Inhibition Of Matrix Metalloproteinase-9 Expression Research Articles

Isoliquiritigenin diminishes invasiveness of human nasopharyngeal carcinoma cells associating with inhibition of MMP-2 expression and STAT3 signalling.

Nasopharyngeal carcinoma (NPC) is prevalent in Asia and exhibits highly metastatic characteristics, leading to uncontrolled disease progression. Isoliquiritigenin (ISL) have attracted attention due to their diverse biological and pharmacological properties, including anticancer activities. However, the impact of ISL on the invasive and migratory ability of NPC remains poorly understood. Hence, this study aimed to investigate the invitro anti-metastatic effects of ISL on NPC cells and elucidate the underlying signalling pathways. Human NPC cell NPC-39 and NPC-BM were utilized as cell models. Migratory and invasive capabilities were evaluated through wound healing and invasion assays, respectively. Gelatin zymography was employed to demonstrate matrix metalloproteinase-2 (MMP-2) activity, while western blotting was conducted to analyse protein expression levels and explore signalling cascades. Overexpression of signal transducer and activator of transcription 3 (STAT3) was carried out by transduction of STAT3-expressing vector. Our findings revealed that ISL effectively suppressed the migration and invasion of NPC cells. Gelatin zymography and Western blotting assays demonstrated that ISL treatment led to a reduction in MMP-2 enzyme activity and protein expression. Investigation of signalling cascades revealed that ISL treatment resulted in the inhibition of STAT3 phosphorylation. Moreover, overexpression of STAT3 restored the migratory ability of NPC cells in the presence of ISL. Collectively, these findings indicate that ISL inhibits the migration and invasion of NPC cells associating with MMP-2 downregulation through suppressing STAT3 activation. This suggests that ISL has an anti-metastatic effect on NPC cells and has potential therapeutic benefit for NPC treatment.

Polydeoxyribonucleotide exerts opposing effects on ERK activity in human skin keratinocytes and fibroblasts.

Polydeoxyribonucleotide (PDRN) is a mixture of deoxyribonucleotides. It serves as an anti‑inflammatory and tissue‑regenerating agent. The mitogen‑activated protein kinase pathway modulates cell growth and collagen accumulation. It also regulates inflammation by suppressing the expression of proinflammatory cytokines. In the present study, it was attempted to elucidate the molecular mechanism of PDRN in skin healing by confirming the effects of PDRN treatment on skin keratinocytes and fibroblasts, and by assessing the levels of collagen and inflammatory cytokines regulated by the extracellular signal‑regulated kinase (ERK) pathway. The potential effects of PDRN on skin regeneration were investigated. Fibroblast and keratinocyte proliferation and migration were analyzed using the water‑soluble tetrazolium‑8 and wound healing assays. The upregulation of collagen synthesis by PDRN‑induced ERK activation was analyzed in fibroblasts with or without an ERK inhibitor. Inflammatory cytokine expression levels in keratinocytes were determined using reverse transcription‑quantitative polymerase chain reaction. PDRN promoted the proliferation and migration of keratinocytes and fibroblasts. However, PDRN‑induced ERK phosphorylation differed between keratinocytes and fibroblasts; PDRN increased ERK phosphorylation and collagen accumulation in fibroblasts, while it inhibited matrix metalloproteinase expression. By contrast, PDRN inhibited ERK phosphorylation in keratinocytes, and it decreased inflammatory cytokine expression levels. PDRN affects skin cell proliferation and migration, and collagen and inflammatory cytokine expression levels via ERK signaling. Overall, PDRN exerts a positive effect on skin regeneration, but the mechanism by which it promotes skin regeneration varies among different skin cell types.

