Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury.

AIM: Exercise training exerts protective effects against sepsis-associated multiple organ dysfunction. This study aimed to investigate whether aerobic exercise protected against sepsis-associated acute kidney injury (AKI) via modulating R-spondin 3 (RSPO3) expression. METHODS: To investigate the effects of aerobic exercise on lipopolysaccharide (LPS)-induced AKI, LPS (20 mg/kg) was intraperitoneally injected after six weeks of treadmill training. To investigate the role of RSPO3 in LPS-induced AKI, wild-type (WT) or inducible endothelial cell-specific RSPO3 knockout (RSPO3EC-/- ) mice were intraperitoneally injected with 12 mg/kg LPS. RSPO3 was intraperitoneally injected 30 min before LPS treatment. RESULTS: Aerobic exercise-trained mice were more resistant to LPS-induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. Exercise training restored the LPS-induced decreases in serum and renal RSPO3 levels. Exercise or RSPO3 attenuated, whereas inducible endothelial cell-specific RSPO3 knockout exacerbated LPS-induced renal glycocalyx loss, endothelial hyperpermeability, inflammation, and AKI. Bioinformatics analysis results revealed significant increases in the expression of matrix metalloproteinases (MMPs) in kidney tissues of mice exposed to sepsis or endotoxaemia, which was validated in renal tissue from LPS-exposed mice and LPS-treated human microvascular endothelial cells (HMVECs). Both RSPO3 and MMPs inhibitor restored LPS-induced downregulation of tight junction protein, adherens junction protein, and glycocalyx components, thus ameliorating LPS-induced endothelial leakage. Exercise or RSPO3 reversed LPS-induced upregulation of MMPs in renal tissues. CONCLUSION: Increased renal expression of RSPO3 contributes to aerobic exercise-induced protection against LPS-induced renal endothelial hyperpermeability and AKI by suppressing MMPs-mediated disruption of glycocalyx and tight and adherens junctions.

The roles of theaflavins in reducing dentin erosion.

This study aimed to evaluate the effect of theaflavins [TFs] on the process of dentin erosion and investigation the potential mechanism. For erosion kinetics of the dentin, 7 experimental groups (n = 5) treated with 10% ethanol [EtOH] (negative control) are erosion for 1, 2, 3, 4, 5, 6, and 7 d erosion cycles (4 cycles/d). For the effect of TFs on dentin erosion, 6 experimental groups (n = 5) were treated with 1% epigallocatechin gallate [EGCG], 1% chlorhexidine [CHX], 1%, 2%, 4%, and 8% TFs for the 30 s and then subjected to erosion cycles (4 cycles/d for 7 d). The erosive dentin wear (µm) and surface morphology were evaluated and compared by laser scanning confocal microscope and scanning electron microscopy. The matrix metalloproteinase inhibition effects of TFs were investigated using in situ zymography and molecular docking. TFs-treated collagen was investigated by ultimate microtensile strength, Fourier-transform infrared spectroscopy, and molecular docking. Data were analyzed by ANOVA, Tukey's test (P < 0.05). The TFs-treated groups (7.56 ± 0.39, 5.29 ± 0.61, 3.28 ± 0.33, and 2.62 ± 0.99 µm for 1%, 2%, 4%, and 8% TFs) had significantly lower erosive dentin wear than the negative control group (11.23 ± 0.82 µm), and the effect was concentration-dependent at low concentrations (P < 0.05). TFs inhibit matrix metalloproteinase [MMP]. Moreover, TFs crosslink dentin collagen and cause hydrophilic changes in dentin collagen. TFs preserve organic matrix within the demineralized dentin by inhibiting MMP activity and simultaneously improving collagen's resistance to enzymes, both of which contribute to preventing or slowing down the progression of dentin erosion.

Silibinin Inhibits Cell Invasion through the Inhibition of MMPs, p-p38, and IL-1ß in Human Fibrosarcoma Cells.

