Low levels of plasma soluble complement receptor type 1 in patients receiving thrombolytic therapy for acute myocardial infarction

Background Administration of recombinant soluble CR1 (sCR1) has been shown to attenuate complement mediated myocardial injury in animal models of acute MI. The plasma level of sCR1 in humans with acute MI is not known. We determined the levels of the complement regulatory protein, complement receptor type-1 (CR1) in plasma and its expression on the surface of leukocytes of patients receiving thrombolysis for acute myocardial infarction (AMI). Methods Plasma sCR1 was measured by a sandwich ELISA. The levels in patients with AMI were compared with those in normal controls. Leukocyte surface expression of CR1 was measured by flowcytometry. We correlated these parameters with clinical outcome and left ventricular ejection fraction. Results Patients had very low plasma sCR1 levels. Mean plasma sCR1 levels were significantly less than in controls (6 ± 3.6 ng/mL vs. 44.6 ± 12.2 ng/mL, P < 0.00001). Patients who had an adverse in-hospital outcome had significantly lower sCR1 levels when compared to those who had an uneventful course (3.8 ± 2.0 ng/mL and 7.1 ± 3.8 ng/mL respectively, P = 0.01). The low plasma sCR1 was despite significantly greater lymphocyte and monocyte surface CR1 (which is a potential source of plasma sCR1). Conclusion Plasma sCR1 levels are reduced in patients receiving thrombolysis for AMI. Replenishing plasma sCR1 might limit complement-mediated injury in this setting.     

Synthesis, crystal structure, and anticancer properties of cyclic monocarbonyl analogs of curcumin

A series of novel indan-2-one and dibenzylidenepiperidin-4-one compounds were synthesized and screened for anticancer activities. The compounds are symmetrical and they have conjugated double bonds. They closely resemble the curcumin analogs which are found to possess anticancer properties. The structure of the compounds was confirmed by single crystal study and wherever the compound is a powder, the structures were confirmed by spectral data (IR, NMR, and Mass).     

From the Cover: Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Ischemia complicates wound closure. Here, we are unique in presenting a murine ischemic wound model that is based on bipedicle flap approach. Using this model of ischemic wounds we have sought to elucidate how microRNAs may be implicated in limiting wound re-epithelialization under hypoxia, a major component of ischemia. Ischemia, evaluated by laser Doppler as well as hyperspectral imaging, limited blood flow and lowered tissue oxygen saturation. EPR oximetry demonstrated that the ischemic wound tissue had pO₂ <10 mm Hg. Ischemic wounds suffered from compromised macrophage recruitment and delayed wound epithelialization. Specifically, epithelial proliferation, as determined by Ki67 staining, was compromised. In vivo imaging showed massive hypoxia inducible factor-1α (HIF-1α) stabilization in ischemic wounds, where HIF-1α induced miR-210 expression that, in turn, silenced its target E2F3, which was markedly down-regulated in the wound-edge tissue of ischemic wounds. E2F3 was recognized as a key facilitator of cell proliferation. In keratinocytes, knock-down of E2F3 limited cell proliferation. Forced stabilization of HIF-1α using Ad-VP16- HIF-1α under normoxic conditions up-regulated miR-210 expression, down-regulated E2F3, and limited cell proliferation. Studies using cellular delivery of miR-210 antagomir and mimic demonstrated a key role of miR-210 in limiting keratinocyte proliferation. In summary, these results are unique in presenting evidence demonstrating that the hypoxia component of ischemia may limit wound re-epithelialization by stabilizing HIF-1α, which induces miR-210 expression, resulting in the down-regulation of the cell-cycle regulatory protein E2F3.     

Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethyl-benz[a]anthracene-induced oral carcinogenesis

Circadian time-dependent treatment with chemotherapeutic drugs (chronotherapy) optimizes the therapeutic index by maximizing treatment efficacy and minimizing toxicity. The circadian time-dependent chemopreventive and anti-lipid peroxidative efficacy of withaferin-A in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated in the present study. We induced oral squamous cell carcinoma in the buccal pouches of golden Syrian hamsters during the day (4:00, 8:00, 12:00,16:00, 20:00 and 24:00) by application of DMBA three times per week for 14 weeks. The circadian time-dependent tumor incidence, volume and burden were observed in hamsters treated with either DMBA alone or DMBA + withaferin-A. The circadian pattern of lipid peroxidation by-products, as measured by the formation of thiobarbituric acid reactive substances (TBARS) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], was also analyzed in the buccal mucosa of DMBA-treated hamsters. We found the highest incidence of tumor formation at 24.00 h in hamsters treated with DMBA alone as compared to other experimental groups. Circadian dysregulation of lipid peroxidation and antioxidant status was observed in DMBA-treated animals as compared to control animals. Oral (po) administration of withaferin-A (20 mg/kg) completely prevented the formation of tumors between 8.00 h and 12.00 h and synchronized the status of lipid peroxidation and antioxidants in the buccal mucosa of hamsters treated with DMBA alone. Also, oral administration of withaferin-A to DMBA-treated animals significantly reduced the formation of tumors and synchronized the status of lipid peroxidation and antioxidants in the rest of the time intervals. Our study thus suggests that withaferin-A has significant chemopreventive and anti-lipid peroxidative potential in DMBA-induced oral carcinogenesis, probably by interfering with DMBA-induced abnormal cell proliferation in the buccal mucosa.     

Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK

Curcumin, a major active component of turmeric, is known to induce apoptosis in several types of cancer cells, but little is known about its activity in chemoresistant cells. Hence, the aim of the present study was to investigate the anticancer properties of curcumin in cisplatin-resistant human ovarian cancer cells in vitro. The results indicated that curcumin inhibited the proliferation of both cisplatin-resistant (CR) and sensitive (CS) human ovarian cancer cells almost equally. Enhanced superoxide generation was observed in both CR and CS cells treated with curcumin. Curcumin induced G(2)/M phase cell-cycle arrest in CR cells by enhancing the p53 phosphorylation and apoptosis through the activation of caspase-3 followed by PARP degradation. Curcumin also inhibited the phosphorylation of Akt while the phosphorylation of p38 MAPK was enhanced. In summary, our results showed that curcumin inhibits the proliferation of cisplatin-resistant ovarian cancer cells through the induction of superoxide generation, G(2)/M arrest, and apoptosis.     

Effects of Aroclor 1254 on femoral bone metabolism in adult male Wistar rats

Environmental pollutants that disrupt endocrine system might also affect the modeling and remodeling of bone. Environmental factors, irrespective of age and sex contribute for the development of secondary osteoporosis. Polychlorinated biphenyls have adverse effects on various organs including bone. The present study was designed to investigate the effects of PCB (Aroclor 1254) on femur bone and the ameliorative role of vitamin C or E. In this regard, four groups of adult male albino rats were used as control, PCB (2mg/kgb.wt.), PCB+vitamin C (100mg/kgb.wt.) and PCB+vitamin E (50mg/kgb.wt.). The bone formation markers (ALP, Collagen), bone resorption marker (TRAP), antioxidant enzymes (SOD, GPX and GST) and lipid peroxidation in the femur were studied. Aroclor 1254 treatment decreased the ALP activity and collagen, but increased the TRAP activity and lipid peroxidation. While it decreased the SOD and GPX activity, GST was unaltered. Interestingly, simultaneous administration of vitamin C or E prevented the adverse effects of Aroclor 1254 in the femur. In conclusion, the present investigation suggests that Aroclor 1254 induced oxidative stress affects femoral bone metabolism. However, vitamin C or vitamin E protected the femur from the oxidative stress.     

Efficacy of grape seed proanthocyanidins on serum and heart tissue lipids in rats subjected to isoproterenol-induced myocardial injury

The present study was aimed to evaluate the preventive role of grape seed proanthocyanidins (GSPs) on serum and tissue lipid enzymes in isoproterenol (ISO)-induced myocardial injury in male Wistar albino rats. GSP was administered orally to rats (150-180 g) in three different doses, by gastric gavage (50, 100 and 150 mg/kg GSP), 6 days a week for 5 weeks. At the end of this period, all the rats, except the normal untreated rats that served as the control group, were administered ISO, 85 mg/kg subcutaneously, for 2 consecutive days to induce myocardial injury. After 48 h, rats (n=6 per group) were anesthetized with anesthetic ether, sacrificed and the levels of biochemical observations of the serum and heart tissues were performed. Biochemical assessment of myocardial injury was done by measuring the activities of serum thiobarbituric acid reactive substances and plasma lactate, which were significantly elevated in the rats administered with ISO. Further, our results suggest that prior administration of GSPs significantly maintained the cholesterol, phospholipids, triglycerides, and free fatty acids levels in serum and heart tissue of the ISO-induced myocardial injury in rats. The experiments conclude that GSPs possess cardioprotective and hypolipidemic effect on the treatment of ISO-induced myocardial injury.     

HPTLC method development, validation, and stress degradation studies for atorvastatin and ezetimibe in multicomponent tablet dosage form

A simple, precise, rapid, selective, and economic high performance thin-layer chromatography method has been established for simultaneous analysis of atorvastatin (ATV) and ezetimibe (EZE) in tablet dosage forms. The chromatography separation was performed on precoated silica gel 60 GF₂₅₄ plates with toluene–ethyl acetate–methanol 12:5:3 (v/v/v) as mobile phase. The plate was developed to a distance of 8.0?cm at ambient temperature. The retention factors for ATV and EZE were 0.31 and 0.57, respectively. The detection band was carried out at 254?nm. The calibration curve was linear in the concentration range of 200–1200?ng/spot for both ATV and EZE. For ATV, the recovery study results ranged from 99.44 to 99.54% with RSD value ranging from 0.067 to 0.107%. For EZE, the recovery results ranged from 98.88 to 99.00% with RSD value ranging from 0.154 to 1.756%. The assay was 99.89% for ATV and 99.84% for EZE. The calibration plots revealed a good linear relationship with r ²?=?0.9991 for ATV and 0.9992 for EZE. Both ATV and EZE were subjected to different stress conditions—acid, alkaline hydrolysis, oxidation, photo degradation, dry, and wet heat treatment—as prescribed by ICH. The degradation products were well resolved from the pure drug with significantly different R _f values. The method was validated for precision, accuracy, specificity, ruggedness, and robustness.