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1.
Artigo em Inglês | MEDLINE | ID: mdl-38243960

RESUMO

Osteoarthritis (OA) is a degenerative disease that results in constriction of the joint space due to the gradual deterioration of cartilage, alterations in subchondral bone, and synovial membrane. Recently, scientists have found that OA involves lesions in the whole joint, in addition to joint wear and tear and cartilage damage. Osteoarthritis is often accompanied by a subclinical form of synovitis, which is a chronic, relatively low-grade inflammatory response mainly mediated by the innate immune system. The "immune-joint" axis refers to an interaction of an innate immune response with joint inflammation and the whole joint range. Previous studies have underestimated the role of the immune-joint axis in OA, and there is no related research. For this reason, this review aimed to evaluate the existing evidence on the influence of innate immune mechanisms on the pathogenesis of OA. The innate immune system is the body's first line of defense. When the innate immune system is triggered, it instantly activates the downstream inflammatory signal pathway, causing an inflammatory response, while also promoting immune cells to invade joint synovial tissue and accelerate the progression of OA. We have proposed the concept of the "immune-joint" axis and explored it from two aspects of Traditional Chinese Medicine (TCM) theory and modern medical research, such as the innate immunity and OA, macrophages and OA, complement and OA, and other cells and OA, to enrich the scientific connotation of the "immune-joint" axis.

2.
Bioact Mater ; 33: 545-561, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38162513

RESUMO

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

3.
Food Funct ; 14(9): 4065-4077, 2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37077156

RESUMO

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degeneration, subchondral bone sclerosis, synovial hyperplasia and inflammation as the main pathological manifestations. This study aims to investigate the protective effect of prebiotics in post-traumatic osteoarthritic (PTOA) mice by modulating the gut barrier and fecal metabolomics. The results suggested that cartilage degeneration, osteophyte formation and inflammation were significantly reduced by prebiotics in PTOA mice. In addition, the gut barrier was protected by the increased expression of tight junction proteins ZO-1 and occludin in the colon. High-throughput sequencing found that 220 fecal metabolites were affected by joint trauma, 81 of which were significantly recovered after probiotic intervention, and some metabolites (valerylcarnitine, adrenic acid, oxoglutaric acid, etc.) were closely associated with PTOA. Our study demonstrates that prebiotics can delay the progression of PTOA by regulating the metabolites of the gut microbiota and protecting the gut barrier, which is expected to be an intervention method for PTOA.


Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Osteoartrite/metabolismo , Prebióticos , Inflamação/metabolismo , Metabolômica , Modelos Animais de Doenças
4.
Int Immunopharmacol ; 113(Pt A): 109349, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36302323

RESUMO

Osteoarthritis (OA) is a common degenerative disease with few treatments. In traditional Chinese medicine (TCM), Radix Angelicae biseratae (RAB) is commonly used to treat OA. Nodakenin (Nod) is one main coumarin active component in RAB and exhibits anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Reactive oxygen species (ROS) produced by mitochondria play a vital role in the pathogenesis of OA. We hypothesized that Nod might ameliorate cartilage degradation and inflammatory responses by regulating the mitochondrial Drp1/ROS/NLRP3 axis. With this, the effects of Nod on a mouse model of knee OA and activated primary chondrocytes were assessed. The results showed that Nod intervention improved bone volume, lowered trabecular separation, and increased trabecular number in the subchondral bone. Nod decreased the Osteoarthritis Research Society International (OARSI) scores and increased collagen II-positive areas in the articular cartilage of the tibial plateau. Compared with OA mice, Nod-treated animals exhibited lower levels of inflammatory factors in the serum and synovitis of the knee joint. In vitro results indicated that Nod suppressed dynamin-related protein 1 (Drp1) phosphorylation and massive ROS production by Drp1-dependent mitochondrial fission in lipopolysaccharide-stimulated chondrocytes. Moreover, Nod inhibited the mRNA levels of inflammatory cytokines (COX 2, IL-1ß, and TNF-α), nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and matrix metalloproteinase 13 expression in activated chondrocytes. In conclusion, Nod attenuates cartilage degradation and inflammatory responses in mice with OA by regulating the mitochondrial Drp1/ROS/NLRP3 axis, suggesting its potential for OA therapy.


