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.     

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.     

Mitochondria-mediated apoptosis in patients with adenocarcinoma of the breast: Correlation with histological grade and menopausal status

The present study was designed to investigate the abnormalities in the expression of apoptosis-associated proteins that lead to the progression of breast cancer. Sixty breast cancer patients histologically categorized as grade I, II and III, and as pre- and post-menopausal were chosen for the study. We analyzed the expression of the anti-apoptotic and pro-apoptotic Bcl-2 family proteins as well as cytochrome C, Apaf-1 and caspases in tumour and adjacent tissues by immunohistochemical and Western blot analyses. The breast tumours analyzed in the present study were characterized by increased expression of Bcl-2, Bcl-xL and Mcl-1, associated with downregulation in the expression of Bax, cytosolic cytochrome C, Apaf-1 and caspases. The magnitude of the changes was however more pronounced in premenopausal patients and in grade III tumours. The results of the present study confirm that differential expression patterns of Bcl-2 family proteins and caspases are involved in evasion of apoptosis and in the progression of breast cancer.     

Correlation of matrix metalloproteinases and their inhibitors with hypoxia and angiogenesis in premenopausal patients with adenocarcinoma of the breast

Objectives

The present study was designed to correlate the expression of proteins regulating invasion and angiogenesis in patients with adenocarcinoma of the breast.

Design and method

Seventy-five premenopausal breast cancer patients histologically categorized as grades I, II and III were chosen for the study. We analyzed the expression of MMP-2, and -9 and their inhibitors TIMP-2 and RECK together with HIF-1α and VEGF in tumor, adjacent tissues and serum samples by immunohistochemical and Western blot analysis.

Results

The breast tumors analyzed in the present study were characterized by increased expression of MMP-2, -9, HIF-1α and VEGF with differential expression patterns of TIMP-2 and downregulation of RECK.

Conclusions

The simultaneous analysis of the expression of these molecular markers is important to understand the intricate network between key molecules involved in invasion and angiogenesis that eventually determines the clinical course of the disease.     

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.