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PubMed2005

Histone H4 lysine 91 acetylation a core domain modification associated with chromatin assembly.

The acetylation of the NH2-terminal tail of histone H4 by type B histone acetyltransferases (HATs) is involved in the process of chromatin assembly. Histone H4 associated with a nuclear type B HAT complex contains modifications in its globular core domain as well. In particular, acetylation was found at lysine 91. A mutation that alters this residue, which lies in the interface between histone H3/H4 tetramers and H2A/H2B dimers, confers phenotypes consistent with defects in chromatin assembly such as sensitivity to DNA damaging agents and derepression and alteration of silent chromatin structure. In addition, this mutation destabilizes the histone octamer, leading to defects in chromatin structure. These results indicate an important role for histone modifications outside the NH2-tail domains in the processes of chromatin assembly, DNA repair, and transcriptional silencing.

Acetylation↗

PubMed2006

Long-term clinical evaluation in patients with Parkinson's disease and early autonomic involvement.

OBJECTIVE: To evaluate in a prospective longitudinal study the evolution of functional disability and the response to dopaminergic therapy in PD patients with and without autonomic involvement. METHODS: Sixty untreated consecutive patients with PD underwent autonomic cardiovascular function evaluation using the five autonomic tests of Ewing. An integrated index (Autonomic Score=AS), taking in account the results of all subtests, was calculated. Patients were treated with pergolide and bromocriptine during a 5-year follow-up until the level of functional disability was sufficient to warrant the initiation of levodopa therapy. RESULTS: Results of autonomic testing were compared with those of a group of age-matched healthy subjects. A value of AS>2 was considered as indicative of autonomic failure. Eighteen patients with PD (35%) showed AS>2 (autonomically impaired group=AI), the remaining 33 (65%) had AS<2 (nonautonomically impaired group=non-AI). During the follow-up levodopa was added to the treatment regimen of 10/18 (55%) patients in AI group, and 6/33 (18%) patients in non-AI group (p<.01). CONCLUSIONS: The increased occurrence of levodopa adjunct in autonomically impaired PD suggests that there is a more rapid deterioration of functional performance in parkinsonian patients with early autonomic involvement.

Aged↗

PubMed1997

Salicylate and quinine affect the central nervous system.

Spontaneous local field potential (LFP) spindle frequencies in cat primary auditory cortex (AI) were estimated from the LFP-trigger autocorrelogram before and after application of sodium salicylate and quinine sulfate. A significant decrease (from 8.7 Hz to 7.6 Hz) was observed. The best modulation frequencies for 251 single units recorded in AI response to periodic click train stimulation also decreased (from 10 Hz to 8.6 Hz) after application of these tinnitus-inducing drugs. The results strongly suggest a central effect of salicylates and quinine in addition to their peripheral ototoxic effects.

Acoustic Stimulation↗

PubMed2004

Expression of caspase-3 and structural changes associated with apoptotic cell death of keratinocytes in oral lichen planus.

OBJECTIVE: Apoptosis appears to be the mode of cell death by which damaged cells are removed from the lesional tissue. The aim of this study was to examine keratinocyte apoptosis and caspase-3 (CPP32) expression in oral lichen planus (OLP). MATERIALS AND METHODS: Paraffin-embedded samples of OLP (n = 30) and normal oral mucosa (NOM; n = 5) were prepared for haematoxylin-eosin (H & E), immunohistochemistry and electron microscopy. The number of apoptotic cells and the proportion of total cells that were either apoptotic (apoptotic index; AI) or mitotic (mitotic index; MI) were assessed in H & E stained sections. An immunostaining-intensity-distribution index (IIDI; proportion of stained cells x staining intensity) was used to assess CPP32 immunoreactivity. RESULTS: Results showed a significant increase in the number of apoptotic cells in OLP (P < 0.001). In OLP, all apoptotic bodies were found in the basal and prickle epithelial layers. Compared with NOM, the AI was significantly greater in atrophic (P < 0.05), reticular (P < 0.001) and plaque-like (P < 0.01) OLP. The MI was significantly greater in plaque-like OLP (P < 0.01). The proportion of CPP32-positive cells and the IIDI were significantly greater in all forms of OLP compared with NOM (P < 0.05). No difference in CPP32 expression was evident between clinical forms of OLP. Electron microscopy confirmed the light microscopic finding of apoptosis. CONCLUSION: Keratinocyte apoptosis and caspase-3 expression co-localized to the basal and parabasal epithelial layers, suggesting that proliferating epithelial cells may be targeted for destruction in OLP. Differences in epithelial AI and MI may underlie the various clinical and histological appearances of OLP.

