The exploration of drug toxicity and mechanisms is a vital component in ensuring the safe use of drugs in clinical practice, as this topic has attracted widespread concern. The intestinal flora holds great significance for drug metabolism, efficacy and mechanism, and is an instrumental metabolic organ that facilitates material information transfer and biotransformation. However, an increasing number of studies have shown that intestinal bacteria are closely related to the toxicity of specific drugs. On the one hand, drugs are transformed into toxic metabolites under the influence of intestinal bacteria, thus inducing direct drug toxicity. On the other hand, the composition and function of the intestinal flora are altered under drug influence, resulting in disruption of endogenous metabolic pathways. Consequently, this disruption compromises the intestinal barrier and affects other organs, leading to indirect drug toxicity. This review meticulously compiles recent examples of drug toxicity attributed to intestinal bacteria, explores in depth the contention that metabolic enzymes of gut microbiota may be of great influence on oral drug toxicity, and outlines prospective avenues for future research on gut microbiota and drug toxicity and mechanisms. This not only provides novel perspectives for the judicious clinical utilization of drugs but also offers insights for the safety assessment of innovative pharmaceuticals.

This study is to investigate the effect of Vam3, a dimeric derivative of resveratrol, on SNP-induced apoptosis and its potential mechanism in rat articular chondrocytes. Isolated rat articular chondrocytes were treated with sodium nitroprusside (SNP), a NO donor, to induce apoptosis. Apoptosis percentage was evaluated by Annexin V-PI and nucleus fracture was examined by DAPI staining. Level of intracellular reactive oxygen species (ROS) was detected using 2, 7'-dichlorofluorescin diacetate (DCFH-DA) as a fluorescence probe by fluorescence microplate reader. The change in mitochondrial membrane potential was detected by TMRE staining. Expressions of SIRT1, acetylated p53 (ac-p53), cleaved caspase 9 and cleaved caspase 3 were determined by Western blotting. It showed that Vam3 up to 10 micromol x L(-1) could significantly reduce SNP-induced rat articular chondrocytes apoptosis (P < 0.01) and nucleus fracture, inhibit the increase of intracellular ROS level (P < 0.01) and reverse the decrease in mitochondrial membrane potential (P < 0.01). Simultaneously, Vam3 could upregulate the expression of SIRT1, deacetylate p53, and inhibit the cleavage of caspase 9 and caspase 3 (P < 0.01) of rat articular chondrocytes exposed to SNP. This study indicates Vam3 could protect rat articular chondrocytes against SNP-induced apoptosis, perhaps through the upregulation of SIRT1 and deacetylation of p53.
Animals ; Apoptosis ; drug effects ; Arabidopsis Proteins ; pharmacology ; Cartilage, Articular ; cytology ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cells, Cultured ; Chondrocytes ; cytology ; metabolism ; Male ; Membrane Potential, Mitochondrial ; drug effects ; Nitric Oxide Donors ; antagonists & inhibitors ; pharmacology ; Nitroprusside ; pharmacology ; Qa-SNARE Proteins ; pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; metabolism ; Sirtuin 1 ; metabolism ; Tumor Suppressor Protein p53 ; metabolism

AIM:To investigate the effect of insulin on vascular smooth muscle cells (VSMCs) proliferation and to evaluate the intracellular signaling pathways involved.METHODS:VSMCs separated from Sprague-Dawley rats were used in this study. The proliferation of VSMCs induced by insulin was assayed by [3H]-thymidin incorporation. The protein expression and activity of p-ERK1/2 were determined by immunblot and [?-32P]ATP incorporation.RESULTS:Insulin induced cell proliferation in a concentration-dependent manner. The proliferative effect of insulin on VSMCs was inhibited partly by LY294002 (48.8%),an inhibitor of PI-3 kinase,and the ERK1/2 inhibitor PD98059 (43.6%),respectively. Moreover,phosphorylation of ERK1/2 and activity of ERK1/2 induced by insulin were also inhibited partly by LY294002.CONCLUSION:PI-3 kinase and ERK1/2 are involved in insulin induced VSMCs proliferation.

