Quercetin inhibits fibronectin production by keloid-derived fibroblasts. Implication for the treatment of excessive scars.
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Antioxidants↗
Biomedical subjects
S Y Chan
Publications and source records attributed to S Y Chan.
Suppression of insulin-like growth factor signalling pathway and collagen expression in keloid-derived fibroblasts by quercetin: its therapeutic potential use in the treatment and/or prevention of keloids.
BACKGROUND: Keloids are characterized by abnormal proliferation of fibroblasts and overproduction of collagen. Insulin-like growth factor (IGF)-I is mitogenic for fibroblasts and a stimulatory factor for collagen synthesis. OBJECTIVES: We have assessed the in vitro effects of quercetin on proliferation, collagen synthesis and the expression of the IGF system in keloid-derived fibroblasts. METHODS: Fibroblasts were isolated from earlobe keloids and exposed to quercetin at different concentrations. The inhibitory effects of quercetin on fibroblast proliferation were assayed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Western and Northern blot analyses. RESULTS: Quercetin inhibited keloid fibroblast (KF) proliferation in a dose-dependent manner. Significant growth inhibition was observed on day 2 of culture. The dose required for 50% growth inhibition was approximately 25 microg mL-1. Collagen 1 expression was significantly decreased while collagen 3 was almost undetectable following quercetin treatment. Basal levels of IGF-I receptor (IGF-IR) beta subunits, p85 subunit of phosphatidylinositol 3-kinase, c-Raf, phospho-Raf-1, phospho-MEK 1/2, phospho-mitogen-activated protein kinase, phospho-Elk-1 and phospho-Akt-1 were significantly reduced when KF cells were exposed to quercetin for 24 h. Blocking IGF-IR activity with IGF-IR antibody or neutralizing endogenous IGF-I activity with IGF-I antibody led to significant growth inhibition suggesting the role of IGF-I in regulation of KF proliferation. CONCLUSIONS: Because the IGF system plays an important part in fibroblast cell proliferation and collagen production, the described activities of quercetin on the IGF system and collagen expression may provide a novel approach for the use of quercetin in treatment and/or prevention of hypertrophic scar and keloid.
Blotting, Northern↗
A potential role for PTTG/securin in the developing human fetal brain.
Human securin, known also as PTTG, has established oncogenic and cell cycle regulatory functions. PTTG/securin transforms cells in vitro, inhibits sister chromatid separation, and regulates secretion of fibroblast growth factor-2. FGF-2 is a key regulator of CNS development and PTTG/securin expression has been reported in murine fetal brain. We examined the expression and function of securin and FGF-2 in the developing human fetal brain and in a fetal neuronal cell line (NT 2). Securin expression was significantly reduced in first and second trimester fetal cerebral cortex compared with adult cerebral cortex, where immunocytochemistry revealed intense securin staining in neuronal cell bodies. FGF-2 protein was concordantly lower in fetal cortex, whereas pretranslational expression of PTTG binding factor (PBF) was not significantly altered in fetal brain compared with adult. PCNA expression demonstrated that high securin levels in adult cortex were associated with absent cell proliferation. In NT-2 cells, securin stimulated FGF-2 expression, which could be abrogated by a carboxyl-terminal mutation. Low transient expression of securin resulted in a significant proliferative effect, whereas high levels of securin expression inhibited cell turnover. We propose a potential role for human PTTG/securin in modulating cell proliferation and FGF-2 expression during human neurogenesis.
Brain↗
Cholestatic jaundice and pseudomembranous colitis following combination therapy with doxorubicin and docetaxel.
We report a case of cholestatic jaundice and pseudomembranous colitis (PMC) following combination therapy with docetaxel and doxorubicin. This clinical syndrome has not been previously reported with this combination. In particular, this is the first report of non-Clostridium difficile-associated PMC with docetaxel-based chemotherapy. Docetaxel is principally metabolized by the hepatic cytochrome p450 mixed-function oxidases, in particular by the isoform CYP3A. This patient was on long-term erythromycin prophylaxis following splenectomy. Erythromycin is a known inhibitor of CYP3A. We postulate that erythromycin probably contributed to the observed clinical syndrome. Clinicians should be aware of potential drug interactions, when unusual toxicities occur with novel combinations of chemotherapeutic agents.
