OBJECTIVE: To explore the effect and mechanism of DNA methyltransferase 1 (DNMT1) knockout on the inhibition of acute myeloid leukemia (AML) by natural killer (NK) cells. METHODS: The peripheral blood NK cells of AML patients and controls were collected, and the mRNA and protein level of DNMT1 were measured by PCR and Western blot, respectively. The DNMT1 knockout mice were constructed to obtain NK^DNMT1-/- cells. The NK cells were stimulated with interleukin (IL)-12, IL-15, and IL-18 to construct memory NK cells, and then the interferon-γ (IFN-γ) levels were measured by ELISA. After co-culturing with memory NK cells and HL60 cells, the killing effect of NK^DNMT1-/- cells on HL60 cells was detected by LDH assay. Then, the HL60 cell apoptosis and NK cell NKG2D level were measured by flow cytometry. The perforin and granzyme B protein levels of NK cells were measured by Western blot. The AML model mice were constructed by injecting HL60 cells into the tail vein, meanwhile, memory NK cells were also injected, and then the mouse weights, CD33 positive rates, and survival time were detected. RESULTS: The mRNA and protein levels of DNMT1 in NK cells of AML patients were significantly higher than those in the control group (both P < 0.01), while the IFN-γ level induced by interleukin was significantly lower than that in the control group (P < 0.05). Compared with NK^DNMT1+/+ cells, the ability of NK^DNMT1-/- cells to secrete IFN-γ after interleukin stimulation was significantly increased (P < 0.05). The killing and apoptosis-inducing effects of NK^DNMT1-/- cells on HL60 cells were significantly stronger than those of NK^DNMT1+/+ cells (both P < 0.05). The NKG2D level and expression of perforin and granzyme B of NK^DNMT1-/- cells were significantly increased compared with NK^DNMT1+/+ cells (all P < 0.05). Compared with AML mice injected with NK^DNMT1+/+ cells, AML mice injected with NK^DNMT1-/- cells showed significantly increased body weight, decreased CD33 positive rate, and prolonged survival time (all P < 0.05). CONCLUSION Knocking out DNMT1 can enhance the inhibitory effect of NK cells on AML, which may be related to enhancing NK cell memory function.
Killer Cells, Natural/metabolism* ; Animals ; Leukemia, Myeloid, Acute ; Humans ; DNA (Cytosine-5-)-Methyltransferase 1 ; Mice ; Mice, Knockout ; HL-60 Cells ; Apoptosis ; Interferon-gamma/metabolism* ; Granzymes/metabolism* ; Perforin/metabolism* ; NK Cell Lectin-Like Receptor Subfamily K/metabolism*

Liver ischemia-reperfusion injury (LIRI) is a pathological process involving multiple injury factors and cell types, with different stages. Currently, protective drugs targeting a single condition are limited in efficacy, and interventions on immune cells will also be accompanied by a series of side effects. In the current bottleneck research stage, the multi-target and obvious clinical efficacy of Chinese medicine (CM) is expected to become a breakthrough point in the research and development of new drugs. In this review, we summarize the roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in various stages of hepatic ischemia-reperfusion and on various types of cells. Combined with the current research progress in reducing ROS/RNS with CM, new therapies and mechanisms for the treatment of hepatic ischemia-reperfusion are discussed.
Reperfusion Injury/drug therapy* ; Reactive Oxygen Species/metabolism* ; Reactive Nitrogen Species/metabolism* ; Humans ; Liver/drug effects* ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