AIM: To identify the non-steroid transcription factors upregulating the expression of L-plastin in hormone-independent prostate cancer, and partly elucidate the mechanism of hormone-refractory prostate cancer. METHODS: TF SEARCH software was used to analysis the possible binding sites of transcription factors in the 3’ end of L-plastin promoter that had been identified as important part of regulation response elements. Gel shift assay and supershift assay were used to confirm the transcription factors binding the speculated response elements. PCR site-mutagenesis technique was performed to delete the binding site of transcription factor and luciferase activity assay was carried out after deletion of the binding site. RESULTS: SP-1 respond element GGTGGGGCGGGGA located at -54- -41 of L-plastin promoter was identified with the TF SEARCH software. Gel shift assay and supershift assay confirmed that SP-1 was the transcription factor binding to GGTGGGGCGGGGA. Mutant deleted the SP-1 binding-site had low-luciferase activity than that of the naive. CONCLUSION: SP-1 plays an important role in the up-regulation of L-plastin expression in hormone-independent prostate cancer.

To investigate the effects of gambognic acid (GA) on TRAIL-induced apoptosis of cancer cells, human colon HT-29 cancer cells were treated with GA to promote apoptosis. Inhibition of the cell proliferation was measured with MTT assay and cell apoptosis was detected with formation of DNA ladders in agarose gel electrophoresis, and activation of caspase activity. The content of cytosolic reactive oxygen species (ROS) was measured with flow cytometry. The activities of Caspase-3, -8, -9 were detected using spectrophotometric assay. The levels of c-FLIP, CHOP, DR4 and DR5 in cells were tested by Western blot. Combination of GA (1 µg · mL(-1)) and TRAIL (40 ng · mL(-1)) significantly reduced proliferation and increased apoptosis of HT-29 cells over those induced by each agent alone. Percentage of apoptotic cells was increased to 45.5%. GA markedly enhanced the intracellular ROS generation. Expression of CHOP, DR4 and DR5 was up-regulated to 7.38, 5.41, and 4.85 times of the control group, respectively. GA promoted activation of Caspase-3, -8, and -9 by TRAIL (P<0.05). Furthermore, the expression of anti-apoptotic protein c-FLIP was down-regulated to 0.22 ± 0.08 times of the control group. In conclusion, GA sensitizes HT-29 cells to TRAIL-induced apoptosis by promoting ROS-activated ERS pathways, up-regulating of DR4 and DR5, and inhibiting c-FLIP expression.
Apoptosis ; Apoptosis Regulatory Proteins ; metabolism ; Caspases ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; Colonic Neoplasms ; metabolism ; Down-Regulation ; HT29 Cells ; Humans ; Reactive Oxygen Species ; metabolism ; TNF-Related Apoptosis-Inducing Ligand ; pharmacology ; Up-Regulation ; Xanthones ; pharmacology

Objective To investigate the clinical effect of axillary vein puncture needle technique in the infusion of low birth weight infants.Methods The study group received axillary venipuncture indwelling needle technique, the control group was given head intravenous indwelling needle technique, compared the related anomalies incidence of two groups of low birth weight infants during intravenous infusion catheter. Results The incidence of abnormal occlusion, phlebitis, oozing of blood in preterm infants with low birth weight infants (2.13%,4.26% and 2.13%) were significantly lower than those in the control group (19.15%,27.66%,17.02%), respectively (P＜0.05). Conclusion The application of axillary vein puncture needle technique can significantly reduce the incidence of adverse reactions associated with infusion of low birth weight infants, and has positive significance in ensuring the efficacy and prognosis.

There are many physical factors affecting the development of cartilage tissue,the mechanical con-dition is the main important one that particularly act.The mechanical conditions used in engineering cartilage tissue,such as compressive and shear force,fluid flow,hydrostatic pressure and tissue deformation or with some of them combined,were reviewed.From the standpoint of bionics,the mechanical environments ap-plied on tissue engineering should work in three aspects:providing adequately mechanical stimuli to the cells seeded in 3-D scaffold;ensuring the efficient mass-transport of the nutrients and waste products in the cells:promoting the development of functionally extracellular matrix in 3-D scaffold.The mechanical environments currently used only represented the part of mechanical conditions of in vive articular cartilage will be reviewed.In our view that rolling depression load may achieve the fit mechanical environment for cultivation of functional cartilage constructs in vitro.

