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PURPOSE: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. METHODS: [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. RESULTS: [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. CONCLUSION: [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.

Background: Collagenases, a subgroup of matrix metalloproteinases (MMPs), play crucial roles in local invasion and metastasis in cancer. While substrate zymography and in situ zymography are commonly used to analyze the collagenases, traditional techniques have limitations in determining their local activities in vitro. Objectives: We aimed to develop a new "cell in situ collagen zymography" technique to enhance the efficiency of studying local collagenase activities in vitro. Methods: We utilized human thyroid cancer cell lines (8505 C, B-CPAP, FTC-133) and normal follicular thyroid cell line (Nhty-ori-3-1). We compared collagenase levels across these cell lines and selected 8505 C as a model due to its highest collagenase activity. We optimized factors including (i) fixation method (methanol, ethanol and zinc), (ii) dye-quenched (DQ) collagen concentration and (iii) collagen gel configuration. For gel configuration, cells were seeded under, on the top of, or between (sandwich) collagen gel layers. As controls, enzymatic activity was suppressed in the presence of EDTA, piroxicam and matrix metalloproteinase 8 inhibitor I. The optimized method was also applied to BCPAP, FTC-133, and Nthy-ori-3-1. Results: Our optimization process revealed that that the best visualization of collagenase activity in 8505 C was provided by the "sandwich model" of gel, containing 25 µg/mL of DQ-collagen with 100% cold methanol fixation. We confirmed the optimized method's applicability in other thyroid cell lines. The use of inhibitors validated the specificity of the fluorescent signal to MMP activity. Conclusion: The innovative "cell in situ collagen zymography" technique offers an efficient, cost-effective, and rapid method for analyzing local collagenase activities in vitro. [ABSTRACT FROM AUTHOR]

Keloid scars (keloids), a prototypical form of aberrant scar tissue formation, continue to pose a significant therapeutic challenge within dermatology and plastic surgery due to suboptimal treatment outcomes. Gelatinases are a subgroup of matrix metalloproteinases (MMPs), a family of enzymes that play an important role in the degradation and remodeling of the ECM (a pivotal factor for keloids development). Gelatinases include gelatinase A (MMP-2) and gelatinase B (MMP-9). Since accumulating evidence has shown that gelatinases played a crucial role in the process of keloid formation, we summarized the current knowledge on the association between MMP-2 and MMP-9 expression and the pathological process of keloids through a comprehensive review. This review demonstrated that the interplay between MMP-2, MMP-9, and their regulators, such as TGF-β1/Smad, PI3K/AKT, and LncRNA-ZNF252P-AS1/miR-15b-5p/BTF3 signaling cascades, involved in the intricate balance governing ECM homeostasis, collectively driving the excessive collagen deposition and altered tissue architecture observed in keloids. In summary, this review consolidates the current understanding of MMP-2 and MMP-9 in keloid pathogenesis, shedding light on their intricate involvement in the dysregulated keloids processes. The potential for targeted therapeutic interventions presents promising opportunities for advancing keloid management strategies. [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]

Water-free transportation (WFT) causes shrimp (Penaeus vannamei) flesh quality deterioration. However, the roles of endogenous protease-induced protein hydrolysis have been neglected in the research. In the present study, calpain zymography, gelatinase zymography, the hematoxylin–eosin staining method, and other methods were applied to investigate the response of various endogenous proteases (cathepsin, calpain, and gelatinase), the myofibril fragmentation index (MFI), and the microscopic morphology of shrimp muscle during WFT in comparison with the shrimp under the conventional water transportation strategy (WT). The results showed that the total activity of proteases in shrimp muscle increased significantly (p ≤ 0.05) after simulated transportation. Cathepsins and gelatinases were activated during WFT. No significant (p > 0.05) changes of the activity of caspase-3 and the muscle cell apoptosis rate were detected in shrimp muscle cells after WFT. In addition, the MFI increased and the gap among muscle fiber bundles enlarged after WFT. Compared with WFT, no significant (p > 0.05) effect on the activities of calpain, gelatinase, and caspase-3 in the muscle of shrimp was found after WT, and only the activity of cathepsin L significantly increased (p ≤ 0.05). Based on the findings, we concluded that the activation of various endogenous proteases was induced during WFT. [ABSTRACT FROM AUTHOR]

