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Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki‐1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p‐ERK/Sp1 and p‐PKCα/Sp1‐mediated MMP1 expression in RCC. [ABSTRACT FROM AUTHOR]

Abstract Talin2 is localized to large focal adhesions and is indispensable for traction force generation, invadopodium formation, cell invasion as well as metastasis. Talin2 has a higher affinity toward β-integrin tails than talin1. Moreover, disruption of the talin2-β-integrin interaction inhibits traction force generation, invadopodium formation and cell invasion, indicating that a strong talin2-β-integrin interaction is required for talin2 to fulfill these functions. Nevertheless, the role of talin2 in mediation of these processes remains unknown. Here we show that talin2 binds to the N-terminus of non-muscle myosin IIA (NMIIA) through its F3 subdomain. Moreover, talin2 co-localizes with NMIIA at cell edges as well as at some cytoplasmic spots. Talin2 also co-localizes with cortactin, an invadopodium marker. Furthermore, overexpression of NMIIA promoted the talin2 head binding to the β1-integrin tail, whereas knockdown of NMIIA reduced fibronectin and matrix metalloproteinase secretion as well as inhibited cell attachment on fibronectin-coated substrates. These results suggest that talin2 binds to NMIIA to control the secretion of extracellular matrix proteins and this interaction modulates cell adhesion.

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti‐tumor, anti‐inflammatory, and anti‐oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non‐toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down‐regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA‐induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti‐invasive effect of AA on osteosarcoma cells via the p‐AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma. [ABSTRACT FROM AUTHOR]

The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs) are crucially involved in this process by promoting the detachment of tumor cells from the primary lesion and their migration to the vasculature. In gray horse melanoma, epithelial–mesenchymal transition (EMT) is poorly understood, prompting us to address MP expression in lesions versus intact skin by transcriptome analyses and the immunofluorescence staining (IF) of gray horse tumor tissue and primary melanoma cells. RNAseq revealed the deregulation of several MPs in gray horse melanoma and, notably, a 125-fold upregulation of matrix metalloproteinase 1 (MMP1) that was further confirmed by RT-qPCR from additional tumor material. The IF staining of melanoma tissue versus intact skin for MMP1 and tumor marker S100 revealed MMP1 expression in all lesions. The co-expression of S100 was observed at different extents, with some tumors scoring S100-negative. The IF staining of primary tumor cells explanted from the tumors for MMP1 showed that the metalloproteinase is uniformly expressed in the cytoplasm of 100% of tumor cells. Overall, the presented data point to MP expression being deregulated in gray horse melanoma, and suggest that MMP1 has an active role in gray horse melanoma by driving EMT-mediated tumor cell dissemination via the degradation of the extracellular matrix. Whilst S100 is considered a reliable tumor marker in human MM, gray horse melanomas do not seem to regularly express this protein. [ABSTRACT FROM AUTHOR]

Background: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC. Methods: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021. Blood samples were drawn before treatment, and 73 soluble factors in the plasma were analyzed using a bead-based multiplex assay. We examined factors associated with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE) using the Chi-squared test, Kaplan–Meier method, and the COX proportional hazards model. Results: Patients exhibited a median PFS and OS of 212 and 783 days, respectively. Significant differences in both PFS and OS were observed for MMP1 (PFS, p < 0.001; OS, p = 0.003), IL-1β (PFS, p = 0.021; OS, p = 0.008), sTNFR-1 (PFS, p = 0.017; OS, p = 0.005), and IL-6 (PFS, p = 0.004; OS, p < 0.001). Multivariate analysis revealed significant differences in PFS for MMP1 (hazard ratio [HR] 5.305, 95% confidence interval [CI], 1.648–17.082; p = 0.005) and OS for IL-6 (HR 23.876, 95% CI, 3.426–166.386; p = 0.001). Moreover, 26 patients experienced irAE, leading to ICI discontinuation or withdrawal. MMP1 was significantly associated with irAE (p = 0.039). Conclusion: MMP1 may be associated with severe irAE, and MMP1, IL-1β, sTNFR-1, and IL-6 could serve as prognostic factors in unresectable or metastatic RCC treated with ICIs. MMP1 and IL-6 were independent predictors of PFS and OS, respectively. Thus, inhibiting these soluble factors may be promising for enhancing antitumor responses in patients with RCC treated with ICIs. [ABSTRACT FROM AUTHOR]

Abstracts: Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging.

Background: Skin aging is a cumulative damage that occurs due to complex biological processes from genetic and environmental factors that are evident in individual's appearance. Clinically photoaging causes wrinkling, telangiectasia, dryness, pigment changes and loss of elasticity. As the predominant element found in green tea, epigallocatechin-3-gallate (EGCG) exhibits an active physiological function observed in both human and animal skin. Exposure to the two components of solar UV radiation that reach the earth surface, UVA (320-400nm) and UVB (290-320nm), leads to protein oxidative damage, lipid oxidation, DNA chain damage, and depletion of antioxidant enzymes. Since 1984, all-trans retinol has been incorporated into over-the-counter (OTC) cosmetic products, yet its potential in treating photoaging continues to be investigated. Methods: Search Profile EGCG, Retinol, Hyaluronan, and then Bioactive Prediction with SAR. Predicted EGCG targets were analyzed using Comparative Toxicogenomics Database. Compound Profile Similarity with Tanimoto Similarity. Using AlphaFold model, we obtained three-dimensional configuration of Hyaluronan Synthase 1, as designated target protein in this study, from Uniprot database (https://www. uniprot.org/) with identifier Q92839. Results: Based on SAR analysis to predict potential bioactivity, it shows that EGCG has better potential than retinol as an antioxidant and free radical scavenger. Target prediction with CTD shows that in curated studies the EGCG CTD is able to target COL1A1, HAS1, NFE2L2, and MMP1. Based on tanimono similarity, the similarity between EGCG and Hyaluron is higher than Hyaluron and Retinol. Conclusions: Docking analysis shows that it is predicted that EGCG is better at interacting with HAS1 and MMP1. [ABSTRACT FROM AUTHOR]

