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Background Material and methods Results Conclusion The objective of the current study was to investigate the potential effects of syringin against dextran sulphate colitis (DSS)‐induced ulcerative colitis (UC) in mice.In vitro study was performed on the RAW 264.7 cells and cytokines and inflammatory level were estimated. The oxidative stress, inflammatory cytokines, apoptosis and inflammatory parameters were estimated. The mRNA expression and faecal samples were estimated in the colon tissue.Syringin treatment enhanced the body weight, colon length and reduced the disease activity index (DAI), spleen index. Syringin treatment remarkably suppressed the level of nitric oxide (NO), myeloperoxidase (MPO), intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) along with alteration of antioxidant parameters. Syringin treatment also altered level of cytokines in the serum and colon tissue; inflammatory parameters viz., platelet‐activating factor (PAF), cyclooxygenase‐2 (COX‐2), prostaglandin (PGE2), inducible nitric oxide synthetase (iNOS), nuclear factor κ‐B (NF‐κB); matrix metalloproteinases (MMP) level. Syringin significantly (p < 0.001) enhanced the level of nuclear factor erythroid 2‐related factor (Nrf2) and heme oxygenase‐1 (HO‐1). Syringin remarkably altered the relative abundance of gut microbiota like Firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia and Actinobacteria.Syringin exhibited the protective effect against DSS‐induced UC in mice via alteration of NF‐κB signalling pathway. [ABSTRACT FROM AUTHOR]

Skin wound healing is a complex process which involves multiple molecular events and the underlying mechanism is not fully understood. We presented a comparative transcriptomic analysis of skin wound healing in humans and mice to identify shared molecular mechanisms across species. We analyzed transcriptomes from three distinct stages of the healing process and constructed protein-protein interaction networks to elucidate commonalities in the healing process. A substantial number of differentially expressed genes (DEGs) were identified in human transcriptomes, particularly upregulated genes before and after wound injury, and enriched in processes related to extracellular matrix organization and leukocyte migration. Similarly, the mouse transcriptome revealed thousands of DEGs, with shared biological processes and enriched KEGG pathways, highlighting a conserved molecular signature in skin wound healing. A total of 21 common DEGs were found across human comparisons, and 591 in mouse comparisons, with four genes (KRT2, MARCKSL1, MMP1, and TNC) consistently differentially expressed in both species, suggesting critical roles in mammalian skin wound healing. The expression trends of these genes were consistent, indicating their potential as therapeutic targets. The molecular network analysis identified five subnetworks associated with collagen synthesis, immunity, cell-cell adhesion, and extracellular matrix, with hub genes such as COL4A1, TLR7, TJP3, MMP13, and HIF1A exhibited significant expression changes before and after wound injury in humans and mice. In conclusion, our study provided a detailed molecular network for understanding the healing process in humans and mice, revealing conserved mechanisms that could help the development of targeted therapies across species. [ABSTRACT FROM AUTHOR]

This study explores the effect of dietary along with Lactobacillus rhamnosus GG (LGG) powder on intestinal and liver damage in broiler chickens challenged by lipopolysaccharide (LPS). A total of 100 healthy 1-day-old Ross 308 broiler chickens were selected and randomly divided into two treatments: the control group and the LGG treatment group. There were five replicates for each group, with 10 chickens per replicate. The chickens in the control group were fed a basal diet, while LGG treatment was supplemented with 1,000 mg/kg LGG along with the basal diet. The experiment lasted 29 days, and the trial included two phases. During the first 27 days, the animals were weighed on the 14th and 27th days to calculate growth performance. Then, on day 29, 2 animals from each replicate were intraperitoneally injected with 1 mg/kg BW LPS, and another 2 animals were treated with an equal volume of saline. The chickens were slaughtered 3 h later for sampling and further analysis. (1) LGG addition to the diet did not affect growth performance, including average daily gain (ADG), average daily feed intake (ADFI), and feed-to-weight ratio (F/G) of broiler chickens; (2) LPS stimulation decreased villus height (VH), and caused oxidative stress and increased the amount of diamine oxidase (DAO) in plasma, and the relative expression of intestinal inflammation genes (interleukin-8 [ IL-8 ], interleukin 1β [ IL-1β ], inducible nitric oxide synthase [ iNOS ], and tumor necrosis factor-α [ TNF-α ]) and the relative expression of liver injury genes (b-cell lymphoma 2 [ BCL2 ], heat shock protein70 [ HSP70 ], and matrix metallopeptidase 13 [ MMP13 ]). (3) Supplementation of LGG increased VH and the relative expression of intestinal barrier genes (mucins 2 [ Mucin2 ] and occludin [ Occludin ]) and decreased the amount of DAO in plasma and the relative expression of intestinal inflammatory factors (IL-8 , iNOS , and IL-1β). LGG supplementation also increased the expression of liver injury-related genes (MMP13 and MMP9). In conclusion, LGG enhanced intestinal barrier function, improved intestinal morphology, and alleviated the intestines' inflammatory response in LPS-stimulated broiler chicken, and it has a slightly protective effect on liver damage. [ABSTRACT FROM AUTHOR]

Aim: This study systematically evaluated the potential efficacy of serum matrix metalloproteinase-9 (MMP-9) concentration as a diagnostic marker for endometriosis through meta-analysis. Early and accurate diagnosis of endometriosis, a common gynecological disease, is crucial for improving patient prognosis. Hence, this study aimed to comprehensively analyze the data from multiple studies to assess the diagnostic value of serum MMP-9 concentration for endometriosis. Methods: Articles investigating the association between MMP-9 and endometriosis, published from the inception of the databases until February 2024, were systematically retrieved from multiple databases, including PubMed, Embase, Cochrane, Web of Science, Scopus, and CNKI. Download and analyze the GSE7305, GSE23339, and GSE51981 datasets. Statistical analyses of all eligible studies were conducted using RevMan 5.4, Stata 11.0, and R software version 4.3.3. Results: Fifteen studies fully met the inclusion criteria for the meta-analysis. The concentration of MMP-9 in the blood of patients with endometriosis was significantly higher compared to that of the control group (p < 0.0001). Subgroup analysis based on different stages of endometriosis revealed a trend towards significantly higher serum MMP-9 concentrations in patients, whether in stages I-II or III-IV. Bioinformatics analysis revealed differences in the expression of MMP-9 in endometrial tissue between EMT patients and healthy controls in the GSE7305 and GSE23339 datasets. Additionally, in the GSE51981 dataset, we found significant differences between the normal group and both mild and severe cases of endometriosis. Conclusion: Both the current meta-analysis and bioinformatics analysis indicate differences in MMP-9 concentration levels between endometriosis patients and healthy individuals, with potentially elevated MMP-9 concentrations in serum samples from patients with endometriosis. Systematic review registration: https://www.crd.york.ac.uk/prospero , identifier CRD42024525864. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of compound Xueshuantong combined with viaminate of oral lichen planus (OLP) complicated with chronic periodontitis (CP). Methods This study collected 305 patients with OLP and CP and randomly divided them into two groups. There were 156 patients in the observation group and 149 patients in the control group. All patients receive systemic treatment for CP. The control group was treated with viaminate capsules, and the observation group was treated with compound Xueshuantong Capsules combined with viaminate capsules. Both groups were treated for 4 weeks. Clinical efficacy, serum inflammatory factors [ matrix metalloproteinase-3 (MMP-3), IFN-gamma (IFN-7), interleukin 6 (IL-6) and IL-35 ], oral mucosal pain Visual Analogue Score (VAS), lesion area of OLP, periodontal condition, and adverse reactions were detected. Results Compared to the control group, the total effective rate in the observation group was higher (P < 0.05 ). After treatment, serum MMP-3 and IL-6 levels, oral mucosal VAS score, lesion area of OLP, gingival index and probing depth all decreased in the two groups (P < 0.05 ). The changes of above indicators were more significant in the observation group (P < 0.05). There was no difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion Compound Xueshuantong combined with viaminate can effectively improve the symptoms of OLP complicated with CP, and alleviate inflammatory reactions, with good therapeutic effects. [ABSTRACT FROM AUTHOR]

