OBJECTIVE To study the antitumor activity and underlying mechanisms of Xiaoaiping injection(Xap)combined with gefitinib(Gef)in nude mice bearing resistant non-small cell lung cancer (NSCLC) cells H460 or H975. METHODS BALB/c nude mice were inoculated with human NSLCL cells H460 or H1975 and the drug treatment did not start until the tumor volume reached 50-100 mm3. The tumor bearing mice were divided into four groups:control group,Xap group(5 g · kg-1,ip),Gef group (50 mg · kg-1,ig),and Xap plus Gef group. All the administration lasted for 21 d continuous. Tumor volumes were measured two or three times per week,and the body weight of animals was re-corded. At the end of the test,tumors were weighed after the sacrifice of mice. Tumor inhibition rate and relative tumor proliferation rate were calculated based on tumor weight and tumor volume. The related biomarkers and proteins in tumor tissues were detected by immunohistochemistry and Western blot assay, respectively. RESULTS Compared with the control group,no significant effect was observed on the growth of H460 and H1975 xenografts in groups of Xap or Gef alone in nude mice. However,the two-drug combination significantly suppressed tumor volume,with (1103 ± 340) versus (3020 ± 450) mm3 for H460 and(487 ± 153)versus(1269 ± 161)mm3 for H1975,respectively(P<0.05). The combined Xap and Gef application also significantly reduced the tumor weight,with(1.20±0.52)versus(2.78± 0.93)g for H460 and(0.52 ± 0.32)versus(0.92 ± 0.42)g for H1975,respectively(P<0.05). The relative tumor proliferation rate and inhibition rate in the combination group was 42.1%and 43.5%for H460(P<0.01),43.0%and 52.5% for H1975(P<0.01). Compared with Xap and Gef drug alone,their combination showed significant difference in reducing tumor weight,suppressing tumor proliferation rate and increasing tumor inhibition rate(P<0.05). Immunohistochemistry results showed that each drug alone had no effect on tumor angiogenesis markers of vascular endothelial growth factor(VEGF)and CD105 expression,or on drug resistance related proteins of p-ERK,p-Akt and p-mTOR,whereas the combination of Xap and Gef obviously reduced the expression of these biomarkers in H460 and H1975 tumor tissues. The decreased drug resistance related proteins of p-PI3K and its downstream molecules p-Akt,p-ERK and p-mTOR by the two-drug combination were also confirmed by Western blot results(P<0.01,compared with control), and showed significant difference compared with each single treatment(P<0.05). CONCLUSION The addition of Xap significantly improves the antitumor activity of Gef in H460 and H1975 xenografts,and this synergistic effect may be ascribed to the inhibition of tumor angiogenesis,the down-regulation of PI3K and its downstream signaling molecules which are associated with drug resistance.

The dosage-efficacy/toxicity relationship of the 50% alcohol extracts of Polygonum multiflorum was comparatively investigated on either normal or CCl4-induced chronic liver injury rats, by determining the general condition, serum biochemical indices and liver histopathology, coupled with the factor analysis. The dosages were 10 and 20 g raw materials per kg body weight. Compared with the normal control group, the normal high dose group showed significant increases of the serum alanine transaminase (ALT), total bilirubin (TBIL), high mobility group box 1 (HMGB-1) and interleukin-1β (IL-1β) (P < 0.05 or P < 0.01), as well the frequent incidences of inflammatory cell infiltration, hepatic sinus enlargement and fiber stripes formation in histopathological sections. Compared with the model control group, the model low dose group showed significant declines of serum ALT, aspartate transaminase (AST) and total bile acid (TBA) (P < 0.05), as well the alleviation of vacuoles of hepatocytes, but no amelioration of the inflammatory cell infiltration and fibrous tissue hyperplasia; moreover, the model high dose group showed significant degeneration declines of serum HMGB-1, tumor necrosis factor-α (TNF-α) and IL-1β (P < 0.05, P < 0.01), as well the evident alleviation of vacuoles degeneration of hepatocytes, inflammatory cells infiltration and fibrosis degree. The factor analysis showed that the low dosage treatment had almost neither injuring effect on the normal rats nor protective effect on the model rats; while the high dosage treatment showed observable injuring effect on the normal rats, expressed by the significant increases of the factor-1 (HMGB-1, TNF-α and IL-1β as the main contributors) and factor-2 (TBIL, ALT and TBA as the main contributors) relative to the normal control group. The liver protective effect of the high dosage treatment could be observed with the significant reduction of the factor-1, indicating the effective alleviation of the expression of inflammatory cytokines. In conclusion, it could illustrated the phenomenon of symptom-based prescription theory of Polygonum multiflorum on rat livers: the high dosage of the herb had either an injuring effect on normal rats, or a therapeutic effect on the rats with chronic liver injury.

