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1.
Nature ; 572(7771): 676-680, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391581

RESUMO

The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, has a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements1,2. In cancer cells, the disruption of CTCF binding at specific loci by somatic mutation3,4 or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ-cell-specific paralogue of CTCF, BORIS (brother of the regulator of imprinted sites, also known as CTCFL)6, is overexpressed in several cancers7-9, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma10 cells that develop resistance to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS-to promote regulatory chromatin interactions that support specific cancer phenotypes.


Assuntos
Cromatina/genética , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Animais , Fator de Ligação a CCCTC/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Camundongos , Terapia de Alvo Molecular , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/enzimologia , Neuroblastoma/genética , Fenótipo , Ligação Proteica
2.
Dermatol Surg ; 47(5): 649-656, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33840781

RESUMO

BACKGROUND: Fibrous septae play a role in contour alterations associated with cellulite. OBJECTIVE: To assess collagenase clostridium histolyticum-aaes (CCH) for the treatment of cellulite. MATERIALS AND METHODS: Two identically designed phase 3, double-blind, randomized studies (RELEASE-1 and RELEASE-2) were conducted. Adult women with moderate/severe cellulite (rating 3-4 on the Patient Reported Photonumeric Cellulite Severity Scale [PR-PCSS] and Clinician Reported PCSS [CR-PCSS]) on the buttocks received up to 3 treatment sessions of subcutaneous CCH 0.84 mg or placebo per treatment area. Composite response (≥2-level or ≥1-level improvement from baseline in both PR-PCSS and CR-PCSS) was determined at Day 71. RESULTS: Eight hundred forty-three women received ≥1 injection (CCH vs placebo: RELEASE-1, n = 210 vs n = 213; RELEASE-2, n = 214 vs n = 206). Greater percentages of CCH-treated women were ≥2-level composite responders versus placebo in RELEASE-1 (7.6% vs 1.9%; p = .006) and RELEASE-2 (5.6% vs 0.5%; p = .002) and ≥1-level composite responders in RELEASE-1 (37.1% vs 17.8%; p < .001) and RELEASE-2 (41.6% vs 11.2%; p < .001). Most adverse events (AEs) in the CCH group were injection site related; few CCH-treated women discontinued because of an AE (≤4.3%). CONCLUSION: Collagenase clostridium histolyticum-aaes significantly improved cellulite appearance and was generally well tolerated.


Assuntos
Celulite/tratamento farmacológico , Colagenase Microbiana/uso terapêutico , Anticorpos Neutralizantes/sangue , Método Duplo-Cego , Feminino , Humanos , Reação no Local da Injeção/etiologia , Colagenase Microbiana/efeitos adversos , Colagenase Microbiana/imunologia , Pessoa de Meia-Idade , Satisfação do Paciente , Resultado do Tratamento
3.
J Urol ; 203(6): 1191-1197, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31922462

RESUMO

PURPOSE: We assessed the long-term safety and immunogenicity profile of collagenase clostridium histolyticum and characterized penile curvature deformity over time in patients previously treated for Peyronie's disease. MATERIALS AND METHODS: This phase 4 study included men who received collagenase clostridium histolyticum in either 12-month, double-blind, placebo controlled clinical trials (IMPRESS I/II), or one of two 9-month open label studies. Eligible patients received no additional collagenase clostridium histolyticum treatment and were followed once yearly for up to 5 years to assess Peyronie's disease clinical symptoms, patient reported outcomes and safety. RESULTS: Of 280 patients enrolled 204 (73%) completed the study. At baseline 247 patients had already experienced a mean±SD penile curvature decrease from 51.8±15.0 to 31.0±16.1 degrees (improvement of 20.9±16.2 degrees or 39.5%). At year 5 in 180 patients, despite no additional treatment, there was an additional 9.1% improvement in mean penile curvature compared with reference data (4.3±13.4 degrees, 95% CI 2.3-6.2, p <0.02). At baseline 183 patients experienced mean Peyronie's Disease Questionnaire bother domain score improvement from 6.5±3.5 to 3.4±3.3. At year 5 there was additional score improvement to 2.4±2.9 (p=0.0003). Adverse events were reported in 17.5% (49) of patients but no adverse events were considered treatment related. No long-term safety issues were identified up to 5 years after treatment. Long-term immunogenicity profiling showed a decreasing trend in the number of anti-AUX-I and anti-AUX-II seropositive cases at years 4 and 5 after collagenase clostridium histolyticum treatment. CONCLUSIONS: Most patients treated with collagenase clostridium histolyticum continued to have penile curvature and Peyronie's Disease Questionnaire domain score improvements through year 5 without additional collagenase clostridium histolyticum treatment, and no additional safety signals were identified.


