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SA restrain IL-1β-induced activation of the MAPK signaling pathway. (A,B) Representative western blots and quantification data showing p-ERK, ERK, p-p38, p38, p-JNK and JNK expression in cells treated with IL-1β for different time points. The data are shown as the mean ± SD. ***p < 0.001, **p < 0.01 vs # the control group (n = 3). (C,D) Representative western blots and quantification data showing p-ERK, ERK, p-p38, p38, p-JNK, and JNK expression in cells after 30 min of IL-1β exposure. The data are shown as the mean ± SD (n = 3). # p < 0.05 vs. the control group; **p < 0.01, *p < 0.05vs. the IL-1β group.
Source publication
Osteoarthritis (OA) is a major cause of cartilage pain and limited mobility in middle-aged and elderly individuals. The degeneration of cartilage induced by inflammation and cartilage anabolic and catabolic disorder plays a key role in OA. Shikimic acid (SA), a natural ingredient extracted from Illicium verum, has been shown to exert notable anti-i...
Citations
... In addition, some studies have proposed that MAP kinase activated by MAPK phosphorylation can cause the upregulation of inflammatory factors in OA by activating and regulating other proteins, and the upregulation of inflammatory factors can further activate MAPK and cause positive feedback of inflammation in OA (60). Some studies have also proposed that the MAPK signaling pathway can regulate autophagy and ECM metabolic disorders in OA, thereby affecting the role of cartilage degradation in OA (66). The role of inflammatory factors and anti-inflammatory factors produced by M1/M2 macrophages in synovial membrane in OA has also been established by some studies, suggesting that macrophage polarization plays a regulatory role in OA (67,68). ...
Osteoarthritis (OA) has been a leading cause of disability in the elderly and there remains a lack of effective therapeutic approaches as the mechanisms of pathogenesis and progression have yet to be elucidated. As OA progresses, cellular metabolic profiles and energy production are altered, and emerging metabolic reprogramming highlights the importance of specific metabolic pathways in disease progression. As a crucial part of glucose metabolism, glycolysis bridges metabolic and inflammatory dysfunctions. Moreover, the glycolytic pathway is involved in different areas of metabolism and inflammation, and is associated with a variety of transcription factors. To date, it has not been fully elucidated whether the changes in the glycolytic pathway and its associated key enzymes are associated with the onset or progression of OA. This review summarizes the important role of glycolysis in mediating cellular metabolic reprogramming in OA and its role in inducing tissue inflammation and injury, with the aim of providing further insights into its pathological functions and proposing new targets for the treatment of OA.
... SW1353 cells are valuable research tools as IL-1β-stimulated SW1353 cells have similar chondrogenic and catabolic profiles to human articular chondrocytes [24]. In the present study, SW1353 cells were treated with IL-1β (10 ng/ml) for 24 h to mimic the initiation and pathogenesis of OA [25][26][27]. ...
Osteoarthritis (OA) is a multifactorial disease of the whole joint that has a complex pathogenesis. There is currently no cure for OA. Tofacitinib is a broad JAK inhibitor that can have an anti-inflammatory effect. The objective of this study was to investigate the effect of tofacitinib on the cartilage extracellular matrix in OA and determine whether tofacitinib exerts a protective effect by inhibiting the JAK1/STAT3 signaling pathway and upregulating autophagy in chondrocytes. We investigated the expression profile of OA in vitro by exposing SW1353 cells to interleukin-1β (IL-1β), and induced OA in vivo using the modified Hulth method in rats. We found that IL-1β promoted the expression of OA-related matrix metalloproteinases (MMP3 and MMP13), reduced the expression of collagen II, reduced the expression of beclin1 and LC3-II/I, and promoted the accumulation of p62 in SW1353 cells. Tofacitinib attenuated IL-1β-stimulated changes in MMPs and collagen II and restored autophagy. In IL-1β-stimulated SW1353 cells, the JAK1/STAT3 signaling pathway was activated. Tofacitinib inhibited the IL-1β-stimulated expression of p-JAK1 and p-STAT3 and prevented translocation of p-STAT3 to the nucleus. In the rat model of OA, tofacitinib reduced articular cartilage degeneration by delaying cartilage extracellular matrix degradation and increasing chondrocyte autophagy. Our study demonstrates that chondrocyte autophagy was impaired in experimental models of OA. Tofacitinib reduced the inflammatory response and restored the damaged autophagic flux in OA.
