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1.
PLoS One ; 17(8): e0272566, 2022.
Article in English | MEDLINE | ID: mdl-35939451

ABSTRACT

BACKGROUND: Although compression therapy is well established for patients with deep venous thrombosis (DVT) and chronic venous disease (CVD), considerable variation exists in its organization in clinical practice which may impact patient outcomes. The current study aims to deepen our understanding of the main drivers of the complex care organization for compression therapy and to identify targets for improvement. METHODS: This realist evaluation includes a mixed-method design consisting of semi-structured interviews with patients and health care professionals involved in compression therapy (n = 30), stakeholder meetings (n = 2) and surveys (n = 114). Data were collected to create the content of context-mechanism-outcome-configurations (CMOcs) important in compression therapy. Based on these CMOcs, targets for improvement to optimize the organization of compression care were identified. RESULTS: We identified overarching context factors and mechanisms targeting four optimal outcomes for the organization of compression therapy: selecting initial compression therapy types that support patient's self-reliance (1), evidence based selection of elastic compression stocking type and class (2), patient-based selection of assistive devices (3), individualizing treatment duration for DVT patients (4a) and providing follow-up for CVD patients (4b). We found that increasing health care professionals' knowledge of compression therapy, the availability of unambiguous protocols and guidelines, increasing patient involvement (and if applicable their informal care giver) in the decision making process, the accessible availability of resources, and increasing interdisciplinary consultation enhanced desirable outcomes. These targets triggered mechanisms such as increased health care professionals' willingness, confidence and motivation to provide patient-based care and increased patients' self-confidence and self-efficacy. CONCLUSIONS: This study provides a detailed insight into what needs to be in place to optimize compression care and identified five main targets for improvement.


Subject(s)
Postthrombotic Syndrome , Vascular Diseases , Chronic Disease , Humans , Postthrombotic Syndrome/etiology , Stockings, Compression/adverse effects , Surveys and Questionnaires , Vascular Diseases/etiology , Veins
2.
Chem Commun (Camb) ; 58(27): 4344-4347, 2022 Mar 31.
Article in English | MEDLINE | ID: mdl-35293913

ABSTRACT

The synthesis of two new tetra- and penta-phenycyclopentadienyldiphenylphosphine pro-ligands which readily undergo selective C-P bond cleavage has allowed for the facile synthesis of bulky divalent octa- and deca-phenylmetallocenes of europium, ytterbium and samarium.


Subject(s)
Lanthanoid Series Elements , Carbon/chemistry , Europium , Lanthanoid Series Elements/chemistry , Phosphorus , Samarium
3.
BMJ Open ; 8(6): e019962, 2018 06 22.
Article in English | MEDLINE | ID: mdl-29934382

ABSTRACT

OBJECTIVE: To evaluate the effects of granting legal full practice authority (FPA) to nurse practitioners (NP) and physician assistants (PA) regarding the performance of specified reserved medical procedures and to support governmental decision-making. DESIGN: Nationwide mixed methods design with triangulation of quantitative (Pre-post test design) and qualitative data (expert interviews and focus groups). METHODS: Surveys focused on the performance of the procedures (monthly number, authorisation mode, consultations and procedural time) and legal cross-compliance requirements (adherence with protocols, competence). Interviews focused on competence, knowledge, skills, responsibilities, routine behaviour, NP/PA role, acceptance, organisational structure, collaboration, consultation, NP/PA positioning, adherence with protocols and resources. Data collection took place between 2011 and 2015. RESULTS: Quantitative data included 1251 NPs, 798 PAs and 504 physicians. Besides, expert interviews with 33 healthcare providers and 28 key stakeholders, and 5 focus groups (31 healthcare providers) were held.After obtaining FPA, the proportion of NPs and PAs performing reserved procedures increased from 77% to 85% and from 86% to 93%, respectively; the proportion of procedures performed on own authority increased from 63% to 76% for NPs and from 67% to 71% for PAs. The mean number of monthly contacts between NPs/PAs and physicians about procedures decreased (from 81 to 49 and from 107 to 54, respectively), as did the mean duration in minutes (from 9.9 to 8.6 and from 8.8 to 7.4, respectively). Utilisation of FPA was dependent on the setting, as scepticism of physicians and medical boards hampered full implementation. Legal cross-compliance requirements were mostly fulfilled. CONCLUSIONS: Informal practice was legalised. The opportunities to independently perform catheterisations, injections, prescribing, punctures and small surgical procedures were highly used. Care processes were organised more efficiently, services were performed by the most appropriate healthcare provider and conditions were met. This led to the recommendation to continue with FPA.