Adult↗

PubMed2006

Proteomic analysis on the alteration of protein expression in the placental villous tissue of early pregnancy loss.

Early pregnancy loss is the most common complication of human reproduction. Given the complexities of early development, it is likely that many mechanisms are involved. Knowledge of differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying early pregnancy loss. To identify proteins with different expression profiles related to early pregnancy loss, we applied a proteomic approach and performed two-dimensional gel electrophoresis (2-DE) on six placental villous tissues from patients with early pregnancy loss and six from normal pregnant women, followed by comparison of the silver-stained 2-DE profiles. It was found that 13 proteins were downregulated and 5 proteins were upregulated significantly (P < 0.05) in early pregnancy loss as determined by spot volume. Among them, 10 downregulated and 2 upregulated spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Anomalies of these proteins, including three principal antioxidant enzymes (copper/zinc-superoxide dismutase, peroxiredoxin 3, and thioredoxin-like 1 protein), S100 calcium binding protein, galectin-1, chorionic somatomammotropin hormone 1, transthyretin, fas inhibitory molecule, eukaryotic translation elongation factor, RNA-binding protein, ubiquitin-conjugating enzyme E2N, and proteasome beta-subunit, indicate widespread failure in cell regulations and processes such as antioxidative defense, differentiation, cell proliferation, metabolism, apoptosis, transcription, and proteolysis in early pregnancy loss. This study has identified several proteins that are associated with placentation and early development, shedding a new insight into the proteins that may be potentially involved in the pathophysiological mechanisms underlying early pregnancy loss.

Abortion, Spontaneous↗

PubMed1997

Beneficial effects of a novel thyromimetic on lipoprotein metabolism.

Although L-triiodothyronine (L-T3) lowers cholesterol, this hormone is not used to treat hypercholesterolemia because of its cardiotoxic effects. Thyromimetics, such as the novel compound CGS 23425, that mimic the beneficial but lack the detrimental effects of T3, may be useful in the treatment of hypercholesterolemia. To show that CGS 23425 has no cardiotoxicity, atrial contractility and force were both measured and found to be unchanged in rats treated with up to 10 mg/kg drug. The lipid lowering actions of this drug resulted in a 44% decrease in low-density lipoprotein (LDL) cholesterol in hypercholesterolemic rats treated with 10 microg/kg of the compound. Normal rats required a higher dose of 1000 microg/kg to elicit a similar 50% reduction in LDL cholesterol. Both CGS 23425 or T3 (10 nM) increased the specific binding of 125I-labeled LDL to Hep G2 cells and increased LDL receptor number by 44 and 49%, respectively. These data indicate that CGS 23425 enhances hepatic clearance of serum LDL cholesterol. Normal and fat-fed animals treated with the drug showed a dose-dependent increase in apolipoprotein AI, a protein that promotes the efflux of cholesterol from peripheral tissues. Transient transfection of a rat apolipoprotein AI promoter-chloramphenicol acetyltransferase construct, in human hepatoma cells, showed a dose-dependent increase in chloramphenicol acetyltransferase activity with EC50 values of 2 x 10(-12) M and 10(-10) M for thyroid hormone receptors beta1 and alpha1, respectively, with maximal responses at 10(-7) M. These data indicate that CGS 23425 is a thyromimetic that increases apolipoprotein AI expression via thyroid hormone receptor. In summary, CGS 23425 ameliorates hypercholesterolemia by increasing apolipoprotein A1 and the clearance of LDL cholesterol. Therefore, a compound like CGS 23425 may be useful for the prevention and reversal of atherosclerosis.

Animals↗

PubMed2001

Future use of selective estrogen receptor modulators and aromatase inhibitors.

