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Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia. Effects on apolipoprotein AI-containing lipoprotein particles.

In order to investigate the effect of Probucol therapy on reverse cholesterol transport, apo AI-containing lipoprotein particles were isolated and characterized, and their cholesterol effluxing capacity and LCAT activity were assayed in four familial hypercholesterolemia patients before and after 12 weeks of Probucol therapy. Four major subpopulations of apo A-containing lipoprotein particles are separated before and after drug treatment; LpAI, LpAI:AII, LpAIV, LpAI:AIV:AII. Probucol reduces both total plasma and LDL-cholesterol (-17 and -14%, respectively). Apo B decreases slightly (-7.6%). Plasma HDL-cholesterol and apo AI decrease by 36.6 and 34.7%. LpA-I showed a marked decrease (-46%). Moreover, plasma LCAT and CETP activities were markedly increased under Probucol treatment. Analysis of lipoprotein particles showed that Probucol induces a decrease of protein content and an increase of cholesterol and triglycerides contents. Interestingly, Probucol induces an enhancement of LCAT activity in LpAI (4.5-fold). This drug induces a trend toward greater cholesterol efflux from cholesterol-preloaded adipose cells promoted by Lp AI and Lp AIV but not by Lp AI:AII. This study confirms the hypothesis, in addition to the lowering LDL-cholesterol levels and antioxidant effects of Probucol, that HDL reduction was not an atherogenic change in HDL system but may cause an antiatherogenic action by accelerating cholesterol transport through HDL system, promoting reverse cholesterol transport from peripheral tissues.

Adipocytes↗

Anti-human immunodeficiency virus type 1 (HIV-1) activity of lectins from Narcissus species.

Mannose-specific lectins (MSLs) were isolated from bulbs of fifteen wild Narcissus species growing in Spain and assayed for their HIV-1 infection inhibitory activity in MT-4 cells and compared to the Narcissus pseudonarcissus agglutinin (NPA), the commercially available MSL obtained from daffodils. Almost all the tested MSLs were found to be active, showing EC50 values (microg/mL) similar to that of NPA, with some being comparable to those obtained with dextran sulfate without significant cytotoxicity. However, on a molar basis almost all of the MSLs tested exhibited lower EC50 values than dextran sulfate whilst six MSLs had values lower than AZT. The most efficacious anti-HIV-1 activity was exhibited by the Narcissus tortifolious MSL, which was 10- (microg/mL) and 100- (molarity) fold more potent than dextran sulfate. Significantly, although this MSL was 15-fold less potent than AZT in terms of quantity (microg/mL), it was 68-fold more potent on a molar basis. The antiviral indices, a ratio of the concentrations that produce cytotoxicity and HIV-1 replication, were calculated and three of the MSLs, N. confusus, N. leonensis and N. tortifolius reported 1.5-, 2- and 8.5-fold greater AI values than dextran sulfate or AZT. Comparison of MSL haemagglutination activities (HAA) to their anti-HIV-1 activities showed that there was no significant correlation. It was suggested that this may be due to a dissociation between both activities as a consequence of multiple isolectin composition.

Anti-HIV Agents↗

The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin-induced pulmonary fibrosis in rats.

OBJECTIVE: The aim of this study was to investigate the inhibitory effect of dexamethasone on the state of proliferation/apoptosis of the pulmonary inflammatory cells in a rat pulmonary fibrosis model induced by bleomycin. METHODOLOGY: Seventy-five pathogen-free Sprague-Dawley (SD) rats were randomly divided into three groups: control, bleomycin (BLM) and dexamethasone (DXM) groups with 25 rats in each group. Each group was then divided into five subgroups based on time of study (1-, 3-, 7-, 14- and 28-days). BAL fluid was obtained, the cells were counted and a differential was performed. A lower DNA content in apoptotic cells was detected and quantitated by flow cytometry. Haematoxylin and eosin staining was performed to observe the extent of alveolitis and fibrosis of lung tissue; the morphological changes in apoptotic cells were discerned by transmission electron-microscopy and a semi-quantitative assessment of apoptotic cells in lung tissue was performed using in situ TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling). RESULTS: The total number of inflammatory cells and the percentage of neutrophils in BAL fluid in almost every subgroup of the DXM group were significantly lower than those in corresponding subgroups of the BLM group (P < 0.01). The percentages of apoptotic cells in BAL fluid in the 14-day and 28-day subgroups of the DXM group were higher than those in corresponding subgroups of the BLM group (P < 0.05). The peak of alveolitis in the DXM group shifted backward and the extent of fibrosis was less than that in the BLM group. The apoptosis index (AI) of inflammatory cells in each of the DXM subgroups was higher than that in corresponding BLM subgroups except for day 14. CONCLUSION: Dexamethasone can induce apoptosis of pulmonary inflammatory cells and reduce the extent of alveolitis and fibrosis in bleomycin-induced pulmonary fibrosis of rats.