UVB radiation significantly threatens skin health, contributing to wrinkle formation and an elevated risk of skin cancer. This study aimed to explore bioactive compounds with potential UVB-protective properties. Using in silico analysis, we chose compounds to reduce binding energy with matrix metalloproteinase-1 (MMP1). Piperitoside, procyanidin C1, and mulberrofuran E emerged as promising candidates through this computational screening process. We investigated the UVB-protective efficacy of the selected compounds and underlying mechanisms in human immortalized keratinocytes (HaCaT). We also investigated the molecular pathways implicated in their action, focusing on the transforming growth factor (TGF)-β and wingless-related integration site (Wnt)/β-catenin signaling pathways. In UVB-exposed HaCaT cells (100 mJ/cm2 for 30 min), piperitoside, procyanidin C1, and mulberrofuran E significantly reduced reactive oxygen species (ROS) and lipid peroxides, coupled with an augmentation of collagen expression. These compounds suppressed MMP1, tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) expression, while they concurrently enhanced collagen-1 (COL1A1), β-catenin (CTNNB1), and superoxide dismutase type-1 (SOD1) expression. Furthermore, Wnt/β-catenin inhibitors, when administered subsequently, partially counteracted the reduction in MMP1 expression and alleviated inflammatory and oxidative stress markers induced by the bioactive compounds. In conclusion, piperitoside, procyanidin C1, and mulberrofuran E protected against UVB-induced damage in HaCaT cells by inhibiting MMP1 expression and elevating β-catenin expression. Consequently, these bioactive compounds emerge as promising preventive agents for UVB-induced skin damage, promoting skin health. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is heterogeneous cancer having a high death rate and poor prognosis. The perioperative variables, such as anesthetics, may affect the cancer progression. Ciprofol is an intravenous anesthetic widely used recently. We aimed to explore the influence of ciprofol on PC and investigate its possible pathway. The proliferation, migration and invasion roles and apoptosis of ciprofol in human PC cells were examined using methylthiazolyldiphenyl-tetrazolium bromide, transwell, and flow cytometery analysis. Then the putative targeted genes were examined using RNA-sequencing (RNA-seq) analysis. When differentially expressed genes (DEGs) were found, a protein-protein interaction network and pathway analyses were made. Moreover, MMP1 gene expression was confirmed in PC cells using quantitative real-time PCR. PANC-1 cells of PC were significantly suppressed with ciprofol in a dose-dependent and time-dependent way, and 20µg/mL ciprofol significantly suppressed tumor cell aggressiveness. Additionally, the RNA-seq analysis demonstrated that ciprofol controls the expression of 929 DEGs. 5 of 20 hub genes with increased connection were selected. Survival analysis demonstrated that MMP1 may be involved in the carcinogenesis and establishment of PC, reflecting the possible roles associated with ciprofol. Moreover, one target miRNA (hsa-miR-330- 5p) of MMP1 was identified. [ABSTRACT FROM AUTHOR]

Inorganic arsenic (NaAsO2) is a naturally occurring metalloid found in water resources globally and in the United States at concentrations exceeding the U.S. Environmental Protection Agency Maximum Contamination Level of 10 ppb. While exposure to arsenic has been linked to cancer, cardiovascular disease, and skin lesions, the impact of arsenic exposure on wound healing is not fully understood. Cultured dermal fibroblasts exposed to NaAsO2 displayed reduced migration (scratch closure), proliferation, and viability with a lowest observable effect level (LOEL) of 10 µM NaAsO2 following 24 h exposure. An enrichment of Matrix Metalloproteinase 1 (MMP1) transcripts was observed at a LOEL of 1 µM NaAsO2 and 24 h exposure. In vivo, C57BL/6 mice were exposed to 10 µM NaAsO2 in their drinking water for eight weeks, then subjected to two full thickness dorsal wounds. Wounds were evaluated for closure after 6 days. Female mice displayed a significant reduction in wound closure and higher erythema levels, while males showed no effects. Gene expression analysis from skin excised from the wound site revealed significant enrichment in Arsenic 3-Methyltransferase (As3mt) and Estrogen Receptor 2 (Esr2) mRNA in the skin of female mice. These results indicate that arsenic at environmentally relevant concentrations may negatively impact wound healing processes in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Epigenetic alterations associated with cancer have been shown to facilitate tumorigenesis and promote metastasis. In the study of cancer metastasis, epigenetics has been revealed to play a crucial role in supporting tumour immune evasion. As a result, epigenetic drugs have been identified as potential agents to activate anti-tumour immune responses and reverse tumour immunologically tolerant states. Mounting evidence is showing aberrant expression of MHC class I antigen processing molecules in cancers and their upregulation as a potential indicator for anti-tumour immunity. In this study, we demonstrate that the epigenetic drug Trichostatin A (TSA), a histone deacetylase inhibitor, can restore MHC I antigen presentation machinery (MHC I APM) genes in human breast cancer cells (MCF-7). Treatment with TSA resulted in the upregulation of MHC I, B2M, and PSMB9 in MCF-7 monolayer cells, and MHC I, B2M, PSMB9, PSMB8, TAP1, and TAP2 in MCF-7 spheroid cells. Interestingly, treatment with TSA also increased CD274 expression in these cells and enhanced the invasion ability of the MCF-7 spheroid. This aggressive behaviour was confirmed by increased expression of metastatic-related genes, nNav1.5 and MMP1. In summary, although the restoration of MHC I APM expression was achieved by TSA, the upregulation of metastatic genes and CD274 also enhanced the invasion ability of breast cancer cells. These findings suggest the need for careful consideration when utilizing epigenetic drugs for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficiency and the mechanism of fractional erbium:yttrium aluminum garnet (Er:YAG) laser for the treatment of morphea in mouse model. Background: Morphea is a rare autoimmune disease characterized by excessive collagen deposition in skin. Fractional Er:YAG laser treatment is a promising treatment to improve morphea, despite limited studies about the therapeutic effect and underlying mechanism. Methods: The mouse model of morphea was established by subcutaneously injecting with bleomycin (BLM). A total of 24 mice received fractional Er:YAG laser treatment once a week for 4 weeks. Objective measurement employed was ultrasonic imaging to measure dermal thickness. Subjective measures included scoring according to the adjusted Localized morphea Cutaneous Assessment Tool (LoSCAT); hematoxylin and eosin (H&E) staining to evaluate the histological grade of fibrosis; and quantitative morphometric studies to determine the expression of transforming growth factor‐β1 (TGF‐β1) and matrix metalloproteinase‐1 (MMP1) by immunohistochemistry. Results: In this self‐controlled study, fractional Er:YAG laser treatment significantly ameliorate the severity of morphea, including lower clinical score (p < 0.01), decreased dermal thickness (p < 0.001), declined histological grade of fibrosis (p < 0.001), increased MMP1 (p < 0.001), and reduced TGF‐β1 (p < 0.01) expression. Conclusions: We found that fractional Er:YAG laser treatment of morphea has good clinical, ultrasonic, and histopathologic efficacy, which may be a promising treatment in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p

The pathogenesis of oral squamous cell carcinoma (OSCC) remains unclear. Therefore, clarifying its pathogenesis and molecular‐level development mechanism has become the focus of OSCC research. N‐acetyltransferase 10 (NAT10) is a crucial enzyme involved in mRNA acetylation, regulating target gene expression and biological functions of various diseases through mediating N4‐acetylcytidine (ac4C) acetylation. However, its role in OSCC progression is not well understood. In this study, we showed that NAT10 was significantly upregulated in OSCC tissues compared to normal oral tissues. Moreover, lentivirus‐mediated NAT10 knockdown markedly suppressed cell proliferation, migration, and invasion in two OSCC cell lines (SCC‐9 and SCC‐15). Interestingly, MMP1 was found to be significantly upregulated in OSCC tissues and was a potential target of NAT10. N‐acetyltransferase 10 knockdown significantly reduced both the total and ac4C acetylated levels of MMP1 mRNA and decreased its mRNA stability. Xenograft experiments further confirmed the inhibitory effect of NAT10 knockdown on the tumorigenesis and metastasis ability of OSCC cells and decreased MMP1 expression in vivo. Additionally, NAT10 knockdown impaired the proliferation, migration, and invasion abilities in OSCC cell lines in an MMP1‐dependent manner. Our results suggest that NAT10 acts as an oncogene in OSCC, and targeting ac4C acetylation could be a promising therapeutic strategy for OSCC treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: Breast cancer is a multifactorial malignancy with different clinicopathological and molecular characteristics. It is the most frequent cancer in women in terms of both incidence and mortality. Matrix metallopeptidase 1 or MMP1 is a zinc‐dependent endopeptidase associated with several physiological processes through the modification of the extracellular matrix and tumor microenvironment. However, previous results did not suggest any concluding remarks on the correlation between MMP1 gene polymorphisms and the risk of breast cancer. Methods: A comprehensive literature search was performed in PubMed database to retrieve relevant articles and extract data from suitable ones. The literature written only in English was selected for this review. Results: A total of 26 articles were included in the present narrative review. From the available studies, it is observed that MMP1 is upregulated in breast cancer tissues and found to be correlated with metastasis and invasion. The expression of MMP1 gene is mediated by numerous factors, including polymorphisms which act as a potential risk factor for the progression of breast cancer. To establish the correlation between genetic polymorphisms in MMP1 and the risk of breast cancer, several case‐control studies, as well as genetic analyses, have been carried out in different ethnicities. The association of genetic polymorphisms in MMP1 with the risk and survival of breast cancer in different populations has been reviewed in this study. Moreover, the structural domain of MMP1 and the role of MMP1 in breast cancer metastasis and invasion are also discussed which will help to understand the potential impact of MMP1 as a genetic biomarker. Conclusions: This review provides an overview of the MMP1 gene polymorphisms in breast cancer. However, we recommend future studies concentrating on combined analysis of multiple SNPs, gene‐gene interactions, and analysis of epigenetics, proteomics, and posttranscriptional modifications that will provide the best outcome. [ABSTRACT FROM AUTHOR]

