Boswellic acid inhibits growth and metastasis of human colorectal cancer in orthotopic mouse model by downregulating inflammatory, proliferative, invasive and angiogenic biomarkers

Numerous cancer therapeutics were originally identified from natural products used in traditional medicine. One such agent is acetyl-11-keto-beta-boswellic acid (AKBA), derived from the gum resin of the Boswellia serrata known as Salai guggal or Indian frankincense. Traditionally, it has been used in Ayurvedic medicine to treat proinflammatory conditions. In this report, we hypothesized that AKBA can affect the growth and metastasis of colorectal cancer (CRC) in orthotopically implanted tumors in nude mice. We found that the oral administration of AKBA (50-200 mg/kg) dose-dependently inhibited the growth of CRC tumors in mice, resulting in decrease in tumor volumes than those seen in vehicle-treated mice without significant decreases in body weight. In addition, we observed that AKBA was highly effective in suppressing ascites and distant metastasis to the liver, lungs and spleen in orthotopically implanted tumors in nude mice. When examined for the mechanism, we found that markers of tumor proliferation index Ki-67 and the microvessel density cluster of differentiation (CD31) were significantly downregulated by AKBA treatment. We also found that AKBA significantly suppressed nuclear factor-κB (NF-κB) activation in the tumor tissue and expression of proinflammatory (cyclooxygenase-2), tumor survival (bcl-2, bcl-xL, inhibitor of apoptosis (IAP-1) and survivin), proliferative (cyclin D1), invasive (intercellular adhesion molecule 1 and matrix metalloproteinase-9) and angiogenic C-X-C (CXC) receptor 4 and vascular endothelial growth factor) biomarkers. When examined for serum and tissue levels of AKBA, a dose-dependent increase in the levels of the drug was detected, indicating its bioavailability. Thus, our findings suggest that this boswellic acid analog can inhibit the growth and metastasis of human CRC in vivo through downregulation of cancer-associated biomarkers.     

miR-10a is aberrantly overexpressed in Nucleophosmin1 mutated acute myeloid leukaemia and its suppression induces cell death

Background

Semaphorins act as chemotactic cues for cell movement via their transmembrane receptors, plexins. Somatic missense mutations in the plexinB1 gene coupled with overexpression of the protein frequently occur in prostate tumours, indicating a role for plexinB1 in the pathogenesis of prostate cancer.

Results

Two specific mutations found in prostate cancer enhance RhoD binding and one other mutation results in loss of inhibition of Rac-dependent Pak1 phosphorylation and lamellipodia formation and in impairment of trafficking of plexinB1 to the membrane. None of the three characterised mutations affect PDZRhoGEF binding, RhoA activity, the interaction of plexinB1with the oncogenes ErbB2 or c-Met or ErbB2 phosphorylation. The mutations have the net effect of increasing cell motility by blocking plexinB1-mediated inhibition of Rac while enhancing the interaction with RhoD, an anti-migratory factor.

Conclusions

PlexinB1 mutations block plexinB1-mediated signalling pathways that inhibit cell motility.     

CYP1A1 and CYP3A4 polymorphic variations in Delhi population of Northern India

Cytochrome P450 (CYP) 1A1 and CYP3A4 are important phase I xenobiotic metabolizing enzymes involved in the metabolism of numbers of toxins, endogenous hormones and pharmaceutical drugs. Polymorphisms in these phase I genes can alter enzyme activity and are known to be associated with cancer susceptibility related to environmental toxins and hormone exposure. Their genotypes may also display ethnicity dependent population frequencies. The present study was aimed to determine the frequencies of commonly known functional polymorphisms of CYP1A1 and CYP3A4 in North Indian population. Allelic frequency of CYP1A1 polymorphisms, m1, m2 and m4 were observed to be 40.3, 31.2 and 0% respectively. Frequency of CYP3A4*1B polymorphism was 0%. We observed inter as well as intra ethnic variation in the distribution of frequency of these polymorphisms. Analysis of polymorphisms in these genes might help in predicting the risk of cancer. Our results emphasize the need for more such studies in "high risk populations".     