Selective estrogen receptor modulators (SERMs) may act as estrogens or antiestrogens depending on the cell and tissue targets. The triphenylethylene SERMs are represented by tamoxifen and toremifene and a new agent with a novel carboxylic acid side chain (GW5638). Because of isomerization in the triphenylethylene molecule, "fixed ring" SERMs were introduced. The major one in development is the benzothiophene arzoxiphene (LY353381), which is now in Phase III clinical trial versus tamoxifen. A fourth group of SERMs is based on the estrogen molecule and comprises the so-called "pure" antiestrogen ICI 182,780 (fulvestrant, Faslodex) and a new oral analogue just entering trials, SR16234. The steroidal aromatase inhibitors [AIs (40H androstenedione 'and exemestane)] inactivate aromatase, whereas the triazole AIs (anastrozole and letrozole) inhibit the enzyme via the heme prosthetic group. Thus, there are two groups of AIs that show relative non-cross-resistance in advanced breast cancer and four groups of SERMs that also show a high degree of non-cross-resistance. With six different treatments and six or more clinical situations (prevention, neoadjuvant, adjuvant, and first- and second-line treatments for advanced disease) in which they may be used, the possible combinations of treatment are enormous. At present, we have few clinical pointers to optimal sequence of treatments. Now that most of the appropriate comparative trials have been performed, it may be the time to initiate novel approaches. These include alternating and sequential treatments, preferably with treatments changed before overt progression occurs.

Aromatase Inhibitors↗

PubMed2003

Hepatitis B virus X protein sensitizes hepatocellular carcinoma cells to cytolysis induced by E1B-deleted adenovirus through the disruption of p53 function.

Replication-selective adenovirus has been reported to kill tumor cells and hold promise for cancer therapy. In this study, we constructed an E1B M(r) 55000-deleted adenovirus, designated Ad5WS1, and examined its cytolytic effect on human hepatocellular carcinoma (HCC) cell lines with various p53 status. The results show that Ad5WS1 lysed HCC cells lacking p53 transcription activity. However, this effect was not observed in cells harboring functional p53. Because loss of p53 transcription activity can be induced by binding to hepatitis B virus X protein (HBx), we generated HBx stable transfectants from Chang liver cells and examined their susceptibility to Ad5WS1-induced cytolysis. Expression of HBx in Chang liver cells changed the location of p53 from the nucleus to the cytoplasm, which mostly coincided with the location of HBx in the cytoplasm. Disruption of p53 transcription activity by HBx in Chang liver cells rendered them susceptible to infection with Ad5WS1. Furthermore, Ad5WS1 exerted antitumor effect, especially when combined with chemotherapeutic agent cisplatin, in BALB/c mice bearing HBx-expressing HCC. Our results suggest that E1B M(r) 55000-deleted adenovirus may have therapeutic potential for the treatment of HCC with loss of p53 transcription activity or with HBx expression.

Adenoviridae↗

PubMed1987

Lowering effect of pantethine on plasma beta-thromboglobulin and lipids in diabetes mellitus.

Pantethine in a dosage of 600 mg for the first 3 months, and in a dosage of 1200 mg for the second 6 months was given to 16 diabetics in whom plasma beta-thromboglobulin was raised (greater than 50 ng/ml). Plasma beta-TG levels decreased significantly with pantethine treatment for 9 months. Plasma triglyceride, total cholesterol, apo E and apo CII levels decreased significantly after 9 months. Plasma LDL-C and atherogenic index (LDL-C/HDL-C ratio or apo B/apo AI ratio) tended to decrease with treatment. It is concluded that administration of pantethine may be beneficial in the prevention of diabetic angiopathy because of its lowering effect on plasma beta-TG, lipids and apolipoproteins.

Adult↗

PubMed2026

In silico identification of DNMT1 inhibitors from the PlantCyc database through computational approach to assess the anti-cancer potential of nutraceutical compounds in breast cancer.

