The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis

Limonoids from the neem tree (Azadirachta indica) have attracted considerable research attention for their cytotoxicity against human cancer cell lines. However, the antiproliferative and apoptosis inducing effects of neem limonoids have not been tested in animal tumour models. The present study was therefore designed to evaluate the relative chemopreventive potential of the neem limonoids azadirachtin and nimbolide in the hamster buccal pouch (HBP) carcinogenesis model by analyzing the expression of proliferating cell nuclear antigen (PCNA), p21^waf1, cyclin D1, glutathione S-transferase pi (GST-P), NF-κB, inhibitor of κB (IκB), p53, Fas, Bcl-2, Bax, Bid, Apaf-1, cytochrome C, survivin, caspases-3, −6, −8 and −9, and poly(ADP-ribose) polymerase (PARP) by RT-PCR, immunohistochemical, and Western blot analyses. The results provide compelling evidence that azadirachtin and nimbolide mediate their antiproliferative effects by downregulating proteins involved in cell cycle progression and transduce apoptosis by both the intrinsic and extrinsic pathways. On a comparative basis, nimbolide was found to be a more potent antiproliferative and apoptosis inducing agent and offers promise as a candidate agent in multitargeted prevention and treatment of cancer.     

Chemoprevention of rat mammary carcinogenesis by Azadirachta indica leaf fractions: Modulation of hormone status,xenobiotic-metabolizing enzymes,oxidative stress,cell proliferation and apoptosis

We evaluated the chemopreventive potential of the ethyl acetate fraction (EAF) and methanolic fraction (MF) of Azadirachta indica (neem) leaf on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Estradiol and estrogen receptor status, xenobiotic-metabolizing enzyme activities, redox status, DNA and protein modifications, and the expression of cell proliferation, and apoptosis related proteins in the mammary gland and liver were used as biomarkers of chemoprevention. Administration of both EAF and MF at a dose of 10 mg/kg bw effectively suppressed tumour incidence. Chemoprevention by neem leaf fractions was associated with modulation of hormone and receptor status, xenobiotic-metabolising enzymes, and lipid and protein oxidation, with upregulation of antioxidants, inhibition of oxidative DNA damage, protein modification, and cell proliferation, and induction of apoptosis. However EAF rich in constituent phytochemicals was more effective than MF in modulating multiple molecular targets. These results provide evidence for the chemopreventive efficacy of neem leaf fractions in the rat mammary tumour model.     

Type-I complex regional pain syndrome of umbilical port site: An unforeseen complication of laparoscopic surgery

Many complications have been observed after laparoscopic surgery. Persisting pain in the umbilical port site is due to infection, hernia, endometriosis, metastasis, etc. There is no case report due to neuralgic complex regional pain syndrome, and we have dealt a case which is described with relevant literature review and etiopathogenesis.     

The utility of IS6110 sequence based polymerase chain reaction in comparison to conventional methods in the diagnosis of extra-pulmonary tuberculosis

IS6110 sequence based polymerase chain reaction (PCR) was compared with conventional bacteriological techniques in the laboratory diagnosis of extra-pulmonary tuberculosis (EPTB). One hundred and ninety one non-repeated clinical samples of EPTB and 17 samples from non-tuberculous cases as controls were included. All the samples were processed for Ziehl-Neelsen staining for acid fast bacilli (AFB) and 143 samples were processed by culture for M. tuberculosis . All the samples were processed for PCR amplification with primers targeting 123 bp fragment of insertion element IS6110 of M. tuberculosis complex. Of the total 191 samples processed, 34 (18%) were positive by smear for AFB. Culture for AFB was positive in 31(22%) samples among the 143 samples processed. Either smear or culture for AFB was found positive in 51(27%) samples. Of the total 191 samples processed 120 (63%) were positive by PCR. In 140 samples, wherein both the conventional techniques were found negative, 74 (53%) samples were positive by PCR alone. Among 51 samples positive by conventional techniques, 46 (90%) were found positive by PCR. PCR assay targeting IS6110 is useful in establishing the diagnosis of EPTB, where there is strong clinical suspicion, especially when the conventional techniques are negative.     

Device-Based Therapy for Drug-Resistant Hypertension: An Update

Drug-resistant hypertension (RH) remains a significant and common cardiovascular risk despite the availability of multiple potent antihypertensive medications. Uncontrolled resistant hypertension contributes substantially to excessive cardiovascular and renal morbidity and mortality. Clinical and experimental evidence suggest that sympathetic nervous system over-activity is the main culprit for the development and maintenance of drug-resistant hypertension. Both medical and interventional strategies, targeting the sympathetic over-activation, have been designed in patients with hypertension over the past few decades. Minimally invasive, catheter-based, renal sympathetic denervation (RDN) and carotid baroreceptor activation therapy (BAT) have been extensively evaluated in patients with RH in clinical trials. Current trial outcomes, though at times impressive, have been mostly uncontrolled trials in need of validation. Device-based therapy for drug-resistant hypertension has the potential to provide alternative treatment options to certain groups of patients who are refractory or intolerant to current antihypertensive medications. However, more research is needed to prove its efficacy in both animal models and in humans. In this article, we will review the evidence from recent renal denervation, carotid baroreceptor stimulation therapy, and newly emerged central arteriovenous anastomosis trials to pinpoint the weak links, and speculate on potential alternative approaches.     

