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Diabetes mellitus (DM), a chronic metabolic disorder caused by uncontrolled high blood glucose levels due to insufficient insulin secretion or insulin resistance, is one of the most common metabolic diseases globally and is responsible for severe socio-economic burden. DM is associated with impaired fracture healing caused by oxidative stress induced-excessive bone resorption. Sirtuin3 (SIRT3), predominantly located in mitochondria, offers great influence on mitochondrial homeostasis, oxidative stress and immune cell function. However, the exact effect of SIRT3 on fracture healing with DM still remains to be elucidated. The present study demonstrated that SIRT3 expression was diminished in diabetic fracture healing and genetic deletion of SIRT3 increased mitochondrial oxidative stress and delayed diabetic bone healing via exacerbating the impact of DM on cartilage and osteoclast. The Honokiol (HKL) extracted from bark of magnolia trees, is a small molecular weight compound with various pharmaceutical properties by activating SIRT3. Our study proved that the SIRT3 agonist HKL could partially reverse the effect of diabetes on fracture healing, which provides a new promising approach for improving fracture healing in DM.
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Diabetes Mellitus , Sirtuína 3 , Regeneração Óssea , Consolidação da Fratura , Humanos , Estresse Oxidativo , Sirtuína 3/metabolismoRESUMO
OBJECTIVE: To evaluate the effects of the combination of basic fibroblast growth factor (bFGF), transforming growth factor-Β1 (TGF-Β1), bone marrow mesenchymal stem cells (BMSCs), and temperature-responsive chitosan hydrogel (TCH) gel on the repair of degenerative intervertebral disc in rat models. METHODS: Rat models of intervertebral disc degeneration were established by acupuncture. The degenerative effects were observed under magnetic resonance imaging (MRI). The BMSCs was cultured in vitro and then transfected by adenovirus with enhanced green fluorescent protein to make it carry the gene of enhanced green fluorescent protein,which functioned as fluorescence labeling. The SD rat models of intervertebral disc degeneration were divided into four groups: group A, treated with the combination of bFGF, TGF-Β1,BMSCs,and TCH gel; group B, treated with the combination of BMSCs and TCH gel;group C, treated with the combination of bFGF,TGF-Β1, and TCH gel;and group D, treated with PBS buffer solution. After the corresponding reagents were injected into the degenerative intervertebral discs of each group, the rats were cultivated for another four weeks and then the repair effects of the intervertebral discs were observed under MRI. Furthermore,the intervertebral discs of each group were taken out and observed by HE and Masson staining. The nucleus pulposus was aspirated and the expressions of aggrecan,collagen 2,Sox-9,and collagen I of nucleus pulposus of each group were tested by reverse transcription polymerase chain reaction and Western blot. RESULTS: The transplanted BMSCs survived in the intervertebral disc and differentiated into nucleus pulposus-like cells. MRI showed that:the signal intensity of the nucleus pulposus of group A was much higher than that of the rest groups, the signal intensity of group B was higher than that of group C, and the signal intensity of group D was the lowest,in which the dura mater spinalis was in compression and the spinal cord changed in beaded shape. The differences of the Pfirrmann grading among the four groups had statistical significance (P<0.05). The results of the HE and Masson stains showed:the intervertebral disc of group A was well-structured,the quantity of nucleus pulposus cells was larger than that of the other three groups,and the boundary between the nucleus pulposus and the annulus fibrosus was clearly defined;the quantity of the nucleus pulposus cells of group B was larger than that of group C, and the broken annulus fibrosus was not observed in group B, while the broken annulus fibrosus could be observed in group C; and, the nucleus pulposus cells of group D were replaced by fibrous tissue. The results of the reverse transcription polymerase chain reaction and Western blot tests showed that,in terms of the expressions of aggrecan,collagen 2 and Sox-9,group A was the highest, followed by group B,group C,and group D (P<0.05); in terms of the expression of collagen 1,there was no obvious difference among these four groups (P>0.05). CONCLUSIONS: The transplanted BMSCs can survive in the degenerative intervertebral disc and differentiate into nucleus pulposus-like cells. The combination of bFGF, TGF-Β1, BMSCs,and TCH gel has obvious repair effect on the degenerative intervertebral discs. The effect of the combination of BMSCs and TCH gel on transplantation therapy of the degenerative intervertebral discs is better than that of the combination of bFGF, TGF-Β1 and TCH gel but worse than that of the combination of bFGF, TGF-Β1, BMSCs, and TCH gel.
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Células da Medula Óssea , Células-Tronco Hematopoéticas , Degeneração do Disco Intervertebral , Animais , Transplante de Medula Óssea , Diferenciação Celular , Colágeno , Modelos Animais de Doenças , Fator 2 de Crescimento de Fibroblastos , Disco Intervertebral , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1 , CicatrizaçãoRESUMO
Spinal cord injury (SCI) represents a complex pathology within the central nervous system (CNS), leading to severe sensory and motor impairments. It activates various signaling pathways, notably the mitogen-activated protein kinase (MAPK) pathway. Present treatment approaches primarily focus on symptomatic relief, lacking efficacy in addressing the underlying pathophysiological mechanisms. Emerging research underscores the significance of the MAPK pathway in neuronal differentiation, growth, survival, axonal regeneration, and inflammatory responses post-SCI. Modulating this pathway post-injury has shown promise in attenuating inflammation, minimizing apoptosis, alleviating neuropathic pain, and fostering neural regeneration. Given its pivotal role, the MAPK pathway emerges as a potential therapeutic target in SCI management. This review synthesizes current knowledge on SCI pathology, delineates the MAPK pathway's characteristics, and explores its dual roles in SCI pathology and therapeutic interventions. Furthermore, it addresses the existing challenges in MAPK research in the context of SCI, proposing solutions to overcome these hurdles. Our aim is to offer a comprehensive reference for future research on the MAPK pathway and SCI, laying the groundwork for targeted therapeutic strategies.
