Tissue Inhibitor Of Metalloproteinase Research Articles

Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells.

Citronellol (CT) is a monoterpene alcohol present in the essential oil of plants of the genus Cymbopogon and exhibits diverse pharmacological activities. The aim of the current study was to investigate the hepatoprotective potential of CT against ethanol-induced toxicity in HepG2 cell lines. Silymarin (SIL) was used as a standard drug. MTT, crystal violet assay, DAPI, and PI staining were carried out to assess the effect of ethanol and CT on cell viability. RT-PCR determined the molecular mechanisms of hepatoprotective action of CT. CT ameliorated cell viability and restricted ethanol-induced cell death. DAPI and PI staining showed distinct differences in cell number and morphology. Less cell viability was observed in the diseased group obviously from strong PI staining when compared to the CT- and SIL-treated group. Moreover, CT showed downregulation of interleukin (IL-6), transforming growth factor-beta 1 (TGF-β1), collagen type 1 A 1 (COL1A1), matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and glutathione peroxidase-7 (GPX-7) levels. Molecular docking studies supported the biochemical findings. It is concluded that the cytoprotective activity of CT against ethanol-induced toxicity might be explained by its anti-inflammatory, immunomodulatory, and collagen-regulating effects.

Estrogen-dependent gene regulation: Molecular basis ofTIMP-1 as a sex-specific biomarker for acute lung injury.

Increased circulating tissue inhibitor of metalloproteinases-1 (TIMP-1) levels have been observed in patients with acute lung injury (ALI). However, the sex-specific regulation of TIMP-1 and the underlying molecular mechanisms have not been well elucidated. In this study, we found that plasma TIMP-1 levels were significantly higher in COVID-19 and H1N1 patients compared with those in healthy subjects (n = 25). TIMP-1 concentrations were significantly different between males and females in each disease group. Among female but not male patients, TIMP-1 levels significantly correlated with the PaO2/FiO2 ratio and hospital length of stay. Using the mouse model of ALI induced by the H1N1 virus, we found that TIMP-1 is strikingly induced in PDGFRα-positive cells in the murine lungs. Moreover, female mice showed a higher Timp-1 expression in the lungs on day 3 postinfection. Mechanistically, we observed that estrogen can upregulate TIMP-1 expression in lung fibroblasts, not epithelial cells. In addition, overexpression of estrogen receptor α (ERα) increased the TIMP-1 promoter activity. In summary, TIMP-1 is an estrogen-responsive gene, and its promoter activity is regulated by ERα. Circulating TIMP-1 may serve as a sex-specific marker, reflecting the severity and worst outcomes in female patients with SARS-CoV2- and IAV-related ALI.

Evaluation of Full Thickness Wounds Following Application of a Visco-Liquid Hemostat in a Swine Model.

Wound healing is a complex dynamic biomechanical process as the body attempts to restore the integrity of traumatized or devitalized tissues. There are four stages of wound of healing that begins with hemostasis followed by inflammation, proliferation and finally weeks later wound remodeling. Full thickness wounds usually are covered with a dressing material after hemostasis, which allows for controlled hydration. We investigated the potential of a visco-liquid hemostat, polyhedral oligomeric silsesquioxane (POSS), for providing hemostasis and to maintain a microenvironment in the wound bed that would maintain moisture content and promote early re-epithelialization. We hypothesized that the hemostatic agent POSS if left in the wound bed would maintain a protective barrier and accelerate wound healing similar to using saline to irrigate the wound to keep the wound moist. We compared the early phase of wound repair (3-7 days) in a porcine full thickness wound model to evaluate the efficacy of the material. Biopsies were taken after 3 and 7 days to determine the acute response of the POSS hemostat or saline on inflammation, cell migration, concentrations of metalloproteinase (MMPs), and tissue inhibitors of metalloproteinase (TIMPs). Accelerated healing was observed in POSS treated wounds by changes in wound contraction, keratinocyte migration, and development of granulation tissue in comparison to saline treated wounds. Increased concentrations at day 3 of MMP-2, MMP-3, and in MMP-1 at day 7 in POSS treated wounds compared to saline coincide with keratinocyte migration observed in the tissue histology and changes in wound contraction. Tissue concentrations of TIMP-1 and TIMP-2 in POSS treated wounds appear to coordinate the sequence of MMP events in the healing tissue. Matrix metalloproteinase-13, a marker for tissue remodeling, was not upregulated in the early wound healing cascade in either POSS or saline treated wounds at 3 or 7 days. Overall, the data suggests POSS treatment contributed to enhanced early cell migration and wound closure compared to saline treatment.