Breast cancer accounts for a disproportionate share of global cancer-related deaths, with 670,000 fatalities and 2.3 million new diagnoses recorded in women during 2022 alone. Existing treatment modalities carry considerable toxicity burdens, and resistance to available agents remains an unresolved clinical problem. DNA methyltransferase 1 (DNMT1), the enzyme chiefly responsible for maintaining genome-wide methylation patterns during DNA replication, has been mapped out as a high-value target in breast cancer because its dysregulation silences tumour suppressor genes through promoter hypermethylation. The present work involves hierarchical in silico workflow to screen 4549 plant-derived compounds from the PlantCyc database (v16.0.3) against the human DNMT1 catalytic domain (PDB ID: 4WXX). Ten top-scoring compounds were taken forward for molecular docking via AutoDock Vina; Quercetin and Kaempferol both recorded the highest binding affinities at -9.5 kcal/mol, Wogonin (-9.3 kcal/mol) and Xanthohumol (-8.1 kcal/mol) also emerged as strong binders. Pharmacokinetic evaluation using ADMET-AI confirmed that all 10 compounds met Lipinski's rule of five, with human intestinal absorption values at or above 0.98. Wogonin and Xanthohumol were selected for a 100 ns all-atom molecular dynamics (MD) simulation in GROMACS due to their well-rounded ADMET profiles and limited existing data on their specific interactions with DNMT1 in breast cancer. Across all measured trajectory metrics, backbone RMSD, residue fluctuation, radius of gyration, solvent-accessible surface area, and intermolecular hydrogen bond count, Wogonin formed a more stable, compact complex. These findings suggest that Wogonin and Xanthohumol are non-toxic nutraceutical candidates suitable for DNMT1 targeted epigenetic therapy, with computational foundation strong enough to facilitate future in vitro and in vivo validation work.

Humans↗

PubMedDate not supplied

Lovastatin versus bezafibrate for hyperlipemia treatment after heart transplantation.

BACKGROUND: Elevation in total and low-density lipoprotein cholesterol levels and a decrease in high-density lipoprotein cholesterol plasma concentrations are common in heart transplant recipients. The pathogenesis of this hyperlipemia after heart transplantation is complex. Currently available antilipemic agents are difficult to use because their adverse effects are potentiated by immunosuppressor treatment. The present investigation was carried out to test the safety and efficacy of lovastatin and bezafibrate in 18 patients with hyperlipemia after heart transplantation. METHODS: In this crossover study, after 3 months of dietary recommendations, the subjects were randomly assigned to an 8-week period of lovastatin treatment (10 mg/day) followed by an additional 8-week period of treatment with bezafibrate (400 mg/day) or vice versa. The two treatments were separated by an 8-week washout period. RESULTS: Both drugs reduced total and low-density lipoprotein cholesterol and apoprotein B concentrations. High-density lipoprotein cholesterol was only increased with bezafibrate. The total cholesterol/high-density lipoprotein cholesterol and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratios were decreased under both treatments, but these changes were greater with bezafibrate. Apo AI levels increased with lovastatin. Bezafibrate produced a rise in high-density lipoprotein cholesterol and reduced total and very low-density lipoprotein triglycerides and very low-density lipoprotein cholesterol. Both drugs decreased intermediate density lipoprotein cholesterol and triglyceride levels, but the effect of bezafibrate on intermediate-density lipoprotein triglycerides was significantly greater. The two drugs were well tolerated and liver enzymes, creatine kinase, and renal function remained stable.

Adult↗

PubMed1993

Platelet activating factor, an endogenous mediator of inflammation, induces phenotypic transformation of rat embryo cells.

The ability of platelet activating factor (PAF), a potent endogenous inflammatory agent, to induce phenotypic transformation of primary rat embryo cells (RECs) was investigated. RECs are composed predominantly of fibroblasts, with some epithelial cells and a few neuronal and muscle cells. A 1 h period of treatment with PAF (1 x 10(-8)-1 x 10(-6) M) increased the ability of RECs to (i) form foci, (ii) reach a high saturation density in complete medium, (iii) grow in low serum-containing medium and (iv) exhibit anchorage-independent (AI) growth. Similar changes were achieved with C-PAF (1 x 10(-10)-1 x 10(-8) M), an active, non-metabolizable analog of PAF, but not by lyso-PAF (1 x 10(-10)-1 x 10(-6) M), a biologically inactive metabolite of PAF. All of the PAF-induced phenotypic changes could be inhibited by pretreatment with a PAF receptor antagonist, CV3988 (1 x 10(-6) M). Pretreatment of RECs with genestein (1 microgram/ml) also completely inhibited all four measures of PAF-induced REC transformation indicating that tyrosine kinase activity may be required for the observed changes in phenotype. Pretreatment with indomethacin (2 x 10(-7) M) blocked the PAF-induced increases in focus formation and saturation density without affecting PAF-induced alterations in growth in low serum or AI growth. This indicates that PAF may exert some of its effects through a cyclooxygenase product. Pretreatment with staurosporine (5 x 10(-8) M) failed to alter any of the PAF-induced effects, suggesting that protein kinase C activity is not involved in REC transformation by PAF. Our results provide the first evidence that PAF, released by activated phagocytes in and around areas of inflammation, may contribute to the process of malignant transformation.