Abstract Background In recent years, there have been breakthroughs in the preclinical research of respiratory diseases, such as organoids and organ tissue chip models, but they still cannot provide insight into human respiratory diseases well. Human lung slices model provides a promising in vitro model for the study of respiratory diseases because of its preservation of lung structure and major cell types. Methods Human lung slices were manually prepared from small pieces of lung tissues obtained from lung cancer patients subjected to lung surgery. To evaluate the suitability of this model for lung fibrosis research, lung slices were treated with CdCl2 (30 μM), TGF-β1 (1 ng/ml) or CdCl2 plus TGF-β1 for 3 days followed by toxicity assessment, gene expression analysis and histopathological observations. Results CdCl2 treatment resulted in a concentration-dependent toxicity profile evidenced by MTT assay as well as histopathological observations. In comparison with the untreated group, CdCl2 and TGF-β1 significantly induces MMP2 and MMP9 gene expression but not MMP1. Interestingly, CdCl2 plus TGF-β1 significantly induces the expression of MMP1 but not MMP2, MMP7 or MMP9. Microscopic observations reveal the pathogenesis of interstitial lung fibrosis in the lung slices of all groups; however, CdCl2 plus TGF-β1 treatment leads to a greater alveolar septa thickness and the formation of fibroblast foci-like pathological features. The lung slice model is in short of blood supply and the inflammatory/immune-responses are considered minimal. Conclusions The results are in favor of the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated by tissue damage and abnormal repair. Induction of MMP1 gene expression and fibroblast foci-like pathogenesis suggest that this model might represent an early stage of IPF.

Abstract Background Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. Methods The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. Results MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. Conclusions Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

The ability of human melanoma cells to switch from an epithelial to a mesenchymal phenotype contributes to the metastatic potential of disease. Metalloproteinases (MPs) are crucially involved in this process by promoting the detachment of tumor cells from the primary lesion and their migration to the vasculature. In gray horse melanoma, epithelial–mesenchymal transition (EMT) is poorly understood, prompting us to address MP expression in lesions versus intact skin by transcriptome analyses and the immunofluorescence staining (IF) of gray horse tumor tissue and primary melanoma cells. RNAseq revealed the deregulation of several MPs in gray horse melanoma and, notably, a 125-fold upregulation of matrix metalloproteinase 1 (MMP1) that was further confirmed by RT-qPCR from additional tumor material. The IF staining of melanoma tissue versus intact skin for MMP1 and tumor marker S100 revealed MMP1 expression in all lesions. The co-expression of S100 was observed at different extents, with some tumors scoring S100-negative. The IF staining of primary tumor cells explanted from the tumors for MMP1 showed that the metalloproteinase is uniformly expressed in the cytoplasm of 100% of tumor cells. Overall, the presented data point to MP expression being deregulated in gray horse melanoma, and suggest that MMP1 has an active role in gray horse melanoma by driving EMT-mediated tumor cell dissemination via the degradation of the extracellular matrix. Whilst S100 is considered a reliable tumor marker in human MM, gray horse melanomas do not seem to regularly express this protein.

Abstract Background and Aims Breast cancer is a multifactorial malignancy with different clinicopathological and molecular characteristics. It is the most frequent cancer in women in terms of both incidence and mortality. Matrix metallopeptidase 1 or MMP1 is a zinc‐dependent endopeptidase associated with several physiological processes through the modification of the extracellular matrix and tumor microenvironment. However, previous results did not suggest any concluding remarks on the correlation between MMP1 gene polymorphisms and the risk of breast cancer. Methods A comprehensive literature search was performed in PubMed database to retrieve relevant articles and extract data from suitable ones. The literature written only in English was selected for this review. Results A total of 26 articles were included in the present narrative review. From the available studies, it is observed that MMP1 is upregulated in breast cancer tissues and found to be correlated with metastasis and invasion. The expression of MMP1 gene is mediated by numerous factors, including polymorphisms which act as a potential risk factor for the progression of breast cancer. To establish the correlation between genetic polymorphisms in MMP1 and the risk of breast cancer, several case‐control studies, as well as genetic analyses, have been carried out in different ethnicities. The association of genetic polymorphisms in MMP1 with the risk and survival of breast cancer in different populations has been reviewed in this study. Moreover, the structural domain of MMP1 and the role of MMP1 in breast cancer metastasis and invasion are also discussed which will help to understand the potential impact of MMP1 as a genetic biomarker. Conclusions This review provides an overview of the MMP1 gene polymorphisms in breast cancer. However, we recommend future studies concentrating on combined analysis of multiple SNPs, gene‐gene interactions, and analysis of epigenetics, proteomics, and posttranscriptional modifications that will provide the best outcome.

Oral cancer is one of the most common cancer types. Many factors can express certain genes that cause the proliferation of oral tissues. Overexpressed genes were detected in oral cancer patients; three were highly impacted. FAP, FN1, and MMP1 were the targeted genes that showed inhibition results in silico by ginsenoside C and Rg1. Approved drugs were retrieved from the DrugBank database. The docking scores show an excellent interaction between the ligands and the targeted macromolecules. Further molecular dynamics simulations showed the binding stability of the proposed natural products. This work recommends repurposing ginsenoside C and Rg1 as potential binders for the selected targets and endorses future experimental validation for the treatment of oral cancer.