Introduction: The role of the complement inhibitory proteins CD46 and CD59 in the immune response to an acute coronary syndrome (ACS) is unknown. We investigated the relationships between the shedding of CD46 and CD59 into the circulation, reflected by plasma levels of soluble CD46 and CD59, and the risk for post-ACS complications. Methods: We measured plasma sCD46 and sCD59 in a cohort of 546 ACS patients within 24 h after hospital admission, and after 6-weeks in a subgroup of 114 patients. Study outcomes were incident heart failure (HF), major adverse cardiovascular events (MACE) and mortality during a median follow-up period of up to 3.3 years. Echocardiography at 1-year was performed in the follow-up subgroup. Results: Elevated sCD46 and sCD59 were correlated with increased levels of inflammatory mediators and metalloproteinases in plasma, and were associated with increased risk for MACE in Cox proportional hazard models adjusted for cardiovascular risk factors and revascularization [HR 95% CI 1.24 (1.02–1.52), p = 0.034 for sCD46 and 1.18 (1.00–1.38), p = 0.049 for sCD59]. Elevated sCD59 was also associated with higher incidence of HF [HR 95% CI 1.41 (1.15–1.74), p = 0.001], and with lower left ventricular ejection fraction at 1-year post-ACS (Spearman r = − 0.234, p = 0.020). We found no associations between plasma levels of the proteins at 6 weeks and outcomes. Conclusions: Shedding of the complement regulators CD46 and CD59 in plasma in the acute phase of ACS is associated with a negative prognosis. Plasma sCD46 and sCD59 could reflect the degree of local immune activation and serve as prognostic biomarkers in ACS patients. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidences have stressed the association between hypoxanthine phosphoribosyl transferase 1 (HPRT1) overexpression and the poor prognosis of various cancers. Our study, herein, preliminarily investigates the involvement of HPRT1 in nasopharyngeal carcinoma (NPC). Methods: Data from TCGA were applied to read HPRT1 expression in diverse cancers including NPC and to predict the prognosis of NPC patients. The total RNA and protein from NPC cells and nasopharyngeal epithelial cells NP460 were extracted to quantify HPRT1 expression. Following the completion of transfection, the proliferation and migration of NPC cells were determined employing MTT, colony formation and western blot assay (the quantification on expressions of protein related to proliferation and migration). Results: HPRT1 was differentially expressed in diverse cancers yet particularly highly expressed in NPC, and high HPRT1 expression was related to the poor prognosis of NPC patients. Also, HPRT1 expression was higher in NPC cells and its silencing diminished the viability and proliferation of NPC cells and reduced the expressions of CyclinD1, CyclinE, Multidrug Resistance Protein 1 (MDR1), matrix metalloproteinase (MMP)-2, and MMP-9. Conclusion: This study preliminarily explored the involvement of HPRT1 in NPC based on some cellular assays in vitro, which may provide evidence for investigating the specific mechanism underlying the effects of HPRT1 in cancers. [ABSTRACT FROM AUTHOR]

In this multi-parameter study, the effect of diverse factors related to adhesive application on the activation of host-derived gelatinases was investigated by gelatin zymography, in-situ zymography, fluorogenic DQ-gelatin assay and micro-tensile bond-strength (μTBS) testing. Gelatin zymography disclosed the presence of gelatinases in phosphoric acid-etched dentin powder, while two gold-standard adhesives generated no measurable MMP activation. In-situ zymography revealed that the interfacial gelatinolytic activity from specimens treated with the two adhesives appeared similar as that of the EDTA negative control, indicating no detectable gelatinases were activated upon adhesive treatment. In solution, MMP-2/9 activity significantly decreased upon interaction with both adhesives (two-way linear mixed effects model [LMEM]: p < 0.05); gelatinases were almost completely deactivated upon 1-week incubation at 37 °C (general linear model: p < 0.05); light-curing adhesives increased temperature up to 55 °C, which appeared sufficient to dramatically decrease MMP-2/9 activity (two-way ANOVA: p < 0.05). Finally, challenging adhesive-dentin interfaces with highly concentrated MMP-9 (at a much higher concentration than present in saliva) for 1 m did not significantly affect μTBS (two-way LMEM: p > 0.05). Taken together, the two adhesives did not activate but rather inhibited the release and activation of dentinal gelatinases. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the therapeutic effects and mechanisms of PRP-exos combined with cyclic peptide-modified β-TCP scaffold in the treatment of rabbit knee cartilage defect. Methods: PRP-exos were extracted and characterized by TEM, NTA and WB. The therapeutic effects were evaluated by ICRS score, HE staining, Immunohistochemistry, qRT-PCR and ELISA. The repair mechanism of PRP-exos was estimated and predicted by miRNA sequencing analysis and protein–protein interaction network analysis. Results: The results showed that PRP-exos had a reasonable size distribution and exhibited typical exosome morphology. The combination of PRP-exos and cyclic peptide-modified β-TCP scaffold improved ICRS score and the expression level of COL-2, RUNX2, and SOX9. Moreover, this combination therapy reduced the level of MMP-3, TNF-α, IL-1β, and IL-6, while increasing the level of TIMP-1. In PRP-exos miRNA sequencing analysis, the total number of known miRNAs aligned across all samples was 252, and a total of 91 differentially expressed miRNAs were detected. The results of KEGG enrichment analysis and the protein–protein interaction network analysis indicated that the PI3K/AKT signaling pathway could impact the function of chondrocytes by regulating key transcription factors to repair cartilage defect. Conclusion: PRP-exos combined with cyclic peptide-modified β-TCP scaffold effectively promoted cartilage repair and improved chondrocyte function in rabbit knee cartilage defect. Based on the analysis and prediction of PRP-exos miRNAs sequencing, PI3K/AKT signaling pathway may contribute to the therapeutic effect. These findings provide experimental evidence for the application of PRP-exos in the treatment of cartilage defect. [ABSTRACT FROM AUTHOR]

Beyond Th2 cells and various immune cells, M2 macrophages have been identified in lesional skin of atopic dermatitis (AD) indicating their involvement in the disease's underlying mechanisms. MMP12, a matrix-degrading enzyme, which is predominantly produced by macrophages, is increased in skin lesions of AD patients. In this study we investigated the expression of MMP12 mRNA in lesional AD skin at single cell level through RNA sequencing (scRNA-seq) and the expression of MMP12 in M2 macrophages from healthy individuals and AD patients in response to Th2 cytokines and histamine using quantitative PCR and ELISA. Additionally, we analyzed macrophages from dupilumab-treated AD patients using the same methods to assess the influence of Th2 cytokines on MMP12 expression ex-vivo. ScRNA-seq identified macrophages as the primary producers of MMP12 in lesional AD skin. In-vitro, both MMP12 mRNA and protein expression were significantly increased in monocytes during differentiation to M2 macrophages in the presence of histamine, of Th2 cytokines or of Th2 cytokines in combination with histamine. In M2 macrophages obtained from dupilumabtreated AD patients, the upregulation of MMP12 expression by IL-4 and IL-13 was attenuated. Our findings unveil a novel mechanism whereby Th2 cytokines and histamine regulate MMP12 expression, potentially impacting skin barrier homeostasis in AD. [ABSTRACT FROM AUTHOR]

Conventional chemotherapeutic agents are limited by their lack of targeting and penetration and their short retention time, and chemotherapy might induce an immune suppressive environment. Peptide self‐assembly can result in a specific morphology, and the resulting morphological changes are stimuli responsive to the external environment, which is important for drug permeation and retention of encapsulated chemotherapeutic agents. In this study, a polypeptide (Pep1) containing the peptide sequences PLGLAG and RGD that is responsive to matrix metalloproteinase 2 (MMP‐2) was successfully developed. Pep1 underwent a morphological transformation from a spherical structure to aggregates with a high aspect ratio in response to MMP‐2 induction. This drug delivery system (DI/Pep1) can transport doxorubicin (DOX) and indomethacin (IND) simultaneously to target tumor cells for subsequent drug release while extending drug retention within tumor cells, which increases immunogenic cell death and facilitates the immunotherapeutic effect of CD4+ T cells. Ultimately, DI/Pep1 attenuated tumor‐associated inflammation, enhanced the body's immune response, and inhibited breast cancer growth by combining the actions of DOX and IND. Our research offers an approach to hopefully enhance the effectiveness of cancer treatment. [ABSTRACT FROM AUTHOR]

Dentin integrity is a critical aspect of tooth structure, with matrix metalloproteinases (MMPs) playing a crucial role in dentinogenesis, caries formation, and dental bonding. It is crucial to accurately assess MMP activity to understand dentin pathophysiology and develop effective clinical strategies. Objectives: The study aimed to conduct a thorough review and comprehensive summary of diverse techniques employed in assessing MMPs in dentin. Data and sources: To conduct the research, electronic databases were systematically searched and manual citation searches were performed. A total of 621 articles were identified. After eliminating duplicates and irrelevant studies, 70 articles were included in the review. 25 articles with overlapping methodologies were also excluded. Study selection: The selection criteria were based on the relevance of the studies to MMPs and MMP inhibitors in dentin without regard to the study design. Only peer-reviewed articles published in English were included. The search was restricted to studies published until November 2022. Conclusion: The comprehensive analysis of various studies has yielded 37 techniques for evaluating MMPs and MMP inhibitors, which hold significant promise in creating diagnostic markers and devising targeted therapeutic interventions. • Collagen degradation products serve as biomarkers for MMP activity, offering valuable insights into MMP-mediated proteolysis. • The classification of methods for assessing MMP provides a framework for analysing and understanding MMPs in dentin. • The assessment of MMP and MMP inhibitors helps us understand the functional consequences of MMP-mediated effects. [ABSTRACT FROM AUTHOR]