BACKGROUND AND AIMS: Normal cells become tumorigenic owing to mutations in oncogenes and tumor suppressor genes modulating cell division. Cancer cells break down extracellular matrix to metastasize other tissues. Therefore, the development of natural and synthetic substances that suppress metastatic enzymes such as matrix metalloproteinase (MMP)-2 and MMP-9 is useful to inhibit metastasis. Silibinin is the main ingredient of silymarin extracted from the seeds of milk thistle plants having lung cancer-suppressing effects and liver protection. The purpose of this study was to investigate the inhibitory effect of silibinin on the invasion of human fibrosarcoma cells. METHODS: The effect of silibinin on cell viability was measured in HT1080 cells using an MTT assay. The MMP-9 and MMP-2 activities were analyzed using a zymography assay. The expression of proteins in cytoplasm related to metastasis was examined by western blot analysis and immunofluorescence assay. RESULTS: In this study, silibinin above 20 µM showed growth inhibitory effects. Silibinin above 20 µM remarkably inhibited the levels of MMP-2 and MMP-9 activation under phorbol myristate acetate (PMA) treatment conditions. Furthermore, silibinin at 25 µM reduced the levels of MMP-2, IL-1ß, ERK-1/2, and p-p38 expression and silibinin above 10 µM inhibited cell invasion on HT1080 cells. CONCLUSIONS: These findings indicate that silibinin may have an inhibitory effect on the enzymes involved in invasion, hence it might influence the metastatic ability of tumor cells.

Effect of Irisin on Human Nucleus Pulposus Cells: New Insights into the Biological Cross-talk Between Muscle and Intervertebral Disk.

STUDY DESIGN: In vitro study. OBJECTIVE: To investigate the effect of irisin on human nucleus pulposus cells (hNPCs) in vitro. SUMMARY OF BACKGROUND DATA: Physical exercise (PE) favours weight loss and ameliorates function in patients with low back pain. Although there is no biological evidence that the intervertebral disk (IVD) can respond to PE, recent studies have shown that running is associated with increased IVD hydration and hypertrophy. Irisin, a myokine released upon muscle contraction, has demonstrated anabolic effects on different cell types, including chondrocytes. MATERIALS AND METHODS: hNPCs were exposed to 5, 10, and 25 ng/mL irisin. Cell proliferation, glycosaminoglycan (GAG) content, metabolic activity, gene expression of collagen type II (COL2), matrix metalloproteinase (MMP)-13, tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-3, aggrecan (ACAN), interleukin (IL)-1ß, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 were assessed. In addition, MTT assay and ADAMTS-5, COL2, TIMP-1, and IL-1ß gene expression were evaluated following incubation with irisin for 24 hours and subsequent culture with 10 ng/mL IL-1ß and vice versa (incubation for 24 hours with IL-1ß and subsequent culture with irisin). RESULTS: Irisin increased hNPC proliferation, metabolic activity, and GAG content, as well as COL2, ACAN, TIMP-1 and TIMP-3 gene expression, while decreasing MMP-13 and IL-1ß mRNA levels. Irisin pretreatment of hNPCs cultured in proinflammatory conditions resulted in a rescue of metabolic activity and a decrease of IL-1ß levels. Similarly, incubation of hNPCs with IL-1ß and subsequent exposure to irisin led to an increment of metabolic activity, COL2 gene expression, and a reduction of IL-1ß and ADAMTS-5 levels. CONCLUSIONS: Irisin increases hNPC proliferation, GAG content, metabolic activity, and promotes anabolic gene expression while reducing catabolic markers. Irisin may be one of the mediators by which PE and muscle tissues modulate IVD metabolism, suggesting the existence of a biological cross-talk between the muscle and IVD.

Damage prevention effect of milk-derived peptides on UVB irradiated human foreskin fibroblasts and regulation of photoaging related indicators.

Long-term exposure to UVB can trigger acute inflammation of the skin and lead to skin photoaging. To scrutinize the anti-photoaging functions of peptides obtained from milk, the physicochemical including molecular weight and amino acid compositions were first analyzed. Totally 267 peptides were screened out and identified by PEAKS X software, and then evaluated through Peptide Ranker and BIOPEP-UMW. Six peptides with the highest antioxidant ability and relative abundance were selected. This study was then conducted in UVB-damaged human foreskin fibroblasts with proadministration of peptides. The results indicated that at concentrations of 0.08-0.10 mg/mL, milk-derived peptides could realize a damage prevention effect through inhibiting the generation of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA). Also, these peptides were found to promote the photoaging related enzyme activities of superoxide dismutase (SOD) and catalase (CAT), while to block the production of matrix metalloproteinases-1. Through this study, we found that milk-derived peptide mixture is effective in preventing photoaging damage. Milk-derived peptides found in this study could serve as raw materials for future development of antioxidant functional foods.