... SW1353 cells are valuable research tools as IL-1β-stimulated SW1353 cells have similar chondrogenic and catabolic pro les to human articular chondrocytes [23] . In the present study, SW1353 cells were treated with IL-1β (10 ng/ml) for 24 hours to mimic the initiation and pathogenesis of OA [24][25][26] . ...
Osteoarthritis (OA) is a multifactorial disease of the whole joint that has a complex pathogenesis. There is currently no cure for OA. Tofacitinib is a broad JAK inhibitor that can have an anti-inflammatory effect. The objective of this study was to investigate the effect of tofacitinib on the cartilage extracellular matrix in OA and determine whether tofacitinib exerts a protective effect by inhibiting the JAK1/STAT3 signaling pathway and upregulating autophagy in chondrocytes. We established an vitro OA model by exposing SW1353 cells to interleukin-1β (IL-1β) and induced OA in rats using the modified Hulth method. We found that IL-1β promoted the expression of OA-related matrix metalloproteinases (MMP-3 and MMP-13), reduced the expression of collagen II, reduced the expression of beclin1 and LC3-II/I, and promoted the accumulation of p62 in SW1353 cells. Tofacitinib attenuated IL-1β-stimulated changes in MMPs and collagen II and restored chondrocyte autophagy. In IL-1β-stimulated SW1353 cells, the JAK1/STAT3 signaling pathway was activated. Tofacitinib inhibited the IL-1β-stimulated expression of p-JAK1 and p-STAT3 and prevented translocation of p-STAT3 to the nucleus. In the rat model of OA, tofacitinib reduced articular cartilage degeneration by delaying cartilage extracellular matrix degradation and increasing chondrocyte autophagy. Our study demonstrates that chondrocyte autophagy was impaired in experimental models of OA. Tofacitinib reduced the inflammatory response and restored the damaged autophagic flux in OA.
... As a natural extract, shikimic acid (SA) shows strong antiinflammatory properties and can promote autophagy by up-regulating the expression of ATG7, BECN1 and LC3, which was related to the inhibition of MAPK and NF-κB pathways. Moreover, the progression of OA was significantly alleviated by SA in a trauma-induced PTOA rat model [150]. [144] (continued) Trehalose was first extracted from Ergot bacteria and is a novel mTOR-independent autophagy inducer. ...
Autophagy, as a fundamental mechanism for cellular homeostasis, is generally involved in the occurrence and progression of various diseases. Osteoarthritis (OA) is the most common musculoskeletal disease that often leads to pain, disability and economic loss in patients. Post-traumatic OA (PTOA) is a subtype of OA, accounting for >12% of the overall burden of OA. PTOA is often caused by joint injuries including anterior cruciate ligament rupture, meniscus tear and intra-articular fracture. Although a variety of methods have been developed to treat acute joint injury, the current measures have limited success in effectively reducing the incidence and delaying the progression of PTOA. Therefore, the pathogenesis and intervention strategy of PTOA need further study. In the past decade, the roles and mechanisms of autophagy in PTOA have aroused great interest in the field. It was revealed that autophagy could maintain the homeostasis of chondrocytes, reduce joint inflammatory level, prevent chondrocyte death and matrix degradation, which accordingly improved joint symptoms and delayed the progression of PTOA. Moreover, many strategies that target PTOA have been revealed to promote autophagy. In this review, we summarize the roles and mechanisms of autophagy in PTOA and the current strategies for PTOA treatment that depend on autophagy regulation, which may be beneficial for PTOA patients in the future.