Therapeutic Hypothermia Combined with Hydrogen Sulfide Treatment Attenuated Early Blood–Brain Barrier Disruption and Brain Edema Induced by Cardiac Arrest and Resuscitation in Rat Model

Brain injury remains a major problem in patients suffering cardiac arrest (CA). Disruption of the blood–brain barrier (BBB) is an important factor leading to brain injury. Therapeutic hypothermia is widely accepted to limit neurological impairment. However, the efficacy is incomplete. Hydrogen sulfide (H2S), a signaling gas molecule, has protective effects after cerebral ischemia reperfusion injury. This study showed that combination of hypothermia and H2S after resuscitation was more beneficial for attenuated BBB disruption and brain edema than that of hypothermia or H2S treatment alone. CA was induced by ventricular fibrillation for 4 min. Hypothermia was performed by applying alcohol and ice bags to the body surface under anesthesia. We used sodium hydrosulphide (NaHS) as the H2S donor. We found that global brain ischemia induced by CA and cardiopulmonary resuscitation (CPR) resulted in brain edema and BBB disruption; Hypothermia or H2S treatment diminished brain edema, decreased the permeability and preserved the structure of BBB during the early period of CA and resuscitation, and more importantly, improved the neurologic function, increased the 7-day survival rate after resuscitation; the combination of hypothermia and H2S treatment was more beneficial than that of hypothermia or H2S treatment alone. The beneficial effects were associated with the inhibition of matrix metalloproteinase-9 expression, attenuated the degradation of the tight junction protein occludin, and subsequently protected the structure of BBB. These findings suggest that combined use of therapeutic hypothermia and hydrogen sulfide treatment during resuscitation of CA patients could be a potential strategy to improve clinical outcomes and survival rate.

Efficiency and Safety of Dextran-PAMAM/siMMP-9 Complexes for Decreasing Matrix Metalloproteinase-9 Expression and Promoting Wound Healing in Diabetic Rats.

Difficult healing of diabetic foot ulcers is associated with overexpression of matrix metalloproteinase 9 (MMP-9) in the local wound. Therefore, strategies aimed at downregulation of MMP-9 levels in ulcer sites may promote tissue regeneration and accelerate healing of diabetic foot ulcers (DFU). To fulfill this aim, we exploited dextran conjugated with poly(amidoamine) (Dextran-PAMAM) as a gene carrier to deliver MMP-9 targeted siRNA (siMMP-9). The prepared complexes could be efficiently endocytosed with low cytotoxicity to HaCat cells. Dextran-PAMAM could efficiently deliver siMMP-9 and significantly inhibit MMP-9 expression in vitro. Diabetic rats wound models showed that topical application of the Dextran-PAMAM/siMMP-9 complex effectively knocked down MMP-9 expression in skin wound tissue, thus accelerating wound healing. Taken together, this study demonstrates that the Dextran-PAMAM/siMMP-9 complex possesses high potential for wound healing and could serve as a promising regenerative platform for improving DFU healing.

Astaxanthin Inhibits Matrix Metalloproteinase Expression by Suppressing PI3K/AKT/mTOR Activation in Helicobacter pylori-Infected Gastric Epithelial Cells.

Helicobacter pylori (H. pylori) increases production of reactive oxygen species (ROS) and activates signaling pathways associated with gastric cell invasion, which are mediated by matrix metalloproteinases (MMPs). We previously demonstrated that H. pylori activated mitogen-activated protein kinase (MAPK) and increased expression of MMP-10 in gastric epithelial cells. MMPs degrade the extracellular matrix, enhancing tumor invasion and cancer progression. The signaling pathway of phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is associated with MMP expression. ROS activates PIK3/AKT/mTOR signaling in cancer. Astaxanthin, a xanthophyll carotenoid, shows antioxidant activity by reducing ROS levels in gastric epithelial cells infected with H. pylori. This study aimed to determine whether astaxanthin inhibits MMP expression, cell invasion, and migration by reducing the PI3K/AKT/mTOR signaling in H. pylori-infected gastric epithelial AGS cells. H. pylori induced PIK3/AKT/mTOR and NF-κB activation, decreased IκBα, and induced MMP (MMP-7 and -10) expression, the invasive phenotype, and migration in AGS cells. Astaxanthin suppressed these H. pylori-induced alterations in AGS cells. Specific inhibitors of PI3K, AKT, and mTOR reversed the H. pylori-stimulated NF-κB activation and decreased IκBα levels in the cells. In conclusion, astaxanthin suppressed MMP expression, cell invasion, and migration via inhibition of PI3K/AKT/mTOR/NF-κB signaling in H. pylori-stimulated gastric epithelial AGS cells.

