Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*

AIM: To study the effect of ligustrazine on the cardiacmyocyte lesion in rats with type 2 diabetes mellitus.METHODS: Male Wistar rats were injected with STZ via tail vein under high-glucose and high-fat feeding for 4 weeks to establish the animal model of type 2 diabetes mellitus.Ligustrazine at different doses was used to treat the diabetic rats.The body weight, blood glucose and the morphology of heart tissues were observed.The myocardial levels of IL-1β, IL-6 and TNF-α were detected by ELISA, and the protein expression of IKKβ and NF-κB in the myocardium was determined by Westeren blotting.RESULTS: Ligustrazine at high dose alleviated the body weight reduction and blood glucose elevation cause by diabetes, and reduced pro-inflammatory factors IL-1β, TNF-α and IL-6.Moreover, the protein expression of IKKβ and NF-κB was significant decreased by ligustrazine.CONCLUSION: Ligustrazine inhibits the myocardial inflammation caused by diabetes through anti-inflammatory pathway.

[Summary] 45 male SD rats with 4 week old were assigned to 3 groups after normal feedstuff for 2 weeks:control group(n=15), diabetic group(n=15), and calcitriol group(n=15).Diabetic rat model were induced using intraperitoneal injection with streptozotocin( STZ) after 12 h fasting.Calcitriol group and diabetic group were treated with calcitriol for 24 weeks.Femoral biomechanics indexes were measured at end of the study.Total 30 SD rats ( 10 rats of each groups) were analyzed.Compared to normal controls, the rats in diabetic group had lower body weight [(437.02±18.66vs267.93±15.64)g,P<0.05],decreasedserumcalciumconcentration[(2.89±0.31vs2.60 ±0.38) mmol/L, P<0.05], and increased serum phosphorus concentration[(2.21 ±0.35 vs 2.80 ±0.66) mmol/L, P<0.05].At the end of the study, the ultimate force[(98.07 ±2.94 vs 70.87 ±5.75) N, P<0.05], ultimate displacement[(0.66 ±0.02 vs 0.51 ±0.02) mm, P<0.05], Young′s modulus[(139 188.51 ±10 617.69 vs 81 969.06 ±6 393.21) N/mm2, P<0.05], and modulus for toughness[(22 492.59 ±2 429.15 vs 8 292.87 ± 1 291.43) N/mm2 , P<0.05 ] of diabetic group were significantly lower than normal control group.However, calcitrol could reverse these changes at some extent.SD rats with diabetes had significant disorder of bone metabolism and decreased bone strength.Calcitriol could improve the decreased bone strength in diabetic rats.

Objective To explore the changes of IL-12,IL-18,IL-10 in the pleural fluid and serum of tuberculosis (TB)patients during the disease course.Methods 60 TB patients were selected as test subjects in this study,all patients with pleural fluid and serum were taken for testing.The pleural fluid and serum IL -12,IL -18 IL-10 changes,more naive patients and patients with pleural effusion retreatment and serum IL -12,IL -18,IL -10 content differences were observed and analyzed.Results Both in the initial treatment or retreatment group of pa-tients,the IL -12 and IL -10 levels in pleural effusion were significantly higher than those in the serum,the differ-ences were statistically significant(all P =0.000),and IL -18 content of pleural effusion in a little early treatment group was lower than that of the serum,the differences was not statistically significant(P =0.151),and the IL -12 and IL -10 contents in the pleural fluid and serum were higher than the retreatment of patients previously untreated patients.The IL -12 level in pleural effusion of Ⅱ type patients was (3 025.80 ±1 324.75)pg/mL,which in the ser-um was (498.84 ±326.73)pg/mL,which in the pleural effusion was significantly higher than in the serum(P =0.020),and the IL -12 levels in pleural effusion of Ⅲ -TB and Ⅳ type TB patients were also significantly higher than those in the serum,the differences were statistically significant(all P =0.000).The IL -18 level in pleural effu-sion of Ⅱ type patients was (1 735.54 ±872.65)pg/mL,which in pleural effusion of Ⅲ patients was (754.63 ± 426.87)pg/mL,in pleural effusion of Ⅳ patients was (655.19 ±412.63)pg/mL or so,and serum IL -18 levels in patients with different types of pleural TB had no obvious rule,the differences were not statistically significant(P =0.998 4).The IL -10 level in pleural effusion of Ⅱ type patients was (29.35 ±8.46)pg/mL,which in pleural effu-sion of Ⅲ patients was (183.49 ±56.76)pg/mL,which in pleural effusion of Ⅳ patients was (162.95 ±52.43)pg/mL,the IL -10 content of pleural in different clinical types of TB patients was different,which were significantly high-er than those in the serum,the differences were statistically significant(P =0.000).Conclusion TB patients in the disease,pleural effusion IL -12 and IL -10 are significantly higher than the serum,and retreatment of patients with pleural effusion IL -12,IL -10 levels are significantly higher than the untreated patients,but IL -18 in serum has no significant variation in pleural fluid.