... The MAPK and NF-kB signaling pathways are crucial factors in the regulation of inflammatory response and are closely related to many diseases, including OA. 47,48 Studies have revealed that the activation of the two signaling pathways could upregulate the expression of inflammatory proteins (iNOS, COX-2, and IL-6) and catabolic proteins (MMP1, MMP3, MMP13, and ADAMTS5), as well as downregulate the expression of anabolic proteins (Aggrecan, Collagen II, and SOX9), which in turn facilitate the degradation of ECM and cartilage destruction. 18,[49][50][51] Measurements of the inhibition of the MAPK and NF-kB signal transduction could prevent or slow the development of OA. 52,53 The PI3K-AKT-mTOR pathway is one of the important inflammatory signaling pathways leading to the progression of OA. 54 Studies have suggested the protein AKT, which regulates the upstream IkB kinases of NF-kB signaling pathway, triggers the activation of NF-kB signal. 37 Inhibiting the PI3K-AKT-mTOR pathway relieves the inflammatory response and is beneficial for the relief of OA. 55 What is more, the PI3K-AKT-mTOR pathway is considered to be a key pathway in the regulation of autophagy. ...
Osteoarthritis (OA) is a trauma-/age-related degenerative disease characterized by chronic inflammation as one of its pathogenic mechanism. Mulberroside A (MA), a natural bioactive withanolide, demonstrates anti-inflammatory properties in various diseases; however, little is known about the effect of MA on OA. We aim to examine the role of MA on OA and to identify the potential mechanisms through which it protects articular cartilage. In vitro, MA improved inflammatory response, anabolism, and catabolism in IL-1β–induced OA chondrocytes. The chondroprotective effects of MA were attributed to the suppressing the MAPK, NF-κB, and PI3K-AKT-mTOR signaling pathways, as well as promoting the autophagy process. In vivo, intra-articular injection of MA reduced the cartilage destruction and reversed the change of anabolic and catabolic-related proteins in destabilized medial meniscus (DMM)–induced OA models. Thus, the study indicates that MA exhibits a chondroprotective effect and might be a promising agent for OA treatment.
... Many studies have reported that autophagy mediates the steady state of articular cartilage (Caramés et al., 2012;Li et al., 2016;Duan et al., 2020). However, the autophagic activity of chondrocytes would be impaired in the process of OA (Feng et al., 2020;You et al., 2021), and the activation of autophagy can significantly slow down OA development (Qin et al., 2017). Hence, strategies to activate autophagy through pharmacological intervention have been used to prevent cartilage degradation, providing a direction for OA treatment (You et al., 2015;Saitoh and Akira, 2016). ...
Osteoarthritis is a worldwide joint disease caused by abnormal chondrocytic metabolism. However, traditional therapeutic methods aimed at anti-inflammation for early-stage disease are palliative. In the present study, we demonstrated that cepharanthine (CEP), extracted from the plant Stephania cepharantha, exerted protective medicinal efficacy on osteoarthritis for the first time. In our in vitro study, CEP suppressed the elevated expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and inducible nitric oxide synthase (iNOS) stimulated by IL-1β or TNF-α by inhibiting the activation of MAPK and NF-κB signaling pathways, and upregulated the protein expression of aggrecan, collagen II, and Sox9. Also, CEP could reverse the reduced level of cellular autophagy in IL-1β or TNF-α–induced chondrocytes, indicating that the protective effect of CEP on osteoarthritis was achieved by restoring MAPK/NF-κB-mediated autophagy. Furthermore, in a murine OA model, CEP mitigated cartilage degradation and prevented osteoarthritis in the CEP-treated groups versus the OA group. Hence, our results revealed the therapeutic prospect of CEP for anti-osteoarthritic treatment.
... In vitro and in vivo experiments have recently demonstrated that SA can delay OA progression by enhancing autophagy-mediated cartilage homeostasis.You et al. found that SA inhibited IL-1β-induced mitogen activation by inhibiting phosphorylation of ERK, p38, JNK, p65, and MAPK and NF-κB pathway activation and attenuated the expression of inflammatory and apoptotic factors, such as iNOS, COX2, MMPs and ADAMTS5, thereby alleviating IL-1β-induced inflammatory responses, dysregulation of cartilage anabolism and catabolism, and autophagic damage in human chondrocytes. In addition, in vivo experiments revealed that SA reduced cartilage erosion and proteoglycan loss in ACLT rats, thus providing new evidence for water-soluble SA to treat and prevent the development of OA(Steimer et al., 2015;You et al., 2021).Sinomenium (SIN) is a natural alkaloid extracted from the medicinal plant Sinomenium acutum (Thunb.) Rehder and E.H.Wilson, which decreases the protein level of MMP-13, a marker of cartilage degradation in rats, thereby resisting cartilage degradation, and blocks collagen-induced arthritis through NF-κB signaling and downregulates the expression of MMP13(Ju et al., 2010;Sun et al., 2014). ...