Antineoplastic Combined Chemotherapy Protocols↗
Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes.
Carvacrol, linalool and alpha-terpineol (5% w/v) in 50% ethanol were used to enhance the permeation of haloperidol (HP) through human skin in vitro and their enhancement mechanism was investigated with HP-stratum corneum (SC) binding studies, fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Carvacrol followed by terpineol and linalool enhanced flux and permeability coefficient but only carvacrol provided the required plasma concentration and the permeated daily doses. All terpenes increased the activity coefficient of HP in the skin. Carvacrol increased the lag time, which could be due to slow redistribution within SC. The thermogram of hydrated SC showed two lipid endotherms T1 and T2 at 65 and 78 degrees C and protein endotherm T3 at 97 degrees C. All endotherms were absent after SC treated for 48 h with 12 ml of terpene solutions and a decrease in melting points (m.p.) of lipids with a shift of protein endotherm were observed after 12 h treatment with 7 ml of terpene solutions. Linalool and terpineol decreased the m.p. of T1 to 33 degrees C. Carvacrol increased the T1 peak area, which was attributed to lateral lipid bilayer swelling. The IR spectra showed decreases in peak areas and heights of CH2 stretchings but did not show shift of these peaks, increase in their peak widths and shift in amide bands. All the three terpenes disrupted the lipid bilayer and extracted the lipids. Moreover, carvacrol increased the partition of HP whilst linalool and terpineol fluidized the lipids at skin temperature. There could be other possible protein-terpene interactions.
Antipsychotic Agents↗
Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry.
The respective alcoholic terpenes carvacrol, linalool, and alpha-terpineol were used at 5% w/v in propylene glycol (PG) to increase the in vitro permeation of haloperidol (HP) through human skin. The possible enhancement mechanism was then elucidated with HP-stratum corneum (SC) binding studies, Fourier transform infrared spectroscopy, and differential scanning calorimetry. The greatest increase in the permeation of HP was achieved with linalool followed by carvacrol and terpineol. HP permeation with linalool was predicted to reach a therapeutic plasma concentration and therapeutic daily-permeated amounts. Carvacrol increased lag time, which was attributed to slow redistribution of the enhancer within SC. Carvacrol increased the partition of the drug to the pulverized SC. Pure PG extracted lipids from SC but less than that achieved by the terpenes in PG. Terpenes extracted lipids to a similar extent. An increase in bilayer cohesion in the remaining lipids present in the SC could be attributed to the alignment of terpenes within the lipid bilayer. The higher permeation with linalool was attributed to its molecular orientation within the lipid bilayer. Terpenes showed different rates of SC dehydration but did not change the percentages of secondary structures of keratin.
Calorimetry, Differential Scanning↗
A ubiquitin-like peptide from the mushroom Pleurotus sajor-caju exhibits relatively potent translation-inhibitory and ribonuclease activities.
The fruiting bodies of the edible mushroom Pleurotus sajor-caju were extracted with an aqueous buffer and then subjected to affinity chromatography on Affi-gel Blue gel, ion exchange chromatography on DEAE-cellulose and gel filtration on Superdex 75. From the fraction of the extract adsorbed on Affi-gel Blue gel and unadsorbed on DEAE-cellulose, a 9.5 kDa peptide with an N-terminal sequence similar to ubiquitin was isolated with a yield of 0.25 mg/kg mushroom. The peptide inhibited cell-free translation with an IC(50) of 30 nM. It exhibited a ribonuclease activity of 450 U/mg toward yeast transfer RNA. The activities were substantially more potent than those of previously isolated mushroom ubiquitin-like protein and peptide.
Fungal Proteins↗
Subdural block--from a spinal? A case report.