Problem drinking among married men in India: comparison between husband's and wife's reports

Introduction and Aims. This study compared the husband's report and wife's report of her husband's problem drinking, among residents of an urban slum in Bangalore, India. Design and Methods. The data come from a feasibility study to prevent HIV infection among at‐risk women in Bangalore. Household enumeration was carried out (n = 509) to choose 100 married men between 18 and 50 years who reported problem drinking (scores 8 and above) on the Alcohol Use Disorder Identification Test (AUDIT). Wives of these married men, considered to be at risk for HIV because of their husband's hazardous drinking, were subsequently recruited for the study (n = 100). Written informed consent was obtained; wives were asked about the drinking history of their husbands through the AUDIT‐WR (Wife's Report) developed for the present study. Results. Prevalence of problem drinking in the enumerated sample (n = 509) was high (n = 186; 37%). The husband's report and his wife's report of his problem drinking was concordant (r = 0.57–0.75) on eight out of 10 items, and the total AUDIT score. Discussion and Conclusions. The AUDIT‐WR is a reliable and culturally relevant measure of husband's problem drinking. In India, men with problem drinking are hard to reach. Therefore, proxy report of the wife may be useful when the husband is either unavailable or uncooperative for assessment.[Satyanarayana VA, Vaddiparti K, Chandra PS, O'Leary CC, Benegal V, Cottler LB. Problem drinking among married men in India: comparison between husband's and wife's reports. Drug Alcohol Rev 2010]     

The divergent roles of protein kinase C epsilon and delta in simulated ischaemia-reperfusion injury in human myocardium

Experimental studies suggest that cardioprotection can be achieved through either the activation of PKC-? prior to the index ischaemic episode or the inhibition of PKC-δ at the onset of reperfusion. However, whether these PKC isoforms exert such divergent roles in human myocardium, subjected to simulated ischaemia-reperfusion injury, is unclear.Human atrial trabeculae were isolated from right atrial appendages harvested from patients undergoing elective cardiac surgery. These were subjected to 90 min of hypoxia followed by 120 min of reoxygenation, at the end of which the recovery of baseline contractile function was determined. Atrial trabeculae were randomised to receive various treatment protocols comprising a peptide activator of PKC-?, a peptide inhibitor of PKC-δ and their respective inactive control peptides.Administering the PKC-δ peptide inhibitor at reoxygenation improved the recovery of function at all the concentrations tested (39.3 ± 1.4% at 5 nM, 52.4 ± 2.9% at 50 nM and 46.8 ± 2.9% at 500 nM versus the control group, 27.5 ± 1.4%: N ≥ 6/group: P < 0.02). Preconditioning with the PKC-? peptide activator improved the recovery of function (40.0 ± 0.8% at 50 nM and 49.7 ± 3.1% at 500 nM versus the control group 27.5 ± 1.4%: N ≥ 6/group: P < 0.02). This cardioprotective effect was comparable to that achieved by a standard hypoxic preconditioning protocol (52.3 ± 3.2%). Interestingly, administering the PKC-? activator (500 nM) at the onset of reperfusion also improved the recovery of contractile function (40.7 ± 2.1% versus 27.5 ± 1.5%: N ≥ 6/group: P < 0.05).In human myocardium, cardioprotection can be achieved by either inhibiting PKC-δ or activating PKC-? at the onset of reperfusion. In addition, PKC-? activation offers cardioprotection when administered as a preconditioning strategy.     

Efficacy of splinting and oral steroids in the treatment of carpal tunnel syndrome: a prospective randomized clinical and electrophysiological study

OBJECTIVE: To study the efficacy of splinting and oral steroids in the management of carpal tunnel syndrome (CTS). DESIGN: Prospective, randomized, open-label, clinical and electrophysiological study with 3-month follow-up. MATERIALS AND METHODS: Forty patients with CTS were randomly divided into splint group (N-20), wearing splint in neutral position for 4 weeks; and steroid group (N-20), who received oral prednisolone 20 mg/day for 2 weeks followed by 10 mg/day for 2 weeks. Clinical and electrophysiological evaluations were done at baseline and at 1-month and 3-month follow-up. Independent 't' test and paired 't' test were used for statistical analysis. OUTCOME MEASURES: Primary outcome measure was the symptom severity score and functional status score. Secondary outcome measures were median nerve sensory and motor distal latency and conduction velocity. RESULTS: At the end of 3 months, statistically significant improvement was seen in symptom severity score and functional status score in both groups (P<0.001). Median nerve sensory distal latency and conduction velocity also improved significantly in both the groups at 3 months. Improvement in motor distal latency was significant (P=0.001) at 3 months in steroid group, while insignificant improvement (P=0.139) was observed in splint group. On comparing the clinical and electrophysiological improvement between the two groups, except for the functional status score, there was no significant difference at 3-month follow-up. Improvement in functional status score was significantly more in steroid group (P=0.03). CONCLUSION: There was significant improvement in both groups, clinically as well as electrophysiologically, at 3 months. On comparing the efficacy of the two treatment methods, except for the functional status score, there was no significant difference between the two groups.