BackgroundObjectiveMethodsResultsConclusionIntegrating aerobic exercise (AE) into rehabilitation programs for post-stroke individuals could enhance motor recovery and cardiovascular health by increasing brain-derived neurotrophic factor (BDNF) and the myokine irisin. Chronic stroke survivors typically exhibit elevated matrix metalloproteinase-9 (MMP-9) activity, which is negatively correlated with steps and time in medium cadence, although the impact of AE on this biomarker remains unclear.To evaluate the effect of high-intensity AE training prior to modified constraint-induced movement therapy (mCIMT) on BDNF and irisin concentration, and on MMP-2 and MMP-9 activity in chronic post-stroke individuals and to associate these results with functional improvements.Nine participants received AE combined with mCIMT for two weeks, while the control group (n = 7) received mCIMT alone. Manual dexterity and functional capacity were assessed before and after the intervention. Serum samples were analyzed for BDNF, irisin, MMP-2 and MMP-9.There were no significant main effects of assessment, group or interaction on molecular biomarkers. However, the AE group had a significant increase in MMP-9 activity post-intervention (p = .033; d = 0.67). For the Box and Block Test, there were significant main effects of assessment (F [1, 14] = 33.27, p = .000, ηp2 = 0.70) and group (F [1, 14] = 5.43, p = .035, ηp2 = .28). No correlations were found between biomarkers and clinical assessments.AE prior to mCIMT did not influence circulating BDNF and irisin levels but did induce an acute rise in MMP-9 activity, suggesting potential effects on cardiovascular remodeling in this population. [ABSTRACT FROM AUTHOR]

Abstract 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). Taken together, the two adhesives did not activate but rather inhibited the release and activation of dentinal gelatinases.

Simple Summary: Natural polyphenols are well-known dietary supplements that have been used for medical purposes for a long time. Consuming foods and beverages of plant origin, especially those rich in polyphenolic compounds, may have chemopreventive and therapeutic effects on cancer due to the health-promoting properties of these compounds. Polyphenols are characterized by high structural diversity, which contributes to their wide range of therapeutic effects, including anti-oxidant and anti-cancer activities. These compounds can modulate the expression and activity of many proteins, including enzymes, and regulate multiple cell signaling pathways. Among the molecular targets of anti-cancer agents are matrix metalloproteinases, particularly metalloproteinase-2 and metalloproteinase-9, and nuclear factor-kappa B. Matrix metalloproteinases can degrade the protein components of the extracellular matrix and play key roles in physiological processes such as tissue repair and morphogenesis, as well as in carcinogenesis and other pathological processes. The inhibition of their synthesis and activity is closely related to a reduction in the metastasis and invasion of cancer cells. This review discusses the current state of knowledge concerning the anti-invasive and anti-metastatic potential of selected polyphenols, with a focus on in vitro and in vivo evidence. Polyphenols are natural compounds found in many plants and their products. Their high structural diversity bestows upon them a range of anti-inflammatory, anti-oxidant, proapoptotic, anti-angiogenic, and anti-metastatic properties, and a growing body of research indicates that a polyphenol-rich diet can inhibit cancer development in humans. Polyphenolic compounds may modulate the expression, secretion, or activity of compounds that play a significant role in carcinogenesis, including type IV collagenases, such as matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), by suppressing cellular signaling pathways such as nuclear factor-kappa B. These enzymes are responsible for the degradation of the extracellular matrix, thus promoting the progression of cancer. This review discusses the current state of knowledge concerning the anti-cancer activity of polyphenols, particularly curcumin, resveratrol, epigallocatechin-3-gallate, genistein, and quercetin, with a specific focus on their anti-invasive and anti-metastatic potential, based on the most recent in vitro and in vivo studies. It appears that polyphenols may be valuable options for the chemoprevention and treatment of cancer via the inhibition of MMP-2 and MMP-9 and the suppression of signaling pathways regulating their expression and activity. [ABSTRACT FROM AUTHOR]