This study compared the effectiveness of various cleaning approaches, including spray rinsing, repreparing with diamond burs, and using phosphoric acid or sodium hypochlorite alone or with polyphenols (resveratrol or myricetin), in removing blood contamination from the dentine after adhesive light-curing. The contact angles of the treated surfaces were measured and scanning electron microscopy/ energy dispersive X-ray spectroscopy observation was performed. The bond strength and nanoleakage were assessed, and in situ zymography was performed before and after aging. Interactions between matrix metalloproteinase (MMP)−9 and polyphenols were evaluated using molecular dynamics and rhMMP-9 inhibition analyses. The destruction of sodium hypochlorite on collagen and the resistance of polyphenols-treated dentine collagen to enzymolysis were evaluated using the hydroxyproline (HYP) assay. The effect of polyphenols on dentine collagen crosslinking was assessed by Fourier Transform Infrared Spectroscopy. The repreparation group had the lowest contact angle compared to the other groups. The spray rinsing group had the lowest bond strength and highest amounts of nanoleakage. Cleaning with phosphoric acid or sodium hypochlorite alone removed the blood contaminants and parts of the adhesive; moreover, applying polyphenols further improved the bond strength and decreased nanoleakage and MMP activity after aging. Both polyphenols inhibited rhMMP-9 activity and promoted collagen crosslinking. Sodium hypochlorite showed the maximum HYP release when used alone, which was decreased after adding polyphenols. Phosphoric acid or sodium hypochlorite cleaning can remove blood contamination from the dentine surface after adhesive curing, and the addition of polyphenols can improve the durability of dentine bonding. [Display omitted] • Phosphoric acid or sodium hypochlorite cleaning removed blood and part of the cured adhesive. • Phosphoric acid or sodium hypochlorite cleaning restored dentine bonding influenced by blood contamination. • Resveratrol and myricetin improved the resistance of collagen to exogenous enzymes. • Resveratrol and myricetin inhibited MMP activity and promoted collagen cross-linking. • Resveratrol and myricetin can contribute to the durability of the dentine bonding. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression levels of tumor necrosis factor a (TNF-α), interleukins (ILs), matrix metalloproteinases (MMPs), and chitinase (YKL-40) in the knee joint fluid of patients with knee osteoarthritis (KOA), and their correlations with Kellgren-Lawrence (K-L) grade of knee imaging. Methods A total of 100 KOA patients undergoing the knee arthroplasty were enrolled and their knee joint fluid was extracted before the joint surgery. The expression levels of TNF-α, IL-1β, IL-6, IL-8, IL-15, and MMP-3, MMP-9, MMP-13, YKL-40 in the knee joint fluid were detected using cytometric bead array and ELISA, respectively. Patients were grouped according to the K-L scores. The independent influencing factors of KL-4 were determined by comparison between the two groups and binary logistic regression. Spearman method was used to analyze the correlations between the above molecules and K-L grades. Results Among 100 patients with KOA, 25 were males and 75 were females. The mean age was 64. 32 years and the mean course of the disease was 8. 98 years. There were 55 with KL-3 grade and 45 with KL-4 grade. TNF-α, IL-1β, MMP-13, and YKL-40 were highly expressed in KL-3, while IL-6, IL-8, IL-15, MMP-3, and MMP-9 were highly expressed in KL-4. IL-15 and MMP-9 were significantly different between the two groups (P < 0.05) . The result of univariate and multivariate logistic regression showed that IL-15 odds ratio (OR) = 1.575 95% confidence interval (CI): 1.286-1.929; P < 0.001 ] and MMP-9 ( OR = 1.032, 95% CI: 1.008-1.056, P = 0.01 ) were independent risk factors for the KL-4. IL-15 ( r = 0.22 P < 0.05 ) and MMP-9 r = 0.297 P < 0.05 ) were positively correlated with K-L grades. Conclusion The expressions of IL-15 and MMP-9 in the knee joint fluid of KOA patients are higher than that of KL-4 patients. IL-15 and MMP-9 are independent risk factors for the KL-4. There is a positive correlation between IL-15 and MMP-9 levels and the progression of radiographic K-L grades. IL-15 and MMP-9 may provide references for clinical evaluation and progression of this disease. [ABSTRACT FROM AUTHOR]

Introduction: Matrix Metalloproteinase 3 (MMP3) is a vital member of the MMP family, known for its wide range of substrate specificity and proteolytic activity against Extracellular Matrix (ECM) components. The role of functional polymorphisms in the MMP genes has been previously investigated in relation to cancer susceptibility, particularly breast cancer. Several Single- Nucleotide Polymorphisms (SNPs) in the MMP3 gene have been linked to a number of clinical illnesses, such as Coronary Artery Disease (CAD); however, the results were not entirely conclusive. Aim: To identify pathogenic missense SNPs in the human MMP3 gene and analyse their effects on structure and function. Materials and Methods: This was a record-based cross-sectional study performed using data retrieved from online resources. The analysis was conducted using a series of different bioinformatic tools, for which ethical clearance was obtained from the institution. The online tools used included Sorting Intolerant from Tolerant (SIFT), PolyPhen-2, PhD-SNP, PANTHER, PROVEAN, and SNPs and GO to predict harmful non synonymous SNPs (nsSNPs). Further analysis was performed using I-Mutant 2.0, MutPred2, Consurf, and HOPE software. These tools were able to filter out damaging SNPs and predict the impact of deleterious SNPs on the structure and function of the MMP3 protein. Results: This study predicted two potentially pathogenic SNPs (D175Y and Y116C) out of 443 missense SNPs from dbSNP, which is a database of SNPs available on the National Centre for Biotechnology Information website. Further analysis revealed that these SNPs were located in highly conserved regions and were predicted to decrease protein stability. Conclusion: In this study, two potentially pathogenic SNPs (D175Y and Y116C) were identified. Characterisation of these SNPs can help us gain a better understanding of the molecular basis of clinical conditions. The results of this study can be further validated by designing population-based studies and wet lab experiments. This will help in augmenting research and personalised medicine. [ABSTRACT FROM AUTHOR]

Overexposure to ultraviolet (UV) radiation accelerates skin aging, resulting in wrinkle formation, reduced skin elasticity, and hyperpigmentation. UV irradiation induces increased matrix metalloproteinases (MMPs) that degrade collagen in the extracellular matrix. Skin aging is also accompanied by epigenetic alterations such as promoter methylation by DNA methyltransferases, leading to the activation or suppression of gene expression. Although carnitine acetyltransferase (CRAT) is implicated in aging, the effect of UV on the expression of CRAT and regulatory mechanisms of UV-induced MMP-1 expression remain unknown. We investigated changes in CRAT expression upon UV irradiation and its effect on MMP-1 expression. Primary human dermal fibroblasts were UV irradiated with either control or 5-AZA-dC. CRAT knockdown or overexpression was performed to investigate its effect on MMP-1 expression. The mRNA level was analyzed by quantitative real-time PCR, and protein level by western blotting. The expression of CRAT was decreased in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. CRAT was downregulated upon UV irradiation by hypermethylation, and treatment with 5-Aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, reversed UV-induced downregulation of CRAT. CRAT knockdown activated the JNK, ERK, and p38 MAPK signaling pathways, which increased MMP-1 expression. Stable overexpression of CRAT alleviated UV-induced MMP-1 induction. CRAT downregulation caused by promoter hypermethylation may play an important role in UV-induced skin aging via upregulation of MMP-1 expression. • CRAT is significantly downregulated by promoter hypermethylation. • CRAT affects skin photoaging by inducing MMP-1 via the ERK, JNK, and p38 pathways. • Epigenetic regulation of CRAT may enable therapeutic approaches for anti-photoaging. [ABSTRACT FROM AUTHOR]

Background: Injuries to the glenoid labrum have been recognized as a source of joint pain and discomfort, which may be associated with the inflammatory responses that lead to the deterioration of labral tissue. However, it is unclear whether the torn labrum prompts mast cell (MC) activation, resulting in synovial inflammatory responses that lead to labral tissue degeneration. Purpose: To determine the potential influence of activated MC on synovial inflammatory responses and subsequent labral tissue degeneration and shoulder function deterioration in a rat model by monitoring MC behavior and sequential inflammatory responses within the synovial tissue and labral tissue after injury, suture repair, and MC stabilizer administration. Study Design: Controlled laboratory study. Methods: Anteroinferior glenoid labral tears were generated in the right shoulder of rats (n = 20) and repaired using a tunneled suture technique. Synovial tissue inflammatory responses were modulated in some rats with intraperitoneal administration of an MC stabilizer—cromolyn (n = 10). At weeks 1 and 3, MC activation, synovial inflammatory responses, and labral degeneration were histologically evaluated. Simultaneously, gait analysis was performed before and after surgical repair to assess the worsening of the shoulder function after the injury and treatment. Results: Resident MC degranulation after labral injury (50.48% ± 8.23% activated at week 1) contributed to the initiation of synovial tissue inflammatory cell recruitment, inflammatory product release, matrix metalloproteinase-13, and subsequent labral tissue extracellular matrix degeneration. The administration of cromolyn, an MC stabilizer, was found to significantly diminish injury-mediated inflammatory responses (inflammatory cell infiltration and subsequent proinflammatory product secretion) and improve shoulder functional recovery. Conclusion: MC activation is responsible for labral tear–associated synovial inflammation and labral degeneration. The administration of cromolyn can significantly diminish the cascade of inflammatory reactions after labral injury. Clinical Relevance: Our findings support the concept that MC stabilizers may be used as a complementary therapeutic option in the treatment and repair of labral tears. [ABSTRACT FROM AUTHOR]