This study investigated the anti-arthritic potential of novel mannich-based derivatives of 2-mercaptobenzimidazole (AK7 and AK9) in rats. The compounds were characterized by NMR and FTIR spectroscopies and their acute anti-inflammatory effects were measured by carrageenan (CRG)-induced paw edema model. The most potent doses of AK7 and AK9 were subsequently evaluated in the complete Freund's adjuvant (CFA)–induced inflammatory arthritis model. AK7 and AK9 inhibited CRG-induced inflammation in a dose-dependent fashion and a similar reduction in CFA-induced paw inflammation was observed. Moreover, X-ray and histopathological analyses of AK7-treated animals displayed normal joint structure whereas AK9, despite of its anti-inflammatory effects, failed to protect against cartilage destruction. Interestingly, biochemical analysis revealed a better safety profile for AK7 than for AK9 and methotrexate. Both compounds suppressed mRNA levels of pro-inflammatory mediators (IRAK1, NF-κB1, TNF-α, IL1B) while only AK7 reduced the transcript levels of interstitial collagenase (MMP1). Molecular docking analysis of AK7 and AK9 with TNF-α and MMP1 also supported the experimental data. These findings clearly highlight the beneficial effects of AK7 in the prevention and/or treatment of inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Background: In recent years, there have been breakthroughs in the preclinical research of respiratory diseases, such as organoids and organ tissue chip models, but they still cannot provide insight into human respiratory diseases well. Human lung slices model provides a promising in vitro model for the study of respiratory diseases because of its preservation of lung structure and major cell types. Methods: Human lung slices were manually prepared from small pieces of lung tissues obtained from lung cancer patients subjected to lung surgery. To evaluate the suitability of this model for lung fibrosis research, lung slices were treated with CdCl2 (30 μM), TGF-β1 (1 ng/ml) or CdCl2 plus TGF-β1 for 3 days followed by toxicity assessment, gene expression analysis and histopathological observations. Results: CdCl2 treatment resulted in a concentration-dependent toxicity profile evidenced by MTT assay as well as histopathological observations. In comparison with the untreated group, CdCl2 and TGF-β1 significantly induces MMP2 and MMP9 gene expression but not MMP1. Interestingly, CdCl2 plus TGF-β1 significantly induces the expression of MMP1 but not MMP2, MMP7 or MMP9. Microscopic observations reveal the pathogenesis of interstitial lung fibrosis in the lung slices of all groups; however, CdCl2 plus TGF-β1 treatment leads to a greater alveolar septa thickness and the formation of fibroblast foci-like pathological features. The lung slice model is in short of blood supply and the inflammatory/immune-responses are considered minimal. Conclusions: The results are in favor of the hypothesis that idiopathic pulmonary fibrosis (IPF) is mediated by tissue damage and abnormal repair. Induction of MMP1 gene expression and fibroblast foci-like pathogenesis suggest that this model might represent an early stage of IPF. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. Methods: The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. Results: MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. Conclusions: Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients. [ABSTRACT FROM AUTHOR]

Allele typing of single-nucleotide polymorphisms (SNPs) may be used in predictive medicine and to determine targets for the most effective treatment strategies for various diseases. The purpose of the present work was to investigate the association between the SNPs of inflammatory genes, e.g., IL10 (C819T; rs1800871; C592A; rs1800872); IL4 (C589T; rs2243250); fibrosis-related factors - TGFβ1 (G915C; rs1800471); MMP1 (1607insG; rs1799750); apoptosis-regulators (TNFRSF11B G1181C; rs2073618); vasoconstricting factors (CRP C3872T; rs1205); CYP1A1 (A2454G; rs1048943), endothelial dysfunction (EDN1 G925T; rs5370); (NOS3 C786T; rs2070744) and development of coronary heart disorders, breast cancer, bronchial asthma (BA) and threatened miscarriage in early pregnancy among population of the Republic of Adygea.DNA samples of unrelated donors and patients (n = 74) with verified diagnoses of bronchial asthma (n = 13), coronary heart disease (n = 10), breast cancer (n = 10) and threatened miscarriage in the first trimester of pregnancy (n = 8) were isolated from peripheral blood leukocytes and typed by allele-specific polymerase chain reaction with electrophoretic detection of results using commercial tests-systems of NPF “Litech”, Moscow.The study in a group of Adygea residents has revealed the statistical significance for the “normal” Arg25-allelic variant of the TGFβ1 gene (p < 0.05; F = 0.038; OR = 3.231; 95% CI = 1.081-9.656) in the development of bronchial asthma. There were no significant differences in SNP rs1800471 of the TGFβ1 gene in the groups with cardiovascular, oncological diseases and gestational disorders (p > 0.05). The frequency distribution of allelic variants NOS3 C786T; TNFRSF11B G1181C; 1607insG of the MMP1 gene; G925T of the EDN1 gene, and CYP1A1 2454G in the examined patients with cardiovascular disease and breast cancer did not significantly differ from the control group (p > 0.05). The statistical significance for the frequency of allelic variants rs1799750 (MMP1 gene) in cases of threatened early miscarriage and in women with a physiological course of pregnancy (F = 0.096; p < 0.05%: OR = 6.0) was close to reliable, but with a confidence interval > 1.0 (95% CI = 0,98036,716), thus requiring further research.The obtained data could be sufficient in order to suggest predisposition for bronchial asthma, as well as to develop a set of preventive measures taking into account the individual characteristics of each patient.

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor worldwide with high morbidity and mortality. However, the diagnosis and molecular mechanisms of HNSCC remains poor. Methods Robust rank aggregation method was performed to excavate the differentially expressed genes (DEGs) in five datasets (GSE6631, GSE13601, GSE23036, GSE30784, GSE107591) from the Gene Expression Omnibus. Search Tool for the Retrieval of Interacting Genes (STRING) database extracted hub genes from the protein‐protein interaction network. The expression of the hub genes was validated using expression profile from The Cancer Genome Atlas and Oncomine database. The module analysis and disease‐free survival analysis of the hub genes were analyzed by Cytoscape and the Kaplan‐Meier curve, respectively. The expression of hub genes was verified in clinical specimens. The functions of MMP1 which is most important in hub genes were explored in vitro and in vivo. Results Totally, 235 DEGs were identified in the present study which consists of 103 up‐regulated and 132 down‐regulated genes which were significantly enriched in the molecular function of calcium ion binding followed in the biological process of skin development. The mainly enriched pathways were ECM (extracellular matrix)‐receptor interaction (hsa04512) and protein digestion and absorption (hsa04974). Six hub genes were screened out which showed dramatically increased expression in HNSCC samples compared with normal samples, including COL4A1, MMP1, PLAU, RBP1, SEMA3C, and COL4A2. These hub genes all showed worse disease‐free survival with higher expression and were up‐regulated in HNSCC clinical samples. MMP1 was proved to promote cell growth, migration, and phosphorylation of AKT in vitro and to promote liver metastasis in vivo. Conclusion Bioinformatics analysis identified six key genes in HNSCC. Of these, MMP1 is the most likely biomarker. It activates the AKT pathway and promotes tumor progression.

Bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exos) can recruit stem cells for bone repair, with neovessels serving as the main migratory channel for stem cells to the injury site. However, existing exosome (Exo) delivery strategies cannot reach the angiogenesis phase following bone injury. To that end, an enzyme-sensitive Exo delivery material that responds to neovessel formation during the angiogenesis phase was designed in the present study to achieve spatiotemporally controlled Exo release. Herein, matrix metalloproteinase-1 (MMP1) was found to be highly expressed in neovascularized bone; as a result, we proposed an injectable MMP1-sensitive hydrogel microspheres (KGE) made using a microfluidic chip prepared by mixing self-assembling peptide (KLDL-MMP1), GelMA, and BMSC-Exos. The results revealed that KGE microspheres had a uniform diameter of 50-70 µm, ideal for minimally invasive injection and could release exosomes in response to MMP1 expression. In vitro experiments demonstrated that KGE had less cytotoxicity and could promote the migration and osteodifferentiation of BMSCs. Furthermore, in vivo experiments confirmed that KGE could promote bone repair during angiogenesis by recruiting CD90+ stem cells via neovessels. Collectively, our results suggest that injectable enzyme-responsive KGE microspheres could be a promising Exo-secreting material for accelerating neovascularized bone healing. Exosomes can spread through blood vessels and activate stem cells to participate in bone repair, but under normal circumstances, exosomes lacking sustained-release delivery materials cannot be maintained until the angiogenesis phase. In this study, we found that MMP1 was highly expressed in neovascularized bone, then we proposed an MMP1-sensitive injectable microsphere that carries exosomes and responds temporally and spatially to neovascularization, which maximizes the ability of exosomes to recruit stem cells. Different from previous strategies that focus on promoting angiogenesis to accelerate bone healing, this is a brand new delivery strategy that is stimuli-responsive to neovessel formation. In addition, the preparation of self-assembled peptide microspheres by a microfluidic chip is also proposed for the first time. [Display omitted] [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis and a lack of specific targets and targeted therapeutics. Previously, we have reported that COL8A1, which is highly expressed in the mesenchymal stem-like (MSL) subtype of TNBC, facilitates TNBC growth via FAK/Src activation. Furthermore, we have found that COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. However, the mechanism of invasion and metastasis by COL8A1 remains unclear. Here, we investigated the biological function of COL8A1 on the invasion and metastasis of MDA-MB-231 cells. The invasion and metastasis of MDA-MB-231 cells were evaluated using three-dimensional (3D) culture methods and xenograft mouse models. DNA microarray analysis examined the gene expression in COL8A1-overexpressing MDA-MB-231 cells and control cells. Gene expression was verified using RT-qPCR. COL8A1-deficient cells showed little or no metastasis, whereas forced expression of COL8A1 in MDA-MB-231 cells, the MSL subtype of TNBC cell lines, significantly promoted distant metastasis after tumor resection. As with in vivo , 3D invasion assay revealed that COL8A1 increased the invasion capacity of MDA-MB-231 and Hs578T cells, classified into the MSL subtype of TNBC. DNA microarray analysis for COL8A1-overexpressing cells indicated that COL8A1 induces interleukin 1B (IL1B) and matrix metalloproteinase-1 (MMP1) expression, both of which are correlated with COL8A1 expression in the mesenchymal subtypes of TNBC, and the Kaplan–Meier plotter provided evidence that the prognosis in the MSL subtype was strongly associated with both gene expressions and COL8A1 expression. Pharmacological inhibitor treatment showed that COL8A1 regulated IL1B and MMP1 expression through a different pathway. Moreover, the knockdown of each gene expression reduced the invasion capacity of COL8A1-overexpressing MDA-MB-231 and Hs578T cells. Our findings indicate that COL8A1-induced IL1B and MMP1 enhanced the invasion and metastasis of the MSL subtype of TNBC. Considering our previous findings that COL8A1 promotes tumor growth, COL8A1 may be a prognostic and practical therapeutic target in TNBC. [Display omitted] • COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. • COL8A1 induces IL1B and MMP1 expression in MDA-MB-231 cells. • Poor prognosis in the MSL subtype was strongly associated with IL1B and MMP1.. • COL8A1 regulated IL1B and MMP1 expression through a different pathway. • Knockdown experiment revealed COL8A1-induced IL1B and MMP1 increased the invasion. [ABSTRACT FROM AUTHOR]

Objective: Cancer remains the leading killer of human health worldwide. It has been shown that matrix metalloproteinase-1(MMP1) is related to poor prognosis in cancers such as BRCA, CESC and COAD. However, systematic pan-cancer analysis about the prognostic and immunological roles of MMP1 has not been explored. Here, the purpose of this study was to investigate the prognostic and immunological roles of MMP1 in pan-cancer and confirm cancer-promoting effect in pancreatic cancer. Methods: In our study, bioinformatics were first used to analyze data from multiple databases. Then, several bioinformatics tools were utilized to investigate the role of MMP1 in 33 tumor types. Finally, molecular biology experiments were carried out to prove the cancer-promoting effect of MMP1 in pancreatic cancer. Results: MMP1 expression was higher in tumor tissues than in control tissues in most tumor types. High expression of MMP1 was associated with poor overall survival (OS) and disease-free survival (DFS) in some tumor types. Further analysis of MMP1 gene mutation data showed that MMP1 mutations significantly influenced the prognosis of STAD. In addition, MMP1 expression was closely related to cancer-associated fibroblast (CAFs) infiltration in a variety of cancers and played an important role on immune infiltration score, tumor mutational burden (TMB) and microsatellite instability (MSI). Gene Ontology enrichment analysis indicated that these 20 genes were mainly related to extracellular structure organization/extracellular matrix organization/ extracellular matrix disassembly/collagen metabolic process in the enriched biological processes. Finally, molecular biology experiments confirmed the cancer-promoting effect of MMP1 in pancreatic cancer. Conclusions: Our pan-cancer analysis comprehensively proved that MMP1 expression is related with clinical prognosis and tumor immune infiltration, and MMP1 can become a prognostic and immunological biomarker. [ABSTRACT FROM AUTHOR]

Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging. • IL-24 is upregulated in both keratinocytes and fibroblasts of PM-treated ex vivo skin. • PM-induced IL-24 spurs MMP1 secretion and collagen degradation akin to skin aging. • PM-induced IL-24 induces cellular senescence in human dermal fibroblasts. • High-throughput screening identified lovastatin as a potent IL-24-STAT3 inhibitor. • IL-24 plays an important role in PM-induced skin aging being a promising target. [ABSTRACT FROM AUTHOR]

Abstract Background Epidemiological studies have reported a positive association between hypercholesterolemia and shoulder disease. Previous studies have focused on the effect of hypercholesterolemia on tendinopathy. Moreover, hypercholesterolemia has also been linked to joint pathology in the knee and hand. However, the effect of hyperlipidemia on glenohumeral joint remain unclear. A hypercholesterolemic condition has been reported to alter levels of A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAMTSs) and matrix metalloproteases (MMPs) in synovium of the knee joint. Here, we evaluated the mRNA expression of ADAMTSs and MMPs in the glenohumeral synovium of patients with and without hypercholesterolemia. Methods Study participants were 73 patients who underwent arthroscopic rotator cuff repair for degenerative rotator cuff tears. They were divided into two groups according to total cholesterol (TC) and triglyceride levels. Synovial membrane samples were harvested at the rotator interval during surgery, and mRNA expression levels of the aggrecanases ADAM-TS4 and ADAM-TS5 and MMPs (MMP-1, 3, 9, and 13) were analyzed quantitatively. Results ADAM-TS5 and MMP1 mRNA levels were significantly higher in the high TC group than in the low TC group (P = 0.023 and P = 0.025, respectively). In contrast, no significant differences were observed in ADAMTS4 or MMPs 3, 9, and 13 (ADAMTS4, P = 0.547; MMP3, P = 0.55; MMP9, P = 0.521; and MMP13, P = 0.785). Conclusion Hypercholesterolemia may alter MMP1 and ADAMTS5 expression in the synovium of the glenohumeral joint.