Reversal mechanism of hepatic fibrosis

There is an increasing histological clinical evidence that both hepatic fibrosis and some degree of cirrhosis reversal can improve prognosis. Hepatic fibrosis involves a variety of cells and steps, and its reversal mechanism is also very complex, mainly including the reduction of hepatocyte necrosis and regeneration, the apoptosis and inactivation of activated hepatic stellate cells, and the reversal of hepatic sinusoidal endothelial cells and microvessels, restorative hepatic macrophages polarization and cell-to-cell interactions. Furthermore, the biochemical basis for reversal of hepatic fibrosis is decreased expression of matrix metalloproteinase inhibitors, up-regulation of matrix metalloproteinase activity, and increased degradation of extracellular matrix. However, at present, there are few studies on the clinicopathological mechanism of liver fibrosis reversal, and the key target groups of different etiologies with different degrees are still unclear, and the corresponding translational application research is lacking. Therefore, an in-depth and systematic understanding of the characteristics and mechanisms of hepatic fibrosis reversal can not only enrich the understanding of the natural history of hepatic fibrosis and cirrhosis, but also provide reference for the development and clinical application of anti-hepatic fibrotic drugs.

Pre-Ischemic Oxytocin Treatment Alleviated Neuronal Injury via Suppressing NF-κB, MMP-9, and Apoptosis Regulator Proteins in A Mice Model of Stroke.

ObjectivesThis study was designed to determine the effects of pre-ischemic administration of oxytocin (OXT) on neuronal injury and possible molecular mechanisms in a mice model of stroke.Materials and Methods In this experimental study, stroke was induced in the mice by middle cerebral artery occlusion (MCAO) for 60 minutes and 24 hours of reperfusion. OXT was given as intranasal daily for 7 consecutive days before ischemic stroke. Neuronal damage, spatial memory, and the expression levels of nuclear factor-kappa B (NF-κB), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF) and apoptosis were assessed 24 hours after stroke. Results Pre-ischemic treatment with OXT significantly reduced the infarct size (P<0.01); but did not recover the neurological and spatial memory dysfunction (P>0.05). Moreover, OXT treatment considerably decreased the expressions of NF-κB, TNF-α, IL-1β, and MMP-9 (P<0.001) and enhanced the level of BDNF protein. OXT treatment also significantly downregulated Bax expression and overexpressed Bcl-2 proteins. ConclusionThe finding of this study indicated that administration of OXT before ischemia could limit brain injury by inhibiting MMP-9 expression, apoptosis, inflammatory signaling pathways, and an increase in the BDNF protein level. We suggested that OXT may be potentially useful in the prevention and/or reducing the risk of the cerebral stroke attack, and could be offered as a new prevention option in the clinics.

Irisin improves BBB dysfunction in SAP rats by inhibiting MMP-9 via the ERK/NF-κB signaling pathway

BackgroundBlood–brain barrier (BBB) damage may lead to life-threatening pancreatic encephalopathy in patients with serious acute pancreatitis (SAP). Irisin alleviates BBB injury caused by cerebral ischemia–reperfusion by repressing matrix metalloproteinase-9 (MMP-9) expression. Serum levels of irisin are decreased in SAP patients. However, the role of irisin in BBB injury in SAP is still unknown. This study aimed to investigate whether irisin protects the BBB in SAP by affecting MMP-9 and its underlying regulatory mechanism. MethodsAn SAP model was established. Pancreatic injury was examined 24 h after SAP induction. Serum amylase and tumor necrosis factor-α (TNF-α) levels were examined by enzyme-linked immunosorbent assay (ELISA), and the brain water content was measured by the wet/dry proportion method. The structure and permeability of the BBB were examined by transmission electron microscopy, Evans blue exudation and transendothelial electrical resistance (TEER). ResultsIn the brains of SAP rats, MMP-9 expression was increased, which was associated with damage to the BBB and the brain. Irisin inhibited this increase in MMP-9 and reduced brain edema and BBB permeability. The ERK/NF-κB axis is involved in irisin -mediated regulation of MMP-9. Irisin inhibited not only MMP-9 expression but also ERK/NF-κB phosphorylation. Furthermore, inhibiting ERK and NF-κB decreased MMP-9 levels and improved BBB dysfunction in SAP in vivo and in vitro. Moreover, irisin prevented the degradation of tight junctions (ZO-1, Claudin-5). The inhibition of ERK and NF-κB had similar effects on ZO-1 and Claudin-5 expression. ConclusionIrisin protects tight junctions and alleviates BBB dysfunction in SAP by inhibiting MMP-9 expression and regulates MMP-9 expression through ERK/NF-κB phosphorylation.

