Tissue Inhibitor Of Metalloproteinase Research Articles

Metalloproteinases between History, Health, Disease, and the Complex Dimension of Social Determinants of Health

Metalloproteinases (MPs) belong to the superfamily of zinc endopeptidases, which are called metzincins. Three families of MPs have been studied in healthy and diseased conditions in humans. The first study on MPs was published in 1962, and following that, several studies characterized their activity and their effect on health and disease. Several diseases have been related to MPs, such as cardiovascular disease, cancer, inflammatory diseases, gynecological disorders, and others. Moreover, tissue inhibitors of metalloproteinases (TIMPs) have been widely studied, and drugs and artificial molecules that could target MP activity have been evaluated. MPs are relevant to public health because of their role in several diseases and, most of all, their role as biomarkers that also impact the quality of life and the psychosocial dimension of affected patients. In this context, new pathways to precision health and precision medicine have been opened in the area of MPs. This review describes, from the initial studies, the complex dimensions of MPs and related issues centered on health and disease dimensions.

Targeting of HBP1/TIMP3 axis as a novel strategy against breast cancer

Malignant proliferation and metastasis are the main causes of breast cancer death. The transcription factor high mobility group (HMG) box-containing protein 1 (HBP1) is an important tumor suppressor whose deletion or mutation is closely related to the appearance of tumors. Here, we investigated the role of HBP1 in breast cancer suppression. HBP1 enhances the activity of the tissue inhibitors of metalloproteinases 3 (TIMP3) promoter, thereby increasing protein and mRNA levels of TIMP3. TIMP3 increases the phosphatase and tensin homolog (PTEN) protein level by inhibiting its degradation and acts as a metalloproteinase inhibitor to inhibit the protein levels of MMP2/9. In this study, we demonstrated that the HBP1/TIMP3 axis plays a crucial role in inhibiting the tumorigenesis of breast cancer. HBP1 deletion interferes with the regulation of the axis and induces the occurrence and malignant progression of breast cancer. In addition, the HBP1/TIMP3 axis promotes the sensitivity of breast cancer to radiation therapy and hormone therapy. Our study opens new perspectives on the treatment and prognosis of breast cancer.

Inhibition of Monoacylglycerol Lipase Decreases Angiogenic Features of Endothelial Cells via Release of Tissue Inhibitor of Metalloproteinase-1 from Lung Cancer Cells.

Despite the well-described anticarcinogenic effects of endocannabinoids, the influence of the endocannabinoid system on tumor angiogenesis is still debated. In the present study, conditioned medium (CM) from A549 and H358 lung cancer cells treated with ascending concentrations of the monoacylglycerol lipase (MAGL) inhibitor JZL184 and 2-arachidonoylglycerol (2-AG), a prominent MAGL substrate, caused a concentration-dependent reduction in human umbilical vein endothelial cell (HUVEC) migration and tube formation compared with CM from vehicle-treated cancer cells. Comparative experiments with MAGL inhibitors JW651 and MJN110 showed the same results. On the other hand, the angiogenic properties of HUVECs were not significantly altered by direct stimulation with JZL184 or 2-AG or by exposure to CM of JZL184- or 2-AG-treated non-cancerous bronchial epithelial cells (BEAS-2B). Inhibition of HUVEC migration and tube formation by CM of JZL184- and 2-AG-treated A549 cells was abolished in the presence of the CB1 antagonist AM-251. Increased release of tissue inhibitor of metalloproteinase-1 (TIMP-1) from JZL184- or 2-AG-stimulated A549 or H358 cells was shown to exert an antiangiogenic effect on HUVECs, as confirmed by siRNA experiments. In addition, JZL184 caused a dose-dependent regression of A549 tumor xenografts in athymic nude mice, which was associated with a decreased number of CD31-positive cells and upregulation of TIMP-1-positive cells in xenograft tissue. In conclusion, our data suggest that elevation of 2-AG by MAGL inhibition leads to increased release of TIMP-1 from lung cancer cells, which mediates an antiangiogenic effect on endothelial cells.

TIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone.

Adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ) serve as a lifelong reservoir for newborn olfactory bulb neurons. Recent studies have identified a slowly dividing subpopulation of embryonic neural stem-progenitor cells (NPCs) as the embryonic origin of adult NSCs. Yet, little is known about how these slowly dividing embryonic NPCs are maintained until adulthood while other NPCs are extinguished by the completion of brain development. The extracellular matrix (ECM) is an essential component of stem cell niches and thus a key determinant of stem cell fate. Here we investigated tissue inhibitors of metalloproteinases (TIMPs)-regulators of ECM remodeling-for their potential roles in the establishment of adult NSCs. We found that Timp2, Timp3, and Timp4 were expressed at high levels in slowly dividing NPCs compared to rapidly dividing NPCs. Deletion of TIMP3 reduced the number of adult NSCs and neuroblasts in the lateral SVZ. In addition, overexpression of TIMP3 in the embryonic NPCs suppressed neuronal differentiation and upregulated the expression levels of Notch signaling relating genes. These results thus suggest that TIMP3 keeps the undifferentiated state of embryonic NPCs, leading to the establishment and maintenance of adult NSCs.

Urinary TIMP-2*IGFBP-7 to diagnose acute kidney injury in children receiving cisplatin.

Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers. We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)). serum creatinine (SCr)-defined AKI (≥ stage 1). At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine)2/1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70). TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease

Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes.

SKIL/SnoN attenuates TGF-β1/SMAD signaling-dependent collagen synthesis in hepatic fibrosis.

The ski-related novel gene (SnoN), encoded by the SKIL gene, has been shown to negatively regulated transforming growth factor-β1 (TGF-β1) signaling pathway. However, the roles of SnoN in hepatic stellate cell (HSC) activation and hepatic fibrosis (HF) are still unclear. To evaluate the role of SnoN in HF, we combined bulk RNA sequencing analysis and single-cell RNA sequencing analysis to analyse patients with HF. The role of SKIL/SnoN was verified using liver samples from rat model transfected HSC-T6 and LX-2 cell lines. Immunohistochemistry, immunofluorescence, PCR, and western blotting techniques were used to demonstrate the expression of SnoN and its regulatory effects on TGF-β1 signaling in fibrotic liver tissues and cells. Furthermore, we constructed competitive endogenous RNA regulatory network and potential drug network associated with the SnoN gene. We identified SKIL gene as a differentially expressed gene in hepatic fibrosis. SnoN protein was found to be widely expressed in the cytoplasm of normal hepatic tissues, whereas it was almost absent in HF tissues. In the rat group subjected to bile duct ligation (BDL), SnoN protein expression decreased, while TGF-β1, collagen III, tissue inhibitor of metalloproteinase 1 (TIMP-1), and fibronectin levels increased. We observed the interaction of SnoN with p-SMAD2 and p-SMAD3 in the cytoplasm. Following SnoN overexpression, apoptosis of HSCs was promoted, and the expression of HF-associated proteins, including collagen I, collagen III, and TIMP-1, was reduced. Conversely, downregulation of SnoN inhibited HSC apoptosis, increased collagen III and TIMP-1 levels, and decreased matrix metalloproteinase 13(MMP-13) expression. In conclusion, SnoN expression is downregulated in fibrotic livers, and could attenuate TGF-β1/SMADs signaling-dependent de-repression of collagen synthesis.

A Sequential Micro-Immunotherapy Medicine Increases Collagen Deposition in Human Gingival Fibroblasts and in an Engineered 3D Gingival Model under Inflammatory Conditions.

Periodontal therapies use immune mediators, but their side effects can increase with dosage. Micro-immunotherapy (MI) is a promising alternative that employs immune regulators at low and ultralow doses to minimize adverse effects. In this study, the effects of 5 capsules and the entire 10-capsule sequence of the sequential MI medicine (MIM-seq) were tested in two in vitro models of periodontitis. Firstly, human gingival fibroblasts (hGFs) exposed to interleukin (IL)-1β to induce inflammation were treated with five different capsules of MIM-seq for 3 days or with MIM-seq for 24 days. Subsequently, MIM-seq was analyzed in a 3D model of human tissue equivalent of gingiva (GTE) under the same inflammatory stimulus. Simultaneously, a non-IL-1β-treated control and a vehicle were included. The effects of the treatments on cytotoxicity, collagen deposition, and the secreted levels of IL-1α, IL-6, prostaglandin E2 (PGE2), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were evaluated. None of the tested items were cytotoxic. The complete sequence of MIM-seq decreased PGE2 release and restored collagen deposition levels induced by IL-1β treatment in hGFs exposed to IL-1β. MIM-seq treatment restored collagen production levels in both models. These promising preclinical findings suggest that MIM-seq should be further investigated for periodontitis treatment.

Expression analysis of MMP14: Key enzyme action in modulating visceral adipose tissue plasticity in patients with obesity.