The role of miR-155-5p in inflammation and mechanical loading during intervertebral disc degeneration

BackgroundIntervertebral disc (IVD) degeneration is a multifactorial pathological process resulting in the dysregulation of IVD cell activity. The catabolic shift observed in IVD cells during degeneration leads to increased inflammation, extracellular matrix (ECM) degradation, aberrant intracellular signaling and cell loss. Importantly, these pathological processes are known to be interconnected and to collectively contribute to the progression of the disease. MicroRNAs (miRNAs) are known as strong post-transcriptional regulators, targeting multiple genes simultaneously and regulating numerous intracellular pathways. Specifically, miR-155-5p has been of particular interest since it is known as a pro-inflammatory mediator and contributing factor to diseases like cancer and osteoarthritis. This study investigated the role of miR-155-5p in IVD degeneration with a specific focus on inflammation and mechanosensing.MethodsGain- and loss-of-function studies were performed through transfection of human Nucleus pulposus (NP) and Annulus fibrosus (AF) cells isolated from degenerated IVDs with miR-155-5p mimics, inhibitors or their corresponding non-targeting control. Transfected cells were then subjected to an inflammatory environment or mechanical loading. Conditioned media and cell lysates were collected for phosphorylation and cytokine secretion arrays as well as gene expression analysis.ResultsIncreased expression of miR-155-5p in AF cells resulted in significant upregulation of interleukin (IL)-8 cytokine secretion during cyclic stretching and a similar trend in IL-6 secretion during inflammation. Furthermore, miR-155-5p mimics increased the expression of the brain-derived neurotrophic factor (BDNF) in AF cells undergoing cyclic stretching. In NP cells, miR-155-5p gain-of-function resulted in the activation of the mitogen-activated protein kinase (MAPK) signaling pathway through increased phosphorylation of p38 and p53. Lastly, miR-155-5p inhibition caused a significant increase in the anti-inflammatory cytokine IL-10 in AF cells and the tissue inhibitor of metalloproteinases (TIMP)-4 in NP cells respectively.ConclusionOverall, these results show that miR-155-5p contributes to IVD degeneration by enhancing inflammation through pro-inflammatory cytokines and MAPK signaling, as well as by promoting the catabolic shift of AF cells during mechanical loading. The inhibition of miR-155-5p may constitute a potential therapeutic approach for IVD degeneration and low back pain.

Accuracy of Gingival Crevicular Fluid Biomarkers of MMP8, TIMP1, RANK, RANKL, and OPG in Differentiating Symptomatic and Asymptomatic Apical Periodontitis.

Apical periodontitis (AP) is the most prevalent chronic inflammatory disease of the teeth. Bone resorption dynamics in symptomatic and asymptomatic AP are still unrecognized. This study examined different inflammatory markers within gingival crevicular fluid, including matrix metalloproteinases 8 (MMP8), tissue inhibitors of metalloproteinases 1 (TIMP1), receptor activator of nuclear factor κB (RANK), its ligand (RANKL), and osteoprotegerin (OPG), to be used in comparing symptomatic apical periodontitis (SAP) and asymptomatic apical periodontitis (AAP) versus healthy teeth. Subjects with SAP, AAP, and a control group were recruited and GCF samples were collected by Periopaper strips. Clinical and radiographical measures were used for diagnosing AP. Levels of MMP8, TIMP, RANK, RANKL, and OPG were determined by ELISA and their abilities to discriminate between examined sites were evaluated by receiver operator characteristic (ROC) curves. All examined biomarkers were statistically significant higher (p < 0.05) in SAP than AAP and the control group, apart from RANK. Significant positive correlations (p < 0.05) were identified between all SAP and AAP biomarkers except TIMP1 and RANK in AAP teeth. TIMP1 and OPG exhibited the highest ability to distinguish between SAP and AAP with areas under the curve of 0.824 and 0.763 in comparing SAP and the control group, and 0.732 and 0.73 when comparing AAP and the control group, respectively. Additionally, TIMP1 and OPG showed the highest AUC of 0.778 and 0.747 when SAP and AAP were compared, respectively. This study concluded that GCF levels of TIMP1 and OPG can be used to differentiate between SAP, AAP, and healthy teeth.

