RESUMO
Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.
Assuntos
Melatonina , Humanos , Melatonina/farmacologia , Triptofano , Disbiose/tratamento farmacológico , MetilaminasRESUMO
Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of "microbiota-gut-joint" axis, which might provide promising therapeutic strategies for OA.
Assuntos
Microbioma Gastrointestinal , Nanopartículas Metálicas , Ouro/farmacologia , Nanopartículas Metálicas/uso terapêutico , Ácidos Graxos Voláteis , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: The incidence of pneumothorax is higher in patients with emphysema who undergo percutaneous lung biopsy. Needle embolization has been shown to reduce the incidence of pneumothorax in patients with emphysema. Existing studies have reported small sample sizes of patients with emphysema, or the degree of emphysema has not been graded. Therefore, the efficacy of biopsy embolization in the prevention of pneumothorax induced by percutaneous pulmonary biopsy in patients with emphysema remains to be determined. METHODS: In this retrospective, controlled study, patients with emphysema who underwent CT-guided PTLB were divided into two groups: group A (n = 523), without tract embolization, and Group B (n = 504), with tract embolization. Clinical and imaging features were collected from electronic medical records and Picture Archiving and Communication Systems. Univariate and multivariate analyses were performed to identify risk factors for pneumothorax and chest tube placement. RESULTS: The two groups did not differ significantly in terms of demographic characteristics and complications other than pneumothorax. The incidence of pneumothorax and chest tube placement in group B was significantly lower than in group A (20.36% vs. 46.12%, p < 0.001; 3.95% vs. 9.18%, p < 0.001, respectively). In logistic regression analyses, variables affecting the incidence of pneumothorax and chest tube placement were the length of puncture of the lung parenchyma (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.07-1.30, p = 0.001; OR = 1.55, 95% CI: 1.30-1.85, p < 0.001, respectively), tract embolization (OR = 0.31, 95% CI: 0.24-0.41, p < 0.001; OR = 0.39, 95% CI: 0.22-0.69, p = 0.001, respectively), and grade of emphysema. CONCLUSIONS: Tract embolization with gelatin sponge particles after CT-guided PTLB significantly reduced the incidence of pneumothorax and chest tube placement in patients with emphysema. Tract embolization, length of puncture of the lung parenchyma, and grade of emphysema were independent risk factors for pneumothorax and chest tube placement. TRIAL REGISTRATION: Retrospectively registered.
Assuntos
Embolização Terapêutica , Biópsia Guiada por Imagem , Pulmão , Pneumotórax , Enfisema Pulmonar , Tomografia Computadorizada por Raios X , Humanos , Pneumotórax/etiologia , Pneumotórax/prevenção & controle , Pneumotórax/epidemiologia , Feminino , Masculino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Biópsia Guiada por Imagem/efeitos adversos , Biópsia Guiada por Imagem/métodos , Embolização Terapêutica/métodos , Pulmão/patologia , Pulmão/diagnóstico por imagem , Fatores de Risco , Modelos Logísticos , Tubos Torácicos , Esponja de Gelatina Absorvível/administração & dosagem , Incidência , Análise Multivariada , Idoso de 80 Anos ou mais , Radiografia Intervencionista/métodosRESUMO
Bile acids (BAs), synthesized in the liver and modified by the gut microbiota, have been widely appreciated not only as simple lipid emulsifiers, but also as complex metabolic regulators and momentous signaling molecules, which play prominent roles in the complex interaction among several metabolic systems. Recent studies have drawn us eyes on the diverse physiological functions of BAs, to enlarge the knowledge about the "gut-bone" axis due to the participation about the gut microbiota-derived BAs to modulate bone homeostasis at physiological and pathological stations. In this review, we have summarized the metabolic processes of BAs and highlighted the crucial roles of BAs targeting bile acid-activated receptors, promoting the proliferation and differentiation of osteoblasts (OBs), inhibiting the activity of osteoclasts (OCs), as well as reducing articular cartilage degradation, thus facilitating bone repair. In addition, we have also focused on the bidirectional effects of BA signaling networks in coordinating the dynamic balance of bone matrix and demonstrated the promising effects of BAs on the development or treatment for pathological bone diseases. In a word, further clinical applications targeting BA metabolism or modulating gut metabolome and related derivatives may be developed as effective therapeutic strategies for bone destruction diseases.