Saikosaponin-d Alleviates Renal Inflammation and Cell Apoptosis in a Mouse Model of Sepsis via TCF7/FOSL1/Matrix Metalloproteinase 9 Inhibition.

Evidence exists reporting that saikosaponin-d (Sa) can prevent experimental sepsis, and this study aims to illustrate the molecular events underlying its renoprotective effects on lipopolysaccharide (LPS)-induced renal inflammation simulating sepsis. Through network pharmacology analysis and bioinformatics analysis, we identified that Sa may influence sepsis development by mediating TCF7. Dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays were used to explore the interactions between TCF7, FOSL1, and matrix metalloproteinase 9 (MMP9). The experimental data suggest that Sa attenuated LPS-induced renal injury, as evidenced by the reduced production of proinflammatory cytokines as well as cell apoptosis in the renal tissues of LPS-induced mice. Mechanically, Sa inhibited FOSL1 by inhibiting TCF7, which reduced the expression of inflammatory factors in renal cells. TCF7 activated the FOSL1 expression and consequently promoted the expression of MMP9. Also, Sa reduced cell apoptosis and the expression of inflammatory factors by inhibiting the TCF7/FOSL1/MMP9 axis in vivo. In conclusion, Sa suppresses FOSL1 transcription by downregulating TCF7, thereby inhibiting MMP9 expression and ultimately reducing the renal inflammation and cell apoptosis induced by sepsis.

Triptolide inhibits matrix metalloproteinase-9 expression and invasion of breast cancer cells through the inhibition of NF-κB and AP-1 signaling pathways.

Triptolide is a diterpenoid epoxide that is endogenously produced by the thunder god vine, Tripterygium wilfordii Hook F. Triptolide has demonstrated a variety of biological activities, including anticancer activities, in previous studies. Invasion and metastasis are the leading causes of mortality for patients with breast cancer, and the increased expression of matrix metalloproteinase-9 (MMP-9) has been shown to be associated with breast cancer invasion. Therefore, the aim of the present study was to investigate the effect of triptolide on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced cell invasion and MMP-9 expression in breast cancer cells. The expression of signal molecules was examined by western blotting, zymography and quantitative polymerase chain reaction; an electrophoretic mobility gel shift assay was also used, and cell invasiveness was measured by an in vitro Matrigel invasion assay. The MCF-7 human breast cancer cell line was treated with triptolide at the highest concentrations at which no marked cytotoxicity was evident. The results demonstrated that triptolide decreased the expression of MMP-9 through inhibition of the TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK) and the downregulation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity. In addition, a Transwell assay revealed that triptolide reduced the ability of MCF-7 cells to invade Matrigel. These data demonstrate that the anti-invasive effect of triptolide is associated with the inhibition of ERK signaling and NF-κB and AP-1 activation, and suggest that triptolide may be a promising drug for breast cancer.

Lentinula edodes extract inhibits matrix metalloproteinase expression and increases type I procollagen expression via the p38 MAPK/c-Fos signaling pathway in ultraviolet A and B-irradiated HaCaT keratinocytes

Objective: To determine the effect of Lentinula edodes extract on ultraviolet (UV) A and UVB-induced changes in matrix metalloproteinase (MMP) and type I procollagen expression using human immortalized HaCaT keratinocytes. Methods: Lentinula edodes ethanol extract (LEE) was obtained by extraction with 80% ethanol for 4 h at 80 °C. Effect of LEE on UV-induced alteration on the expression and production of MMPs and type I procollagen in keratinocytes was investigated using ELISA, RT-PCR, and Western blotting assay. To determine the underlying mechanism of LEE-mediated effects, mitogen-activated protein kinase (MAPK) and activator protein 1 signaling pathways were analysed by Western blotting assay. Results: LEE significantly inhibited the expression of MMP-1 and MMP-9 and increased the expression of type I procollagen in UVA and UVB-irradiated HaCaT keratinocytes. The phosphorylation levels of p38 were significantly inhibited by LEE whereas it did not affect c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation. Suppression of p38 phosphorylation was also accompanied by downregulation of UVA and UVB-induced increase in c-Fos. Conclusions: LEE effectively inhibits the expression of MMP-1 and MMP-9 and increases type I procollagen production through the p38 MAPK/c-Fos signaling pathway in UVA and UVB-irradiated HaCaT keratinocytes. This findings suggest that Lentinula edodes may be developed as a cosmetic material to suppress UV exposuremediated skin aging.

