Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective:To explore application effect of early respiratory training schemes based on 4E mode (Engage, Educate, Execute, Evaluate) in children with bronchiolitis obliterans (BO) and provide evidence for the clinical implementation of early respiratory rehabilitation in children with BO.Methods:This was a quasi-experimental study. The children with BO who were admitted to 2 wards of the Department of Respiratory Medicine of Hunan Children's Hospital from January 1 to December 31, 2021 were selected as the research objects. They were randomly divided into the control group and the experimental group, with 23 cases in each group. The control group received routine treatment, nursing and rehabilitation guidance. The experimental group established a multidisciplinary team based on the control group, and used the early respiratory training program based on the 4E model to implement intervention. The clinical symptom severity scale was used to evaluate the improvement of the clinical symptoms of the children within 24 hours of being diagnosed as BO, the day of discharge, and 1 and 3 months after discharge for re-examination, and the hospitalization time of the children and the incidence of adverse events related to respiratory training were counted by using medical records and questionnaires.Results:The clinical symptom severity scores of the experimental group within 24 hours of admission diagnosis and the day of discharge were (20.00 ± 2.51) and (11.30 ± 2.46)points respectively, while those of the control group were (20.57 ± 2.21) and (11.70 ± 2.42) points respectively, with no statistically significant difference ( t=0.81, 0.54, both P>0.05). The clinical symptom severity scores of the experimental group were(10.52 ± 2.31) and (8.55 ± 1.06) points, lower than (12.32 ± 1.39) and (12.45 ± 2.19) points of the control group when they returned to the hospital for re-examination 1 and 3 months after discharge, with a statistically significant difference ( t=3.14, 7.25, both P<0.05). The experimental group was hospitalized for (11.78 ± 1.17) days, which was showter than (13.74 ± 1.63) days in the control group, with a statistically significant difference ( t=4.68, P<0.05). No respiratory training-related adverse events occurred in both groups of children during hospitalization. During home respiratory training after discharge, 1 and 2 respiratory training-related adverse events occurred in the experimental group 1 and 3 months after discharge, respectively, compared with 6 and 9 in the control group. The difference was statistically significant ( χ2=4.64, 5.94, both P<0.05). Conclusions:Early respiratory training solutions based on the 4E mode can improve the clinical symptoms of BO children, shorten the hospitalization time, reduce the number of adverse events related to respiratory training, and promote the recovery of children.

Atherosclerosis (AS) is a chronic and progressive arterial disease. It is an important cause of the occurrence and development of cardiovascular and cerebrovascular diseases. With the development of Traditional Chinese Medicine (TCM), TCM has many advantages in the therapy of AS, with less adverse reactions. Studies have shown that TCM can resist AS, and the mechanism mainly belongs to regulating lipid metabolism, anti-lipid peroxidation, anti-inflammation, anticoagulation, and protecting the structure and function of vascular endothelial cells. The mechanism of TCM for AS is warranted to be studied systematically, and the chemical components need to be further clarified.

Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.
Adipocytes ; metabolism ; Animals ; Brain ; metabolism ; Carrier Proteins ; metabolism ; Epilepsy ; metabolism ; Glucose ; metabolism ; Glycoproteins ; metabolism ; Humans ; Insulin Resistance ; Lipid Metabolism ; Neurons ; metabolism ; Signal Transduction

Objective To investigate the effects of artesunate combined with arsenic trioxide (ATO) on the proliferation and apoptosis of NB4 cells.Methods The NB4 cells were treated with different concentrations of artesunate and arsenic trioxide respectively for 48 h.The cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) method.The cells were divided into 4 groups:control group,artesunate group,arsenic trioxide group,and the combination of artesunate and arsenic trioxide group.The cell cycle and apoptosis were detected by flow cytometry (FCM).The protein expression levels of Bcl-2 and Bax were detected by Western blot.Results The MTT results showed that compared with the control group,the proliferation inhibition rates of 0.25,0.50,1.00,2.00,4.00 μmol/L artesunate group (19.26％ ± 3.59％,36.53％ ± 2.67％,61.32％ ± 2.50％,70.30％ ± 3.15％,86.92 ± 0.02％) significantly increased (P＜0.05);the proliferation inhibition rates of 1,2,4,8,16 μmol/L arsenic trioxide group (12.69％ ± 2.43％,64.26％ ± 2.02％,85.10％ ± 2.67％,92.06％ ± 2.21％,93.67％ ± 3.36％) significantly increased (P＜0.05);and the proliferation inhibition rate (40.17％ ± 5.49％ vs.32.23％ ± 3.52％) of combination of artesunate and arsenic trioxide group significantly higher than the arsenic trioxide group (P＜0.05).Compared with the arsenic trioxide group,the percentage of G0/G1 phase cells (74.20％ ± 1.43％ vs.66.14％ ± 1.78％),the apoptosis rate (58.00％ ± 2.41％ vs.34.57％ ± 1.22％),and the expression level of Bax protein (1.35 ± 0.09 vs.1.13 ± 0.09) in the combination of artesunate and arsenic trioxide group significantly increased (P＜0.05),the expression level of Bcl-2 protein (0.45 ± 0.09 vs.1.03 ± 0.10) in the combination of artesunate and arsenic trioxide group significantly decreased (P＜0.05).Conclusions Artesunate can significantly enhance the proliferation inhibition and apoptosis induced by arsenic trioxide on NB4 cells.The possible mechanism of proliferation inhibition and apoptosis of NB4 cells by artesunate combined with arsenic trioxide may be related to reduce the expression of anti-apoptotic protein Bcl-2 and increase the expression of apoptotic protein Bax.