Background: Erectile dysfunction has been associated with leisure sedentary behavior in several epidemiological and observational studies. However, the interpretation of these findings is difficult due to residual confounding or reverse causality. Objectives: To explore the causal association between leisure sedentary behavior and erectile dysfunction, and to explore the underlying mechanism using Mendelian randomization. Materials and methods: In the present study, publicly available large‐scale genome‐wide association studies of leisure sedentary behaviors (television watching, computer use, and driving), erectile dysfunction, sex hormones (total testosterone, bioactive testosterone, estradiol, follicle‐stimulating hormone, luteinizing hormone, prolactin, and sex hormone binding globulin), biomarkers of endothelial function (C reactive protein, E‐selectin, and matrix metalloproteinase 7), and psychiatric symptoms (depression and anxiety) were used to perform two‐sample Mendelian randomization analyses. The inverse variance weighting method was the main method used to estimate the association, and sensitivity analyses were also performed. Results: A greater risk of erectile dysfunction was significantly associated with a higher genetic susceptibility to leisure computer usage (odds ratio = 3.57; 95% confidence interval = 1.78–7.16; p < 0.001). No evidence was obtained to suggest that watching television or driving for leisure increased the risk of erectile dysfunction. No association was found between computer use and depression, anxiety, C reactive protein, E‐selectin, matrix metalloproteinase 7, or other sex hormones, with the exception of follicle‐stimulating hormone levels (odds ratio = 0.29; 95% confidence interval = 0.12–0.69; p = 0.01). No indication of heterogeneity or pleiotropy was identified by sensitivity analysis. Discussion: Extended computer usage for leisure raised the likelihood of developing erectile dysfunction, which may be associated to lower follicle‐stimulating hormone levels; however, the role of endothelial dysfunction and psychological disorders in the development of erectile dysfunction should not be underestimated. Moderate physical activity may help to correct the dysfunction. Conclusion: The present study offered substantial evidence for a positive causal association between computer use and the risk of erectile dysfunction. However, a definitive causal association needs to be established by further research. [ABSTRACT FROM AUTHOR]

Inflammation and autoimmunity are known as central processes in many skin diseases, including psoriasis. It is therefore important to develop pre-clinical models that describe disease-related aspects to enable testing of pharmaceutical drug candidates and formulations. A widely accepted pre-clinical model of psoriasis is the imiquimod (IMQ)-induced skin inflammation mouse model, where topically applied IMQ provokes local skin inflammation. In this study, we investigated the abundance of a subset of matrix metalloproteinases (MMPs) in skin from mice with IMQ-induced skin inflammation and skin from naïve mice using targeted proteomics. Our findings reveal a significant increase in the abundance of MMP-2, MMP-7, MMP-8, and MMP-13 after treatment with IMQ compared to the control skin, while MMP-3, MMP-9, and MMP-10 were exclusively detected in the IMQ-treated skin. The increased abundance and broader representation of MMPs in the IMQ-treated skin provide valuable insight into the pathophysiology of skin inflammation in the IMQ model, adding to previous studies on cytokine levels using conventional immunochemical methods. Specifically, the changes in the MMP profiles observed in the IMQ-treated skin resemble the MMP patterns found in skin lesions of individuals with psoriasis. Ultimately, the differences in MMP abundance under IMQ-induced inflammation as compared to non-inflamed control skin can be exploited as a model to investigate drug efficacy or performance of drug delivery systems. [Display omitted] • MMP landscape in skin inflammation mouse model analyzed for the first time using MS. • Increase in MMP-2, MMP-7, MMP-8 and MMP-13 abundance in inflamed mouse skin samples. • MMP-3, MMP-9, and MMP-10 were exclusively detected in inflamed mouse skin. • MMP profiles in inflamed mouse skin resemble those in skin of psoriasis patients. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis (OA) is a degenerative disease of the joints characterized by inflammation and cartilage degeneration. Zinc finger E-box binding homeobox 2 (ZEB2) contains various function domains that interact with multiple transcription factors involved in various cellular functions. However, the function of ZEB2 in OA has not been clearly illustrated. Method: Interleukin-1β (IL-1β) was used to establish an OA model in vitro. We quantified the ZEB2 expression in cartilage tissues from OA patients and IL-1β-induced chondrocytes through reverse transcription–quantitative polymerase chain reaction and Western blot. We then used functional assays to explore the function of ZEB2 during OA progression. Results: ZEB2 expression was increased in OA cartilage tissues and chondrocytes. The silencing of ZEB2 increased aggrecan and collagen II levels, and reduced the content of matrix metalloproteinase-3 (MMP-3), MMP-9, and MMP-13. ZEB2 knockdown inhibited the effects of IL-1β on the production of nitric oxide and prostaglandin E2, and the expression of inducible nitric oxide synthase and cyclooxygenase-2. ZEB2 inhibition also suppressed the levels of IL-6 and tumour necrosis factor-α, and increased the IL-10 level in IL-1β-treated cells. Mechanically, ZEB2 knockdown blocked the activation of the Wnt/β-catenin pathway in chondrocytes. Conclusion: Knockdown of ZEB2 alleviated IL-1β-induced cartilage degradation and the inflammatory response through the Wnt/β-catenin pathway in chondrocytes. [ABSTRACT FROM AUTHOR]

Different therapeutic modalities, including steroids, have been used to treat corneal scarring. However, the ability of steroids to reduce corneal scarring is limited and associated with numerous side effects. Our previous studies have demonstrated that topical hepatocyte growth factor (HGF) after corneal injury suppresses the development of stromal scars. Here, we investigated whether HGF can re-establish corneal clarity and normalize tissue structure in corneas with pre-existing scars. Corneal scarring was induced by mechanically removing the corneal epithelium and the anterior third of the stroma using a hand-held Algerbrush II in C57BL/6 mice. Substantial scar tissue formed by day 10 post-injury, at which time the epithelium was debrided and treated with 0.1% recombinant mouse HGF, 0.1% dexamethasone (steroid) or 0.1% control protein thrice a day for 10 days. Corneal clarity was significantly restored in the HGF treatment group, compared to both the steroid and control protein treatment groups. Moreover, HGF treatment downregulated the expression of αSMA and upregulated the expression of extracellular matrix-remodeling matrix metalloproteinases 1 and 10 (MMP1 and MMP10), suggesting HGF upregulates tissue remodeling molecule MMP1 and 10 to promote tissue restoration. These findings offer novel insights into the mechanisms by which HGF re-establishes corneal clarity, and promotes epithelial regeneration in corneas with pre-existing stromal scarring. [ABSTRACT FROM AUTHOR]

Purpose: To explore the expression of matrix metalloproteinase-3 (MMP-3) in the aqueous humor of patients with Posner-Schlossman syndrome (PSS), and the association between MMP-3 and PSS. Methods: Peripheral blood and aqueous humor were routinely collected from 29 patients with PSS (PSS group) and 30 patients with age-related-cataract (ARC) (control group). The content of MMP-3 in serum and aqueous humor was measured by immunoturbidimetry. The correlation between MMP-3 and ophthalmic examination results were verified by Spearman's correlation analysis. Results: The MMP-3 level in the aqueous humor of the PSS group was (25.86 ± 13.4)ng/ml, significantly higher than that in the control group (3.9 ± 2.7)ng/ml(p < 0.001), while there was no significant difference in serum MMP-3 level between the two groups (p = 0.125). The endothelial cell density (ECD) in the aqueous humor of the PSS group was (2078 ± 440) cell/mm2, intraocular pressure (IOP) in the aqueous humor of the PSS group was (33 ± 12) mmHg. The correlation analysis of aqueous humor MMP-3 and various ophthalmic examination results showed that aqueous humor MMP-3 had a moderate correlation with IOP and the difference in ECD between the affected eye and the fellow eye. Conclusions: MMP-3 level is elevated in the aqueous humor of PSS patients, and it may play an important role in the pathogenesis of PSS. [ABSTRACT FROM AUTHOR]

Aim: To investigate the influence of diabetes mellitus (DM) in a murine model of peri‐implantitis (PI). Materials and Methods: Twenty‐seven 4‐week‐old C57BL/6J male mice had their first and second maxillary left molars extracted. Eight weeks later, one machined implant was placed in each mouse. Four weeks after osseointegration, the mice were divided into three groups: (a) control (C), (b) PI and (c) DM + PI. DM was induced by streptozotocin (STZ) administration. After DM induction, PI was induced using ligatures for 2 weeks. The hemimaxillae were collected for micro‐CT and histological analyses. The primary outcomes consisted of linear (mm) and volumetric (mm3) bone loss. Secondary outcomes were based on histological analysis and included inflammatory infiltrate, osteoclastic activity, matrix organization, composition and remodelling. Data are presented as means ± SEM. Statistical analyses were performed using one‐way ANOVA, followed by Tukey's test. Results: Gingival tissue oedema was detected in the PI and DM + PI groups. Micro‐CT showed significantly increased linear and volumetric bone loss in the DM + PI group compared to the C and PI groups. H&E staining showed greater inflammatory response and bone resorption in the PI and DM + PI groups than in the C group. The DM + PI group had significantly higher osteoclast numbers than the C and PI groups. Picrosirius red stained less for types I and III collagen in the PI and DM + PI groups than in the C group. There was a significant increase in monocyte/macrophage (CD‐11b) counts and matrix metalloproteinases (MMP‐2 and MMP‐8) marker levels and a significant decrease in the matrix metalloproteinases inhibition marker (TIMP‐2) levels in the DM + PI group compared to the C and PI groups. Conclusions: DM exacerbates PI‐induced soft‐tissue inflammation, matrix degradation and bone loss. [ABSTRACT FROM AUTHOR]

