scholarly journals Wang-Bi Tablet Ameliorates DMM-Induced Knee Osteoarthritis through Suppressing the Activation of p38-MAPK and NF-κB Signaling Pathways in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Hui Li ◽  
Yan You ◽  
Bing Jiang ◽  
Haidong Li ◽  
Xiang Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Knee Osteoarthritis ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Cartilage Injury ◽  
Signal Pathways ◽  
Therapeutic Effects ◽  
Wang Bi ◽  
Safranine O

Background. Traditional Chinese medicine (TCM) exhibits outstanding therapeutic effects on the treatment of osteoarthritis (OA). Wang-Bi tablets (WBTs) have been used in clinics to treat knee osteoarthritis (KOA) by alleviating joint swelling and paining, and thus, the quality of life in patients with KOA was improved. However, its underlying molecular mechanism of anti-inflammatory response remains unclear. Therefore, further investigation is required. Purpose. This study aimed to explore the function of WBT in KOA mice and uncover the possible molecular mechanisms. Study Design. A KOA model was constructed by destabilizing the medial meniscus (DMM). IL-1β-treated chondrocytes were used to investigate the precise mechanism in vitro. Methods. (1) C57BL/6 male mice (8-week-old) were divided into Model, Sham, WBT-L, WBT-M, and WBT-H groups. After intragastric administration of 0.5% CMC-Na or WBT for 4 weeks, inflammation and pathological change were analyzed by ELISA, RT-qPCR, hematoxylin and eosin (H & E) and safranine O staining. (2) Isolated chondrocytes were stimulated with IL-1β followed by WBT-containing serum treatment, and then, the expression of inflammatory cytokines was analyzed by ELISA and RT-qPCR. (3) The effects of WBT on inflammatory signaling cascades in mice knee joint and chondrocytes were detected by WB. Results. The results indicated that WBT could alleviate inflammation and prevent cartilage injury in KOA mice. Compared with 0.5% CMC-Na-treated mice, the serum glycosaminoglycans (GAG) level in WBT-treated mice was notably increased, while the proinflammatory cytokine interleukin- (IL-) 6 level was decreased. In addition, WBT treatment suppressed the activation of NF-κB and p38 signaling pathways both in vivo and in vitro. Conclusion. WBT can effectively inhibit articular cartilage injury and inflammatory response in KOA mice. The protective role of WBT in mice KOA was a result of the downregulation of NF-κB and p38-MAPK signal pathways.

scholarly journals A Novel Combination of Vitamin C, Curcumin and Glycyrrhizic Acid Potentially Regulates Immune and Inflammatory Response Associated with Coronavirus Infections: A Perspective from System Biology Analysis

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1193 ◽  
Author(s):  
Liang Chen ◽  
Chun Hu ◽  
Molly Hood ◽  
Xue Zhang ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Vitamin C ◽  
Inflammatory Response ◽  
Signaling Pathways ◽  
System Biology ◽  
Glycyrrhizic Acid ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Gene Target

Novel coronaviruses (CoV) have emerged periodically around the world in recent years. The recurrent spreading of CoVs imposes an ongoing threat to global health and the economy. Since no specific therapy for these CoVs is available, any beneficial approach (including nutritional and dietary approach) is worth investigation. Based on recent advances in nutrients and phytonutrients research, a novel combination of vitamin C, curcumin and glycyrrhizic acid (VCG Plus) was developed that has potential against CoV infection. System biology tools were applied to explore the potential of VCG Plus in modulating targets and pathways relevant to immune and inflammation responses. Gene target acquisition, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment were conducted consecutively along with network analysis. The results show that VCG Plus can act on 88 hub targets which are closely connected and associated with immune and inflammatory responses. Specifically, VCG Plus has the potential to regulate innate immune response by acting on NOD-like and Toll-like signaling pathways to promote interferons production, activate and balance T-cells, and regulate the inflammatory response by inhibiting PI3K/AKT, NF-κB and MAPK signaling pathways. All these biological processes and pathways have been well documented in CoV infections studies. Therefore, our findings suggest that VCG Plus may be helpful in regulating immune response to combat CoV infections and inhibit excessive inflammatory responses to prevent the onset of cytokine storm. However, further in vitro and in vivo experiments are warranted to validate the current findings with system biology tools. Our current approach provides a new strategy in predicting formulation rationale when developing new dietary supplements.

scholarly journals HBO Promotes the Differentiation of Neural Stem Cells via Interactions Between the Wnt3/β-Catenin and BMP2 Signaling Pathways

