Withanolide Z, a new chlorinated withanolide from Withania somnifera

Reverse-phase preparative HPLC analysis of the n-butanol fraction of the methanolic extract of Withania somnifera Dunal (leaves) afforded a novel chlorinated withanolide, namely withanolide Z (1), along with four known withanolides, withanolide B (2), withanolide A (3), 27-hydroxywithanolide B (4) and withaferin A (5). Their structures were elucidated by IR, MS, CD and a combination of 1 D and 2 D NMR spectral analyses. The Leishmania donovani DNA topoisomerase I inhibitory activities of the isolated compounds were determined.     

Post-marketing surveillance of buprenorphine

PURPOSE: This study was undertaken to evaluate the adverse consequences of recently introduced higher strength (0.4 and 2.0 mg per tablet) buprenorphine in Indian market. Buprenorphine, a partial opiate agonist and antagonist, is an emerging alternative to methadone as an agent for long-term treatment of opiate dependence. METHODS: The current investigation was conducted through a multi-centric post-marketing surveillance (PMS) study using a structured performa from patients receiving buprenorphine as routine therapy from de-addiction centres. Evaluation included subjective and objective assessments and recording of adverse events. RESULTS: Of the 5551 observations from ten centres, common subjective symptoms were generalised weakness (48.9%), sense of high (euphoria) (44.5%), muscle aches (39.5%) and relief from pain (37.2%). About 5% observations recorded systolic hypertension. Among 55 subjects where laboratory tests were conducted, 12 showed raised levels of AST ad 9 had elevated ALT. Twelve adverse events reported included seizure, epistaxis, panic attacks, constipation and dyspnoea. Significant relation was seen between duration of use and time since last dose, and total number of subjective symptoms reported. CONCLUSIONS: Majority of the adverse effects could be understood as either effects related to intoxication or withdrawal from agonists.     

Haemangioma of Cheek Different Presentation and Management

Though haemangioma of cheek is not a very uncommon entity, here we are presenting a case series of four such cases of haemangioma cheek of completely different presentation. One of which is classical maxillary haemangioma and the rest of the others have different and unusual presentations. They all have different radiological features and were managed successfully by different surgical approaches without any recurrence.     

Menopausal symptoms in women treated for breast cancer: the prevalence and severity of symptoms and their perceived effects on quality of life.

OBJECTIVES: To determine, first, the prevalence and severity of various symptoms related to estrogen deficiency in women within a few years of receiving treatment for breast cancer, second, how women perceive the effects of these symptoms on their quality of life and, third, what measures have been taken to relieve vasomotor symptoms. METHODS: Two hundred women (aged 29-65 years) who had received treatment for breast cancer within the last 5 years were included in this cross-sectional survey. Information was collected about their breast cancer treatment, menopausal symptoms (Menopausal Rating Scale), the perceived effects of menopausal symptoms on their and their partner's quality of life and any treatments they were receiving for hot flushes. RESULTS: All but one woman reported at least one symptom related to the menopause (95.9% vasomotor; 83.3% psychological; 89.7% somatic). Current treatment with tamoxifen or previous chemotherapy did not influence the prevalence or the severity of hot flushes. Current antidepressant treatment was, however, significantly associated with a higher prevalence and severity of most menopausal symptoms, including hot flushes and sweats (p = 0.008). The severity of hot flushes and sweats was significantly correlated with self-assessed effects on overall quality of life (r(s) = 0.47); 56.4% of the respondents believed that menopausal symptoms had affected their partner's quality of life, the strongest correlations being with severity of sexual symptoms (r(s) = 0.56) and vaginal dryness (r(s) = 0.5). Only 21% of women experiencing hot flushes were receiving any treatment for hot flushes, with most women describing no knowledge or poor knowledge of treatment options. CONCLUSIONS: The majority of women receiving treatment for breast cancer report menopausal symptoms, which negatively correlate, not only with their own, but also with their partner's quality of life. Most women experiencing hot flushes are not receiving treatment due to lack of both awareness and confidence in the existing treatment options.     