Compromised adipose tissue plasticity is a hallmark finding of obesity orchestrated by the intricate interplay between various extracellular matrix components. Collagen6 (COL6) is well characterized in obese visceral adipose tissue (VAT), not much is known about MMP14 which is hypothesized to be the key player in matrix reorganization. Subjects with obesity (BMI ≥40; n = 50) aged 18-60 years undergoing bariatric surgery and their age-matched controls (BMI < 25; n = 30) were included. MMP14, Col6A3 and Tissue inhibitor of metalloproteinase 2 (TIMP2) mRNA expression was assessed in VAT and their serum levels along with endotrophin were estimated in both groups preoperatively and post-operatively in the obese group. The results were analysed statistically and correlated with anthropometric and glycaemic parameters, namely fasting glucose and insulin, HbA1c, HOMA-IR, HOMA-β and QUICKI. Circulating levels as well as mRNA expression profiling revealed significant differences between the individuals with and without obesity (p < .05), more so in individuals with diabetes and obesity (p < .05). Follow-up serum analysis revealed significantly raised MMP14 (p < .001), with decreased Col6A3, endotrophin and TIMP2 levels (p < .01, p < .001 and p < .01, respectively). A rise in serum MMP14 protein, simultaneous with post-surgical weight loss and decreased serum levels of associated extracellular matrix (ECM) remodellers, suggests its crucial role in modulating obesity-associated ECM fibrosis and pliability of VAT.

Correlation of TIMP1-MMP2/MMP9 Gene Expression Axis Changes with Treatment Efficacy and Survival of NSCLC Patients.

In the course of lung cancer, normal cells are transformed into cancerous ones, and changes occur in the microenvironment, including the extracellular matrix (ECM), which is not only a scaffold for cells, but also a reservoir of cytokines, chemokines and growth factors. Metalloproteinases (MMPs) are among the elements that enable ECM remodeling. The publication focuses on the problem of changes in the gene expression of MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP1) in the blood of NSCLC patients during therapy (one year after surgical resection of the tumor). The paper also analyzes differences in the expression of the studied genes in the tumor tissue, as well as data collected in publicly available databases. The results of blood tests showed no differences in the expression of the tested genes during therapy; however, changes were observed in cancerous tissue, which was characterized by higher expression of MMP2 and MMP9, compared to non-cancerous tissue, and unchanged expression of TIMP1. Nevertheless, higher expression of each of the studied genes was associated with shorter patient survival. Interestingly, it was not only the increased expression of metalloproteinase genes, but also the increased expression of the metalloproteinase inhibitor (TIMP1) that was unfavorable for patients.

Serum TGF-β1 and CD14 Predicts Response to Anti-TNF-α Therapy in IBD.

Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.

The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.

To determine macrophage-specific alterations in epigenetic enzyme function contributing to the development of abdominal aortic aneurysms (AAAs). AAA is a life-threatening disease, characterized by pathologic vascular remodeling driven by an imbalance of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Identifying mechanisms regulating macrophage-mediated extracellular matrix degradation is of critical importance to developing novel therapies. The role of SET Domain Bifurcated Histone Lysine Methyltransferase 2 (SETDB2) in AAA formation was examined in human aortic tissue samples by single-cell RNA sequencing and in a myeloid-specific SETDB2 deficient murine model induced by challenging mice with a combination of a high-fat diet and angiotensin II. Single-cell RNA sequencing of human AAA tissues identified SETDB2 was upregulated in aortic monocyte/macrophages and murine AAA models compared with controls. Mechanistically, interferon-β regulates SETDB2 expression through Janus kinase/signal transducer and activator of transcription signaling, which trimethylates histone 3 lysine 9 on the TIMP1-3 gene promoters thereby suppressing TIMP1-3 transcription and leading to unregulated matrix metalloproteinase activity. Macrophage-specific knockout of SETDB2 ( Setdb2f/fLyz2Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to the removal of the repressive histone 3 lysine 9 trimethylation mark on the TIMP1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the Janus kinase/signal transducer and activator of the transcription pathway with an FDA-approved inhibitor, Tofacitinib, limited SETDB2 expression in aortic macrophages. These findings identify SETDB2 as a critical regulator of macrophage-mediated protease activity in AAAs and identify SETDB2 as a mechanistic target for the management of AAAs.

Acute kidney injury biomarkers and hydration assessments following prolonged mild hypohydration in healthy young adults.