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Sistema de Sinalização das MAP Quinases , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/terapia , Humanos , Animais , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismoRESUMO
INTRODUCTION: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. CONCLUSION: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.
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Camundongos Endogâmicos C57BL , Polissacarídeos , Recuperação de Função Fisiológica , Remielinização , Traumatismos da Medula Espinal , Animais , Polissacarídeos/farmacologia , Camundongos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Remielinização/efeitos dos fármacos , Remielinização/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Feminino , Microambiente Celular/efeitos dos fármacosRESUMO
Four crisping diets were designed to conduct a feeding experiment to investigate the use of broad bean in the formulated feed of Nile tilapia and optimize its use. The growth performance, muscle characteristics, antioxidant capacity, and intestinal health of Nile tilapia with an initial body weight of 617.32 ± 1.64 g were evaluated after being fed with different diets for 90 days. The results showed no adverse effect on the growth performance of Nile tilapia fed with broad bean diets. Contrastingly, some improvements were found in WGR and SGR, but a lower FCR was obtained. The supplementation of broad beans weakened the antioxidant capacity of fish but did not influence liver health and the immune system. Increasing the amount of broad bean addition can increase muscle quality values, and an embrittling functional package being added to the diet can also improve muscle hardness, adhesiveness, and chewiness of Nile tilapia muscle. In addition, the crisping functional package can be applied to tilapia crisping formulated feed, which helps to improve the integrity of the intestinal tissue structure and optimize the intestinal microbiota of Nile tilapia. The final achievement of this study is to provide a theoretical reference for optimizing the breeding technology of crispy Nile tilapia and developing a specialized crisping diet for the species.
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Gut microbiota has been reported to participate in bone metabolism. However, no article has quantitatively and qualitatively analyzed this crossing field. The present study aims to analyze the current international research trends and demonstrate possible hotspots in the recent decade through bibliometrics. We screened out 938 articles meeting the standards from 2001 to 2021 in the Web of Science Core Collection database. Bibliometric analyses were performed and visualized using Excel, Citespace, and VOSviewer. Generally, the annual number of published literatures in this field shows an escalating trend. The United States has the largest number of publications, accounting for 30.4% of the total. Michigan State University and Sichuan University have the largest number of publications, while Michigan State University has the highest average number of citations at 60.00. Nutrients published 49 articles, ranking first, while the Journal of Bone and Mineral Research had the highest average number of citations at 13.36. Narayanan Parameswaran from Michigan State University, Roberto Pacifici from Emory University, and Christopher Hernandez from Cornell University were the three professors who made the largest contribution to this field. Frequency analysis showed that inflammation (148), obesity (86), and probiotics (81) are keywords with the highest focus. Moreover, keywords cluster analysis and keywords burst analysis showed that "inflammation", "obesity", and "probiotics" were the most researched topics in the field of gut microbiota and bone metabolism. Scientific publications related to gut microbiota and bone metabolism have continuously risen from 2001 to 2021. The underlying mechanism has been widely studied in the past few years, and factors affecting the alterations of the gut microbiota, as well as probiotic treatment, are emerging as new research trends.
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Targeted transfection of siRNA to preosteoclasts features the potential of anti-osteoporosis, yet challenge arises from the development of satisfied delivery vehicles. Here, we design a rational core-shell nanoparticle (NP) composed of cationic and responsive core for controlled load and release of small interfering RNA (siRNA) and compatible polyethylene glycol shell modified with alendronate for enhanced circulation and bone-targeted delivery of siRNA. The designed NPs perform well on transfection of an active siRNA (siDcstamp) that interferes Dcstamp mRNA expression, leading to impeded preosteoclast fusion and bone resorption, as well as promoted osteogenesis. In vivo results corroborate the abundant siDcstamp accumulation on bone surfaces and the enhanced trabecular bone mass volume and microstructure in treating osteoporotic OVX mice by rebalancing bone resorption, formation, and vascularization. Our study validates the hypothesis that satisfied transfection of siRNA enables preserved preosteoclasts that regulate bone resorption and formation simultaneously as potential anabolic treatment for osteoporosis.
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Reabsorção Óssea , Nanopartículas , Osteoporose , Camundongos , Animais , RNA Interferente Pequeno/metabolismo , Polieletrólitos , Nanopartículas/química , Osteoporose/tratamento farmacológico , Osteoporose/genética , TransfecçãoRESUMO
Spinal cord ischemia reperfusion injury (SCIRI) can cause spinal cord dysfunction and even devastating paraplegia. Calcium-sensing receptor (CaSR) and calpain are two calcium related molecules which have been reported to be involved in the ischemia reperfusion injury of cardiomyocytes and the subsequent apoptosis. Here, we studied the expression of CaSR and calpain in spinal cord neurons and tissues, followed by the further investigation of the role of CaSR/calpain axis in the cellular apoptosis process during SCIRI. The results of in vitro and in vivo studies showed that the expression of CaSR and calpain in spinal cord neurons increased during SCIRI. Moreover, the CaSR agonist GdCl3 and antagonist NPS-2390 enhanced or decreased the expression of CaSR and calpain respectively. The expressions of CaSR and calpain were also consistent with the cellular apoptosis in spinal cord. Taken together, CaSR-calpain contributes to the SCIRI apoptosis, and CaSR antagonist might be a helpful drug for alleviating SCIRI.