Animals↗

Action of aluminum on high voltage-dependent calcium current and its modulation by ginkgolide B.

AIM: To investigate the effect of aluminum (Al) on high voltage-dependent calcium current (I(HVA)) and its modulation by ginkgolide B (Gin B). METHODS: The whole-cell, patch-clamp technique was used to record IHVA from acutely isolated hippocampal CA1 pyramydal neurons in rats. RESULTS: Al 0.1 mmol/L (low concentration) reduced I(HVA); Al 0.75 and 1.0 mmol/L (high concentrations) increased I(HVA), and Al decreased and increased I(HVA) at intermediate concentrations of 0.25 and 0.5 mmol/L. The increase of I(HVA) by Al 1.0 mmol/L was enhanced by the adenylyl cyclase (AC) agonist forskolin and was partly abolished by the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) antagonist H-89, whereas the decrease observed with Al 0.1 mmol/L was neither reversed by forskolin nor affected by H-89. Gin B had no effect on I(HVA) in normal neurons, but canceled the increase in I(HVA) by 1.0 mmol/L Al. CONCLUSION: The results indicate that the mechanism of Al affecting I(HVA) differs at different concentrations, and this may be attributed to its complex actions. Gin B could prevent neurons from injury by inhibiting calcium influx.

Aluminum Chloride↗

[Epidemiology of acute coronary syndromes in cardiology departments of the Emilia Romagna region: the AI-CARE2 study].

BACKGROUND: The aim of this study was to better delineate the characteristics, treatments and outcomes of patients with acute coronary syndromes in Emilia Romagna, a region of Italy, with 4 million inhabitants. METHODS: From January 10 to March 12, 2000, we performed a prospective survey (24/27 hospitals of the region) on 1074 consecutive patients with a discharge diagnosis of acute coronary syndrome. RESULTS: Based on the initial electrocardiogram, patients were classified as having an ST-elevation acute coronary syndrome in 41% of cases, a non-ST-elevation acute coronary syndrome in 54%, and an acute coronary syndrome with an undetermined electrocardiographic pattern in 5%. The discharge diagnosis was Q wave myocardial infarction in 43%, non-Q wave myocardial infarction in 26%, and unstable angina in 31% of patients. The use of antiplatelet, beta-blockers, ACE-inhibitors, and antithrombin agents for patients with ST-elevation acute coronary syndromes were 96, 62, 56, and 93%, respectively, with corresponding rates of 93, 63, 53, and 87% for non-ST-elevation acute coronary syndromes. During the initial admission, coronary angiography, percutaneous coronary intervention, and coronary bypass surgery were performed in 31, 15, and 1% of ST-elevation acute coronary syndrome patients, respectively, with corresponding rates of 43, 15, and 5% for non-ST-elevation acute coronary syndromes. Among patients with ST-elevation acute coronary syndromes, 61% received a reperfusion treatment; 58% coronary thrombolysis, and 3% primary percutaneous coronary intervention. The in-hospital mortality of patients with ST-elevation acute coronary syndromes was 10%, of patients with non-ST-elevation acute coronary syndromes 3%, and of patients with underdetermined electrocardiographic acute coronary syndromes 8%. At 6 months, the mortality rate increased to 16, 8, and 18%, respectively. CONCLUSIONS: Our data show the use of evidence-based pharmacological treatments in this population. This is associated with clinical outcomes which favorably compare with those observed in clinical trials. However, there is still room for improvement in the implementation of the invasive treatment.