The high prevalence of inadequate hydration (e.g., hypohydration and underhydration) is concerning given that extreme heat increases excess hospitalizations for fluid/electrolyte disorders and acute kidney injury (AKI). Inadequate hydration may also be related to renal and cardiometabolic disease development. This study tested the hypothesis that prolonged mild hypohydration increases the urinary AKI biomarker product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) compared with euhydration. In addition, we determined the diagnostic accuracy and optimal cutoffs of hydration assessments for discriminating positive AKI risk ([IGFBP·TIMP-2] >0.3 (ng/mL)2/1,000). In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) completed 24 h of fluid deprivation (hypohydrated group) or 24 h of normal fluid consumption (euhydrated group) separated by ≥72 h. Urinary [IGFBP7·TIMP-2] and other AKI biomarkers were measured following the 24-h protocols. Diagnostic accuracy was assessed via receiver operating characteristic curve analysis. Urinary [IGFBP7·TIMP-2] [1.9 (95% confidence interval: 1.0-2.8) vs. 0.2 (95% confidence interval: 0.1-0.3) (ng/mL)2/1,000, P = 0.0011] was markedly increased in hypohydrated versus euhydrated groups. Urine osmolality (area under the curve: 0.91, P < 0.0001) and urine specific gravity (area under the curve: 0.89, P < 0.0001) had the highest overall performance for discriminating positive AKI risk. Optimal cutoffs with a positive likelihood ratio of 11.8 for both urine osmolality and specific gravity were 952 mosmol/kgH2O and 1.025 arbitrary units. In conclusion, prolonged mild hypohydration increased urinary [IGFBP7·TIMP-2] in males and females. Urinary [IGFBP7·TIMP-2] corrected to urine concentration was elevated in males only. Urine osmolality and urine specific gravity may have clinical utility for discriminating positive AKI risk following prolonged mild hypohydration.NEW & NOTEWORTHY This study found that prolonged mild hypohydration in healthy young adults increased the Food and Drug Administration approved acute kidney injury (AKI) biomarker urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 [IGFBP7·TIMP-2]. Urine osmolality and specific gravity demonstrated an excellent ability to discriminate positive AKI risk. These findings emphasize the importance of hydration in protecting renal health and lend early support for hydration assessment as an accessible tool to assess AKI risk.

#5471 THE URINARY BIOMARKERS IGFBP7 AND IGFBP7 X TIMP2 PRE-EMPTIVELY IDENTIFY PATIENTS AT RISK OF CONTRAST NEPHROTOXICITY

Abstract Background and Aims Drug nephrotoxicity is a serious medical and economic concern. In fact, 25% of the 100 most used drugs in intensive care units are toxic to the kidney, which limits their use and, therefore, the correct therapy for the patient. The administration of contrast media (CM) during diagnostic tests or surgical interventions carries the risk of contrast-induced nephropathy (CIN), which is a clinical condition defined as an increase in plasma creatinine of 25% or 0.5 mg/dL above baseline within 3-5 days after administration. Because once installed CIN has no treatment, identification of new biomarkers predicting patients at risk of CIN before receiving CM may be crucial to prevent future kidney complications. Clinical studies conducted in other medical areas have identified new urinary biomarkers, such as insulin like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP2), that anticipate the risk of developing kidney damage after the administration of different potentially nephrotoxic compounds. The objective of this work was to evaluate the usefulness of these biomarkers to predict CIN in cardiac patients. Method A clinical study was carried out with 154 patients from the University Hospital of Salamanca Cardiology Department who subsequently received a CM. Prior to contrast administration, urine samples were collected. In addition, their plasma creatinine level was registered for the following 5 days to evaluate the development of CIN. Patients were divided into Controls (who did not develop CIN) and Cases (who developed CIN). IGFBP7 and TIMP2 biomarkers were quantified in urine samples by ELISA. Subsequently, the differences between both groups were evaluated using the Mann-Whitney U test and the diagnostic capacity of each biomarker was analyzed through the generation of its receiver operating characteristic (ROC) curve. Results Of the total number of patients, 123 were assigned to the Controls group and 31 to the Cases group. In both groups the distribution of sex and risk factors was similar, except for the case of age and body mass index, which was slightly lower and higher, respectively, in the Controls group. IGFBP7 was significantly higher in Cases (p &amp;lt; 0.01) compared to the Controls, and the IGFBP7 x TIMP2 product further improved this significance (p &amp;lt; 0.001). Specifically, the area under the ROC curve for IGFBP7 was 0.67 (95% confidence interval of 0.56-0.78); while that for IGFBP7 x TIMP2 increased to 0.73 (with a 95% confidence interval of 0.63-0.84). In contrast, TIMP2 alone showed no differences between both groups of patients. Conclusion The biomarkers IGFBP7 and IGFBP7 x TIMP2 could therefore be used for the prophylactic identification and management of patients at risk of developing CIN.

