNA， SIRT3 and isocitrate dehydrogenase 2 （IDH2）. 8-hydroxy-2'-deoxyguanosine levels were detected by enzyme-linked immunosorbent assay. The protein expression levels of p-eNOS， eNOS， SIRT3 and IDH2 were detected by Western blot. ResultsNMN supplementation reduced blood pressure （P<0.001） and improved endothelial function and arterial stiffness （P<0.001） in hypertensive mice. In vitro， NMN improved endothelial function in AngII-stimulated endothelial cells （P<0.05） and attenuated mitochondrial oxidative stress levels （P<0.001）. Mechanistically， NMN elevated SIRT3 activity （P<0.001）， which subsequently enhanced IDH activity （P<0.001） and reduced oxidative stress levels in endothelial cells. Conversely， knockdown of IDH2 would reverse the effect of SIRT3 in improving endothelial function （P<0.001）. ConclusionNAD⁺ lowers blood pressure and enhances vascular function in hypertension by reducing the level of oxidative stress in endothelial cells through activation of the SIRT3/IDH2 signal pathway.

Objective To investigate the predictive value of the combined tumor burden score (TBS) and platelet-albumin-bilirubin (PALBI) score model for postoperative tumor recurrence in liver transplant recipients with hepatocellular carcinoma (HCC). Methods The general information of 158 recipients diagnosed with HCC and underwent liver transplantation at the 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army from 2008 to 2021 was collected. Lasso regression analysis combined with multivariate Cox regression analysis were used to identify independent risk factors for postoperative tumor recurrence after liver transplantation with HCC. A nomogram prediction model was constructed based on variables selected by Lasso regression analysis, and the predictive performance of the model was verified by calibration curve and clinical decision curve. The optimal cut-off values for postoperative tumor recurrence in liver transplant recipients with HCC were determined by receiver operating characteristic (ROC) curve, and Kaplan-Meier analysis was used to compare survival differences among different groups. Results Among the 158 liver transplant recipients with HCC, 82 experienced tumor recurrence, with a recurrence rate of 51.9% and a median tumor-free survival time of 10 (4, 25) months. Results of Lasso regression analysis and multivariate Cox regression analysis showed that alpha-fetoprotein (AFP) ≥400 ng/mL, TBS and PALBI score were all independent risk factors for postoperative tumor recurrence in liver transplant recipients with HCC (all P<0.05). The combined high TBS-high PALBI score showed the highest predictive value (hazard ratio 6.909, 95% confidence interval 3.067-15.563, P<0.001). A nomogram prediction model was constructed based on six variables selected by Lasso regression analysis. Calibration curve showed good consistency between the model's predicted results and the ideal curve. Decision curve analysis indicated that the nomogram prediction model provided the highest clinical benefit for predicting 1-year tumor-free survival after liver transplantation with HCC. Time-dependent ROC curves at 1, 3 and 5 years after surgery showed that TBS-PALBI model had good predictive performance, with no significant difference in area under the curve (AUC) compared with TBS-PALBI-AFP model. The optimal cut-off values for predicting postoperative tumor recurrence were determined by ROC curve, with a PALBI score cut-off of −2.334 and a TBS cut-off of 5.305. Recipients were divided into a low TBS-low PALBI score group (n=47) and a low/high TBS-low/high PALBI score group (at least one score was high) (n=111). Kaplan-Meier survival analysis showed that the low TBS-low PALBI score group had a higher tumor-free survival rate than the low/high TBS-low/high PALBI score group, with a significant difference (P<0.05). Conclusions TBS-PALBI model provides a novel, simple and effective tool for assessing the prognosis of liver transplant recipients with HCC. The nomogram model constructed based on this has significant advantages in predictive performance and may serve as a reference for guiding individualized treatment plans and improving clinical outcomes.