Subject(s)
Clinical Competence , Nurse Practitioners/legislation & jurisprudence , Physician Assistants/legislation & jurisprudence , Health Care Reform , Humans , Netherlands , Nurse Practitioners/supply & distribution , Physician Assistants/supply & distribution , Quality Assurance, Health Care/methods
4.
J Vasc Surg ; 66(6): 1806-1813, 2017 12.
Article in English | MEDLINE | ID: mdl-29169540

ABSTRACT

OBJECTIVE: The objective of this study was to assess the reduction in quality of life (QoL) caused by the persistence of primary plantar hyperhidrosis (PPH) symptoms and the level of satisfaction in PPH patients after retroperitoneoscopic lumbar sympathectomy (RLS). The efficacy, safety, and procedure of bilateral RLS in both sexes are also described in this study. METHODS: This is a longitudinal study of consecutive patients who sought specific treatment from a private practitioner for severe PPH as classified on the Hyperhidrosis Disease Severity Scale (HDSS) from October 2005 to October 2014. The patients were asked to report the symptoms of PPH experienced in the immediate preoperative period and to complete a standardized QoL questionnaire developed by de Campos at least 12 months after RLS. Disease outcomes, recurrence of symptoms, and any adverse effects of surgery were evaluated after 30 days and at least 12 months after RLS. RESULTS: Lumbar sympathectomy was performed 116 times in 58 patients; 30 days after surgery, PPH was resolved in all patients. Three patients (5.2%) reported transient thigh neuralgia, and 19 (32.7%) reported transient paresthesia in the lower limbs. There were no reports of retrograde ejaculation. At a minimum of 12 months after RLS, 49 of the 58 patients had fully and correctly answered the follow-up questionnaire and noted a mild (HDSS 2) to moderate (HDSS 3) increase in pre-existing compensatory sweating. One patient had a PPH relapse within 6 months. Improvement in QoL due to the resolution of PPH was reported in 98% of the 49 patients. None of the operations necessitated a change in the laparotomy approach, and none of the patients died. CONCLUSIONS: RLS is safe and effective for the treatment of severe PPH in both sexes. There were no reports of retrograde ejaculation after resection of L3 and L4 ganglia. There was a mild to moderate increase in compensatory sweating in about half of the patients, but without any regret or dissatisfaction for having undergone the surgery because of a significant improvement in QoL.


Subject(s)
Endoscopy , Ganglia, Sympathetic/surgery , Hyperhidrosis/surgery , Sweat Glands/innervation , Sweating , Sympathectomy/methods , Cost of Illness , Endoscopy/adverse effects , Female , Foot , Ganglia, Sympathetic/physiopathology , Humans , Hyperhidrosis/diagnosis , Hyperhidrosis/physiopathology , Longitudinal Studies , Lumbosacral Region , Male , Patient Satisfaction , Postoperative Complications/etiology , Private Practice , Quality of Life , Recurrence , Retrospective Studies , Severity of Illness Index , Surveys and Questionnaires , Sympathectomy/adverse effects , Time Factors , Treatment Outcome
5.
J Pathol ; 238(5): 651-64, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26800240

ABSTRACT

Enhancer of zeste homolog 2 (EZH2) catalyses histone H3 lysine 27 trimethylation (H3K27me3) to silence tumour-suppressor genes in hepatocellular carcinoma (HCC) but the process of locus-specific recruitment remains elusive. Here we investigated the transcription factors involved and the molecular consequences in HCC development. The genome-wide distribution of H3K27me3 was determined by chromatin immunoprecipitation coupled with high-throughput sequencing or promoter array analyses in HCC cells from hepatitis B virus (HBV) X protein transgenic mouse and human cell models. Transcription factor binding site analysis was performed to identify EZH2-interacting transcription factors followed by functional characterization. Our cross-species integrative analysis revealed a crucial link between Yin Yang 1 (YY1) and EZH2-mediated H3K27me3 in HCC. Gene expression analysis of human HBV-associated HCC specimens demonstrated concordant overexpression of YY1 and EZH2, which correlated with poor survival of patients in advanced stages. The YY1 binding motif was significantly enriched in both in vivo and in vitro H3K27me3-occupied genes, including genes for 15 tumour-suppressive microRNAs. Knockdown of YY1 reduced not only global H3K27me3 levels, but also EZH2 and H3K27me3 promoter occupancy and DNA methylation, leading to the transcriptional up-regulation of microRNA-9 isoforms in HCC cells. Concurrent EZH2 knockdown and 5-aza-2'-deoxycytidine treatment synergistically increased the levels of microRNA-9, which reduced the expression and transcriptional activity of nuclear factor-κB (NF-κB). Functionally, YY1 promoted HCC tumourigenicity and inhibited apoptosis of HCC cells, at least partially through NF-κB activation. In conclusion, YY1 overexpression contributes to EZH2 recruitment for H3K27me3-mediated silencing of tumour-suppressive microRNAs, thereby activating NF-κB signalling in hepatocarcinogenesis.


