The aim of this study was to evaluate the role of chronic cadmium exposure in modulating cardiac matrix metalloproteinases (MMPs) in the heart of rats. Adult male Sprague-Dawley rats were exposed to 15 ppm CdCl2 in drinking water for 10 weeks followed by withdrawal of cadmium treatment for 4 weeks. Following the completion of the treatment, gene expression of inflammatory mediators (IL-1β, IL-6, IL-10, TNF-α and NF-κB), protein expression of MMP-2, MMP-9 and their respective inhibitors- TIMP-1 and TIMP-2, and gelatinolytic activity of MMP-2 and MMP-9 were determined. At the protein level, cadmium incites a differential effect on the expression and activity of gelatinases and their endogenous inhibitors in an exposure-dependent manner. Results also show that the administered cadmium dose elicits an inflammatory response until week 10 that slightly diminishes after 4 weeks. This study provides evidence of cadmium-induced imbalance in the MMP-TIMP system in the cardiac tissue. This imbalance may be mediated by cadmium-induced inflammation that could contribute to various cardiovascular pathologies.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease hallmarked by irreversible damage of cartilage and bone. Matrix metalloproteinases (MMPs) involved in connective tissue remodeling play an important role in this process. Numerous MMPs have been examined in humans and animals, but their functions are still not fully understood. Therefore, we investigated the role of MMPs in the K/BxN serum-transfer model of RA with the broad-spectrum MMP inhibitor subantimicrobial dose doxycycline (SDD) using complex in vivo and in vitro methodolgy. Methods: Chronic arthritis was induced by repetitive i.p. injections of K/BxN serum in C57BL/6J mice. SDD was administered daily in acidified drinking water (0.5 mg/mL, 80 mg/kg) during the 30 days experimental period. Mechanonociceptive threshold of the paw was evaluated by aesthesiometry, grasping ability by grid test, arthritis severity by scoring, neutrophil myeloperoxidase activity by luminescence, vascular hyperpermeability and MMP activity by fluorescence in vivo imaging and the latter also by gelatin zymography, bone structure by micro-computed tomography (micro-CT). Plasma concentrations of doxycycline were determined by liquid chromatography-mass spectrometry analysis. Results: K/BxN serum induced significant inflammatory signs, mechanical hyperalgesia, joint function impairment, increased myeloperoxidase activity and vascular hyperpermeability. Significant increase of MMP activity was also observed both in vivo and ex vivo with elevation of the 57-60, 75, and 92 kDa gelatinolytic isoforms in the arthritic ankle joints, but neither MMP activity nor any above described functional parameters were influenced by SDD. Most importantly, SDD significantly reduced bone mineral density in the distal tibia and enhanced the Euler number in the ankle. Arthritis-induced microarchitectural alterations demonstrating increased irregularity and cancellous bone remodeling, such as increased Euler number was significantly elevated by SDD in both regions. Conclusion: We showed increase of various MMP activities in the joints by in vivo fluorescence imaging together with ex vivo zymography, and investigated their functional significance using the broad-spectrum MMP inhibitor SDD in the translational RA model. This is the first demonstration that SDD worsens arthritis-induced bone microarchitectural alterations, but it appears to be independent of MMP inhibition.

Osteoarthritis (OA) is a degenerative joint disease that primarily affects people over 65 years old. During OA progression irreversible cartilage, synovial membrane and subchondral bone degradation is observed, which results in the development of difficult-to-treat chronic pain. One of the most important factors in OA progression is joint inflammation. Both proinflammatory and anti-inflammatory factors, as well as extracellular matrix degradation enzymes (matrix metalloproteinases (MMPs), play an important role in disease development. One of the most widely used animal OA models involves an intra-articular injection of sodium monoiodoacetate (MIA) directly into the joint capsule, which results in glycolysis inhibition in chondrocytes and cartilage degeneration. This model mimics the degenerative changes observed in OA patients. However, the dose of MIA varies in the literature, ranging from 0.5 to 4.8 mg. The aim of our study was to characterize grading changes after injection of 1, 2 or 3 mg of MIA at the behavioral and molecular levels over a 28-day period. In the behavioral studies, MIA injection at all doses resulted in a gradual increase in tactile allodynia and resulted in abnormal weight bearing during free walking sequences. At several days post-OA induction, cartilage, synovial membrane and synovial fluid samples were collected, and qPCR and Western blot analyses were performed. We observed significant dose- and time-dependent changes in both gene expression and protein secretion levels. Inflammatory factors (CCL2, CXCL1, IL-1β, COMP) increased at the beginning of the experiment, indicating a transient inflammatory state connected to the MIA injection and, in more severe OA, also in the advanced stages of the disease. Overall, the results in the 1 mg MIA group were not consistently clear, indicating that the lowest tested dose may not be sufficient to induce long-lasting OA-like changes at the molecular level. In the 2 mg MIA group, significant alterations in the measured factors were observed. In the 3 mg MIA group, MMP-2, MMP-3, MMP-9, and MMP-13 levels showed very strong upregulation, which may cause overly strong reactions in animals. Therefore, a dose of 2 mg appears optimal, as it induces significant but not excessive OA-like changes in a rat model.

