Targets Involved in Skin Aging and Photoaging and their Possible Inhibitors: A Mini-review.

BACKGROUND: Skin aging is a natural process resulting from intrinsic (hormonal and genetic) and extrinsic (environmental) factors. Photoaging occurs due to prolonged exposure of the skin to ultraviolet radiation, accounting for 80% of facial aging. INTRODUCTION: Characteristics of aging skin include reduced elasticity, the appearance of fine wrinkles, uneven tone, and dryness. Clinical signs of photoaging involve the presence of deeper wrinkles, rough texture, dyschromia and a greater loss of elasticity compared to chronological aging. METHODS: This work reported several scientific articles that used computational techniques, such as molecular docking, molecular dynamics and quantitative structure-activity relationship (QSAR) to identify natural products and their derivatives against skin aging and photoaging. RESULTS: The in silico analyses carried out by the researchers predicted the binding affinity and interactions of the natural products with the targets matrix metalloproteinase-1, matrix metalloproteinase- 3, matrix metalloproteinase-9 and tyrosinase. Furthermore, some studies have reported the stability of the protein-ligand complex and the physicochemical properties of the studied compounds. Finally, this research proposes promising molecules against the targets. CONCLUSION: Thus, studies like this one are relevant to guide new research related to skin aging and photoaging.

MicroRNA-18a-5p Suppresses Tumor Growth via Targeting Matrix Metalloproteinase-3 in Cisplatin-Resistant Ovarian Cancer.

Cumulating evidence indicates that dysregulation of microRNAs (miRNAs) plays a central role in the initiation, progression, and drug resistance of cancer cells. However, the specific miRNAs contributing to drug resistance in ovarian cancer cells have not been fully elucidated. Aimed to identify potential miRNAs involved in platinum resistance, we performed a miRNA expression profile in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells, and we found several differentially abundant miRNAs in the pair of cell lines. Notably, miR-18a-5p (miR-18a), a member of the oncogenic associated miR-17-92 cluster, was decreased in cisplatin-resistant as compared with cisplatin-sensitive cells. Real-time PCR analysis confirmed these findings. We then studied the biological, molecular, and therapeutic consequences of increasing the miR-18a levels with oligonucleotide microRNA mimics (OMM). Compared with a negative control OMM, transient transfection of a miR-18a-OMM reduced cell growth, cell proliferation, and cell invasion. Intraperitoneal injections of miR-18a-OMM-loaded folate-conjugated liposomes significantly reduced the tumor weight and the number of nodules in ovarian cancer-bearing mice when compared with a control-OMM group. Survival analysis using the Kaplan-Meier plotter database showed that ovarian cancer patients with high miR-18a levels live longer in comparison to patients with lower miR-18a levels. Bioinformatic analyses, real-time-PCR, Western blots, and luciferase reporter assays revealed that Matrix Metalloproteinase-3 (MMP-3) is a direct target of miR-18a. Small-interfering RNA (siRNA)-mediated silencing of MMP-3 reduced cell viability, cell growth, and the invasiveness potential of cisplatin-resistant ovarian cancer cells. Our study suggests that targeting miR-18a is a plausible therapeutic strategy for cisplatin-resistant ovarian cancer.

Study of the polymorphism rs3025058 of the MMP-3 gene and risk of pelvic organ prolapse in Brazilian women.

OBJECTIVE: To analyze the polymorphism -1171 5A / 6A rs3025058 of the MMP-3 gene and the risk for pelvic organ prolapse (POP). STUDY DESIGN: This is a cohort study. All patients attended the Urogynecology and Vaginal Surgery Section of the FMABC, from 2014 to 2016 and they were randomly recruited by the researchers at the first medical appointment. We selected 112 patients with symptomatic POPs and 180 patients with normal pelvic floors. The single nucleotide polymorphism (SNP) 5A / 6A of MMP-3 was determined by polymerase chain reaction (PCR) and analysis of the restriction fragments in both groups. Chi-squared test was used to compare the frequencies of polymorphisms between the groups. For those characteristics with statistical relevance, the crude odds ratio (OR) and its respective 95% confidence intervals were calculated; and, by logistic regression, were adjusted for each of the other characteristics, obtaining the adjusted OR. Hardy-Weinberg gene balance was determined using Pearson's Chi-squared test. Values of p < 0.05 were considered statistically significant. RESULTS: Logistic regression of factors associated with genital prolapse showed that age (adjusted OR = 11.89, 95% CI, 3.53-40) and home delivery (adjusted OR = 9.645, 95% CI, 3.35-27.7) remained risk factors for genital prolapse in the sample studied. There was no statistically significant difference between the groups in the distribution of genotypes, even after calculating the contribution of the 5A recessive allele in the aggregated genotypes (5A / 5A + 5A / 6A). CONCLUSION: The polymorphism -1171 5A / 6A rs3025058 of the MMP-3 gene was not associated with the risk for POP. Age and home delivery were significantly associated with increased risk for the disease.

Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study.

OBJECTIVE: Endometriosis has a complex and multifactorial pathology, and it is considered one of the main causes of infertility nowadays. The angiogenic process, which involves remodeling of extracellular matrix, is crucial for the development of this disease, mainly by the action of the matrix metalloproteinase 3 (MMP-3). It is known that genetic factors can influence endometriosis, thus; we investigated the role of MMP3 276G>A polymorphism as a risk factor for the development of the disease and its symptoms. STUDY DESIGN: This case-control study included 283 women with endometriosis (cases) and 217 women without the disease (controls) who were submitted to laparoscopic or laparotomy surgery. Real-time polymerase chain reaction performed by TaqMan system was applied for all polymorphisms. A multivariate logistic regression was performed to evaluate the association between polymorphism and endometriosis or clinical and gynecological characteristics of the disease, using their respective odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The allelic frequency of the MMP3 276 G > A polymorphism was 33.6% in controls and 40.3% in endometriosis cases. The allelic distribution was significantly different between the two (P = 0.03). The variant genotype of MMP3 276AA was associated with increased endometriosis risk in the advanced endometriosis cases (OR: 2.08, 95% CI: 1.05 - 4.07 and OR: 1.87, 95% CI: 1.01 - 3.45). Regarding the symptoms, endometriosis-related infertile women had a positive association with the presence of MMP3 276 G > A polymorphism (OR: 3.13, 95% CI: 1.08-9.08 and OR: 3.30, 95% CI: 1.31 - 8.33). CONCLUSIONS: These findings suggest that the MMP3 276A polymorphism is involved with advanced endometriosis cases and infertility, and these associations may implicate in the behavior of disease.

In-vitro study of gonadotrophin signaling pathways in human granulosa cells in relation to progesterone receptor expression.

In humans, data on gonadotrophin-activated (LH, HCG and FSH) progesterone receptor expression and signalling pathways involved in matrix metalloproteinases (MMPs) expression presumably linked to the follicle rupture, are limited. Our hypothesis is LH, HCG and FSH increase progesterone receptor expression in granulosa cells through different signalling pathways, leading to an increased expression of ADAMTS-1 and MMP3/10, which may mediate follicular rupture through the transcription factor, HIF1A. Human granulosa cells were isolated from follicular aspirates obtained from 22 healthy women participating in our IVF programme for male-factor infertility. Progesterone receptor and HIF1A expression was assessed by immunofluorescence, and PKA-PKC-PI3K- ERK1/2, ADAMTS-1 and MMP3/10 expression by Western blot in pre-ovulatory and in cultured granulosa cells. Results show that HCG, LH and FSH regulate progesterone receptor expression and activate PKA, PKC, PI3K and ERK1/2 signalling pathways in granulosa cells but progesterone receptor expression is only mediated by PKA, PKC and ERK pathways. HCG, FSH and LH regulated MMPs expression through progesterone receptors. Moreover, HCG-progesterone-receptor-dependent HIF1A expression stimulated MMP3/10 expression but not that of ADAMTS-1. These results suggest differential downstream progesterone receptor signalling, as progesterone receptor regulates MMP3/10 expression via HIF1A, which is not involved in ADAMTS-1 expression.