There are many physical factors affecting the development of cartilage tissue,the mechanical con-dition is the main important one that particularly act.The mechanical conditions used in engineering cartilage tissue,such as compressive and shear force,fluid flow,hydrostatic pressure and tissue deformation or with some of them combined,were reviewed.From the standpoint of bionics,the mechanical environments ap-plied on tissue engineering should work in three aspects:providing adequately mechanical stimuli to the cells seeded in 3-D scaffold;ensuring the efficient mass-transport of the nutrients and waste products in the cells:promoting the development of functionally extracellular matrix in 3-D scaffold.The mechanical environments currently used only represented the part of mechanical conditions of in vive articular cartilage will be reviewed.In our view that rolling depression load may achieve the fit mechanical environment for cultivation of functional cartilage constructs in vitro.

Objective:To compare and explore the effects of needling acupoints at different nerve segmentson the oxytocin (OT) neurons in the paraventricular nucleus of hypothalamus (PVN) and the intragastric pressure, and discuss the possible mechanisms. Methods: Thirty-two healthy adult Sprague-Dawley (SD) rats were numbered and divided into 4 groups according to the random number table, a Zusanli (ST 36) group, a Neiguan (PC 6) group, a Weishu (BL 21) group and a control group, with 8 rats in each group. Except the control group, rats in the other three groups received acupuncture at the corresponding acupoints. To observe the differences in double-labeled OT neurons and c-fos neurons of the hypothalamic PVN and the intragastric pressure after acupuncture among the three groups of needling acupoints at different nerve segments. Results:Compared with the control group, the numbers of double-labeled cells in the PVN of the Zusanli (ST 36) group and the Neiguan (PC 6) group decreased significantly, while the intragastric pressure increased significantly (allP<0.05), and the inter-group differences were statistically significant (P<0.05). The intragastric pressure in the Weishu (BL 21) group decreased significantly, and the inter-group difference was statistically significant (P<0.05). Compared with the Weishu (BL 21) group, the numbers of OT/c-fos double-labeled cells in PVN of the Zusanli (ST 36) group and the Neiguan (PC 6) group decreased significantly, and the intragastric pressure increased significantly, the inter-group differences were statistically significant (allP<0.01). Conclusion:Acupoints at different nerve segments have different regulation effects on intragastric pressure. The difference may be related to the different nerve conduction pathways by acupoints at different nerve segments in regulating the intragastric pressure. The PVN may be one common integration center for the regulation of gastric function in the three acupoints [Zusanli (ST 36), Neiguan (PC 6) and Weishu (BL 21)] at different nerve segments.

Objective To investigate the relationship between myocardial ischemia and slow coronary flow phenomenon with 99Tcm-methoxyisobutylisonitrile (MIBI) adenosine myocardial perfusion SPECT imaging. Methods Forty-four patients were divided to three groups according to the result of coronary angiography(CAG). There were GAG-positive(P-GAG) (n=12),slow coronary flow (CSF) (n =22),and normal coronary flow (NCF) (n = 10). Results of adenosine myocardial perfusion imaging were compared among these three groups. Semi-quantitative visual scoring method was used to evaluate the myocardial perfusion:0 = normal,1 = mild decrease,2 = moderate decrease,3 = severe decrease,4 = defect. Statistical analysis was performed using variance analysis,t-test and x2-test. Results No significance was observed at age ( t =0.27,0. 54 and 0. 59),sex (x2 = 0. 92),hypertension,hyperlipemia and diabetes (x2 = 1.23,all P ＞ 0.05 ) among the three groups. A significantly higher frames of the coronary thrombolysis in myocardial infarction (TIMI) flow was noted in CSF than in NCF groups (33.7 ±5.5 vs 17.6 ±3.9,t = 9. 58,P ＜0. 001 ). The positive adenosine myocardial perfusion imaging rate were significant among these three groups with 100% (12/12) in P-CAG group,77.3% (17/22) in CSF group,and 20% (2/10) in NCF group. When using semi-quantitative visual scoring method,significantly higher average ischemia segments were noted in CSF group than in NCF group ( 1.06 ± 0.77 and 0. 91 ± 0.80,t = - 2. 02,P ＜ 0. 05 ),but was less than that in P-CAG group (2.41 ±0.79,t =4. 54,P ＜0.001 ). The degree of ischemia of CSF group was higher than that in NCF group ( 8.01 ± 6.06,and 2.73 ± 2.60,t = - 2.07,P ＜ 0.05 ) and was less than that in P-CAG group (14. 07 ±12. 77 ,t=1.44,P＞0. 05). Conclusion Slow coronary flow phenomenon can be detected by adenosine myocardial perfusion image to offer the evidence of diagnosis and treatment for the chest pain patients with negative coronary angiography results.