Anti-migratory effect of curcumin on A-549 lung cancer cells via epigenetic reprogramming of RECK/ matrix metalloproteinase axis.

OBJECTIVES: The aim of this study was to investigate the effects of curcumin on the viability, migration, and apoptosis of A549 lung cancer cells. Furthermore, RECK/MMPs axis as a probable regulator of cancer cell migration was assessed. METHODS: In this study, effect of curcumin on viability changes, cell migration, and percentage of apoptosis of A549 non-small cell lung carcinoma was examined. The methylation status of RECK gene was investigated using MS-HRM technique. Moreover, expression changes of genes involved in apoptosis and migration (including CASP3, CASP8, CASP9, BAX, BCL2, MMP9, MMP2, and RECK) were investigated by quantitative Real-Time PCR. RESULTS: The results of MTT assay showed that the cytotoxic effect of curcumin was in a dose dependent manner. Flow cytometry results demonstrated a significant increase in the percentage of apoptotic cells in curcumin treated group. In addition, curcumin inhibited migration rate in lung cancer cells. qRT-PCR revealed that expression of the candidate genes was in line with suppressed growth and migration. This could be due to, decreased methylation of the RECK gene promoter after curcumin treatment. CONCLUSIONS: Curcumin inhibited lung cancer cells through various molecular pathways. RECK/MMPs axis as a regulator of cancer cell migration was modulated after curcumin treatment and invasion of lung cancer cells was decreased.

Ascaridole exerts the leishmanicidal activity by inhibiting parasite glycolysis.

BACKGROUND: The global burden of leishmaniasis is exacerbated by the limited repertoire of drugs, resulting in an urgent need to develop new therapeutic alternatives. Endoperoxides like ascaridole have emerged as promising anti-parasitic candidates, and its effectiveness was established in an animal model of cutaneous leishmaniasis (CL). However, its impact on Leishmania donovani parasites, causative of visceral leishmaniasis (VL) remains to be established. PURPOSE: This study aimed to delineate the underlying mechanisms contributing towards the leishmanicidal effect of ascaridole in terms of its impact on the cellular redox status and metabolic bioenergetics of L. donovani parasites. METHODOLOGY: The anti-promastigote activity of ascaridole was established by a cell viability assay in L. donovani [MHOM/IN/1983/AG83] and anti-amastigote activity by microscopy and ddPCR (droplet digital polymerase chain reaction). The cellular redox status, mitochondrial membrane potential (MMP), annexin V positivity and cell cycle arrest was evaluated by flow cytometry, while cellular and mitochondrial bioenergetics was assessed using Agilent XFp Analyzer, and the levels of ATP was measured by chemiluminescence. RESULTS: Ascaridole demonstrated strong anti-promastigote and anti-amastigote activities in l. donovani, IC50 (half maximal Inhibitory concentration) being 2.47 ± 0.18 µM and 2.00±0.34 µM respectively, while in J774.A1 and murine peritoneal macrophages, the CC50 (half maximal cytotoxic concentration) was 41.47 ± 4.89 µM and 37.58 ± 5.75 µM respectively. Ascaridole disrupted the redox homeostasis via an enhanced generation of reactive oxygen species (ROS), lipid peroxidation and concomitant depletion of thiols. However, it failed to increase the generation of mitochondrial superoxide, which minimally impacted on mitochondrial respiration and was corroborated by energy metabolism studies. Instead, ascaridole inhibited glycolysis of promastigotes, caused a loss in MMP, which translated into ATP depletion. In promastigotes, ascaridole enhanced annexin-V positivity and caused a cell cycle arrest at sub- G0/G1 phase. CONCLUSION: In summary, ascaridole displays its leishmanicidal activity possibly due to its ability to auto-generate free radicals following cleavage of its endoperoxide bridge that led to disruption of the redox homeostasis, inhibition of glycolysis and culminated in an apoptotic like cell death.

Plumbagin relieves rheumatoid arthritis through nuclear factor kappa-B (NF-κB) pathway.

