RESUMO
AIM: Haemophiliac arthritis (HA) is caused by spontaneous intra-articular hemorrhage and repeated intra-articular hematomas, leading to iron overload, which, in turn, induces M1 macrophage polarisation and inflammatory cytokine secretion, resulting in synovitis. Here, we explored the mechanism by which iron overload in HA induces the polarisation of M1 macrophages, providing a new approach for the treatment of HA synovitis. METHODS: The synovium from the knee joints of normal amputees and patients with HA was collected. Pathological changes in the synovial tissues were analysed using hematoxylin and eosin staining. Iron tissue deposition was evaluated using the iron assay kit and Prussia Blue staining, while macrophage phenotype was determined using immunofluorescence. The levels of pro-inflammatory cytokines and p53 acetylation were determine using western blotting. An in vitro iron overload model was established by inducing THP-1 macrophages with ferric ammonium citrate, and the involvement of acetylated p53 in M1 macrophage polarisation was investigated. RESULTS: Compared to control samples, the iron content in the synovium of patients with HA was significantly increased. The protein levels of M1 macrophage markers, pro-inflammatory cytokines, and acetylated p53, were also significantly elevated in the synovial tissues of patients with HA. Similar results were observed in the in vitro iron overload model. Furthermore, the inhibition of p53 acetylation in vitro reversed these iron overload-induced effects. CONCLUSION: In patients with HA, iron overload induced synovial p53 acetylation, leading to macrophage polarisation toward the M1 phenotype and increased inflammatory cytokine secretion, resulting in synovitis. HIGHLIGHTS: Synovial iron overload is associated with changes in P53 acetylation in hemophiliac arthritis (HA). Acetylated p53, a known regulator of macrophage polarization, is highly expressed in HA synovium, suggesting a potential role in M1 polarization. HA synovial macrophages predominantly polarize into the pro-inflammatory M1 phenotype, secreting elevated levels of pro-inflammatory cytokines.
Assuntos
Sobrecarga de Ferro , Osteoartrite , Sinovite , Humanos , Proteína Supressora de Tumor p53/metabolismo , Membrana Sinovial/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Sinovite/complicações , Osteoartrite/patologia , Fenótipo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Ferro/metabolismo , Citocinas/metabolismoRESUMO
Iron deposition is closely related to developing haemophilic arthropathy (HA). Studying the relationship between ferroptosis signal expression and iron overload in HA synovium facilitates understanding the pathogenesis of joint synovial hyperplasia in bloodborne arthritis and the development of new protective methods. The knee synovium was collected from HA and osteoarthritis (OA) patients, and pathological changes were analysed by HE and Prussian blue staining. Ferroptosis phenotypes were examined by immunohistochemistry and western blotting. Moreover, ferric ammonium citrate (FAC)-induced was used to construct an in vitro iron overload model to investigate the relationship between iron overload and ferroptosis in synovial fibroblasts (FLS). Furthermore, the factors influencing ferroptosis in FLS were explored. Iron deposition, cell proliferation, and vascular proliferation in the synovium of HA were more obvious. Ferroptosis in HA synovium appears to inhibit. FLS ferroptosis increased with iron accumulation, malondialdehyde (MDA) in cells, and glutathione (GSH) depletion. TNF-α plays a protective role in this process. Blocking the action of TNF-α and inducing ferroptosis significantly reduced synovial proliferation. TNF-α inhibitors combined with a ferroptosis inducer may be a new therapeutic method for HA synovitis.
