ABSTRACT
BACKGROUND: Platinum complexes are commonly used for cancer chemotherapy; however, they are not only highly-priced but also have various side effects. It is, therefore, important to design affordable anticancer drugs with minimal side effects. METHODS: We synthesized a new gold(I) complex, PF6{(BDPEA)(TPPMS) digold(I)} (abbreviated as PBTDG) and tested its cytotoxicity in MCF-7 breast cancer cells. We also evaluated the effects of PBTDG on mitochondrial membrane potential, generation of reactive oxygen species (ROS) and apoptosis in breast cancer cells. RESULTS: The IC50 values for PBTDG and sorafenib were found to be 1.48 µM and 4.45 µM, respectively. Exposure to PBTDG caused significant and concentration-dependent depletion of ATP and disruption of mitochondrial membrane potential. PBTDG induced 2.6, 3.6, and 5.7-fold apoptosis for 1 µM, 3 µM, and 10 µM concentrations, respectively. The induction of apoptosis by the same concentrations of sorafenib was 1.2, 1.3, and 1.6-fold, respectively. The low concentration of PBTDG (1 µM) induced the generation of ROS by 99.83%, which was significantly higher than the ROS generation caused by the same concentration of sorafenib (73.76%). The ROS induction caused by higher concentrations (5 µM) of PBTDG and sorafenib were 104.95% and 122.11%, respectively. CONCLUSION: The lower concentration of PBTDG produced similar cytotoxicity and apoptotic effects that were caused by a comparatively higher concentration of known anticancer drug (sorafenib). The anticancer effects of PBTDG are attributed to its tendency to disrupt mitochondrial membrane potential, induction of apoptosis and generation of ROS. Further studies are warranted to test the anticancer effects of PBTDG in animal models of cancer.
Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Animals , Reactive Oxygen Species , Sorafenib/pharmacology , Antineoplastic Agents/pharmacology , MCF-7 Cells , Apoptosis , Cell Line, Tumor , Membrane Potential, MitochondrialABSTRACT
OBJECTIVE: To determine high sensitivity C-reactive protein (hsCRP) levels in patients with acute myocardial infarction (AMI) and its correlation with classical enzyme markers of myocardial damage. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Emergency Medicine at King Khalid University Hospital, King Saud University, Riyadh and Department of Physiology, from August 2010 to December 2011. METHODOLOGY: Consecutive eligible patients with either ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI) who were admitted to the Emergency Department of King Khalid University Hospital were recruited. A total of 71 subjects were finally selected for the study. The hsCRP, Troponin I (Trop I), creatine kinase myocardial bound (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) concentrations of all patients with an acute myocardial infarction (AMI) were measured. RESULTS: Among all patients 34 (47.9%) patients had diabetes mellitus, 21 (29.6%) were hypertensive, and 16 (22.5%) had no associated illness. Patients with STEMI had significantly higher levels of CKMB (p=0.0348), LDH (p=0.0471) and hsCRP (p=0.0231) compared to NSTEMI patients. While the differences were non-significant for Trop I (p=0.7022), AST (p=0.9729) and Lp(a) (p=0.5985). Spearman's correlations revealed that CRP correlated significantly with Trop I, CK-MB and LDH. There was a significant predictive relationship of hsCRP with Trop I, LDH and CK-MB while with AST it was nonsignificant. CONCLUSION: High sensitivity CRP levels is a significant predictor of standard markers for myocardial damage and it may be a useful prognostic marker in acute coronary syndromes.
Subject(s)
Biomarkers/blood , C-Reactive Protein/metabolism , Myocardial Infarction/diagnosis , Adult , Aged , Aged, 80 and over , Aspartate Aminotransferases/blood , Body Mass Index , C-Reactive Protein/analysis , Coronary Angiography , Creatine Kinase, MB Form/blood , Female , Humans , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Myocardial Infarction/blood , Predictive Value of Tests , Sensitivity and Specificity , Troponin I/bloodABSTRACT
Recently, American Diabetic Association has recommended glycated hemoglobin (HbA1c ≥6.5%) as an alternate to fasting plasma glucose (FPG ≥7.0 mmol/L) for diagnosis of diabetes. However, studies from different groups showed inconsistent results with the use of HbA1c criteria. We examined the validity of HbA1c cut-point of 6.5% for diagnosis of diabetes. A total of 12 785 male diabetic patients (FGP ≥7.0 mmol/L), aged 56.27 ± 13.32 years were included. The average values of FPG and HbA1c of all the 12 785 patients were 10.127 ± 0.026 mmol/L and 8.729 ± 0.013%, respectively. Sub-grouping of patients into different age categories showed significantly high levels of FPG (10.934 ± 0.123 mmol/L) in the youngest group (age, ≥20-35 years) as compared to FPG (ranged from 10.021 ± 0.052 to 10.190 ± 0.050 mmol/L) in patients with other age categories. The level of HbA1c was highest in the youngest group (8.809 ± 0.056%) and lowest in the oldest group (8.653 ± 0.082%). There was a significant correlation between FPG and HbA1c (R = 0.571, p < 0.001). There were 484 patients below the diagnostic threshold (HbA1c <6.5%), resulting in 3.78% false negative predictions. Majority of the false negative patients were in the age group of 40-75 years and had borderline FPG (7.0-8.0 mmol/L) and HbA1c (6.0-6.5%). These findings suggest that Saudi individuals with HbA1c between 6.0% and 6.5% may be considered as "probable diabetic" and their status should be verified by combined FPG and HbA1c criteria.