Polymorphisms in myeloperoxidase and tissue inhibitor of metalloproteinase-1 genes and their association with preeclampsia in the Chinese Han population

Hypertensive disorders of pregnancy (HDP) are multifaceted syndromes unique to pregnancy, characterized by increased blood pressure, edema, and proteinuria. Patients with HDP exhibit signs of endothelial dysfunction, possibly linked to increased myeloperoxidase (MPO) level and aberrant oxidative stress. Additionally, altered level of tissue inhibitor of metalloproteinase-1 (TIMP1) protein is associated with placental ischemia, hypoxia, and maternal vascular endothelial damage. Preeclampsia (PE) represents a critical stage of HDP that poses severe threats to maternal and fetal safety. This study aimed to determine the relationship between MPO and TIMP1 polymorphisms and the risk of PE in the Chinese Han population. Single nucleotide polymorphisms (SNPs), including MPO rs7208693, MPO rs2243828, and TIMP1 rs6609533, were genotyped in 170 patients with PE and 303 control participants. No significant association was observed between MPO polymorphisms (rs7208693 and rs2243828) and the risk of PE, whereas significant association between the TIMP1 rs6609533 A > G SNP and PE susceptibility was found. Specifically, individuals with the GG or AG genotypes had elevated risk of PE compared to those harboring the AA genotype. Furthermore, in the PE group, patients carrying the G allele were more likely to experience fetal growth restriction (FGR). In the non-PE group, the association between the G allele and the risk of FGR was not evident. In conclusion, the TIMP1 rs6609533 G allele in Chinese Han women was identified as a risk factor for PE. Our results indicated that the TIMP1 rs6609533 SNP can serve as a biomarker for the clinical diagnosis and treatment of PE.

Expression of matrix metalloproteinases and their inhibitors in corneal stromal fibroblasts and keratocytes from healthy and keratoconus corneas.

To examine the in-vitro expression of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in corneal stromal cells by distinguishing between fibroblasts and keratocytes of healthy and keratoconus (KC) corneas. Stromal cells were isolated from healthy and KC corneas (n = 8). A normal-glucose, serum-containing cell culture medium (NGSC-medium) was used for cultivation of healthy human corneal fibroblasts (HCFs) and KC human corneal fibroblasts (KC-HCFs). In order to obtain a keratocyte phenotype, the initial cultivation with NGSC-medium was changed to a low-glucose, serum-free cell culture medium for healthy (Keratocytes) and KC cells (KC-Keratocytes). Gene and protein expression of MMP-1, -2, -3, -7, -9 and TIMP-1, -2, -3 were measured by quantitative PCR and Enzyme-Linked Immunosorbent Assay (ELISA) from the cell culture supernatant. KC-HCFs demonstrated a lower mRNA gene expression for MMP-2 compared to HCFs. In contrast to their respective fibroblast groups (either HCFs or KC-HCFs), Keratocytes showed a higher mRNA gene expression of TIMP-3, whereas TIMP-1 mRNA gene expression was lower in Keratocytes and KC-Keratocytes. Protein analysis of the cell culture supernatant revealed lower concentrations of MMP-1 in KC-HCFs compared to HCFs. Compared to Keratocytes, TIMP-1 concentrations was lower in the cell culture supernatant of KC-Keratocytes. In HCFs and KC-HCFs, protein levels of MMP-1 and TIMP-1 were higher and MMP-2 was lower compared to Keratocytes and KC-Keratocytes, respectively. This study indicates an imbalance in MMP and TIMP expression between healthy and diseased cells. Furthermore, differences in the expression of MMPs and TIMPs exist between corneal fibroblasts and keratocytes, which could influence the specific proteolytic metabolism in-vivo and contribute to the progression of KC.