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Osteoporosis (OP) is a metabolic bone disease characterized by decreased bone mass and increased bone fragility. The imbalance of bone homeostasis modulated by osteoclasts and osteoblasts is the most crucial pathological change in osteoporosis. As a novel treatment strategy, nanomedicine has been applied in drug delivery and targeted therapy due to its high efficiency, precision, and fewer side effects. Gold nanospheres (GNS), as a common kind of gold nanoparticles (GNPs), possess significant antimicrobial and anti-inflammatory activity, which have been applied for the treatment of eye diseases and rheumatoid arthritis. However, the effect of GNS on osteoporosis remains elusive. In this study, we found that GNS significantly prevented ovariectomy (OVX)-induced osteoporosis in a gut microbiota-dependent manner. 16S rDNA gene sequencing demonstrated GNS markedly altered the gut microbial diversity and flora composition. In addition, GNS reduced the abundance of TMAO-related metabolites in OVX mice. Low TMAO levels might alleviate the bone loss phenomenon by reducing the inflammation response. Therefore, we investigated the alteration of cytokine profiles in OVX mice. GNS inhibited the release of pro-osteoclastogenic or proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin (IL)-6, and granulocyte colony-stimulating factor (G-CSF) in the serum. In conclusion, GNS suppressed estrogen deficiency-induced bone loss by regulating the destroyed homeostasis of gut microbiota so as to reduce its relevant TMAO metabolism and restrain the release of proinflammatory cytokines. These results demonstrated the protective effects of GNS on osteoporosis as a gut microbiota modulator and offered novel insights into the regulation of the "gut-bone" axis.
Assuntos
Microbioma Gastrointestinal , Nanopartículas Metálicas , Nanosferas , Osteoporose , Feminino , Camundongos , Animais , Ouro/farmacologia , Citocinas , Interleucina-6RESUMO
INTRODUCTION: Hepatitis B virus-associated glomerulonephritis (HBV-GN) is one of the main types of secondary glomerular diseases, and podocyte injury is an important pathogenic mechanism of HBV-GN, participating in the occurrence and development of HBV-GN. However, the specific mechanism of podocyte injury remains to be studied. METHODS: Human renal podocytes cultured in vitro were divided into six groups. The podocyte morphology was observed under a transmission electron microscope, and the expression of M-type phospholipase A2 receptor (M-PLA2R) on the podocyte membrane was observed by indirect immunofluorescence staining under a fluorescence microscope. The pyroptosis rate and reactive oxygen species (ROS) of podocytes were assessed by FLICA/PI double staining and flow cytometry. Western blot (WB) and quantitative real-time PCR (qPCR) were used to determine the expression of PLA2R, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing card (ASC), caspase-1, IL-1ß, and IL-18. RESULTS: Hepatitis B virus X (HBx) transfected into human renal podocytes in vitro induced the overexpression of PLA2R. Moreover, the overexpressed PLA2R combined with secretory phospholipase A2 group IB (sPLA2-IB) aggravated podocyte injury and increased the pyroptosis rate. In addition, the expression of ROS, the NLRP3 inflammasome and downstream inflammatory factors was increased. In contrast, after inhibiting the expression of PLA2R and ROS, podocyte damage was alleviated, and the pyroptosis rate and the expression of genes related to the ROS-NLRP3 signaling pathway were decreased. CONCLUSION: HBx-induced PLA2R overexpression on the podocyte membrane can significantly upregulate the ROS-NLRP3 signaling pathway, thereby mediating podocyte pyroptosis.