Assuntos
Colagenase Microbiana/uso terapêutico , Induração Peniana/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Induração Peniana/diagnóstico , Induração Peniana/imunologia , Induração Peniana/patologia , Estudos Prospectivos , Resultado do Tratamento
4.
Pediatr Res ; 87(3): 463-471, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31493768

RESUMO

BACKGROUND: Magnesium sulfate (MgSO4) is utilized for fetal neuroprotection in preterm birth but its mechanism of action is still poorly understood. P2X7 receptor (P2X7R) is required for secretion of IL-1ß, and can be blocked by divalent cations such as magnesium (Mg) and its own antagonist, Brilliant Blue G (BBG). We sought to determine whether during inflammation MgSO4 can block endothelial IL-1ß secretion, using an in-vitro model. METHODS: Human umbilical vein endothelial cell (HUVEC) cultures were treated with varying doses of LPS, 2'(3)-Ο-(4-Benzoylbenzoyl) adenosine-5'-triphosphate (BzATP), BBG and MgSO4 for 3- or 24 h. We determined cell cytotoxicity, apoptosis, IL-1ß mRNA expression, IL-1ß production and secretion and P2X7R expression on HUVECs. RESULTS: We demonstrated that MgSO4 is efficacious in blocking IL-1ß-mediated-inflammation in HUVECs, at both the initiation and propagation phases of inflammation. MgSO4 exerts these anti-inflammatory effects via downregulation of P2X7Rs on HUVECs. CONCLUSION: LPS-exposure increases IL-1ß production and secretion in HUVECs, which is further intensified by P2X7R agonist, BzATP while MgSO4 inhibits IL-1ß in both presence and absence of BzATP. This effect is similar to the results of P2X7R antagonist, BBG, suggesting that the anti-inflammatory effects of MgSO4 is through P2X7R.


Assuntos
Anti-Inflamatórios/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inflamação/prevenção & controle , Sulfato de Magnésio/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Via Secretória , Transdução de Sinais
5.
Dermatol Surg ; 46(12): 1628-1635, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33009069

RESUMO

BACKGROUND: The Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) and Patient Reported PCSS (PR-PCSS) are newly developed tools for assessing cellulite severity. OBJECTIVE: To report on the reliability, validity, and ability to detect a change in cellulite severity on the buttocks of adult women with the CR-PCSS and PR-PCSS. MATERIALS AND METHODS: Content validity of both scales was established through concept elicitation and cognitive interviews. Test-retest reliability was evaluated, and intra-rater (both scales) and inter-rater (CR-PCSS only) reliability were estimated using intraclass correlation coefficients (ICCs) for agreement and consistency. Ability to detect a change was determined using the Subject-Global Aesthetic Improvement Scale (GAIS) or Investigator-GAIS as anchors. RESULTS: For the CR-PCSS (n = 6) at baseline and Day 2, the mean interrater ICCs were ≥0.70 and mean intrarater ICCs (95% confidence interval [CI]) were ≥0.81 (0.72-0.90) for both buttocks. For the PR-PCSS (n = 99) at baseline and Day 14, the mean test-retest reliability ICCs (95% CI) were ≥0.86 (0.79-0.91) for both buttocks. A clinically meaningful change was 1.0 point on the PR-PCSS and 1.0 on the CR-PCSS. CONCLUSION: The CR-PCSS and PR-PCSS reliably assess cellulite severity of the buttocks and can detect a clinically meaningful change after treatment for cellulite.