This study aimed to explore the effects of plumbagin on rheumatoid arthritis (RA) and its mechanism. The RA cell model was simulated following the treatment of interleukin-1ß (IL-1ß). After the treatment of various concentrations of plumbagin, the impact of plumbagin on the cell viability was examined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The collagen-induced arthritis (CIA) model was established using the solution of bovine type II collagen. Hematoxylin-eosin staining was used to observe the changes of ankle joint tissue, while enzyme-linked immunosorbent assay and western blot were applied to detect the level of inflammatory cytokines. Plumbagin inhibited the viability of human fibroblast-like synoviocytes (HFLS) at the concentration of 1 ~ 3.5 µM. The inhibitory effect of 1 µM plumbagin on cell proliferation was similar to that of methotrexate, the drug used as the positive control. Plumbagin downregulated the levels of inflammatory cytokines and matrix metalloproteinases (MMPs) in IL-1ß-treated HFLS, and suppressed the activation of IκB and nuclear factor kappa-B (NF-κB) as well as the entry of p65 into the nucleus. It was also demonstrated in animal experiments that plumbagin inhibited the activation of NF-κB pathway, down-regulated the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and MMPs, and alleviated joint damage in CIA-modeled mice. Collectively speaking, plumbagin might down-regulate the levels of inflammatory cytokines and MMPs through inhibiting the activation of the NF-κB pathway, thereby attenuating RA-induced damage to cells and joints.Abbreviations: CIA: Collagen-induced arthritis; ELISA: Enzyme-linked immuno sorbent assay; HFLS: Human fibroblast-like synoviocytes; IL-6: Interleukin-6; IL-1ß: Interleukin-1ß; NF-κB: nuclear factor kappa-B; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MMPs: Matrix metalloproteinase; OD: Optical density; RA: Rheumatoid arthritis; SDS: Sodium dodecyl sulfate; SD: Standard deviation; TNF-α: Tumor necrosis factor-α; PVDF: Polyvinylidene fluoride.

Construction of a New Dual-Responsive Nano-Drug Delivery System for Matrix Metalloproteinases and Adenosine Triphosphate in Ovarian Cancer Using Nanomicelles.

In this manuscript we constructed a dual-responsive nano-drug delivery system for matrix metalloproteinases and ATP in ovarian cancer microenvironment. The nanomicelle PCL-DNA/DOX-Peptide-PEG was prepared by intercalating doxorubicin hydrochloride between C and G base pairs of DNA double helix structure. Another ATP-responsive nanomicelle PCL-DNA/DOX-PEG was prepared. Then we analyzed the characterization of nanomicelles (particle size, potential, surface morphology, etc.) and drug loading binding and drug release behavior. In addition, the effect of nanomicelles on the viability of mouse ovarian epithelial tumor cell ID-8 was detected by CCK-8 method. CCK-8 assay detected that different concentrations of carrier had no difference on the proliferation of ID-8 cells, and the survival rate of ID-8 cells by different concentrations of DOX preparations was statistically significant and the same results were observed in cytotoxicity comparison. Confocal microscopy showed that DOX in the drug-loaded micelle group was concentrated in the nucleus, while free DOX was concentrated in the cytoplasm. ID-8 cells took up the drug-loaded micelles faster. The semi-quantitative analysis of the DOX uptake of ID-8 cells with different treatments showed extremely significant statistical differences. In conclusion, the prepared self-assembled dual-responsive nanomicelle PCL-DNA/DOX-Peptide-PEG is novel anti-tumor agent, and is expected to have good tumor tissue penetration ability with a low toxicity.

Research on Orientation of Basic Fibroblast Growth Factor with Magnetic Nanoparticles (MNPs) on Regeneration and Recovery of Rats' Dampened Skeletal Muscle and Expressed Level of Matrix Metalloproteinase.

The basic fibroblast growth factor (bFGF) has a special role in improving proliferation and differentiation of fiber cells in growth of muscle. The function of bFGF with magnetic nanoparticles (MNPs) on regeneration and recovery of rats' dampened skeletal muscle and expression of MMPS were studied in our research. The MNPs packed with bFGF were prepared and 95 experimental rats were selected. These 30 rats were equally divided into control group, model group (self-healing without obstruction after model was established), bFGF group (disposed with bFGF packaged with MNP). The contractility and stress relaxation of rats' skeletal muscle were observed at the 48th h, 10th, 17th, 24th and 30th days after damage. The remaining 65 rats were divided randomly into control group (5 rats) and experimental group (60 rats intervened with MNPs packaged with bFGF). The groups were randomly divided into 0.5 h, 1 h, 3 h, 6 h, 12 h, 1 d, 2 d, 3 d, 4 d, 7 d, 10 d and 14 d according to different executed time. The levels of bFGF and MMPS were detected by HE staining method and immunohistochemical staining. There was a significant declining tendency of shrinkage stress of muscle in the model, sham-operation, BSA and bFGF groups compared with control group in the second day. The contractility after contusion wound in the regeneration and recovery of rats' skeletal muscle was effectively alleviated with MNPs packaged with bFGF.