Acute Disease↗

Intragraft events after heart transplantation: an experimental study comparing cytology in coronary sinus blood, peripheral blood, and daily histology.

Acute rejection is a frequent consequence after heart transplantation. To expand our knowledge of the rejection process and to investigate some intragraft events during acute rejection, the following experimental transplantation model was designed. Right cervical heart transplantation was performed in 12 mongrel dogs. Two experimental groups of six animals each received different immunosuppressive regimens. All animals were treated with daily triple drug therapy. In contrast to group 1, the animals in group 2 received high-dose steroids during rejection. The condition of the hearts was examined by daily transmural biopsies, graded according to the Billingham classification. To detect and quantify alterations in the mononuclear cell subsets of the myocardial venous return, blood samples from the coronary sinus blood (CS) and from peripheral blood (PB) were taken simultaneously with the biopsy. The total number of lymphoblasts and activated lymphocytes was determined and an activation index (AI) was calculated. The data referred to was established from 337 transmural biopsies. The AI of PB (n = 287) correlated well with the different stages of acute rejection (grade B0: AI = 2.2 +/- 2.1; grade B1 + 2: AI = 6.3 +/- 1.7; grade B3: AI = 10.0 +/- 4.7; P < 0.001). The rejection kinetics of both groups, including the rejection-free interval following high-dose steroid administration in group 2, could be expressed accurately by the AI. The time course of the total number of lymphoblasts in CS versus PB demonstrated that the lymphoproliferative response started 4 days prior to the first intramyocardial signs of rejection (mean = 3.8 +/- 0.7; n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines.

Pentamidine, DAPI and some related compounds (DAI, 6-Br-AI, DPTN, DIPI, 3-Am-DAI, DiaPBF) were investigated in 2 different screening test systems for their potential mutagenic and cytotoxic effects, in the light of their binding to DNA. In the Ames test using Salmonella typhimurium strains TA98 and TA100 with and without metabolic activation no mutagenic effects could be observed. All diamidines tested, except DAI, were toxic at concentrations of 0.5 and 1.0 mumole/plate. In the sister-chromatid exchange (SCE) assay with human peripheral lymphocytes all compounds tested were growth-retarding particularly in the G0 phase. A significant induction of SCEs could only be seen after treatment with the monoamidino compound 6-Br-AI at a concentration of 100 mumole/l. It is concluded from the data obtained that pentamidine and related diamidines in the 2 assays tested show no mutagenic or genotoxic effects, in spite of their tight binding to DNA.

Amidines↗

Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines.

PURPOSE: Aromatase inhibitors (AIs) are now established as adjuvant therapy for early hormone receptor-positive breast cancer in postmenopausal women. Their use is sometimes extended to younger women after chemotherapy-induced amenorrhoea; we have audited this in one institution's breast unit, and we propose guidelines for use in such circumstances. PATIENTS AND METHODS: The use of aromatase inhibitors as adjuvant therapy in younger women age > or = 40 with hormone receptor-positive early breast cancer and chemotherapy-induced amenorrhea has been audited clinically and biochemically. Results A total of 45 such women were identified in the audit, with a median age of 47 years (range, 39 to 52 years). Twelve women (27%) showed a return of ovarian function (10 renewed menses, one pregnancy, one biochemically premenopausal) after starting an AI. Median age at restart of ovarian function was 44 years (range, 40 to 50 years). CONCLUSION: AIs may promote recovery of ovarian function in some women with chemotherapy-induced amenorrhea and should be used with caution. Biochemical monitoring of ovarian function requires highly sensitive immunoassays. Guidelines for the selection and delivery of adjuvant endocrine therapy in such patients are proposed.

Adult↗

Recombinant human thrombopoietin in myelosuppressive chemotherapy.

