Matrix Metalloproteinase Gene Expression Research Articles

MicroRNA-140-3p modulates invasiveness, motility, and extracellular matrix adhesion of breast cancer cells by targeting syndecan-4.

Syndecan-4, a predicted target of the microRNA miR-140-3p, plays an important role in multiple steps of tumor progression and is the second most abundant heparan sulfate proteoglycan produced by breast carcinoma cell lines. To investigate the potential functional relationship of miR-140-3p and syndecan-4, MDA-MB-231, SKBR3, and MCF-7 breast cancer (BC) cells were transiently transfected with pre-miR-140-3p, syndecan-4 small interfering RNAJ, or control reagents, respectively. Altered cell behavior was monitored by adhesion, migration, and invasion chamber assays. Moreover, the prognostic value of syndecan-4 was assessed by Kaplan-Maier Plotter analysis of gene expression data from tumor samples of 4929 patients. High expression of syndecan-4 was associated with better relapse-free survival in the whole collective of BC patients, but correlated with a worse survival in the subgroup of estrogen receptor negative and estrogen/progesterone-receptor negative patients. miR-140-3p expression was associated with improved survival irrespective of hormone receptor status. miR-140-3p overexpression induced posttranscriptional downregulation of syndecan-4, as demonstrated by quantitative real-time PCR (qPCR), flow cytometry, and luciferase assays, resulting in decreased BC cell migration and matrigel invasiveness. Furthermore, miR-140-3p overexpression and syndecan-4 silencing increased the adhesion of BC to fibronectin and laminin. qPCR analysis demonstrated that syndecan-4 silencing leads to altered gene expression of adhesion-related molecules, such as fibronectin and focal adhesion kinase, as well as in the gene expression of the proinvasive factors matrix metalloproteinase 2 and heparanase (also known as HPSE). We conclude that syndecan-4 is a novel target of miR-140-3p that regulates BC cell invasiveness and cell-matrix interactions in the tumor microenvironment.

Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis

Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA. We used SphK1LysMCre and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1LysMCre mice or wild type mice treated with S1P2 receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry. The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P2 signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1LysMCre mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation. Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA.

Cionin, a vertebrate cholecystokinin/gastrin homolog, induces ovulation in the ascidian Ciona intestinalis type A

Cionin is a homolog of vertebrate cholecystokinin/gastrin that has been identified in the ascidian Ciona intestinalis type A. The phylogenetic position of ascidians as the closest living relatives of vertebrates suggests that cionin can provide clues to the evolution of endocrine/neuroendocrine systems throughout chordates. Here, we show the biological role of cionin in the regulation of ovulation. In situ hybridization demonstrated that the mRNA of the cionin receptor, Cior2, was expressed specifically in the inner follicular cells of pre-ovulatory follicles in the Ciona ovary. Cionin was found to significantly stimulate ovulation after 24-h incubation. Transcriptome and subsequent Real-time PCR analyses confirmed that the expression levels of receptor tyrosine kinase (RTK) signaling genes and a matrix metalloproteinase (MMP) gene were significantly elevated in the cionin-treated follicles. Of particular interest is that an RTK inhibitor and MMP inhibitor markedly suppressed the stimulatory effect of cionin on ovulation. Furthermore, inhibition of RTK signaling reduced the MMP gene expression in the cionin-treated follicles. These results provide evidence that cionin induces ovulation by stimulating MMP gene expression via the RTK signaling pathway. This is the first report on the endogenous roles of cionin and the induction of ovulation by cholecystokinin/gastrin family peptides in an organism.