Objective To explore the factors of relapse in alcohol-induced psychiatric and behavioral disorders.Methods103 male inpatients met with the diagnostic criteria of alcohol-induced psychiatric and behavioral disorders according to ICD-10 were enrolled.All patients were hospitalized from Wuxi Mental Center from January 2013 to August 2015.As baseline,information was obtained within all patients,and relapse was evaluated one year after discharge.The Kaplan-Meier method was used to statistically analyze the alcohol relapse time of patients with different length of hospitalization.Cox regression was used to explore the risk factors for alcohol relapse,including age,education level,marital status,family history,smoking,fixed income,number of hospitalizations,duration of alcohol intake,average daily alcohol intake,time of psychosis,psychiatric symptoms,length of hospitalization,physical condition and mental condition.Results(1)The analysis (log rank) showed that the length of hospitalization had no significant statistical differences with relapse(χ2=0.069,P=0.966).(2) The number of hospitalizations (RR=1.074,95%CI=1.002-1.151,P=0.042) and average daily alcohol intake(RR=1.035,95%CI=1.012-1.059,P=0.003) were the risk factors for relapse.ConclusionThe number of hospitalizations and average daily alcohol intake are risk factors for relapse within a year in male inpatients with alcohol-induced psychiatric and behavioral disorders.Prolonged hospital stay has no help to reduce relapse in those people.

Objective:To explore the calvarial critical size defect (CSD)in rats with type 2 diabetes mellitus(T2DM).Methods:T2DM model of SD rats(weighted 300-320 g)was induced by high fat and high sugar diet and low dose intraperitoneal streptozotocin (STZ)injection.The rats with T2DMand the normal controls were divided into 4 groups(n=3)respectively.Defects with the diame-ter(mm)of 2,3,4 and 5 were made on the central calvaria of each rat.General observation,X-ray examination and histological study were performed 8 weeks postoperatively.Results:In the T2DM group,only the defects of 2 mm diameter were healed completely,X-ray resistance and new bone formation were observed;the defects of 3,4 and 5 mm diameter were unhealed,X-ray transmission was observed and newly formed bone was insufficient.In the control group,the defects of 2,3 and 4 mm diameter were healed completely, X-ray resistance and new bone formation were observed;the defects of 5 mm diameter were unhealed,X-ray transmission was ob-served,newly formed bone was insufficient.Conclusion:The calvarial CSD of T2DM rat model can be defined as the defect with the diameter of 3 mm.

Objective To investigate the effects of 17-methoxyl-7-hydroxy-benzene-furabcgakcone( MHBFC ) on isoproterenol-induced ventricular remodeling in mice. Methods Isoproterenol(ISO)was given subcutaneously(1 mg·kg-1, twice per day for 7 d)to induce ventricular remodeling in mice. Mice were divided into normal control group,model group, captopril group,MHBFC low and high-dose groups. 65 mg·kg-1 captopril was given by intragastric administration in captopril group,2. 5,5. 0 mg·kg-1 MHBFC were given by intravenous injection in MHBFC low and high-dose groups. At the end of the 7th day,the hearts of the mice were weighted,and myocardial hypertrophy index was expressed as heart weight/body weight, double kidneys weight/body weight and lung weight/body weight( HW/BW,KW/BW and LW/BW). Colorimetric method was used to determine the content of hydroxyproline( Hyp)in heart,the activity of superoxide dismutase( SOD)and the content of malondialdehyde( MDA)in serum. The histological changes were observed by HE and Masson’s staining,the changes of cross section area( CSA),collagen volume fraction,( CVF)and perivascular circumferential collagen area( PVCA)were determined. Results Compared with the model group,MHBFC potently inhibited cardiomyocyte hypertrophy,decreased the HW/BW, KW/BW and LW/BW,improved cardiac pathology changed,increased the of activity SOD,decreased the content of MDA in serum and the content of Hyp in heart tissue(P﹤0. 01 or P﹤0. 05),decreased the CVF and PVCA(P﹤0. 01). Conclusion MHBFC possesses protective effects against ISO-induced ventricular remodeling in mice,which may be related to its actions in reducing the oxidative stress and improving the antioxidant activity of the body.