The dosage-efficacy/toxicity relationship of the 50% alcohol extracts of Polygonum multiflorum was comparatively investigated on either normal or CCl4-induced chronic liver injury rats, by determining the general condition, serum biochemical indices and liver histopathology, coupled with the factor analysis. The dosages were 10 and 20 g raw materials per kg body weight. Compared with the normal control group, the normal high dose group showed significant increases of the serum alanine transaminase (ALT), total bilirubin (TBIL), high mobility group box 1 (HMGB-1) and interleukin-1β (IL-1β) (P < 0.05 or P < 0.01), as well the frequent incidences of inflammatory cell infiltration, hepatic sinus enlargement and fiber stripes formation in histopathological sections. Compared with the model control group, the model low dose group showed significant declines of serum ALT, aspartate transaminase (AST) and total bile acid (TBA) (P < 0.05), as well the alleviation of vacuoles of hepatocytes, but no amelioration of the inflammatory cell infiltration and fibrous tissue hyperplasia; moreover, the model high dose group showed significant degeneration declines of serum HMGB-1, tumor necrosis factor-α (TNF-α) and IL-1β (P < 0.05, P < 0.01), as well the evident alleviation of vacuoles degeneration of hepatocytes, inflammatory cells infiltration and fibrosis degree. The factor analysis showed that the low dosage treatment had almost neither injuring effect on the normal rats nor protective effect on the model rats; while the high dosage treatment showed observable injuring effect on the normal rats, expressed by the significant increases of the factor-1 (HMGB-1, TNF-α and IL-1β as the main contributors) and factor-2 (TBIL, ALT and TBA as the main contributors) relative to the normal control group. The liver protective effect of the high dosage treatment could be observed with the significant reduction of the factor-1, indicating the effective alleviation of the expression of inflammatory cytokines. In conclusion, it could illustrated the phenomenon of symptom-based prescription theory of Polygonum multiflorum on rat livers: the high dosage of the herb had either an injuring effect on normal rats, or a therapeutic effect on the rats with chronic liver injury.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Bile Acids and Salts ; metabolism ; Bilirubin ; blood ; Chemical and Drug Induced Liver Injury ; drug therapy ; Drugs, Chinese Herbal ; pharmacology ; Fallopia multiflora ; chemistry ; HMGB1 Protein ; metabolism ; Hepatocytes ; drug effects ; Interleukin-1beta ; metabolism ; Liver ; drug effects ; pathology ; Plant Extracts ; pharmacology ; Rats ; Tumor Necrosis Factor-alpha ; metabolism

The liver injury induced by Polygonum multiflorum Thunb. (PM) was investigated based on idiosyncratic hepatotoxicity model co-treated with lipopolysaccharide (LPS) at a non-hepatotoxic dose. Sprague-Dawley (SD) rats were intragastrically administered with three doses (18.9, 37.8, 75.6 g crude drug per kg body weight) of 50% alcohol extracts of PM alone or co-treated with non-toxic dose of LPS (2.8 mg·kg(-1)) via tail vein injection. The plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were assayed and the isolated livers were evaluated for histopathological changes. The dose-toxicity relationships of single treatment of PM or co-treatment of LPS were investigated comparatively to elucidate the idiosyncratic hepatotoxicity of PM. The results showed that no significant alterations of plasma ALT and AST activities were observed in the groups of solo-administration of LPS (2.8 mg·kg(-1), i.v.) or different dosage (18.9, 37.8 and 75.6 g·kg(-1), i.g.) of PM, compared to normal control group (P > 0.05); while significant elevations were observed in the co-administration groups of PM and LPS. Treatment with LPS alone caused slight infiltration of inflammatory cells in portal area but no evident hepatocytes injury. Co-treatment with LPS and PM (75.6 g·kg(-1), i.g.) caused hepatocyte focal necrosis, loss of central vein intima and a large number of inflammatory cell infiltration in portal areas. When further reduce the dosage of PM, significant increases of plasma ALT and AST activities (P < 0.05) were still observed in co-administration groups of LPS and PM (1.08 or 2.16 g·kg(-1)), but not in LPS or PM solo-administration groups. Nevertheless, the co-treatment of low dosage of PM (0.54 g·kg(-1)) with LPS did not induce any alteration of plasma ALT and AST. In conclusion, intragastric administration with 75.6 g·kg(-1) of PM did not induce liver injury in normal rats model; while the 2 folds of clinical equivalent dose of PM (1.08 g·kg(-1)) could result in liver injury in the LPS-based idiosyncratic hepatotoxicity model, which could be used to evaluate the idiosyncratic hepatotoxicity of PM.