Recombinant human thrombopoietin (rhTPO) is a full-length glycosylated molecule that has been under evaluation in the setting of chemotherapy-induced myelosuppression. It has been shown to be a potent stimulator of platelet production in cancer patients when administered prior to chemotherapy. The peak platelet response to a single dose of rhTPO is observed around day 12, and is accompanied by a significant increase in the number of mature megakaryocytes in bone marrow. Consistent with this biologic effect, rhTPO administered postchemotherapy has been shown to be effective in attenuating severe thrombocytopenia induced by carboplatin, which produces a late platelet nadir. Early clinical experience with a regimen that produces an early nadir, however, such as AI (doxorubicin [Adriamycin] and ifosfamide [Ifex]), suggests that administration of rhTPO both prior to and following chemotherapy might be important to reduce thrombocytopenia severity. Treatment with rhTPO in these clinical trials has been well tolerated with a favorable safety profile. Randomized clinical trials have been initiated to determine further the importance of schedule in the prevention and treatment of severe thrombocytopenia in cancer patients.

Antineoplastic Agents↗

[The use of Enduracin--a prolonged-action form of nicotinic acid--in correcting atherogenic dyslipidemias].

The hypolipidemic effects of induracin, a new long-acting nicotinic acid dosage form based on the waxy matrix, and its tolerance were studied in 31 patients with Types IIa and IIb hyperlipoproteinemias in a 6-month blind crossover study. There were decreases in the levels of total cholesterol by 9-13% and low density lipoprotein cholesterol by 12-22%, an increase in high density lipoprotein cholesterol by 12-15%, and a good dynamics in the ratio of blood lipid-transport proteins--a 12-16% increase to the levels of apoprotein AI to a 29% decrease in those of apoprotein B. The drug is well tolerated by patients and may be recommended for correction of atherogenic dyslipidemias.

Adult↗

Acaricidal properties of a Chenopodium-based botanical.

The emulsifiable concentrate UDA-245 [25% EC (vol:vol)], based on an essential oil extract from Chenopodium ambrosioides variety ambrosioides, a North American herbaceous plant, was compared with commercially available pesticides for their effectiveness to control the adult stage and egg hatch of the twospotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae) and the European red mite, Panonychus ulmi (Koch) (Acari: Tetranychidae). After a laboratory bioassay with adult twospotted spider mites, a 0.5% concentration of UDA-245 was more effective than 0.7% (AI) of neem oil (Neem Rose Defense). After a similar bioassay with the European red mite, a 0.5% concentration UDA-245 was as effective as 0.006% (AI) of abamectin (Avid). UDA-245 at 0.5% significantly reduced egg hatch of the twospotted spider mite, 5 and 9 d after treatment and of the European red mite 6 d after treatment. Egg hatch was significantly lower using 0.006% (AI) of abamectin, 0.7% of neem oil, and 1.0% insecticidal soap than UDA-245. Residual tests indicated that UDA-245 may be persistent in the environment only for a few hours. Only 23% mortality was noted when mites were introduced on bean leaves 1 h after treatment with a 2% concentration of UDA-245. At the recommended dose of 0.5%, UDA-245 was not considered phytotoxic for most plants tested, i.e., lettuce, roses, and tomatoes. Results suggest that a greenhouse integrated pest management program using UDA-245 could effectively and selectively control mite infestations by treating "hot spots" with negligible effect on biological control agents when treating before introduction or when natural enemies are absent.

Acari↗

AI-driven CRISPR screening: optimizing gene editing through automation and intelligent decision support.

BACKGROUND: CRISPR-based genetic screening has become a central methodology in functional genomics, enabling systematic interrogation of gene function, genetic interactions and context-dependent vulnerabilities at scale. However, the rapid expansion of screening modalities-including multi-condition designs, combinatorial perturbations, in vivo applications and single-cell readouts-has exposed fundamental limitations of heuristic-driven experimental design and post hoc statistical analysis. MAIN BODY: This Review synthesizes how artificial intelligence is reshaping CRISPR screening by introducing predictive, adaptive and system-level intelligence across the experimental lifecycle. We organize recent advances into two tightly coupled modules. First, machine learning and deep learning (ML/DL) methods optimize experimental design by learning context-dependent perturbation behavior, anticipating confounding effects and enabling iterative, information-efficient screening strategies. Second, large language model-agent (LLM-agent) systems complement these advances by externalizing scientific reasoning, integrating biological knowledge at scale and coordinating analysis and decision-making in human-in-the-loop workflows. CONCLUSIONS: Together, ML/DL and LLM-agent approaches reframe CRISPR screening from a static analytical pipeline into an intelligent experimental system, with important implications for robustness, scalability and biological discovery.