Assuntos
Cartilagem Articular , Osteoartrite do Joelho , Camundongos , Animais , Osteoartrite do Joelho/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Condrócitos , Cartilagem Articular/patologia , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Modelos Animais de Doenças , Mitocôndrias , Dinaminas/metabolismo
5.
Front Pharmacol ; 13: 951860, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36188596

RESUMO

Background: Knee osteoarthritis (KOA), a chronic degenerative disease, is mainly characterized by destruction of articular cartilage and inflammatory reactions. At present, there is a lack of economical and effective clinical treatment. Zhuifeng Tougu (ZFTG) capsules have been clinically approved for treatment of OA as they relieve joint pain and inflammatory manifestations. However, the mechanism of ZFTG in KOA remains unknown. Purpose: This study aimed to investigate the effect of ZFTG on the TLR4/MyD88/NF-κB signaling pathway and its therapeutic effect on rabbits with KOA. Study design: In vivo, we established a rabbit KOA model using the modified Videman method. In vitro, we treated chondrocytes with IL-1ß to induce a pro-inflammatory phenotype and then intervened with different concentrations of ZFTG. Levels of IL-1ß, IL-6, TNF-α, and IFN-γ were assessed with histological observations and ELISA data. The effect of ZFTG on the viability of chondrocytes was detected using a Cell Counting Kit-8 and flow cytometry. The protein and mRNA expressions of TLR2, TLR4, MyD88, and NF-κB were detected using Western blot and RT-qPCR and immunofluorescence observation of NF-κB p65 protein expression, respectively, to investigate the mechanism of ZFTG in inhibiting inflammatory injury of rabbit articular chondrocytes and alleviating cartilage degeneration. Results: The TLR4/MyD88/NF-κB signaling pathway in rabbits with KOA was inhibited, and the levels of IL-1ß, IL-6, TNF-α, and IFN-γ in blood and cell were significantly downregulated, consistent with histological results. Both the protein and mRNA expressions of TLR2, TLR4, MyD88, NF-κB, and NF-κB p65 proteins in that nucleus decreased in the ZFTG groups. Moreover, ZFTG promotes the survival of chondrocytes and inhibits the apoptosis of inflammatory chondrocytes. Conclusion: ZFTG alleviates the degeneration of rabbit knee joint cartilage, inhibits the apoptosis of inflammatory chondrocytes, and promotes the survival of chondrocytes. The underlying mechanism may be inhibition of the TLR4/MyD88/NF-kB signaling pathway and secretion of inflammatory factors.

6.
Front Pharmacol ; 12: 788392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35082670

RESUMO

As life expectancy increases, Osteoarthritis (OA) is becoming a more frequently seen chronic joint disease. The main characteristics of OA are loss of articular cartilage, subchondral bone sclerosis, and synovial inflammation. Baicalein (Bai), a traditional Chinese medicine extracted from Scutellaria baicalensis Georgi, has been demonstrated to exert notable anti-inflammatory effects in previous studies, suggesting its potential effect in the treatment of OA. In this study, we first predicted the action targets of Bai, mapped target genes related to OA, identified potential anti-OA targets for Bai, performed gene ontology (GO) enrichment, and KEGG signaling pathway analyses of the action targets, and analyzed the molecular docking of key Bai targets. Additionally, the effect and potential mechanism of Bai against OA were verified in mouse knee OA models induced by destabilized medial meniscus (DMM) surgery. GO and KEGG analyses showed that 19 anti-OA targets were mainly involved in the response to oxidative stress, the response to hypoxia and apoptosis, and the PI3K-Akt and p53 signaling pathways. Molecular docking results indicated that BAX, BCL 2, and Caspase 3 enriched in the apoptotic signaling pathway have high binding affinity with Bai. Validation experiments showed that Bai can significantly attenuate the loss of articular cartilage (OARSI score), suppress synovial inflammation (synovitis score), and ameliorate subchondral bone resorption measured by micro-CT. In addition, Bai notably inhibited the expression of apoptosis-related proteins in articular cartilage (BAX, BCL 2, and Caspase 3). By combining network pharmacology with experimental validation, our study identifies and verifies the importance of the apoptotic signaling pathway in the treatment of OA by Bai. Bai may have promising application and potential therapeutic value in OA treatment.