(Carboxymethyl-stevioside)-coated magnetic dots for enhanced magnetic hyperthermia and improved glioblastoma treatment

The use of different types of biomaterials as surfactant moities has a defined role in magnetic hyperthermia-mediated cancer therapy (MHCT). In this work, we present carboxymethyl-stevioside (CMS)-modified magnetic dots (MDs) as efficient magnetic hyperthermia agents for glioma therapy. The synthesized MDs with CMS biosurfactant coating exhibited significant water stability that resulted in a remarkable specific absorption rate of 209.25 W/g on application of alternating magnetic field of strength 359 kHz and 188 Oe. The MDs further demonstrated significant anti-migratory and anti-invasive effect on glioma C6 cells by inhibiting the gene expression of matrix metalloproteinases-2 and -9. The effect of immediate and long term hyperthermia treatment was then evaluated after repetitive exposure to hyperthermia, in terms of glioma cell viability, the effect of treatment on cell morphology, the cell cycle distribution and oxidative stress generation. The results obtained suggest the promising potential of CMS-modified nano-heaters for excellent magnetic hyperthermia-mediated glioma therapy.

The Emerging Role of Epigenetic Mechanisms in the Causation of Aberrant MMP Activity during Human Pathologies and the Use of Medicinal Drugs.

Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.

Changes in gene expression of cervical collagens, metalloproteinases, and tissue inhibitors of metalloproteinases after partial cervical excision-induced preterm labor in mice.

We investigated changes in gene expression of cervical collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) during pre-gestational uterine cervical excision and/or inflammation-induced preterm labor in mice. Forty sexually mature female mice were uniformly divided into four groups: sham, cervical excision, lipopolysaccharide (LPS) injection, and cervical excision plus LPS injection. Partial cervical tissue excision was performed at five weeks of age before mating. LPS was injected into the lower right uterine horn near the cervix on gestational day 16. Mice were sacrificed immediately postpartum. Uterine cervices were collected and subjected to quantitative real-time PCR. Col4α1 and Col5α1 expression increased significantly in the cervical excision plus LPS injection group compared to the sham group (p < 0.01 and p = 0.024, respectively). MMP-14 expression levels increased in the cervical excision plus LPS injection group compared to the sham group (p < 0.01). TIMP-1 expression was not significantly decreased in this group. Increased expression levels of Col4α1, Col5α1, and MMP-14 were associated with cervical excision plus inflammation-induced preterm labor. Thus, pre-gestational cervical remodeling through specific collagen metabolism and MMP activation may involve the pathogenesis of spontaneous preterm labor.

Curcumin and cancer biology: Focusing regulatory effects in different signalling pathways.

Cancer is the second-leading cause of death worldwide. Till date, many such effective treatments are available, for example chemotherapy, surgery, and radiation therapy, but there are severe associated side effects, such as increased infection risk, constipation, hair loss, anaemia, among others. Thus, the need for effective therapeutic strategies and screening methodology arises. Researchers around the world are increasingly trying to discover anticancer therapies with as few side effects as possible and many are now focusing on phytochemicals, like curcumin. Curcumin is a bright yellow substance isolated from the plant rhizomes of Curcuma longa L. To this molecule a high therapeutic benefit has been underlined, being able to alter the development of cancer by different mechanisms, such as regulating multiple microRNA expression, modifying a series of signalling pathways, that is, Akt, Bcl-2, PTEN, p53, Notch, and Erbb. Another major pathway that curcumin targets is the matrix metalloproteinase (MMP) gene expression. In fact, MMPs are responsible for the degradation of the cell-extracellular matrix, which can lead to the diseased condition and many different pathways contribute to its activity, such as JAK/STAT, NF-κB, MAPK/ERK, COX-2, ROS, TGF-β, among others. In this review, we have attempted to describe the curcumin regulatory effect on different cell signalling pathways involved in the progression of different types of cancers.

