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1.
Eur J Clin Pharmacol ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31463578

RESUMO

PURPOSE: Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients' resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity. METHODS: The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients. RESULTS: Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2-25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10-3-6.7 × 10-1). Significant results were confirmed in the entire cohort. CONCLUSIONS: Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.

2.
Bioorg Med Chem ; 27(17): 3805-3812, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31326241

RESUMO

The antiproliferative action of hispolon derivatives is stronger than that of related curcumin against several tumor cell lines. Hispolon size, smaller than curcumin, fits better than curcumin into the active site of HDAC6, an enzyme involved in deacetylation of lysine residues. HDACs are considered potential targets for tumor drug discovery and hydroxamates are known inhibitors of HDACs. One of them, SAHA (Vorinostat) is used in clinical studies. Investigations into possible mechanisms for hispolon derivatives active against the HCT116 colon tumor cell line are done after examining the structural results obtained from hispolon X-ray crystal structures as well as performing associated computational docking and Density Functional Theory techniques on HDAC6. These studies show preference for the HDAC6 active site by chelating the Zn center, in contrast with other ineffective hispolon derivatives, that establish only a single bond to the metal center. Structure activity relationships make clear that hydrogenation of the hispolon bridge also leads to single bond (non chelate) hispolon-Zn binding, and consistently nullifies the antiproliferative action against HCT116 tumor.

3.
J Photochem Photobiol B ; 195: 39-50, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31075653

RESUMO

Photodynamic therapy (PDT) of cancer uses photosensitizers (PS), a light source and oxygen to generate high levels of reactive oxygen species (ROS), that exert a cytotoxic action on tumor cells. Recently, it has been shown that mixed non-symmetrical diaryl porphyrins, with two different pendants, are more photodynamically active than symmetrical diaryl porphyrins. In the present study, we investigate the in vitro photodynamic effects of four novel non-symmetrical diaryl porphyrins, two of which bear one pentafluoro-phenyl and one bromo-alkyl (apolar) pendant, whereas the two others bear one pentafluoro-phenyl and one cationic pyridine pendant. The four compounds were tested in a small panel of human cancer cell lines, and their photodynamic activities were compared with that of m-THPC (Foscan), currently the most successful PS approved for clinical use in cancer PDT. The results of the cytotoxicity studies indicate that the two molecules bearing the cationic pendant are more potent in vitro than those with the apolar pendant, and that they are as potent as Foscan. To gain further insights into the mechanism of PS-induced phototoxicity, induction of apoptotic, autophagic and necrotic cell death, and generation of reactive oxygen species (ROS) were evaluated in cancer cells following exposure to the PSs and irradiation. The effect of the PSs on the migratory activity of the cells was also assessed. The data obtained from this work support a greater potency of diaryl porphyrins with a positive charge in inducing cell death, as compared to those with the bromo-alkyl pendant; most importantly, some of these novel compounds exhibit features that might make them superior to the clinically approved PS Foscan.


Assuntos
Fármacos Fotossensibilizantes/síntese química , Porfirinas/química , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Humanos , Luz , Neoplasias/tratamento farmacológico , Fotodegradação , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
4.
Target Oncol ; 13(5): 657-665, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30090970

RESUMO

BACKGROUND: Hypovitaminosis D is associated with an adverse prognosis in colon cancer patients, possibly due to the effects of the vitamin on the immune system. Antibody-dependent cell-mediated cytotoxicity (ADCC) significantly contributes to the anti-tumor effects of monoclonal antibodies, including cetuximab, an epidermal growth factor receptor (EGFR)-targeted monoclonal antibody that is frequently added to chemotherapy in the treatment of colon cancer. OBJECTIVE: The present study evaluates the association between vitamin D serum levels and the ability of ex vivo NK cells to support cetuximab-mediated ADCC in colon cancer cell lines. METHODS: Blood samples were obtained from 124 healthy volunteers and serum vitamin D was determined by RIA. NK cells were isolated from each sample and added to human colorectal carcinoma cells with or without cetuximab, and ADCC was assessed using a colorimetric lactate dehydrogenase assay. RESULTS: Correlation analysis indicates a significant, gender- and age-independent association between vitamin D levels and cetuximab-induced ADCC on HT29 cells, where NK cells from samples with vitamin D < 20 ng/mL are significantly less efficient in inducing ADCC. A confirmatory study on two additional colon cancer cell lines yielded similar results. CONCLUSIONS: These data suggest that vitamin D supplementation in vitamin-deficient/insufficient colorectal cancer patients could improve cetuximab-induced ADCC.