Elucidation of the anti-colorectal cancer mechanism of Atractylodes lancea by network pharmacology and experimental verification.

Atractylodes lancea which was listed in "Shennong's Materia Medica" and could be used to treat gastrointestinal-associated diseases. However, its roles, core and active ingredients, and mechanisms in treatment of colorectal cancer (CRC) were still unknown. Therefore, network pharmacology and experimental validation were used to clarify the effects, core active ingredients and molecular mechanisms of Atractylodes lancea. We found that Atractylodes lancea has 28 effective active components and 213 potential targets. Seventy-three genes which demonstrate interaction between the Atractylodes lancea and CRC were confirmed. Enrichment analysis showed that 2033 GO biological process items and 144 KEGG pathways. Survival and molecular docking analysis revealed that luteolin as the core component interacted with these genes (Matrix metalloproteinase 3 (MMP3), Matrix metalloproteinase 9 (MMP9), Tissue inhibitor of metalloproteinases 1 (TIMP1), Vascular endothelial growth factor A (VEGFA)) with the lowest binding energy, and these genes were involved in building a prognostic model for CRC. Cellular phenotyping experiments showed that luteolin could inhibit the proliferation and migration of CRC cells and downregulate the expression of MMP3, MMP9, TIMP1, VEGFA probably by Phosphoinositide 3-kinase/ serine/threonine kinase Akt (PI3K/AKT) pathway. To conclude, Atractylodes lancea could inhibit proliferation and migration of CRC cells through its core active ingredient (luteolin) to suppress the expression of MMP3, MMP9, TIMP1, VEGFA probably by PI3K/AKT pathway.

Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology.

Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, β2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.

NLRP3 inflammasome inhibition decreases Schistosomiasis japonica-induced granulomatous inflammation and fibrosis in BALB/c mice.

To research the role of the NLRP3 inflammasome in Schistosoma japonicum-induced granuloma formation and liver fibrosis. In in vivo tests, BALB/c mice were used. shNLRP3 plasmid based on adeno-associated virus serotype 8 (AAV8-shNLRP3) was injected to block NLRP3 inflammasome via tail vein. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected to assess liver injury. H&E staining was used for routine histopathological assessment; Masson's trichrome staining was used to detect fibrous tissues and collagen fibers. Hepatic expression of NLRP3, procaspase-1, bioactive caspase-1, collagen-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and α-smooth muscle actin (α-SMA) were detected by western blot. Serum levels of IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). The inflammatory cell infiltration and hepatic expression of IL-1β around the granuloma were detected by immunohistochemistry staining. Treatment of S. japonicum infected mice with AAV8-shNLRP3 significantly reduced the hepatic levels of bioactive caspase-1 and IL-1β, as well as circulating IL-1β concentrations, while reducing the amounts of myeloperoxidase (MPO) and F4/80 positive cells around the granuloma. Moreover, collagen deposition, TIMP-1, and α-SMA, which are markers of hepatic stellate cell (HSC) activation, were reduced around the liver granuloma. These findings highlight a therapeutic potential of AAV8-shNLRP3 in schistosomiasis cirrhosis.

TIMP1 promotes thyroid cancer cell progression through macrophage phenotypic polarization via the PI3K/AKT signaling pathway

Increasing evidence suggests that tissue inhibitor of metalloproteinase 1 (TIMP1) played a pivotal role in immune regulation. Our study focused on examining the expression and function of TIMP1 in humans, particularly in its regulation of tumor-associated macrophages (TAMs) in papillary thyroid carcinoma (PTC). We observed an upregulation of TIMP1 in 16 different types of malignancies, including thyroid cancer. TIMP1 shaped the inflammatory TME in PTC. Inhibiting the expression of TIMP1 has been demonstrated to reduce the malignant biological traits of PTC cells. Furthermore, reducing TIMP1 expression impeded M2 macrophage polarization as well as facilitated M1 macrophage polarization in PTC. ELISA results demonstrated that downregulated TIMP1 expression correlated with decreased levels of IL10 and TGF-β in cell supernatants. Furthermore, the supernatant from polarized macrophages in the TIMP1-silenced group inhibited the motility of wild-type PTC cells. Therefore, TIMP1 may enhance the progression of PTC by stimulating the PI3K/AKT pathway via the secretion of IL10 and TGF-β, consequently influencing M2-type polarization in TAMs.