MiR-100 alleviates the inflammatory damage and apoptosis of H2O2-induced human umbilical vein endothelial cells via inactivation of Notch signaling by targeting MMP9.

Thromboangiitis obliterans is a nonatherosclerotic segmental inflammatory disease, and miR-100 plays an anti-inflammatory role in chronic inflammation. Therefore, we hypothesized that miR-100 might alleviate the inflammatory damage and apoptosis of H2O2-induced ECV304 cells and aimed to investigate the relationship between miR-100 and thromboangiitis obliterans and the related molecular mechanism. Cell counting kit-8 was used to detect cell viability, and the expression of inflammatory factors and oxidative stress was measured by ELISA. TUNEL assay was used to detect the apoptosis of human umbilical vein endothelial cells after induction by H2O2. Furthermore, the interaction between miR-100 and matrix metalloproteinase-9 was verified by dual-luciferase assay. Quantitative reverse transcription polymerase chain reaction and western blot were used to detect the expression of the adhesion factors, apoptosis-related proteins and Notch pathway-related protein. The results revealed that miR-100 was decreased in H2O2-induced human umbilical vein endothelial cells. Overexpression of miR-100 attenuated inflammatory response and cell apoptosis in H2O2-induced human umbilical vein endothelial cells. The overexpression of miR-100 inhibited matrix metalloproteinase-9 expression in H2O2-induced human umbilical vein endothelial cells. miR-100 inhibited H2O2-induced human umbilical vein endothelial cell inflammation, oxidative stress, and cell apoptosis via inactivation of Notch signaling by targeting matrix metalloproteinase. Our study demonstrated that miR-100 reduced the inflammatory damage and apoptosis of H2O2-induced human umbilical vein endothelial cells via inactivation of Notch signaling by targeting matrix metalloproteinase. These findings suggested that miR-100 might be a novel therapeutic target for the prevention of thromboangiitis obliterans.

Nuclear factor-κB plays an important role in Tamarixetin-mediated inhibition of matrix metalloproteinase-9 expression

Flavonoids possess a broad spectrum of pharmacological properties, including anti-cancer, anti-oxidant and immunomodulatory activities. The current study explored the potential of some less-studied flavonoids in inhibiting Matrix Metalloproteinase-9 (MMP-9), a prominent biomarker, upregulated in a variety of cancers and known to promote migration and invasion of cancer cells. Amongst these, Tamarixetin, a naturally occurring flavonoid derivative of Quercetin, demonstrated significant dose-dependent inhibition of MMP-9 expression. Furthermore, a substantial inhibition of migration, invasion and clonogenic potential of HT1080 cells was also observed in the presence of Tamarixetin, which further suggests its role as a potential anti-cancer agent. It is noteworthy that Tamarixetin inhibits nuclear translocation as well the activity of nuclear factor kappa B (NFκB), both of which are functions essential for the activation of MMP-9 in promoting tumorigenesis. Additionally, the endogenous regulators of MMP-9 that tightly control its activity were also modulated by Tamarixetin, as evident from the 1.9 fold increase in the expression of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), with a concomitant 2.2 fold decrease in Matrix Metalloproteinase-14 (MMP-14) expression. The results obtained were further corroborated in three dimensional (3D) tumor models, which showed significant inhibition of MMP-9 activity as well as reduced invasive potential in the presence of Tamarixetin. Taken together, our observations demonstrate for the first time, the anti-invasive potential of Tamarixetin in cancer cells, indicating its possible use as a template for novel therapeutic applications.