Artificial Intelligence↗

Regulation of angiotensin converting enzyme activity in cultured human vascular endothelial cells.

Angiotensin converting enzyme (ACE) of vascular endothelial cells is suggested to control vascular wall tonus through the conversion of angiotensin I (AI) to angiotensin II (AII) and the degradation of bradykinin. To obtain more insight into the pathophysiological significance of ACE of vascular endothelial cells, we studied the regulation of ACE produced by cultured human umbilical vein endothelial cells (EC). Phorbol 12-myristate 13-acetate (PMA) increased the cellular and medium ACE activity, accompanied by a marked morphological change in EC. N'-O'-dibutylyladenosine 3';5'-cyclic monophosphate (db-cAMP) increased only the cellular ACE activity and not the medium ACE activity. The effect of isoproterenol with 0.1mM theophylline mimicked that of db-cAMP. These findings suggest that PMA and cAMP-related agents participate in the control of vascular wall tonus through the positive regulation of ACE produced by vascular endothelial cells.

Bucladesine↗

Effect of probucol on hypercholesterolemia in renal transplant patients.

BACKGROUND: Hypercholesterolemia is a well-known complication in kidney transplant recipients, although its pathogenesis may be multifactorial. The therapeutic effect of probucol on post-transplant hypercholesterolemia was prospectively evaluated. METHODS: Twelve hypercholesterolemic kidney transplant patients with serum total cholesterol > or = 250 mg/dl without diabetes mellitus or hypoproteinemia were prospectively treated with probucol (250 mg, bid, for three months). Before initiating and at the end of treatment, blood was drawn after at least a 12-hour fast to measure lipids in serum and lipoprotein fractions, apoproteins (apo), lipoprotein fractions, lethicin cholesterol acyl transferase (LCAT), free fatty acids (FFAs), and cholesterol ester. The lipid profiles of 17 healthy subjects were also examined. RESULTS: After treatment with probucol, serum total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apo AI were significantly decreased, whereas cholesterol ester increased significantly. CONCLUSIONS: Post-transplant hypercholesterolemia is featured with abnormalities in very low-density lipoprotein (VLDL) metabolism. Although HDL cholesterol decreased, probucol might have acted as an antiatherogenic by modulating HDL metabolism and stimulating reverse transfer of cholesterol from peripheral tissue.

Adult↗

[Aromatase inhibitors--new horizons in breast cancer endocrine therapy].

The knowledge that breast cancers in a great percent of patients have specific estrogen (ER) and progesterone (PgR) receptors, which made them hormonal dependent, induced the development of a large choice of hormonal drugs for the treatment. The mortality rate of hormonal responsible breast cancer has been drastically decreased by different sequential hormonal manipulations. It is mostly due to tamoxifen, which is an ER blocator. As the synthesis of estrogens in postmenopausal women occurs through the aromatization of androgens, the third generation of new nonsteroidal aromatase inhibitors (AI), have been showed as strong drugs for endocrine therapy. Since they showed the advantage over tamoxifen in advanced breast cancer of postmenopausal women, there are currently the investigations of their value in early breast cancer adjuvant therapy, as well as the side-effects of the therapy. So far, tamoxifen remains a gold standard of adjuvant hormonal therapy for endocrine-dependent breast cancer.

Antineoplastic Agents↗

[Pravastatin, cholestyramine and gemfibrozil in long-term therapy of primary hypercholesterolemia. An open randomized comparative study].