Background: Metastasis represents an advanced stage of cancers, and matrix metalloproteinases are critical regulators. Calcium signal is crucial for appropriate cell behaviors. The efficacy and effects of calcium channel blockers in treating cancers are individually differ from each other. Here, we attempt to investigate the effects of nicardipine, a FDA-approved calcium channel blocker, in advanced breast cancers. Methods: We analyzed the influence of nicardipine on the colony-forming ability of triple negative breast cancer cell lines. Using cell culture inserts, cell migration was also examined. The expression of regulatory proteins was evaluated by real-time PCR, Western blot, and ELISA. Results: We have confirmed that nicardipine inhibits the breast cancer cells migration and colony formation. In addition, we also revealed that nicardipine increases the Nrf2 and HO-1 expression. The inhibition of HO-1 abrogates nicardipine-reduced matrix metalloproteinase-9 expression. Moreover, the end products of HO-1, namely, CO, Fe2+, and biliverdin (will converted to bilirubin), also decreases the expression of matrix metalloproteinase-9. Conclusion: These findings suggest that nicardipine-mediated matrix metalloproteinase-9 reduction is regulated by Nrf2/HO-1 axis and its catalytic end products. Therefore, nicardipine may be a potential candidate for repurposing against advanced breast cancers.

Astragalin, as a bioactive flavonoid with anti-inflammatory, antioxidant, and protective properties, provides a potential agent for rheumatoid arthritis (RA). In this study, its therapeutic efficacy and the underlying mechanisms were explored using DBA/1J mice with collagen-induced arthritis (CIA). It was demonstrated that astragalin could significantly attenuate inflammation of CIA mice. The effects were associated with decreased severity of arthritis (based on the arthritis index), joint swelling and reduced bone erosion and destruction. Furthermore, astragalin treatment suppressed the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), and inhibited the expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-13) in chondrocytes and synovial cells of CIA mice. Fibroblast-like synoviocytes derived from RA patients (MH7A cells) were applied to verify these effects. In vitro, astragalin inhibited the expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-13) dose-dependently in TNF-α-induced MH7A cells, with no apparent cytotoxicity. Furthermore, astragalin suppressed the phosphorylation of p38, JNK, and the activation of c-Jun/AP-1 in TNF-α-induced MH7A cells. In conclusion, it has proven that astragalin could attenuate synovial inflammation and joint destruction in RA at least partially by restraining the phosphorylation of MAPKs and the activating of c-Jun/AP-1. Therefore, astragalin can be a potential therapeutic agent for RA.

Background: Melanoma is a highly aggressive, lethal, and malignant cancer. Once diagnosed early, it can be easily removed and cured with satisfaction. Although many methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have been used to treat this disease at an advanced stage, the outcomes are poor. Terminalia catappa leaves have been shown to have various biological benefits, including antitumor activity. The specific effects and molecular mechanisms of Terminalia catappa leaf in treating A2058 and A375 melanoma cells in vitro need to be clarified. Methods: The A2058 and A375 melanoma cancer cells were treated with Terminalia catappa leaf extracts, and then the effect of Terminalia catappa leaf extracts on migration and invasion was examined. The cell migration/invasion capacities of A2058 and A375 cells were investigated by a modified Boyden chamber assay. Zymography was used to clarify the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. We performed a Western blot to verify the related expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin. Results: Modified Boyden chamber assays demonstrated that treatment of Terminalia catappa leaf extracts significantly inhibited A2058 and A375 cell migration/invasion capacities. In the zymography results, we showed that Terminalia catappa leaf extracts negatively modulated the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. Western blot indicated that Terminalia catappa leaf extracts reduced the expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin. Conclusion: Terminalia catappa leaf extracts affected the antimetastasis of the A2058 and A375 melanoma cell lines by inhibiting the Focal adhesion kinase/Src interaction and Wingless-int1/β-catenin pathways in vitro. Terminalia catappa leaf extracts may serve as an effective chemopreventive agent against metastasis of melanoma cancer.

Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated β-galactosidase (SA-β-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP.

Geminin, an inhibitor of the DNA replication licensing factor, chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression, but the molecular details are largely unknown. Here, we found that lysophosphatidic acid (LPA)-induced upregulation of geminin was specific to gastric cancer cells. LPA acted via LPA receptor (LPAR) 3 and matrix metalloproteinases (MMPs) signaling to transactivate epidermal growth factor receptor (EGFR) (Y1173) and thereby stabilize geminin expression level during the S phase. LPA also induced the expression of deubiquitinating protein (DUB) 3, which prevented geminin degradation. These results reveal a novel mechanism underlying gastric cancer progression that involves the regulation of geminin stability by LPA-induced EGFR transactivation and provide potential targets for the signaling pathway and tumor cell-specific inhibitors.

Hypertrophic scar (HPS) presents as excessive extracellular matrix deposition and abnormal function of fibroblasts. However, there is no single satisfactory method to prevent HPS formation so far. Here, we found that honokiol (HKL), a natural compound isolated from Magnolia tree, had an inhibitory effect on HPS both in vitro and in vivo. Firstly, HKL could dose-dependently down-regulate the mRNA and protein levels of type I collagen, type III collagen, and α-smooth muscle actin (α-SMA) in hypertrophic scar-derived fibroblasts (HSFs). Secondly, HKL suppressed the proliferation, migration abilities of HSFs and inhibited HSFs activation to myofibroblasts, but had no effect on cell apoptosis. Besides, the in vivo rabbit ear scar model further affirmed the inhibitory effects of HKL on collagen deposition, proliferating cell nuclear antigen and α-SMA. Finally, Western blot results showed that HKL reduced the phosphorylation status of Smad2/3, as well as affected the protein levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase1. Taken together, this study demonstrated that HKL alleviated HPS by suppressing fibrosis-related molecules and inhibiting HSFs proliferation, migration as well as activation to myofibroblasts via Smad-dependent pathway. Therefore, HKL could be used as a potential agent for treating HPS and other fibrotic diseases.

Myocardial fibrosis (MF) is an important pathological process in which a variety of cardiovascular diseases transform into heart failure. The main manifestation of MF is the excessive deposition of collagen in the myocardium. Here, we explored whether Huangqi Shengmai Yin (HSY) can inhibit isoprenaline (ISO)-induced myocardial collagen deposition in rats, thereby reducing the cardiac dysfunction caused by MF. The results of echocardiography showed that HSY upregulated fractional shortening and ejection fraction, and reduced the left ventricular systolic dysfunction in the rats with MF. Pathological results showed that HSY protected myocardium, inhibited apoptosis, and effectively reduced collagen deposition. HSY also inhibited the expression of collagen I and III and α-smooth muscle actin (α-SMA) in the heart tissue. HSY increased the expression of Sirtuin 3 (Sirt3) and inhibited the protein levels of the components in the transforming growth factor-β (TGF-β)/Smad pathway. At the same time, it also regulated the expression of related proteins in the matrix metalloproteinases family. In summary, HSY played a therapeutic role in rats with ISO-induced MF by protecting myocardium and inhibiting collagen deposition. Therefore, HSY is a potential therapeutic agent for ameliorating MF.

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.

Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.

Capsaicin, a major ingredient in chili pepper, has broad pharmaceutical applications, including relieving pain, anti-inflammation, and treating psoriasis. In dermatological biology, capsaicin has been shown to prevent the ultraviolet (UV)-induced melanogenesis via TRPV1 receptor. To strengthen the roles of capsaicin in skin function, the damaged skin, triggered by exposure to UV, was reversed by capsaicin in both in vitro and in vivo models. In cultured dermal fibroblasts, the exposure to UV induced a decrease of collagen synthesis and increases expression of matrix metalloproteinases (MMPs), generation of reactive oxygen species (ROS), and phosphorylation of Erk and c-Jun, and these events subsequently led to skin damage. However, the UV-mediated damages could be reversed by pre-treatment with capsaicin in a dose-dependent manner. The effect of capsaicin in blocking the UV-mediated collagen synthesis was mediated by reducing generation of ROS in dermal fibroblasts, instead of the receptor for capsaicin. Hence, capsaicin has high potential value in applying as an agent for anti-skin aging in dermatology.