Subject(s)
Chemistry, Clinical/standards , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/diagnosis , Glycated Hemoglobin/metabolism , Hyperglycemia/blood , Hyperglycemia/diagnosis , Adult , Aged , Aged, 80 and over , Blood Glucose/metabolism , Humans , Male , Middle Aged , ROC Curve , Reference Values , Reproducibility of Results , Retrospective Studies , Saudi Arabia , Young AdultABSTRACT
Ischemic and reperfusion injuries in acute myocardial infarction (AMI) lead to mitochondrial dysfunction in heart cells. Lipid metabolism takes place in mitochondria where carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into matrix to provide substrates for beta-oxidation. We sequenced the coding regions of CPT1B and CPT2 genes to identify the single nucleotide polymorphism (SNP) in 23 AMI patients and 23 normal subjects. We also determined blood carnitine levels in these samples to study the impact of these SNPs on carnitine homeostasis. The sequencing of coding regions revealed 4 novel variants in CPT1B gene (G320D, S427C, E531K, and A627E) and 2 variants in CPT2 gene (V368I and M647V). There were significant increases in total carnitine (54.18±3.11 versus 21.49±1.03µmol/l) and free carnitine (37.78±1.87 versus 10.06±0.80µmol/l) levels in AMI patients as compared to normal subjects. CPT1B heterozygous variants of G320D and S427C among control subjects showed significantly higher levels of total and free carnitine in the blood. The homozygous genotype (AA) of CPT2 variant V368I had significantly less blood carnitine in AMI patients. Serum troponin T was significantly less in GG genotype of CPT1B variant S427C whereas the genotype AA of CPT2 variant V368I showed significantly higher serum troponin T levels. Further studies on large number of patients are necessary to confirm the role of CPT1B and CPT2 polymorphism in AMI.
Subject(s)
Carnitine O-Palmitoyltransferase/genetics , Carnitine/blood , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Case-Control Studies , DNA Primers/genetics , Diabetes Mellitus/pathology , Exons , Female , Genetic Association Studies , Heterozygote , Homozygote , Humans , Hypertension/pathology , Male , Middle Aged , Myocardial Infarction/pathology , Sequence Analysis, DNA , Troponin T/bloodABSTRACT
Earlier studies have implicated reactive oxygen species and transitional metals in the pathogenesis of gastric lesions. In this study, we have evaluated the effect of 2,3-dimercaptopropanol (DMP), a thiol compound and metal chelator, on chemically induced gastroduodenal ulcers in rats. Acid secretion studies were undertaken using pylorus-ligated rats pretreated with DMP (3-100 mg/kg, i.p.). The effect of orally administered DMP on cysteamine-induced duodenal ulcers and ethanol-induced gastric ulcers was also tested. The level of nonprotein sulfhydryls (NP-SH) and gastric wall mucus was measured in the glandular stomach of rats treated with ethanol. None of the dose of DMP affected the volume or acidity of gastric secretion. Low doses of DMP (3 and 10 mg/kg) significantly reduced cysteamine-induced duodenal ulcers, whereas the high doses (30 and 100 mg/kg) were ineffective in this model. All the doses of DMP significantly and dose dependently attenuated ethanol-induced gastric lesions. The adverse effects of ethanol on gastric wall mucus and NP-SH were significantly and dose dependently reversed by DMP. In conclusion, the protective effects of DMP appear to be independent of gastric acid secretion and may be associated with counteracting the oxidative stress by replenishing glutathione and reducing the pool of transition metals.
Subject(s)
Chelating Agents/therapeutic use , Dimercaprol/therapeutic use , Peptic Ulcer/drug therapy , Sulfhydryl Compounds , Animals , Chelating Agents/pharmacology , Dimercaprol/pharmacology , Female , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Male , Peptic Ulcer/metabolism , Peptic Ulcer/pathology , Rats , Rats, WistarABSTRACT
Radiation therapy is a key modality in the treatment of different cancer types. Fatigue is the most common side effect of radiotherapy, while others include nausea, hair loss, skin irritation, anemia, infertility, cardiovascular disease, cognitive impairment and even the development of second cancers. Studies in experimental animals have shown protective effects of carnitine against exposure of various organs to ionizing radiation, whereas carnitine deficiency is known to enhance radiation-induced toxicity. This report summarizes the recent literature on the adverse effects of radiotherapy and the impact of radiation on carnitine homeostasis. Although some studies have demonstrated the prophylactic benefits of carnitine against the toxic effects of chemotherapy, the role of carnitine in the prognosis and management of cancer patients receiving radiotherapy is not clear and needs to be explored.
