RESUMO
Muscle atrophy usually occurs under mechanical unloading, which increases the risk of injury to reduce the functionality of the moving system, while there is still no effective therapy until now. It was found that miR-194 was significantly downregulated in a muscle atrophy model, and its target protein was the myocyte enhancer factor 2C (MEF2C). miR-194 could promote muscle differentiation and also inhibit ubiquitin ligases, thus miR-194 could be used as a nucleic acid drug to treat muscle atrophy, whereas miRNA was unstable in vivo, limiting its application as a therapeutic drug. A gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA here. Exogenous miR-194 was loaded in GNs and injected into the muscle atrophy model. It demonstrated that the muscle fiber cross-sectional area, in situ muscle contractile properties, and myogenic markers were increased significantly after treatment. It proposed miR-194 loaded in GNs as an effective treatment for muscle atrophy by promoting muscle differentiation and inhibiting ubiquitin ligase activity. Moreover, the developed miRNA delivery system, taking advantage of its tunable composition, degradation rate, and capacity to load various drug molecules with high dosage, is considered a promising platform to achieve precise treatment of muscle atrophy-related diseases.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Gelatina/química , MicroRNAs/administração & dosagem , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Nanosferas/química , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley , Células Satélites de Músculo Esquelético/metabolismo , Resultado do TratamentoRESUMO
Recent studies demonstrate that diet quercetin (Quer) has obvious bone protective effects on ovariectomized rodents but thus far there is no direct evidence to support the inhibitory effect of Quer on bone loss caused by long-term unloading. In the present study, we investigated whether Quer could prevent bone loss induced by unloading in mice. Mice were subjected to hindlimb suspension (HLS) and received Quer (25, 50, 100 mg· kg-1 ·day-1, ig) for 4 weeks. Before euthanasia blood sample was collected; the femurs were harvested and subjected to MicroCT analysis. We showed that Quer administration markedly improved bone microstructure evidenced by dose-dependently reversing the reduction in bone volume per tissue volume, trabecular number, and bone mineral density, and the increase of trabecular spacing in mice with HLS. Analysis of serum markers and bone histometric parameters confirmed that Quer at both middle and high doses significantly decreased bone resorption-related markers collagen type I and tartrate-resistant acid phosphatase 5b, and increased bone formation-related marker procollagen 1 N-terminal propeptide as compared with HLS group. Treatment with Quer (1, 2, 5 µM) dose-dependently inhibited RANKL-induced osteoclastogenesis through promoting the expression of antioxidant hormone stanniocalcin 1 (STC1) and decreasing ROS generation; knockdown of STC1 blocked the inhibitory effect of Quer on ROS generation. Knockdown of STC1 also significantly promoted osteoclastogenesis in primary osteoclasts. In conclusion, Quer protects bones and prevents unloading-caused bone loss in mice through STC1-mediated inhibition of osteoclastogenesis. The findings suggest that Quer has the potential to prevent and treat off-load bone loss as an alternative supplement.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/prevenção & controle , Glicoproteínas/metabolismo , Osteogênese/efeitos dos fármacos , Quercetina/uso terapêutico , Animais , Reabsorção Óssea/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Elevação dos Membros Posteriores , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Ligante RANK/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
To explore novel antifatigue agents targeting with AMPA receptor, 10 compounds were synthesized and their structures were confirmed by 1H NMR, ESI-MS and elemental analysis. 1-BCP was treated as the leading compound. The antifatigue activities were evaluated by weight-loaded forced swimming test, and the AMPA receptor binding affinities were tested with radioligand receptor binding assays. The results unveiled that 5b appeared to possess potent antifatigue activities and high affinity with AMPA receptor, which deserved further studies.