Assuntos
Ferroptose , Doenças Hematológicas , Sobrecarga de Ferro , Osteoartrite , Sinovite , Humanos , Fator de Necrose Tumoral alfa , Sinovite/etiologia , Sinovite/metabolismo , Sinovite/patologia , Osteoartrite/complicações , Osteoartrite/metabolismo , Osteoartrite/patologia , Sobrecarga de Ferro/complicações , Doenças Hematológicas/complicações , Ferro/metabolismoRESUMO
INTRODUCTION: Clarifying the links between iron and FGF23, SOX9 expression in chondrocytes would be helpful for comprehending articular cartilage degradation pathogenesis in blood-induced arthritis and exploring new protective methods. AIM: The purpose of this study was to determine iron regulation of fibroblast growth factor 23 (FGF23) and SRY-box 9 (SOX9) in human chondrocytes, an area which is unexplored in blood-induced arthritis cartilage degradation pathogenesis. METHODS: Expression of FGF23, SOX9, MMP13 and collagen â ¡ in articular cartilage of patients with osteoarthritis (OA) or haemophilic arthritis (HA) was determined by western blot (WB). Iron-induced FGF23 and SOX9 mRNA and protein expression in primary human normal chondrocyte cells (HUM-iCell-s018) was quantified by qRT-PCR and WB, respectively. RESULTS: We found that compared with OA patients, the expression of FGF23, MMP13 in articular cartilage of patients with HA was up-regulated, while the expression of SOX9, collagen â ¡ was down-regulated. Iron-induced FGF23 and suppressed SOX9 expression in chondrocytes in a dose-dependent manner. CONCLUSIONS: These findings demonstrated that iron was involved in hemophilic cartilage lesion directly via changing cartilage phenotype through regulation of FGF23 and SOX9 expression in chondrocytes.
Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Colágeno/metabolismo , Ferro/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/farmacologia , Osteoartrite/genética , Osteoartrite/patologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOX9/farmacologiaRESUMO
INTRODUCTION: Studying the pathological changes of ligaments in patients with haemophilic arthritis (HA) has important significance for guiding the release of ligaments during total knee arthroplasty (TKA) and exploring interventions to prevent ligament lesions. AIM: This study was conducted to show the pathological changes and investigate the lysine oxidase (LOX) and matrix metalloproteinase (MMP)-1, -2, and -3 levels in the ligaments of patients with HA compared with those of patients with osteoarthritis (OA). METHODS: Ligaments obtained during the TKA were stained with Masson trichrome, Verhoeff-Van Gieson and haematoxylin and eosin to show the basic pathological changes. Collagen I, elastin, LOXs and MMP-1, -2, and -3 expression levels were detected via western blot. LOX and MMP-1, -2, and -3 mRNA expression levels were analysed via quantitative real-time PCR. RESULTS: Compared with OA ligaments, HA ligaments were constructed more loosely with wider gaps, more breaks, haemocytodeposition and local hypertrophy among the fibres. LOXs and MMP mRNA expression levels were upregulated in the HA tissues, which was consistent with the western blot results. Collagen I and elastin levels were also higher in patients with HA. CONCLUSIONS: The metabolism of the ligaments in patients with HA is more complex than in those with OA, and the ligaments of patients with HA have stronger healing and destruction processes. This pathology is related to iron overload and imbalanced inflammatory factors due to repeated intra-articular bleeding.
