The Anti-Epileptic Drug Valproic Acid (VPA) Inhibits Steroidogenesis in Bovine Theca and Granulosa Cells in Vitro.

The Anti-Epileptic Drug Valproic Acid (VPA) Inhibits Steroidogenesis in Bovine Theca and Granulosa Cells In Vitro.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e49553
Glister C, Satchell L, Michael AE, Bicknell AB, Knight PG

Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their ‘follicular’ phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC(50) 67±10 µg/ml) and LH-induced (93% suppression; IC(50) 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC. HubMed – drug


Quercetin Suppresses Drug-Resistant Spheres via the p38 MAPK-Hsp27 Apoptotic Pathway in Oral Cancer Cells.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e49275
Chen SF, Nieh S, Jao SW, Liu CL, Wu CH, Chang YC, Yang CY, Lin YS

BACKGROUND: Treatment failure in oral squamous cell carcinoma (OSCC) leading to local recurrence(s) and metastases is mainly due to drug resistance. Cancer stem cells (CSCs) are thought be responsible for the development of drug resistance. However, the correlations between CSCs, drug resistance, and new strategy against drug resistance in OSCC remain elusive. METHODS: A drug-resistant sphere (DRSP) model was generated by using a nonadhesive culture system to induce drug-resistant cells from SCC25 oral cancer cells. A comparative analysis was performed between the parent control cells and DRSPs with a related treatment strategy focusing on the expression of epithelial-mesenchymal transition (EMT)-associated markers, drug-resistance-related genes, and CSC properties in vitro, as well as tumorigenicity and the regimen for tumor regression in vivo. RESULTS: Our data show the presence of a phenomenon of EMT with gradual cellular transition from an epithelioid to mesenchymal-like spheroid morphology during induction of drug resistance. The characterization of DRSPs revealed the upregulation of the drug-resistance-related genes ABCG2 and MDR-1 and of CSC-representative markers, suggesting that DRSPs have greater resistance to cisplatin (Cis) and stronger CSC properties compared with the control. Moreover, overexpression of phosphorylated heat-shock protein 27 (p-Hsp27) via the activation of p38 MAPK signaling was observed in DRSPs. Knockdown of Hsp27 decreased Cis resistance and induced apoptosis in DRSPs. Furthermore, an inhibitor of Hsp27, quercetin (Qu), suppressed p-Hsp27 expression, with alterations of the EMT signature, leading to the promotion of apoptosis in DRSPs. A xenographic study also confirmed the increase of tumorigenicity in DRSPs. The combination of Qu and Cis can reduce tumor growth and decrease drug resistance in OSCC. CONCLUSIONS: The p38 MAPK-Hsp27 axis plays an important role in CSCs-mediated drug resistance in OSCC. Targeting this axis using Qu combined with Cis may be a treatment strategy to improve prognosis in patients with OSCC.
HubMed – drug


Should Sputum Smear Examination Be Carried Out at the End of the Intensive Phase and End of Treatment in Sputum Smear Negative Pulmonary TB Patients?

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e49238
Malhotra S, Zodpey SP, Chandra S, Vashist RP, Satyanaryana S, Zachariah R, Harries AD

BACKGROUND: The Indian guidelines on following up sputum smear-negative Pulmonary tuberculosis (PTB) patients differ from the current World Health Organization (WHO) guidelines in that the former recommends two follow up sputum examinations (once at the end of intensive phase and the other at the end of treatment) while the latter recommends only one follow up sputum smear microscopy examination, which is done at the end of the intensive phase. This study was conducted to examine if there was any added value in performing an additional sputum smear examination at the end of treatment within the context of a national TB program. METHODS: This study was a descriptive record based review conducted in nine tuberculosis (TB) units in Delhi, India. All consecutive new sputum smear-negative PTB patients registered in these nine TB units from 1(st) January 2009 to 31(st) December 2009 were included in the study. RESULTS: Of 2567 new sputum smear-negative TB patients, 1973 (90%) had sputum specimens examined at the end of the intensive phase, of whom 36 (2%) were smear-positive: the majority (n?=?28) successfully completed treatment with either the same or a re-treatment regimen. At treatment completion, 1766 (85%) patients had sputum specimens examined, of whom 16 (0.9%) were smear-positive: all these were changed to a re-treatment regimen. Amongst the sputum-positive patients identified as a result of follow up (n?=?52), four were diagnosed with multi-drug resistant TB (MDR-TB), three of whom were detected after smear examination at the end of treatment. CONCLUSIONS: Given the high burden of TB in India, a 0.9% additional yield of smear-positive sputum smears at the end of treatment translates to 3,297 cases of smear-positive PTB. End-of-treatment smear is a low-yield strategy for detection of smear-positive TB cases, although further studies are needed to determine its population-level impact and cost, particularly in relation to other TB control interventions.
HubMed – drug



Richard “Buzzy” Gaiennie – 2009 Peoples Health Champion – On June 3, 2008, at the age of 70, Richard Buzzy Gaiennie broke ground on the future home of Bridge House, the internationally heralded drug and alcohol rehabilitation program he has guided since 1984. When they move in next month, Bridge House staff and residents will enter a million, state-of-the-art facility with significantly enhanced capacity to serve the programs mission of rebuilding lives. Bridge House is a mission of love for Buzzy Gaiennie. A recovering alcoholic now 35 years sober, Buzzy experienced first-hand the seductive and destructive power of addiction. He witnessed as it claimed the lives of friends and even his parents. Determined to resist that same downward spiral, Buzzy fought and prevailed against his own addiction. Life experience taught Buzzy an invaluable lesson — how to take control of your own life. Buzzy felt compelled to share this lesson and help others escape their pain and start new, productive lives. Twenty-five years ago, he was the sole employee of Bridge House. Buzzy has since grown the organization to 65 employees, increased the annual budget from 0000 to more than .5 million, expanded the program to other cities and countries, and saved thousands of lives along the way. Unlike other national recovery programs that rely on federal funds, 85% of Bridge House funding is self-generated through such enterprising outlets as thrift shops and refurbishing donated cars for re-sale. These programs do more than generate funds; they


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