Assuntos
Benzamidas/farmacologia , Fadiga/prevenção & controle , Animais , Benzamidas/química , Dioxóis/química , Dioxóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ensaio Radioligante , Receptores de AMPA/metabolismo , NataçãoRESUMO
The purpose of this systematic review is to assess the efficacy and pharmacological profiles of Herba Epimedii in osteoporosis therapy. Four databases were extensively retrieved that include two Chinese electronic databases (VIP Information and CNKI) and two English electronic databases (CA and MEDLINE). Herba Epimedii has been an important traditional herbal medicine for centuries in China and other Asian countries. Recently, quite a few pharmacological effects of Herba Epimedii, its extracts and active components have been identified that include improving bone health and cardiovascular function, regulating hormone level, modulating immunological function, and inhibiting tumor growth. The anti-osteoporosis activity of Herba Epimedii and its extracts have attracted world-wide attention. The literature search has revealed that a lot of studies have recently been carried out related to the bone-strengthening activity of Herba Epimedii and some of its active compounds, such as total flavonoids and icariin. Pharmacokinetic and toxicity studies have confirmed the efficacy and safety of Herba Epimedii and its most abundant active component icariin, while only a few authors have reviewed the anti-osteoporosis properties of the plants. So we summarize the work of various investigators on the effects of Herba Epimedii, its extracts and active components against osteoporosis. The underlying mechanism of osteoprotective action, derivatives of icariin, animal models and cell lines used in the research were also reviewed in this paper.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Epimedium/química , Osteoporose/tratamento farmacológico , Animais , Linhagem Celular , Bases de Dados Factuais , Modelos Animais de Doenças , Etnofarmacologia , Flavonoides/química , Flavonoides/uso terapêutico , Humanos , Extratos Vegetais/uso terapêuticoRESUMO
OBJECTIVE: To investigate the effects of naringin on the proliferation, differention and maturaion of rat calvarial osteoblasts (ROB). METHOD: Segregated neonatal SD rat skull, enzyme digestion to obtain ROB. The culture medium was replaced every three days. Serial subcultivation proceeded when cells covered with 80% culture dish. Naringin supplemented into the culture at 1 x 10(-4), 1 x 10(-5), 1 x 10(-6), 1 x 10(-7) mol x L(-1) respectively. MTT method was adopted in proliferation analysis and the activity of ALP was examined after induced 9 days. Search the best concentration and supplemented into the medium, then the osteogenic differentiation markers including the secretion amount of osteocalcin, osteopontin and bone morphogenetic protein-2 were compared between the naringin-supplemented group and the control. Total RNA was isolated and the mRNA level of bFGF, IGF-1, Runx-2, Osterix, ERa and ERbeta was investigated by Real time RT-PCR. Total protein also was isolated and the expression ERa, ERbeta and collagen I was examined by Western blot. After the addition of ICI 182.780, an inhibitor of the estrogen signal pathway, these index also was examined and the changes were compared. RESULT: The ROB proliferation was motivated by naringin dose-dependently. And it evidently leads to osteogenic process and maturation. 1 x 10(-5) mol x L(-1) is the best concentration. Naringin improved the secretion of osteocalcin, osteopontin, bone morphogenetic protein-2 and collagen I significantly. Besides, it can also enhanced the mRNA level of bFGF, IGF-1, Runx-2, Osterix, ERalpha and ERbeta. While all these effects can be restrained by ICI 182.780. CONCLUSION: The naringin with final concentration of 1 x 10(-5) mol x L(-1) enhances the osteogenic differentiation and maturation of ROB significantly, while the promoting effects vanished after the addition of ICI 182.780. These results suggesting that naringin is one of the phytoestrogens and have the activity of bone formation may via estrogen signal pathway, it can be developed into a new drug for osteoporosis therapy.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Osteoblastos/efeitos dos fármacos , Crânio/citologia , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Células Cultivadas , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Ratos , Ratos Sprague-Dawley , Crânio/efeitos dos fármacos , Crânio/metabolismoRESUMO
To explore novel antitumor agents with high efficiency and low toxicity, riluzole alkyl derivatives (4a-4i) were synthesized. Their anti-proliferative activities against HeLa, HepG2, SP2/0, and MCF-7 cancer cell lines were assessed by the CCK-8 assay and compared with human normal liver (LO2) cells. Most of them showed potent cytotoxic effects against four human tumor cell lines and low toxic to LO2 cells. In particular, 2-(N-ethylamine)-6-trifluoromethoxy- benzothiazole (4a) showed a IC50 value of 7.76 µmol/L in HeLa cells and was found to be nontoxic to LO2 cells up to 65 µmol/L. Furthermore, flow cytometry indicated that 4a could induce remarkable early apoptosis and G2/M cell cycle arrest in HeLa cells. It also impaired the migration ability of HeLa cells in wound healing assays. Western blot results demonstrated that 4a suppressed Bcl-2 protein expression but increased the level of Bax in HeLa cells, and elevated the Bax/Bcl-2 expression ratio. These new findings suggest that 4a exhibited beneficially anti-cervical cancer effect on HeLa cells by inducing HeLa cell apoptosis.
RESUMO
Variations of CGG repeats in the FRAXE fragile site were determined by PCR amplification followed by polyacrylamide gel electrophoresis and sequencing in randomly collected Qinba Mountain Area children whose intelligence level was determined by China-Wechsler Intelligence Scale for Children (C-WISC). Correlations between IQ score and the number of CGG repeats were analyzed. Results indicated a difference in the range of CGG repeats among populations from different regions, but no difference in the distribution of allele frequency in such a population. CGG repeats were not associated with IQ scores in randomly collected subjects (r=0.083, P>0.05), in males and females (r(m)=0.225, r(f)=-0.041, P>0.05), or in subjects with different intelligent levels (F=0.195, P>0.05). It can be inferred that variation in the size of CGG repeats was not associated with intellectual performance in the Qinba Mountain area children.