[Purpose]To analyze the trends of mortality and disease burden of gastric cancer among residents aged 30 and above from 2009 to 2023 in Wuxi City of Jiangsu Province and to estimate the age-period-cohort effect.[Methods]The gastric cancer mortality data from 2009 to 2023 were collected from Wuxi Death Registration System,and the crude mortality rate,age-standardized mortality rate,years of life lost(YLL)and YLL rate were calculated.The average annual percen-tage change(AAPC)was calculated with Joinpoint regression to analyze the trends of mortality and YLL rate of gastric cancer.The age-period-cohort model was used to analyze the effect of age,pe-riod and birth cohort on gastric cancer mortality.[Results]From 2009 to 2023,there were 32 348 gastric cancer deaths in Wuxi,the crude mortality rate was 44.24/105,and the age-standard mor-tality rate was 25.10/105,with a total YLL of 681 618.33 person-years.The crude mortality rate,age-standardized mortality rate and YLL rate showed decreasing trends,with AAPC of-1.77％(95％CI:-2.10％～-1.43％),-4.59％(95％CI:-4.97％～-4.20％)and-2.14％(95％CI:-2.56％～-1.74％),respectively.From 2009 to 2023,crude mortality rate,age-tandardized mortality rate,YLL in men were higher than those in women,and the decline rates of all indicators in women were faster than those in men.The age effect showed that the overall risk of gastric cancer death increased with age;the period effect showed a gradual decrease in the mortality risk and death burden of gastric cancer over time;the cohort effect showed that the later born cohort had a lower risk of death and death burden.[Conclusion]From 2009 to 2023,the disease burden of gastric cancer mortality in Wuxi showed a decreasing trend,with age and sex being the primary influencing factors.In the future,emphasis should be placed on gastric cancer screening and early intervention in middle-aged and elderly men.

Objective:To investigate the effect of triglyceride-glucose(TyG) index and alkaline phosphatase(ALP) on brachial-ankle pulse wave conduction velocity(baPWV) in postmenopausal women.Methods:A cross-sectional study was conducted, enrolling 3 483 postmenopausal women who underwent health checkup at Taihu Sanatorium in Jiangsu Province from March 2020 to June 2021. The physical activity, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein-cholesterol(HDL-C), low-density lipoprotein-cholesterol(LDL-C), ALP, and baPWV were collected.Results:Age, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, and LDL-C levels were significantly lower in the normal baPWV group( n=1 971) than those in the elevated baPWV group( n=1 512; P<0.001). Logistic regression identified the TyG index( OR=1.75) and ALP level( OR=1.20) as independent risk factors for elevated baPWV( P<0.001), besides with age, body mass index, systolic blood pressure, diastolic blood pressure, and regular exercise. Individuals with both high TyG index and elevated ALP had a 2.51-fold higher risk of elevated baPWV(95% CI 2.01-3.14). Adjusted interaction measures(including age, body mass index, systolic blood pressure, diastolic blood pressure, and regular exercise) showed RERI=2.825(95% CI 1.255-3.905), AP=0.348(95% CI 0.180-0.875), and SI=1.657(95% CI 0.628-3.374). Conclusions:The TyG index and ALP levels are independent risk factors for elevated baPWV in postmenopausal women and exhibit an additive interaction effect on arterial stiffness in this population.

This study aimed to explore the therapeutic mechanisms of Colquhounia Root Tablets(CRT) in treating diabetic kidney disease(DKD) by integrating biomolecular network mining with animal model verification. By analyzing clinical transcriptomics data, an interaction network was constructed between candidate targets of CRT and DKD-related genes. Based on the topological eigenvalues of network nodes, 101 core network targets of CRT against DKD were identified. These targets were found to be closely related to multiple pathways associated with type 2 diabetes, immune response, and metabolic reprogramming. Given that immune-inflammatory imbalance driven by metabolic reprogramming is one of the key pathogenic mechanisms of DKD, and that many core network targets of CRT are involved in this pathological process, receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)-phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)-nuclear factor-κB(NF-κB)-NOD-like receptor family pyrin domain containing 3(NLRP3) signaling axis was selected as a candidate target for in-depth research. Further, a rat model of DKD induced by a high-sugar, high-fat diet and streptozotocin was established to evaluate the pharmacological effects of CRT and verify the expression of related targets. The experimental results showed that CRT could effectively correct metabolic disturbances in DKD, restore immune-inflammatory balance, and improve renal function and its pathological changes by inhibiting the activation of the RAGE-ROS-PI3K-AKT-NF-κB-NLRP3 signaling axis. In conclusion, this study reveals that CRT alleviates the progression of DKD through dual regulation of metabolic reprogramming and immune-inflammatory responses, providing strong experimental evidence for its clinical application in DKD.
Animals ; Diabetic Nephropathies/metabolism* ; Receptor for Advanced Glycation End Products/genetics* ; NF-kappa B/genetics* ; Signal Transduction/drug effects* ; Rats ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Phosphatidylinositol 3-Kinases/genetics* ; Reactive Oxygen Species/metabolism* ; Humans ; Plant Roots/chemistry* ; Rats, Sprague-Dawley ; Tablets/administration & dosage*