2019 ◽  
Vol 28 (12) ◽  
pp. 1686-1699 ◽  
Author(s):  
Chongfeng Chen ◽  
Yujia Yang ◽  
Yue Yao
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Signaling Pathways ◽  
System Development ◽  
Nervous System Development ◽  
Bmp Signaling ◽  
Nuclear Proteins ◽  
Therapeutic Effects ◽  
Morphogenetic Protein

Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of Wnt3a, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of Wnt3a, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.

scholarly journals Decursin Isolated fromAngelica gigasNakai Rescues PC12 Cells from Amyloidβ-Protein-Induced Neurotoxicity through Nrf2-Mediated Upregulation of Heme Oxygenase-1: Potential Roles of MAPK

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Li Li ◽  
Ji-kun Du ◽  
Li-yi Zou ◽  
Tie Wu ◽  
Yong-woo Lee ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Nuclear Translocation ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Competitive Inhibitor ◽  
Heme Oxygenase 1 ◽  
Signal Pathways ◽  
Therapeutic Effects ◽  
Nrf2 Activation

Decursin (D), purified fromAngelica gigasNakai, has been proven to exert neuroprotective property. Previous study revealed that D reduced Aβ25‒35-induced cytotoxicity in PC12 cells. Our study explored the underlying mechanisms by which D mediates its therapeutic effectsin vitro. Pretreatment of cells with D diminished intracellular generation of ROS in response to Aβ25‒35. Western blot revealed that D significantly increased the expression and activity of HO-1, which was correlated with its protection against Aβ25‒35-induced injury. Addition of ZnPP, an HO-1 competitive inhibitor, significantly attenuated its protective effect in Aβ25‒35-treated cells, indicating the vital role of HO-1 resistance to oxidative injury. Moreover, D induced Nrf2 nuclear translocation, the upstream of HO-1 expression. While investigating the signaling pathways responsible for HO-1 induction, D activated ERK and dephosphorylated p38 in PC12 cells. Addition of U0126, a selective inhibitor of ERK, blocked D-induced Nrf2 activation and HO-1 induction and meanwhile reversed the protection of D against Aβ25‒35-induced cell death. These findings suggest D augments cellular antioxidant defense capacity through both intrinsic free radical scavenging activity and activation of MAPK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction, thereby protecting the PC12 cells from Aβ25‒35-induced oxidative cytotoxicity.

TM-233 Exerts Anti-Myeloma Activity and Overcomes Bortezomib-Resistance In Human Multiple Myeloma Cells By Targeting NF-κB and JAK/STAT Dual-Signaling Pathways

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4427-4427
Author(s):  
Morihiko Sagawa ◽  
Tatsuki Tomikawa ◽  
Tomoe Anan ◽  
Takayuki Tabayashi ◽  
Reiko Watanabe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Signaling Pathways ◽  
Conflicts Of Interest ◽  
Subcutaneous Administration ◽  
Cellular Growth ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Grade 3