Osteoarthritis (OA) is a common degenerative joint disease and is a leading cause of disability and reduced quality of life worldwide. There are currently no clinical treatments that can stop or slow down OA. Drugs have pain-relieving effects, but they do not slow down the course of OA and their long-term use can lead to serious side effects. Therefore, safe and clinically appropriate long-term treatments for OA are urgently needed. Autophagy is an intracellular protective mechanism, and targeting autophagy-related pathways has been found to prevent and treat various diseases. Attenuation of the autophagic pathway has now been found to disrupt cartilage homeostasis and plays an important role in the development of OA. Therefore, modulation of autophagic signaling pathways mediating cartilage homeostasis has been considered as a potential therapeutic option for OA. Phytochemicals are active ingredients from plants that have recently been found to reduce inflammatory factor levels in cartilage as well as attenuate chondrocyte apoptosis by modulating autophagy-related signaling pathways, which are not only widely available but also have the potential to alleviate the symptoms of OA. We reviewed preclinical studies and clinical studies of phytochemicals mediating autophagy to regulate cartilage homeostasis for the treatment of OA. The results suggest that phytochemicals derived from plant extracts can target relevant autophagic pathways as complementary and alternative agents for the treatment of OA if subjected to rigorous clinical trials and pharmacological tests.
Background
Diarrhea is the increase of excretion of human water content and an imbalance in the physiologic processes of the small and large intestine while shikimic acid is an important biochemical metabolite in plants. This study aims to study the anti-diarrheal activity of shikimic acid through restoring kidney function, antioxidant activity, inflammatory markers, sodium/potassium-ATPase activity, apoptosis genes, and histology of the kidney in SD rats fed lactose diet to induce diarrhea.
Results
Thirty-six male SD rats (150 ± 10 g, 12 weeks old) were divided into 2 equal groups (18 rats/group) as follows: normal and diarrheal rats. Normal rats were divided into 3 equal groups of 6 rats each: the control, shikimic acid, and desmopressin drug groups. Diarrheal rats were also divided into 3 equal groups of 6 rats each: diarrheal , diarrheal rats + shikimic acid, and diarrheal rats + desmopressin drug groups. Shikimic acid restored serum urea and creatinine, urinary volume, kidney weight, sodium, potassium, and chloride balance in serum and urine. The acid returned the antioxidant (superoxide dismutase, glutathione peroxidase, catalase, malondialdehyde, NADPH oxidase activity, conjugated dienes, and oxidative index) activity and the inflammatory markers (tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-10) to values approaching the control values. Shikimic acid also restored the sodium/potassium-ATPase activity, the apoptosis genes p 53 and bcl-2, and the histology of kidney tissue in diarrheal rats to be near the control group.
Conclusions
Shikimic acid rescues diarrhea and its complications through restoring kidney function, serum and urinary electrolytes, antioxidant activity, inflammatory markers, sodium/potassium-ATPase activity, the apoptosis genes, and the histology of the kidney in diarrheal rats to approach the control one.
Numerous studies have shown that neuroinflammation is involved in the process of neuronal damage in neurodegenerative diseases such as Parkinson’s disease (PD), for example, and that inhibiting neuroinflammation help improve PD. Shikimic acid (SA) has anti-inflammatory, analgesic and antioxidant activities in numerous diseases. However, its effect and mechanism in PD remain unclear. In this experiment, we found that SA inhibits production of pro-inflammatory mediators and ROS in LPS-induced BV2 cells. Mechanistic studies demonstrated that SA suppresses neuro-inflammation by activating the AKT/Nrf2 pathway and inhibiting the NF-κB pathway. Further in vivo study, we confirmed that SA ameliorated the neurological damage and behavioral deficits caused by LPS injection in mice. In summary, these study highlighted the beneficial role of SA as a novel therapy with potential PD drug by targeting neuro-inflammation.