Assuntos
Nádegas/diagnóstico por imagem , Celulite/diagnóstico , Medidas de Resultados Relatados pelo Paciente , Índice de Gravidade de Doença , Adulto , Idoso , Celulite/terapia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Dermatologistas/estatística & dados numéricos , Estética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Fotografação/estatística & dados numéricos , Pesquisa Qualitativa , Reprodutibilidade dos Testes , Cirurgiões/estatística & dados numéricos , Resultado do Tratamento , Adulto Jovem
6.
J Drugs Dermatol ; 19(9): 852-856, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026751

RESUMO

BACKGROUND: Clostridium collagenase histolyticum (CCH) is being evaluated in women as a cellulite treatment. OBJECTIVE: To report preclinical safety and human pharmacokinetics (PK) and safety data for CCH. METHODS: Across 3 PK studies, 41 women received 12 subcutaneous injections per thigh/buttock in 1 session (up to 3.36 mg/dose). Blood samples were taken at baseline; at 5, 10, 20, and 30 minutes postdose; and at 1, 2, 4, 8, 12, 24, 48, 168, and 504 hours postdose. In a preclinical study, rats received 0, 0.029, 0.13, or 0.29 mg/dose of CCH intravenously (IV) every other day (QOD) for 16 days (total, 8 doses) and were evaluated for histopathologic changes. RESULTS: In human PK studies, no quantifiable plasma concentrations of AUX-I or AUX-II were observed postdose (n= 39 evaluable). Adverse events were injection site–related (bruising [97.6%], pain [87.8%], and edema/swelling [46.3%]). Antidrug antibodies were seen in most women at 504 hours postdose. In rats, plasma concentrations of AUX-I and AUX-II (CCH components) were measurable for 30 minutes and 1-2 hours, respectively, after IV administration. At ≥43× proposed human therapeutic dose on a mg/kg basis, rats experienced elevated liver enzyme levels, increased liver weights, and histologic changes that were mostly reversed during a 14-day recovery period. CONCLUSIONS: In human studies, no quantifiable circulating CCH levels were observed after a single subcutaneous dose of CCH up to 3.36 mg. Preclinical data indicated that repeat IV dosing (QOD; 8 doses) at ≥43× proposed human dose on a mg/kg basis for CCH was generally well tolerated.J Drugs Dermatol. 2020;19(9):852-856. doi:10.36849/JDD.2020.5048THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.


Assuntos
Celulite/tratamento farmacológico , Colagenase Microbiana/farmacocinética , Adulto , Idoso , Animais , Nádegas , Celulite/sangue , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Injeções Intralesionais , Injeções Intravenosas , Masculino , Colagenase Microbiana/administração & dosagem , Colagenase Microbiana/sangue , Colagenase Microbiana/toxicidade , Pessoa de Meia-Idade , Ratos , Coxa da Perna , Testes de Toxicidade Subaguda , Resultado do Tratamento
7.
Biol Reprod ; 101(5): 1046-1055, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31403169

RESUMO

Maternal inflammation (MI) is associated with many adverse perinatal outcomes. The placenta plays a vital role in mediating maternal-fetal resource allocation. Studies have shown that MI contributes to placental dysfunction, which then leads to adverse birth outcomes and high health risks throughout childhood. Placental mammalian target of rapamycin complex 1 (mTORC1) signaling pathway links maternal nutrient availability to fetal growth; however, the impact of MI on mTORC1 signaling in the placenta remains unclear. In this study, we sought to explore the changes of mTORC1 signaling in the mouse placenta at late gestation by using two models of MI employing lipopolysaccharide (LPS) and interleukin-1ß (IL-1ß) to mimic acute (aMI) and sub-chronic (cMI) inflammatory states, respectively. We determined placental mTORC1 activity by measuring the activity of mTORC1 downstream molecules, including S6k, 4Ebp1, and rpS6. In the aMI model, we found that mTORC1 activity was significantly decreased in the placental decidual and junctional zone at 2 and 6 h after LPS surgery, respectively; however, mTORC1 activity was significantly increased in the placental labyrinth zone at 2, 6, and 24 h after LPS treatment, respectively. In the cMI model, we observed that mTORC1 activity was increased only in the placental labyrinth zone after consecutive IL-1ß exposure. Our study reveals that different parts of the mouse placenta react differently to MI, leading to variable mTORC1 activity throughout the placenta. This suggests that different downstream molecules of mTORC1 from different parts of the mouse placenta may be used in clinical research to monitor the fetal well-being during MI.