5.
J Photochem Photobiol B ; 186: 169-177, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30064063

RESUMO

Photodynamic therapy (PDT) is an anticancer modality that exploits singlet oxygen and other reactive oxygen species, that are formed by selective irradiation of photosensitive molecules, to kill cancer cells. Most photosensitizers (PS) are hydrophobic and poorly soluble in water and several nanoplatforms have been established to achieve a more efficient delivery. Moreover, the covalent binding of the PS to nanoparticles could in principle reduce unwanted bleaching of the PS, while preserving its photodynamic activity. In this study we report the synthesis of a novel non-symmetrical diaryl-porphyrin suitably modified with a polymerizable pendant, that was used for the preparation of core-shell poly-methyl methacrylate nanoparticles covalently loaded with the diaryl-porphyrin (PMMA@PorVa). Particles, which were prepared with two different porphyrin loadings, are spherical in shape and with a narrow hydrodynamic diameter around 70 nm and a positive zeta potential. Their photo-toxicity was tested against the human colon carcinoma cell line HCT116 and the human ovarian adenocarcinoma cell line SKOV3. PMMA@PorVa were able to inhibit tumor cells proliferation similarly to the free porphyrin, thus confirming that the covalent attachment of the PS to PMMA nanoparticles allows to preserve PS photodynamic activity and in vitro efficacy. Flow cytometric analysis of apoptotic cells demonstrates that, especially in SKOV3 cells, the free diaryl-porphyrin is more effective in inducing apoptosis.


Assuntos
Nanopartículas/química , Fármacos Fotossensibilizantes/química , Polimetil Metacrilato/química , Porfirinas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico
6.
Mater Sci Eng C Mater Biol Appl ; 90: 476-484, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29853116

RESUMO

Doxorubicin is one of the most effective chemotherapeutic agents for the treatment of several neoplastic conditions, such as leukemia, neuroblastoma, soft tissue and bone sarcomas, breast cancer, ovarian cancer and others. However, its clinical application is limited by cardiotoxicity, such as cardiomyopathy, that once developed carries a poor prognosis and is frequently fatal. The controlled release of doxorubicin by means of a smart carrier is a strategy to overcome the aforementioned drawback. Herein, doxorubicin/keratin nanoparticles were prepared by loading the drug through ionic gelation and aggregation methods, without using cross linkers, organic solvents neither surfactants. Both methodologies afford nanoparticles with yields up to 100 wt%, depending on the loading amount of doxorubicin. Although aggregation yield smaller nanoparticles (≈100 nm), ionic gelation allows a higher drug loading (up to 30 wt%,). More importantly, nanoparticles obtained through this procedure display a pH-responsive release of the drug: indeed Peppas-Salhin model suggests that, the doxorubicin release mechanism is predominantly controlled by diffusion at pH 7.4 and by protein swelling at pH 5. Moreover, nanoparticles prepared by ionic gelation resulted in more efficient cell killing of MDA-MB-231 and MCF-7 breast cancer cells than those prepared by aggregation. Based on the herein presented preliminary results, ionic gelation emerges as a promising approach for the preparation of keratin-based doxorubicin nanocarriers for cancer therapy, that is worth to further investigate.


Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Queratinas/química , Nanopartículas/química , Solventes/química , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7
7.
Dalton Trans ; 47(25): 8268-8282, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29892758

RESUMO

Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance. Indeed, cisplatin and clofibric acid, the metabolites of the Pt(iv) → Pt(ii) intracellular reduction, proved to act synergistically. The adjuvant action of clofibric acid relies on the activation of peroxisome proliferator-activated receptor α (PPARα) that, in turn, decreases the level of Hypoxia-Inducible Factor-1α. Both compounds induced extensive apoptosis in tumor cells, also via oxidative stress. Finally, 2 exhibited excellent performances also under the hypoxic conditions typical of solid tumors, where cisplatin is less effective.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Ácido Clofíbrico/química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/química
9.
Eur J Appl Physiol ; 117(3): 551-566, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28194519