Background: Syndecan 4 (SDC4), a type I transmembrane proteoglycan, serves as a critical link between chondrocytes and the extracellular matrix. Objective: This study aimed to explore the role of SDC4 in cartilage degeneration of temporomandibular joint osteoathritis (TMJOA). Methods: Condylar chondrocytes were stimulated with varying concentrations of recombinant rat interleukin‐1β (rrIL‐1β) and SDC4 small interfering RNA (si‐SDC4). Anti‐SDC4 ectodomain‐specific antibodies or IgG were intra‐articularly administrated in a TMJOA model rats. SDC4 conditional knockout (SDC4‐cKO) and Sdc4flox/flox mice were induced TMJOA. Cartilage degeneration was assessed using haematoxylin & eosin (H&E) and safranin O (SO) staining. Protein levels of SDC4, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with a thrombospondin motifs 5 (ADAMTS5), tumour necrosis factor α (TNFα), type II collagen (Col‐II), aggrecan (ACAN), cleaved caspase 3 (CASP3), Ki67 and related pathways in condylar cartilage were evaluated by immunohistochemical (IHC) staining or western blot assays. Results: SDC4 expression was evidently increased in MIA‐model animals compared to control groups. rrIL‐1β stimulation increased the expression of SDC4, MMP3 and ADAMTS5 expression in chondrocytes, while decreasing the expression of Col‐II. These effects were reversed by si‐SDC4 in vitro. In vivo, SDC4 blockade reduced the death of chondrocytes and the loss of cartilage matrix, which was evidenced by increased expression of Col‐II and ACAN, and a decrease in SDC4, MMP13 and cleaved‐CASP3‐positive cells. Furthermore, the protein levels of ACAN and Ki67 were elevated, and the ERK1/2 and P38 signalling pathways were activated following SDC4 inhibition. Conclusions: SDC4 inhibition significantly ameliorates condylar cartilage degeneration, which was mediated, at least partly, through P38 and ERK1/2 signalling. Inhibition of SDC4 may be of great value for the treatment of TMJOA. [ABSTRACT FROM AUTHOR]

Parecoxib, a well‐recognized nonsteroidal anti‐inflammatory drug, has been reported to possess anticancer properties in various tumor types. In this work, we aimed to investigate the potential anticancer effects of parecoxib on hepatocellular carcinoma (HCC) cells. To assess the impact of parecoxib on HCC cell proliferation, we employed Cell Counting Kit‐8, colony formation, and 5‐ethynyl‐2′‐deoxyuridine assays. Hoechst/propidium iodide (PI) double staining and flow cytometry were performed to evaluate apoptosis and cell cycle analysis. Wound healing and transwell assays were utilized to assess cell migration and invasion. Tube formation assay was employed to analyze angiogenesis. Protein levels were determined using western blotting, and mRNA expression levels were assessed using quantitative real‐time polymerase chain reaction (PCR). A xenograft mouse model was used to confirm the antitumor effects of parecoxib on HCC tumors in vivo. Our data demonstrated that parecoxib effectively inhibited the proliferation of HCC cells in a dose‐ and time‐dependent manner. In addition, parecoxib induced cell cycle arrest in the G2 phase and promoted apoptosis. Moreover, parecoxib hindered tumor migration and invasion by impeding the epithelial–mesenchymal transition process. Further investigation showed that parecoxib could significantly suppress angiogenesis through the inhibition of extracellular signal‐regulated kinase (ERK)–vascular endothelial growth factor (VEGF) axis. Notably, treatment with the ERK activator phorbol myristate acetate upregulated the expression of matrix metalloproteinase (MMP)‐2, MMP‐9, and VEGF and reversed the function of parecoxib in HCC cells. Besides, parecoxib displayed its antitumor efficacy in vivo. Collectively, our results suggest that parecoxib ameliorates HCC progression by regulating proliferation, cell cycle, apoptosis, migration, invasion, and angiogenesis through the ERK–VEGF/MMPs signaling pathway. [ABSTRACT FROM AUTHOR]

Fluoroquinolones (FQ), commonly prescribed antibiotics, may trigger aortic and carotid dissections. We report three successive cases of visceral artery dissection: one patient with celiac trunk dissection and two with dissection of the superior mesenteric artery. These events occurred up to 4 months after 7 to 14 days of FQ treatment (2 cases of ofloxacin, 1 of norfloxacin). There was no other apparent cause of dissection. These dissections were isolated, apart from a minimal aortic dissection separate from the visceral arterial dissection in one case. A case series cannot certify the relationship between dissection and FQ, but it can be hypothesized. The association between fluoroquinolone use and higher occurrence of aneurysm and dissection remains discussed in aortic syndrome. The potential link between FQ and visceral artery dissection is even less described but should be reported in the absence of previous cases in the literature. The pathophysiological theory is the induction of overexpression of some matrix metalloproteinases and a decrease of their inhibitors, provoking a dysregulation in collagen synthesis and degradation of the extracellular matrix. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of applying a matrix metalloproteinase (MMP) inhibitor on the fracture resistance of root-filled teeth restored with Everstick fiber-reinforced composite resin. Subjects and Methods: After the selection of 60 freshly extracted human mandibular first molar, root canal access and standard uniformly sized mesio-occluso-distal (MOD) cavities were made and the teeth were randomly assigned into three groups (n = 20 each): Group I, the MOD cavity was first lined with flowable composite resin and then restored with composite resin. In Group II, Everstick fiber was placed into the bed of flowable composite in buccal–pulpal–lingual direction before the composite restoration was placed. In Group III, after etching of the cavity, a 2% chlorhexidine MMP inhibitor was applied. Then, the MOD cavity was restored same as group II. A universal testing machine was employed to compressively load the teeth at a cross-head speed of 0.5 mm/min till fracture. The maximum fracture loads were recorded in Newtons (N) and data were analyzed with one-way ANOVA and post-hoc Tukey tests. Results: Group III exhibited significantly higher fracture resistance compared to all other groups (P < 0.001), whereas Group I demonstrated the lowest fracture resistance. Conclusion: The utilization of Everstick glass fiber, combined with MMP inhibitor treatment, yielded the greatest fracture resistance. Hence, this method may be prioritized over conventional restoration techniques for strengthening root canal-treated teeth with structurally compromised crowns. [ABSTRACT FROM AUTHOR]

The role of liver X receptors (LXR) in rheumatoid arthritis (RA) remains controversial. We studied the effect of LXR agonists on fibroblast‐like synoviocytes (FLS) from RA patients and the K/BxN arthritis model in LXRα and β double‐deficient (Nr1h2/3−/−) mice. Two synthetic LXR agonists, GW3965 and T0901317, were used to activate LXRs and investigate their effects on cell growth, proliferation and matrix metalloproteinases, and chemokine production in cultured FLS from RA patients. The murine model K/BxN serum transfer of inflammatory arthritis in Nr1h2/3−/− animals was used to investigate the role of LXRs on joint inflammation in vivo. LXR agonists inhibited the FLS proliferative capacity in response to TNF, the chemokine‐induced migration, the collagenase activity in FLS supernatant and FLS CXCL12 production. In the K/BxN mouse model, Nr1h2/3−/− animals showed aggravated arthritis, histological inflammation, and joint destruction, as well as an increase in synovial metalloproteases and expression of proinflammatory mediators such as IL‐1β and CCL2 in joints compared with wild type animals. Taken together, these data underscore the importance of LXRs in modulating the joint inflammatory response and highlight them as potential therapeutic targets in RA. [ABSTRACT FROM AUTHOR]

Laminitis is a serious health condition that can cause severe pain and lameness in horses. Due to lack of understanding of laminitis, treatments often fail to achieve the desired results. In recent years, we have begun to recognize that laminitis may involve a complex interaction between local and systemic inflammation. Dysbiosis of the gut microbiota has been linked in the development of systemic inflammation, and our previous findings suggest that the development of laminitis is closely linked to the production of harmful metabolites of the gut microbiota. In addition, it was found that localized lesions in the hoof, especially lamellar injuries, are the most direct cause of laminitis. Matrix metalloproteinases have been found to be strongly associated with the development of laminitis. Recent discovery has found that methylated tirilazad has a role in repairing laminar tissue in vitro. However, its efficacy in horses never has been studied. Therefore, we aimed to investigate the efficacy of methylated tirilazad (product name: PTP-102) in the prevention/treatment of oligofructose-induced laminitis. The results showed that oligofructose successfully induced laminitis in horses, resulting in detreated clinical signs. Blood indices (including inflammation-related indices and other related indices) were significantly increased. Observations of dissection and staining showed significant bleeding, swelling, and damage to hoof tissue. Analysis of the gut microbiota showed a significant decrease in abundance and diversity, and a significant increase in the relative abundance of specific bacteria. Following methylated tirilazad intervention, there were a significant improvement in clinical signs, blood markers and lamellar tissue damage. Additionally, methylated tirilazad positively influenced the gut microbiota structure by reducing the relative abundance of genera closely associated with the development of equine laminitis. This suggests that some of the therapeutic mechanism of methylated tirilazad may be linked to its effects on the gut microbiota. Notably, methylated tirilazad had better effect in the treatment group than the prophylactic group, indicating the post-diagnosis utility of methylated tirilazad for laminitis management. [ABSTRACT FROM AUTHOR]