Subject(s)
Carcinoma, Hepatocellular/metabolism , Gene Silencing , Liver Neoplasms/metabolism , MicroRNAs/metabolism , NF-kappa B/metabolism , YY1 Transcription Factor/metabolism , Animals , Apoptosis , Binding Sites , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Cell Line, Tumor , Cell Proliferation , DNA Methylation , Enhancer of Zeste Homolog 2 Protein , Gene Expression Regulation, Neoplastic , Histones/metabolism , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/virology , Lysine , Methylation , Mice, Nude , Mice, Transgenic , MicroRNAs/genetics , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Promoter Regions, Genetic , RNA Interference , Signal Transduction , Time Factors , Trans-Activators/genetics , Trans-Activators/metabolism , Transfection , Tumor Burden , Up-Regulation , Viral Regulatory and Accessory Proteins , YY1 Transcription Factor/genetics
6.
J Adv Nurs ; 70(11): 2673-82, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24684631

ABSTRACT

AIM: The study protocol is designed to evaluate the effects of granting independent authorization for medical procedures to nurse practitioners and physician assistants on processes and outcomes of health care. BACKGROUND: Recent (temporarily) enacted legislation in Dutch health care authorizes nurse practitioners and physician assistants to indicate and perform specified medical procedures, i.e. catheterization, cardioversion, defibrillation, endoscopy, injection, puncture, prescribing and simple surgical procedures, independently. Formerly, these procedures were exclusively reserved to physicians, dentists and midwives. DESIGN: A triangulation mixed method design is used to collect quantitative (surveys) and qualitative (interviews) data. METHODS: Outcomes are selected from evidence-based frameworks and models for assessing the impact of advanced nursing on quality of health care. Data are collected in various manners. Surveys are structured around the domains: (i) quality of care; (ii) costs; (iii) healthcare resource use; and (iv) patient centredness. Focus group and expert interviews aim to ascertain facilitators and barriers to the implementation process. Data are collected before the amendment of the law, 1 and 2·5 years thereafter. Groups of patients, nurse practitioners, physician assistants, supervising physicians and policy makers all participate in this national study. The study is supported by a grant from the Dutch Ministry of Health, Welfare and Sport in March 2011. Research Ethics Committee approval was obtained in July 2011. CONCLUSION: This study will provide information about the effects of granting independent authorization for medical procedures to nurse practitioners and physician assistants on processes and outcomes of health care. Study findings aim to support policy makers and other stakeholders in making related decisions. The study design enables a cross-national comparative analysis.


Subject(s)
Clinical Competence , Nurse Practitioners , Physician Assistants , Netherlands
7.
Pharm Biol ; 51(6): 798-805, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23675839