Polygonatum sibiricum， as a traditional Chinese medicine with both medicinal and edible properties， has attracted considerable attention due to its functions of nourishing Yin and moistening the lungs， tonifying the spleen and benefiting Qi， and nourishing the kidneys and filling essence. Recent studies have demonstrated that Polygonatum sibiricum plays a significant role in regulating the immune system， effectively enhancing and improving the morphology and function of immune organs， stimulating the proliferation and activation of immune cells， and regulating the secretion and release of immune factors， thereby enhancing the immune function of the body and improving various immune-related diseases. Although a large number of studies have explored the pharmacological effects and mechanisms of P. sibiricum， there has been no systematic review and summary of its immune regulatory activity and mechanisms. Therefore， this article comprehensively reviews the research achievements of P. sibiricum polysaccharides and saponins in the field of immune regulation in recent years， and further sorts out the immune regulatory mechanisms of P. sibiricum in multiple aspects： including increasing the organ index of the spleen and thymus， increasing the number and activity of tumor-suppressive bone marrow hematopoietic stem cells， improving intestinal flora imbalance， regulating the quantity and proportion of T lymphocyte subsets， increasing the level of immunoglobulin， promoting the proliferation of macrophages， enhancing the activity of natural killer cells， increasing the number of white blood cells， and promoting the maturation of dendritic cells， providing a solid theoretical basis and scientific evidence for the research and application of P. sibiricum， and promoting its development and application in traditional Chinese medicine immune enhancers and various functional products.

ObjectiveTo explore the medication patterns of Professor Zhang Farong in treating type 2 diabetes mellitus （T2DM） and the clinical efficacy of his core prescription. MethodsClinical case records of T2DM treated by Professor Zhang Farong were collected to establish a prescription database. Frequency statistics， visual analysis， and factor analysis were employed to investigate the characteristics and principle of the prescriptions， and a core prescription was derived. A randomized controlled trial was conducted， enrolling 60 T2DM patients with the dampness-heat syndrome. The patients were allocated into an observation group （core prescription + metformin） and a control group （metformin alone）， with both groups undergoing a 12-week treatment course. Changes in TCM symptom scores， glucose metabolism indicators ［fasting plasma glucose （FPG）， 2-hour postprandial blood glucose （2 hPG）， and glycated hemoglobin （HbA1c）］， pancreatic function indicators ［fasting C-peptide （FCP）， 2-hour postprandial C-peptide （2 hCP）， and area under the C-peptide curve （AUCcp）］， and lipid profiles were measured before and after treatment. The adverse reactions were observed and recorded. ResultsA core prescription named modified Gegen Qinlian Decoction was formulated， comprising Puerariae Lobatae Radix， Coptidis Rhizoma， Scutellariae Radix， Astragali Radix， Lycii Cortex， Mori Cortex， Jineijin Endothelium Corneum Gigeriae Galli， Rehmanniae Radix Praeparata， Atractylodis Rhizoma， Polygonati Rhizoma， and Pogostemonis Herba. The clinical trial results showed that both groups had significantly decreased FPG， 2 hPG， and HbA1c （P0.05）， and the observation group outperformed the control group in recovering the level of HbA1c （P0.05）. After treatment， both groups had declined TCM symptoms scores （P0.05）， and the declines in the observation group were larger than those in the control group （P0.05）. After treatment， the TC and LDL-C levels declined in the observation group （P 0.05）， while the lipid levels showed a decreasing trend with no statistically significant difference in the control group. After treatment， both groups showed increases in FCP and AUCcp （P0.05）， and the 2 hCP in both groups presented a recovering trend with no statistically significant difference. There was no statistically significant difference in the incidence of adverse reactions between the two groups. ConclusionModified Gegen Qinlian Decoction embodies Professor Zhang Farong's academic philosophy of treating consumptive thirst by tonifying the spleen and kidney， replenishing Qi and Yin， clearing deficiency and heat， unblocking stasis in collaterals， and addressing both deficiency and stasis. The combination of the core prescription with metformin alleviates clinical symptoms in T2DM patients with the dampness-heat syndrome， demonstrating potential effects in restoring pancreatic islet function， regulating blood glucose， and improving lipid profiles. It serves as a therapeutic option for T2DM in the patients with the dampness-heat syndrome under syndrome differentiation， meriting broader clinical application.