Kaempferol is a major flavonoid in Ginkgo Folium and other edible plants, which is being proposed here to have roles in angiogenesis. Angiogenesis is important in both physiological and pathological development. Here, kaempferol was shown to bind with vascular endothelial growth factor (VEGF), probably in the heparin binding domain of VEGF: this binding potentiated the angiogenic functions of VEGF in various culture models. Kaempferol potentiated the VEGF-induced cell motility in human umbilical vein endothelial cells (HUVECs), as well as the sub-intestinal vessel sprouting in zebrafish embryos and formation of microvascular in rat aortic ring. In cultured HUVECs, application of kaempferol strongly potentiated the VEGF-induced phosphorylations of VEGFR2, endothelial nitric oxide synthase (eNOS) and extracellular signal-regulated kinase (Erk) in time-dependent and concentration-dependent manners, and in parallel the VEGF-mediated expressions of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, were significantly enhanced. In addition, the potentiation effect of kaempferol was revealed in VEGF-induced migration of skin cell and monocyte. Taken together, our results suggested the pharmacological roles of kaempferol in potentiating VEGF-mediated functions should be considered.

Rheumatoid arthritis (RA) is a progressive autoimmune disease specific to synovial joints; it causes joint damage and other systemic abnormalities, thereby leading to physical disability and early mortality. Marine sponge-derived fungi, Pestalotiopsis sp., secrete immunosuppressive compounds in the culture broth. In the present study, we isolated 4-(hydroxymethyl)catechol (4-HMC) from these fungal species, and evaluated its anti-RA effects using a murine collagen-induced arthritis model and tumor necrosis factor-α-stimulated human RA synovial fibroblasts. Oral 4-HMC administration decreased the clinical arthritis score, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. It prevented the proliferation of helper T (Th) 1/Th17 CD4+ lymphocytes isolated from inguinal lymph nodes, thereby reducing inflammatory cytokine production in CIA mice. It decreased the expression of inflammatory mediators, including cytokines and matrix metalloproteinases (MMPs), both in vitro and in vivo. We observed that 4-HMC suppresses Th immune responses and MMP expression to inhibit inflammatory cytokine production in human RA synovial fibroblasts by modulating the PI3K/Akt/NF-κB pathway. These results verify the anti-RA potential of 4-HMC.

The synthetic triazolylpeptidyl penicillin derivative, named TAP7f, has been previously characterized as an effective antitumor agent in vitro and in vivo against B16-F0 melanoma cells. In this study, we investigated the anti-metastatic potential of this compound on highly metastatic murine B16-F10 and human A375 melanoma cells. We found that TAP7f inhibited cell adhesion, migration and invasion in a dose-dependent manner. Additionally, we demonstrated that TAP7f downregulated integrin αvβ3 expression and Wnt/β-catenin pathway, a signaling cascade commonly related to tumor invasion and metastasis. Thus, TAP7f reduced both the enzymatic activity and the expression levels of matrix-metalloproteinases-2 and -9 in a time dependent manner. Moreover, TAP7f inhibited the expression of the transcription factor Snail and the mesenchymal markers vimentin, and N-cadherin, and up-regulated the expression of the epithelial marker E-cadherin, suggesting that the penicillin derivative affects epithelial-mesenchymal transition. Results obtained in vitro were supported by those obtained in a B16-F10-bearing mice metastatic model, that showed a significant TAP7f inhibition of lung metastasis. These findings suggest the potential of TAP7f as a chemotherapeutic agent for the treatment of metastatic melanoma.

Hemorrhage transformation is the most challenging preventable complication in thrombolytic therapy and is related to recombinant tissue plasminogen activator (rt-PA)-induced blood-brain barrier (BBB) damage. Intraperitoneal injections of normal or high doses of rosuvastatin were administered to Balb/c mice 20 min prior to middle cerebral artery occlusion (MCAO) surgery for 3 h followed by reperfusion with rt-PA thrombolytic therapy and cerebral blood flow monitoring to investigate whether a high or normal dose of rosuvastatin reduces BBB damage after brain ischemia and rt-PA reperfusion. The integrity of the BBB was ameliorated by normal and high doses of rosuvastatin as determined from Evans blue staining, ultrastructure assessments and immunochemistry at 24 h after reperfusion. The levels of TJ proteins were preserved, potentially by targeting platelet-derived growth factor receptor α (PDGFR-α) and low-density lipoprotein receptor-related protein 1 (LRP1) to inhibit the expression of matrix metalloproteinase proteins (MMPs) by reducing the levels of phosphorylated c-jun-N-terminal kinase (pJNK), phosphorylated mitogen-activated protein kinase (MAPK) p38 (pP38) and increasing the levels of phosphorylated extracellular regulated protein kinases (pERK), and tissue inhibitor of metalloproteinases (TIMPs), as inferred from Western blotting and molecular docking analyses. In summary, rosuvastatin reduced rt-PA therapy-associated BBB permeability by PDGFR-α- and LRP1-associated MAPK pathways to reduce the mortality of mice, and a normal dose of rosuvastatin exerted greater preventative effects on reducing BBB damage than did a high dose in the time window of thrombolytic therapy.