Clinical trial of arthroscopic debridement combined with functional exercise in the treatment of advanced knee osteoarthritis: A retrospective observational study.

Advanced knee osteoarthritis (KOA) impacts both knees, resulting in pain, deformity, and substantial restrictions in joint mobility. This study aims to examine the effectiveness of combining arthroscopic debridement with functional exercise in treating advanced KOA. A total of 296patients diagnosed with advanced KOA were divided into two groups: the observation group (n= 152) received arthroscopic debridement combined with functional exercise, while the control group (n= 144) underwent arthroscopic debridement only. The study compared and observed the outcomes between the two groups. There were no significant differences in knee joint function, inflammation level, and oxidative stress between the two groups before treatment (P> 0.05). Following treatment for six months, the observation group exhibited significantly lower visual analog scale (VAS) score, tissue inhibitors of metalloproteinase-1 (TIMP-1), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), matrix metalloproteinase-3 (MMP-3), and malondialdehyde (MDA) levels compared to the control group (P< 0.05). Meanwhile, the observation group showed significantly higher levels of Lysholm score, hospital for special surgery (HSS) score, range of motion (ROM) of knee, peak torque (PT) and total work (TW) for knee extension and flexion, superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione (GSH) compared to the control group (P< 0.05). Besides, the effective treatment rate in the observation group was notably higher than that in the control group (80.92% vs. 69.44%, P< 0.05). The combination of arthroscopic debridement with functional exercise is an effective treatment for advanced KOA. This approach not only enhances the function and strength of knee joint and reduces inflammatory response but also boosts the body's antioxidant capacity. The treatment exhibits encouraging outcomes and warrants broad implementation.

Taurine and Polyphenol Complex Repaired Epidermal Keratinocyte Wounds by Regulating IL8 and TIMP2 Expression.

The healing process after acne lesion extraction provides a miniature model to study skin wound repair mechanisms. In this study, we aimed to identify solutions for acne scars that frequently occur on our faces. We performed acne scar cytokine profiling and found that Interleukin 8 (IL8) and Tissue inhibitor of metalloproteinases 2 (TIMP2) were significant factors at the wounded site. The effect of chlorogenic acid and taurine on human epidermal cells and irritated human skin was investigated. Chlorogenic acid and taurine regulated IL8 and TIMP2 expression and accelerated keratinocyte proliferation. Moreover, tight junction protein expression was upregulated by chlorogenic acid and taurine synergistically. Further, these compounds modulated the expression of several inflammatory cytokines (IL1α, IL1β, and IL6) and skin hydration related factor (hyaluronan synthase 3; HAS3). Thus, chlorogenic acid and taurine may exert their effects during the late stages of wound healing rather than the initial phase. In vivo experiments using SLS-induced wounds demonstrated the efficacy of chlorogenic acid and taurine treatment compared to natural healing, reduced erythema, and restored barrier function. Skin ultrasound analysis revealed their potential to promote denser skin recovery. Therefore, the wound-restoring effect of chlorogenic acid and taurine was exerted by suppression of inflammatory cytokines, and induction of cell proliferation, tight junction expression, and remodeling factors.

Gestation-dependent increase in cervicovaginal pro-inflammatory cytokines and cervical extracellular matrix proteins is associated with spontaneous preterm delivery within 2 weeks of index assessment in South African women.