Assuntos
Ligamentos/enzimologia , Osteoartrite , Humanos , Metaloproteinase 1 da Matriz , Metaloproteinase 2 da Matriz , Metaloproteinase 3 da Matriz , Osteoartrite/enzimologia , Proteína-Lisina 6-OxidaseRESUMO
The role of gut-kidney crosstalk in the progression of diabetic nephropathy (DN) is receiving increasing concern. On one hand, the decline in renal function increases circulating uremic toxins and affects the composition and function of gut microbiota. On the other hand, intestinal dysbiosis destroys the epithelial barrier, leading to increased exposure to endotoxins, thereby exacerbating kidney damage by inducing systemic inflammation. Dietary inventions, such as higher fiber intake, prebiotics, probiotics, postbiotics, fecal microbial transplantation (FMT), and engineering bacteria and phages, are potential microbiota-based therapies for DN. Furthermore, novel diabetic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, may affect the progression of DN partly through gut microbiota. In the current review, we mainly summarize the evidence concerning the gut-kidney axis in the advancement of DN and discuss therapies targeting the gut microbiota, expecting to provide new insight into the clinical treatment of DN.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Inibidores da Dipeptidil Peptidase IV , Microbioma Gastrointestinal , Probióticos , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Rim , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Probióticos/uso terapêuticoRESUMO
Neuroinflammation and cognitive decline are the key pathological features in aging that bring detrimental impacts upon quality of life. However, there is no effective anti-aging pharmacological therapy thus far. Dietary supplements in particular essence of chicken (EC) has been found to be an effective remedy for alleviating mental stress and improving memory. In addition, a novel hydrolyzed chicken extract, ProBeptigen/CMI-168 (PB), showed beneficial effects on cognitive ability. However, the antiaging effect and possible mechanism of PB and EC are still unknown. Here, we investigated the antiaging effects of PB and EC on hippocampus-related cognitive decline and neuroinflammation in aged mice. PB and EC were administered for 16 weeks in 10-month-old mice. Both PB and EC treatments ameliorated age-related deterioration of learning and memory, and attenuated oxidative stress and inflammation in the hippocampus. These results were associated with decreased inflammatory cytokine levels and increased neurotransmitter levels in the hippocampus. The overall effects of improving aging-induced cognitive decline were more robust in PB-treated mice, while EC was effective in decreasing oxidative stress and inflammation. Moreover, alterations in the diversity and composition of the gut microbiota in aged mice were also regulated by both PB and EC, which induced distinguished features in the gut microbiota and their related functions. This study showed that PB exerts neuroprotective effects in aged mice, the mechanism of which might be different from that of EC. Therefore, PB has a potential as dietary supplement for ameliorating cognitive dysfunction and neuroinflammation in elderly individuals.
Assuntos
Envelhecimento/metabolismo , Disfunção Cognitiva/prevenção & controle , Suplementos Nutricionais , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Envelhecimento/patologia , Animais , Galinhas , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Hipocampo/patologia , Inflamação , Masculino , Camundongos , Fármacos Neuroprotetores/química , Especificidade da EspécieRESUMO
BACKGROUND: A supination-adduction (SAD) ankle fracture is a special type of ankle fracture that results in collapse of the distal tibial articular surface; as such, orthopaedic surgeons require greater awareness of this type of fracture. The severity of this injury lies between that of an ordinary ankle fracture and a pilon fracture, and the treatment of such fractures based on the ankle fracture concept leads to extremely high rates of postoperative complications and a poor prognosis. In this retrospective study, we aimed to explore the treatment of SAD fractures based on the pilon fracture concept. METHODS: We retrospectively analysed the clinical data of 67 patients with Lauge-Hansen supination-adduction type II (SAD-II) ankle fractures, most of whom had a 44-A AO classification. Patients underwent surgical treatment at the Second Affiliated Hospital of Anhui Medical University from January 2009 to June 2019. The patients were divided into two groups based on the surgical concept employed: 43 patients were included in the ankle fracture surgical concept group, and 24 patients were included in the medial pilon fracture surgical concept group. The therapeutic effect was evaluated based on the Burwell-Charnley radiological reduction standard, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and postoperative visual analogue scale (VAS) pain score 1 year after surgery using regression with adjustment for confounding factors. RESULTS: All 67 patients were followed up. Twenty-four patients were treated according to the medial pilon fracture concept, and forty-three patients were treated according to the ankle fracture concept. The AOFAS score 1 year after surgery in the medial pilon group (89.83 ± 2.77) was higher than that in the ankle fracture group (83.63 ± 7.97) (p < 0.05). The VAS score 1 year after surgery in the medial pilon fracture group (1.17 ± 0.96) was significantly better than that in the ankle fracture group (2.28 ± 0.96) (p < 0.05). CONCLUSION: Patients with Lauge-Hansen SAD-II ankle fractures treated based on the medial pilon fracture surgical concept had better postoperative outcomes than those treated based on the ankle fracture surgical concept. LEVEL OF EVIDENCE: Level III, retrospective cohort study.