Assuntos
Podócitos , Humanos , Podócitos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fosfolipases/metabolismo , Poliésteres/metabolismoRESUMO
Hepatitis B virus (HBV) and its related protein, HBV X (HBx), play an important role in podocyte injury in HBV-associated glomerulonephritis (HBV-GN). The microRNA MiR-223 is expressed in several diseases, including HBV-associated disease, while the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome plays a major role in pyroptosis. In this study, we investigated the function and mechanism of action of miR-223 in HBx-induced podocyte pyroptosis. A quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay showed that miR-223 was downregulated in HBx-transfected podocytes. Transfection with an miR-223 mimic abolished the expression of the NLRP3 inflammasome and the cytokines that are released as a result of NLRP3 overexpression. Moreover, transfection with HBx and NLRP3 overexpression plasmids increased the expression of pyroptosis-related proteins, especially in the presence of miR-223 inhibitors. Thus, miR-223 downregulation plays an important role in HBx-induced podocyte pyroptosis by targeting the NLRP3 inflammasome, suggesting that miR-223 is a potential therapeutic target for alleviating HBV-GN inflammation.
Assuntos
MicroRNAs , Podócitos , Regulação para Baixo , Vírus da Hepatite B/genética , Inflamassomos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Podócitos/metabolismo , Piroptose/genéticaRESUMO
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs) with immunosuppressive functions, whereas IMCs originally differentiate into granulocytes, macrophages, and dendritic cells (DCs) to participate in innate immunity under steady-state conditions. At present, difficulties remain in identifying MDSCs due to lacking of specific biomarkers. To make identification of MDSCs accurately, it also needs to be determined whether having immunosuppressive functions. MDSCs play crucial roles in anti-tumor, angiogenesis, and metastasis. Meanwhile, MDSCs could make close interaction with osteoclasts, osteoblasts, chondrocytes, and other stromal cells within microenvironment of bone and joint, and thereby contributing to poor prognosis of bone-related diseases such as cancer-related bone metastasis, osteosarcoma (OS), rheumatoid arthritis (RA), osteoarthritis (OA), and orthopedic trauma. In addition, MDSCs have been shown to participate in the procedure of bone repair. In this review, we have summarized the function of MDSCs in cancer-related bone metastasis, the interaction with stromal cells within the bone microenvironment as well as joint microenvironment, and the critical role of MDSCs in bone repair. Besides, the promising value of MDSCs in the treatment for bone-related diseases is also well discussed.
Assuntos
Neoplasias Ósseas/patologia , Regeneração Óssea/fisiologia , Tolerância Imunológica/imunologia , Células Supressoras Mieloides/citologia , Artrite Reumatoide/patologia , Doenças Ósseas/patologia , Neoplasias Ósseas/secundário , Microambiente Celular/fisiologia , Células Dendríticas/citologia , Granulócitos/citologia , Humanos , Imunidade Inata/imunologia , Macrófagos/citologia , Células Supressoras Mieloides/imunologia , Osteoartrite/patologiaRESUMO
BACKGROUND: Xp21 contiguous gene deletion syndrome is a rare genetic metabolic disorder with poor prognosis in infants, involving deletions of one or more genes in Xp21. When deletions of adrenal hypoplasia (AHC), Duchenne muscular dystrophy (DMD), and chronic granulomatosis (CGD) loci are included, complex glycerol kinase deficiency (CGKD) can be diagnosed. We present a case of CGKD that was initially misdiagnosed and died during treatment in our hospital in terms of improving our understanding of the clinical features and diagnosis of this disease, as well as highlighting the need for more precise dosing of corticosteroid replacement therapy. CASE PRESENTATION: A 48-day-old full-term male infant was transferred to our medical center with global growth delay and persistent vomiting. Routine laboratory tests revealed hyperkalemia, hyponatremia, and a high level of creatine kinase. The initial diagnosis was adrenal cortical hyperplasia (ACH), then revised to adrenocortical insufficiency with a normal level of ACTH detected. After supplementing the routine lipid test and urinary glycerol test, CGKD was diagnosed clinically due to positive triglyceridemia and urinary glycerol, and the follow-up gene screening further confirmed the diagnosis. The boy kept thriving after corticosteroid replacement and salt supplementation. While levels of serum ACTH and cortisol decreased and remained low after corticosteroid replacement was administered. The patient died of acute type 2 respiratory failure and hypoglycemia after an acute upper respiratory tract infection, which may be the result of adrenal crisis after infection. Infants with CGKD have a poor prognosis, so physicians should administer regular follow-ups, and parents counseling during treatment to improve the survival of patients. CONCLUSIONS: Overall, CGKD, although rare, cannot be easily excluded in children with persistent vomiting. Extensive blood tests can help to detect abnormal indicators. Adrenal crisis needs to be avoided as much as possible during corticosteroid replacement therapy.