Assuntos
Inflamação/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Placenta/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Interleucina-1beta/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Fosforilação , Gravidez , Distribuição Aleatória , Proteína S6 Ribossômica/genética , Proteína S6 Ribossômica/metabolismo
8.
Brain Behav Immun ; 75: 129-136, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30261304

RESUMO

Interleukin-1 beta (IL-1ß) is a cytokine mediator of perinatal brain injury. The effect of sub-chronic systemic IL-1ß exposure in perinatal and offspring outcomes is unclear. The aim of this study was to examine the effects of maternal IL-1ß exposure on pregnancy and offspring outcomes. At E15, CD1 dams were allocated to receive intraperitoneal injection of phosphate buffered saline or mouse recombinant IL-1ß (1 mcg) for four consecutive days. We analyzed pup survivaland neurobehavioral status. At E18, placental H&E staining and fetal brain Nissl staining was performed. Placental gene expression was analyzed by qPCR and T cell infiltration was analyzed by flow cytometry. Effects of inflammation on feto-placental blood flow were analyzed by Doppler ultrasonography. IL-1ß decreased pup survival (P < .0001) and adversely affected offspring performance on neurodevelopmental tests (P < .05). Placentas of exposed dams exhibited significant thinning of maternal and fetal sides, and fetal brain exhibited cortical thinning. Placental qPCR analysis revealed significant upregulation of NFκB2 (P = .0021) and CXCL11 (P = .0401). While maternal IL-1ß exposure did not affect feto-placental blood flow, placental flow cytometry showed an increase in placental infiltration of CD4+ T cells at 24 h post-injection (hpi, P < .0001) and CD8+ T cells at 72 hpi (P = .0217). Maternal sub-chronic, systemic inflammation with IL-1ß decreased pup survival and played a key role in perinatal brain injury. The mechanisms behind these outcomes may involve immune system activation and alterations in placental T cell trafficking.


Assuntos
Interleucina-1beta/efeitos adversos , Placenta/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Lesões Encefálicas/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Feminino , Feto/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/fisiologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Gravidez
9.
J Pineal Res ; 67(3): e12591, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231832

RESUMO

Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.


Assuntos
Inflamação/tratamento farmacológico , Inflamação/metabolismo , Melatonina/uso terapêutico , Placenta/efeitos dos fármacos , Placenta/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hemodinâmica/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Camundongos , Insuficiência Placentária/tratamento farmacológico , Insuficiência Placentária/metabolismo , Gravidez , Ultrassonografia Doppler
10.
Dermatol Surg ; 45(8): 1047-1056, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30829779

RESUMO

BACKGROUND: Edematous fibrosclerotic panniculopathy (EFP; cellulite) is associated with thickening and contraction of collagen-rich subdermal septae. Collagenase clostridium histolyticum (CCH) may disrupt collagen-rich septae. OBJECTIVE: To evaluate the safety and efficacy of CCH for treatment of EFP. MATERIALS AND METHODS: In a randomized, double-blind study, women with moderate or severe EFP of the buttocks or posterolateral thighs (i.e., Clinician Reported Photonumeric Cellulite Severity Scale [CR-PCSS] and Patient Reported Photonumeric Cellulite Severity Scale [PR-PCSS] ratings of 3 to 4, and Hexsel Cellulite Severity Scale score ≤13) received up to 3 treatment sessions (Days 1, 22, and 43) of subcutaneous CCH 0.84 mg or placebo injections. End points included the percentage of 2-level and 1-level composite responders (i.e., had ≥2-level or ≥1-level improvement in CR-PCSS and PR-PCSS) at Day 71. RESULTS: Three hundred seventy-five women (mean age, 46.5 years; 86.4% white) were randomly assigned to CCH (n = 189) or placebo (n = 186). At Day 71, the percentages of 2-level and 1-level composite responders were greater with CCH (10.6% and 44.6%, respectively) versus placebo (1.6% and 17.9%; p < .001 for both). The most common adverse events were injection-site related. CONCLUSION: CCH significantly improved EFP appearance versus placebo; further evaluation of CCH for EFP (cellulite) is warranted.