Objective To investigate the impacts of low-grade inflammation on the correlation of serum testosterone (T) and carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM) men.Methods Based on the concentration of C-reactive protein (CRP) and T,a total of 247 patients was divided into low-grade inflammation with low T group (LI-LT,CRP ≥ 2.0 mg/L,T ＜ 12.0 nmol/L,n =65),low-grade inflammation with normal T group (LI-NT,n =67),non-low-grade inflammation with low T group (NLI-LT,n =56),and non-low-grade inflammation with normal T group (NLI-NT,n =59).General information,medical history,and anthropometry data were collected.Glycosylated hemoglobin AI c (HbA1c),blood fat,and CIMT were detected.Results Compared to NLI-NT group,CIMT in NLI-LT group was increased without statistical significance [(0.87 ±0.09) vs (0.90 ±0.10)mm,t =1.693,P =0.090].CIMT in LI-LT group was increased significantly compared to that of LI-NT group [(0.99 ± 0.10) vs (1.07 ±0.12)mm,t =5.208,P =0.000].Correlation analysis indicated that serum T correlated negatively with CIMT (n =247,r =-0.368,P ＜0.01) in whole.The correlation coefficient of T and CIMT was-0.582 (P =0.000),and-0.098 (P =0.087) in patients with (n =132) and without (n =115) low-grade inflammation,respectively.To make CIMT dependent coefficient and serum T independent coefficient in multiple regression analysis,the partial regression coefficient was-0.062 (95％ CI:-0.094 ～-0.029,P =0.008),and-0.045 (95％ CI:-0.087 ～-0.002,P =0.036),respectively,before and after the adjustment of age,smoking,family history,T2DM course,body mass,blood pressure,HbAlc,and blood fat.After the additional adjustment of CRP,the partial regression coefficient was-0.019 (95％ CI:-0.120 ～ 0.042,P =0.287).Conclusions The negative relationship between serum T and CIMT in T2DM men might be modulated by low-grade inflammation.

AIM:To investigate the effects of C1q/TNF related protein 3 (CTRP3) on the insulin sensitivity of insulin resistant 3T3-L1 adipocytes.METHODS: The insulin resistance model of 3T3-L1 adipocytes was induced by palmic acid cultivation.The adipocytes were treated with different concentrations of recombinant CTRP3 protein (10, 50, 250,1 250 μg/L) for 12 h, and for different times (2, 6, 12, 24 h) at the concentration of 250μg/L.The glucose con-sumption was detected by the glucose oxidase method.The glucose transport ratio was measured by 2-deoxidation-[3H]-glucose intake method.The contents of TNF-αand IL-6 in the supernatant were detected by ELISA.The mRNA expression of TNF-α, IL-6 and glucose transporter-4 (GLUT-4) was measured by real-time PCR.The protein expression of GLUT-4 was detected by Western blotting.RESULTS:Compared with normal control ( NC) group, the glucose consumption and glucose intake ratio of insulin resistance ( IR) group was decreased by 50.6%and 57.9%, respectively.Compared with IR group, with the increase in CTRP3 (10, 50, 250,1 250 μg/L) in intervention groups, the glucose consumptions were in-creased by 22.1%, 42.9%, 76.6% and 80.5%, respectively, and the glucose intake ratios were increased by 39.0%, 68.0%, 108.0%and 111.0%, respectively.With the increased duration (2, 6, 12 and 24 h) of CTRP3 treatment at the concentration of 250 μg/L, the glucose intake ratio was increased by 23.0%, 79.0%, 109.0%and 114.0%, respectively. The contents of TNF-αand IL-6 in the supernatant were decreased by 17.4%and 17.1%respectively as treated with CTRP3 at the concentration of 250 μg/L for 12 h, and the mRNA expression of TNF-αand IL-6 was decreased by 26.0% and 18.9%respectively, while the mRNA and protein expression of GLUT-4 was increased by 61.5%and 55.6%respectively. CONCLUSION:CTRP3 may increase the insulin sensitivity of insulin resistant 3T3-L1 adipocytes by down-regulating the expression of inflammatory factors, improving the insulin signal transduction and increasing the expression of GLUT-4.