Hydrolytically and enzymatically-stable multi-acrylamides have been proposed to increase the long-term durability of dental adhesive interfaces as alternatives to methacrylates. The aim of this study was to investigate the mechanical and biochemical properties of experimental adhesives containing multi-functional acrylamides concerning collagen reinforcement and metalloproteinases (MMP) activity. Multi-functional acrylamides, TMAAEA (Tris[(2-methylaminoacryl) ethylamine) and DEBAAP (N,N-Diethyl-1,3-bis(acrylamido) propane), along with the commercially available DMAM (N,N-dimethylacrylamide) (monofunctional acrylamide) and HEMA (2-Hydroxyethyl methacrylate) (monofunctional methacrylate - control) were tested for stability against enzymatic hydrolysis by cholesterol esterase/pseudocholinesterase (PC/PCE) solutions for up to 30 days. Collagen-derived substrate and gelatin zymography were performed to examine the effect of the compounds on the biological activity of human recombinant and dentin-extracted gelatinases MMP-2 and MMP-9. In situ zymography was carried out by fluorescent collagen degradation combined with confocal microscopy analysis. Hydroxyproline content was measured in collagen derived from dentin extracts though reaction with Ehrlich's reagent p -dimethylaminobenzaldehyde (DMAB), generating a stable chromophore measured at 550 nm. Storage shear modulus of demineralized dentin discs treated with the tested compounds was measured by oscillatory rheometry, in order to investigate potential collagen reinforcement. FT-IR was performed to determine qualitative differences in collagen based on observed changes in amide bands. The results were analyzed by ANOVA/Tukey's test (α = 0.05). Multi-acrylamides survived 30 days of incubation in cholinesterase/pseudo-cholinesterase (PC/PCE) solutions, while HEMA showed approximately 70 % overall degradation. Incubation with multi-acrylamides reduced collagen degradation as evidenced by the reduced hydroxyproline levels and by the 30 % increase inshear storage modulus. Biochemical and zymography assays showed no noticeable inhibition of recombinant and extracted MMPs enzymatic activity. The infra-red spectroscopy results for multi-functional acrylamides treated samples demonstrated shifts of the amide II bonds and marked increase in intensity of the bands 1200 cm-1, which may indicate partial collagen denaturation and some degree of cross-linking of the compounds with collagen, respectively. The multi-acrylamides exhibited not only comparable mechanical properties but also demonstrated significantly enhanced biochemical stability when compared to the widely used methacrylate control. Clinical relevance: These findings highlight the potential of multi-acrylamides to increase the bonding stability to tissues and, ultimately, contribute to the longevity of dental restorations. [ABSTRACT FROM AUTHOR]

Lactobacillus rhamnosus is commonly found in several fermented dairy products. The safety of probiotic L. rhamnosus OP268117 strain 6481 was evaluated in this study using hemolytic and gelatinase activity tests. Hemolysins or gelatinases were not detected for this probiotic candidate and so it is considered safe for human use. Three different concentrations of gum arabic (GA) were added to the like-yogurt, which was previously inoculated with the probiotic starter stated earlier. The utilization of concentrations of 0.25%, 0.5%, and 1% GA, namely B, C, and D, respectively, resulted in a significant improvement (p < 0.001) in the viable count of L. rhamnosus compared to the control samples, namely A, with the highest number (18.93 × 109 CFU/ml) observed in treatment D containing 1% GA on the 14th day. Adding GA had a substantial impact on the moisture, protein, and fiber content of the samples, but it did not influence the percentage of fat. The treatment with 1% GA (D) exhibited the highest fiber content. The pH decreased gradually as GA concentration increased during storage. Furthermore, the yogurt with 1% and 0.75% GA (D and C) showed the highest viscosity measurements on the 14th day of storage. The addition of GA had a significant impact on all sensory attributes, except for flavor, which was only minimally affected. The grades for appearance and texture were improved as the GA content increased. Thus, it is recommended to incorporate L. rhamnosus in the production of yogurt, together with 1% GA as a prebiotic to enhance the nutritional composition, overall appeal, and survival rate of the probiotics employed in the fermentation process. [ABSTRACT FROM AUTHOR]