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Insuficiência Adrenal , Glicerol Quinase , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Hormônio Adrenocorticotrópico , Criança , China , Diagnóstico Tardio , Glicerol , Glicerol Quinase/genética , Humanos , Hipoadrenocorticismo Familiar , Lactente , Masculino , VômitoRESUMO
Flexible enzyme-free glucose sensors have attracted widespread attention due to their importance and potential applications in clinical diagnosis, flexible wearable devices, and implanted devices in vivo. At present, there are still major problems in fabricating flexible enzyme-free glucose sensors with low detection limits, high stability, and high sensitivity at low cost, hindering their practical application. Here, we report a facile strategy for the fabrication of flexible non-enzymatic glucose sensors using ginkgo leaf as a template. NiO film and PEDOT:PSS composite film were deposited on the surface of the ginkgo leaf induced micro-nano hierarchical structure as a sensitive layer and a conductive layer, respectively. The as-prepared, flexible, enzyme-free glucose sensor exhibited excellent electrochemical performance toward glucose oxidation with a sensitivity of 0.7413 mA·mM-1/cm-2, an operating voltage of 0.55 V, a detection limit of 0.329 µM, and good anti-interference. Due to the simple fabrication process and performance reliability, the novel flexible enzyme-free glucose sensor is an attractive candidate for next generation wearable and implantable non-enzymatic glucose diagnostic devices.
Assuntos
Nanoestruturas , Dispositivos Eletrônicos Vestíveis , Ginkgo biloba , Glucose/química , Nanoestruturas/química , Reprodutibilidade dos TestesRESUMO
The repair of bone defects, especially for the large segment of bone defects, has always been an urgent problem in orthopedic clinic and attracted researchers' attention. Nowadays, the application of tissue engineering bone in the repair of bone defects has become the research hotspot. With the rapid development of tissue engineering, the novel and functional scaffold materials for bone repair have emerged. In this review, we have summarized the multi-functional roles of osteoclasts in bone remodeling. The development of matrix-based tissue engineering bone has laid a theoretical foundation for further investigation about the novel bone regeneration materials which could perform high bioactivity. From the point of view on preserving pre-osteoclasts and targeting mature osteoclasts, this review introduced the novel matrix-based tissue engineering bone based on osteoclasts in the field of bone tissue engineering, which provides a potential direction for the development of novel scaffold materials for the treatment of bone defects.
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Osteoclastos , Engenharia Tecidual , Regeneração Óssea , Osso e Ossos , HumanosRESUMO
Osteoarthritis (OA) is a degenerative joint disease in the elderly. Although OA has been considered as primarily a disease of the articular cartilage, the participation of subchondral bone in the pathogenesis of OA has attracted increasing attention. This review summarises the microstructural and histopathological changes in subchondral bone during OA progression that are due, at the cellular level, to changes in the interactions among osteocytes, osteoblasts, osteoclasts (OCs), endothelial cells and sensory neurons. Therefore, we focus on how pathological cellular interactions in the subchondral bone microenvironment promote subchondral bone destruction at different stages of OA progression. In addition, the limited amount of research on the communication between OCs in subchondral bone and chondrocytes (CCs) in articular cartilage during OA progression is reviewed. We propose the concept of 'OC-CC crosstalk' and describe the various pathways by which the two cell types might interact. Based on the 'OC-CC crosstalk', we elaborate potential therapeutic strategies for the treatment of OA, including restoring abnormal subchondral bone remodelling and blocking the bridge-subchondral type H vessels. Finally, the review summarises the current understanding of how the subchondral bone microenvironment is related to OA pain and describes potential interventions to reduce OA pain by targeting the subchondral bone microenvironment.