Regeneration of collagen fibrils at the papillary dermis by reconstructing basement membrane at the dermal-epidermal junction.

The epidermal basement membrane deteriorates with aging. We previously reported that basement membrane reconstruction not only serves to maintain epidermal stem/progenitor cells in the epidermis, but also increases collagen fibrils in the papillary dermis. Here, we investigated the mechanism of the latter action. Collagen fibrils in the papillary dermis were increased in organotypic human skin culture treated with matrix metalloproteinase and heparinase inhibitors. The expression levels of COL5A1 and COL1A1 genes (encoding collagen type V α 1 chain and collagen type I α 1 chain, respectively) were increased in fibroblasts cultured with conditioned medium from a skin equivalent model cultured with the inhibitors and in keratinocytes cultured on laminin-511 E8 fragment-coated plates. We then examined cytokine expression, and found that the inhibitors increased the expression of PDGF-BB (platelet-derived growth factor consisting of two B subunits) in epidermis. Expression of COL5A1 and COL1A1 genes was increased in cultured fibroblasts stimulated with PDGF-BB. Further, the bifunctional inhibitor hydroxyethyl imidazolidinone (HEI) increased skin elasticity and the thickness of the papillary dermis in the skin equivalent. Taken together, our data suggests that reconstructing the basement membrane promotes secretion of PDGF-BB by epidermal keratinocytes, leading to increased collagen expression at the papillary dermis.

Pharmacology and molecular docking study of cartilage protection of Chinese herbal medicine Fufang Shatai Heji (STHJ) by inhibiting the expression of MMPs in collagen-induced arthritis mice.

BACKGROUND: This study aims to explore whether Fufang Shatai Heji (STHJ), as a mixture collected by a decoction of a variety of Chinese herbal medicines for immune system diseases, can improve the cartilage destruction of rheumatoid arthritis (RA). METHODS: The therapeutic effects of STHJ were studied using collagen induced arthritis (CIA) mice. The improvement effect of STHJ on synovitis and cartilage damage caused by arthritis was studied by joint pathological analysis. The inhibitory effect of STHJ on related degradation enzymes in cartilage was studied by immunohistochemistry and real-time polymerase chain reaction (PCR). The specific targets of STHJ were predicted by molecular docking. RESULTS: After successfully inducing CIA, the paws of the mice showed significant swelling, and athological analysis of the ankle and knee joints also showed significant cartilage destruction and synovial hyperplasia. However, synovial hyperplasia and cartilage destruction were markedly alleviated after administration of STHJ. And after STHJ treatment, the expression of ADAMTS-4, ADAMTS-5, MMP-9 and MMP-13, in the cartilage layer of CIA mice was significantly inhibited. Through molecular docking assays, we proved that acteoside in STHJ could directly bind to the Glu111, Phe110 residues in MMP-9 and glycyrrhizic acid in STHJ bind to the Glu382, Asn433 residues in MMP-13. CONCLUSIONS: Our results suggested that STHJ may alleviate synovial hyperplasia and cartilage destruction in CIA mice and protect cartilage by inhibiting the expression of MMP-9 and other enzymes.

Resistin induces chemokine and matrix metalloproteinase production via CAP1 receptor and activation of p38-MAPK and NF-κB signalling pathways in human chondrocytes.

OBJECTIVES: Adipokine resistin is highly expressed in the serum and synovial uid (SF) of patients with knee osteoarthritis (KOA) but its pathogenic role in KOA remains unclear. We aimed to explore the mechanism of resistin/CAP1 in human KOA chondrocytes. METHODS: We enrolled 103 patients with radiographic KOA and 86 healthy participants as controls. Resistin levels in serum and SF were determined by enzyme-linked immunosorbent assay (ELISA). CAP1 expression was measured in cartilage tissues using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Effects of resistin on chondrocytes and CAP1 were evaluated via qRT-PCR and co-immunoprecipitation. The roles of CAP1, p38-MAPK, and NF-κB signalling pathways in KOA development were evaluated using adenovirus-mediated CAP1 short hairpin RNA, qRT-PCR, western blot, and ELISA. RESULTS: Resistin expression in serum and SF was elevated in severe radiographic KOA. CAP1 levels were higher in KOA cartilage and were positively correlated with resistin expression. Resistin promoted CCL3, CCL4, MMP13, and ADAMTS-4 expression through the CAP1 receptor. Resistin also directly bound to CAP1, as confirmed by co-immunoprecipitation. CAP1 knockdown in chondrocytes attenuated resistin-induced expression of CCL3, CCL4, MMP13, and ADAMTS-4 and activated p38-MAPK and NF-κB signalling pathways. CONCLUSIONS: Resistin binds CAP1 and upregulates the expression of proinflammatory cytokines and matrix-degrading enzymes via p38-MAPK and NF-κB signalling in human chondrocytes.