Keloid scars (keloids), a prototypical form of aberrant scar tissue formation, continue to pose a significant therapeutic challenge within dermatology and plastic surgery due to suboptimal treatment outcomes. Gelatinases are a subgroup of matrix metalloproteinases (MMPs), a family of enzymes that play an important role in the degradation and remodeling of the ECM (a pivotal factor for keloids development). Gelatinases include gelatinase A (MMP-2) and gelatinase B (MMP-9). Since accumulating evidence has shown that gelatinases played a crucial role in the process of keloid formation, we summarized the current knowledge on the association between MMP-2 and MMP-9 expression and the pathological process of keloids through a comprehensive review. This review demonstrated that the interplay between MMP-2, MMP-9, and their regulators, such as TGF-β1/Smad, PI3K/AKT, and LncRNA-ZNF252P-AS1/miR-15b-5p/BTF3 signaling cascades, involved in the intricate balance governing ECM homeostasis, collectively driving the excessive collagen deposition and altered tissue architecture observed in keloids. In summary, this review consolidates the current understanding of MMP-2 and MMP-9 in keloid pathogenesis, shedding light on their intricate involvement in the dysregulated keloids processes. The potential for targeted therapeutic interventions presents promising opportunities for advancing keloid management strategies.

The Correction Notice in the Journal of Functional Biomaterials addresses errors in Figure 3 and the Materials and Methods section of a study on bioceramic endodontic materials. The corrected figure shows the inhibitory capacity of EndoSequence towards gelatinolytic activity. The study involved evaluating the activity of metalloproteinases using human saliva samples and polyacrylamide gel electrophoresis. The correction does not impact the scientific conclusions of the original publication. [Extracted from the article]

Chronic inflammatory lung diseases are characterized by disease-specific extracellular matrix accumulation resulting from an imbalance of matrix metalloproteinases (MMPs) and their inhibitors. Zinc is essential for the function of MMPs, and zinc deficiency has been associated with enhanced tissue remodeling. This study assessed if zinc iodide (ZnI) supplementation through dimethyl sulfoxide (DMSO) modifies the action of MMPs in isolated human lung fibroblasts. The expression and activity of two gelatinases, MMP-2 and MMP-9, were determined by gelatin zymography and enzyme-linked immuno-sorbent assay (ELISA). Collagen degradation was determined by cell-based ELISAs. Collagen type I and fibronectin deposition was stimulated by human recombinant tumor growth factor β1 (TGF-β1). Untreated fibroblasts secreted MMP-2 but only minute amounts of MMP-9. TGF-β1 (5 ng/mL) reduced MMP-2 secretion, but stimulated collagen type I and fibronectin deposition. All the effects of TGF-β1 were significantly reduced in cells treated with ZnI-DMSO over 24 h, while ZnI and DMSO alone had a lower reducing effect. ZnI-DMSO alone did not increase MMP secretion but enhanced the ratio of active to inactive of MMP-2. ZnI alone had a lower enhancing effect than ZnI-DMSO on MMP activity. Furthermore, MMP-2 activity was increased by ZnI-DMSO and ZnI in the absence of cells. Soluble collagen type I increased in the medium of ZnI-DMSO- and ZnI-treated cells. Blocking MMP activity counteracted all the effects of ZnI-DMSO. Conclusion: The data suggest that the combination of ZnI with DMSO reduces fibrotic processes by increasing the degradation of collagen type I by up-regulating the activity of gelatinases. Thus, the combination of ZnI with DMSO might be considered for treatment of fibrotic disorders of the lung. DMSO supported the beneficial effects of ZnI. [ABSTRACT FROM AUTHOR]