Inflammation-induced remodelling of gestational tissues that underpins spontaneous preterm birth (sPTB, delivery < 37 weeks' gestation) may vary by race and context. To explore relationships between markers of these pathological processes, we (a) characterised the cervicovaginal fluid (CVF) cytokine profiles of pregnant South African women at risk of PTB; (b) determined CVF matrix-metalloproteinase-9 (MMP-9) and its regulator tissue inhibitor of metalloproteinase-1 (TIMP-1); and (c) explored the predictive potential of these markers for sPTB. The concentrations of 10 inflammatory cytokines and MMP-9 and TIMP-1 were determined by ELISA in CVF samples from 47 non-labouring women at high risk of PTB. We studied CVF sampled at three gestational time points (GTPs): GTP1 (20-22 weeks, n = 37), GTP2 (26-28 weeks, n = 40), and GTP3 (34-36 weeks, n = 29) and analysed for changes in protein concentrations and predictive capacities (area under the ROC curve (AUC) and 95% confidence interval (CI)) for sPTB. There were 11 (GTP1), 13 (GTP2), and 6 (GTP3) women who delivered preterm within 85.3 ± 25.9, 51.3 ± 15.3, and 11.8 ± 7.5 (mean ± SD) days after assessment, respectively. At GTP1, IL-8 was higher (4-fold, p = 0.02), whereas GM-CSF was lower (~1.4-fold, p = 0.03) in the preterm compared with term women with an average AUC = 0.73. At GTP2, IL-1β (18-fold, p < 0.0001), IL-8 (4-fold, p = 0.03), MMP-9 (17-fold, p = 0.0007), MMP-9/TIMP-1 ratio (9-fold, p = 0.004), and MMP-9/GM-CSF ratio (87-fold, p = 0.005) were higher in preterm compared with term women with an average AUC = 0.80. By contrast, IL-10 was associated with term delivery with an AUC (95% CI) = 0.75 (0.55-0.90). At GTP3, IL-1β (58-fold, p = 0.0003), IL-8 (12-fold, p = 0.002), MMP-9 (296-fold, p = 0.03), and TIMP-1 (35-fold, p = 0.01) were higher in preterm compared with term women with an average AUC = 0.85. Elevated IL-1β was associated with delivery within 14 days of assessment with AUC = 0.85 (0.67-0.96). Overall, elevated MMP-9 at GTP3 had the highest (13.3) positive likelihood ratio for distinguishing women at risk of sPTB. Lastly, a positive correlation between MMP-9 and TIMP-1 at all GTPs (ρ ≥ 0.61, p < 0.01) for women delivering at term was only observed at GTP1 for those who delivered preterm (ρ = 0.70, p < 0.03). In this cohort, sPTB is associated with gestation-dependent increase in pro-inflammatory cytokines, decreased IL-10 and GM-CSF, and dysregulated MMP-9-TIMP-1 interaction. Levels of cytokine (especially IL-1β) and ECM remodelling proteins rise significantly in the final 2 weeks before the onset of labour when sPTB is imminent. The signalling mechanisms for these ECM remodelling observations remain to be elucidated.

Inflammation-Derived and Clinical Indicator-Based Predictive Model for Ischemic Stroke Recovery.

Neuroinflammatory responses are closely associated with poststroke prognosis severity. This study aimed to develop a predictive model, combining inflammation-derived markers and clinical indicators, for distinguishing functional outcomes in patients with subacute ischemic stroke. Based on activities of daily living assessments, ischemic stroke participants were categorized into groups with little effective (LE) recovery and obvious effective (OE) recovery. Initial biocandidates were identified by overlapping differentially expressed proteins from proteomics of clinical serum samples (5 LE, 5 OE, and 6 healthy controls) and differentially expressed genes from an RNA sequence of the ischemic cortex in middle cerebral artery occlusion mice (n=3). Multidimensional validations were conducted in ischemia-reperfusion models and a clinical cohort (15 LE, 11 OE, and 18 healthy controls). Models of robust biocandidates combined with clinical indicators were developed with machine learning in the training data set and prediction in another test data set (15 LE and 11 OE). We identified 194 differentially expressed proteins (LE versus healthy controls) and 174 differentially expressed proteins (OE versus healthy controls) in human serum, and 5121 differentially expressed genes (day 3) and 5906 differentially expressed genes (day 7) in middle cerebral artery occlusion mice cortex. Inflammation-derived biomarkers TIMP1 (tissue inhibitor metalloproteinase-1) and galactosidase-binding protein LGLAS3 (galectin-3) exhibited robust increases under ischemic injury in mice and humans. TIMP1 and LGALS3 coupled with clinical indicators (hemoglobin, low-density lipoprotein cholesterol, and uric acid) were developed into a combined model for differentiating functional outcome with high accuracy (area under the curve, 0.8). The combined model is a valuable tool for evaluating prognostic outcomes, and the predictive factors can facilitate development of better treatment strategies.