Interleukin-17A Expression Correlated with the Prognosis of Chronic Rhinosinusitis with Nasal Polyps and the Anti-Interleukin-17A Effect in a Murine Nasal Polyps Model

Objective: To investigate the expression of interleukin-17A (IL-17A) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and to analyze its effect on prognosis and to explore the role and mechanism of anti-IL-17A effect in vivo by establishing a murine nasal polyps (NP) model. Methods: Patients with CRSwNP who underwent endoscopic sinus surgery and matched control subjects were collected. We investigated IL-17A expression in human NP tissues using immunohistochemistry and analyzed their clinical features, including Lund-Mackay computed tomography scoring (LMCS) before surgery, Lund-Kennedy endoscopic scoring (LKES) before surgery (LKES B), LKES 6 months after surgery (LKES A), and reduction of LKES (LKES R). Then, after establishing the murine NP model to detect the expression and correlation of IL-17A and matrix metalloproteinase-9 (MMP-9) in nasal tissue, we studied nasal lavage fluid and serum by PCR and enzyme-linked immunosorbent assay in vivo. Anti-IL-17A treatment was administered in the murine NP model to confirm the function of IL-17A during the pathogenic processes. Results: IL-17A expression was upregulated in NP tissues from patients with CRSwNP compared with control subjects (p < 0.001). The number of IL-17A⁺ cells was significantly negatively correlated with LKES R in patients with CRSwNP (p < 0.01). However, there was no significant correlation between IL-17A and LMCS or LKES B (all p < 0.05). Further, IL-17A and MMP-9 were more abundant in nasal mucosa of the murine NP model compared with that of control mice (all p < 0.05), and severe polypoid lesions were apparently observed in murine NP models. Anti-IL-17A treatment downregulated the mRNA and protein expression of MMP-9 in nasal mucosa and reduced the number of polypoid lesions in the murine NP model (all p < 0.05). Conclusion: Our results suggest that IL-17A plays a crucial role and may affect the prognosis of CRSwNP. Anti-IL-17A treatment may reduce the formation of polypoid lesions through inhibition of MMP-9 expression.

Therapeutic effects of mangiferin on sepsis-associated acute lung and kidney injuries via the downregulation of vascular permeability and protection of inflammatory and oxidative damages

BackgroundSepsis is a serious systemic inflammatory response that primarily affects the lungs and kidneys. Moreover, a few drugs can effectively treat this disease. Mangiferin (MF) is a xanthone glucoside that possesses many pharmacological effects. This study aims to assess the effects of MF on capillary endothelial permeability and inflammatory responses and oxidative damages in mice with sepsis-associated lung and kidney injuries. MethodsMice were randomly divided into the control, lipopolysaccharide (LPS), and MF+LPS (20, 50, and 100 mg/kg) groups (n = 8). Mice in the MF+LPS group were treated with MF via oral administration once a day for 7 days before injection of LPS. Mice in the LPS and MF+LPS groups were treated with LPS (1 mg/kg body weight, tail vein injection) to establish a sepsis model. Six hours after LPS administration, lung, kidney, blood, and urine samples were further analyzed. ResultsPathological results revealed that MF reduced the pathological injuries of the lung and kidney in LPS-induced sepsis. Immunofluorescence and ELISA results showed that MF reduced the permeability of capillary to albumin of the lung and kidney in LPS-induced sepsis. Further analysis indicated that the protective effects of MF on the permeability of capillary to albumin was associated with the upregulation of occludin expression and protection of syndecan-1 (SDC-1) damage. MF was also involved in the inhibition of matrix metalloproteinase-9 expression, which is an SDC-1-degrading factor. MF might relieve oxidative damages by inhibiting the production of reactive oxygen species and malondialdehyde, and boosting the superoxide dismutase activity to increase the total antioxidant capacity of the lung and kidney in LPS-induced sepsis. Western blot analysis results further revealed that MF can inhibit the activation of NF-κB and high-mobility group box 1 inflammatory signaling of the lung and kidney in LPS-induced sepsis. ConclusionsThe downregulation of vascular permeability and protection of inflammatory and oxidative damages by MF may be used as treatment targets for sepsis-associated acute lung and kidney injuries.

Dioscorea nipponica Makino suppresses TPA-induced migration and invasion through inhibition of matrix metalloproteinase-9 in human cervical cancer cells.