The effects of resveratrol on the expression of VEGF, TGF-\u03b2, and MMP-9 in endometrial stromal cells of women with endometriosis

Resveratrol is a phytochemical with anti-angiogenic, anti-inflammatory, and antioxidant properties. The present study has evaluated the effect of resveratrol on the expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and matrix metalloproteinase-9 (MMP-9) as factors related to endometriosis progression. Thirteen eutopic (EuESCs) and 8 ectopic (EESCs) endometrial stromal cells from women with endometriosis and 11 control endometrial stromal cells (CESCs) were treated with resveratrol (100 µM) for 6, 24 and 48 h. The gene and protein expression levels of VEGF, TGF-β, and MMP-9 were measured using real-time PCR and ELISA methods, respectively. Results showed that the basal gene and protein expression of VEGF and MMP-9 were higher in EESCs compared to EuESCs and CESCs (P < 0.01 to < 0.001 and P < 0.05 to < 0.01 respectively). Also, resveratrol treatment decreased the gene and protein expression of VEGF and MMP-9 in EuESCs, EESCs and CESCs (P < 0.05 to < 0.01 and P < 0.05 to < 0.01 respectively) and gene and protein expression of TGF-β in EESCs and EuESCs (P < 0.05 to < 0.01). The effect of resveratrol in reduction of VEGF gene expression was statistically more noticeable in EESCs compared to EuESCs and CESCs (P < 0.05). According to the findings, resveratrol may ameliorate endometriosis progression through reducing the expression of VEGF, TGF-β, and MMP-9 in endometrial stromal cells (ESCs).

The Effect of Piperine on MMP-9, VEGF, and E-cadherin Expression in Breast Cancer MCF-7 Cell Line

Background: Vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and E-cadherin play a vital role in the behavior of angiogenesis, metastasis, and invasion of breast tumor cells. Piperine, the main component of Piper Nigrum, has shown anti-cancer properties in various malignancies. This Study investigates the potential effect of piperine on MMP-9, E-cadherin, and VEGF expression in breast cancer MCF-7 cell line. Methods: MTT assay was applied to assess the viability of MCF-7 cells. The mRNA levels of MMP-9, VEGF, and E-cadherin were assayed by qRT-PCR. Western blot was performed to identify the protein level of MMP-9. Results: MTT assay results showed that piperine treatment (5, 10, 25, 50, 75, and 100 μM) for 24 hours effectively inhibited cell viability of MCF-7 cells as compared with the control group. Furthermore, the gene expression of VEGF, MMP-9, and E-cadherin was dose-dependently suppressed by piperine treatment (5, 10 and 25 μM) (P&lt;0.05; P&lt;0.01). The results also indicated that piperine (5, 10, and 25 μM) significantly suppressed MMP-9 protein expression after 24 hours of piperine treatment (P&lt;0.01). Conclusion: These results suggest that piperine may prevent angiogenesis, migration, and invasion of MCF-7 cells by suppressing MMP-9 and VEGF, and by inducing E-cadherin expression. Hence, it may be a suitable candidate for designing new drugs in cancer therapy.

A novel gastroprotective effect of zeaxanthin against stress-induced gastritis in male rats targeting the expression of HIF-1α, TFF-1 and MMP-9 through PI3K/Akt/JNK signaling pathway

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 β (IL-1β) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.

ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor–activated cancer

Both gene repressor (Polycomb-dependent) and activator (Polycomb-independent) functions of the Polycomb protein enhancer of zeste homolog 2 (EZH2) are implicated in cancer progression. EZH2 protein can be phosphorylated at various residues, such as threonine 487 (T487), by CDK1 kinase, and such phosphorylation acts as a Polycomb repressive complex 2 (PRC2) suppression "code" to mediate the gene repressor-to-activator switch of EZH2 functions. Here we demonstrate that the histone reader protein ZMYND8 is overexpressed in human clear cell renal cell carcinoma (ccRCC). ZMYND8 binds to EZH2, and their interaction is largely enhanced by CDK1 phosphorylation of EZH2 at T487. ZMYND8 depletion not only enhances Polycomb-dependent function of EZH2 in hypoxia-exposed breast cancer cells or von Hippel-Lindau (VHL)-deficient ccRCC cells, but also suppresses the FOXM1 transcription program. We further show that ZMYND8 is required for EZH2-FOXM1 interaction and is important for FOXM1-dependent matrix metalloproteinase (MMP) gene expression and EZH2-mediated migration and invasion of VHL-deficient ccRCC cells. Our results identify a previously uncharacterized role of the chromatin reader ZMYND8 in recognizing the PRC2-inhibitory phosphorylation "code" essential for the Polycomb-dependent to -independent switch of EZH2 functions. They also reveal an oncogenic pathway driving cell migration and invasion in hypoxia-inducible factor-activated (hypoxia or VHL-deficient) cancer.