Correlation of Stromelysin-1 and Tissue Inhibitor of Metalloproteinase-1 with Lipid Profile and Atherogenic Indices in End-Stage Renal Disease Patients: A Neural Network Study

End-stage renal disease (ESRD) patients are prone to cardiovascular disease (CVD). The search for a biomarker that determines patients at great risk of CVD is still a hot topic of study. In the present study, stromelysin-1 and its inhibitor (TIMP1), in addition to atherogenic indices, were studied in ESRD patients. We assessed stromelysin-1, TIMP1, and lipid profile parameters in the serum of 60 ESRD patients and 30 healthy controls. A neural network study was conducted to determine the best factors for predicting ESRD patients more susceptible to developing CVD using the cut-off value of the atherogenic index of plasma (AIP) &gt;0.24. ESRD patients have dyslipidemia, high atherogenic indices, and elevated levels of stromelysin-1 and TIMP1. There is a correlation between the rise in stromelysin-1 and its inhibitor and several atherogenic indices and lipids in those patients. The neural network results indicated that the area under the curve predicting CVD, using the measured eight parameters, was 0.833, with 80 % sensitivity and 100% specificity. The relative importance of the top four most effective input variables that represent the most important determinants for the prediction of high risk of CVD stromelysin-1 (100%), followed by eGFR (77.9%), TIMP1 (66.0%), and TIMP1/stromelysin-1 (30.7%). ESRD patients have dyslipidemia and are prone to CVD, and stromelysin-1 is the best parameter for predicting CVD in ESRD patients.

PTEN Inhibitor Treatment Lowers Muscle Plasma Membrane Damage and Enhances Muscle ECM Homeostasis after High-Intensity Eccentric Exercise in Mice.

Exercise-induced muscle damage (EIMD) is a common occurrence in athletes and can lead to delayed onset muscle soreness, reduced athletic performance, and an increased risk of secondary injury. EIMD is a complex process involving oxidative stress, inflammation, and various cellular signaling pathways. Timely and effective repair of the extracellular matrix (ECM) and plasma membrane (PM) damage is critical for recovery from EIMD. Recent studies have shown that the targeted inhibition of phosphatase and tension homolog (PTEN) in skeletal muscles can enhance the ECM environment and reduce membrane damage in Duchenne muscular dystrophy (DMD) mice. However, the effects of PTEN inhibition on EIMD are unknown. Therefore, the present study aimed to investigate the potential therapeutic effects of VO-OHpic (VO), a PTEN inhibitor, on EIMD symptoms and underlying mechanisms. Our findings indicate that VO treatment effectively enhances skeletal muscle function and reduces strength loss during EIMD by upregulating membrane repair signals related to MG53 and ECM repair signals related to the tissue inhibitor of metalloproteinases (TIMPs) and matrix metalloproteinase (MMPs). These results highlight the potential of pharmacological PTEN inhibition as a promising therapeutic approach for EIMD.

Evaluation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human cases with orofacial clefts: A systematic review

The interaction between several cell populations or many genes and the coordination of multiple signal transmission pathways can lead to defects such as orofacial clefts (OFCs). Herein, a systematic review was designed to evaluate a group of important biomarkers (matrix metalloproteinases [MMPs] and tissue inhibitors of metalloproteinases [TIMPs]) in human cases with OFCs. Four databases including PubMed, Scopus, Web of Science, and Cochrane Library databases were searched until March 10, 2023, without any restriction. STRING, the protein-protein interaction (PPI) network software, was applied to investigate the functional interactions among the examined genes. The effect sizes including odds ratio (OR) dealing with a 95% confidence interval (CI), were extracted by the Comprehensive Meta-Analysis version 2.0 (CMA 2.0) software. Thirty-one articles were entered into the systematic review that four articles were analyzed in the meta-analysis. Single studies reported that several polymorphisms of MMPs (rs243865, rs9923304, rs17576, rs6094237, rs7119194, and rs7188573); and TIMPs (rs8179096, rs7502916, rs4789936, rs6501266, rs7211674, rs7212662, and rs242082) had an association with OFC risk. There was no significant difference for MMP-3 rs3025058 polymorphism in allelic (OR: 0.832; P=0.490), dominant (OR: 1.177; P=0.873), and recessive (OR: 0.363; P=0.433) models and MMP-9 rs17576 polymorphism in an allelic model (OR: 0.885; P=0.107) between the OFC cases and the controls. Based on immunohistochemistry reports, three MMPs (MMP-2, MMP-8, and MMP-9) and TIMP-2 had significant correlations with several other biomarkers in OFC cases. MMPs and TIMPs can impact the tissue and cells affected by OFCs and the process of apoptosis. The interaction between some biomarkers with MMPs and TIMPs (e.g., TGFb1) in OFCs can be interesting for future research.