Assuntos
Celulite/tratamento farmacológico , Colagenase Microbiana/uso terapêutico , Nádegas , Método Duplo-Cego , Edema/tratamento farmacológico , Feminino , Humanos , Injeções Intralesionais , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Coxa da Perna
11.
Biol Blood Marrow Transplant ; 23(2): 255-261, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27888016

RESUMO

Lapses in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) warrant novel approaches. Such approaches include, among others, the use of post-transplantation cyclophosphamide (PTC) and proteasome inhibitors. Although PTC alone consistently produces low rates of chronic GVHD, the incidence of acute GVHD remains significant. Inversely, prolonged post-transplantation administration of proteasome inhibitors carries a risk of paradoxical aggravation of GVHD. We examined whether the combination of cyclophosphamide and ixazomib addresses the limitations of each of these agents when used alone to prevent GVHD in mice subjected to allogeneic HSCT across MHC barriers. We chose ixazomib, an orally bioavailable proteasome inhibitor, because of its favorable physiochemical characteristics. The combination of cyclophosphamide and ixazomib improved overall survival of mice in comparison to an untreated control group and to groups receiving either cyclophosphamide alone or ixazomib alone. Furthermore, cyclophosphamide prevented the surge of IL-1ß, GVHD aggravation, and sudden death associated with prolonged administration of ixazomib after HSCT. Finally, we demonstrated that although ixazomib was administered before cyclophosphamide, it did not impair the preferential depletion of proliferating as opposed to resting donor T cells. Our data suggest that the combination of cyclophosphamide and ixazomib for the prevention of GVHD after allogeneic HSCT is promising and merits further investigation in clinical trials.


Assuntos
Compostos de Boro/uso terapêutico , Ciclofosfamida/uso terapêutico , Glicina/análogos & derivados , Doença Enxerto-Hospedeiro/prevenção & controle , Inibidores de Proteassoma/uso terapêutico , Animais , Transplante de Medula Óssea/efeitos adversos , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/farmacologia , Citocinas/sangue , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Glicina/administração & dosagem , Glicina/farmacologia , Glicina/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Intestino Delgado/patologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/farmacologia , Quimera por Radiação , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/transplante
12.
J Neuroinflammation ; 14(1): 180, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874190

RESUMO

BACKGROUND: Recent evidence suggests that exposure to intrauterine inflammation causes acute fetal brain injury and is linked to a spectrum of neurobehavioral disorders. In a rodent model of intrauterine inflammation induced by lipopolysaccharide (LPS) exposure in utero, activated microglia can be detected in the hippocampus of offspring survivors, as late as 60 days postnatal (DPN). Given that the hippocampus is important for learning and memory, these results suggest that in utero inflammation underlies long-term cognitive deficits observed in children/survivors. METHODS: An established mouse model of LPS-induced intrauterine inflammation was used to study hippocampal function from offspring at 44-59 DPN. Microgliosis was examined at 45 DPN. Extracellular field recordings of synaptic transmission were performed on acute hippocampal slices. RESULTS: LPS offspring mice displayed persistent microglial activation and increased CA3-CA1 excitatory synaptic strength, which can be explained in part by an increase in the probability of glutamate release, and reduced long-term synaptic potentiation compared to control mice. CONCLUSIONS: These results offer a mechanistic explanation for the cognitive and behavioral deficits observed in survivors of preterm birth caused by intrauterine inflammation.


Assuntos
Modelos Animais de Doenças , Hipocampo/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transmissão Sináptica/fisiologia , Útero/metabolismo , Animais , Feminino , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Técnicas de Cultura de Órgãos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sobreviventes , Transmissão Sináptica/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/patologia
13.
Inorg Chem ; 55(10): 5000-13, 2016 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-27119456

RESUMO

The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-ß (Aß) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as a useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure-reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure-reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the Aß sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced Aß aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, Aß, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.


Assuntos
Aminoquinolinas/química , Peptídeos beta-Amiloides/química , Antioxidantes/química , Dimetilaminas/química , Fragmentos de Peptídeos/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Aminoquinolinas/síntese química , Aminoquinolinas/toxicidade , Animais , Antioxidantes/síntese química , Antioxidantes/toxicidade , Linhagem Celular Tumoral , Cobre/química , Dimetilaminas/síntese química , Dimetilaminas/toxicidade , Humanos , Camundongos , Simulação de Acoplamento Molecular , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Multimerização Proteica , Espécies Reativas de Oxigênio/química , Relação Estrutura-Atividade , Zinco/química
14.
Urology ; 175: 126-131, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36863600