In this open controlled clinical trial the lipid-lowering effect, the tolerance and clinical safety of the new hydrophilic HMG-CoA reductase inhibitor pravastatin and cholestyramine were compared in the treatment of 45 patients with primary hypercholesterolaemia over a period of 16 weeks. Following a dietary lead-in of six weeks, patients were randomized at a ratio of 3:2 to receive either pravastatin 10 mg b.i.d. or cholestyramine 8 g b.i.d. The dose of pravastatin was increased to 40 mg per day after eight weeks of treatment and after 16 weeks cholestyramine 8 g b.i.d. was added. Two thirds of the patients in the cholestyramine group were switched to gemfibrocil 900 mg. At the end of the 48 week treatment period the mean reduction rates of total cholesterol, LDL-cholesterol and triglycerides for the pravastatin combination compared to cholestyramine (in brackets values for gemfibrocil) were -30, -35 and -17% versus -17 (-19), -25 (-22) and +27 (-24)%. Pravastatin lead to an increase of the HDL concentration of approximately 8%, gemfibrocil to approximately 13%, whilst cholestyramine alone did not change this lipid fraction. The reduction of total cholesterol and LDL-cholesterol was associated with a decrease in the apolipoprotein B concentration. However, the apolipoprotein AI and AII levels remained unchanged. Due to the absence of clinically relevant side effects and laboratory abnormalities coupled with the excellent compliance in this study, pravastatin proved to be a convincing therapeutic alternative to cholestyramine and gemfibrocil. The combination therapy of pravastatin and cholestyramine offers a potentially highly efficacious and safe therapeutic regimen for the future.

Adult↗

Facial skin rejuvenation.

PURPOSE OF REVIEW: In recent years, many new products and techniques have arisen that are useful in the rejuvenation of facial skin. Most of the therapies are directed at improving the results of photoaging. These cutaneous changes occur from chronic exposure to ultraviolet B light (290 to 320 nm) associated with sunburn, and ultraviolet AII light (320 to 340 nm), and ultraviolet AI light (340 to 400 nm) associated with photoaging. Clinically chronic photoaging may result in fine wrinkles, texture abnormalities, pigment dyschromias, and actinic keratoses. RECENT FINDINGS: Many methods of patient assessment are available, but the most useful include the Fitzpatrick skin type classification and the Glogau photoaging scale. Although many therapies are available to reduce or even reverse many of these aging changes, patient education regarding lifestyle changes (especially smoking cessation) and sun avoidance need to be a critical foundation of treatment. Indeed, patient participation in their own skin care regimen is important for any program to be effective. Topical therapy including tretinoins, hydroxy acids, bleaching agents, and sunscreens are discussed herein. SUMMARY: The physician has an important role in understanding which treatment options are appropriate for mild, moderate, and severe photoaging, and in educating patients on the risks and benefits of each. This includes resurfacing modalities with microdermabrasion, chemical peels, and laser skin resurfacing.

Cosmetic Techniques↗

Cytotoxic effect of oxidized low density lipoprotein on macrophages.

Macrophage or macrophage-derived foam cell death is one of the characteristic events in the development of cell-poor lipid-rich cores of the advanced atherosclerotic plaques. Although the in vivo mechanism for the death of macrophages is unclear, one possible candidate for the agent which induces macrophage cell death is oxidized low density lipoprotein (Ox-LDL). To investigate the mechanism of Ox-LDL-induced macrophage cell death, we have recently employed macrophage cell genetics and isolated mutant cells resistant to the cytotoxic effect of Ox-LDL from mutagenized populations of murine macrophage-derived J774 cells (Hakamata, H., Miyazaki, A., Sakai, M., Matsuda, H., Suzuki, H., Kodama, T., and Horiuchi, S. (1998) J. Lipid Res. 39, 482-494). The results obtained showed that one mutant form, JO21b cells, was characterized by reduced expression of type I and type II class A macrophage scavenger receptors (MSR-AI/AII) with a concomitant decrease in the uptake of Ox-LDL. Moreover, peritoneal macrophages obtained from MSR-AI/AII-knockout mice showed a higher resistance to the cytotoxic effect of Ox-LDL compared to those of their wild-type littermates. From these results, we have concluded that Ox-LDL cytotoxicity to macrophages is enhanced by effective endocytic uptake of Ox-LDL through MSR-AI/AII. These findings imply a possibility that formation of the cell-poor lipid-rich core is also enhanced by MSR-AI/AII-mediated uptake of Ox-LDL and subsequent macrophage cell death in atherosclerotic lesions.

Animals↗