The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma.

Inhibition of the protein neddylation process by the small-molecule inhibitor MLN4924 has been recently indicated as a promising direction for cancer treatment. However, the knowledge of all biological consequences of MLN4924 for cancer cells is still incomplete. Here, we report that MLN4924 inhibits tumor necrosis factor-alpha (TNF-α)-induced matrix metalloproteinase 9 (MMP9)-driven cell migration. Using real-time polymerase chain reaction (PCR) and gelatin zymography, we found that MLN4924 inhibited expression and activity of MMP9 at the messenger RNA (mRNA) and protein levels in both resting cells and cells stimulated with TNF-α, and this inhibition was closely related to impaired cell migration. We also revealed that MLN4924, similar to TNF-α, induced phosphorylation of inhibitor of nuclear factor kappa B-alpha (IκB-α). However, contrary to TNF-α, MLN4924 did not induce IκB-α degradation in treated cells. In coimmunoprecipitation experiments, nuclear IκB-α which formed complexes with nuclear factor kappa B p65 subunit (NFκB/p65) was found to be highly phosphorylated at Ser32 in the cells treated with MLN4924, but not in the cells treated with TNF-α alone. Moreover, in the presence of MLN4924, nuclear NFκB/p65 complexes were found to be enriched in c-Jun and cyclin dependent kinase inhibitor 1 A (CDKN1A/p21) proteins. In these cells, NFκB/p65 was unable to bind to the MMP9 gene promoter, which was confirmed by the chromatin immunoprecipitation (ChIP) assay. Taken together, our findings identified MLN4924 as a suppressor of TNF-α-induced MMP9-driven cell migration in esophageal squamous cell carcinoma (ESCC), likely acting by affecting the nuclear ubiquitin–proteasome system that governs NFκB/p65 complex formation and its DNA binding activity in regard to the MMP9 promoter, suggesting that inhibition of neddylation might be a new therapeutic strategy to prevent invasion/metastasis in ESCC patients.

Periodontitis aggravates renal inflammatory response in a mouse model of renal fibrosis.

To assess the effects of periodontitis on renal interstitial fibrosis in a mouse model. Thirty C57BL/6 male mice were divided into control, periodontitis (PD), unilateral ureteral ligation (UUO) and PD+UUO groups. Unilateral ureteral ligation was performed 6days after periodontitis. After 2weeks, all mice were sacrificed, and samples were collected for the assessment of gene expression, immune cells, biochemical indicators and renal pathology. Expression of tumour necrosis factor-α, interleukin-1β, and Ly6G in the kidneys in the PD+UUO group was significantly greater than in the UUO group. The percentage of CD11b+ Ly6G+ cells was significantly higher in the PD+UUO than in the UUO group. Fibrotic areas in the kidneys in the PD+UUO group were slightly, but not significantly, greater than those in the UUO group. Kidneys from the PD+UUO group showed markedly higher gene expression of matrix metalloproteinase-9, but not α-smooth muscle actin or collagen I, than those in the UUO group. There were no significant differences in blood urea nitrogen, serum creatinine and uric acid between the PD+UUO and UUO groups. Periodontitis increases the renal inflammatory response without showing a significant influence on renal interstitial fibrosis or renal function in the UUO mouse model.

Isolated isoquercitrin from Green ball apple peel inhibits photoaging in CCD-986Sk fibroblasts cells via modulation of the MMPs signaling.