Assuntos
Cartilagem Articular , Osteoartrite , Idoso , Osso e Ossos/metabolismo , Cartilagem Articular/metabolismo , Células Endoteliais/metabolismo , Humanos , Osteoartrite/patologia , DorRESUMO
Human class I homeobox A13 (HOXA13) was initially identified as a transcription factor and has an important role in embryonic development and malignant transformation. However, the clinical significance and the molecular mechanisms of HOXA13 in colon cancer development and progression are still unknown. In this study, we found that HOXA13 was highly expressed in colon cancer tissues, and its expression was associated with histological grade, T stage, N stage and tumour size. In vitro studies showed that HOXA13 promoted colon cancer cell proliferation, migration and invasion. Bioinformatics analysis revealed that HOXA13 expression was positively correlated with the WNT signalling pathway. In vitro studies showed that HOXA13 promoted the malignant phenotype of colon cancer cells by facilitating the nuclear translocation of ß-Catenin. Moreover, XAV939, an inhibitor of ß-Catenin, reversed the HOXA13-mediated effects on invasion and proliferation of colon cancer cells. In vivo studies further verified that HOXA13 promoted tumour formation through the Wnt/ß-Catenin pathway. Collectively, these results suggest that HOXA13 is a potential oncogene that functions by promoting the nuclear translocation of ß-Catenin, thereby maintaining the proliferation and metastasis of colon cancer.
Assuntos
Neoplasias do Colo/metabolismo , Proteínas de Homeodomínio/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Colo/metabolismo , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , HumanosRESUMO
Cancer metastasis is a unique feature of malignant tumours. Even bone can become a common colonization site due to the tendency of solid tumours, including breast cancer (BCa) and prostate cancer (PCa), to metastasize to bone. Currently, a previous concept in tumour metabolism called tumour dormancy may be a promising target for antitumour treatment. When disseminated tumour cells (DTCs) metastasize to the bone microenvironment, they form a flexible regulatory network called the "bone-tumour-inflammation network". In this network, bone turnover as well as metabolism, tumour progression, angiogenesis and inflammatory responses are highly unified and coordinated, and a slight shift in this balance can result in the disruption of the microenvironment, uncontrolled inflammatory responses and excessive tumour growth. The purpose of this review is to highlight the regulatory effect of the "bone-tumour-inflammation network" in tumour dormancy. Osteoblast-secreted factors, bone turnover and macrophages are emphasized and occupy in the main part of the review. In addition, the prospective clinical application of tumour dormancy is also discussed, which shows the direction of future research.
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Neoplasias Ósseas/metabolismo , Neoplasias da Mama/metabolismo , Inflamação/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia , Neoplasias da Próstata/patologia , Microambiente Tumoral/genéticaRESUMO
Sphingosine-1-phosphate (S1P) is a natural bioactive lipid molecule and a common first or second messenger in the cardiovascular and immune systems. By binding with its receptors, S1P can serve as mediator of signalling during cell migration, differentiation, proliferation and apoptosis. Although the predominant role of S1P in bone regeneration has been noted in many studies, this role is not as well-known as its roles in the cardiovascular and immune systems. In this review, we summarize previous research on the role of S1P receptors (S1PRs) in osteoblasts and osteoclasts. In addition, S1P is regarded as a bridge between bone resorption and formation, which brings hope to patients with bone-related diseases. Finally, we discuss S1P and its receptors as therapeutic targets for treating osteoporosis, inflammatory osteolysis and bone metastasis based on the biological effects of S1P in osteoclastic/osteoblastic cells, immune cells and tumour cells.