Protective effect of Schizonepeta tenuifolia Briq. ethanolic extract against UVB-induced skin aging and photodamage in hairless mice.

The purpose of this study was to illuminate the mechanism by which Schizonepeta tenuifolia Briq. (ST) ethanolic extract prevents skin photoaging in HR-1 hairless mice (HR-1). The ST ethanolic extract alleviated wrinkle formation, epidermal skin thickness, and collagen degradation in skin tissues of ultraviolet B (UVB)-irradiated HR-1 mice. Expression of matrix metalloproteinases (a wrinkle-related marker) was reduced, and tissue inhibitor of metalloproteinase 1 expression was upregulated following application of ST ethanolic extract. Furthermore, skin dehydration and levels of hyaluronidase-1 and -2 (enzymes that break hyaluronic acid) were decreased. Moreover, protein expression of hyaluronan synthases (markers of skin hydration) and hyaluronic acid levels increased following ST ethanolic extract treatment in UVB-induced photoaging HR-1 mice. In addition, the phosphorylation of mitogen-activated protein kinases (MAPKs), including p38, extracellular signal-regulated kinase, and Jun N-terminal kinase was suppressed, and expression of nuclear factor-kappa was reduced. Treatment with ST ethanolic extract also reduced advanced glycation end product (AGE) accumulation and expression of the receptor for AGE (RAGE) in skin tissue. These results suggest that ST ethanolic extract moderates skin damage caused by UVB irradiation via regulating the expression of wrinkle- and hydration-related proteins, MAPKs, and RAGE.

Clinical value of combined serum MMP-2, MMP-9 and TIMP-1 for the prognosis of perianal fistula patients who received minimally invasive surgery.

This study aimed to investigate the clinical value of combined serum matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) for the prognosis of perianal fistula patients. Patients diagnosed and treated for perianal fistula by minimally invasive surgery (MIS) were enrolled. The concentrations of serum MMP-2, MMP-9 and TIMP-1 were measured at 24 h after surgery. Different levels of wound secretion, growth of granulation tissue and wound pain were used as criteria to evaluate surgical incision healing. The receiver operating characteristic curve was used to analyze the predicted assessment value. The concentrations of serum MMP-2 and MMP-9 were significantly higher, while the concentrations of serum TIMP-1 at 24 h after surgery were significantly lower in the poor healing group than in the good healing group. It was further found that high levels of serum MMP-2 and MMP-9 were risk factors for poor healing, while high concentrations of serum TIMP-1 at 24 h after surgery were protective factors for poor healing. High concentrations of serum MMP-2 and MMP-9 and low concentrations of serum TIMP at 24 h after surgery are risk factors for poor healing in perianal fistula patients who receive MIS, and the combined test has a higher predictive value.

A salivary biomarker panel to detect liver cirrhosis

Limited access to diagnostic tests for liver fibrosis remains one of the main reasons for late diagnosis, especially in rural and remote communities. Saliva diagnostics is accessible with excellent patient compliance. The aim of this study was to develop a saliva-based diagnostic tool for liver fibrosis/cirrhosis. Salivary concentrations of hyaluronic acid (HA), tissue inhibitor of metalloproteinase-1 (TIMP-1), and α-2-macroglobulin (A2MG) were significantly increased (p<0.05) in patients with liver fibrosis/cirrhosis. By combining these biomarkers, we developed the Saliva Liver Fibrosis (SALF) score, which identified patients with livercirrhosis with an area under the receiver operating characteristic curve (AUROC) of 0.970 and 0.920 in a discovery and validation cohorts, respectively. The SALF score had a performance that was similar to that of the current Fibrosis-4 (AUROC:0.740) and Hepascore (AUROC:0.979). We demonstrated the clinical utility of saliva to diagnose liver fibrosis/cirrhosis with a potential to improve the screening for cirrhosis in asymptomatic populations.