The liver injury induced by Polygonum multiflorum Thunb. (PM) was investigated based on idiosyncratic hepatotoxicity model co-treated with lipopolysaccharide (LPS) at a non-hepatotoxic dose. Sprague-Dawley (SD) rats were intragastrically administered with three doses (18.9, 37.8, 75.6 g crude drug per kg body weight) of 50% alcohol extracts of PM alone or co-treated with non-toxic dose of LPS (2.8 mg·kg(-1)) via tail vein injection. The plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were assayed and the isolated livers were evaluated for histopathological changes. The dose-toxicity relationships of single treatment of PM or co-treatment of LPS were investigated comparatively to elucidate the idiosyncratic hepatotoxicity of PM. The results showed that no significant alterations of plasma ALT and AST activities were observed in the groups of solo-administration of LPS (2.8 mg·kg(-1), i.v.) or different dosage (18.9, 37.8 and 75.6 g·kg(-1), i.g.) of PM, compared to normal control group (P > 0.05); while significant elevations were observed in the co-administration groups of PM and LPS. Treatment with LPS alone caused slight infiltration of inflammatory cells in portal area but no evident hepatocytes injury. Co-treatment with LPS and PM (75.6 g·kg(-1), i.g.) caused hepatocyte focal necrosis, loss of central vein intima and a large number of inflammatory cell infiltration in portal areas. When further reduce the dosage of PM, significant increases of plasma ALT and AST activities (P < 0.05) were still observed in co-administration groups of LPS and PM (1.08 or 2.16 g·kg(-1)), but not in LPS or PM solo-administration groups. Nevertheless, the co-treatment of low dosage of PM (0.54 g·kg(-1)) with LPS did not induce any alteration of plasma ALT and AST. In conclusion, intragastric administration with 75.6 g·kg(-1) of PM did not induce liver injury in normal rats model; while the 2 folds of clinical equivalent dose of PM (1.08 g·kg(-1)) could result in liver injury in the LPS-based idiosyncratic hepatotoxicity model, which could be used to evaluate the idiosyncratic hepatotoxicity of PM.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Chemical and Drug Induced Liver Injury ; pathology ; Hepatocytes ; pathology ; Lipopolysaccharides ; Polygonum ; toxicity ; Rats ; Rats, Sprague-Dawley

To investigate the difference of liver injury in rats gavaged with crude and processed Polygoni Multiflori Radix. The 75% ethanol extract of crude and processed Polygoni Multiflori Radix (50 g · kg(-1) crude medicine weight/body weight) were continuous oral administered to rats for 6 weeks. Serum biochemical indicators were dynamically detected, the change of liver histopathology was assessed 6 weeks later. Principal component analysis (PCA) was adopted to screen sensitive indicator of the liver damage induced by polygoni multiflori radix. Biochemical tests showed that the crude Polygoni Multiflori Radix group had significant increase of serum ALT, AST, ALP, DBIL and TBIL (P < 0.01 or P < 0.05) and significant decreases of serum IBIL and TBA (P < 0.01 or P < 0.05), while the processed Polygoni Multiflori Radix group showed no obvious changes, compared to the untreated normal group. Histopathologic analysis revealed that crude Polygoni Multiflori Radix group exhibited significant inflammatory cells infiltration in portal area around the blood vessels, tissue destruction and local necrosis of liver cells. There were not obvious pathological changes in processed Polygoni Multiflori Radix group. The results demonstrated that the injury effect of processed Polygoni Multiflori Radix on liver injury of rats was significantly lower than that of unprocessed, and that processing can effectively reduce the hepatotoxicity of Polygoni Multiflori Radix. Traditional transaminase liver function indicators were not sensitive for crude Polygoni Multiflori Radix induced liver damage. The serum content of DBIL and TBIL can reflect the liver damage induced by crude Polygoni Multiflori Radix early and can be sensitive indicators for clinical monitoring the usage of it.
Animals ; Chemical and Drug Induced Liver Injury ; etiology ; Chemistry, Pharmaceutical ; methods ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; toxicity ; Female ; Liver ; drug effects ; injuries ; Male ; Plant Roots ; chemistry ; toxicity ; Polygonum ; chemistry ; toxicity ; Rats

BACKGROUNDType 2 diabetes is a chronic disease characterized by a progressive loss of beta cell functions. However, the evaluation of beta cell functions is either expensive or inconvenient for clinical practice. We aimed to elucidate the association between the changes of insulin responsiveness and the fasting plasma glucose (FPG) during the development of diabetes.