Animals↗

PubMed2004

The estrogen suppression after sequential treatment with formestane in advanced breast cancer patients.

In postmenopausal patients, estrogens have an important role in breast cancer growth and aromatase inhibitors (AI) suppress the aromatase enzyme system which converts androgens into estrogens. The aim of this study was to evaluate the effect on estrogen suppression of formestane 250 mg i.m. fortnightly, given immediately after the failure of a previous treatment with non-steroidal AI. Twenty-two advanced breast cancer patients progressing on letrozole, anastrozole and aminoglutethimide entered the study. At the beginning of the study, the serum estrogen levels were suppressed by the previous treatment with non-steroidal AI, and the following treatment with formestane moderately maintained this suppression; in four patients serum estrogen levels increased fivefold after 10 weeks. Neither complete nor partial responses were observed; 11 patients (50%) showed a stable disease lasting > or = 6 months, and the median time to progression was 6 months (range 3-9 months). No correlation was observed between clinical responses and serum estrogen suppression. Tolerability was satisfactory, and no patient withdrew from the study due to adverse events. In conclusion, formestane has demonstrated a moderate activity in estrogen suppression, and there is evidence that, at the failure of a previous treatment with non-steroidal AI, the sequential use of steroidal AI is feasible. This approach can be used in clinical practice in order to offer a disease control with a satisfactory quality of life.

Adult↗

PubMed1984

Changes in serum apo-lipoprotein AI and sex-hormone-binding globulin levels after treatment with two different progestins administered alone and in combination with ethinyl estradiol.

Twenty women, oophorectomized as part of the surgical treatment for cervical carcinoma in either clinical stage IB or IIA but otherwise healthy, participated in the study. After a period of six weeks without hormonal treatment, ten of them were given 150 micrograms desogestrel (DG) daily for three weeks followed by 150 micrograms DG + 30 micrograms ethinyl estradiol (EE) for six weeks and, finally, 30 micrograms EE alone for three weeks. The remaining ten women were given 150 micrograms levonorgestrel (NORG) and EE in a similar regimen. Before treatment and after each period of treatment, apo-lipoprotein AI and sex-hormone-binding globulin (SHBG) were assayed in serum. Both progestins decreased apo-AI and SHBG when given alone, thereby indicating an "androgenic" influence. In combination with EE, however, DG seems to be less "anti-oestrogenic" than NORG, as judged from the higher apo-AI and SHBG values after the combination DG + EE compared to those after NORG + EE.

Adult↗

PubMed2006

Optimising adjuvant endocrine treatment of breast cancer with aromatase inhibitors.

There is mounting evidence that aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant treatment for postmenopausal women with oestrogen receptor positive breast cancer. Nevertheless, tamoxifen still remains a useful and relatively nontoxic treatment, and further work is necessary to determine which patients need an AI. In terms of cost-effectiveness, letrozole has been estimated to be superior to tamoxifen. Anastrozole, letrozole and exemestane have not been compared directly in an adjuvant setting but letrozole proved superior to anastrozole in patients with advanced breast cancer. Although tumour receptor phenotype may be useful in selection for tamoxifen or AI, the evidence is mixed. Optimal sequencing and duration of treatment have yet to be determined. If nationally funded and organised trials could be instigated, these would give timely and reliable data, so that adjuvant endocrine treatment of breast cancer could be tailored to needs of the individual patient.