Objective To evaluate efficacy of healthy canteen based-nutritional health promotion so as to provide evidence for popularization and application.Methods A total of 429 college professors and administrative staffs with a healthy canteen were selected as the intervention group in 2012 in Changzhou,and another 947 counterparts without a healthy canteen were selected as the control group.Those of the intervention group was further assigned to the ≥2 times/week and＜2 times/week subgroups.Blood pressure,fatty liver,serum triglycerides,blood glucose,total cholesterol,uric acid,low-density lipoprotein cholesterol,high-density lipoprotein cholesterol and body mass index(BMI)were tested before and after the intervention.Results After the intervention,the mean serum glucose[(5.06±0.62)mmol/L],uric acid[(310.57 ± 71.79)μmol/L],total cholesterol[(4.88 ± 0.86)mmol/L],triglycerides[(1.39 ± 0.67)mmol/L]and low-density lipoprotein cholesterol[(2.51 ±0.62)mmol/L]of the intervention group were significantly decreased(t values were 7.513,2.126,2.062,3.731 and 8.891,respectively; all P＜0.05),and mean high-density lipoprotein cholesterol[(1.43±0.34)mmol/L]were significantly increased(t=-2.309,P＜0.05).After the intervention,mean serum glucose and uric acid of the control group were significantly increased(t values were-3.491 and-7.703,respectively; both P＜0.05),although there was no statistically significant difference of mean serum triglycerides,total cholesterol,low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in the control group before and after the intervention(all P＞0.05).The abnormality rates of serum glucose,uric acid,total cholesterol,triglycerides,low-density lipoprotein cholesterol and BMI as well as the incidence of hypertension of the intervention group were significantly decreased after the intervention(x2 values were 4.202,3.940,4.031,7.305,59.422,4.273 and 7.385,respectively; P＜0.05).In the control group,although the abnormality rate of serum uric acid and the incidence of fatty liver were significantly inclined after the intervention(x2 values were 23.740 and 7.408,respectively; both P＜0.05),there were no significant difference of abnormal serum triglycerides,glucose,total cholesterol,low-density lipoprotein cholesterol and BMI as well as the incidence of hypertension before and after the intervention(all P＞0.05).Mean serum triglycerides[(1.15 ±0.68)mmol/L]and low-density lipoprotein cholesterol[(2.4 1±0.60)mmol/L]in the ≥2 times/ week subgroup were significantly lower than those of the＜2 times/week subgroup(t values were-4.884 and-2.513,respectively; both P＜0.05),and mean high-density lipoprotein cholesterol[(1.46±0.33)mmo]/L]of the ≥2 times/week subgroup was significantly higher than that of the＜2 times/week subgroup(t=2.032,P＜0.05).The abnormality rates of serum total cholesterol,triglyceride and low-density lipoprotein cholesterol in the ≥ 2 times/week subgroup were significantly lower than those in the＜2 times/week subgroup(x2 values were 3.963,9.947 and 4.589,respectively; all P＜0.05).Conclusion Healthy canteen based-nutritional health promotion model may provide an effective method to prevent and control the development of noncommunicable chronic diseases.

Objective To explore the relationships of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) with growth of very low birth weight (VLBW) infants in the early postnatal stage. Methods According to the individual gestational age and birth weight, 32 cases of VLBW infants were divided into small for gestational age (SGA) group and appropriate for gestational age (AGA) group. After birth, all the infants were given the same nutritional intake. The body weight, body length, head circumference and body mass index (BMI) were monitored at different time points (d0, d7, d14 and d28 after birth). Serum IGF-1 and IGFBP-3 levels were measured by radiommunoassay, and IGF-1/IGFBP-3 molar ratio was calculated. Results There was no signiifcant difference of body weight, body length, head circumference and BMI between two groups at d0, d7, d14 after birth. Body weight and BMI in SGA group were less than those in AGA group at d28 after birth (P<0.05). The levels of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 in SGA group and IGF-1/IGFBP-3 in AGA group did not change with age after birth. The levels of IGF-1 and IGFBP-3 were increased in AGA group after birth. The level of IGF-1 in AGA group at d14 and d28 after birth was higher than that in AGA group at d0 after birth (P<0.05). The level of IGFBP-3 in AGA group at d28 after birth was higher than that in AGA group at d0 after birth (P<0.05). The levels of IGF-1 and IGFBP-3 in SGA group at d28 after birth were lower than those in AGA group at d28 after birth (P<0.05). Conclusions Serum IGF-1 and IGFBP-3 levels in SGA group are lower than those in AGA group. Low levels of IGF-1 and IGFBP-3 may result in growth retardation.