RESUMO

PURPOSE: The partitioning of the electromechanical delay by an electromyographic (EMG), mechanomyographic (MMG) and force combined approach can provide further insight into the electrochemical and mechanical processes involved with skeletal muscle contraction and relaxation. The aim of the study was to monitor by this combined approach the changes in delays' electrochemical and mechanical components throughout a fatiguing task and during recovery in patients with myotonic dystrophy type 1 (DM1), who present at the skeletal muscle level fibres rearrangement, muscle weakness and myotonia, especially in the distal muscles. METHODS: After assessing maximum voluntary contraction (MVC), 14 male patients with DM1 and 14 healthy controls (HC) performed a fatiguing exercise at 50% MVC until exhaustion. EMG, MMG, and force signals were recorded from tibialis anterior and vastus lateralis muscles. The electromechanical delay during contraction (DelayTOT) and relaxation (R-DelayTOT) components, EMG and MMG root mean square (RMS) and mean frequency (MF) were calculated off-line. RESULTS: The fatiguing exercise duration was similar in both groups. In patients with DM1, delays components were significantly longer compared to HC, especially in the distal muscle during relaxation. Delays components recovered quickly from the fatiguing exercise in HC than in patients with DM1 in both muscles. CONCLUSIONS: The alterations in delays observed in DM1 during the fatiguing exercise may indicate that also the lengthening of the electrochemical and mechanical processes during contraction and relaxation could play a role in explaining exercise intolerance in this pathology.


Assuntos
Exercício , Fadiga Muscular , Distrofia Miotônica/fisiopatologia , Tempo de Reação , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Tolerância ao Exercício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Músculo Esquelético/fisiopatologia
10.
Eur J Appl Physiol ; 117(1): 95-107, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27858153

RESUMO

PURPOSE: Peripheral fatigue involves electrochemical and mechanical mechanisms. An electromyographic, mechanomyographic and force combined approach may permit a kinetic evaluation of the changes at the synaptic, skeletal muscle fiber, and muscle-tendon unit level during a fatiguing stimulation. METHODS: Surface electromyogram, mechanomyogram, force and stimulation current were detected from the gastrocnemius medialis muscle in twenty male participants during a fatiguing stimulation (twelve blocks of 35 Hz stimulations, duty cycle 9 s on/1 s off, duration 120 s). The total electromechanical delay and its three components (between stimulation current and electromyogram, synaptic component; between electromyogram and mechanomyogram signal onset, muscle fiber electrochemical component, and between mechanomyogram and force signal onset, mechanical component) were calculated. Interday reliability and sensitivity were determined. RESULTS: After fatigue, peak force decreased by 48% (P < 0.05) and the total electromechanical delay and its synaptic, electrochemical and mechanical components lengthened from 25.8 ± 0.9, 1.47 ± 0.04, 11.2 ± 0.6, and 13.1 ± 1.3 ms to 29.0 ± 1.6, 1.56 ± 0.05, 12.4 ± 0.9, and 17.2 ± 0.6 ms, respectively (P < 0.05). During fatigue, the total electromechanical delay and the mechanical component increased significantly after the 40th second, and then remained stable. The synaptic and electrochemical components lengthened significantly after the 20th and 30th second, respectively. Interday reliability was high to very high, with an adequate level of sensitivity. CONCLUSIONS: The kinetic evaluation of the delays during the fatiguing stimulation highlighted different onsets and kinetics, with the events at synaptic level being the first to reveal a significant elongation, followed by those at the intra-fiber level. The mechanical events, which were the most affected by fatigue, were the last to lengthen.


Assuntos
Contração Muscular , Fadiga Muscular , Músculo Esquelético/fisiologia , Tempo de Reação , Adulto , Humanos , Masculino , Músculo Esquelético/inervação , Miografia/métodos , Transmissão Sináptica
11.
Arch Ital Urol Androl ; 89(4): 259-265, 2017 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-29473374