Assuntos
Povo Asiático/genética , Sítios Frágeis do Cromossomo/genética , Síndrome do Cromossomo X Frágil/genética , Inteligência/genética , Polimorfismo Genético , Repetições de Trinucleotídeos/genética , Adolescente , Criança , China , Feminino , Frequência do Gene , Humanos , Testes de Inteligência , MasculinoRESUMO
Although the incidence of colorectal cancer (CRC) has been declining in recent decades, it remains a major public health issue as a leading cause of cancer mortality and morbidity worldwide. Prevention is one milestone for this disease. Extensive study has demonstrated that a diet containing fruits, vegetables, and spices has the potential to prevent CRC. The specific constituents in the dietary foods which are responsible for preventing CRC and the possible mechanisms have also been investigated extensively. Various phytochemicals have been identified in fruits, vegetables, and spices which exhibit chemopreventive potential. In this review article, chemopreventive effects of phytochemicals including curcumin, polysaccharides (apple polysaccharides and mushroom glucans), saponins (Paris saponins, ginsenosides and soy saponins), resveratrol, and quercetin on CRC and the mechanisms are discussed. This review proposes the need for more clinical evidence for the effects of phytochemicals against CRC in large trials. The conclusion of the review is that these phytochemicals might be therapeutic candidates in the campaign against CRC.
Assuntos
Anticarcinógenos/uso terapêutico , Neoplasias Colorretais/prevenção & controle , Dieta , Compostos Fitoquímicos/uso terapêutico , Animais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Dieta/efeitos adversos , Frutas , Humanos , Fatores de Risco , Comportamento de Redução do Risco , Especiarias , VerdurasRESUMO
Radix Dipsaci total saponins (RTS) are primary active components of Radix Dipsaci, which is administered orally for the treatment of osteoporosis according to Chinese Medicine. RTS have also been shown to reduce the risk of bone fractures in rats. However, the detailed molecular mechanisms underlying their action remain elusive. In the present study, the ability of RTS to increase alkaline phosphatase activity, osteocalcin levels and the degree of mineralization was investigated in MC3T3E1 mouse osteoblast precursor cells. In addition, the associated molecular mechanism was detected. The results revealed that RTS exerted an effect on osteoblastic maturation and differentiation. Induction of differentiation by RTS was associated with an increase in the expression levels of bone morphogenetic protein2 (BMP2), phosphorylated (P)Smad1/5/8, PERK1/2, Pp38 and Runtrelated transcription factor 2 (Runx2). Blocking BMP2 expression with noggin significantly reduced the levels of osteoblastic differentiation and subsequently attenuated the expression levels of PSmad1/5/8, PERK1/2, Pp38 and Runx2. This indicated that RTS induced osteoblastic differentiation through BMP2/mitogenactivated protein kinase/Smad1/5/8dependent Runx2 signaling pathways and that it may be a promising agent for enhancing bone formation.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Gastrópodes/química , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Gastrópodes/metabolismo , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Proteínas Smad/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-κB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects.
RESUMO
Radix Scutellariae (RS), a medicinal herb, is extensively employed in traditional Chinese medicines and modern herbal prescriptions. Two major flavonoids in RS were known to induce osteoblastic differentiation and inhibit osteoclast differentiation, respectively. This study aimed to investigate the effect of Radix Scutellariae extract (RSE) against bone loss induced by mechanical inactivity or weightlessness. A hindlimb unloading tail-suspended rat model (TS) was established to determine the effect of RSE on bone mineral density and bone microarchitecture. Treatment of RSE at 50 mg/kg/day and alendronate (ALE) at 2 mg/kg/day as positive control for 42 days significantly increased the bone mineral density and mechanical strength compared with TS group. Enhanced bone turnover markers by TS treatment were attenuated by RSE and ALE administration. Deterioration of bone trabecula induced by TS was prevented. Moreover, both treatments counteracted the reduction of bone volume fraction, trabecular thickness and number, and connectivity density. In conclusion, RSE was demonstrated for the first time to prevent osteoporosis induced by TS treatment, which suggests the potential application of RSE in the treatment of disuse-induced osteoporosis.
RESUMO
Radix Astragalus has been identified to exert beneficial effects in preventing postmenopausal bone loss. However, the active ingredients and mechanism of action remain unknown. In this study, we examined the effect of Astragaloside II (AST II), which is a monomer of Astragalus saponin, on the viability, proliferation, differentiation and maturation of rat primary osteoblasts, as well as its relevant molecular mechanism. We found that AST II exhibits a significant induction of proliferation, differentiation and mineralization in primary osteoblasts. AST II stimulates osteoblast differentiation at various stages, from early to late stage of differentiated osteoblasts. Furthermore, induction of differentiation by AST II is associated with increased expression of bone morphogenetic protein-2 (BMP-2), activation of Smad1/5/8, ERK1/2 and p38, and increased expression of core-binding factor 1 (Cbfa1)/Runx2. BMP antagonist (Noggin) blocks the effect of AST II on cell differentiation, and Smad1/5/8, p38, Cbfa1 expression, but only partly decreases ERK1/2 activation. This indicates that BMP-2 is essential in AST II-mediated osteoblast differentiation and Smad1/5/8, p38, Cbfa1 activation, and is partly involved in ERK1/2 activation. In conclusion, although in vivo studies are required in the future, as a phyto-saponin of Radix Astragalus, AST II may become a novel candidate that is beneficial for stimulating the osteoblastic activity resulting in bone formation, which has not been recognized and reported previously.