ABSTRACT

CONTEXT: Medicinal plants are a potential source of antidiabetic drugs. Terminalia bellerica Roxb. (Combretaceae) is used in Indian traditional systems of medicine to treat diabetes mellitus. OBJECTIVE: The aim of this study was to isolate and identify antihyperglycemic principle(s) from the fruits of T. bellerica and assess the bioactivity in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Bioassay-guided fractionation was followed to isolate the active compound(s), structure was elucidated using (1)H and (13)C NMR, IR and mass spectrometry and administered intragastrically to diabetic Wistar rats at different doses (5, 10 and 20 mg/kg, body weight) for 28 d. Plasma glucose, insulin, C-peptide and other biochemical parameters were studied. RESULTS: Octyl gallate (OG) isolated first time from the fruit rind of T. bellerica significantly (p < 0.05) reduced plasma glucose to near normal values (108.47 ± 6.9 mg/dl) after 14 d at the dose of 20 mg/kg. In addition, OG significantly increased plasma insulin, C-peptide, total protein, albumin, tissue glycogen, body weight and markedly decreased serum total cholesterol, triglyceride, LDL-cholesterol, urea, uric acid and creatinine in diabetic rats. Also OG restored the altered regulatory enzymes of carbohydrate metabolism. DISCUSSION AND CONCLUSION: OG might have augmented the secretion of insulin by the modulation of cAMP and intracellular calcium levels in the ß cells of the pancreas. Our findings indicate that OG isolated first time from the fruit rind of T. bellerica has potential antidiabetic effect as it augments insulin secretion and normalizes the altered biochemical parameters in experimental diabetic rat models.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Gallic Acid/analogs & derivatives , Hypoglycemic Agents/pharmacology , Terminalia/chemistry , Animals , Blood Glucose/drug effects , Calcium/metabolism , Cyclic AMP/metabolism , Diabetes Mellitus, Experimental/physiopathology , Dose-Response Relationship, Drug , Fruit , Gallic Acid/administration & dosage , Gallic Acid/isolation & purification , Gallic Acid/pharmacology , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/isolation & purification , India , Insulin/blood , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Male , Medicine, Ayurvedic , Rats , Rats, Wistar , Spectrum Analysis/methods , Streptozocin
9.
Sci China Life Sci ; 55(12): 1109-19, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23233226

ABSTRACT

In this work, the most detrimental missense mutations of aspartoacylase that cause Canavan's disease were identified computationally and the substrate binding efficiencies of those missense mutations were analyzed. Out of 30 missense mutations, I-Mutant 2.0, SIFT and PolyPhen programs identified 22 variants that were less stable, deleterious and damaging respectively. Subsequently, modeling of these 22 variants was performed to understand the change in their conformations with respect to the native aspartoacylase by computing their root mean squared deviation (RMSD). Furthermore, the native protein and the 22 mutants were docked with the substrate NAA (N-Acetyl-Aspartic acid) to explain the substrate binding efficiencies of those detrimental missense mutations. Among the 22 mutants, the docking studies identified that 15 mutants caused lower binding affinity for NAA than the native protein. Finally, normal mode analysis determined that the loss of binding affinity of these 15 mutants was caused by altered flexibility in the amino acids that bind to NAA compared with the native protein. Thus, the present study showed that the majority of the substrate-binding amino acids in those 15 mutants displayed loss of flexibility, which could be the theoretical explanation of decreased binding affinity between the mutant aspartoacylases and NAA.


Subject(s)
Amidohydrolases/genetics , Canavan Disease/genetics , Mutation, Missense , Amidohydrolases/chemistry , Canavan Disease/enzymology , Humans , Models, Molecular , Protein Conformation , Substrate Specificity
10.
Phytomedicine ; 19(10): 912-23, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22739413

ABSTRACT

PURPOSE: Diallyl Disulfide (DADS) is one of the major components of garlic, which inhibits the proliferation of various cancer cells. Our previous studies showed that DADS inhibits cell growth and induces apoptosis on prostate cancer cells. Insulin like growth factor signaling pathway plays a significant role on prostate cancer cell growth and survival and it's over expression also identified in human prostate cancers. The molecular mechanism of IGF mediated PI3K/Akt signaling remains to be elucidated. The present study was designed to evaluate the effects of diallyl disulfide on IGF signaling in androgen independent prostate cancer cells (PC-3). METHODS: DADS (10-50 µM) caused dose-dependent inhibition of PC-3 cells, were analyzed by MTT, IC50 value of PC-3 cells was 40 µM for 24h. Interestingly, DADS also altered the mRNA and protein expressions of IGF signaling and apoptotic molecules which were confirmed by semi quantitative PCR and western blot method. Further the docking study of DADS with IGF receptor was carried out by Ligand Fit of Discovery studio. Accord Excel Package was used for the prediction of ADME properties of the compound. RESULTS: The results suggests that DADS decreases the survival rate of androgen independent prostate cancer cells by modulating the expression of IGF system, which leads to inhibition of phosphorylation of Akt, thereby inhibits cell cycle progression and survival by lowering the expression of cyclin D1, NFkB and anti-apoptotic Bcl-2 molecule and increasing the level of pro-apoptotic (Bad and Bax) signaling molecules which leads to apoptosis. CONCLUSION: The present investigation showed downregulation of Akt and a concomitant increase in apoptosis in DADS treated prostate cancer cells. Since inhibition of this Akt pathway by DADS leads to inhibition in cancer cell progression, it is highly suggested that DADS has the potential use as a therapy for prostate cancer.