INTRODUCTION: Multicompartmental blocks are commonly described in epidurals but not spinals. We describe a case of subarachnoid block performed in an obese patient which resulted in a clinical presentation resembling that of a subdural block. CLINICAL PICTURE: A 29-year-old woman, scheduled for saucerisation of thigh carbuncle, was administered 2.1 mL of hyperbaric bupivacaine. The spinal resulted in a late onset of sensory block that extended to the neck and upper limbs. There was no sympathetic or motor blockade. TREATMENT/OUTCOME: The block receded spontaneously without causing any cardiovascular or respiratory compromise. CONCLUSIONS: The diagnosis of subdural block must be considered in patients with unusual presentations after a spinal anaesthetic. Factors affecting spread of hyperbaric bupivacaine are also highlighted.
Adult↗
Folate receptor-alpha is a cofactor for cellular entry by Marburg and Ebola viruses.
Human infections by Marburg (MBG) and Ebola (EBO) viruses result in lethal hemorrhagic fever. To identify cellular entry factors employed by MBG virus, noninfectible cells transduced with an expression library were challenged with a selectable pseudotype virus packaged by MBG glycoproteins (GP). A cDNA encoding the folate receptor-alpha (FR-alpha) was recovered from cells exhibiting reconstitution of viral entry. A FR-alpha cDNA was recovered in a similar strategy employing EBO pseudotypes. FR-alpha expression in Jurkat cells facilitated MBG or EBO entry, and FR-blocking reagents inhibited infection by MBG or EBO. Finally, FR-alpha bound cells expressing MBG or EBO GP and mediated syncytia formation triggered by MBG GP. Thus, FR-alpha is a significant cofactor for cellular entry for MBG and EBO viruses.
Animals↗
High frequency of promoter hypermethylation of RASSF1A in nasopharyngeal carcinoma.
We have investigated the genetic and epigenetic changes of a newly isolated tumor suppressor gene on 3p21.3, RASSF1A, in nasopharyngeal carcinoma (NPC). Four xenografts, four cell lines and 21 primary tumors were examined. Promoter hypermethylation of the 5'CpG island of RASSF1A was detected in 4 of 4 (100%) xenografts, in 3 of 4 (75%) cell lines, and in 14 of 21 (66.7%) primary tumors but not in the normal nasopharyngeal epithelia. Mutations were found in 2 of 21 (9.5%) primary tumors. In the cell lines and xenografts with extensive methylation, no RASSF1A gene expression was found. After treatment with 5'-aza-2'deoxycytidine, reexpression and demethylation of the RASSF1A gene were detected in a NPC cell line. These findings suggest that promoter hypermethylation may participate in the transcriptional inactivation of the RASSF1A gene in NPC. The high incidence of RASSF1A alterations suggest that it is the critical target gene on chromosome 3p21.3 involved in the development of NPC.
Chromosomes, Human, Pair 3↗
Hospital care by hospital-based and clinic-based faculty: a prospective, controlled trial.
BACKGROUND: The hospital length of stay decreases and clinical outcomes are maintained when teaching hospitals involve hospital-based attending physicians in comparison with traditional attending physicians. The attending physician's time commitment, including the number of hours per day and months per year, required to achieve this result is unknown. This study compared the clinical outcomes and cost of care for patients treated by hospital-based and clinic-based attending physicians devoting dramatically different amounts of time to supervising residents on the medical wards of a suburban county hospital. METHODS: Patients were alternately admitted to 2 groups of ward teams. Faculty who attended 10 months of the year supervised one group. The comparison group's attending physicians were on service for 2 months or less and maintained clinic responsibilities while on service. The cost of patient care was compared by means of the length of stay, total hospital costs, and costs for ancillary services. Hospital mortality and readmission rates compared clinical outcomes. RESULTS: There were 4456 patients hospitalized on the medical wards of a teaching service. No differences were detected in the length of stay (4.37 +/- 0.1 days for hospital-based and 4.39 +/- 0.1 days for clinic-based attending physicians). Hospital cost was observed to be similar (average cost, $5989 and $5977 per patient, respectively). The clinical outcomes were equivalent, with adjusted mortality rates for hospital-based attending physicians of 3.2% vs 3.9% for clinic-based attending physicians (P =.28). CONCLUSION: An increase of faculty time and involvement for supervision of resident-managed hospital care did not improve clinical outcomes or decrease costs during the 1-year study period.