Current trends in the anti-photoaging activities and mechanisms of dietary non-starch polysaccharides from natural resources.

Photoaging is a complex and multistage process triggered mainly by ultraviolet (UV) radiation due to exposure to sunlight. Photoaging induces DNA damage and oxidative stress that initiate an inflammatory response and an increase of matrix metalloproteinases (MMPs) expression, which results in cumulative changes in skin appearance, structure, and functions, and eventually causes skin carcinogenesis. Dietary polysaccharides from bio-resources have been utilized as functional ingredients in healthy food, cosmetics, and drug due to their good bioactivities. However, a systematic introduction to their effects and underlying mechanisms in anti-photoaging is limited. This review discusses the damage and pathogenesis of UV-induced photoaging and summarizes the up-to-date advances in research on the anti-photoaging activity of non-starch polysaccharides from natural edible resources considering the influence of oxidative stress, DNA damage, MMPs regulation, inflammation, and melanogenesis, primarily focusing on the cellular and molecular mechanisms. This paper will help to understand the anti-photoaging functions of dietary non-starch polysaccharides from natural resources and further application in drug and functional food.

Understanding angiogenesis and the role of angiogenic growth factors in the vascularisation of engineered tissues.

Tissue engineering is a rapidly developing field with many potential clinical applications in tissue and organ regeneration. The development of a mature and stable vasculature within these engineered tissues (ET) remains a significant obstacle. Currently, several growth factors (GFs) have been identified to play key roles within in vivo angiogenesis, including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), FGF and angiopoietins. In this article we attempt to build on in vivo principles to review the single, dual and multiple GF release systems and their effects on promoting angiogenesis. We conclude that multiple GF release systems offer superior results compared to single and dual systems with more stable, mature and larger vessels produced. However, with more complex release systems this raises other problems such as increased cost and significant GF-GF interactions. Upstream regulators and pericyte-coated scaffolds could provide viable alternative to circumnavigate these issues.

Acacetin Suppresses IL-1ß-Induced Expression of Matrix Metalloproteinases in Chondrocytes and Protects against Osteoarthritis in a Mouse Model by Inhibiting NF-κB Signaling Pathways.

Osteoarthritis (OA) is a very common chronic joint dysfunction, and there is currently a poor understanding of its etiology and pathogenesis. Therefore, there are no active disease-modifying drugs currently available for clinical treatment. Several natural compounds have been shown to play a role in inhibiting OA progression. The present study is aimed at investigating the curative effects of acacetin, a natural flavonoid compound, against OA. Our results demonstrated that MMP-1, MMP-3, and MMP-13 were highly expressed in OA specimens. Acacetin inhibited the interleukin-1ß- (IL-1ß-) induced expression of MMP-1, MMP-3, and MMP-13in chondrocytes by blocking nuclear factor-κB (NF-κB) signaling pathways. Furthermore, we found that acacetin suppressed OA progression and inhibited the expression of MMP-1, MMP-3, and MMP-13 in ACLT-induced OA mice. Taken together, our study revealed that acacetin may serve as a potential drug for treating OA.

The Versatile Role of Matrix Metalloproteinase for the Diverse Results of Fibrosis Treatment.