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

Human breast tumors comprise a minor sub-population of tumor-initiating cells (TICs), commonly termed cancer stem cells. TICs are thought to sustain tumor growth and to confer resistance to current anticancer therapies. Hence, targeting TIC may be essential to achieving durable cancer cures. To identify molecular targets in breast TIC, we employed a transgenic mouse model of ERBB2 breast cancer; tumors arising in this model comprise a very high frequency of TIC, which is maintained in tumor cell populations propagated in vitro as non-adherent tumorspheres. The Notch pathway is dysregulated in human breast tumors and overexpression of constitutively active Notch proteins induces mammary tumors in mice. The Notch pathway has also been implicated in stem cell processes including those of mammary epithelial stem cells. Hence, we investigated the potential that the Notch pathway is required for TIC activity. We found that an antagonist of Notch signaling, a gamma (γ)-secretase inhibitor termed MRK-003, inhibited the survival of tumorsphere-derived cells in vitro and eliminated TIC as assessed by cell transplantation into syngeneic mice. Whereas MRK-003 also inhibited the self-renewal and/or proliferation of mammosphere-resident cells, this effect of the inhibitor was reversible thus suggesting that it did not compromise the survival of these cells. MRK-003 administration to tumor-bearing mice eliminated tumor-resident TIC and resulted in rapid and durable tumor regression. MRK-003 inhibited the proliferation of tumor cells, and induced their apoptosis and differentiation. These findings suggest that MRK-003 targets breast TIC and illustrate that eradicating these cells in breast tumors ensures long-term, recurrence-free survival.     

A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression

Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.     

Inflammatory bowel disease-related colorectal cancer: Past,present and future perspectives

Inflammatory bowel disease-related colorectal cancer (IBD-CRC) is one of the most serious complications of IBD contributing to significant mortality in this cohort of patients. IBD is often associated with diet and lifestyle-related gut microbial dysbiosis, the interaction of genetic and environmental factors, leading to chronic gut inflammation. According to the “common ground hypothesis”, microbial dysbiosis and intestinal barrier impairment are at the core of the chronic inflammatory process associated with IBD-CRC. Among the many underlying factors known to increase the risk of IBD-CRC, perhaps the most important factor is chronic persistent inflammation. The persistent inflammation in the colon results in increased proliferation of cells necessary for repair but this also increases the risk of dysplastic changes due to chromosomal and microsatellite instability. Multiple pathways have been identified, regulated by many positive and negative factors involved in the development of cancer, which in this case follows the ‘inflammation-dysplasia-carcinoma’ sequence. Strategies to lower this risk are extremely important to reduce morbidity and mortality due to IBD-CRC, among which colonoscopic surveillance is the most widely accepted and implemented modality, forming part of many national and international guidelines. However, the effectiveness of surveillance in IBD has been a topic of much debate in recent years for multiple reasons — cost-benefit to health systems, resource requirements, and also because of studies showing conflicting long-term data. Our review provides a comprehensive overview of past, present, and future perspectives of IBD-CRC. We explore and analyse evidence from studies over decades and current best practices followed globally. In the future directions section, we cover emerging novel endoscopic techniques and artificial intelligence that could play an important role in managing the risk of IBD-CRC.     

Antidepressant-like effects of 3,4-methylenedioxymethamphetamine in an animal model of depression

Increased synaptic serotonin (5-hydroxytryptamine) levels may underlie antidepressant-like effects of 3,4-methylenedioxymethamphetamine (MDMA) that may be more prominent in subjects with mood disturbance. The Flinders Sensitive Line (FSL) strain is an important animal model of depression. These rats are more immobile in the forced swimming test (FST), and their immobility is reversed by known antidepressants after prolonged administration. The objective of this study was to determine whether MDMA administration has a dose-dependent antidepressant-like effect in this animal model of depression. The effects of MDMA at 5 and 10 mg/kg following single and repeated administration were assessed in FSL rats using the FST. Sprague-Dawley rats were used as a control. During both FST sessions, saline-treated FSL rats were significantly more immobile than Sprague-Dawley rats (P<0.001). Acute MDMA administration had a dose-dependent antidepressant-like effect in FSL rats, which was most evident after 10 mg/kg. This effect was diminished after repeated administration. Methamphetamine 2 mg/kg, which was used as a positive control for locomotor activity induction, did not affect the depressive-like state in FSL rats. There were no changes in the cortical levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid after treatments. It is concluded that MDMA exhibited an antidepressant-like effect in FSL rats, which was most evident following acute administration.