Association of blood inflammatory phenotypes and asthma burden in children with moderate-to-severe asthma

BackgroundUnderlying immunological mechanisms in children with moderate-to-severe asthma are complex and unclear. We aimed to investigate the association between blood inflammatory parameters and asthma burden in children with moderate-to-severe asthma.MethodsBlood inflammatory parameters (eosinophil(E) and neutrophil(N) counts and inflammatory mediators using multiplex immunoassay technology) were measured in children (6–17 years) with moderate-to-severe asthma from SysPharmPediA cohort across four European countries. Based upon low(L)/high(H) blood(B) eosinophil (LBE/HBE: &lt;/≥0.3×109/L, respectively) and neutrophil counts (LBN/HBN: &lt;/≥4×109/L, respectively), mixed(HBE-HBN), eosinophilic(HBE-LBN), neutrophilic(LBE-HBN), and paucigranulocytic(LBE-LBN) phenotypes were defined. Inflammatory mediator profiles and burden of disease (asthma control status, exacerbations and school days missed in the past year) were compared between phenotypes using adjusted logistic regression models.ResultsAmong 126 included children (41% girls and mean(sd) age of 11.94(2.76)), 22%, 44%, 11%, and 23% were classified as mixed, eosinophilic, neutrophilic, and paucigranulocytic phenotypes respectively. Neutrophilic children had lowest lung function (FEV1%predicted pre-salbutamol) compared to other groups. Children with mixed asthma were most often uncontrolled and had highest asthma-related school absence in the past year. Interleukin-6(IL-6) and matrix metalloproteinase-9(MMP-9) levels were significantly higher in patients with mixed or neutrophilic asthma, while tissue inhibitor of metalloproteinase-2(TIMP-2) was lower in patients with neutrophilic asthma compared to eosinophilic or paucigranulocytic asthma. Interleukin-5(IL-5) was increased in eosinophilic group compared to neutrophilic and paucigranulocytic groups, irrespective of the chosen cut-off for eosinophilia.ConclusionDifferences in asthma burden-related clinical expression and distinct blood inflammatory mediator profiles were found between phenotypes, highlighting implications for optimizing personalized treatment and management strategies in children with moderate-to-severe asthma.

Electroacupuncture ameliorates blood-brain barrier disruption after ischemic stroke through histone acetylation regulation at the matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 2 genes.

To explore whether the regulation of matrix metalloproteinase 9 (MMP-9)/ tissue inhibitors of MMPs (TIMPs) gene expression through histone acetylation is a possible mechanism by which electroacupuncture (EA) protects blood-brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) rat model. Male Sprague-Dawley rats were divided into four groups: the sham group, the MCAO group, the MCAO + EA (MEA) group, and the MCAO + EA + HAT inhibitor (HATi) group. The MCAO model was generated by blocking the middle cerebral artery. EA was applied to Baihui (GV20). Samples were collected 1 or 3 d after reperfusion. Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury. The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and chromatin immunoprecipitation (ChIP). Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption. The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression, but HATi reversed these effects of EA. In addition, ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter. EA treatment at Baihui (GV20) regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke, which preserves the structural integrity of the BBB in MCAO rats. These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.