Fibrosis is a type of chronic organ failure, resulting in the excessive secretion of extracellular matrix (ECM). ECM protects wound tissue from infection and additional injury, and is gradually degraded during wound healing. For some unknown reasons, myofibroblasts (the cells that secrete ECM) do not undergo apoptosis; this is associated with the continuous secretion of ECM and reduced ECM degradation even during de novo tissue formation. Thus, matrix metalloproteinases (MMPs) are considered to be a potential target of fibrosis treatment because they are the main groups of ECM-degrading enzymes. However, MMPs participate not only in ECM degradation but also in the development of various biological processes that show the potential to treat diseases such as stroke, cardiovascular diseases, and arthritis. Therefore, treatment involving the targeting of MMPs might impede typical functions. Here, we evaluated the links between these MMP functions and possible detrimental effects of fibrosis treatment, and also considered possible approaches for further applications.

Pathological and therapeutic aspects of matrix metalloproteinases: Implications in osteosarcoma.

Osteosarcoma (OS) is one of the most common malignant bone tumors in children and adolescents, and the eighth leading form of childhood cancer. Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in certain cancers including OS. In this review, we discuss the mechanism of actions of MMPs in progression of OS, and the therapeutic use of MMPs inhibitors in the treatment of OS with subsequent clinical studies and future management. The expression of MMPs is upregulated in cancer cells by a variety of cytokines and growth factors, and upregulation of MMPs induces degradation of the extracellular matrix that contributes to cell proliferation by releasing growth factors. MMPs promote the detachment and migration of endothelial cells, cross the basement membrane as well as invade the surrounding lymphatic vessels and causes cancer metastasis. The use of selective MMP inhibitors with limited side effects might be promising therapeutic strategy in the treatment of OS. More clinical trials are necessary to evaluate the role of selective MMPs inhibitors in the prevention and treatment of OS along with their assessment of toxicity.

Marfan syndrome: A therapeutic challenge for long-term care.

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the fibrillin-1 gene. Acute aortic dissection is the leading cause of death in patients suffering from MFS and consequence of medial degeneration and aneurysm formation. In addition to its structural function in the formation of elastic fibers, fibrillin has a major role in keeping maintaining transforming growth factor ß (TGF-ß) in an inactive form. Dysfunctional fibrillin increases TGF-ß bioavailability and concentration in the extracellular matrix, leading to activation of proinflammatory transcription factors. In turn, these events cause increased expression of matrix metalloproteinases and cytokines that control the migration and infiltration of inflammatory cells into the aorta. Moreover, TGF-ß causes accumulation of reactive oxygen species leading to further degradation of elastin fibers. All these processes result in medial elastolysis, which increases the risk of vascular complications. Although MFS is a hereditary disease, symptoms and traits are usually not noticeable at birth. During childhood or adolescence affected individuals present with severe tissue weaknesses, especially in the aorta, heart, eyes, and skeleton. Considering this, even young patients should avoid activities that exert additional stress and pressure on the aorta and the cardiovascular system. Thus, if the diagnosis is made and prophylactic treatment is initiated in a timely fashion, MFS and its preliminary pathophysiologic vascular remodeling can be successfully ameliorated reducing the risk of life-threatening complications. This commentary focuses on new research opportunities and molecular findings on MFS, discusses future challenges and possible long-term therapies.

Dual Cross-Linked Biofunctional and Self-Healing Networks to Generate User-Defined Modular Gradient Hydrogel Constructs.

Gradient hydrogels have been developed to mimic the spatiotemporal differences of multiple gradient cues in tissues. Current approaches used to generate such hydrogels are restricted to a single gradient shape and distribution. Here, a hydrogel is designed that includes two chemical cross-linking networks, biofunctional, and self-healing networks, enabling the customizable formation of modular gradient hydrogel construct with various gradient distributions and flexible shapes. The biofunctional networks are formed via Michael addition between the acrylates of oxidized acrylated hyaluronic acid (OAHA) and the dithiol of matrix metalloproteinase (MMP)-sensitive cross-linker and RGD peptides. The self-healing networks are formed via dynamic Schiff base reaction between N-carboxyethyl chitosan (CEC) and OAHA, which drives the modular gradient units to self-heal into an integral modular gradient hydrogel. The CEC-OAHA-MMP hydrogel exhibits excellent flowability at 37 °C under shear stress, enabling its injection to generate gradient distributions and shapes. Furthermore, encapsulated sarcoma cells respond to the gradient cues of RGD peptides and MMP-sensitive cross-linkers in the hydrogel. With these superior properties, the dual cross-linked CEC-OAHA-MMP hydrogel holds significant potential for generating customizable gradient hydrogel constructs, to study and guide cellular responses to their microenvironment such as in tumor mimicking, tissue engineering, and stem cell differentiation and morphogenesis.