Objective: To investigate the characteristics of malignant tumor incidence and mortality in cancer registration areas of Zhejiang Province in 2021. Methods: Based on the 2021 cancer registration data from 22 national cancer registries in Zhejiang Province, the crude incidence, crude mortality, and cumulative rate for 0 to 74 years were calculated. Age standardized was performed using the age composition of the standard population from the Fifth National Population Census in 2000 and Segi's world standard population. The incidence and mortality characteristics of malignant tumor in different genders, urban/rural areas and ages were described. The order of crude incidence and mortality of malignant tumor were analyzed. Results: In 2021, there were 116 639 new malignant tumor cases in Zhejiang Province. The crude, Chinese population standardized, and world population-standardized incidences were 530.93/100 000, 304.83/100 000, and 288.20/100 000, respectively. The cumulative incidence for 0 to 74 years was 31.92%. There were 40 475 death cases. The crude, Chinese population-standardized, and world population-standardized mortalities were 184.24/100 000, 79.40/100 000, and 78.97/100 000, respectively. The cumulative mortality for 0 to 74 years was 8.37%. The Chinese population-standardized incidence for males and females were 286.34/100 000 and 323.45/100 000, respectively, and the Chinese population-standardized mortality were 106.25/100 000 and 54.17/100 000, respectively. The Chinese population-standardized incidence for urban and rural were 316.85/100 000 and 285.11/100 000, respectively, and the Chinese population-standardized mortality were 75.59/100 000 and 85.48/100 000, respectively. The crude incidence and crude mortality of malignant tumor both increased with age, peaking in the groups aged 80-<80 and ≥85 years at 1 845.06/100 000 and 1 656.88/100 000, respectively. The top ten malignant tumors with the highest crude incidence were, in descending order: lung cancer, thyroid cancer, breast cancer, prostate cancer, colorectal cancer, gastric cancer, liver cancer, cervical cancer, lymphoma, and brain tumors. These accounted for 80.34% of all new malignant tumor cases. The top ten malignant tumors with the highest crude mortality were, in descending order: lung cancer, liver cancer, colorectal cancer, gastric cancer, pancreatic cancer, prostate cancer, breast cancer, esophageal cancer, lymphoma, and gallbladder cancer. These accounted for 82.26% of all malignant tumor deaths. Conclusions In 2021, the cancer registration areas of Zhejiang Province were characterized by a relatively high malignant tumor incidence and a comparatively low mortality compared to national data. Males and the elderly emerged as key populations for targeted prevention and control. It is recommended to enhance screening, early diagnosis, and early treatment for lung cancer, thyroid cancer, prostate cancer, breast cancer, and gastric cancer malignancies.

The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationship between them. The serum levels of ApoA5 and Mfge8 in obese and healthy people were compared, and the obesity mouse model induced by the high-fat diet (HFD) was established. In addition, primary cardiomyocytes were purified and identified from the hearts of suckling mice. The 0.8 mmol/L sodium palmitate treatment was used to establish the lipid deposition cardiomyocyte model in vitro. ApoA5-overexpressing adenovirus was used to observe its effects on cardiac function and lipids. The expressions of the fatty acid uptake-related molecules and Mfge8 on transcription or translation levels were detected. Co-immunoprecipitation was used to verify the interaction between ApoA5 and Mfge8 proteins. Immunofluorescence was used to observe the co-localization of Mfge8 protein with ApoA5 or lysosome-associated membrane protein 2 (LAMP2). Recombinant rMfge8 was added to cardiomyocytes to investigate the regulatory mechanism of ApoA5 on Mfge8. The results showed that participants in the simple obesity group had a significant decrease in serum ApoA5 levels (P < 0.05) and a significant increase in Mfge8 levels (P < 0.05) in comparison with the healthy control group. The adenovirus treatment successfully overexpressed ApoA5 in HFD-fed obese mice and palmitic acid-induced lipid deposition cardiomyocytes, respectively. ApoA5 reduced the weight of HFD-fed obese mice (P < 0.05), shortened left ventricular isovolumic relaxation time (IVRT), increased left ventricular ejection fraction (LVEF), and significantly reduced plasma levels of triglycerides (TG) and cholesterol (CHOL) (P < 0.05). In myocardial tissue and cardiomyocytes, the overexpression of ApoA5 significantly reduced the deposition of TG (P < 0.05), transcription of fatty acid translocase (FAT/CD36) (P < 0.05), fatty acid-binding protein (FABP) (P < 0.05), and fatty acid transport protein (FATP) (P < 0.05), and protein expression of Mfge8 (P < 0.05), while the transcription levels of Mfge8 were not significantly altered (P > 0.05). In vitro, the Mfge8 protein was captured using ApoA5 as bait protein, indicating a direct interaction between them. Overexpression of ApoA5 led to an increase in co-localization of Mfge8 with ApoA5 or LAMP2 in cardiomyocytes under lipid deposition status. On this basis, exogenous added recombinant rMfge8 counteracted the improvement of lipid deposition in cardiomyocytes by ApoA5. The above results indicate that the overexpression of ApoA5 can reduce fatty acid uptake in myocardial cells under lipid deposition status by regulating the content and cellular localization of Mfge8 protein, thereby significantly reducing myocardial lipid deposition and improving cardiac diastolic and systolic function.
Animals ; Humans ; Mice ; Myocytes, Cardiac/metabolism* ; Obesity/physiopathology* ; Male ; Apolipoprotein A-V/blood* ; Lipid Metabolism/physiology* ; Milk Proteins/blood* ; Myocardium/metabolism* ; Diet, High-Fat ; Antigens, Surface/physiology* ; Mice, Inbred C57BL ; Cells, Cultured ; Female