Breast cancer remains the most common malignancy in women and constantly threatens the lives of patients worldwide. State-of-the-art renewal has indicated the involvement of RUNX-associated transcription factor 2 (RUNX2) in tumorigenesis and cancer progression, yet the detailed information during breast cancer is largely obscure. Herein, we took advantage of breast cancer cell lines and in vivo tumorigenicity test as well as multifaceted phenotypic analyses (e.g., RNA-sequencing, ChIP and qRT-PCR assay) to verify the pathogenic mechanism of RUNX2 in triple negative breast cancer aggressiveness and chemoresistance. Strikingly, the proliferation, migration, invasion and chemoresistance of resistant cell lines in triple negative breast cancer was effectively suppressed by RUNX2 silencing, and the in vivo tumorigenicity was significantly weakened as well. Furthermore, with the aid of transcriptomic and bioinformatic analyses, we found MMP1 was highly expressed in triple negative breast cancer (TNBC) and showed a strong correlation with the poor prognosis of the patients, which was consistent with the expression pattern of RUNX2. Finally, by conducting ChIP and qRT-PCR assessment, we verified that RUNX2 functioned via directly binding to the specific motifs in the promoter of MMP1 and thus activating the transcriptional process. Collectively, our data demonstrated the facilitating effect of RUNX2 during triple negative breast cancer progression by directly orchestrating the expression of MMP1, which supplied overwhelming new references for RUNX2-MMP1 axis serving as a novel candidate for breast cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) leads to ischemia and afterward to left ventricular (LV) remodeling. Matrix metalloproteinase−1 (MMP1) and −3 (MMP3) belong to the family of endopeptidases and together they can dissolve most of the components of the extracellular matrix. MMP1 and MMP3 variants have been investigated solely in association with ischemic heart disease and LV dysfunction, but not in haplotype. The aims of this study were to investigate the association of haplotypes inferred from MMP1 rs1799750 (−1607 1G/2G; NC_000011.9:g.102670497del) and MMP3 rs35068180 (−1612 5A/6A; NC_000011.9:g.102715952dup) with MI and their effect on the change in echocardiographic parameters of LV structure and function in patients within 6 months after MI. Methods: The study included 325 patients with the first MI and 283 healthy controls. Gene variants were detected by PCR‐RFLP method. Parameters of LV structure and function were assessed by conventional 2D echocardiography, 3–5 days and 6 months after the first MI, on a subgroup of 160 patients. Haplotype analysis was performed with Thesias software. Results: Haplotypes 2G‐5A and 1G‐6A were significantly and independently associated with MI compared with the reference haplotype 2G‐6A (adjusted, p = 0.009 and p = 0.026, respectively). After Bonferroni correction for multiple testing, MMP1 and MMP3 haplotypes lost their association with the change in LV long diameter and stroke volume within 6 months after MI. Conclusion: MMP1 and MMP3 haplotypes are strongly associated with MI. Further studies are needed to validate this result and to examine their association with echocardiographic parameters of LV structure and function after MI. [ABSTRACT FROM AUTHOR]

Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Background: Lung cancer often metastasizes to the bone, which significantly complicates treatment and worsens patient prognosis. Thus, new therapeutic strategies need to be established. Using network pharmacology and bioinformatics analysis, this study sought to determine the molecular targets and associated mechanisms of the traditional Chinese medicine (TCM) Sophorae Flavescentis radix in the treatment of lung cancer bone metastasis., Methods: The active components of Sophorae Flavescentis radix were screened using the TCM Systems Pharmacology (TCMSP) platform based on drug-likeness and oral bioavailability. The target genes of these active compounds were obtained from the DrugBank database. Differentially expressed genes (DEGs) between primary and bone metastatic lung cancer samples were screened in the GSE175601 dataset from the Gene Expression Omnibus (GEO) database using GEO2R. The intersecting DEGs from both groups were used to construct a Venn diagram to identify the candidate target genes. The expression and prognostic relevance of these genes were validated in The Cancer Genome Atlas (TCGA) database. The GeneMania and Search Tool for Recurring Instances of Neighbouring Genes (STRING) databases were used to generate the protein-protein interaction networks. Molecular docking was performed using the PubChem, Protein Data Bank (PDB), and CB-DOCK2 databases. A Gene Set Enrichment Analysis (GSEA) was conducted to explore the possible mechanisms of action., Results: In the TCMSP database, 28 active compounds and 227 target genes of the Sophorae Flavescentis radix were identified. In total, 952 DEGs related to lung cancer bone metastasis were found in the GSE175601 dataset from the GEO database. Five common DEGs were identified via Venn diagram construction (i.e., F10, JUN, AKR1B1, MMP1, and CCND1 ). MMP1 was selected as the candidate gene. MMP1 was upregulated in lung cancer tissues, and patients with low MMP1 expression had better survival rates than those with high MMP1 expression (P<0.05). MMP1 has an affinity of -8.9 with luteolin. The GSEA results suggested that MMP1 might influence biological processes in lung cancer by participating in pathways such as chemokine signaling, apoptosis, Wingless/Integrated (Wnt) signaling, tumor protein p53-regulated cell cycle arrest, Hedgehog signaling, and mitogen-activated protein kinase signaling., Conclusions: Patients with lower MMP1 levels had prolonged overall survival and may serve as a novel predictive biomarker for lung cancer. Sophorae Flavescentis radix appears to exert therapeutic effects on lung cancer bone metastasis by inhibiting MMP1 expression and modulating the abnormal activation of the Wnt pathway. Our findings further extend the understanding of the pathogenic mechanisms and potential therapeutic interventions of Sophorae Flavescentis radix in lung cancer bone metastasis, providing a theoretical basis for clinical diagnosis and treatment research., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1947/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Papillary thyroid cancer (PTC) is one of the malignancies with an excellent prognosis. However, in PTC, progression or dedifferentiation into poorly differentiated thyroid cancer (PDTC) or anaplastic thyroid cancer (ATC) extremely jeopardizes patients’ prognosis. MMP1 is a zinc-dependent endopeptidase, and its role in PTC progression and dedifferentiation is unclear. In this study, transcriptome data of PDTC/ATC and PTC from the Gene Expression Omnibus and The Cancer Genome Atlas databases were utilized to perform an integrated analysis of MMP1 as a potential regulator of tumor progression and dedifferentiation in PTC. Both bulk and single-cell RNA-sequencing data confirmed the high expression of MMP1 in ATC tissues and cells, and further study verified that MMP1 possessed good diagnostic and prognostic value in PTC and PDTC/ATC. Up-regulated MMP1 was found to be positively related to more aggressive clinical characteristics, worse survival, extracellular matrix-related pathways, oncogenic immune microenvironment, more mutations, higher stemness, and more dedifferentiation of PTC. Meanwhile, in vitro experiments verified the high level of MMP1 in PDTC/ATC cell lines, and MMP1 knockdown and its inhibitor triolein could both inhibit the cell viability of PTC and PDTC/ATC. In conclusion, our findings suggest that MMP1 is a potential regulator of tumor progression and dedifferentiation in PTC, and might become a novel therapeutic target for PTC, especially for more aggressive PDTC and ATC.

Abstract Background Myocardial infarction (MI) leads to ischemia and afterward to left ventricular (LV) remodeling. Matrix metalloproteinase−1 (MMP1) and −3 (MMP3) belong to the family of endopeptidases and together they can dissolve most of the components of the extracellular matrix. MMP1 and MMP3 variants have been investigated solely in association with ischemic heart disease and LV dysfunction, but not in haplotype. The aims of this study were to investigate the association of haplotypes inferred from MMP1 rs1799750 (−1607 1G/2G; NC_000011.9:g.102670497del) and MMP3 rs35068180 (−1612 5A/6A; NC_000011.9:g.102715952dup) with MI and their effect on the change in echocardiographic parameters of LV structure and function in patients within 6 months after MI. Methods The study included 325 patients with the first MI and 283 healthy controls. Gene variants were detected by PCR‐RFLP method. Parameters of LV structure and function were assessed by conventional 2D echocardiography, 3–5 days and 6 months after the first MI, on a subgroup of 160 patients. Haplotype analysis was performed with Thesias software. Results Haplotypes 2G‐5A and 1G‐6A were significantly and independently associated with MI compared with the reference haplotype 2G‐6A (adjusted, p = 0.009 and p = 0.026, respectively). After Bonferroni correction for multiple testing, MMP1 and MMP3 haplotypes lost their association with the change in LV long diameter and stroke volume within 6 months after MI. Conclusion MMP1 and MMP3 haplotypes are strongly associated with MI. Further studies are needed to validate this result and to examine their association with echocardiographic parameters of LV structure and function after MI.