Faculty, Medical↗
Effect of some enhancers on the permeation of haloperidol through rat skin in vitro.
The objective of this work is to enhance the permeation of haloperidol through the rat skin in vitro by using various enhancers at a concentration of 1 mg/ml in the saturated drug solution and analysing the dose-dependent diffusion profile for the enhancers which significantly increased permeation at this concentration compared with the control. Enhancers belonging to various chemical classes like the vitamins (ascorbic acid), surfactants (cetrimide, polysorbate 20), sulfoxides (dimethyl sulfoxide), glycols (polyethylene glycol 400, propylene glycol) and amides (urea) were used. Amber glass Franz-type diffusion cells were used for the permeation studies and haloperidol was made soluble in aqueous solution with the aid of lactic acid. Ascorbic acid and cetrimide increased flux and permeability coefficient significantly. From the dose-dependent permeation studies, it was concluded that ascorbic acid enhanced the permeation by increasing the solubility of the drug in the vehicle thus providing a high concentration gradient across the skin, whereas cetrimide enhanced the permeation by increasing the thermodynamic activity which may be due to solubilization of skin lipids by micelles. Polysorbate 20 decreased the enhancer index by decreasing the thermodynamic activity. None of the enhancers changed the lag time except for urea which decreased the lag time probably by its binding with keratin. Dimethyl sulfoxide, polyethylene glycol 400 and propylene glycol did not have a significant effect on haloperidol permeation compared with control.
Animals↗
Pharmacokinetic study of all-trans-retinoyl-beta-D-glucuronide in Sprague-Dawley rats after single and multiple intravenous administration(s).
All-trans-retinoyl-beta-D-glucuronide (RAG) is an endogenous active metabolite of all-trans-retinoic acid (ATRA). In the present study, the pharmacokinetics of RAG was examined after the administration of a single intravenous does (5, 10, or 15 micromol/kg) and of multiple daily intravenous doses (5 micromol/kg) to rats for 8 days. The plasma concentrations of RAG and ATRA were measured by a reverse-phase HPLC method. A rapid distribution phase of approximately 1 h was observed in all of the rats after single or multiple doses. Thereafter, RAG was eliminated through a first-order process, in accord with a typical two-compartment first order pharmacokinetic profile. After single intravenous doses, the AUC of RAG increased proportionally with the dose and the clearance remained unchanged within the tested doses. There was no statistical significant difference in distribution rate constants from central compartment to peripheral compartment (K(12)) and from peripheral compartment to central compartment (K(21)) between different doses. However, as the dose increased from 5 micromol/kg to 10 micromol/kg, the volume of distribution at the steady state (V(ss)) and the volume of peripheral compartment (V(p)) decreased significantly (p < 0.05) from 1.290 +/- 0.269, 0.928 +/- 0.232. L/kg to 0.961 +/- 0.149, 0.647 +/- 0.107 L/kg, respectively. V(ss) and V(p) at a dose of 15 micromol/kg (0.924 +/- 0.187, 0.698 +/- 0.165 L/kg) were not significantly different from that at 10 micromol/kg. Thus, RAG might saturate the tissue-binding sites at higher doses. ATRA was detected as a metabolite of RAG at low levels (usually < 0.05 microM) only in the first 2 h after intravenous administration. RAG clearly was not extensively hydrolyzed to ATRA in our study. After multiple daily intravenous administration of RAG, the clearance (Cl) and the elimination rate constant (K(10)) remained unchanged (p > 0.05), indicating that long-term daily administration of RAG did not induce its accelerated metabolism. However, K(12), V(p), and V(ss) declined significantly (p < 0.05) from 1.67 +/- 0.54 h(-1), 0.928 +/- 0.232 L/kg, and 1.290 +/- 0.269 L/kg to 0.96 +/- 0.48 h(-1), 0.494 +/- 0.147 L/kg, and 0.818 +/- 0.187 L/kg, respectively. Therefore, long-term daily dosing of RAG seemed to decrease its distribution profile. Although the AUC of RAG did not change significantly after multiple dosing, the AUC of ATRA after RAG dosing significantly declined (p < 0.05) from 0.032 +/- 0.019 microM x h to 0.010 +/- 0.006 microM x h. The decline in the AUC of ATRA might reflect an increase in its uptake by tissue and/or in its metabolism. Because enhanced clearance is not associated with RAG after multiple administrations, RAG could be considered as an alternate to ATRA in appropriate clinical applications.