Dioscorea nipponica Makino has been used for the treatment of chronic bronchitis, rheumatoid arthritis, cough, and asthma. Several studies have established the antitumor effect of D. nipponica Makino extract (DNE). However, no investigations have considered the antimetastatic potential of DNE in cervical cancer cells. The present study examined the effects of DNE on cervical cancer cells treated with 12-O-tetradecanoylphorbol-13-acetate and characterized the possible molecular mechanisms. MTT assay results indicated that DNE exhibited very low cytotoxicity, and DNE significantly reduced the invasion and migration abilities of cervical cancer cells. Gelatin zymography analysis revealed that DNE significantly inhibited matrix metalloproteinase-9 (MMP-9) activity. Reverse transcription-polymerase chain reaction assay results revealed that DNE treatment inhibited the MMP-9 mRNA levels of HeLa and SiHa cells. Western blot results revealed that DNE significantly diminished the ERK1/2 phosphorylation. In conclusion, we revealed that the antimetastatic effects of DNE on cervical cancer cells are due to its inhibition of MMP-9 expression through the ERK1/2 pathway.

Total phenolic extract of Euscaphis konishii hayata Pericarp attenuates carbon tetrachloride (CCl4)-induced liver fibrosis in mice

Liver fibrosis is a crucial pathological process involved in the hepatogenic morbidity and mortality. The pericarp of Euscaphis konishii Hayata is usually used in the cooking soup to improve liver function in Southern China, and high level of phenolic compounds has been found in the E. konishii pericarp. The total phenolic compounds extracted from E. konishii pericarp (TPEP) was obtained by polyamide column chromatograph, and 9 phenolic compounds of TPEP were identified through LC/MS and NMR. TPEP exhibited strong free radicals scavenging activity in vitro, and the chronic CCl4-induced liver fibrosis mice were established to elucidate the hepatoprotective mechanism of TPEP in vivo. TPEP treatment (50, 100 and 200 mg/kg) ameliorated the oxidative stress, immune dysfunction, inflammatory response and hepatic fibrosis induced by CCl4 introduction, alleviated the histopathological alteration and hepatocyte apoptosis in the liver tissue. Pretreatment with TPEP suppressed the activation of NADPH oxidase (NOX) signaling to attenuate oxidative stress in the liver tissue. TPEP administration inhibited the translocation of NF-κB into the nucleus to prevent the expression of downstream proinflammatory cytokines. TPEP treatment downregulated the activation of TGF-β/Smad pathway, and facilitated the degradation of extracellular matrix through enhancing matrix metalloproteinases (MMPs) activity and decreasing the expression of matrix metalloproteinase inhibitors (TIMPs). In conclusion, TPEP inhibited CCl4-induced hepatic fibrosis through its antioxidant, anti-inflammatory and anti-fibrotic activities.

Naturally-occurring bacterial cellulose-hyperbranched cationic polysaccharide derivative/MMP-9 siRNA composite dressing for wound healing enhancement in diabetic rats

The anomalous high expression of matrix metalloproteinase 9 (MMP-9) is one important factor that impedes diabetic wound healing. Therefore, inhibition of MMP-9 expression in a diabetic wound could be a feasible method to promote wound healing. In this study, we studied the possibility of self-therapy using wound dressings that contain bacterial cellulose-hyperbranched cationic polysaccharide (BC-HCP) derivatives that encapsulate siRNA (BC-HCP/siMMP-9) and have controlled release properties. Herein, we used four HCPs (Gly-DMAPA, Gly-D4, Amyp-DMAPA, Amyp-D4) as gene carriers. Our results showed that all HCP derivatives were minimally toxic to cells in vitro, while the cationic properties of HCP could be used as a complexation agent for MMP-9 siRNA (siMMP-9). Upon exposure to bacterial cellulose (BC), the BC slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein levels of MMP-9 in a human immortalized epithelial cell line (HaCAT) and in diabetic rat wounds. Inhibition of MMP-9 in the wounds of diabetic rats resulted in a significant enhancement of wound healing, suggesting that the BC-HCP/siMMP-9 composite dressing could be used as a safe and effective dressing to promote wound healing in diabetic rats. STATEMENT OF SIGNIFICANCE: In this work, we evaluated the possibility of using bacterial cellulose-hyperbranched cationic polysaccharide derivatives (BC-HCP) as a self-therapeutic wound dressing with siRNA encapsulated and controlled release properties. Our results showed that the BC-HCP/siMMP-9 composite dressing slowly released HCP/siMMP-9. The released siMMP-9 effectively reduced the gene expression and protein level of MMP-9 in human immortalized epithelial cell line and in the wound of diabetic rats. The BC-HCP/siMMP-9 composite dressing promoted diabetic wound healing by the unique nanostructure of BC and by releasing siMMP-9 for specific MMP-9 inhibition. Therefore, it could be used as a safe and effective dressing to promote wound healing in diabetic rats. This is the first evidence on the study of using BC as a dressing composite by encapsulating HCP/siRNA complexes for efficient RNAi gene silencing for better wound healing in diabetic rats.