Assuntos
Fraturas do Tornozelo , Fraturas da Tíbia , Fraturas do Tornozelo/diagnóstico por imagem , Fraturas do Tornozelo/cirurgia , Fixação Interna de Fraturas , Humanos , Estudos Retrospectivos , Supinação , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgia , Resultado do TratamentoRESUMO
Recent telepresence systems have shown significant improvements in quality compared to prior systems. However, they struggle to achieve both low cost and high quality at the same time. In this work, we envision a future where telepresence systems become a commodity and can be installed on typical desktops. To this end, we present a high-quality view synthesis method that uses a cost-effective capture system that consists of commodity hardware accessible to the general public. We propose a neural renderer that uses a few RGBD cameras as input to synthesize novel views of a user and their surroundings. At the core of the renderer is Multi-Layer Point Cloud (MPC), a novel 3D representation that improves reconstruction accuracy by removing non-linear biases in depth cameras. Our temporally-aware renderer further improves the stability of synthesized videos by conditioning on past information. Additionally, we propose Spatial Skip Connections (SSC) to improve image upsampling under limited GPU memory. Experimental results show that our renderer outperforms recent methods in terms of view synthesis quality. Our method generalizes to new users and challenging content (e.g., hand gestures and clothing deformation) without costly per-video optimization, object templates, or heavy pre-processing. The code and dataset will be made available.
RESUMO
Spermidine exerts protective roles in obesity, while the mechanism of spermidine in adipose tissue thermogenesis remains unclear. The present study first investigated the effect of spermidine on cold-stimulation and ß3-adrenoceptor agonist-induced thermogenesis in lean and high-fat diet-induced obese mice. Next, the role of spermidine on glucose and lipid metabolism in different types of adipose tissue was determined. Here, we found that spermidine supplementation did not affect cold-stimulated thermogenesis in lean mice, while significantly promoting the activation of adipose tissue thermogenesis under cold stimulation and ß3-adrenergic receptor agonist treatment in obese mice. Spermidine treatment markedly enhanced glucose and lipid metabolism in adipose tissues, and these results were associated with the activated autophagy pathway. Moreover, spermidine up-regulated fibroblast growth factor 21 (FGF21) signaling and its downstream pathway, including PI3K/AKT and AMPK pathways in vivo and in vitro. Knockdown of Fgf21 or inhibition of PI3K/AKT and AMPK pathways in brown adipocytes abolished the thermogenesis-promoting effect of spermidine, suggesting that the effect of spermidine on adipose tissue thermogenesis might be regulated by FGF21 signaling via the PI3K/AKT and AMPK pathways. The present study provides new insight into the mechanism of spermidine on obesity and its metabolic complications, thereby laying a theoretical basis for the clinical application of spermidine.