Subject(s)
Carnitine/pharmacology , Neoplasms/radiotherapy , Radiation Injuries/prevention & control , Radiation Oncology/methods , Radiotherapy/adverse effects , Vitamin B Complex/pharmacology , Animals , Biomarkers , Disease Management , Disease Models, Animal , Homeostasis , Humans , Prognosis , Radiation-Protective Agents/pharmacologyABSTRACT
This investigation was aimed to study the effects of individual and concomitant exposures of the two nitrile compounds, the industrially important acrylonitrile (ACN; 5, 15, 45 mg/kg/day) and the positive control iminodipropionitrile (IDPN; 100 mg/kg/day) in rats. The six treatment groups were 1 (control), 2 (ACN 5), 3 (ACN 15), 4 (ACN 45), 5 (IDPN), and 6 (IDPN + ACN 15). Both the drugs were started on the same day and continued for 9 days (IDPN was given daily 30 min before ACN but stopped a day earlier). The animals were daily observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of righting reflex. There was no dyskinetic behavioral abnormality in the animals treated with any of the three doses of ACN whereas all the rats in IDPN alone treated group developed clear symptoms of excitation, circling, and chorea syndrome (ECC syndrome) on day 9. Concomitant treatment of rats with ACN significantly attenuated the severity of IDPN-induced behavioral deficits. Administration of ACN significantly depleted glutathione (GSH) in striatum, hippocampus and cerebral cortex; IDPN significantly reduced the GSH only in striatum. The anterior striatum showed intense tyrosine hydroxylase (TH) expression in IDPN alone treated rat as compared to control and ACN alone treated rat. Cotreatment with ACN reduced the intensity of TH immunostaining in IDPN-treated rats. Administration of IDPN alone caused massive loss of vestibular sensory hair cells in the crista ampullaris whereas the sensory epithelium appeared intact in ACN alone treated groups. The animals receiving the combination of ACN and IDPN showed comparatively less degeneration of sensory hair cells than IDPN alone group. These findings suggest that ACN and IDPN produce different behavioral effects that are exerted through entirely different mechanisms; the nervous and vestibular systems appear to be the major target sites of these toxins, respectively.
Subject(s)
Acrylonitrile/toxicity , Behavior, Animal/drug effects , Brain/drug effects , Hair Cells, Vestibular/drug effects , Nitriles/toxicity , Analysis of Variance , Animals , Body Weight/drug effects , Brain/metabolism , Chorea/chemically induced , Glutathione/metabolism , Male , Rats , Rats, Wistar , Tyrosine 3-Monooxygenase/metabolismABSTRACT
This study reports the utilization of serum fructosamine and blood glucose for the screening of gestational diabetes mellitus (GDM). Blood samples from 165 pregnant women were analyzed for fasting blood glucose (FBG), random blood glucose (RBG) and serum fructosamine. The actual fructosamine levels were corrected for serum protein (c-Fruct) for more precise presentation. Two cut-off values of FBG (>5.3 mmol/L and >7.0 mmol/L) and RBG (>7.8 mmol/L and >11.0 mmol/L) were used to classify hyperglycemic subjects for subsequent evaluation. The average values±standard deviations for FBG, RBG and cFruct were 5.865±1.95, 7.767±3.21 and 2.387±0.47 mmol/L, respectively. FBG levels were significantly correlated with RBG (Pearson correlation=0.597, P<0.001). Significant correlations were also observed between cFruct and FBG (Pearson correlation=0.673, P<0.001) or RBG (Pearson correlation=0.641, P<0.001). Out of 165 subjects, 24 (14.5%) cases were classified as hyperglycemic on the basis of FBG>7.0 mmol/L or RBG>11.0 mmol/L; use of lower cut-off values resulted higher frequencies of hyperglycemia. Whereas, a combined criteria of FBG>5.3 mmol/L and cFruct >2.5 mmol/L predicted 35 patients as the most probable hyperglycemic as compared to 32 patients identified using the criteria of RBG >7.8 mmol/L and cFruct >2.5 mmol/L. These criteria were associated with 4.8% and 3.6% false-positivity at the expense of 3.6% and 3.0% false-negative outcomes, respectively. The levels of FBG, RBG and cFruct were significantly higher in hyperglycemic groups (irrespective of grouping criteria) as compared to the respective normal groups. In conclusion, these findings clearly indicate that the paired values of cFruct with FBG or RBG could help in filtering high-risk individuals for OGTT and therefore avoiding a unnecessary OGTT.