7.
Neural Regen Res ; 14(11): 1919-1931, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31290450

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of MK-801 and its effect on lesion volume in rat models of acute brain injury. DATA SOURCES: Key terms were "stroke", "brain diseases", "brain injuries", "brain hemorrhage, traumatic", "acute brain injury", "dizocilpine maleate", "dizocilpine", "MK-801", "MK801", "rat", "rats", "rattus" and "murine". PubMed, Cochrane library, EMBASE, the China National Knowledge Infrastructure, WanFang database, the VIP Journal Integration Platform (VJIP) and SinoMed databases were searched from their inception dates to March 2018. DATA SELECTION: Studies were selected if they reported the effects of MK-801 in experimental acute brain injury. Two investigators independently conducted literature screening, data extraction, and methodological quality assessments. OUTCOME MEASURES: The primary outcomes included lesion volume and brain edema. The secondary outcomes included behavioral assessments with the Bederson neurological grading system and the water maze test 24 hours after brain injury. RESULTS: A total of 52 studies with 2530 samples were included in the systematic review. Seventeen of these studies had a high methodological quality. Overall, the lesion volume (34 studies, n = 966, MD = -58.31, 95% CI: -66.55 to -50.07; P < 0.00001) and degree of cerebral edema (5 studies, n = 75, MD = -1.21, 95% CI: -1.50 to -0.91; P < 0.00001) were significantly decreased in the MK-801 group compared with the control group. MK-801 improved spatial cognition assessed with the water maze test (2 studies, n = 60, MD = -10.88, 95% CI: -20.75 to -1.00; P = 0.03) and neurological function 24 hours after brain injury (11 studies, n = 335, MD = -1.04, 95% CI: -1.47 to -0.60; P < 0.00001). Subgroup analysis suggested an association of reduction in lesion volume with various injury models (34 studies, n = 966, MD = -58.31, 95% CI: -66.55 to -50.07; P = 0.004). Further network analysis showed that 0-1 mg/kg MK-801 may be the optimal dose for treatment in the middle cerebral artery occlusion animal model. CONCLUSION: MK-801 effectively reduces brain lesion volume and the degree of cerebral edema in rat models of experimental acute brain injury, providing a good neuroprotective effect. Additionally, MK-801 has a good safety profile, and its mechanism of action is well known. Thus, MK-801 may be suitable for future clinical trials and applications.

8.
J Neurochem ; 150(1): 6-27, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30786027

RESUMO

Spinal cord injury (SCI) is a devastating condition that has few treatment options. Riluzole, a sodium channel blocker used to treat amyotrophic lateral sclerosis, has been initially trialed in human SCI. We performed a systematic review to critically assess the efficacy of riluzole in locomotor recovery and damage extension in SCI rat models, and the potential for clinical translation. PubMed, Embase, Cochrane Library, and Chinese databases were searched from their inception date to March 2018. Two reviewers independently selected animal studies that evaluated neurological recovery and lesion area following riluzole treatment in SCI rat models, extracted data and assessed methodological quality. Pairwise meta-analysis, subgroup analysis, and network meta-analysis were performed to assess the effects of riluzole on SCI. Ten eligible studies were included. Two studies had high methodological quality. Overall, the Basso, Beattie, and Bresnahan scores were increased in riluzole-treated animals versus controls, and effect sizes showed a gradual increase from the 1st (five studies, n = 104, mean difference = 1.24, 95% CI = 0.11 to 2.37, p = 0.03) to 6th week after treatment (five studies, n = 120, mean difference = 2.34, 95% CI = 1.26 to 3.42, p < 0.0001). Riluzole was associated with improved outcomes in the inclined plane test and the tissue preservation area. Subgroup analyses suggested an association of locomotor recovery with riluzole dose. Network meta-analysis showed that 5 mg/kg riluzole exhibited greater protection than 2.5 and 8 mg/kg riluzole. Collectively, this review suggests that riluzole has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials or applications. However, animal results should be interpreted with caution given the known limitations in animal experimental design and methodological quality.


Assuntos
Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Riluzol/farmacologia , Traumatismos da Medula Espinal , Medula Espinal/efeitos dos fármacos , Animais , Ratos , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia
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