Antineoplastic Agents, Hormonal↗

PubMed2005

[A clinical analysis of 22 cases of Pneumocystis pneumonia in acquired immunodeficiency syndrome].

OBJECTIVE: To investigate the clinical characteristics, therapeutical approaches and outcome of Pneumocystis pneumonia (PCP) in patients with AIDS. METHODS: The clinical data of 22 PCP patients with AIDS who were treated in Peking Union Medical College Hospital from January 1992 to October 2004 were analyzed, including the routes of HIV infection, clinical profiles, immunological status, chest radiological characteristics, therapeutic managements and outcome. RESULTS: (1) Of the 22 PCP patients, 16 were male and 6 female. The average age was (35.0 +/- 9.4) years old. The majority of patients got HIV infection through blood transfusion (54.5%) and sexual transmission (27.3%). (2) The common clinical presentations were fever (21/22), progressive exertional dyspnea (20/22), cough (16/22), sputum (12/22) and weight loss (18/22). 68.2% (15/22) of the patients had normal or mild coarse breath sounds on auscultation. 14 patients had an PaO(2) less than 60 mm Hg (1 mm Hg = 0.133 kPa). (3) All the 22 PCP cases were in their late stage of AIDS. For the 20 patients who had an immunological test, the peripheral CD(4)(+) T lymphocyte count was ranging from 3 x 10(6)/L to 148 x 10(6)/L and 90% of the cases had a CD(4)(+) T cell count less than 100 x 10(6)/L, 95% of the cases had a CD(4)(+)/CD(8)(+) ratio less than 0.20; (4) The most common abnormal chest radiological findings were bilateral diffuse interstitial infiltrations (19/22) and patchy shadows (14/22); (5) All patients were given trimethoprim-sulfamethoxazole (SMZco) and 86.4% of the patients were treated with corticosteroids concomitantly. Of the 22 PCP patients, 13 recovered, 5 gave up after knowing their definite diagnosis, 4 died. Comparing with the recovery patients, the 4 patients who died of PCP had much lesser CD(4)(+) T cell count (P = 0.07). CONCLUSIONS: Most PCP occurred in patients who were in their late stage of AIDS and with a CD(4)(+) T cell count below 100 x 10(6)/L. For these reasons, we suggest that whenever encountering a young patient presenting with fever, dyspnea, hypoxia, loss of weight, the possibility of PCP complicating AIDS should be considered, especially when chest radiological study revealed interstitial infiltration or patchy shadows. If HIV was confirmed to be positive, the combined therapy of SMZco and corticosteroids should be started immediately.

AIDS-Related Opportunistic Infections↗

PubMed1990

[Short-term metabolic compensation improves the lipo-apoprotein profile in type II diabetics in secondary insufficiency].

In the present study the effect of short-term metabolic control on plasma lipids and apoproteins in a group of subjects with type II diabetes mellitus in insulin treatment for secondary failure to oral agent therapy (sulphonylureas) was examined. For this reason 40 diabetic patients and 40 normal controls were studied. The lipoapoproteic pattern at the admission in the study and after a steady metabolic control, achieved by conventional insulin therapy and estimated by seric fructosamine, was evaluated. Diabetic patients, when compared with normal controls, showed a more atherogenic lipo-apoproteic profile and after achieving metabolic control, showed a reduction of triglyceride and apo B levels and a significant increase of the apo AI levels. The achievement of a good metabolic control, even after a short time, was associated with an improvement of the lipo-apoproteic profile, altered in diabetes mellitus in secondary failure.

Apoproteins↗

PubMed2005

Specific therapies for ischaemic stroke: rTPA and others.

In the last few years there have been several important advances in the understanding of cerebrovascular disorder pathophysiology that have impacted on stroke management. The development of timely and effective treatment strategies was and is still considered a high priority issue. Therapeutic options dramatically increased both in the prevention and overall in the treatment of acute ischaemic stroke (AIS). At present, whereas neuroprotection remains experimental, intravenous (i.v.) thrombolysis is the only specific therapy effective in reducing mortality and disability associated with stroke. The efficacy and safety of the antithrombotic therapy in AIS treatment are not well established, and few issues in clinical stroke management are more controversial. However, some studies have brought new light and new doubts on the roles of these traditional therapies.

Brain Ischemia↗