METHODSA total of 1192 Chinese individuals with normal blood glucose or hyperglycemia were enrolled for the analysis. The early insulinogenic index (DeltaI30/DeltaG30), the area under the curve of insulin (AUC-I), and homeostasis model assessment were applied to evaluate the early phase secretion, total insulin secretion, and insulin resistance respectively. Polynomial regression analysis was performed to estimate the fluctuation of beta cell functions.

RESULTSThe DeltaI30/DeltaG30 decreased much more rapidly than the AUC-I accompanying with the elevation of FPG. At the FPG of 110 mg/dl (a pre-diabetic stage), the DeltaI30/DeltaG30 lost 50% of its maximum while the AUC-I was still at a compensated normal level. The AUC-I exhibited abnormal and decreased gradually at the FPG of from 130 mg/dl to higher (overt diabetes), while the DeltaI30/DeltaG30 almost remained at 25% of its maximum value. When hyperglycemia continuously existed at > 180 mg/dl, both the DeltaI30/DeltaG30 and AUC-I were totally lost.

CONCLUSIONThe increased fasting plasma glucose reflects progressive decompensation of beta cell functions, and could be used to guide the strategy of clinical treatments.

Adult ; Aged ; Aged, 80 and over ; Blood Glucose ; analysis ; Diabetes Mellitus ; blood ; physiopathology ; Fasting ; blood ; Female ; Humans ; Insulin ; secretion ; Insulin Resistance ; Insulin-Secreting Cells ; physiology ; Male ; Middle Aged

To study the method for Rhesus box test and its significance, the sequence specific primers of upstream, downstream and hybrid Rhesus boxes were designed according to RhD gene sequence; the upstream, downstream and hybrid Rhesus boxes were determined by PCP-SSP and mismatched PCR. The results showed that this method was confirmed by DNA Standard test. It was shown that in unrelative RhD positive individuals RHD(+)/RHD(-), RHD(+)/RHD(+) genotype accounted for 9.00%, 91.00% respectively, and in RhD negative individuals RHD(+)/RHD(-), RHD(+)/RHD(+), RHD(-)/RHD(-) genotype were 26.14%, 3.92%, 69.94% respectively. It is concluded that the method of Rhesus box test was confirmed to be reliable and can be used for the identification of RhD haplotype gene structure, as well as for study on inheritance, clinical transfusion and neonatal hemolytic diseases.
Base Sequence ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Polymerase Chain Reaction ; methods ; Rh-Hr Blood-Group System ; analysis ; genetics

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQ-containing regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients. Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM. Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups. Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Objective:This study aimed to evaluate the accuracy of a portable REF-XT01 uric acid meter in measuring blood uric acid concentration, and to determine whether the results of the uric acid meter could be used to guide the adjustment of uric acid-lowering drugs.Methods:1 551 subjects were enrolled from the Gout Clinical Medical Center of the Affiliated Hospital of Qingdao University. The fasting venous blood was collected and the serum uric acid was measured by an automatic biochemical analyzer. Meanwhile, the capillary blood uric acid was measured by fingertip puncture using the REF-XT01 uric acid meter. Linear regression, intra-group correlation coefficient(ICC), and Bland-Altman plots were used to analyze the uric acid concentration correlation between the biochemical analyzer(sUA BA)and the uric acid meter(sUA UM). The receiver operating characteristic curve(ROC curve)was conducted to evaluate whether sUA UM can be used as a reference for the gout patients to take uric acid-lowering drugs. Results:The regression analysis showed correlation between sUA BA and sUA UM, with the regression formula Y=0.875X+ 39.525( r=0.84, P<0.01)and the ICC was 0.829(95% CI 0.814-0.844, P<0.01). The Bland-Altman diagram showed a good consistence(the absolute deviation was-143.4-114.5 μmol/L, mean deviation was -14.4 μmol/L)between sUA BA and sUA UM. The sensitivity was 96.61%, specificity was 48.81%, and the area under the ROC curve(AUC)was 0.926( P<0.01)when 300 μmol/L was defined as the detection threshold of the uric acid meter, the sensitivity was 90.98%, specificity was 66.78%, and the area under the ROC curve(AUC)was 0.914( P<0.01)when 360 μmol/L was defined as the detection threshold of the uric acid meter. Conclusion:REF-XT01 uric acid meter is applicable for the adjustment of uric acid-lowering drugs for the gout patients, because of its high accuracy for the detection of uric acid.