Subject(s)
Allyl Compounds/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis/drug effects , Disulfides/therapeutic use , Garlic/chemistry , Phytotherapy , Prostatic Neoplasms/drug therapy , Somatomedins/metabolism , Allyl Compounds/pharmacology , Androgens/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disulfides/pharmacology , Dose-Response Relationship, Drug , Humans , Inhibitory Concentration 50 , Male , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/metabolism , Signal Transduction/drug effects
11.
Int J Nanomedicine ; 7: 1189-202, 2012.
Article in English | MEDLINE | ID: mdl-22419867

ABSTRACT

Cassia fistula stem bark was used for the preparation of aqueous extract and synthesis of gold nanoparticles to evaluate the hypoglycemic effects of the plant. The synthesized gold nanoparticles were characterized by ultraviolet-visible spectroscopy for their absorbance pattern, Fourier transform infrared spectroscopy to identify possible functional groups, and scanning electron microscopy to determine the size of the nanoparticles. The present investigation reports the efficacy of the gold nanoparticles as promising in the treatment of hyperglycemia. Body weight, serum glucose concentrations, liver function tests, kidney function tests, and lipid profile were analyzed. A significantly larger decrease in serum biochemistry parameters and an increase in body weight, total protein levels, and high-density lipoprotein were observed in rats with streptozotocin-induced diabetes treated with gold nanoparticles than in the ones treated with the aqueous extract. The results of this study confirm that C. fistula gold nanoparticles have promising antidiabetic properties.


Subject(s)
Blood Glucose/drug effects , Cassia/chemistry , Gold/chemistry , Hypoglycemic Agents/pharmacology , Metal Nanoparticles/chemistry , Plant Extracts/pharmacology , Analysis of Variance , Animals , Body Weight/drug effects , Creatinine/blood , Diabetes Mellitus, Experimental , Drug Carriers/chemistry , Drug Carriers/pharmacology , Gold/pharmacology , Hemoglobins/metabolism , Hypoglycemic Agents/chemistry , Lipids/blood , Liver/chemistry , Liver/metabolism , Male , Plant Bark/chemistry , Plant Extracts/chemistry , Rats , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Urea/blood , Uric Acid/blood
12.
Indian J Pharm Sci ; 74(3): 217-22, 2012 May.
Article in English | MEDLINE | ID: mdl-23440996

ABSTRACT

Tuberculosis is a highly communicable and chronic respiratory disease caused by pathogenic bacterium Mycobacterium tuberculosis. The drug - resistant species of Mycobacterium tuberculosis are tough to cure due to its resistant activity toward potential drugs. Available inhibitors of tuberculosis include few antimicrobial fluoroquinolone agents like ciprofloxacin, ofloxacin, and moxifloxacin to treat resistant Mycobacterium strains. Literature study elucidates that macromolecular target namely, HtrA2 of Mycobacterium tuberculosis play a dual role of protease and chaperone. These two activities are dependent on temperature, with low temperatures promoting the chaperone function and high temperatures promoting serine protease activity. Under normal physiological conditions HtrA2 acts as a quality control factor and promotes cell survival. In the present investigation, we screened fluoroquinolone such as ciprofloxacin, moxifloxacin and ofloxacin and their analogues based on better Docking score, absorption, distribution, metabolism and excretion screening and Lipinski's rule of 5, to find out their efficiency on resistant strain through in silico study. From the results observed, the analogues are suggested to be potent inhibitors of HtrA2 with sufficient scope for further exploration.