Breast cancer is the most common malignancy in women and is a molecularly heterogeneous disease. Signal transducer and activator of transcription 3 (Stat3) is overexpressed and hyperactivated in a variety of human tumours, including breast cancer, thus representing a promising target for breast cancer treatment. In the present study, we evaluated the activities of a novel Stat3 inhibitor named Statmp-151 in the human breast cancer cell lines MCF-7 and MDA-MB-231 and the murine mammary carcinoma cell line 4T1. The in vitro results showed that Statmp-151 inhibited the proliferation of breast cancer cell lines in a dose- and time-dependent manner and suppressed the phosphorylation of Stat3 in a dose-dependent manner. Flow cytometry (FCM) assays revealed that Statmp-151 affected mitochondrial membrane potential and reactive oxygen species (ROS) production. Furthermore, Statmp-151 inhibited cell migration, as shown by analysis of the matrix metalloproteinases MMP2 and MMP9. Finally, in a 4T1 tumour-bearing mouse model, intraperitoneal injection of 30 mg/kg/day Statmp-151 significantly suppressed the growth of tumours without obvious toxicity. These results indicated that Statmp-151 might be a potential candidate for the treatment of breast cancer.

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by aortic dilatation and predominantly affects an elderly population. Accumulating evidence suggests that Interleukin-6 (IL-6) and the signal transducer and activator of transcription 3 (STAT3) play an important role in formation of AAAs. However, it remains unclear whether Bazedoxifene (BAZ) could suppress the activation of IL-6/GP130/STAT3 in vascular cells and the formation of AAA. Here we explored the effect of BAZ on AngII-stimulated AAA formation. ApoE-/- mice infused with AngII for 28 days using osmotic minipumps were treated with placebo or 5mg/kg BAZ. In our results most of the AngII-induced mice developed AAA with exacerbated inflammation, degradation of elastin fibers, STAT3 phosphorylation, and increased expression of matrix metalloproteinases (MMPs). These effects were markedly attenuated by BAZ. Furthermore, BAZ suppressed the stimuli-induced (IL-6 or AngII) expression of P-STAT3, MMP2 and MMP9 in vascular smooth muscle cells (VSMCs). BAZ inhibited wound healing, colony formation and suppressed STAT3 nuclear translocation in vitro. In conclusion, these results indicated that BAZ downregulated IL-6/GP130/STAT3 signaling and interfered with AAA formation induced by AngII in ApoE-/- mice, which indicates a novel potential strategy for the prevention and therapy of AAA.

Osteoarthritis (OA), the most common form of arthritis, is a very common joint disease that often affects middle-aged to elderly people. However, current treatment options for OA are predominantly palliative. Thus, understanding its pathological process and exploring its potential therapeutic approaches are of great importance. Rat chondrocytes were isolated and exposed to hydrogen peroxide (H2O2) to mimic OA. The effects of H2O2 on ubiquitin-specific protease 7 (USP7) expression, reactive oxygen species (ROS) levels, proliferation, inflammatory cytokine release, and pyroptosis were measured. USP7 was knocked down (KD) or overexpressed to investigate the role of USP7 in OA. Co-immunoprecipitation (Co-IP) was used to study the interaction between USP7 and NAD(P)H oxidases (NOX)4 as well as NOX4 ubiquitination. NOX4 inhibitor was applied to study the involvement of NOX4 in USP7-mediated OA development. USP7 inhibitor was given to OA animals to further investigate the role of USP7 in OA in vivo. Moreover, H2O2 treatment significantly increased USP7 expression, enhanced ROS levels, and inhibited proliferation in rat chondrocytes. The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1β and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition. The USP7 KD protected rat chondrocytes against H2O2-induced injury. Co-IP results showed that USP7 interacted with NOX4, and USP7 KD enhanced NOX4 ubiquitinylation. The inhibition of NOX4 blocked the pro-OA effect of USP7. Moreover, the USP7 inhibitor given to OA animals suppressed OA in vivo. USP7 inhibited NOX4 ubiquitination for degradation which leads to elevated ROS production. ROS subsequently activates NLPR3 inflammasome, leading to enhanced production of IL-1β and IL-18, GSDMD-N-dependent pyroptosis, and extracellular matrix remodeling. Thus, UPS7 contributes to the progression of OA via NOX4/ROS/NLPR3 axis.