A study on genetic polymorphism in Matrix Metalloproteinases-3 in oral submucous fibrosis patients and in healthy individuals

Background: OSF is a potentially malignant condition affecting the oral cavity and oropharynx. MMP-3 also known as Stromelysin -I is a key member of the MMP family which is responsible for degradation of collagen type II,IV,V,IX and X, proteoglycans, gelatins, fibronectin, laminin and elastin. It plays an important role in activation of pro MMP-1 into the active form of MMP-1 in malignant tissues. MMP-3 expression is low in normal tissues but it is altered during tumour formation, where remodeling of ECM is required. Purpose of the study: To assess the association of single-nucleotide polymorphisms, Adenosine (Insertion/Deletion) in -1171 5A > 6A in the MMP-3 promoter regions of patients with oral submucous fibrosis and in healthy individuals (controls). Methods: Thirty cases of OSF were categorized according to Khanna et al classification into four groups and Twenty age and sex matched controls were included in the study. Blood samples were collected in EDTA coated vacutainers and PCR restriction analysis was done. A statistical analysis was done using Chi-square test and Fisher's exact test to assess the frequency and association of the alleles in the case-control group. Results: The result showed a statistical significance difference between the duration of habit and disease severity with polymorphisms. The result also showed a higher frequency of the 5A allele in the study group as compared to the controls. Conclusion: A long-term follow up of these patients is mandatory to see the prognosis and their susceptibility to malignancy. The positive outcome of an association of the disease with polymorphisms would result in the development of potential diagnostic and therapeutic possibilities in potentially malignant and malignant lesions (AU)

Niveles de MMP-3 y MMP-8 en pacientes con periodontitis crónica antes y después del tratamiento periodontal no quirúrgico / MMP-3 and MMP-8 levels in patients with chronic periodontitis before and after nonsurgical periodontal therapy

En la periodontitis crónica (PC) se desencadenan procesos inmunoinflamatorios, donde se liberan metaloproteinasas de la matriz (MMPs), enzimas involucradas en la degradación de la matriz extracelular, las cuales pueden ser detectadas en el fluido gingival crevicular (FGC). El propósito del estudio fue determinar los niveles de MMP-3 y MMP-8 en FGC, antes y después del tratamiento periodontal no quirúrgico (TPNQ) para evaluar actividad de la enfermedad y respuesta terapéutica. Once pacientes con periodontitis crónica y 11 controles sanos fueron seleccionados. Se evaluaron los parámetros clínicos: índice gingival, índice de placa, profundidad al sondaje y pérdida de inserción; en todos los dientes de cada individuo y en seis sitios por diente. Muestras de FGC fueron tomadas de un diente por cuadrante, con profundidad de saco ≥ 4mm y pérdida de inserción ≥ 5 mm, los niveles de MMP-3 y MMP-8 fueron determinados por ELISA. Diferencias estadísticamente significativas fueron observadas entre los parámetros clínicos del grupo control y los pacientes con PC antes del tratamiento, registrándose posterior al TPNQ disminución significativa de todos los índices. Las concentraciones iniciales de MMP-3 y 8 en el grupo con PC fueron significativamente mayores a las obtenidas luego del TPNQ y en el grupo control, sin observar correlación entre parámetros clínicos y niveles de MMPs. La disminución significativa de los valores de MMP-3 y 8 en FGC de los pacientes con PC, posterior al TPNQ, indican la participación importante de estas enzimas en la degradación del tejido, y la efectividad del tratamiento periodontal para su control.

Immune-inflammatory processes are trigged in chronic periodontitis (CP), where matrix metalloproteinases (MMPs) are released and involved in the degradation of the extracellular matrix components that can be detected in the gingival crevicular fluid (GCF). The purpose of the study was to determine the levels of MMP-3 and MMP-8 in GCF, before and after nonsurgical periodontal treatment (NSPT), to evaluate disease activity and therapy response. Eleven patients with PC and eleven healthy controls were selected. Clinical measurements to evaluate gingival index (GI), plaque index (PI), probing depth (PD) and clinical attachment loss (CAL) were made in all the teeth of each individual and in six sites per tooth. GCF samples were taken from one tooth per quadrant, with a pocket depth ≥ 4 mm and a clinical attachment loss ≥ 5 mm, and the levels of MMP-3 and MMP-8 measured using an ELISA test. Statistically significant differences in clinical parameters were observed (p < 0.05) between patients with CP and control groups before the periodontal treatment, with significant decrease in all indexes after the NSPT. The initial concentrations of MMP-3 and MMP-8 were significantly higher than those obtained after the NSPT and in the control group, without observing a correlation between the clinical parameters and the levels of MMPs. Increased levels of MMP-3 and MMP-8 in the GCF of patients with PC declined significantly after NSPT, and the difference between the levels in healthy individuals and patients, suggests the important participation of these MMPs in tissue destruction in PC disease.