RESUMO

OBJECTIVE: The main outcome of this review was the association between a history of clinical chronic prostatitis (NIH category II or III) and a histologically confirmed diagnosis of prostate cancer. MATERIALS AND METHODS: Crude odds ratios and 95% confidence intervals (CI) were calculated to analyze dichotomous data. For analysis of pooled data we adopted a random-effects model and the inverse variance weighing method. Heterogeneity was assessed by calculating the I2 value. RESULTS: Out of 2794 screened records, we retrieved 16 full-text articles written in English, reporting the data of 15 case-control studies, involving 422.943 patients. Pooled analysis resulted in a significant crude odds ratio of 1.83 (95% CI: 1.43 to 2.35; P < 0.00001). The total set of data showed considerable heterogeneity (I2 = 91%). Both the Egger's test and the Begg's test for funnel plot asymmetry did not reach statistical significance. The 'trim and fill' method applied to the funnel plot imputed 3 missing studies and the resulting adjusted estimate of the odds ratio was 2.12 (95% CI: 1.38 to 3.22). According to GRADE criteria, the overall quality of the meta-analysis data is low, mainly due to the presence of bias, confounders and extreme effect size outliers. Five among the included studies reported data assessed in 8015 African-American subjects. Pooled analysis resulted in a non-significant crude odds ratio of 1.59 (95% CI: 0.71 to 3.57; P = 0.26), and considerable heterogeneity (I2 = 90%). CONCLUSIONS: Meta-analysis of 15 case-control studies shows that a history of clinical chronic prostatitis can significantly increase the odds for prostate cancer in the general population, whereas such association in African-American individuals remains uncertain.

12.
Biomacromolecules ; 17(9): 2882-90, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27463471

RESUMO

Photoactivatable keratin sponges were prepared from protein aqueous solutions by the freeze-drying method, followed by photofunctionalization with two different photosensitizers (PS): Azure A (AzA) and 5,10,15,20-tetrakis [4-(2-N,N,N-trimethylethylthio)-2,3,5,6-tetrafluorophenyl]porphyrin tetraiodide salt (TTFAP). The prepared sponges have a porosity between 49% and 80% and a mean pore size in the 37-80 µm range. As compared to AzA, TTFAP interacts more strongly with the sponges as demonstrated by a lower PS release (6% vs 20%), a decreased swelling ratio (1.6 vs 7.4), and a slower biodegradation rate. Nevertheless, AzA-loaded sponges showed the highest photoactivity, as also demonstrated by their higher antibactericidal activity toward both Gram-positive and Gram-negative bacteria. The obtained results suggest that the antimicrobial photodynamic effect can be finely triggered through a proper selection of the amount and type of photosensitizer, as well as through the irradiation time. Finally, all the prepared sponges support human fibroblast cells growth, while no significant cell viability impairment is observed upon light irradiation.


Assuntos
Anti-Infecciosos/farmacologia , Queratinas/química , Queratinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Lã/química , Animais , Anti-Infecciosos/química , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Humanos , Luz , Pseudomonas aeruginosa/efeitos da radiação , Staphylococcus aureus/efeitos da radiação
13.
J Inorg Biochem ; 162: 44-51, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27293144

RESUMO

The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC50 (µM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC50 are halved. Therefore, after replacing OH curcumin groups with OCH3, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity.


Assuntos
Antineoplásicos/síntese química , Derivados de Benzeno/química , Benzeno/química , Complexos de Coordenação/síntese química , Curcumina/química , Monoterpenos/química , Rutênio/química , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Células MCF-7 , Especificidade de Órgãos , Relação Estrutura-Atividade
14.
Arch Ital Urol Androl ; 88(1): 38-46, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-27072174