13.
Dalton Trans ; 41(1): 267-77, 2012 Jan 07.
Article in English | MEDLINE | ID: mdl-22020558

ABSTRACT

A series of alkaline earth metallocene complexes carrying the diphenylphosphanocyclopentadienyl ligand, [Ae(L)(x)(η(5)-C(5)H(4)PPh(2))(2)] (Ae = Ca, L = thf, x = 1 (6a); Ae = Ca, L = dme, x = 1 (6b); Ae = Sr, L = thf, x = 1 (7); Ae = Ba, L = thf, x = 1 (8a); Ae = Ba, L = dme, x = 2 (8b)), were prepared by redox transmetallation/protolysis from the free metals, diphenylmercury and diphenylphosphanocyclopentadiene. These complexes were characterised using multinuclear NMR spectroscopy and two by single crystal X-ray diffraction. [Ca(dme)(η(5)-C(5)H(4)PPh(2))(2)] (6b) is a discrete neutral monomeric eight coordinate molecule in which the phosphorus atoms are not coordinated to the calcium ion and the larger barium analogue, ten-coordinate [Ba(dme)(2)(η(5)-C(5)H(4)PPh(2))(2)] (8b), has an extremely bent sandwich structure due to the two dme ligands attached to the metal. Bimetallic complexes, [Ae(thf)(x)(η(5)-C(5)H(4)PPh(2))(2)Pt(Me)(2)].(solv) (Ae = Ca, L = thf, x = 2, solv = 1.5thf (9); Ae = Sr, L = thf, x = 3, solv = 1.5thf (10); Ae = Ba, L = thf, x = 3, solv = thf (11)) were obtained by reaction of the homometallic complexes with [Pt(cod)(Me)(2)]. The crystal structures of [Ca(thf)(2)(η(5)-C(5)H(4)PPh(2))(2)Pt(Me)(2)].1.5thf (9), [Sr(thf)(3)(η(5)-C(5)H(4)PPh(2))(2)Pt(Me)(2)].1.5thf (10) and [Ba(thf)(3)(η(5)-C(5)H(4)PPh(2))(2)Pt(Me)(2)].thf (11) show the eight (calcium) and nine coordinate (strontium and barium) fragments acting as a chelating metalloligand attached to the square planar platinum through the phosphorus donor atoms. The solution chemistry of these bimetallic complexes has been investigated by NMR spectroscopy, electro-spray ionisation mass spectrometry and conductivity experiments which indicate that the bimetallic compounds persist in solution.

14.
J Clin Invest ; 121(8): 3159-75, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21747169

ABSTRACT

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling - cell cycle-related kinase (CCRK) - that drives hepatocarcinogenesis via a signaling pathway dependent on ß-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen-responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated ß-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active ß-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and ß-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of ß-catenin/TCF signaling.


Subject(s)
Cyclin-Dependent Kinases/physiology , Gene Expression Regulation , Liver Neoplasms/metabolism , Receptors, Androgen/metabolism , TCF Transcription Factors/metabolism , beta Catenin/metabolism , Aged , Animals , Binding Sites , Cell Cycle , Cyclin-Dependent Kinases/metabolism , Female , Genome-Wide Association Study , Humans , Male , Mice , Mice, Nude , Middle Aged , Neoplasm Transplantation , Signal Transduction , Transcription, Genetic , Cyclin-Dependent Kinase-Activating Kinase
15.
Pharm Res ; 28(10): 2477-89, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21614634

ABSTRACT

PURPOSE: Stromal-derived factor-1 alpha (SDF-1α) is a chemoattractant that has been investigated for treating various diseases, with the goal of recruiting endogenous stem cells to the site of injury. Biodegradable PLGA microspheres were investigated as a means to deliver SDF-1α in a sustained-release manner. METHODS: We encapsulated SDF-1α into biodegradable poly(lactide-co-glycolide) (PLGA) microspheres using a double-emulsion solvent extraction/evaporation technique. We varied several formulation parameters, characterized the in vitro release profile of SDF-1α and the size and morphology of microspheres, and determined the bioactivity of the released SDF-1α of stimulating migration of mesenchymal stem cells (MSCs). RESULTS: We found that microspheres fabricated using end-capped PLGA, BSA as an excipient, and low solvent volumes yielded a high encapsulation efficiency (>64%) and released SDF-1α over a >50-day timeframe. The released SDF-1α was bioactive and caused significant migration of MSCs throughout the duration of release from the microspheres. CONCLUSIONS: We have identified several variables that led to successful encapsulation of SDF-1α into PLGA microspheres. We envision that SDF-lα-loaded microspheres may serve as injectable sources of sustained-release chemokine for promoting the recruitment of endogenous stem cells to the site of injury.