Assuntos
Tecido Adiposo Marrom , Espermidina , Camundongos , Animais , Espermidina/farmacologia , Espermidina/metabolismo , Espermidina/uso terapêutico , Tecido Adiposo Marrom/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Obesos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tecido Adiposo/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Obesidade/metabolismo , Glucose/metabolismo , Termogênese , Tecido Adiposo Branco/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Inibidores da Dipeptidil Peptidase IV , Metformina , Camundongos , Animais , Linagliptina/farmacologia , Linagliptina/uso terapêutico , Quimiocina CCL3/farmacologia , Microglia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , InflamaçãoRESUMO
Cognitive decline is inevitable with age, and due to the lack of well-established pharmacotherapies for neurodegenerative disorders, dietary supplements have become important alternatives to ameliorate brain deterioration. Hydrolyzed chicken meat extract (HCE) and its bioactive components were previously found to improve neuroinflammation and cognitive decline by regulating microglia polarization. However, the effects and mechanisms of these bioactives on neurons remain unclear. Here, the most potent bioactive component on neural function in HCE was screened out, and the detailed mechanism was clarified through in vivo and in vitro experiments. We found that HCE, cyclo(Val-Pro), cyclo(Phe-Phe), cyclo(His-Pro), cyclo(Leu-Lys), and arginine exerted stronger anti-inflammatory and antioxidant effects among the 12 bioactives in amyloid ß (Aß)-treated HT-22 cells. Further transcriptome sequencing and polymerase chain reaction (PCR) array analysis showed that these bioactives participated in different signaling pathways, and cyclo(Val-Pro) was identified as the most potent cyclic dipeptide. In addition, the antiapoptotic and neuroprotective effect of cyclo(Val-Pro) was partly regulated by the activation of PI3K/AKT and AMPK pathways, and the inhibition of these pathways abolished the effect of cyclo(Val-Pro). Moreover, cyclo(Val-Pro) enhanced cognitive function and neurogenesis and alleviated neuroinflammation and oxidative stress in middle-aged mice, with an effect similar to HCE. Hippocampal transcriptome analysis further revealed that HCE and cyclo(Val-Pro) significantly enriched the neuroactive ligand-receptor interaction pathway, verified by enhanced neurotransmitter levels and upregulated neurotransmitter receptor-related gene expression. Therefore, the mechanism of cyclo(Val-Pro) on neural function might be associated with PI3K/AKT and AMPK pathway-mediated antiapoptotic effect and neurogenesis and the activation of the neurotransmitter-receptor pathway.
Assuntos
Proteínas Quinases Ativadas por AMP , Apoptose , Galinhas , Neurônios , Fármacos Neuroprotetores , Peptídeos Cíclicos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Camundongos , Apoptose/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/química , Carne/análise , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/genética , Humanos , Camundongos Endogâmicos C57BL , Peptídeos beta-Amiloides/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
Dislocation is a complication of acetabular fractures involving the posterior wall, but whether dislocation is an absolute factor impacting the short- to medium-term prognosis of the hip joint remains controversial. This study aimed to compare the short- to medium-term clinical and radiological results among patients diagnosed with an acetabular fracture involving the posterior wall, with or without dislocation.Seventy-nine patients diagnosed with an acetabular fracture involving the posterior wall were retrospectively divided into posterior dislocation and non-dislocation groups. All fractures were open reduction + internal fixation with a plate screw combination through the single Kocher-Langenbeck approach. The short- to medium-term radiographic outcomes of follow-up were evaluated using the Matta radiologic grading system, while the clinical outcomes were evaluated using the modified Merle d'Aubigné-Postel evaluation system.The mean follow-up duration for all patients was 43.90 (range 24-75) months. Both groups achieved similar short- to medium-term clinical and radiographic results. There seems to be no significant differences between the two groups regarding the short- to medium-term assessment of clinical and radiographic results and the occurrence of postoperative complications (p > 0.05).In patients with acetabular fractures involving the posterior wall, hip dislocation is probably not an absolute determinant of a poor outcome. Even with early reduction, the short- to medium-term prognosis results appear similar to those of patients without dislocation.
RESUMO
Osteoarthritis (OA) is the most prevalent degenerative musculoskeletal disease, severely impacting the function of patients and potentially leading to disability, especially among the elderly population. Natural products (NPs), obtained from components or metabolites of plants, animals, microorganisms etc., have gained significant attention as important conservative treatments for various diseases. Recently, NPs have been well studied in preclinical and clinical researches, showing promising potential in the treatment of OA. In this review, we summed up the main signaling pathways affected by NPs in OA treatment, including NF-κB, MAPKs, PI3K/AKT, SIRT1, and other pathways, which are related to inflammation, anabolism and catabolism, and cell death. In addition, we described the therapeutic effects of NPs in different OA animal models and the current clinical studies in OA patients. At last, we discussed the potential research directions including in-depth analysis of the mechanisms and new application strategies of NPs for the OA treatment, so as to promote the basic research and clinical transformation in the future. We hope that this review may allow us to get a better understanding about the potential bioeffects and mechanisms of NPs in OA therapy, and ultimately improve the effectiveness of NPs-based clinical conservative treatment for OA patients.