Objectives: The role of matrix metalloproteinases (MMPs) in Skin Cutaneous Melanoma (SKCM) development and progression is unclear so far. This comprehensive study delved into the intricate role of MMPs in SKCM development and progression. Methods: RT-qPCR, bisulfite sequencing, and WES analyzed MMP gene expression, promoter methylation, and mutations in SKCM cell lines. TCGA datasets validated findings. DrugBank and molecular docking identified potential regulatory drugs, and cell line experiments confirmed the role of key MMP genes in tumorigenesis. Results: Our findings unveiled significant up-regulation of MMP9, MMP12, MMP14, and MMP16, coupled with hypomethylation of their promoters in SKCM cell lines, implicating their involvement in disease progression. Mutational analysis highlighted a low frequency of mutations in these genes, indicating less involvement of mutations in the expression regulatory mechanisms. Prognostic assessments showcased a significant correlation between elevated expression of these genes and poor overall survival (OS) in SKCM patients. Additionally, functional experiments involving gene silencing revealed a potential impact on cellular proliferation, further emphasizing the significance of MMP9, MMP12, MMP14, and MMP16 in SKCM pathobiology. Conclusion: This study identifies Estradiol and Calcitriol as potential drugs for modulating MMP expression in SKCM, highlighting MMP9, MMP12, MMP14, and MMP16 as key diagnostic and prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is featured as cartilage loss, joint pain and loss of labor, which the inflammatory reaction may play critical roles. Ononin is an isoflavone isolating from medicinal plants and has anti-inflammatory effects. Our study investigated the anti-inflammation response of ononin on OA. Methods: Anterior cruciate ligament transection (ACLT)–induced OA operation was used to establish research model, then treated with ononin for 8 weeks. The condition of joint injury was assessed using pathological staining. The concentration of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in serum were measured by Elisa kit. The expression of collagen II and matrix metalloproteinase 13 (MMP-13) proteins to assess cartilage metabolism level by immunohistochemistry and Western blot. We detected the expression of proteins involved in the MAPK and NF-κB signaling pathways. Finally, we used molecular docking to assess the affinity of ononin for the target proteins ERK1/2, JNK1/2, p38 and p65. Results: Our results confirmed that ononin ameliorated cartilage impairment through histopathological analysis by improving the morphological structures and cartilage tidal lines and decreasing Osteoarthritis Research Society International (OARSI) scores in OA rats. Moreover, ononin inhibited the secretion of above factors in OA rats. Furthermore, ononin has been shown to improve cartilage content levels in OA rats. In addition, ononin inhibited the reactivity of MAPK and NF-κB pathways in OA rats. And molecular docking indicated the ligand molecules could stably bind to the proteins of above receptors. Conclusion: Our results demonstrated that ononin may ameliorate cartilage damage and inflammatory response in OA rats by downgrading MAPK and NF-κB pathways, thus identifying ononin as a potential novel drug to treat OA. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) have been recognized as viable prognostic and therapeutic indicators for numerous human malignancies. Nonetheless, the operational roles and fundamental mechanisms of important lncRNAs that impact esophageal squamous cell carcinoma (ESCC) remain predominantly obscure. Recently, lncRNAs have been identified to exert regulatory influence on epithelial-mesenchymal transition (EMT) via intricate interplay with EMT-associated transcription factors (TFs) and signaling pathways. The current experimental study aimed to elucidate the expression of four lncRNAs in ESCC patients and explain their potential involvement in the EMT process and the pathogenesis of ESCC. Methods: In the study, the expression levels of lncRNAs (AGAP2-AS1, DLEU2, HMBOX1_1 (AC108449.2), and UGDH-AS1) and mRNAs (TWIST1, MMP13, and CD44S) between fifty ESCC and adjacent normal tissue samples were measured using quantitative real-time PCR. Results: The upregulation of CD44S (36%), TWIST1 (52%), DLEU2 (58%), AGAP2-AS1 (62%), and MMP13 (74%), were indicated in ESCC samples, while the downregulation of UGDH-AS1 and HMBOX1_1 were found in 62% and 64% of patients, respectively. The expression levels of lncRNAs and EMT-related markers were found to be significantly correlated in several patient clinicopathological traits (P < 0.05), representing correlations between AGAP2-AS1, DLEU2, HMBOX1_1 (AC108449.2), and UGDH-AS1 with EMT status in ESCC. Conclusion: Our results have unveiled that these lncRNAs, which regulate EMT, may play a crucial role in the regulatory process of EMT via the CD44S-TWIST1-MMP13 axis. Moreover, it may be assumed that lncRNAs present a promising avenue for both diagnosis and therapeutic intervention in the context of ESCC. [ABSTRACT FROM AUTHOR]

Oral cancer (ORCA) is the most prevalent histological subtype of oral malignancies in which immune modulation is relevant. The goal of this work was to employ Mendelian randomization (MR) to investigate the causal connection between the immune-related proteins MICB, CTSA, MMP9, and ORCA. The Open GWAS database of the Integrative Epidemiology Unit (IEU) was accessed to collect GWAS data for ORCA (ieu-b-4961), MICB (prot-a-1898), CTSA (prot-a-717) and MMP9 (prot-a-1921). From 372,373 samples, the ORCA dataset comprises 7,723,107 single nucleotide polymorphisms (SNPs). MICB, CTSA, and MMP9 all have 10,534,735 SNPs and 3,301 sample sizes. Then, the primary SVMR implementation approaches were weighted mode, simple mode, inverse variance weighted (IVW), weighted median, and MR-Egger. IVW was the most effective technique. A sensitivity study was also carried out to assess the correctness of SVMR data, with special focus devoted to heterogeneity, horizontal pleiotropy, and Leave-One-Out (LOO). MVMR was eventually implemented as well. A Mendelian randomization analysis of the three exposure factors in the dataset (ieu-b-94, ebi-a-GCST012237) was also performed to validate the study results. According to the SVMR results, there was a noteworthy causal interaction between ORCA and MICB (P = 0.0014), MMP9 (P = 0.0343), and CTSA (P = 0.0003). Furthermore, odds ratios (ORs) values revealed that MMP9 (OR = 1.0005) was an ORCA risk factor, whereas MICB (OR = 0.9994) and CTSA (OR = 0.9993) were security factors. The robustness of the SVMR findings was confirmed by the p-values of the heterogeneity and horizontal pleiotropy, both of which were greater than 0.05. The MVMR result did not affect any of the safety or hazard features of these three exposure factors. However, the P value for MMP9 was greater than 0.05, implying that MICB and CTSA may have a greater influence on ORCA than MMP9. The validation outcomes in both datasets harmonized with the findings from previous research, thereby solidifying the reliability of results. Our investigation provided a crucial resource for further research on the subject by demonstrating a causal relationship between ORCA and MICB, CTSA, and MMP9. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease is characterized by chronic and relapsing inflammation of the gastrointestinal tract, including two prominent forms: Crohn's disease and ulcerative colitis. Determining diagnostic biomarkers for predicting disease activity and treatment response remains a challenging aspect. Aim of the work: The purpose of our research was to compare fecal CP and fecal MMP-9, two non-invasive biomarkers for inflammatory bowel disease (IBD), and to find out how fecal MMP-9 levels relate to disease activity by looking at how they relate to clinical, endoscopic, and histologic scores of disease activity. Patients and methods: This study was performed on 80 subjects divided into 3 groups: group A: 30 patients with Crohn's disease evidenced by endoscopy ileocolonoscopy, upper GI endoscopy, and tissue biopsy (15 patients with active disease and 15 patients in remission). Group B: 30 patients with ulcerative colitis disease evidenced by colonoscopy and tissue biopsy (15 patients with active disease and 15 patients in remission). Group C: 20 age-matched and sex-matched healthy controls. All participants underwent a thorough history review, comprehensive physical examination, complete laboratory tests, and C-reactive protein measurements. A quantitative enzyme-linked immunosorbent assay was used to determine the levels of fecal matrix metalloproteinase MMP 9 for both the patients and the controls. Ulcerative colitis was evaluated using the Mayo score, Montreal classification, and the Riley histological score. Additionally, Crohn's disease was assessed with the Crohn's Disease Activity Index, the Simple Endoscopic Score for Crohn's Disease, and the D'Haens histological score. Results: Comparing fecal MMP-9 with fecal calprotectin (FC), we found that fecal MMP-9 was superior to FC in differentiating active Crohn's disease from inactive Crohn's disease, although there was no significant difference between FC and MMP-9 (P-value = 0.561). However, in ulcerative colitis, FC was superior to MMP-9 in distinguishing active UC from inactive UC, but again, there was no significant difference between FC and MMP-9 (P-value = 0.0731).In both the ulcerative colitis and Crohn's disease groups, fecal MMP-9 could discriminate between patients in remission and those with active disease. Fecal matrix metalloproteinase-9 (MMP-9) was discovered to be a significant marker for assessing the clinical activity of both Crohn's disease (CD) and ulcerative colitis (UC), with an AUC of 0.998 for CD and 0.991 for UC. Fecal MMP-9 demonstrated great sensitivity (93.33%), specificity (100%), positive predictive value (PPV) of 100%, and negative predictive value (NPV) of 93.7% (with a P-value < 0.001) using cutoff values of > 0.34 ng/mL for CD and > 0.36 ng/mL for UC. There was a strong positive correlation between fecal MMP-9 and endoscopic and clinical scores of disease activity. Conclusion: Fecal MMP-9 has emerged as a promising biomarker for evaluating the clinical activity of both Crohn's disease and ulcerative colitis. It demonstrated superior diagnostic performance compared to fecal calprotectin in distinguishing active from inactive disease, especially in Crohn's disease. Although fecal calprotectin outperformed MMP-9 in identifying active ulcerative colitis, the differences between the two markers were not statistically significant, suggesting that they may complement each other in clinical practice. Furthermore, fecal MMP-9 is capable of assessing the activity of endoscopically visible inflammatory bowel disease (IBD), which could help reduce the need for invasive endoscopic procedures. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionsTo evaluate matrix metalloprotease-1 (MMP-1), matrix metalloprotease-3 (MMP-3), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) levels in the eyelid skin and fibroadipose tissue in patients with inactive moderate-to-severe Graves’ orbitopathy (GO).This prospective study included 23 patients with inactive moderate-to-severe GO who underwent upper blepharoplasty and medial fat excision, and 22 age- and sex-matched healthy subjects. MMP-1, MMP-3, TNF-α, and IL-6 levels in the skin and fibroadipose tissue obtained during surgery were measured using the ELISA method.The mean MMP-1 level in the eyelid skin (p = .003) and the mean MMP-3 level in the fibroadipose tissue (p = .04) were significantly lower in the GO group compared to the healthy control group. There were no differences in other mediators in both tissues between the two groups (p > .05).The lower levels of proteolytic enzymes such as MMP-1 and MMP-3 in the eyelid skin and orbital fibroadipose tissue of patients with chronic inactive GO may play a role in the increase of collagen and glycosaminoglycans in orbital soft tissues. [ABSTRACT FROM AUTHOR]