RESUMO

OBJECTIVE: To evaluate cumulative and incremental changes in penile curvature after each treatment cycle of collagenase clostridium histolyticum (CCH) in men with Peyronie's disease (PD). METHODS: Data from 2 phase 3, randomized, placebo-controlled trials were analyzed post hoc. Treatment was administered in up to 4 treatment cycles (per cycle: 2 injections, 1-3 days apart, of CCH 0.58 mg or placebo; subsequent penile modeling) at 6-week intervals. Penile curvature was measured at baseline and after each treatment cycle (weeks 6, 12, 18, and 24). Successful response was defined as ≥20% reduction from baseline penile curvature. RESULTS: Overall, 832 men (CCH, n = 551; placebo, n = 281) were included in the analysis. After each cycle, mean cumulative percent reduction from baseline penile curvature was significantly greater with CCH vs placebo (P <.001). Following one cycle, 29.9% of CCH recipients exhibited a successful response. Among nonresponders, additional cycles of injections led to further successful responses: 60.8% of first cycle failures achieved response after fourth cycle (8 injections), 42.7% of cycle 1-2 failures achieved response after fourth cycle, and 23.5% of cycle 1-3 failures achieved response after fourth cycle. CONCLUSION: Data showed incremental benefits from each of the 4 CCH treatment cycles. Completion of a full series of 4 CCH treatment cycles may optimize improvements in penile curvature in men with PD, including among those who did not clinically respond to previous treatment cycles.


Assuntos
Colagenase Microbiana , Induração Peniana , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Colagenase Microbiana/administração & dosagem , Induração Peniana/tratamento farmacológico , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como Assunto
15.
Am J Reprod Immunol ; 89(3): e13662, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36458539

RESUMO

PROBLEM: Protective effects for adult neurological disorders have been attributed to sex hormones. Using a murine model of prematurity, we evaluated the role of estrogen signaling in the process of perinatal brain injury following exposure to intrauterine inflammation. METHOD OF STUDY: Intrauterine lipopolysaccharide (LPS) was used to invoke preterm labor and fetal neuroinflammation. Fetal brains were analyzed for changes in Esr1, Esr2 and Cyp19. Dams heterozygous for the Esr1 knockout allele were also given intrauterine LPS to compare delivery and offspring viability to wild type controls. RESULTS: The upregulation in inflammatory cytokines was accompanied by an increase in Esr1 and Esr2 transcripts, though protein levels declined. Cyp19 did not differ by mRNA or protein abundance. Offspring from Esr1 mutants were larger, had a longer gestation and significantly greater mortality. CONCLUSIONS: Estrogen signaling is altered in the fetal brains of preterm offspring exposed to neuroinflammatory injury. The reduction of Esr1 and Esr2 proteins with LPS suggests that these proteins are degraded. It is possible that transcriptional upregulation of Esr1 and Esr2 occurs to compensate for the loss of these proteins. Alternatively, the translation of Esr1 and Esr2 mRNAs may be disrupted with LPS while a feedback mechanism upregulates transcription. Intact Esr1 signaling is also associated with early preterm delivery following exposure to intrauterine LPS. A loss of one Esr1 allele delays this process, but appears to do so at the cost of fetal viability. These results suggest estrogen signaling plays opposing roles between maternal and fetal responses to preterm birth.


Assuntos
Receptor alfa de Estrogênio , Viabilidade Fetal , Nascimento Prematuro , Animais , Feminino , Camundongos , Gravidez , Aromatase , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Viabilidade Fetal/genética , Lipopolissacarídeos , Nascimento Prematuro/genética , Nascimento Prematuro/metabolismo
16.
Plast Reconstr Surg Glob Open ; 10(5): e4306, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35646496