Objective:To explore the latent categories of barriers to PhaseⅡ cardiac rehabilitation in patients after coronary artery bypass grafting (CABG), and to analyze the influencing factors of different latent classes.Methods:A total of 340 CABG patients in PhaseⅡ cardiac rehabilitation were recruited by convenience sampling from two Class Ⅲ Grade A hospitals in Shanghai between January and August 2024. Data were collected using a general information questionnaire, the Cardiac Rehabilitation Barriers Scale (CRBS), and the Fear of Exercise Scale for Cardiac Patients. Latent profile analysis was used to classify the cardiac rehabilitation barriers, and multinomial Logistic regression was conducted to identify influencing factors for different latent classes.Results:Of the 340 questionnaires distributed, 319 valid responses were obtained after excluding incomplete or patterned questionnaires, with a valid response rate of 93.82% (319/340). The cardiac rehabilitation barriers among the 319 CABG patients were classified into three latent profiles: low-barrier, active rehabilitation type; moderate-barrier, poor-functioning type; and moderate-barrier, insufficient-perception type. Multinomial logistic regression analysis indicated that smoking, comorbidities, age, educational level, and fear of exercise were statistically significant influencing factors for different barrier profiles ( P<0.05) . Conclusions:Cardiac rehabilitation barriers in CABG patients exhibit heterogeneity. Medical staff should adopt targeted intervention strategies based on the specific barrier profiles, reduce patients' fear of exercise, and thereby improve rehabilitation outcomes.

[Purpose]To analyze the trends of mortality and disease burden of gastric cancer among residents aged 30 and above from 2009 to 2023 in Wuxi City of Jiangsu Province and to estimate the age-period-cohort effect.[Methods]The gastric cancer mortality data from 2009 to 2023 were collected from Wuxi Death Registration System,and the crude mortality rate,age-standardized mortality rate,years of life lost(YLL)and YLL rate were calculated.The average annual percen-tage change(AAPC)was calculated with Joinpoint regression to analyze the trends of mortality and YLL rate of gastric cancer.The age-period-cohort model was used to analyze the effect of age,pe-riod and birth cohort on gastric cancer mortality.[Results]From 2009 to 2023,there were 32 348 gastric cancer deaths in Wuxi,the crude mortality rate was 44.24/105,and the age-standard mor-tality rate was 25.10/105,with a total YLL of 681 618.33 person-years.The crude mortality rate,age-standardized mortality rate and YLL rate showed decreasing trends,with AAPC of-1.77％(95％CI:-2.10％～-1.43％),-4.59％(95％CI:-4.97％～-4.20％)and-2.14％(95％CI:-2.56％～-1.74％),respectively.From 2009 to 2023,crude mortality rate,age-tandardized mortality rate,YLL in men were higher than those in women,and the decline rates of all indicators in women were faster than those in men.The age effect showed that the overall risk of gastric cancer death increased with age;the period effect showed a gradual decrease in the mortality risk and death burden of gastric cancer over time;the cohort effect showed that the later born cohort had a lower risk of death and death burden.[Conclusion]From 2009 to 2023,the disease burden of gastric cancer mortality in Wuxi showed a decreasing trend,with age and sex being the primary influencing factors.In the future,emphasis should be placed on gastric cancer screening and early intervention in middle-aged and elderly men.

Objective:To explore the latent categories of barriers to PhaseⅡ cardiac rehabilitation in patients after coronary artery bypass grafting (CABG), and to analyze the influencing factors of different latent classes.Methods:A total of 340 CABG patients in PhaseⅡ cardiac rehabilitation were recruited by convenience sampling from two Class Ⅲ Grade A hospitals in Shanghai between January and August 2024. Data were collected using a general information questionnaire, the Cardiac Rehabilitation Barriers Scale (CRBS), and the Fear of Exercise Scale for Cardiac Patients. Latent profile analysis was used to classify the cardiac rehabilitation barriers, and multinomial Logistic regression was conducted to identify influencing factors for different latent classes.Results:Of the 340 questionnaires distributed, 319 valid responses were obtained after excluding incomplete or patterned questionnaires, with a valid response rate of 93.82% (319/340). The cardiac rehabilitation barriers among the 319 CABG patients were classified into three latent profiles: low-barrier, active rehabilitation type; moderate-barrier, poor-functioning type; and moderate-barrier, insufficient-perception type. Multinomial logistic regression analysis indicated that smoking, comorbidities, age, educational level, and fear of exercise were statistically significant influencing factors for different barrier profiles ( P<0.05) . Conclusions:Cardiac rehabilitation barriers in CABG patients exhibit heterogeneity. Medical staff should adopt targeted intervention strategies based on the specific barrier profiles, reduce patients' fear of exercise, and thereby improve rehabilitation outcomes.