RESUMO
The circadian clock is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), and the target pathways of many NASH candidate drugs are controlled by the circadian clock. However, the application of chronopharmacology in NASH is little considered currently. Here, the time-dependent effect of REV-ERBα agonist SR9009 on diet-induced NASH and microbiota was investigated. C57BL/6J mice were fed a high-cholesterol and high-fat diet (CL) for 12 weeks to induce NASH and then treated with SR9009 either at Zeitgeber time 0 (ZT0) or ZT12 for another 6 weeks. Pharmacological activation of REV-ERBα by SR9009 alleviated hepatic steatosis, insulin resistance, liver inflammation, and fibrosis in CL diet-induced NASH mice. These effects were accompanied by improved gut barrier function and altered microbial composition and function in NASH mice, and the effect tended to be stronger when SR9009 was injected at ZT0. Moreover, SR9009 treatment at different time points resulted in a marked difference in the composition of the microbiota, with a stronger effect on the enrichment of beneficial bacteria and the diminishment of harmful bacteria when SR9009 was administrated at ZT0. Therefore, the time-dependent effect of REV-ERBα agonist on NASH was partly associated with the microbiota, highlighting the potential role of microbiota in the chronopharmacology of NASH and the possibility of discovering new therapeutic strategies for NASH.
Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ritmo Circadiano , Camundongos Endogâmicos C57BL , Dieta HiperlipídicaRESUMO
OBJECTIVE: Proinflammatory cytokines are considered to be one of the key causes of haemophilic cartilage destruction by inducing chondrocyte apoptosis and extracellular matrix degradation. However, few studies have focused on how proinflammatory cytokines regulate the phenotypic changes of chondrocytes, which may be an important factor in haemophilic cartilage degradation pathogenesis. More understanding is needed about the effect of proinflammatory cytokines on phenotypic changes of the chondrocyte. The objective of this study was to examine how IL-6, TNF-α and IL-1ß regulate the chondrocyte phenotype, which may be an important factor in haemophilic cartilage degradation pathogenesis. METHODS: HUM-iCell-s018 chondrocytes were treated with increasing concentrations of TNF-α, IL-6 or IL-1ß (0, 1, 5, 10â ng/ml) for 24â h, then FGF23 and SOX9 expression was determined by qRT-PCR and WB, respectively. RESULTS: We found that TNF-α, IL-6 and IL-1ß induced FGF23 and suppressed SOX9 expression in chondrocytes in a dose-dependent manner. IL-1ß had a stronger regulatory effect on FGF23, while TNF-α and IL-6 had stronger regulatory effects on SOX9. CONCLUSIONS: These findings suggest that IL-6, IL-1ß and TNF-α may be involved in haemophilic cartilage destruction pathogenesis by altering the chondrocyte phenotype through modulation of FGF23 and SOX9 gene expression.