Subject(s)
Chemokine CXCL12/chemistry , Lactic Acid/chemistry , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Microspheres , Polyglycolic Acid/chemistry , Animals , Chemokine CXCL12/metabolism , Chemokines/metabolism , Delayed-Action Preparations , Emulsions/chemistry , Excipients/chemistry , Mice , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/chemistry , Solvents/chemistry , Wound Healing/drug effects
16.
J Gastroenterol Hepatol ; 26(1): 19-27, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21175789

ABSTRACT

EZH2 is the histone H3 lysine 27 methyltransferase of polycomb-repressive complex 2. It transcriptionally silences cohorts of developmental regulators in stem/progenitors and cancer cells. EZH2 is essential in maintaining stem cell identity by globally repressing differentiation programs. Analogously, it plays a key role in oncogenesis by targeting signaling molecules that control cell differentiation. Emerging data indicate that EZH2 promotes cancer formation and progression through epigenetic activation of oncogenic signaling cascades and inhibition of pro-differentiation pathways. Genome-wide mapping analysis has been expanding the repertoire of target genes and the associated signaling pathways regulated by EZH2. Better understanding of the molecular basis of such regulations in various cancer types will help establish EZH2-mediated epigenetic silencing as a therapeutic target.


Subject(s)
DNA-Binding Proteins/genetics , Epigenesis, Genetic , Neoplasms/genetics , Signal Transduction/genetics , Transcription Factors/genetics , Animals , Cell Differentiation/genetics , DNA Methylation , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolism , DNA-Binding Proteins/metabolism , Enhancer of Zeste Homolog 2 Protein , Epigenesis, Genetic/drug effects , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Genotype , Humans , Neoplasms/enzymology , Neoplasms/pathology , Neoplasms/therapy , Phenotype , Polycomb Repressive Complex 2 , Prognosis , Signal Transduction/drug effects , Transcription Factors/metabolism
17.
Chem Biol Interact ; 189(1-2): 112-8, 2011 Jan 15.
Article in English | MEDLINE | ID: mdl-21078310

ABSTRACT

Diabetes mellitus causes derangement of carbohydrate, protein and lipid metabolism which eventually leads to a number of secondary complications. Terminalia bellerica is widely used in Indian medicine to treat various diseases including diabetes. The present study was carried out to isolate and identify the putative antidiabetic compound from the fruit rind of T. bellerica and assess its chemico-biological interaction in experimental diabetic rat models. Bioassay guided fractionation was followed to isolate the active compound, structure was elucidated using (1)H and (13)C NMR, IR, UV and mass spectrometry and the compound was identified as gallic acid (GA). GA isolated from T. bellerica and synthetic GA was administered to streptozotocin (STZ)-induced diabetic male Wistar rats at different doses for 28 days. Plasma glucose level was significantly (p<0.05) reduced in a dose-dependent manner when compared to the control.Histopathological examination of the pancreatic sections showed regeneration of ß-cells of islets of GA-treated rats when compared to untreated diabetic rats. In addition, oral administration of GA (20mg/kg bw) significantly decreased serum total cholesterol, triglyceride, LDL-cholesterol, urea, uric acid, creatinine and at the same time markedly increased plasma insulin, C-peptide and glucose tolerance level. Also GA restored the total protein, albumin and body weight of diabetic rats to near normal. Thus our findings indicate that gallic acid present in fruit rind of T. bellerica is the active principle responsible for the regeneration of ß-cells and normalizing all the biochemical parameters related to the patho-biochemistry of diabetes mellitus and hence it could be used as a potent antidiabetic agent.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Gallic Acid/pharmacology , Phytotherapy/methods , Terminalia/chemistry , Animals , Blood Glucose/metabolism , Blood Proteins/analysis , C-Peptide/blood , Cholesterol/blood , Creatinine/blood , Diabetes Mellitus, Experimental/metabolism , Fruit/chemistry , Gallic Acid/isolation & purification , Histocytochemistry , Insulin/blood , Liver/metabolism , Male , Mass Spectrometry , Nuclear Magnetic Resonance, Biomolecular , Pancreas/metabolism , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Rats , Rats, Wistar , Spectrophotometry, Infrared , Urea/blood , Uric Acid/blood
18.
Chem Biol Interact ; 188(3): 467-72, 2010 Dec 05.
Article in English | MEDLINE | ID: mdl-20709041