Animals↗
Locally advanced primary breast cancer: medium-term results of a randomised trial of multimodal therapy versus initial hormone therapy.
We report the medium-term (median follow-up=52 months) results of a prospective randomised trial of multimodal therapy (neoadjuvant chemotherapy, Patey mastectomy, postoperative radiotherapy and adjuvant hormone therapy) (n=56) versus initial hormone therapy (n=52) for locally advanced primary breast cancer. Compared with multimodal therapy, initial hormone therapy was associated with reduced number of therapies for disease control (mean=3.6 versus 4.9) and mastectomy rate (31%). Multimodal therapy conferred better initial locoregional control and a longer disease-free interval. Nevertheless, there was no statistically significant differences in the rates of survival, metastasis and uncontrolled locoregional disease, as well as in the time to metastasis between the two therapy groups. Regardless of the therapy groups, oestrogen receptor positivity conferred a lower metastasis rate, better survival and locoregional control. Thus, initial hormone therapy may be a reasonable option for managing locally advanced primary breast cancer, especially for oestrogen receptor-positive tumours.
Adult↗
Epidermal growth factor receptor: a transcription factor?
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Animals↗
Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study.
TEL/AML1 gene fusion that results from a cryptic t(12;21) is the most common genetic aberration in childhood B-lineage acute lymphoblastic leukemia (ALL). While the translocation may initiate the leukemic process, critical secondary genetic events are currently believed to be pivotal for leukemogenesis. We investigated 12 cases of childhood ALL with TEL/AML1 gene fusion by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) and documented additional or secondary genetic changes in seven patients (58%). Three patients showed extra copies of chromosome 21 including a case in which the trisomy 21 (+21) clone was distinct from the one harboring TEL/AML1 gene fusion. Interestingly, one patient without +21 showed amplification of the AML1 gene on chromosome 21q, supporting the contention that AML1 amplification may be an important additional genetic event. Gene expression study by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) in two of these four patients showed an increase in AML1 transcripts that paralleled the increase in gene copy number. Deletion of the normal TEL allele was detected in two patients, with one of them showing loss of chromosome 12 together with duplication of the der(12)t(12;21). Finally, one patient showed duplication of the fusion signal. Our findings confirm that additional or secondary genetic changes including AML1 amplification are commonly encountered in childhood ALL with TEL/AML1 gene fusion, which are envisaged to play significant roles in disease progression.
Adolescent↗
No association between human herpesvirus 8 and arsenical skin cancers.
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Arsenicals↗
Imaging of metastatic breast cancer: distribution and radiological assessment at presentation.
This prospective study was performed to document the distribution of sites of disease in breast cancer patients with newly diagnosed metastatic disease, and to identify those with assessable or measurable disease by International Union Against Cancer (UICC) criteria. Data were collected on a consecutive series of 100 patients presenting with metastatic breast cancer. Imaging findings recorded included whether patients had assessable or measurable disease and which potentially assessable sites were rendered unassessable by radiotherapy. Radiologically diagnosable complications were recorded. Skeletal metastases comprised the majority, with 67 patients having skeletal involvement, although of these only 33 (49%) had assessable disease and 24 (36%) measurable disease. Sixteen (24%) patients had radiographically occult metastases. Liver ultrasound examination showed metastatic disease in 32 patients, of whom 28 (88%) had measurable lesions and 12% diffuse disease. Chest radiographs demonstrated metastatic disease in 42 patients, with assessable disease in 39 (93%) and measurable disease in 18 (43%). In total, 80 patients had radiologically assessable disease, with five rendered unassessable by the administration of radiotherapy to the only assessable site. Therefore, of the 100 patients, 75% (95% confidence interval (CI) 65-83) had radiologically assessable disease, with 55% (95% 45-65 CI) having measurable lesions by UICC criteria.
Adult↗