RESUMO

OBJECTIVE: To analyze the clinical evidence on the efficacy of phytotherapy in the treatment of calculi in the urinary tract. METHODS: To be eligible, full-length articles should include the results of randomized controlled trials enrolling patients affected by urolithiasis, reporting any comparison between an experimental herbal agent versus placebo or any active comparator, aimed at preventing the formation or facilitating the dissolution of calculi in any portion of the urinary tract. Fifteen databases were searched for relevant references. The primary outcomes investigated were (i) the reduction of stone size and/or number and (ii) the urinary excretion rates of calcium, urate, or oxalate. The secondary outcome of the review was the adverse effects (AE) of treatment. Risk of bias (ROB) and quality of the evidence were assessed according to Cochrane and GRADE guidelines. We performed a random-effect meta-analysis. RESULTS: 541 articles were retrieved and 16 studies were finally confirmed as eligible. Multiple Cochrane ROB tool items were rated as having high risk of bias in each analyzed trial report. Pooled analysis of continuous data could be performed for three different comparisons: (i) phytotherapy versus citrate as single agent (ii) phytotherapy versus placebo, (iii) preparation of Didymocarpus pedicellata (DP)--combined with other herbal agents--versus placebo. Results showed that citrate is superior to phytotherapy in significantly decreasing both the size of urinary stones (mean difference: phytotherapy, 0.42 mm higher; 95% CI: 0.23 to 0.6; Z = 4.42, P < 0.0001; I2 = 30%) and the urinary excretion rate of urate (mean difference: 42.32 mg/24h higher, 95% CI: 19.44 to 65.19; Z = 3.63, P = 0.0003; I2 = 96%), assessed after 3 months on-therapy. No significant differences in the excretion rates of urinary calcium or oxalate were found. The DP preparation was superior to placebo in inducing total clearance (risk ratio: 6.19, 95% CI: 2.60 to 14.74; Z = 4.12, P < 0.0001; I2 = 0%) and size reduction (mean difference: DP preparation, 4.93 mm lower; 95% CI: -9.18 to -0.67; Z = 2.27, P = 0.02; I2 = 99%) of renal and ureteral stones after 3 months of therapy. No significant differences in the inter-arm variation of excretion rates of urinary calcium or urate were found as result of the pooled phytotherapy-placebo comparison. Herbal remedies were in general devoid of side effects and in few cases citrate appeared to induce GI disturbances in a higher fraction of patients. Most reports did not provide inferential data concerning AE, and meta-analysis was not feasible. CONCLUSIONS: Citrate is more effective than phytotherapy in decreasing the size of existing calculi in the urinary tract and in decreasing the urinary excretion rate of uric acid. A preparation containing Didymocarpus pedicellata combined with other herbal agents induces stone size reduction and clearance significantly better than placebo. Mayor limitations in the applicability of these results are the low quality of the evidence and the multiple sources of bias assessed in the studies included in the present review.


Assuntos
Preparações de Plantas/uso terapêutico , Plantas Medicinais/química , Cálculos Urinários/tratamento farmacológico , Cálcio/urina , Ácido Cítrico/efeitos adversos , Ácido Cítrico/uso terapêutico , Humanos , Ácido Oxálico/urina , Fitoterapia/métodos , Preparações de Plantas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Úrico/urina , Cálculos Urinários/patologia
15.
Neuromuscul Disord ; 26(1): 60-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26520850

RESUMO

The electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Component duration and measurement reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n = 13) and in healthy controls (n = 13). EMG, mechanomyogram, and force were recorded in DM1 and in age- and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles. Measurement reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions.


Assuntos
Contração Muscular/fisiologia , Relaxamento Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/patologia , Acelerometria , Adolescente , Adulto , Idoso , Análise de Variância , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicofísica , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Detecção de Sinal Psicológico , Adulto Jovem
16.
Arch Ital Urol Androl ; 87(2): 121-9, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26150028

RESUMO

OBJECTIVE: We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC) that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel). MATERIALS AND METHODS: We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS) and severe adverse effects (grade 3 or higher). RESULTS: Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebo-treated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001). Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05). CONCLUSIONS: In docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or to best of care at the time of study (mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. Further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. Large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona , Androstenos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Medicina Baseada em Evidências , Humanos , Imidazóis/administração & dosagem , Ipilimumab , Masculino , Naftalenos/administração & dosagem , Feniltioidantoína/administração & dosagem , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/secundário , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Análise de Sobrevida , Taxoides/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
17.
Cancer Lett ; 364(2): 12017 Apr, 2015 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-25979228

RESUMO

Activation of hypoxia-inducible factor (HIF)-1 is a feature of hypoxic solid tumors that has been associated with drug resistance, mainly due to disruption of Bcl-2 family dynamics. Resetting the balance in favor of proapoptotic family members is an attractive therapeutic goal that has been pursued by developing BH3-mimetic compounds. In the present study we evaluated the response of human colon adenocarcinoma cells to the BH3-mimetic obatoclax (OBX), in terms of growth arrest, apoptosis and autophagy, in the presence or absence of HIF-1α-stabilizing conditions; its possible effect on HIF-1α expression and HIF-1 activity; and the possibility to improve the response of colon cancer cells to cytotoxic chemotherapeutics by combining them with OBX. Colon cancer cell response to the BH3-mimetic was unmodified by HIF-1 activation and OBX induced a decrease in HIF-1α protein levels and HIF-1 transcriptional activity, probably by decreasing HIF-1α synthesis and facilitating a VHL-independent proteasomal degradation pathway. Finally, a chemosensitizing effect of OBX with respect to 5-fluorouracil or oxaliplatin treatment was observed, highlighting the possibility that patients with hypoxic colon tumors might benefit from combined regimens including OBX.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/genética , Pirróis/farmacologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Fluoruracila/administração & dosagem , Células HCT116 , Células HT29 , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pirróis/administração & dosagem , Ativação Transcricional/efeitos dos fármacos
18.
Oncotarget ; 6(10): 7851-65, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25797262