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Neoplasias Ósseas/genética , Reabsorção Óssea/genética , Lisofosfolipídeos/genética , Receptores de Esfingosina-1-Fosfato/genética , Esfingosina/análogos & derivados , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/patologia , Humanos , Metástase Neoplásica , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteólise/genética , Osteólise/patologia , Osteoporose/genética , Osteoporose/patologia , Esfingosina/genética , Receptores de Esfingosina-1-Fosfato/metabolismoRESUMO
The balance between bone formation and bone resorption is closely related to bone homeostasis. Osteoclasts, originating from the monocyte/macrophage lineage, are the only cell type possessing bone resorption ability. Osteoclast overactivity is thought to be the major reason underlying osteoclast-related osteolytic problems, such as Paget's disease, aseptic loosening of prostheses and inflammatory osteolysis; therefore, disruption of osteoclastogenesis is considered a crucial treatment option for these issues. WKYMVm, a synthetic peptide, which is a potent FPR2 agonist, exerts an immunoregulatory effect. This peptide inhibits the production of inflammatory cytokines, such as (IL)-1ß and TNF-α, thus regulating inflammation. However, there are only few reports on the role of WKYMVm and FPR2 in osteoclast cytology. In the current study, we found that WKYMVm negatively regulates RANKL- and lipopolysaccharide (LPS)-induced osteoclast differentiation and maturation in vitro and alleviates LPS-induced osteolysis in animal models. WKYMVm down-regulated the expression of osteoclast marker genes and resorption activity. Furthermore, WKYMVm inhibited osteoclastogenesis directly through reducing the phosphorylation of STAT3 and NF-kB and indirectly through the CD9/gp130/STAT3 pathway. In conclusion, our findings demonstrated the potential medicinal value of WKYMVm for the treatment of inflammatory osteolysis.
Assuntos
Receptor gp130 de Citocina/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Osteólise/metabolismo , Substâncias Protetoras/farmacologia , Fator de Transcrição STAT3/metabolismo , Tetraspanina 29/metabolismo , Animais , Reabsorção Óssea/patologia , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Osteocalcina/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ligante RANK/farmacologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Crânio/diagnóstico por imagem , Crânio/efeitos dos fármacos , Crânio/patologiaRESUMO
Skeletal homeostasis is closely effectuated by the regulation of bone formation and bone resorption. Osteoclasts are multinuclear giant cells responsible for bone resorption. Overactivated osteoclasts and excessive bone resorption result in various lytic bone diseases, such as osteoporosis, osteoarthritis, periprosthetic infection, and inflammatory aseptic loosening of orthopedic implants. In consideration of the severe side effects caused by the currently available drugs, exploitation of novel drugs has gradually attracted attention. Because of its anti-inflammatory, antioxidant, and antitumor capacities, diallyl disulfide (DADS), a major oil-soluble organosulfur ingredient compound derived from garlic, has been widely researched. However, the effects of DADS on osteoclasts and lytic bone diseases are still unknown. In this study, we investigated the effects of DADS on receptor activator of NF-κB ligand (RANKL)- and LPS-mediated osteoclastogenesis, LPS-stimulated proinflammatory cytokines related to osteoclasts, and LPS-induced inflammatory osteolysis. The results showed that DADS significantly inhibited RANKL-mediated osteoclast formation, fusion, and bone resorption in a dose-dependent manner via inhibiting the NF-κB and signal transducer and activator of transcription 3 signaling and restraining the interaction of NF-κB p65 with nuclear factor of activated T cells cytoplasmic 1. Furthermore, DADS also markedly suppressed LPS-induced osteoclastogenesis and reduced the production of proinflammatory cytokines with LPS stimulation to indirectly mediate osteoclast formation. Consistent with the in vitro results, DADS prevented the LPS-induced severe bone loss by blocking the osteoclastogenesis. All of the results indicate that DADS may be a potential and exploitable drug used for preventing and impeding osteolytic lesions.-Yang, J., Tang, R., Yi, J., Chen, Y., Li, X., Yu, T., Fei, J. Diallyl disulfide alleviates inflammatory osteolysis by suppressing osteoclastogenesis via NF-κB-NFATc1 signal pathway.