Simple Summary: Insect hemolymph transports, exchanges, and eliminates soluble compounds from the hemocoel. These processes play a critical role in many physiological processes, including development and immunity. Since matrix metalloproteases (MMPs) are the major circulating gelatinases in the blood of various species, including mammals, we used gel zymography to analyze gelatinase and caseinase activities in Drosophila larval hemolymph under normal and pathological conditions. Our investigations demonstrate that the major gelatinases and caseinases in Drosophila larval hemolymph are not MMPs but serine proteases (SPs). We identified more than 60 SPs in these proteolytic active bands. While a role in immunity has been suggested for some of these circulating SPs, the physiological functions of most of them remain to be elucidated. After separation on gel zymography, Drosophila melanogaster hemolymph displays gelatinase and caseinase bands of varying sizes, ranging from over 140 to 25 kDa. Qualitative and quantitative variations in these bands were observed during larval development and between different D. melanogaster strains and Drosophila species. The activities of these Drosophila hemolymph gelatinase and caseinase were strongly inhibited by serine protease inhibitors, but not by EDTA. Mass spectrometry identified over 60 serine proteases (SPs) in gel bands corresponding to the major D. melanogaster gelatinases and caseinases, but no matrix metalloproteinases (MMPs) were found. The most abundant proteases were tequila and members of the Jonah and trypsin families. However, the gelatinase bands did not show any change in the tequila null mutant. Additionally, no clear changes could be observed in D. melanogaster gel bands 24 h after injection of bacterial lipopolysaccharides (LPS) or after oviposition by Leptopilina boulardi endoparasitoid wasps. It can be concluded that the primary gelatinases and caseinases in Drosophila larval hemolymph are serine proteases (SPs) rather than matrix metalloproteinases (MMPs). Furthermore, the gelatinase pattern remains relatively stable even after short-term exposure to pathogenic challenges. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol abuse is one of the main health problems in the modern world. One of the consequences of alcoholism is chronic pancreatitis (CP). The pathogenesis of CP is not fully explained, but during CP, metabolic changes occur in the connective tissue of the pancreas. Our goal was to evaluate the fluctuations of selected extracellular enzymes in the course of alcoholic CP. Material and methods: Fifty-seven patients with alcoholic CP diagnosed according to M-ANNHEIM criteria were enrolled in the study. Twenty sex- and age-matched healthy individuals were enrolled as controls. MMP-2 and MMP-9, along with the concentrations of TIMP-1 and TIMP-2 in patients with CP and hyaluronic acid (HA) level were evaluated in serum using commercially available ELISA kits. Results: A significant increase in TIMP-1 level and a decrease in MMP-2/TIMP-1 ratio were noted in patients with alcoholic CP compared to controls (282.8 ng/ml vs. 247.2 ng/ml and 0.65 vs. 0.73; median values of TIMP-1 and MMP-2/TIMP-1 ratio in study and control patients respectively, p < 0.05). The observed increase in HA level did not reach statistical significance. The negative correlation between combined MMP/TIMP ratio vs. HA level was statistically insignificant. Conclusions: The elevation of TIMP-1 and decrease in MMP-2/TIMP-1 ratio in CP patients indicate the reduced gelatinolytic activity of serum during CP. [ABSTRACT FROM AUTHOR]