Effect of nonsurgical periodontal therapy with additional photodynamic therapy on the level of MMP-9 and TIMP-1 in GCF in chronic periodontitis patients-a preliminary pilot study

PurposeMatrix metalloproteinases (MMPs) catalyze degradation of extracellular matrix proteins. The activity of MMPs is controlled by tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the MMP-9/TIMP-1 ratio has been linked with chronic periodontitis (CP). Photodynamic therapy (PDT) uses visible light, photosensitizer and oxygen to eradicate pathogens. The aim of the study was to evaluate the presence of MMP-9 and TIMP-1 in gingival crevicular fluid (GCF) in chronic periodontitis patients before and after nonsurgical periodontal therapy with additional PDT. MethodsNineteen patients, each with CP, were included in the study. After periodontal examination one site with a probing depth (PD) ​≥ ​4 ​mm was selected. The patients received scaling and root planing (SRP) with additional PDT by means of HELBO® diode minilaser. Prior to treatment, and after 3 and 6 months, the following parameters were estimated from the same site: PD, gingival recession (GR), clinical attachment level (CAL), plaque index (PI), bleeding on probing (BOP) and sulcus fluid flow rate (SFFR). The levels of MMP-9 and TIMP-1 in GCF were determined. ResultsCompared to baseline, the levels of MMP-9 and TIMP-1 did not show statistically significant differences after 3 and 6 months. According to Spearman's rank correlations, MMP-9 was positively correlated with SFFR at all time points. PD, CAL and PI showed a statistically significant decrease compared to baseline (p ​< ​0.001). SFFR decreased but not significantly. ConclusionNonsurgical periodontal therapy in conjunction with PDT was clinically effective but it had no effect on the levels of MMP-9 and TIMP-1 in GCF.

Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance.

Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found that higher predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans. We first identified 12 proteins with aging or rejuvenating effects on murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we computed polygenic scores as proxies for plasma protein levels and validated their prediction accuracy in two independent cohorts. Association models between genetic proxies and cognitive performance highlighted the significance of TIMP2, also when the models were stratified by sex, APOE -ε4, and Aβ42 status. This finding aligns with TIMP2's brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.

Correlation between matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 and white matter hyperintensities in patients with cerebral small vessel disease based on cranial magnetic resonance 3D imaging

ObjectiveThe objective of this study was to investigate the correlation between serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels and their ratios with the severity of white matter hyperintensities (WMHs) in patients with cerebral small vessel disease (CSVD). MethodsThis cross-sectional study was done on a prospective cohort of patients with CSVD. Qualitative and quantitative analyses of WMHs were performed using Fazekas grading and lesion prediction algorithm (LPA) methods. Biomarkers MMP-2, MMP-9, and TIMP-1 were measured to explore their correlation with the severity of WMHs. ResultsThe sample consisted of 144 patients with CSVD. There were 63 male and 81 female patients, with an average age of 67.604 ± 8.727 years. Among these, 58.33% presented with white matter hyperintensities at Fazekas grading level 1, with an average total template volume of WMHs of 4.305 mL. MMP-2 (P = 0.025), MMP-9 (P = 0.008), TIMP-1 (P = 0.026), and age (P = 0.007) were identified as independent correlates of WMHs based on Fazekas grading. Independent correlates of the total template volume of WMHs included MMP-2 (P = 0.023), TIMP-1 (P = 0.046), age (P = 0.047), systolic blood pressure (P = 0.047), and homocysteine (Hcy) (P = 0.014). In addition, age (P = 0.003; P < 0.001), interleukin-6 (IL-6) (P < 0.001; P = 0.044), Hcy (P < 0.001; P < 0.001), glycated hemoglobin (HbA1c) (P = 0.016; P = 0.043), and chronic kidney disease (P < 0.001; P < 0.001) were associated with both WMHs Fazekas grading and the total template volume of WMHs. ConclusionSerum levels of MMP-9, MMP-2, and TIMP-1 were independently associated with the Fazekas grading, while serum TIMP-1 and MMP-2 levels were independently related to the total template volume of WMHs. The association of TIMP-1 and MMP-2 with the severity of CSVD-related WMHs suggests their potential role as disease-related biomarkers. However, further research is required to uncover the specific mechanisms underlying these interactions.