Prevalence and correlates of psychosocial conditions among people living with HIV in southern India

Psychosocial conditions such as depression, intimate partner violence (IPV), and history of childhood sexual abuse (CSA) have been associated with poor HIV-related outcomes. In India, which has the third largest HIV epidemic in the world, little is understood about the impact of psychosocial conditions on people living with HIV (PLHIV). We aimed to understand the prevalence and correlates of psychosocial conditions among PLHIV entering into HIV care at the Y.R. Gaitonde Centre for AIDS Research and Education in Chennai, India. Thirteen questions were added to the standard voluntary counseling and testing questionnaire, including the Patient Health Questionnaire-9 (a depression scale) and questions assessing for CSA and IPV. We fitted logistic regression models, stratified by gender, with psychosocial condition as the outcome of interest and substance use variables and socio-demographic variables as the correlates of interest. Three hundred and eighty-three persons were enrolled into the study; of these, 253 (66%) tested positive for HIV, including 149 men and 104 women, and were included in the models. More than one-quarter (28%) of the men and 19% of the women reported at least one psychosocial condition (probable depression, CSA, or IPV). In adjusted analysis, current alcohol use was associated with greater than two times higher odds of a psychosocial condition (Adjusted Odds Ratio?=?2.24, 95% CI, 1.04–4.85) among men. In conclusion, we estimated the prevalence of probable depression, CSA, and IPV among PLHIV presenting for HIV care in southern India and found that, among male PLHIV, alcohol use was associated with a markedly higher odds of reporting a psychosocial condition. Further study is needed to characterize alcohol use among male PLHIV and the possible deleterious impact of psychosocial conditions and alcohol use on HIV-related outcomes in India.     

The Flavonoid Quercetin Modulates the Hallmark Capabilities of Hamster Buccal Pouch Tumors

Epidemiological studies have consistently demonstrated the protective effects of dietary phytochemicals against cancer risk. Quercetin, a ubiquitous dietary flavonoid, has attracted considerable attention owing to its potent antioxidant and antiproliferative activities. The present study was designed to investigate the chemopreventive as well as the therapeutic ability of quercetin to modulate the key hallmark capabilities of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinomas. We analyzed the expression of markers associated with cell proliferation and survival (PCNA, p21, p53, cyclin D1, GST-P), apoptosis (Fas, Fas-L, Bcl-2 family proteins, cytochrome-C, Apaf-1, caspases, PARP, survivin, cFLIP, API1), invasion (MMPs, TIMP-2, RECK), angiogenesis (PlGF, VEGF, VEGF receptors, HIF-1α), as well as the epigenetic markers (HDAC-1, DNMT1) by immunohistochemical, Western blot, and RT-PCR analyses. Simultaneous administration of quercetin to DMBA-painted hamsters reduced tumor incidence and tumor burden, while posttreatment of quercetin resulted in a significant tumor growth delay. In addition, quercetin administration induced cell cycle arrest and apoptosis and blocked invasion and angiogenesis. We found a positive correlation between the inhibition of HDAC-1 and DNMT1 by quercetin and its anticancer properties. A dietary phytochemical such as quercetin that modulates a plethora of molecules offers promise as an ideal candidate for multitargeted cancer prevention and therapy.     

Correlation of xenobiotic-metabolizing enzymes,oxidative stress and NFκB signaling with histological grade and menopausal status in patients with adenocarcinoma of the breast

BackgroundAdenocarcinoma of the breast is the most common cancer worldwide and accounts for the highest morbidity and mortality. The increasing global incidence of breast cancer emphasizes the need to understand the molecular mechanisms of breast tumorigenesis. The present study was designed to correlate changes in xenobiotic-metabolizing enzymes (XME), oxidative stress and NFκB signaling with histological grading and menopausal status in breast cancer patients.MethodSixty breast cancer patients histologically categorized as grades I, II and III, and as pre- and postmenopausal were chosen for the study. We analyzed phase I and phase II XME activities as well as the expression of the CYP isoforms CYP1A1 and CYP1B1, oxidative stress markers, and the expression of NFκB family members in tumor and adjacent tissues by immunohistochemical localization and Western blot analyses.ResultsThe breast tumors analyzed in the present study were characterized by increased activities of xenobiotic-metabolizing enzymes and enhanced oxidative damage to lipids, proteins, and DNA associated with variations in the expression of NFκB family members. The magnitude of the changes was however more pronounced in premenopausal patients and in grade III breast tumors.ConclusionThe present study delineates the correlation between XME-mediated oxidative stress and NFκB signaling that leads to the development of breast cancer.