RESUMO

Background: Collagen-rich fibrous septae and subcutaneous adipose protrusions play a role in cellulite pathophysiology. Collagenase clostridium histolyticum-aaes (CCH-aaes) injection causes enzymatic release of septae to resolve cellulite depressions and create a skin smoothing effect. This analysis pooled data from two identically designed, phase-3, randomized, double-blind, placebo-controlled studies to examine the efficacy and safety of CCH-aaes. Methods: Adult women with moderate/severe cellulite (3-4 on Clinician Reported Photonumeric Cellulite Severity Scale and Patient Reported Photonumeric Cellulite Severity Scale) on the buttocks received up to three treatment sessions (Days 1, 22, and 43) of subcutaneous CCH-aaes 0.84 mg or placebo per treatment area. Composite and individual component response (≥2-level or ≥1-level improvement from baseline in Patient Reported Photonumeric Cellulite Severity Scale and/or Clinician Reported Photonumeric Cellulite Severity Scale) and additional patient-reported outcomes were determined at Day 71. Results: Analysis included 424 CCH-aaes-treated and 419 placebo-treated women. CCH-aaes-treated women were 5.9 times more likely than placebo-treated women to be ≥2-level composite responders at Day 71 (odds ratio [95% confidence interval], 5.9 [2.2-15.4]; P < 0.001). A significantly greater percentage of CCH-aaes-treated women versus placebo-treated women were ≥1-level composite responders at Day 71 (39.4% versus 14.6%; P < 0.001). Subgroup analyses indicated no apparent impact of Fitzpatrick skin type category and baseline cellulite severity (moderate/severe) on CCH-aaes efficacy. An inverse relationship between age and CCH-aaes response was observed in those with a body mass index less than 32 kg per m2. The most common adverse events with CCH-aaes were injection-site bruising and injection-site pain. Conclusion: CCH-aaes treatment significantly improved moderate-to-severe buttock cellulite appearance and was generally well tolerated.

17.
Synapse ; 65(12): 1368-72, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21633976

RESUMO

A number of published studies have questioned the serotonin neurotoxic potential of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and related drugs (fenfluramine, p-chloroamphetamine) based upon results from Western blot studies using a custom synthesized serotonin transporter (SERT) antibody that found no reduction in the abundance of a 50kDa protein after substituted amphetamine treatment. The purpose of this study was to collect Western blot data using the same SERT antibody used in those studies, but with positive and negative controls to identify the SERT protein signal. A 63-68 kDa band that had the regional distribution expected of rat brain SERT, was decreased by 5,7-DHT, and was absent in SERT KO animals was identified as the SERT protein. Significant, lasting decreases in the abundance of the 63-68 kDa band were evident in the rat brain after treatment with MDMA and related drugs (FEN, PCA). Thus, when the band corresponding to the SERT protein is identified in Western blots through the use of positive and negative controls, reduced abundance of the SERT protein can be readily demonstrated after substituted amphetamine treatment. These data provide further evidence of lasting loss of the SERT protein after exposure to MDMA and other substituted amphetamines.


Assuntos
Western Blotting/métodos , Western Blotting/normas , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Animais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Técnicas de Inativação de Genes , Valor Preditivo dos Testes , Ratos , Serotonina/deficiência , Serotoninérgicos/toxicidade , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
18.
J Cosmet Dermatol ; 20(6): 1643-1647, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33735499

RESUMO

BACKGROUND: Collagenase clostridium histolyticum (CCH-aesthetic formulation [CCH-aaes]; QWO™ [Endo Aesthetics, Malvern PA, USA] is approved as a subcutaneous injection for treatment of cellulite. In the aesthetic practice, dilution of marketed products is commonly employed to tailor treatments to individual patients or off-label locations. Dilution beyond the 0.23 mg/ml achievable with the proprietary diluent supplied with the CCH-aaes lyophilized powder requires diluents readily available in clinic. AIM: To characterize the functionality and stability of CCH-aaes when reconstituted and/or diluted with alternative diluents, including normal saline, bacteriostatic saline, and/or proprietary diluent. PATIENTS/METHODS: Each dilution was assessed for purity using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE), activity using collagenase (AUX-I) and gelatinase (AUX-II) assays, and aggregation using size-exclusion chromatography. RESULTS: When reconstituted with either saline or proprietary diluent, and diluted with proprietary diluent or saline, purity, activity, and stability of CCH-aaes is maintained for up to 24 h at 5°C or 25°C. In contrast, use of bacteriostatic saline to reconstitute and/or dilute CCH-aaes results in up to a 40% decrease in activity and aggregation of 5.3% of CCH-aaes protein. Importantly, inclusion of 2% lidocaine and 1:200 000 epinephrine does not negatively impact CCH-aaes purity, concentration, or activity for up to 24 h at 5°C or 25°C. CONCLUSIONS: From an efficacy and safety perspective, CCH-aaes must not be/should not be reconstituted and/or diluted with bacteriostatic saline to avoid injection of protein aggregates. Ideally, CCH-aaes should be reconstituted in proprietary diluent: further dilution with normal saline and addition of lidocaine and epinephrine is acceptable.