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Compostos Alílicos/farmacologia , Anti-Inflamatórios/farmacologia , Dissulfetos/farmacologia , NF-kappa B/fisiologia , Osteoclastos/efeitos dos fármacos , Osteólise/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Compostos Alílicos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Dissulfetos/uso terapêutico , Endotoxemia/complicações , Feminino , Inflamação , Lipopolissacarídeos/toxicidade , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/patologia , Osteólise/etiologia , Ligante RANK/antagonistas & inibidores , Ligante RANK/farmacologia , Células RAW 264.7 , Distribuição Aleatória , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Our aim was to investigate the clinical efficacy and complications of antibiotic treatment regimens for patients with bone infection. METHODS: We retrospectively analysed patients with bone infection admitted to our hospital between March 2013 and October 2018. After surgical debridement was performed, the patients were divided into three groups: IV group (intravenous antibiotics for 2 weeks); oral group (intravenous antibiotics for 2 weeks followed by oral antibiotics for 4 weeks); and rifampicin group (intravenous antibiotics for 2 weeks followed by oral antibiotics plus rifampicin for 4 weeks). The infection control rate and complications were compared among the three groups. RESULTS: A total of 902 patients were enrolled. The infection sites included 509 tibias, 228 femurs, 32 humeri, 23 radii and ulnae, 40 calcanei, and 47 miscellaneous sites, as well as 23 multiple-site infections. After at least 6 months of follow-up, 148 (16.4%) patients had an infection recurrence. The recurrence rate of the IV group was 17.9%, which was not significantly higher than the recurrence rates of the oral group (10.1%) and rifampicin group (10.5%), P = 0.051. The incidence of abnormal alanine aminotransferase (ALT) levels in the IV group was 15.1%, which was lower than that in the oral group (18.0%) and rifampicin group (27.4%), P = 0.026. The rates of proteinuria in the three groups were 3.2, 4.5, and 9.3%, respectively, P = 0.020. CONCLUSIONS: After debridement of bone infection, short-term antibiotic treatment regimens might offer similar rates of infection eradication while avoiding the risk of renal and hepatic damage associated with prolonged antibiotic use. THE LEVEL OF CLINICAL RELEVANCE: Stage III.
Assuntos
Antibacterianos/uso terapêutico , Desbridamento , Fraturas Ósseas/complicações , Infecções/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Excessive osteoclast formation is one of the important pathological features of inflammatory bone destruction. Interleukin-37 (IL-37) is an anti-inflammatory agent that is present throughout the body, but it displays low physiological retention. In our study, high levels of the IL-37 protein were detected in clinical specimens from patients with bone infections. However, the impact of IL-37 on osteoclast formation remains unclear. Next, IL-37 alleviated the inflammatory bone destruction in the mouse in vivo. We used receptor activator of nuclear factor-κB ligand and lipopolysaccharide to trigger osteoclastogenesis under physiological and pathological conditions to observe the role of IL-37 in this process and explore the potential mechanism of this phenomenon. In both induction models, IL-37 exerted inhibitory effects on osteoclast differentiation and bone resorption. Furthermore, IL-37 decreased the phosphorylation of inhibitor of κBα and p65 and the expression of nuclear factor of activated T cells c1, while the dimerization inhibitor of myeloid differentiation factor 88 reversed the effects. These data provide evidence that IL-37 modulates osteoclastogenesis and a theoretical basis for the clinical application of IL-37 as a treatment for bone loss-related diseases.