Parturition is the final and essential step for mammalian reproduction. While the uterus is quiescent during pregnancy, fundamental changes arise in the myometrial contractility, inducing fetal expulsion. Extracellular matrix (ECM) remodeling is fundamental for these events. The gelatinases subgroup of matrix metalloproteinases (MMPs), MMP2 and MMP9, participate in uterine ECM remodeling throughout pregnancy and parturition. However, their loss-of-function effect is unknown. Here, we determined the result of eliminating Mmp2 and/or Mmp9 on parturition in vivo, using single- and double-knockout (dKO) mice. The dystocia rates were measured in each genotype, and uterine tissue was collected from nulliparous synchronized females at the ages of 2, 4, 9 and 12 months. Very high percentages of dystocia (40–55%) were found in the Mmp2−/− and dKO females, contrary to the Mmp9−/− and wild-type females. The histological analysis of the uterus and cervix revealed that Mmp2−/− tissues undergo marked structural alterations, including highly enlarged myometrial, endometrial and luminal cavity. Increased collagen deposition was also demonstrated, suggesting a mechanism of extensive fibrosis in the Mmp2−/− myometrium, which may result in dystocia. Overall, this study describes a new role for MMP2 in myometrium remodeling during mammalian parturition process, highlighting a novel cause for dystocia due to a loss in MMP2 activity in the uterine tissue. [ABSTRACT FROM AUTHOR]

• Active MMP9 targets TIMPs when in molar excess. • All TIMPs are cleaved at their C-terminus. • TIMP2/4 are processed further, producing 14 kDa N-terminal peptides. • Cleavage has functional consequences on TIMP function. Extracellular proteolysis and turnover are core processes of tissue homeostasis. The predominant matrix-degrading enzymes are members of the Matrix Metalloproteinase (MMP) family. MMPs extensively degrade core matrix components in addition to processing a range of other factors in the extracellular, plasma membrane, and intracellular compartments. The proteolytic activity of MMPs is modulated by the Tissue Inhibitors of Metalloproteinases (TIMPs), a family of four multi-functional matrisome proteins with extensively characterized MMP inhibitory functions. Thus, a well-regulated balance between MMP activity and TIMP levels has been described as critical for healthy tissue homeostasis, and this balance can be chronically disturbed in pathological processes. The relationship between MMPs and TIMPs is complex and lacks the constraints of a typical enzyme-inhibitor relationship due to secondary interactions between various MMPs (specifically gelatinases) and TIMP family members. We illustrate a new complexity in this system by describing how MMP9 can cleave members of the TIMP family when in molar excess. Proteolytic processing of TIMPs can generate functionally altered peptides with potentially novel attributes. We demonstrate here that all TIMPs are cleaved at their C-terminal tails by a molar excess of MMP9. This processing removes the N-glycosylation site for TIMP3 and prevents the TIMP2 interaction with latent proMMP2, a prerequisite for cell surface MMP14-mediated activation of proMMP2. TIMP2/4 are further cleaved producing ∼14 kDa N-terminal proteins linked to a smaller C-terminal domain through residual disulfide bridges. These cleaved TIMP2/4 complexes show perturbed MMP inhibitory activity, illustrating that MMP9 may bear a particularly prominent influence upon the TIMP:MMP balance in tissues. [ABSTRACT FROM AUTHOR]

Chronic inflammatory lung diseases are characterized by disease-specific extracellular matrix accumulation resulting from an imbalance of matrix metalloproteinases (MMPs) and their inhibitors. Zinc is essential for the function of MMPs, and zinc deficiency has been associated with enhanced tissue remodeling. This study assessed if zinc iodide (ZnI) supplementation through dimethyl sulfoxide (DMSO) modifies the action of MMPs in isolated human lung fibroblasts. The expression and activity of two gelatinases, MMP-2 and MMP-9, were determined by gelatin zymography and enzyme-linked immuno-sorbent assay (ELISA). Collagen degradation was determined by cell-based ELISAs. Collagen type I and fibronectin deposition was stimulated by human recombinant tumor growth factor β1 (TGF-β1). Untreated fibroblasts secreted MMP-2 but only minute amounts of MMP-9. TGF-β1 (5 ng/mL) reduced MMP-2 secretion, but stimulated collagen type I and fibronectin deposition. All the effects of TGF-β1 were significantly reduced in cells treated with ZnI-DMSO over 24 h, while ZnI and DMSO alone had a lower reducing effect. ZnI-DMSO alone did not increase MMP secretion but enhanced the ratio of active to inactive of MMP-2. ZnI alone had a lower enhancing effect than ZnI-DMSO on MMP activity. Furthermore, MMP-2 activity was increased by ZnI-DMSO and ZnI in the absence of cells. Soluble collagen type I increased in the medium of ZnI-DMSO- and ZnI-treated cells. Blocking MMP activity counteracted all the effects of ZnI-DMSO. Conclusion: The data suggest that the combination of ZnI with DMSO reduces fibrotic processes by increasing the degradation of collagen type I by up-regulating the activity of gelatinases. Thus, the combination of ZnI with DMSO might be considered for treatment of fibrotic disorders of the lung. DMSO supported the beneficial effects of ZnI.