Simvastatin Attenuates Hippocampal MMP-9 Expression in the Streptozotocin-Induced Cognitive Impairment

Background:Matrix metalloproteinase-9 (MMP-9) expression has been implicated in molecular mechanisms of neurodegenerative disorders, and its abnormal level has been reported in Alzheimer’s disease (AD). Some protective mechanisms of statins against neurodegeneration might be mediated by the inhibition of MMP-9 expression. Here, we investigated the effect of simvastatin on the hippocampal MMP-9 expression in the context of AD.Methods:We examined the influence of three-week simvastatin (5 mg/kg) administration on hippocampal MMP-9 expression in a rat model of cognitive decline induced by streptozotocin (STZ). Spatial long-term memory and MMP-9 expression were assessed by Morris water maze (MWM) test and quantitative polymerase chain reaction, respectively.Results:The results showed a decline in the learning and memory in STZ group when compared with the control group. The MMP-9 up-regulated (1.41 ± 0.2 vs. 0.980 ± 0.02, p < 0.05), and cresyl violet staining showed hippocampal cell damage in STZ group compared with the control group. Simvastatin prevented the up-regulation of MMP-9 (1.05 ± 0.05 vs. 1.41 ± 0.2, p < 0.05), improved spatial memory impairment and attenuated hippocampal cell damage. Furthermore, we found a negative correlation (r = 0.77) between MMP-9 expression and cognitive function.Conclusion:Our findings suggest that the neuroprotective influence of simvastatin in battle to cognitive impairment is mediated in part by the modulation of MMP-9 expression. The reduction of MMP-9 expression in simvastatin-treated animals is in correlation with the improvement of cognitive functions. Understanding the protective mechanism of simvastatin will shed light on more efficient therapeutic modalities in AD.

Simvastatin Attenuates Hippocampal MMP-9 Expression in the Streptozotocin-Induced Cognitive Impairment

Matrix metalloproteinase-9 (MMP-9) expression has been implicated in molecular mechanisms of neurodegenerative disorders, and its abnormal level has been reported in Alzheimer’s disease (AD). Some protective mechanisms of statins against neurodegeneration might be mediated by the inhibition of MMP-9 expression. Here, we investigated the effect of simvastatin on the hippocampal MMP-9 expression in the context of AD. We examined the influence of three-week simvastatin (5 mg/kg) administration on hippocampal MMP-9 expression in a rat model of cognitive decline induced by streptozotocin (STZ). Spatial long-term memory and MMP-9 expression were assessed by Morris water maze (MWM) test and quantitative polymerase chain reaction, respectively. The results showed a decline in the learning and memory in STZ group when compared with the control group. The MMP-9 up-regulated (1.41 ± 0.2 vs. 0.980 ± 0.02, p < 0.05), and cresyl violet staining showed hippocampal cell damage in STZ group compared with the control group. Simvastatin prevented the up-regulation of MMP-9 (1.05 ± 0.05 vs. 1.41 ± 0.2, p < 0.05), improved spatial memory impairment and attenuated hippocampal cell damage. Furthermore, we found a negative correlation (r = 0.77) between MMP-9 expression and cognitive function. Our findings suggest that the neuroprotective influence of simvastatin in battle to cognitive impairment is mediated in part by the modulation of MMP-9 expression. The reduction of MMP-9 expression in simvastatin-treated animals is in correlation with the improvement of cognitive functions. Understanding the protective mechanism of simvastatin will shed light on more efficient therapeutic modalities in AD.