Assuntos
Colagenase Microbiana , Induração Peniana , Colagenases , Humanos , Injeções Intralesionais , Masculino , Colagenase Microbiana/uso terapêutico , Induração Peniana/tratamento farmacológico , Resultado do Tratamento
19.
Urology ; 146: 145-151, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32896582

RESUMO

OBJECTIVE: To examine the long-term (5-year) efficacy and safety of collagenase clostridium histolyticum (CCH) therapy in men with Peyronie's disease and varying degrees of plaque calcification. MATERIALS AND METHODS: CCH-treated adult men from the 12-month Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies I/II or 9-month open-label studies were eligible. Degree of plaque calcification (no calcification, noncontiguous stippled calcification, or calcification that did not interfere with CCH injection) was determined by penile x-ray or ultrasound. Penile curvature deformity and Peyronie's Disease Questionnaire responses were assessed annually for up to 5 years, with ≥6 months between consecutive visits. RESULTS: For no calcification group, from baseline to last (Reference) visit during the prior studies (n = 160), mean penile curvature improved by 20.9° ± 16.3° (39.3%) with CCH. Similar improvements with CCH from baseline to Reference were observed in stippled calcification (n = 27; improvement of 24.1° ± 20.2° [42.7%]) and calcification (n = 27; improvement of 21.7° ± 14.8° [43.3%]) subgroups. At Year 5 follow-up in no calcification group (n = 119), an additional 10.0% improvement in mean penile curvature vs Reference (4.3°) occurred. Penile curvature improvements seen at Reference in stippled calcification and calcification groups were maintained through Year 5. Additional numeric improvements in 3 Peyronie's Disease Questionnaire domains were observed at Year 5 visit vs baseline scores. No long-term safety issues were identified. CONCLUSION: This first report of long-term (5-year) CCH clinical trial outcomes in a population with penile plaque calcification demonstrates that nonsurgical intralesional CCH therapy is an appropriate Peyronie's disease treatment in men with penile plaque calcification that is stippled or does not impede CCH injection.


Assuntos
Calcinose/diagnóstico , Colagenase Microbiana/efeitos adversos , Induração Peniana/tratamento farmacológico , Pênis/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Calcinose/etiologia , Calcinose/patologia , Seguimentos , Humanos , Injeções Intralesionais , Masculino , Colagenase Microbiana/administração & dosagem , Pessoa de Meia-Idade , Satisfação do Paciente , Induração Peniana/complicações , Pênis/efeitos dos fármacos , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Plast Reconstr Surg Glob Open ; 8(12): e3316, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33425621

RESUMO

Collagenase clostridium histolyticum-aaes (CCH) enzymatically releases fibrous septa that contribute to the skin dimpling characteristic of cellulite. Long-term safety/duration of efficacy (durability) results from an open-label extension (OLE) of a randomized, double-blind, placebo-controlled trial (RCT) evaluating CCH efficacy/safety for moderate-to-severe cellulite of the buttocks or posterolateral thighs in women was assessed. Efficacy/safety of CCH treatment/retreatment during OLE was also evaluated. METHODS: After RCT unblinding, women could enroll in OLE for assessment of long-term CCH durability (observation only, up to day 720) or CCH treatment/retreatment, the latter in women with moderate-to-severe buttock/posterolateral thigh cellulite [Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) and Patient Reported PCSS (PR-PCSS) scores of 3/4; Hexsel Cellulite Severity Scale score ≤13]. A treatment/retreatment course comprised 1 or 2 courses of 3 sessions (0.84-mg CCH injected at days 1, 22, and 43). CCH efficacy/safety was assessed at baseline, days 22, 43, 71, and quarterly at day 360. RESULTS: Of the 259 OLE participants, 53 were observed for long-term CCH durability. For those who were ≥2-level composite responders during RCT (≥2-point CR-PCSS/PR-PCSS score improvements), CCH effect was durable (scores did not reach RCT baseline levels) in all women on days 180 (19/19), 360 (16/16), and 720 (7/7). Of the 200 women receiving CCH treatment/retreatment, more than 75% had ≥1-level improvement in patient and clinical assessments at day 71. The most common adverse events were injection-site bruising and pain. CONCLUSIONS: CCH treatment provided durable improvement in moderate-to-severe buttock/thigh cellulite and was generally well tolerated. Repeated CCH exposure did not increase adverse event risk or reduce efficacy.

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