Sophorae Flavescentis Radix is one of the commonly used traditional Chinese medicine in China, and a large amount of pharmaceutical residue generated during its processing and production is discarded as waste, which not only wastes resources but also pollutes the environment. Therefore, elucidating the chemical composition of the residue of Sophorae Flavescentis Radix and the differences between the residue and Sophorae Flavescentis Radix itself is of great significance for the comprehensive utilization of the residue. This study, based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) technology combined with multivariate statistical methods, provides a thorough characterization, identification, and differential analysis of the overall components of Sophorae Flavescentis Radix and its residue. Firstly, 61 compounds in Sophorae Flavescentis Radix were rapidly identified based on their precise molecular weight, fragment ions, and compound abundance, using a self-constructed compound database. Among them, 41 compounds were found in the residue, mainly alkaloids and flavonoids. Secondly, through principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA), 15 key compounds differentiating Sophorae Flavescentis Radix from its residue were identified. These included highly polar alkaloids, such as oxymatrine and oxysophocarpine, which showed significantly reduced content in the residue, and less polar flavonoids, such as kurarinone and kuraridin, which were more abundant in the residue. In summary, this paper clarifies the overall composition, structure, and content differences between Sophorae Flavescentis Radix and its residue, suggesting that the residue of Sophorae Flavescentis Radix can be used as a raw material for the extraction of its high-activity components, with promising potential for development and application in cosmetics and daily care. This research provides a scientific basis for the future comprehensive utilization of Sophorae Flavescentis Radix and its residue.
Drugs, Chinese Herbal/chemistry* ; Chromatography, High Pressure Liquid/methods* ; Mass Spectrometry/methods* ; Sophora/chemistry* ; Flavonoids/chemistry* ; Alkaloids/chemistry*

This study aims to investigate the antipyretic effects and mechanisms of ethanol extracts from Arisaematis Rhizoma fermented with bile from different sources on a rat model of fever induced by a dry-yeast suspension. The rat model of fever was established by subcutaneous injection of 20% dry-yeast suspension into the rat back. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6) in the serum, as well as prostaglandin E_2(PGE_2) and cyclic adenosine monophosphate(cAMP) in the hypothalamus, were determined by ELISA. Metabolomics analysis was then performed on serum and hypothalamus samples based on UPLC-Q-TOF MS to explore the potential biomarkers and metabolic pathways. The results showed that the body temperatures of rats significantly rose 4 h after modeling. After oral administration of high-dose ethanol extracts of Arisaematis Rhizoma fermented with bovine bile(NCH) and porcine bile(ZCH), the body temperatures of rats declined(P<0.05), and the NCH group showed better antipyretic effect than the ZCH group. Additionally, compared with the model group, the NCH and ZCH groups showed lowered levels of IL-1β, IL-6, TNF-α, PGE_2, and cAMP(P<0.01). The results of serum and hypothalamus metabolomics analysis indicated that both NCH and ZCH exerted antipyretic effects by regulating phenylalanine metabolism, sphingolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Collectively, both NCH and ZCH can play an obvious antipyretic role in the rat model of dry yeast-induced fever, and the underlying mechanism might be closely associated with inhibiting inflammation and regulating metabolic disorders. Moreover, NCH demonstrates better antipyretic effect.
Animals ; Rats ; Male ; Fermentation ; Rats, Sprague-Dawley ; Rhizome/metabolism* ; Drugs, Chinese Herbal/chemistry* ; Bile/chemistry* ; Antipyretics/chemistry* ; Fever/metabolism* ; Cattle ; Swine ; Tumor Necrosis Factor-alpha/metabolism* ; Ethanol/chemistry* ; Interleukin-6/blood* ; Interleukin-1beta/blood*