Although the introduction of bortezomib and immunomodulatory drugs (IMiDs) has led to improved outcomes in patients with multiple myeloma (MM), the disease remains incurable. Bortezomib, a proteasome inhibitor, is widely used in the treatment of MM and has resulted in marked therapeutic effects; however, this therapy is often complicated by peripheral neuropathy (PN), of which grade ≥3 PN is dose-limiting toxicity and can necessitate cessation of therapy. Subcutaneous administration of bortezomib can reduce the incidence of PN; however, among cases of PN that still occur, 24% are grade 2 PN and 6% are grade 3 PN. These data suggest that the incidence of PN higher than grade 2 is not attenuated by the subcutaneous delivery of bortezomib. In addition, patients often become refractory to bortezomib after long-term use. In an effort to identify potent and well-tolerated agents, clinical trials of novel agents (e.g., carfilzomib, pomalidomide, and monoclonal antibody against CS-1) are being conducted both in patients with newly diagnosed MM and in those with relapsed/refractory disease. We previously reported that 1’-acetoxychavicol acetate (ACA) obtained from the rhizomes of the plant Languas galanga induces cell death of MM cells in vitro and in vivo through inhibition of NF-κB-related functions (Cancer Res, 2005; 65: 4417). Subsequently, we developed several ACA analogs based on quantitative structure-activity relationship (QSAR) analysis to develop more potent NF-κB inhibitors, and successfully synthesized a novel benzhydrol-type analog of ACA, named TM-233, that exerted potent growth inhibition against various MM cells (U266, RPMI8226, and MM-1S cells) in a dose- and time-dependent manner when compared with ACA (Chem Pharm Bull., 2008; 56: 1490). Further, TM-233 inhibited constitutive phosphorylation of JAK2 and STAT3 and down-regulated the expression of anti-apoptotic Mcl-1 protein. TM-233 directly bound and activated the transcription of the Mcl-1 gene promoter. Mcl-1 is the downstream molecule of STAT3; therefore, these results suggest that TM-233 induces cell death in MM cells with down-regulated Mcl-1 via modulation of the JAK/STAT pathway. In addition, we examined the DNA-binding activity of NF-κB in TM-233-treated MM cells and found that NF-κB was inhibited by TM-233. Further, Western blotting showed that TM-233 rapidly decreased the nuclear expression of NF-κB but increased the accumulation of NF-κB in the cytosol, suggesting that TM-233 inhibits the translocation of NF-κB from the cytosol to the nucleus. Immunohistochemical analysis confirmed that the p50/RelA dimer of NF-κB was located in the cytosol and not in the nucleus in TM-233-treated MM cells. We then examined the effects of TM-233 on bortezomib-resistant MM cells. Bortezomib-resistant MM cell lines (i.e., KMS-11/BTZ and OPM-2/BTZ) were established by limiting dilution. We found that these cells have a unique point mutation, G322A, in the gene encoding the proteasome β5 subunit (Leukemia 2010; 24: 1506). TM-233, but not bortezomib, inhibited cellular growth and induced cell death in KMS-11/BTZ and OPM-2/BTZ cells in a time- (0-48 hours) and dose- (0-5 μM) dependent manner. Furthermore, the combination of low-dose TM-233 (less than 2 μM) and bortezomib (10 nM) significantly induced cell death in bortezomib-resistant MM cells via inhibition of NF-κB activity. These results indicate that TM-233 could overcome bortezomib resistance in MM cells by acting via different mechanisms from those of bortezomib. In conclusion, TM-233 induced cell death in MM cells, and this effect was mediated through the JAK/STAT and NF-κB dual-signaling pathways. These data indicate that TM-233 might be a more potent and more specific NF-κB inhibitor than that of original compound (ACA), and might be able to overcome bortezomib-resistance in MM cells. Therefore, further studies investigating clinical approaches, including combination therapy, are warranted. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tussilagone Inhibits Osteoclastogenesis and Periprosthetic Osteolysis by Suppressing the NF-κb and p38 MAPK Signaling Pathways

2019 ◽  
Author(s):  
Xuantao Hu ◽  
Zhengxiao Ouyang ◽  
Dan Peng ◽  
Ziqing Yin ◽  
Xia Chen ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Signaling Pathways ◽  
P38 Mapk ◽  
Western Blotting ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Periprosthetic Osteolysis ◽  
Prosthetic Loosening ◽  
Mapk Signaling Pathways

Abstract Backgroud: Aseptic prosthetic loosening is one of main factor producing poor prognosis of limb function after joint replacement and requiring troublesome revision surgery. It is featured by wear particle–induced periprosthetic osteolysis mediated by excessive osteoclasts activated in inflammatory cell context. In our previous study, some natural compounds showing anti-osteoclast trait with high cost-efficiency and few side effects. Tussilagone (TUS), as the main functional extract from Tussilago Farfara precedently used for relieving cough, asthma and eliminating phlegm in traditional medicine, has been proved to appease several RAW264.7-mediated inflammatory diseases via suppressing osteoclast-related signaling cascades. However, whether and how TUS can improve aseptic prosthetic loosening via modulating osteoclast-mediated bone resorption still need to be answered. Methods: We established a murine calvarial osteolysis model to detect the preventative effect of TUS on osteolysis in vivo. Micro-CT scanning and histomorphometric analysis were used to determine the variation of bone resorption and osteoclastogenesis in samples. The anti-osteoclast-differentiation and anti-bone-resorption bioactivities of TUS in vitro were investigated using bone slice resorption pit evaluation and interference caused by cytotoxicity of TUS was excluded according to CCK-8 assay. Quantitative PCR analysis was applied to prove the decreased expression of osteoclast-specific genes after TUS treatment. The inhibition effect of TUS on NF-κb and p38 MAPK signaling pathways was testified by western blotting and NF-κB-linked luciferase reporter gene assay.Results: TUS demonstrated bone protective effect against osteolysis in murine calvarial osteolysis model with reduced osteoclasts compared to the control group. Following studies in vitro witnessed that TUS exert anti-osteoclastogenesis and anti-bone-resorption effects in both BMMs and RAW264.7 cells, as evidenced by the decline of osteoclast specific genes according to quantative PCR. Western blotting revealed that TUS-treated demonstrated inhibited IκBα degradation and p38 phosphorylation.Conclusions: Collectively, for the first time our studies prove that TUS inhibits osteoclastogenesis by suppressing the NF-κb and p38 MAPK signaling pathways, therefore serving as a potential natural compound to treat periprosthetic osteolysis-induced aseptic prosthetic loosening.