Ultraviolet B (UVB) irradiation is viewed as the main factor of skin aging, associated with acceleration of elastin, collagen degradation and expression of matrix metalloproteinases (MMPs). Apples are one of the most commonly eaten fruits in the world, and isoquercitrin is the main active ingredient in new bred varieties "Green ball" apple. Therefore, we are studying the functionality of the active ingredient of apple, a natural raw material that does not have toxicity or sensitivity problems. The aim of this study, we scrutinized the effects of isoquercitrin on skin photoaging in UVB-exposed human fibroblasts (CCD-986Sk). To investigate the inhibition effect on photoaging factor regulation, isolated isoquercitrin were treated with UVB, which induces photoaging-related factors in CCD-986Sk fibroblast cells. Pro-inflammatory factors were measured by ELISA, Western blotting and real-time PCR. Isoquercitrin exhibited antioxidant activity and UVB-induced generation of photoaging-related factor inhibition without showing any toxicity. Anti-photoaging effect for protein levels using Isoquercitin was competent, of both the combate MMP-1 and MMP-9. Also, effect of COL1A2 product significantly increase, from up regulating the TIMP-1 mediated pathway in CCD-986Sk cells via the inhibition of MMPs. Isoquercitrin also downregulated the mRNA gene expression of MMPs while upregulating type I procollagen, HAS2 by modulating TIMP-1 and TGF-β in UVB-irradiated CCD-986Sk cells. Collectively, our results show that isoquercitrin might be useful as a functional food while being a good candidate in the development of cosmetic products and medicines for the remedy of UVB-induced skin photoaging.

Myostatin Increases the Expression of Matrix Metalloproteinase Genes to Promote Preadipocytes Differentiation in Pigs

Myostatin (MSTN) resulted in reduced backfat thickness in MSTN-knockout (MSTN-KO) pigs, whereas the underlying mechanism remains elusive. In this study, RNA sequencing (RNA-seq) was used to screen differentially expressed genes (DEGs) in porcine fat tissues. We identified 285 DEGs, including 4 adipocyte differentiation-related genes (ADRGs). Matrix Metalloproteinase-2/7 (MMP-2/7), fibronectin (FN), and laminin (LN) were differentially expressed in MSTN-KO pigs compared with wild-type (WT) pigs. To investigate the molecular mechanism, we treated the preadipocytes with siRNA and recombinant MSTN protein. The results indicated that MSTN increased the expression of MMP-2/7/9 and promoted the preadipocyte differentiation. To further validate the effect of MSTN on MMP-2/7/9 expression, we treated MSTN-KO PK15 cells with recombinant MSTN protein and detected the expression of MMP-2/7/9. The data showed that MSTN increases the expression of MMP-2/7/9 in PK15. This study revealed MSTN promoted the preadipocyte differentiation and provided the basis for the mechanism of fatty deposition in pigs.

Epigallocatechin-3-Gallate Suppresses the Expression of TNF-α-Induced MMP-1 via MAPK/ERK Signaling Pathways in Human Dermal Fibroblasts.

Deeper wrinkles and loss of elasticity are one of the skin-aging symptoms. Collagen breakdown by matrix metalloproteinase-1 (MMP-1), which is induced by reactive oxygen species (ROS) and pro-inflammatory cytokines, has been known to be responsible for these skin-aging symptoms. Therefore, much attention has been paid to chemicals to suppress the MMP-1 activity. Epigallocatechin-3-gallate (EGCG), catechin rich in green tea, has been reported to show antioxidant and protect skin from various stimuli such as UV and chemicals. In this study, we evaluated the inhibitory effect of EGCG on MMP-1 gene expression and secretion in tumor necrosis factor-α (TNF-α)-treated human dermal fibroblast cells (Hs68 cells). Pre-treatment with EGCG (10 and 20 µM) suppressed TNF-α-induced MMP-1 expression and secretion. EGCG also reduced the phosphorylation of extracellular signal regulated kinase (ERK) significantly but not that of p38 activation and c-Jun N-terminal kinase (JNK). Besides, EGCG (10 and 20 µM) showed the inhibitory effect on mitogen-activated protein extracellular kinase (MEK) and Src phosphorylation which is reported to be upstream signal proteins of ERK signal pathway. Based on these results, EGCG might have potential activity to slow down the skin-aging through inhibition of collagen breakdown, which remains to be elucidated.