Assuntos
Condrócitos , Interleucina-1beta , Interleucina-6 , Fator de Necrose Tumoral alfa , Humanos , Células Cultivadas , Condrócitos/metabolismo , Citocinas , Interleucina-1beta/metabolismo , Interleucina-6/genética , Fenótipo , Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVE: Our previous study demonstrated that iron overload could lead to haemophilic cartilage destruction by changing chondrocyte phenotype. This change was caused by iron's effect on chondrocyte expression of FGF23 and SOX9, in addition to iron-induced chondrocyte apoptosis and cartilage extracellular matrix degradation. However, the underlying mechanisms remain unclear. This study aimed to determine the mechanism by which iron influences chondrocyte phenotype in the pathogenesis of haemophilic cartilage destruction. METHODS: The expression of the PTEN/PI3K/AKT/FOXO1 signal pathway in the articular cartilage of patients with haemophilic arthritis (HA) or osteoarthritis (OA) was determined using western blot (WB). Additionally, we quantified the expression of iron-induced PTEN, PI3K, p-PI3K, AKT, p-AKT, FOXO1, and p-FOXO1 in primary human normal chondrocyte cells (HUM-iCell-s018) using WB. RESULTS: We found that compared to that in patients with OA, the expression of PTEN, PI3K, AKT, and FOXO1 in the articular cartilage of patients with HA was up-regulated, while the expression of p-PI3K, p-AKT, and p-FOXO1 was down-regulated. Additionally, iron increased the expression of PTEN, PI3K, AKT, and FOXO1 and suppressed that of p-PI3K, p-AKT, and p-FOXO1 in chondrocytes in a dose-dependent manner. CONCLUSIONS: Our findings demonstrated that iron was involved in the pathogenesis of haemophilic cartilage destruction by affecting chondrocyte phenotype through the inhibition of the PTEN/PI3K/AKT/FOXO1 pathway.
Assuntos
MicroRNAs , Osteoartrite , Humanos , Condrócitos/metabolismo , Condrócitos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Ferro/metabolismo , MicroRNAs/genética , Cartilagem/metabolismo , Cartilagem/patologia , Osteoartrite/metabolismo , Apoptose , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/farmacologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismoRESUMO
AIMS: Inflammatory bowel disease (IBD) patients are accompanied by impaired intestinal barrier integrity and gut microbiota dysbiosis. Strategies targeting the gut microbiota are potential therapies for preventing and ameliorating IBD. MAIN METHODS: The potential roles of two probiotic stains, Bifidobacterium longum BL986 (BL986) and Lactobacillus casei LC122 (LC122), on intestinal mucosal barrier function and microbiota in IBD zebrafish of different ages were investigated. KEY FINDINGS: BL986 and LC122 treatment promoted the development and increased the microbiota diversity in larval zebrafish. Both probiotic treatment ameliorated mortality, promoted intestinal mucus secretion, and reduced the expression of inflammatory markers, thereby improving intestinal mucosal barrier function in dextran sulfate sodium salt (DSS)-induced ulcerative colitis (UC) and 2,4,6-trinitro-benzenesulfonicacid (TNBS)-induced Crohn's disease (CD) models in zebrafish. Moreover, the composition and function of microbiota were altered in IBD zebrafish, and probiotics treatment displayed prominent microbiota features. BL986 was more potent in the DSS-induced UC model, and increased the abundance of Faecalibaculum and butyric acid levels. LC122 exerted better protection against TNBS-induced CD, and increased the abundance of Enhydrobacter and acetic acid levels. Furthermore, the effect of probiotics was stronger in larval and aged zebrafish. CONCLUSION: The impact of probiotics on IBD might differ from the subtypes of IBD and the age of the zebrafish, suggesting the types of disease and age should be taken into full consideration during the practical usage of probiotics.
Assuntos
Colite Ulcerativa , Colite , Doença de Crohn , Doenças Inflamatórias Intestinais , Microbiota , Probióticos , Animais , Peixe-Zebra , Lactobacillus , Bifidobacterium , Colite Ulcerativa/microbiologia , Probióticos/farmacologia , Probióticos/uso terapêutico , Sulfato de Dextrana , Modelos Animais de Doenças , Colite/induzido quimicamenteRESUMO
BACKGROUND: Abnormal epiphyseal growth plate development of the proximal tibia in hemophilia patients leads to notable morphological changes in the mature knee joint. This study aimed to compare the morphological characteristics of tibial component placement cut surface in patients with hemophilic arthritis (HA) and osteoarthritis (OA) and to determine the tibial component rotational alignment axis' best position for HA patients. METHODS: Preoperative computed tomography scans of 40 OA and 40 HA patients who underwent total knee arthroplasty were evaluated using a three-dimensional (3D) software. The tibial component's placement morphological parameters were measured. The tibial component's rotational mismatch angles were evaluated, and the most appropriate 0°AP axis position for HA patients was investigated. RESULTS: In the two groups, the morphology was significantly different in some of the parameters (p < 0.05). The tibial component rotational mismatch angles were significantly different between both groups (p < 0.05). The medial 9.26° of the medial 1/3 of the patellar tendon was the point through which 0°AP axis passed for the HA patients. Similarly, the medial 13.02° of the medial 1/3 of the tibial tubercle was also the point through which the 0°AP axis passed. CONCLUSIONS: The ratio of the anteroposterior length to the geometric transverse length of the placement section of the tibial component in HA patients was smaller than that in OA patients. The medial 9.26° of the medial 1/3 of the patellar tendon or the medial 13.02° of the medial 1/3 of the tibial tubercle seem to be an ideal reference position of the rotational alignment axis of the tibial component for HA patients.