To observe the differences in clinical effect on knee osteoarthritis (KOA) between the holistic stratification acupotomy and the joint injection with sodium hyaluronate so as to provide a safe and effective treatment for KOA. A total of 100 KOA patients were randomly divided into an acupotomy group and a sodium hyaluronate group, 50 patients in each one. In the acupotomy group, the holistic stratification acupotomy was adopted. In the sodium hyaluronate group, sodium hyaluronate injection was applied in the joints. The index of Western Ontario and McMaster University (WOMAC) and the expressions of MMP1 and MMP13 in bursal fluid of the patients were compared before and after treatment in the patients between two groups before and after treatment, and the clinical therapeutic effect was observed. After treatment, WOMAC score of each dimension and the concentrations of MMP1 and MMP13 in bursal fluid of the patients of either group were all lower than those before treatment (all P < 0.05). After treatment, WOMAC score of each dimension and the concentrations of MMP1 and MMP13 in bursal fluid in the acupotomy group were lower than the sodium hyaluronate group (all P < 0.05). The total effective rate in the acupotomy group was higher than that of the sodium hyaluronate group (P < 0.05). Both the holistic stratification acupotomy and the joint injection with sodium hyaluronate are effective on KOA in this trial. However, the therapeutic effect of holistic stratification acupotomy is remarkable, which is probably related to the improvements in inflammatory response. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor worldwide with high morbidity and mortality. However, the diagnosis and molecular mechanisms of HNSCC remains poor. Methods: Robust rank aggregation method was performed to excavate the differentially expressed genes (DEGs) in five datasets (GSE6631, GSE13601, GSE23036, GSE30784, GSE107591) from the Gene Expression Omnibus. Search Tool for the Retrieval of Interacting Genes (STRING) database extracted hub genes from the protein‐protein interaction network. The expression of the hub genes was validated using expression profile from The Cancer Genome Atlas and Oncomine database. The module analysis and disease‐free survival analysis of the hub genes were analyzed by Cytoscape and the Kaplan‐Meier curve, respectively. The expression of hub genes was verified in clinical specimens. The functions of MMP1 which is most important in hub genes were explored in vitro and in vivo. Results: Totally, 235 DEGs were identified in the present study which consists of 103 up‐regulated and 132 down‐regulated genes which were significantly enriched in the molecular function of calcium ion binding followed in the biological process of skin development. The mainly enriched pathways were ECM (extracellular matrix)‐receptor interaction (hsa04512) and protein digestion and absorption (hsa04974). Six hub genes were screened out which showed dramatically increased expression in HNSCC samples compared with normal samples, including COL4A1, MMP1, PLAU, RBP1, SEMA3C, and COL4A2. These hub genes all showed worse disease‐free survival with higher expression and were up‐regulated in HNSCC clinical samples. MMP1 was proved to promote cell growth, migration, and phosphorylation of AKT in vitro and to promote liver metastasis in vivo. Conclusion: Bioinformatics analysis identified six key genes in HNSCC. Of these, MMP1 is the most likely biomarker. It activates the AKT pathway and promotes tumor progression. [ABSTRACT FROM AUTHOR]

Benzimidazole ring system is an important pharmacophore with diverse pharmacological activities. In this study, we explored the anti-arthritic effects of newly synthesized acetamide derivatives of 2-aminobenzimidazole (N1 and N2) in rats. FTIR and NMR spectroscopies were used to characterize these compounds. Carrageenan (CRG) induced paw edema model was used to test the acute anti-inflammatory activity of various doses (10, 20 and 30 mg/kg) of N1 and N2 compounds. Based on acute anti-inflammatory effects, the most potent dose of each compound was selected and investigated in complete freund's adjuvant (CFA) induced inflammatory arthritis (RA) model (n = 4 in each group). Histopathological, hematological, radiographic, and RT-qPCR analyses were performed to assess the progression or resolution of inflammatory arthritis. The tested compounds produced a dose-dependent anti-inflammatory activity against CRG induced paw inflammation and similarly reduced edema in CFA induced inflammatory arthritis model. Histopathological and X-ray analyses of ankle joints revealed minimal inflammation and normal joint structures in N1 and N2 treated groups. The tested compounds also reduced the levels of autoantibodies and restored hematological parameters. Interestingly, the tested compounds did not elevate aspartate aminotransferase and alanine transaminase levels and displayed a better safety profile than methotrexate. N1 and N2 compounds also attenuated the transcript levels of IRAK1, NF-kB1, TNF-α, IL-1β, IL17 and MMP1. In addition, N1 displayed a greater inhibition of mRNA levels of COX1, COX2, mPGES1 and PTGDS as compared to N2. Our findings demonstrate that N1 and N2 compounds possess strong anti-arthritic activity which can be attributed to the suppression of pro-inflammatory mediators. [ABSTRACT FROM AUTHOR]

Background: the impact of knee osteoarthritis (OA) poses a formidable challenge to older adults. Studies have reported that genetic factors, such as MMP1, are one of important risk factors for knee OA. Although the relationship between the genetic polymorphism of MMP1 rs1799750 and the risk of knee OA has been explored, conclusions have been nonunanimous and pending due to research sample sizes, one of determinants in studying genetic polymorphisms associated with disease. Objective: to establish a model to assess whether the genetic polymorphism of MMP1 rs1799750 is associated with knee OA based on an estimation of sample sizes. Methods: samples were collected from a case–control and meta-analysis study. In the case–control study, patients who underwent knee X-ray examinations based on the Kellgren–Lawrence Grading System (KL) as diagnostic criteria were recruited at the Health Examination Center of the Tri-Service General Hospital from 2015 to 2019. Gene sequencing was conducted using iPLEX Gold. Those with unsuccessful gene sequencing were excluded. Finally, there were 569 patients in the knee OA group (KL ≥ 2) and 534 participants in the control group (KL < 2). In the meta-analysis, we used the databases PubMed, EMBASE, and Cochrane to search for studies on the relationship between MMP1 rs1799750 and knee OA. Next, we adopted the trial sequential analysis (TSA) method to assess whether sample sizes were sufficient or not to determine the risk of the genetic polymorphism of MMP1 rs1799750 on knee OA in Caucasians and Asians. Results: in Caucasians, the MMP1 rs1799750 was not significantly associated with knee OA with an odds ratios (OR) of 1.10 (95% confidence interval, CI: 0.45–2.68). Some extra 8559 samples were needed to conclude this relationship in Caucasians by the TSA model. In Asians, neither our case–control study results (n = 1103) nor a combination of samples from the case–control and meta-analysis results showed an association between MMP1 rs1799750 and knee OA. The OR (95% CI) was 1.10 (0.81–1.49) in a combination of Asian samples. Some extra 5517 samples were needed to justify this relationship in Asians by the TSA model. Conclusions: this research shows that an extra 8559 and 5517 samples are needed in Caucasians and Asians, respectively, in order to justify the association between MMP1 rs1799750 and knee OA. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are single‐stranded RNAs which form a covalently closed continuous loop. Although originally shown to be non‐protein‐coding, some circRNAs can give rise to micropeptides. circRNAs have also been shown to play essential regulatory roles in a variety of developmental and disease processes. In a previous study, hsa_circ_0030998 was identified as a circRNA downregulated in lung cancer, but its potential implications and mechanisms in lung cancer were not addressed. Here, we showed that overexpressing circ_0030998 decreased proliferation, migration, and invasion of lung cancer cells, while also dampening resistance to Taxol, a classical antitumor drug. Depleting circ_0030998 reversed these phenotypic effects. A high circ_0030998 expression was correlated with a high survival rate in lung cancer patients. Additionally, we found circ_0030998 could downregulate miR‐558 expression, serving as a microRNA sponge. In conclusion, our data support that hsa_circ_0030998 can slow down the progression of lung cancer by targeting miR‐558 and suppress malignant phenotypes such as proliferation, migration, and invasion progression of lung cancer cells. Therefore, we highlight that circ_0030998 could be a novel tumor suppressor of lung cancer.