Kaempferol inhibits pseudorabies virus replication in vitro through regulation of MAPKs and NF-κB signaling pathways

2020 ◽  
Author(s):  
Xu Chen ◽  
Yaqin Chen ◽  
Zhongqiong Yin ◽  
Rui Wang ◽  
Huaiyue Hu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Virus Replication ◽  
Pseudorabies Virus ◽  
Target Genes ◽  
Control Measure ◽  
Control Measures ◽  
Economic Losses ◽  
Signal Pathways ◽  
Dependent Manner

Abstract Pseudorabies virus (PRV), belonging to the family Herpesviridae, is a pathogen of Aujeszky’s disease leading great economic losses to pig industry. Re-outburst of pseudorabies implies that new control measures are urgent needed. The present study provides a candidate drug for PRV infection that kaempferol possesses the ability to inhibit PRV replication in a dose-dependent manner in vitro. Kaempferol at a concentration of 52.40 μM could decrease PRV-induced cell death by 90%. Kaempferol with a IC50 of 25.57μM is more effective than acyclovir (Positive control) with a IC 50 of 54.97 μM. Mode of action study indicated that kaempferol inhibited viral penetration and replication stages and virus load was decreased by 4-fold and 30-fold, respectively. Addition of kaempferol within 16 hours post infection (hpi) could significantly inhibit virus replication, and the DNA copies were decreased by almost 15-fold when kaempferol was added at 2 hpi. Kaempferol could regulate NF-κB and MAPKs signal pathways involved in PRV infection and change the levels of the target genes of MAPKs (ATF-2 and c-Jun) and NF-κB (IL-1α, IL-1β and IL-2) signaling pathways. All the results indicated that kaempferol has the ability to be an alternative control measure for PRV infection.¶ These authors contribute equally to this work and should be considered as the first author.

scholarly journals Pulsed Electromagnetic Field Stimulation in Osteogenesis and Chondrogenesis: Signaling Pathways and Therapeutic Implications

2021 ◽  
Vol 22 (2) ◽  
pp. 809
Author(s):  
Katia Varani ◽  
Fabrizio Vincenzi ◽  
Silvia Pasquini ◽  
Irene Blo ◽  
Simona Salati ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Signaling Pathways ◽  
Tissue Repair ◽  
Chondrogenic Differentiation ◽  
Cartilage Defects ◽  
Invasive Treatment ◽  
Local Inflammatory Response ◽  
Pulsed Electromagnetic

Mesenchymal stem cells (MSCs) are the main cell players in tissue repair and thanks to their self-renewal and multi-lineage differentiation capabilities, they gained significant attention as cell source for tissue engineering (TE) approaches aimed at restoring bone and cartilage defects. Despite significant progress, their therapeutic application remains debated: the TE construct often fails to completely restore the biomechanical properties of the native tissue, leading to poor clinical outcomes in the long term. Pulsed electromagnetic fields (PEMFs) are currently used as a safe and non-invasive treatment to enhance bone healing and to provide joint protection. PEMFs enhance both osteogenic and chondrogenic differentiation of MSCs. Here, we provide extensive review of the signaling pathways modulated by PEMFs during MSCs osteogenic and chondrogenic differentiation. Particular attention has been given to the PEMF-mediated activation of the adenosine signaling and their regulation of the inflammatory response as key player in TE approaches. Overall, the application of PEMFs in tissue repair is foreseen: (1) in vitro: to improve the functional and mechanical properties of the engineered construct; (2) in vivo: (i) to favor graft integration, (ii) to control the local inflammatory response, and (iii) to foster tissue repair from both implanted and resident MSCs cells.

scholarly journals TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Jiawei Zhang ◽  
Yu Liu ◽  
Yaling Zheng ◽  
Yan Luo ◽  
Yu Du ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Impairment ◽  
Inflammatory Response ◽  
P38 Mapk ◽  
High Glucose ◽  
Mapk Signaling ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion

Abstract Background Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown. Methods To investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively. Results Cognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent pro-inflammatory mediator production under high glucose and hypoxia condition. Conclusions These results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH.

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