ABSTRACT

Antioxidant properties of many medicinal plants have been widely recognized and some of them have been commercially exploited. Plant derived antioxidants play a very important role in alleviating problems related to oxidative stress. The present study was aimed at assessing the antioxidant property of costunolide and eremanthin isolated from a medicinal plant Costus speciosus (Koen ex. Retz) Sm. rhizome. Experimental diabetes was induced by a single dose of STZ (60mg/kg, i.p.) injection. The oxidative stress was measured by tissue thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) content and enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in brain, liver, heart, kidney and pancreas. An increase in TBARS level, a significant reduction in GSH content along with decreased enzymatic activities of SOD, CAT, and GPx were seen in untreated diabetic rats. Administration of either costunolide (20mg/kg day) or eremanthin (20mg/kg day) for 60 days caused a significant reduction in TBARS level and a significant increase in GSH content along with increased enzymatic activities of SOD, CAT and GPx in the treated rats when compared to untreated diabetic rats. Acute toxicity test revealed the non-toxic nature of the compounds. The results indicated for the first time the protective effect of costunolide and eremanthin from oxidative stress, thus opening the way for their use in medication.


Subject(s)
Antioxidants/isolation & purification , Antioxidants/pharmacology , Costus/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Animals , Antioxidants/toxicity , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Experimental/metabolism , Glucose Tolerance Test , Glutathione/metabolism , Male , Oxidative Stress/drug effects , Rats , Rats, Wistar , Sesquiterpenes/toxicity , Thiobarbituric Acid Reactive Substances/metabolism , Toxicity Tests, Acute
19.
Pharm Biol ; 48(4): 405-10, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20645718

ABSTRACT

Seeds of Eugenia jambolana Lam. (Myrtaceae) are used by many tribes in India to treat diarrhea and dysentery. The crude extracts of seeds of this plant demonstrated zones of inhibition in the range of 14- 21 mm against the isolated beta-lactamase-producing drug-resistant bacteria. The methanol extract showed promising antibacterial activity which was subjected to fractionation. The effective fraction (F2) showed a minimum inhibitory concentration (MIC) ranging from 31.75 to 62.5 microg/mL. Phytochemical analysis and thin layer chromatography of the most promising fraction showed the presence of saponin as the active phytoconstituent. The active fraction was further tested for its in vitro hemolytic activity in sheep and human erythrocytes and no hemolysis was seen. Thus, the use of this plant by tribals to treat bacterial infections has some scientific basis.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Gram-Negative Bacteria/drug effects , Medicine, Traditional/methods , Plant Extracts/pharmacology , Syzygium/chemistry , Animals , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/toxicity , Cells, Cultured , Erythrocytes/drug effects , Gram-Negative Bacteria/growth & development , Hemolysis/drug effects , India , Microbial Sensitivity Tests , Plant Extracts/isolation & purification , Plant Extracts/toxicity , Seeds/chemistry , Sheep/blood
20.
Rev. habanera cienc. méd ; 9(1)ene.-mar. 2010. tab
Article in Spanish | CUMED | ID: cum-43540

ABSTRACT

Se aplicó un instrumento evaluativo de las esencialidades de la asignatura Microbiología y Parasitología Médicas (Agentes biológicos), en forma de encuesta anónima, a los estudiantes de Medicina de la Facultad General Calixto García, quienes cursaron la asignatura en el 4to Semestre del curso 2003-2004, en varios Cortes: I antes de Propedéutica, al iniciar el 5to Semestre; II después de Medicina Interna, al finalizar el 6to Semestre; III después de Pediatría, al finalizar el 8vo Semestre y IV después de MGI II, en el Internado, para conocer si el futuro Médico General Básico (MGB), se había apropiado de esos conocimientos en la asignatura y valorar su consolidación en el Área Clínica. Los alumnos no demostraron el conocimiento esperado de los agentes causales de enfermedades infecciosas frecuentes en la población, no hubo retención de los objetivos instructivos de la asignatura y en el área clínica no se logró la consolidación de dichos objetivos(AU)


An assessment instrument for the main objectives of the subjects Medical Microbiology and Parasitology (Biological Agents) was applied, as an anonymous survey, to 4th semester Medical Students from General Calixto Garcia Medical School in the school term 2003_2004. It was applied at four different times: I) Before Propedeutics, at the beginning of their 5th semester; II) After Internal Medicine, at the end of their 6th semester; III) After Pediatrics at the end of their 8th semester and IV) After Family Medicine II, during their 11th and 12th semester, to find out if the future General Practitioner has acquired the main knowledge of the subject and to assess its consolidation in the Clinical Area.The students did not know what was expected about the agents that cause frequent infectious diseases in our population; they had no retention of the subject's instructive goals nor was the consolidation of these goals achieved in the clinical area(AU)


Subject(s)
Teaching , Data Collection , Students, Medical , Microbiology
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