Objective:To investigate the effect of triglyceride-glucose(TyG) index and alkaline phosphatase(ALP) on brachial-ankle pulse wave conduction velocity(baPWV) in postmenopausal women.Methods:A cross-sectional study was conducted, enrolling 3 483 postmenopausal women who underwent health checkup at Taihu Sanatorium in Jiangsu Province from March 2020 to June 2021. The physical activity, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein-cholesterol(HDL-C), low-density lipoprotein-cholesterol(LDL-C), ALP, and baPWV were collected.Results:Age, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, and LDL-C levels were significantly lower in the normal baPWV group( n=1 971) than those in the elevated baPWV group( n=1 512; P<0.001). Logistic regression identified the TyG index( OR=1.75) and ALP level( OR=1.20) as independent risk factors for elevated baPWV( P<0.001), besides with age, body mass index, systolic blood pressure, diastolic blood pressure, and regular exercise. Individuals with both high TyG index and elevated ALP had a 2.51-fold higher risk of elevated baPWV(95% CI 2.01-3.14). Adjusted interaction measures(including age, body mass index, systolic blood pressure, diastolic blood pressure, and regular exercise) showed RERI=2.825(95% CI 1.255-3.905), AP=0.348(95% CI 0.180-0.875), and SI=1.657(95% CI 0.628-3.374). Conclusions:The TyG index and ALP levels are independent risk factors for elevated baPWV in postmenopausal women and exhibit an additive interaction effect on arterial stiffness in this population.

Objective To investigate the therapeutic effect of cnithol on acute pancreatitis(AP)rats and its regulatory mechanism on phosphoinositol 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway.Methods SPF-grade SD male rats were randomly divided into control group,model group(50 μg·kg-1 hyranin+10 mg·kg-1 LPS),positive control group(2 mg·kg-1 dexamethasone),experimental-L group(20 mg·kg-1 osthol)and experimental-H group(40 mg·kg-1 osthol),experimental-H+740Y-P group(40 mg·kg-1 osthol+2 mg·kg-1 PI3K activator 740Y-P),15 mice in each group.The activities of amylase and lipase in serum of rats were detected by automatic biochemical analyzer 24 h after the last administration.The levels of inflammatory factors tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in serum,the content of malondialdehyde(MDA)and the activity of superoxide dismutase(SOD)in pancreas were detected by enzyme-linked immunosorbent assay(ELISA).Hematoxylin-eosin(HE)staining was used to observe the pathological changes of pancreatic tissue and score the pathological damage.Western blot was used to detect the expression of PI3K/Akt pathway related proteins in rat pancreas.Results The activities of serum amylase in control group,model group,positive control group,experimental-H group and experimental-H+740Y-P group were(135.67±12.89),(1 027.84±32.16),(174.31±15.27),(186.70±17.39)and(835.92±28.78)U·mL-1,respectively;the contents of TNF-α were(35.69±3.10),(223.54±15.23),(48.76±4.25),(52.31±4.68)and(208.46±13.65)pg·mL-1,respectively;the contents of MDA were(2.15±0.14),(6.37±0.42),(2.78±0.17),(2.81±0.15)and(5.96±0.36)nmol·mg-1,respectively;the histopathological injury scores were 1.12±0.07,10.23±0.38,3.14±0.21,3.25±0.23 and 9.68±0.40,respectively;p-PI3K/PI3K ratios were 0.82±0.05,1.96±0.15,1.07±0.06,1.10±0.07 and 1.69±0.14,respectively.The above indexes were compared with the control group in the model group,the positive control group,experimental-H group and the model group,and the above indexes of experimental-H+740Y-P group and experimental-H group,and the differences were statistically significant(all P＜0.05).Conclusion Gossetin can play a therapeutic role in AP,and its mechanism may be related to the inhibition of PI3K/Akt signaling pathway.