Objective To investigate the different impacts of the components of metabolic syndrome (MS) on cardiovascular disease (CVD) risk factors and Framingham risk value (FRV) in newly-diagnosed type 2 diabetes mellitus (T2DM) patients without coronary heart disease (CHD).Methods A total of 212 newly-diagnosed T2DM patients was divided into three groups based on the components of MS,including body mass index (BMI),triglyceride (TG),high density lipoproteins cholesterol (HDL-C),and mean arterial pressure (MAP) tertile,respectively.The general CVD risk factors [smoking,BMI,TG,HDL-C,total cholesterol (TC),low density lipoproteins cholesterol (LDL-C),HbA1 C,homeostasis model assessment of insulin resistance (HOMA-IR),and FRV] were compared among the groups.Logistic regression analysis was used to observe the different impact of MS components on CVD risk.Results With the increasing of BMI,TG and MAP tertiles,all the CVD risk factors and the ratio of FRV middle-risk group or high-risk group had the tendency of augmentation.With the increasing of HDL-C tertiles,all the CVD risk factors and the ratio of FRV middle-risk group or high-risk group was in downtrend.Binary logistic regression analysis indicted that BMI,systolic pressure,diastolic pressure,HbA1 c and TG were risk factors of FRV non-low-risk group (middle-risk and high-risk groups),HDL-C was the protective factor.The odds ratios (ORs) of BMI,systolic pressure,diastolic pressure,HbA1 c,TG and HDL-C were 2.794 (95％ CI:2.390-2.408),2.601 (95 ％ CI:1.974-3.701),1.476 (95 ％ CI:1.231-2.048),2.964 (95 ％ CI:1.925-3.282),1.464(95％ CI:0.934-2.294),and 0.732(95％ CI:0.023-0.962),respectively.Logistic stepwise regression analysis indicated that systolic pressure,BMI,HbA1 C,and HDL-C were entered into the regression equation,and the partial regression coefficient was 0.784,1.213,1.679,and-0.854,respectively (P ＜ 0.05 or P ＜ 0.01).Conclusions All the components of MS in newly-diagnosed T2DM were correlated with CVD risk factors.However,they should be weighed differently.

The mechanism of damage in monocytes with the oxidation inhibitor α-lipoic acid (ALA) was observed under intermittent high glucose condition.The results showed that fluctuating high blood glucose levels led to more damage than that under constant high blood glucose level in monocyte,and antioxidant α-ALA could ameliorate the oxidative stress.The high level of nuclear factor-κB and monocyte chemotactic protein-1 are probably among the factors that cause vascular damage by deposit of monocytes.

Objective To study the effects of.breathing booster training and aerosol inhalation with terbutaline and ambroxol on pulmonary function in postoperative lung cancer patients. Methods A total of 84 patients requiring resection operations for lung cancer were randomly divided into treatment and control groups.In the peri-operative period,breathing booster training and terbutaline and ambroxol aerosol inhalation were given to the treatment group,while only aerosol inhalation was given to the control group.Therapeutic effects were evaluated according to patients pulmonary function and postoperative complications 2 weeks and 1 day before the operation,and again 2 weeks after the operation.Postoperative quality of life (QOL) was evaluated with St.George's respiratory questionnaire (SGRQ) 1 month after the operation. Results There was no statistically significant difference in average pulmonary function between the two groups 2 weeks before the operation.Two weeks after the operation,pulmonary function had decreased in both groups,but it was significantly better in the treatment group than in the control group.The treatment group also had significantly fewer pulmonary complications.The QOL of patients in the treatment group had improved significantly 1 month after the operation. Conclusion Breathing booster training and inhalation of terbutaline and ambroxol aerosol during the peri-operative period can significantly improve pulmonary function,reduce respiratory complications and improve the QOL of patients requiring lung cancer resection operations.This is most important for promoting their early recovery.

Objective To investigate the relationship between human leptin receptor(LEPR)gene G3057A polymorphism and type 2 diabetes complicated with non-alcoholic fatty liver disease(NAFLD).Methods 216 cases of newly diagnosed type 2 diabetes(104 cases complicated with NAFLD)and 108 cases of normal glucose tolerances(NGT)were recruited.Hemi-nested PCR-RFLP and PCR direct sequence analysis were conducted to detect the polymorphisms of LEPR G3057A polymorphism.The plasma leptin and insulin levels were measured by ELISA kit.Plasma lipid and glucose metabolic parameters were measured routinely.Liver ultrasound scanning Was carried out among all subjects.Results Type 2 diabetic patients complicated with NAFLD had higher plasma alanine aminotransferase(ALT),triglycerides(TG),low density lipaprotein cholesterol(LDL-C),leptin levels and lower plasma insulin levels than those cages without NAFLD and NGT.The variant frequency at nucleotide 3057 G to A transversion Was 76.0% in type 2 diabetic patients complicated with NAFLD,which Was also significant higher than those cases without NAFLD(62.1%)or NGT cases(53.2%)(x2=14.63,P＜0.01).Conclusions The polymorphism of LEPR gene 3057 probably contributes to the onset of NAFLD in type 2 diabetes by regulating lipid metabolism and affecting insulin sensitivity.