Light-emitting diode stimulates radiodermatitis recovery

ABSTRACTPurposeTo evaluate the effect of light-emitting diode (LED) in an experimental model of radiodermatitis.MethodsTen male Wistar rats weighing 200–250 g were analyzed. Radiation was delivered in a single dose (20 Gy with Strontium-90 dermatological plaques), two areas per animal. After 15 days, they were divided into two groups: control group (n = 5) and LED group (n = 5), which was treated during 21 days later (LED 660 nm, 10 min in alternate days). The endpoints were radiodermatitis scale, histological analysis HE, Picrius Sirius and the gene expression of interleukin-10 (IL-10) and matrix metalloproteinase-9 (MMP-9).ResultsThe LED group showed a higher number of dermal appendages (p = 0.04) and angiogenesis(p = 0.007), a tendency towards higher IL-10 (p = 0.06) and an increase in MMP-9 (p = 0.004) when compared to the control group.ConclusionsThis study suggested that the use of LED for radiodermatitis increased skin regeneration.

Enamel Matrix Derivative and TGF-Beta 1 Target Genes in Human Tongue Carcinoma Cells

Enamel matrix derivative (EMD) can enhance proliferation and migration of different oral cell lines, including malignant oral carcinoma cells, in vitro and in vivo. The composition of EMD is not known, but part of the effects have been postulated to be caused by transforming growth factor-beta-1 (TGF-beta 1). This study aimed to compare target genes of EMD and TGF-beta 1 on highly malignant oral carcinoma HSC-3 cells. Microarrays were used to examine differentially expressed genes in HSC-3 cells after 6h and 24h incubations with EMD (200 µg/ml) or TGF-beta 1 (10 ng/ml). Gene Ontology (GO) enrichment analysis of the regulated genes was also conducted. After 6h and 24h of EMD treatments 42 and 12 genes, respectively, were statistically significantly (P&lt;0.05) up- or down-regulated. However, as many as 393 and 346 genes were statistically significantly (P&lt;0.05) up- or down-regulated by TGF-beta 1. Among the most up-regulated genes by both of the study reagents were MMP-9 and -10. The expression of MMP-10 by EMD treated carcinoma cells was also verified in protein level. In conclusion, TGF-beta 1 regulates more and mostly different genes compared with EMD, but both regulate the expression of matrix metalloproteinase genes in oral carcinoma cells.

Cytokine and Gene Expression Profiling in Patients with HFE-Associated Hereditary Hemochromatosis according to Genetic Profile

Background: Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is characterized by downregulation of hepcidin synthesis, leading to increased intestinal iron absorption. Objectives: The objectives were to characterize and elucidate a possible association between gene expression profile, hepcidin levels, disease severity, and markers of inflammation in HFE-associated HH patients. Methods: Thirty-nine HFE-associated HH patients were recruited and assigned to 2 groups according to genetic profile: C282Y homozygotes in 1 group and patients with H63D, as homozygote or in combination with C282Y, in the other group. Eleven healthy first-time blood donors were recruited as controls. Gene expression was characterized from peripheral blood cells, and inflammatory cytokines and hepcidin-25 isoform were quantified in serum. Biochemical disease characteristics were recorded. Results: Elevated levels of interleukin 8 were observed in a significant higher proportion of patients than controls. In addition, compared to controls, gene expression of ζ-globin was significantly increased among C282Y homozygote patients, while gene expression of matrix metalloproteinase 8, and other neutrophil-secreted proteins, was significantly upregulated in patients with H63D. Conclusion: Different disease signatures may characterize HH patients according to their HFE genetic profile. Studies on larger populations, including analyses at protein level, are necessary to confirm these findings.

Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice

Despite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.