Introduction: We assessed the prognostic utility of circulating levels of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry. Methods: MMP and TIMP concentrations were quantified by ELISA in plasma from 300 patients. A Cox proportional hazard regression model was used to assess associations between select MMPs and TIMPs and death and disease progression (absolute decline in forced vital capacity ≥10% predicted, death, or lung transplant). Results: Over a median follow-up of 30.4 months, 98 patients died and 182 patients had disease progression. In unadjusted analyses, higher concentrations of MMPs 2, 3, 8 and 9 and TIMPs 1, 2 and 4 were associated with an increased risk of death. MMPs 2 and 8 and TIMP1 remained associated with death after adjustment for clinical factors. In unadjusted analyses, higher concentrations of MMPs 8 and 9 and TIMPs 1 and 4 were associated with an increased risk of disease progression. MMPs 8 and 9 and TIMP1 remained associated with progression after adjustment for clinical factors. Conclusion: Circulating levels of MMP8 and TIMP1 may provide information on the risk of outcomes in patients with IPF not captured by clinical measures. [ABSTRACT FROM AUTHOR]

The endothelial glycocalyx (eGC) is a carbohydrate‐rich layer on the vascular endothelium, and its damage can lead to endothelial and organ dysfunction. Heparanase (HPSE) degrades the eGC in response to cellular stress, but its role in organ dysfunction remains unclear. This study investigates HPSE's role in lung ischemia–reperfusion (I/R) injury. A left lung hilar occlusion model was used in B6 wildtype (WT) and HPSE genetic knockout (−/−) mice to induce I/R injury in vivo. The left lungs were ischemic for 1 h followed by reperfusion for 4 h prior to investigations of lung function and eGC status. Data were compared between uninjured lungs and I/R‐injured lungs in WT and HPSE−/− mice. WT lungs showed significant functional impairment after I/R injury, whereas HPSE−/− lungs did not. Inhibition or knockout of HPSE prevented eGC damage, inflammation, and cellular migration after I/R injury by reducing matrix metalloproteinase activities. HPSE−/− mice exhibited compensatory regulation of related gene expressions. HPSE facilitates eGC degradation leading to inflammation and impaired lung function after I/R injury. HPSE may be a therapeutic target to attenuate graft damage in lung transplantation. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify new therapeutic strategies, effective and with a safety profile, is necessary. The Hedgehog (Hh) signaling pathway involved in tumorigenesis is active in OS. Hh components Patched receptor 1 (PTCH1), Smoothened (SMO), and glioma-associated oncogene homolog transcription factors (GLI1 and GLI2) are overexpressed in OS cell lines and patient samples. Curcumin (CUR)—with antioxidant and anti-cancer properties—downregulates Hh components in cancer, inhibiting progression. This study investigates CUR effects on the MG-63 OS cell line, alone and combined with MTX, to propose a novel therapeutic approach. Our study suggests CUR as a novel therapeutic agent in OS, particularly when combined with MTX. Targeting the Hh signaling pathway, CUR and MTX showed significant pro-apoptotic effects, increasing the BAX/Bcl-2 ratio and total apoptotic cell percentage. They reduced the expression of Hh pathway components (PTCH1, SMO, GLI1, and GLI2), inhibiting OS cell proliferation, survival, and invasion. CUR and MTX combined determined a β-Catenin decrease and a trend toward reducing NF-kB and matrix metalloproteinases (MMP-2 and MMP-9). Our findings suggest CUR as a support to OS treatment, improving outcomes and reducing the adverse effects of current therapies. [ABSTRACT FROM AUTHOR]

Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of Lal knockout (Lal KO) mice. Both models develop progressive lymphocyte dysfunction and expansion of myeloid-derived suppressor (CD11b+ Gr-1+) cells. To study whether MMP-12 might be a detrimental contributor to the pathology of LAL-D, we have generated Lal/Mmp12 double knockout (DKO) mice. The phenotype of Lal/Mmp12 DKO mice closely resembled that of Lal KO mice, while the weight and morphology of the thymus were improved in Lal/Mmp12 DKO mice. Cytological examination of blood smears showed a mildly reversed lymphoid-to-myeloid shift in DKO mice. Despite significant decreases in CD11b+ Ly6G+ cells in the peripheral blood, bone marrow, and spleen of Lal/Mmp12 DKO mice, the hematopoietic bone marrow progenitor compartment and markers for neutrophil chemotaxis were unchanged. Since the overall severity of LAL-D remains unaffected by the deletion of Mmp12, we conclude that MMP-12 does not represent a viable target for treating the inflammatory pathology in LAL-D. [ABSTRACT FROM AUTHOR]

Periodontal disease is considered one of the diabetic complications with high morbidity and severity. Recent studies demonstrated the involvement of the epigenome on diabetic complications. Histone modifications change chromatin architecture and gene activation. Histone modifications have been reported to alter chromatin structure and regulate gene transcription. In this study, we investigated the impacts of H3 lysine 4 trimethylation (H3K4me3) and specific histone methyltransferases of H3K4 methylation, su(var)3-9, enhancer-of-zeste, and trithorax domain 1A (SETD1A) on periodontal tissue affected by the diabetic condition. We observed the increase in H3K4me3 and SETD1A in gingival tissue of diabetic rats compared with the normal rats. Cultured human fibroblasts (hGFs) confirmed a high glucose-induced increase in H3K4me3 and SETD1A. We further demonstrated that high glucose increased the gene expression of matrix metalloproteinase (MMP) 1 and MMP13, which were canceled by sinefungin, an SETD1A inhibitor. Our investigation suggests that diabetes triggers histone modifications in the gingival tissue, resulting in gingival inflammation. Histone modifications may play crucial roles in the development of periodontal disease in diabetes. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG2k modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R. [ABSTRACT FROM AUTHOR]

Wound healing performance of sustained release of hydrogen from Fe@PLGA+CA dressing. [Display omitted] Diabetic wound, which is chronic skin disease, poses a significant challenge in clinical practice because of persistent inflammation and impaired angiogenesis. Recently, hydrogen has emerged as a novel therapeutic agent due to its superior antioxidant and anti-inflammatory properties. In this study, we engineered a poly (lactic- co -glycolic acid) (PLGA) electrospun nanofibre membrane loaded with citric acid (CA) and iron (Fe) nanoparticles, referred to as Fe@PLGA + CA. Our in vitro assays demonstrated that the Fe@PLGA + CA membrane continuously generated and released hydrogen molecules via a chemical reaction between Fe and CA in an acidic microenvironment created by CA. We also discovered that hydrogen can ameliorate fibroblast migration disorders by reducing the levels of matrix metalloproteinase 9 (MMP9). Furthermore, we confirmed that hydrogen can scavenge or biochemically neutralise accumulated reactive oxygen species (ROS), inhibit pro-inflammatory responses, and induce anti-inflammatory reactions. This, in turn, promotes vessel formation, wound-healing and accelerates skin regeneration. These findings open new possibilities for using elemental iron in skin dressings and bring us one step closer to implementing hydrogen-releasing biomedical materials in clinical practice. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis into the airways. Recent studies indicate that kallikrein-related peptidase 12 (KLK12) regulate MMP-1 and MMP-9, suggesting that targeting the KLK12 gene could be a promising tuberculosis (TB) treatment. To maximise therapeutic potential, this strategy of silencing KLK12 needs to be delivered to the pathogenic cell population while preserving the immunoprotective and tissue homeostatic functions of other lung macrophages. Our research found that KLK12 is highly expressed in M2 macrophages, leading us to design mannose-based bovine serum albumin nanoparticles (MBNPs) for delivering siRNA to silence KLK12 in these cells. The results of in vitro experiments showed that MBNPs could accurately enter M2 macrophages and sustainably release KLK12-siRNA with the help of mannose and mannose receptor targeting. The results of the in vivo experiments showed that MBNPs could reach the lungs within 1 h after intraperitoneal injection and peaked at 6 h. MBNPs increased collagen fibre content in the lungs by decreasing the levels of KLK12/MMPs thereby limiting the progression of TB. Importantly, MBNPs provided greater alleviation of pulmonary TB symptoms and reduced bacterial load in both TB and drug-resistant TB models. These findings provide an alternative and effective option for the treatment of TB, especially when drug resistance occurs. RNA interference using small interfering RNA (siRNA) can target various genes and has potential for treating diseases such as tuberculosis (TB). However, siRNAs are unstable in the blood and within cells. This study presents bovine serum albumin nanoparticles encapsulating KLK12-siRNA (BNPs) synthesized via desolvation. A mannose layer was added (MBNPs) to target mannose receptors on M2 macrophages, facilitating endocytosis. The low pH-responsive MBNPs enhance lysosomal escape for siRNA delivery, downregulating the KLK12 pathway. Tests confirmed that MBNPs effectively inhibited Mycobacterium bovis proliferation, reduced granulomas, and decreased inflammation in a mouse model. This research aims to reduce antibiotic use, shorten treatment duration, and provide a novel TB treatment option. [Display omitted] [ABSTRACT FROM AUTHOR]