RESUMO

As widely recognized, tumor growth entails a close and complex cross-talk among cancer cells and the surrounding tumor microenvironment. We recently described the human RNASET2 gene as one key player of such microenvironmental cross-talk. Indeed, the protein encoded by this gene is an extracellular RNase which is able to control cancer growth in a non-cell autonomous mode by inducing a sustained recruitment of immune-competent cells belonging to the monocyte/macrophage lineage within a growing tumor mass. Here, we asked whether this oncosuppressor gene is sensitive to stress challenges and whether it can trigger cell-intrinsic processes as well. Indeed, RNASET2 expression levels were consistently found to increase following stress induction. Moreover, changes in RNASET2 expression levels turned out to affect several cancer-related parameters in vitro in an ovarian cancer cell line model. Of note, a remarkable rearrangement of the actin cytoskeleton organization, together with changes in cell adhesion and motility, emerged as putative mechanisms by which such cell-autonomous role could occur. Altogether, these biological features allow to put forward the hypothesis that the RNASET2 protein can act as a molecular barrier for limiting the damages and tissue remodeling events occurring during the earlier step of cell transformation.


Assuntos
Neoplasias Ovarianas/genética , Ribonucleases/genética , Proteínas Supressoras de Tumor/genética , Animais , Processos de Crescimento Celular/fisiologia , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Feminino , Células HeLa , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ribonucleases/biossíntese , Ribonucleases/metabolismo , Transdução de Sinais , Microambiente Tumoral , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/metabolismo
19.
Hum Mutat ; 36(3): 357-68, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25545067

RESUMO

Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression.


Assuntos
Condroitina Sulfatases/genética , Mucopolissacaridose IV/diagnóstico , Mucopolissacaridose IV/genética , Mutação , RNA Mensageiro/genética , Adolescente , Adulto , Linhagem Celular , Condroitina Sulfatases/química , Feminino , Fibroblastos , Humanos , Linfócitos , Masculino , Fenótipo , Prognóstico , Isoformas de Proteínas/genética , Pele/citologia , Adulto Jovem
20.
Inorg Chem ; 53(7): 3668-77, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24611608

RESUMO

We report on the synthesis of novel water-soluble [(arene)Ru(II)(Q)Cl] and [(arene)Ru(II)(Q)(X)]BF4 compounds (arene = p-cymene, benzene, hexamethylbenzene; HQ = 1,3-dimethyl-4-R-(C═O)-5-pyrazolone, HQ(Me), R = methyl, HQ(Ph), R = phenyl, HQ(Naph), R = naphthyl; X = H2O, 9-ethylguanine), and their in vitro antitumor activity toward the cell lines MCF7 (HTB-22, human breast adenocarcinoma), HCT116 (CCL-247, human colorectal carcinoma), A2780 (human ovarian carcinoma), A549 (CCL-185, human lung carcinoma), and U87 MG (HTB-1, human glioblastoma). The X-ray crystal structures of two complexes were determined. One of them, {chlorido-(p-cymene)-[(1,3-dimethyl-4-(1-naphthoyl)-pyrazolon-5-ato]ruthenium(II)}, was also studied with density functional theory methods and was selected for docking on a DNA octamer showing intercalation between DNA bases by the naphthyl moiety and for Ru-N7(guanine) bonding.


Assuntos
Antineoplásicos/química , DNA de Neoplasias/efeitos dos fármacos , Substâncias Intercalantes/química , Compostos de Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Guanina/química , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/farmacologia , Ligantes , Modelos Moleculares , Compostos de Rutênio/síntese química , Compostos de Rutênio/farmacologia
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