Based on the high-fat diet-induced hyperlipidemia rat model, this study aimed to evaluate the lipid-lowering effect of Arisaema Cum Bile and explore its mechanisms, providing experimental evidence for its clinical application. Biochemical analysis was used to detect serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C), triglycerides(TG), and total cholesterol(TC) to assess the lipid-lowering activity of Arisaema Cum Bile. Additionally, 16S rDNA sequencing and metabolomics techniques were employed to jointly elucidate the lipid-lowering mechanisms of Arisaema Cum Bile. The experimental results showed that high-dose Arisaema Cum Bile(PBA-H) significantly reduced serum ALT, AST, LDL-C, TG, and TC levels(P<0.01), and significantly increased HDL-C levels(P<0.01). The effect was similar to that of fenofibrate, with no significant difference. Furthermore, Arisaema Cum Bile significantly alleviated hepatocyte ballooning and mitigated fatty degeneration in liver tissues. As indicated by 16S rDNA sequencing results, PBA-H significantly enhanced both alpha and beta diversity of the gut microbiota in the model rats, notably increasing the relative abundance of Akkermansia and Subdoligranulum species(P<0.01). Liver metabolomics analysis revealed that PBA-H primarily regulated pathways involved in arachidonic acid metabolism, vitamin B_6 metabolism, and steroid biosynthesis. In summary, Arisaema Cum Bile significantly improved abnormal blood lipid levels and liver pathology induced by a high-fat diet, regulated hepatic metabolic disorders, and improved the abundance and structural composition of gut microbiota, thereby exerting its lipid-lowering effect. The findings of this study provide experimental evidence for the clinical application of Arisaema Cum Bile and the treatment of hyperlipidemia.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Metabolomics ; Hyperlipidemias/microbiology* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Hypolipidemic Agents/pharmacology* ; Liver/metabolism* ; Humans ; Alanine Transaminase/metabolism* ; Triglycerides/metabolism* ; Aspartate Aminotransferases/metabolism*

OBJECTIVES: To investigate the medium- and long-term efficacy of percutaneous mechanical thrombectomy (PMT) combined with stent implantation for treatment of iliac vein stenosis with lower extremity deep venous thrombosis (LEDVT). METHODS: Clinical and follow-up data of 125 patients with iliac vein stenosis and LEDVT who underwent PMT and stent implantation at five hospitals in northern Zhejiang province from January 2017 to June 2021 were collected. The thrombus clearance rate, thrombus recurrence rate, patency rate of iliac vein stents and post-thrombotic syndrome (PTS) occurrence rate were documented, and safety indicators such as bleeding, death, pulmonary embolism, stent fracture and displacement were assessed. RESULTS: Among 125 patients, for clearance of limb thrombosis, there were 8 cases of grade I (6.4%), 10 cases of grade II (8.0%), and 107 cases of grade III (85.6%). Patients were followed up for a median period of 74 months. According to the Villalta score, the recurrence rates of limb thrombosis at 12, 24 and 36 months were 8.48%, 8.93% and 10.91%; the iliac vein patency rates were 91.52%, 91.07%, and 89.09%; and the incidences of PTS were 5.08%, 5.36% and 6.36%, respectively. There were no major adverse events such as death, massive pulmonary embolism or severe hepatic and renal insufficiency, and no readmission intervention events due to stent fracture or other incidence were found. CONCLUSIONS PMT combined with iliac vein stent implantation is effective for patients with iliac vein stenosis complicated by LEDVT with good medium- and long-term efficacy and safety, which is worthy of clinical application.
Humans ; Stents ; Iliac Vein/pathology* ; Venous Thrombosis/surgery* ; Thrombectomy/methods* ; Female ; Male ; Middle Aged ; Aged ; Adult ; Constriction, Pathologic/surgery* ; Treatment Outcome ; Follow-Up Studies