Assuntos
Artroplastia do Joelho , Hemofilia A , Osteoartrite do Joelho , Artroplastia do Joelho/métodos , Hemofilia A/complicações , Hemofilia A/diagnóstico por imagem , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/etiologia , Osteoartrite do Joelho/cirurgia , Rotação , Tíbia/anatomia & histologia , Tíbia/diagnóstico por imagem , Tíbia/cirurgiaRESUMO
AIMS: The therapeutic effects of spermidine on preexisting obese mice have been not fully elucidated. In this study, we assessed the anti-obesity impact of spermidine on high-fat diet (HFD)-induced obese mice. MAIN METHODS: C57BL/6J mice were fed a HFD for 16 weeks to induce obesity, and then treated with or without spermidine via drinking water for additional 8 weeks. The contributions of spermidine in regulating obesity phenotypes and metabolic syndrome were further evaluated. KEY FINDINGS: Spermidine administration lowered fat mass and plasma lipid profile in HFD-induced obese mice without affecting body weight. In addition, spermidine attenuated hepatic steatosis by regulating lipid metabolism and enhancing antioxidant capacity. Moreover, spermidine reduced adipose tissue inflammation by decreasing inflammatory cytokine and chemokines expression, and these results might contributed to the enhanced thermogenic gene expression in brown adipose tissue. Furthermore, spermidine treatment enhanced gut barrier function by up-regulating tight junction- and mucin-related gene expression. SIGNIFICANCE: Spermidine-mediated protective impacts involve the regulation of lipid metabolism, inflammation response, gut barrier function and thermogenesis. These findings demonstrate that spermidine has potentials in treating obesity.
Assuntos
Fígado Gorduroso/fisiopatologia , Espermidina/farmacologia , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Espermidina/metabolismo , Termogênese/efeitos dos fármacosRESUMO
Obesity is associated with impaired intestinal barrier function and dysbiosis of the gut microbiota. Spermidine, a polyamine that acts as an autophagy inducer, has important benefits in patients with aging-associated diseases and metabolic dysfunction. However, the mechanism of spermidine on obesity remains unclear. Here, we show that spermidine intake is negatively correlated with obesity in both humans and mice. Spermidine supplementation causes a significant loss of weight and improves insulin resistance in diet-induced obese (DIO) mice. These effects are associated with the alleviation of metabolic endotoxemia and enhancement of intestinal barrier function, which might be mediated through autophagy pathway and TLR4-mediated microbial signaling transduction. Moreover, spermidine causes the significant alteration of microbiota composition and function. Microbiota depletion compromises function, while transplantation of spermidine-altered microbiota confers protection against obesity. These changes might partly be driven by an SCFA-producing bacterium, Lachnospiraceae NK4A136 group, which was decreased in obese subjects and subsequently increased by spermidine. Notably, the change of Lachnospiraceae NK4A136 group is significantly correlated with enhanced gut barrier function induced by spermidine. Our results indicate that spermidine supplementation may serve as a viable therapy for obesity.