RESUMO
Periventricular leukomalacia (PVL) is one of the foremost neurological conditions leading to long-term abnormalities in premature infants. Since it is difficult to prevent initiation of this damage in utero, promoting the innate regenerative potential of the brain after birth may provide a more feasible, prospective therapy for PVL. Treatment with UDP-glucose (UDPG), an endogenous agonist of G protein-coupled receptor 17 (GPR17) that may enhance endogenous self-repair potentiality, glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor associated with the growth and survival of nerve cells, and memantine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors that block ischemia-induced glutamate signal transduction, has been reported to achieve functional, neurological improvement in neonatal rats with PVL. The aim of the present study was to further explore whether UDPG, GDNF and/or memantine could promote corresponding self-repair of the subventricular zone (SVZ) and white matter (WM) in neonatal rats with ischemia-induced PVL. SVZ or WM tissue samples and cultured glial progenitor cells derived from a 5 day-old neonatal rat model of PVL were utilized for studying response to UDPG, GDNF and memantine in vivo and in vitro, respectively. Labeling with 5'-bromo-2'-deoxyuridine and immunofluorescent cell lineage markers after hypoxia-ischemia or oxygen-glucose deprivation (OGD) revealed that UDPG, GDNF and memantine each significantly increased glial progenitor cells and preoligodendrocytes (preOLs), as well as more differentiated immature and mature oligodendrocyte (OL), in both the SVZ and WM in vivo or in vitro. SVZ and WM glial cell apoptosis was also significantly reduced by UDPG, GDNF or memantine, both in vivo and in vitro. These results indicated that UDPG, GDNF or memantine may promote endogenous self-repair by stimulating proliferation of glial progenitor cells derived from both the SVZ and WM, activating their differentiation into more mature OLs, and raising the survival rate of these newly generated glial cells in neonatal rats with ischemic PVL.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Leucomalácia Periventricular/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Nicho de Células-Tronco/efeitos dos fármacos , Substância Branca/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Glucose/deficiência , Leucomalácia Periventricular/patologia , Leucomalácia Periventricular/fisiopatologia , Memantina/administração & dosagem , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neuroglia/patologia , Neuroglia/fisiologia , Distribuição Aleatória , Ratos Endogâmicos SHR , Nicho de Células-Tronco/fisiologia , Uridina Difosfato Glucose/administração & dosagem , Substância Branca/patologia , Substância Branca/fisiopatologiaRESUMO
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Osteoartrite/enzimologia , Inibidores de Proteases/farmacologia , Cartilagem/enzimologia , Humanos , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
AIM: To study molecular mechanism of epristeride in the treatment of benign prostatic hyperplasia and discuss the possibility of using prostate acid phosphatase (ACP) as a marker of the atrophy of prostatic gland in vivo. METHODS: Morphological changes in cells were observed by light microscope. TdT-mediated dUTP-biotin nick end labeling (TUNEL) technique and agarose gel electrophoresis were performed to detect the nucleosomal DNA fragmentation. The activity of pACP was also assayed. RESULTS: Apoptosis occurred in both castration- and epristeride- treatment group. Both the degree and extent of apoptosis are much larger in the group of castration than that of epristeride-treated group. Both epristeride and castration decreased the prostate wet weight and DNA content but increased the prostate DNA concentration. Maximal or near maximal decreases were seen by d 10 in both groups. The activity of ACP was decreased by both castration and epristeride treatment. Changes in the ACP activity during treatment were coincide with other changes such as the prostate wet weight and DNA content. CONCLUSION: Apoptosis induced by epristeride was one of mechanisms in the treatment of benign prostatic hyperplasia and the activity of ACP could be used as a marker of prostate atrophy.
Assuntos
Inibidores de 5-alfa Redutase , Androstadienos/efeitos adversos , Apoptose , Hiperplasia Prostática/induzido quimicamente , Fosfatase Ácida/metabolismo , Animais , Atrofia/induzido quimicamente , Biomarcadores/análise , Masculino , Tamanho do Órgão/efeitos dos fármacos , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-DawleyRESUMO
AIM: To evaluate the ability of epristeride to inhibit the prostatic glandular regrowth. METHODS: Normal rats were castrated. Testosterone was injected to induce the regrowth of glandular cells. HE staining was performed. The height of the glandular epithelium and the acinar luminal areas were determined, and dihydrotestosterone (DHT) was detected by immunohistochemistry. RESULTS: Both the height and the acinar luminal areas were reduced by 48 % and 55 % in epristeride-treated group compared with control group respectively. The staining of DHT was comparatively strong in the control group. After 30-d of treatment, it turned much weaker. CONCLUSION: The regrowth of glandular cells was inhibited by epristeride via declining of the DHT concentration in the rat prostate.
Assuntos
Inibidores de 5-alfa Redutase , Androstadienos/farmacologia , Próstata/crescimento & desenvolvimento , Animais , Depressão Química , Di-Hidrotestosterona/análise , Células Epiteliais/metabolismo , Masculino , Orquiectomia , Próstata/citologia , Próstata/metabolismo , Ratos , Ratos Sprague-Dawley , Testosterona/farmacologiaRESUMO
AIM: To study the effect of nomegestrol acetate, a new synthetic progesterone on granulosa cells' viability and steroidogenesis function. METHODS: Granulosa cells were cultured in McCoy's 5A medium. Trypan blue stain was used to measure viable cells. FSH and testosterone were added to stimulate the steroid secretion. Specific RIA assay was used to evaluate the estrogen and progesterone secretion respectively. RESULTS: IC50 of nomegestrol acetate to damage cells is 6.85 mg/L (95 % confidence limits 5.36-8.75 mg/L). Nomegestrol acetate 0.45, 0.9, and 1.8 mg/L greatly inhibited the estrogen secretion from granulosa cells by 7.6 %, 12.5 %, 28.3 % in the presence of testosterone 0.5 micromol/L and FSH 10 U/L without affecting the number of viable cells. The secretion of progesteron were markedly decreased by 44.5 %, 53.3 %, and 62.0 % concurrently. CONCLUSION: Nomegestrol acetate directly inhibited the steroidogenesis of granulosa cells.
Assuntos
Estrogênios/metabolismo , Células da Granulosa/efeitos dos fármacos , Megestrol , Norpregnadienos/farmacologia , Progesterona/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Hormônio Foliculoestimulante/antagonistas & inibidores , Células da Granulosa/citologia , Células da Granulosa/metabolismo , Congêneres da Progesterona/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Intravenous pyogenic granuloma is a rare form of pyogenic granuloma in which the whole lesion appears as a single polypoid mass projecting into the lumen of a vein. Histologically, this benign lesion is similar to pyogenic granuloma of other locations and is characterized by lobular proliferation of capillaries embedded in a fibromyxoid stroma. The following report illustrated the classic findings associated with an intravenous pyogenic granuloma in a young woman. A brief review of this rare entity follows the case report. Although the history and physical findings were approximately the same in each patient, they do not seem characteristic enough to allow for a definite preoperative diagnosis. The clinical differential diagnosis of intravenous pyogenic granuloma is varied and requires careful pathologic attention if excised. Complete local excision with a small portion of the vein is the treatment of choice.