The immunosuppressive tumor microenvironment, such as lactic acid and matrix metalloproteinases (MMPs) overexpression, has been well confirmed to be adverse for tumor therapy. In current study, a tumor microenvironment modulatory hydrogel was successfully developed to treat melanoma by taking advantage of the synergistic effects of nano-hydroxyapatite (nHA) with well-documented selective anti-tumor action, lactate dehydrogenase A inhibitor (R)-GNE-140 (GNE), and matrix metalloproteinase-2 (MMP-2) sensitive peptide. The hydrogel was acquired by the reaction of 4-arm-polyethylene glycol-maleic anhydride (4-arm-PEG-MAL) and MMP-2 sensitive peptide (CC-14), in which nHA and GNE were co-encapsulated physically. The in vitro degradation tests confirmed the accelerated release of nHA and GNE from the hydrogel under less-acidic (pH 6.8) and MMP-2 containing conditions compared to those neutral or without MMP-2 conditions, demonstrating the pH and MMP-2 responsive properties of as-prepared hydrogel. Findings from in vitro cell experiments revealed that the hydrogel could stop the proliferation of melanoma cells by stacking cell cycle via lactic acid metabolic dysregulation and boosting cell apoptosis via nHA direct killing effect. Moreover, after hydrogel treatment, the rate of migration and aggressiveness of melanoma cells both reduced significantly. An in vivo anti-melanoma study showed that the hydrogel could inhibit tumor growth significantly and result in more CD8+ T cells and antigen-presenting cells but less T reg cells infiltration, ultimately leading to an enhanced therapeutic efficacy. As thus, the fabricated hydrogel demonstrated great promise for treating melanoma and could be a new potent strategy for efficient melanoma therapy. Nano-hydroxyapatite (nHA) has the capability of selectively killing cancer cells. The study reported a tumor microenvironment (TME) modulatory hydrogel with the goal of enhancing melanoma therapy efficacy by combining nHA administration with immunosuppressive microenvironment modulation. The hydrogel demonstrated pH and MMP-2 sensitivity. Hence, controlled release of nHA and lactate dehydrogenase A inhibitor (GNE) could be observed, and in situ MMP-2 consumption at the tumor site occurred. The hydrogel effectively inhibited the growth of melanoma cells. Furthermore, hydrogel increased the production of CD8+ T cells and antigen-presenting cells while decreasing the infiltration of T reg cells at the tumor site. This could transform the initial "cold" tumor into a "hot" tumor, ultimately resulting in an enhanced therapeutic effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Post-tuberculosis (post-TB) lung disease is increasingly recognized as a major contributor to the global burden of chronic lung disease, with recent estimates indicating that over half of TB survivors have impaired lung function after successful completion of TB treatment. However, the pathologic mechanisms that contribute to post-TB lung disease are not well understood, thus limiting the development of therapeutic interventions to improve long-term outcomes after TB. This report summarizes the work of the Pathogenesis and Risk Factors Committee for the Second International Post-Tuberculosis Symposium, which took place in Stellenbosch, South Africa, in April 2023. The committee first identified six areas with high translational potential: 1) tissue matrix destruction, including the role of matrix metalloproteinase dysregulation and neutrophil activity; 2) fibroblasts and profibrotic activity; 3) granuloma fate and cell death pathways; 4) mycobacterial factors, including pathogen burden; 5) animal models; and 6) the impact of key clinical risk factors, including HIV, diabetes, smoking, malnutrition, and alcohol. We share the key findings from a literature review of those areas, highlighting knowledge gaps and areas where further research is needed. [ABSTRACT FROM AUTHOR]

Eriodictyol, a flavonoid distributed in citrus fruits, has been known to exhibit anti-inflammatory activity. In this study, destabilized medial meniscus (DMM)-induced OA model was used to investigate the protective role of eriodictyol on OA. Meanwhile, we used an IL-1β-stimulated human osteoarthritis chondrocytes model to investigate the anti-inflammatory mechanism of eriodictyol on OA. The production of nitric oxide was detected by Griess reaction. The productions of MMP1, MMP3, and PGE2 were detected by ELISA. The expression of LXRα, ABCA1, PI3K, AKT, and NF-κB were measured by western blot analysis. The results demonstrated that eriodictyol could alleviate DMM-induced OA in mice. In vitro, eriodictyol inhibited IL-1β-induced NO, PGE2, MMP1, and MMP3 production in human osteoarthritis chondrocytes. Eriodictyol also suppressed the phosphorylation of PI3K, AKT, NF-κB p65, and IκBα induced by IL-1β. Meanwhile, eriodictyol significantly increased the expression of LXRα and ABCA1. Furthermore, eriodictyol disrupted lipid rafts formation through reducing the cholesterol content. And cholesterol replenishment experiment showed that adding water-soluble cholesterol could reverse the anti-inflammatory effect of eriodictyol. In conclusion, the results indicated eriodictyol inhibited IL-1β-induced inflammation in human osteoarthritis chondrocytes through suppressing lipid rafts formation, which subsequently inhibiting PI3K/AKT/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Laminitis is a serious health condition that can cause severe pain and lameness in horses. Due to lack of understanding of laminitis, treatments often fail to achieve the desired results. In recent years, we have begun to recognize that laminitis may involve a complex interaction between local and systemic inflammation. Dysbiosis of the gut microbiota has been linked in the development of systemic inflammation, and our previous findings suggest that the development of laminitis is closely linked to the production of harmful metabolites of the gut microbiota. In addition, it was found that localized lesions in the hoof, especially lamellar injuries, are the most direct cause of laminitis. Matrix metalloproteinases have been found to be strongly associated with the development of laminitis. Recent discovery has found that methylated tirilazad has a role in repairing laminar tissue in vitro. However, its efficacy in horses never has been studied. Therefore, we aimed to investigate the efficacy of methylated tirilazad (product name: PTP-102) in the prevention/treatment of oligofructose-induced laminitis. The results showed that oligofructose successfully induced laminitis in horses, resulting in detreated clinical signs. Blood indices (including inflammation-related indices and other related indices) were significantly increased. Observations of dissection and staining showed significant bleeding, swelling, and damage to hoof tissue. Analysis of the gut microbiota showed a significant decrease in abundance and diversity, and a significant increase in the relative abundance of specific bacteria. Following methylated tirilazad intervention, there were a significant improvement in clinical signs, blood markers and lamellar tissue damage. Additionally, methylated tirilazad positively influenced the gut microbiota structure by reducing the relative abundance of genera closely associated with the development of equine laminitis. This suggests that some of the therapeutic mechanism of methylated tirilazad may be linked to its effects on the gut microbiota. Notably, methylated tirilazad had better effect in the treatment group than the prophylactic group, indicating the post-diagnosis utility of methylated tirilazad for laminitis management. [ABSTRACT FROM AUTHOR]

VAMP-associated protein (VAP) is a type IV integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 is transported to the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis. VAPB is a type IV transmembrane protein at the ER, and Iiis unknown how the VAPB MSP domain facing the cytosol is secreted. Here, the authors show that secretion of ER the protein VAPB requires topological inversion and Mmp1-mediated cleavage. [ABSTRACT FROM AUTHOR]

Background: Advances in in vivo MRI techniques enable cerebral barrier transfer rates (Ktrans) measurement in patients with vascular cognitive impairment and dementia (VCID). However, a consensus has not been reached on the dynamic contribution and importance of cerebral barrier abnormalities to the differential diagnosis of dementia subtypes. Our goal was to investigate the dynamics of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) Ktrans in patients with VCID longitudinally and determine the effect of aging. Methods: We studied subjects at two time points over two years; they were 65.5 years of age (SD = 15.94, M/F = 24/14) at the first visit. We studied 38 patients, 18 of whom had two visits. We calculated the BBB and BCSFB Ktrans with dynamic contrast-enhanced T1 MR, and we used 1H-MR spectroscopy to measure N-acetylaspartate (NAA) levels in the white matter as a marker of injury. In addition, we measured CSF levels of active-matrix metalloproteinase-3 (MMP3) as an inflammatory biomarker to aid in patient clustering. Results: Longitudinal BBB measurements revealed variable dynamic behavior: after two years, the BBB Ktrans increased in 55% of patients and decreased in the remaining 45% unpredictably. We did not find a significant linear model of BBB Ktrans versus age for VCID. For healthy controls, the model was Ktrans = 0.0014 + 0.0002 age, which was significant (p = 0.046). VCID patients showed a reduction in BCSFB Ktrans compared to healthy controls (p = 0.01). Combining NAA, CSF MMP3, and Ktrans in a clustering analysis separated patients into groups. Conclusion: These results suggest that BBB Ktrans in VCID is dynamic and BCSFB Ktrans reduced by age. By combining inflammatory biomarkers with BBB Ktrans data, it is possible to separate VCID patients into distinct groups with different underlying pathologies. [ABSTRACT FROM AUTHOR]

To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid-producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC’s invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation. [ABSTRACT FROM AUTHOR]