An approach towards the synthesis of novel isosteres of benzonaphthyridines and benzonaphthonaphthyridines from the condensation reaction between 4-chloro-2-methylquinolines/4-chloro-2-methylbenzo[ h ]quinoline and appropriate o -amino aromatic and heteroaromatic carboxylic acids by using solvent (ethanol)/solvent free (neat) condition to yield the intermediate followed by the cyclization with PPA. The intermediate yield has been slightly increased in neat (solvent-free) conditions compared to solvent conditions. Further, the target isosteres of benzonaphthyridines and benzonaphthonaphthyridines were achieved in the one-pot synthesis using a CuI catalyst with a higher yield than the stepwise method. Quantum chemical calculations of synthesized compounds are performed by using M06-2X with 6-311+G(d,p) basis set in water, DFT calculations of the molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs), and the optimized geometry of the XRD values are compared with experimental values. All the synthesized novel isosteres molecules are investigated under molecular docking studies using MMP1 and MMP2 proteins, which showed all the molecules have the potential to heal pancreatic cancer. The most potent molecules among them are 3i and 3h due to their better docking scores. Furthermore, the molecules' pharmacokinetic (ADME) parameters have been observed to be effective in future biological evaluations of these compounds to be active. [Display omitted] • Naphthyridines derivatives were synthesized using CuI catalyst. • The biological activity of synthesized ones was investigated against MMP1 and MMP2 proteins. • DFT analyses of synthesized compounds were performed using M06-2X method. • ADME analyses were done in detail. [ABSTRACT FROM AUTHOR]

[Display omitted] • Irbesartan attenuated oxidative stress, pro-inflammatory mediators and NLRP3 inflammasome/CASP-1 pathway. • Irbesartan serves as a cytoprotective agent, owing to its anti-inflammatory and immunomodulatory activities. • Irbesartan as a novel treatment against cyclophosphamide neurotoxicity. • Irbesartan as an immunomodulatory agent for the treatment of immunological disorders associated with inflammation. IIrbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has been widely employed in the medical field for its effectiveness in managing hypertension. However, there have been no documented investigations regarding the immunostimulatory properties of IRB. To address this gap, this study has been performed to assess the neuroprotective impact of IRB as an immunostimulatory agent in mitigating acute neurotoxicity induced by cyclophosphamide (CYP) in rats. mRNA levels of nuclear factor erythroid 2 (Nrf-2), interleukin (IL)-18, IL-1β, and MMP-1 have been assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the levels of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) has been evaluated to assess the oxidative stress. Additionally, macrophage inflammatory protein 2 (MIP2) has been evaluated using enzyme-linked immunosorbent assay (ELISA). Western blotting has been used to investigate the protein expression of nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) and caspase-1 (CASP-1), along with an assessment of histopathological changes. Administration of IRB protected against oxidative stress by augmenting the levels of GSH and SOD as well as reducing MDA level. Also, administration of IRB led to a diminishment in the brain levels of MIP2 and MMP1. Furthermore, it led to a suppression of IL-1β and IL-18 levels, which are correlated with a reduction in the abundance of NLRP3 and subsequently CASP-1. This study provides new insights into the immunomodulatory effects of IRB in the context of CYP-induced acute neurotoxicity. Specifically, IRB exerts its effects by reducing oxidative stress, neuroinflammation, inhibiting chemokine recruitment, and mitigating neuronal degeneration through the modulation of immune markers. Therefore, it can be inferred that the use of IRB as an immunomodulator has the potential to effectively mitigate immune disorders associated with inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Ca (OH)2 has long been regarded as the “gold standard” of direct pulp-capping materials, Ca(OH)2 is very saoluable in oral fluid, that make tunnel defect and unable to withstand bacterial recolonization. Propolis is a material created from resin gathered by bees (Apis mellifera) from a range of plants and combined with saliva and enzymes to form a nest. Propolis possesses anti-inflammatory properties that are superior to Ca (OH)2. Objective: The purpose of the research was carried out to integrate calcium hydroxide and propolis as pulp capping ingredients. Methods: This study used 30 samples maxillary first molars of Rattus norvegicus divided into 3 groups which were all preparated until perforation; The combination Ca (OH)2 and propolis extract group, calcium hydroxide group, and control group. The cavity was closed with Cention. Teeth section samples were taken from rats after 3 and 7 days then underwent decalcification and histological evaluation under light microscope to identify the presence of odontoblast-like cells, inflammatory cells, and dentinal bridges. Expression of MMP-1 and Collagen type 1 density evaluated with immunohistochemistry (IHC) method. Results: According to the observations, the majority of cells in the Calcium Hydroxide and Propolis extract group showed Collagen type 1 density, whereas the least number of cells showed MMP-1. Conclusion: Compared to calcium hydroxide to a combination of Ca (OH)2 and Propolis extract, MMP1 expression was lower and collagen type 1 density was higher in the rat’s pulp. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have reported a positive association between hypercholesterolemia and shoulder disease. Previous studies have focused on the effect of hypercholesterolemia on tendinopathy. Moreover, hypercholesterolemia has also been linked to joint pathology in the knee and hand. However, the effect of hyperlipidemia on glenohumeral joint remain unclear. A hypercholesterolemic condition has been reported to alter levels of A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAMTSs) and matrix metalloproteases (MMPs) in synovium of the knee joint. Here, we evaluated the mRNA expression of ADAMTSs and MMPs in the glenohumeral synovium of patients with and without hypercholesterolemia. Methods: Study participants were 73 patients who underwent arthroscopic rotator cuff repair for degenerative rotator cuff tears. They were divided into two groups according to total cholesterol (TC) and triglyceride levels. Synovial membrane samples were harvested at the rotator interval during surgery, and mRNA expression levels of the aggrecanases ADAM-TS4 and ADAM-TS5 and MMPs (MMP-1, 3, 9, and 13) were analyzed quantitatively. Results: ADAM-TS5 and MMP1 mRNA levels were significantly higher in the high TC group than in the low TC group (P = 0.023 and P = 0.025, respectively). In contrast, no significant differences were observed in ADAMTS4 or MMPs 3, 9, and 13 (ADAMTS4, P = 0.547; MMP3, P = 0.55; MMP9, P = 0.521; and MMP13, P = 0.785). Conclusion: Hypercholesterolemia may alter MMP1 and ADAMTS5 expression in the synovium of the glenohumeral joint. [ABSTRACT FROM AUTHOR]