INTRODUCTION: Cluster of differentiation 44 (CD44), a transmembrane glycoprotein and Matrix metalloproteinase 2 (MMP2), a gelatinase enzyme have been implicated in several malignancies for their role in prognostication and diagnosis. We, therefore, made an effort to use these markers in urothelial malignancies and discuss their importance along with review of the literature. METHODS: A prospective study conducted for 1 year using light microscopy and immunohistochemistry for CD44 and MMP2. RESULTS: CD44 showed concordance with low-grade tumors while MMP 2 was found to show positivity in high-grade tumors. Score 3 in CD44 expression was seen exclusively (100%) in low-grade tumors while similar score of MMP2 expression was seen in 90.9% of high-grade tumors. CONCLUSION: CD44 and MMP2 expression can, therefore, serve as an important tool to predict the clinical behavior and prognosis in patients of urothelial carcinoma of the bladder. The management and survival rate varies according to grade; hence, these markers can be used for prognostication of disease. [ABSTRACT FROM AUTHOR]

The coexistence of depression and diabetes is a serious challenge in cardiovascular disease. However, extracellular matrix (ECM) under stress model associated or not with diabetes remains unknown. This study aims to investigate the involvement of diabetes and unpredictable chronic mild stress (UCMS) on ECM remodelling. Rats were exposed to UCMS, diabetes or combined treatment. mRNA expression of matrix metalloproteinases (MMP-2 and MMP-9), plasminogen activator (t-PA) and inhibitor (PAI-1) was examined by Q-RT-PCR. ECM was determined by ELISA. MMP-2 and MMP-9 mRNA was lower in diabetes (P <0.05). UCMS increased MMP-2 and MMP-9 compared to control and diabetic group. Compared to the control and diabetes groups, MMP-2 and MMP-9 mRNA was significantly increased in the combined treatment group. UCMS increased MMP-2 expression in the diabetic group (P <0.01). Compared to control, gelatinase activity was higher in diabetes and UCMS (P <0.05). Combined diabetes and UCMS significantly increased gelatinase activity compared to T2D and UCMS groups. Collagen, hydroxyproline and fibronectin content were significantly increased in diabetes and combined groups. UCMS combined with diabetes exacerbated diabetes-induced MMPs and fibronectin deposition. In conclusion, comorbidity between diabetes and UCMS may exacerbate ECM remodelling. These findings will be useful in understanding diabetes-induced cardiovascular disease. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMP)-2 and -9 are gelatinases which are capable of degrading type IV collagen and have been linked to cancer invasion and metastatic development. MMP-2 and MMP-9 gene polymorphisms may affect their biological function, and thus their role in cancer development and progression. We analyzed the association of the polymorphism frequencies of MMP-2-735C/T and MMP-9-1562C/T with MMP-2 and MMP-9 serum concentrations, as well as their potential effects in lung cancer patients. We conducted a retrospective, case-control study consisting of 112 lung cancer patients and 100 healthy individuals from a Caucasian population in Poland. Polymerase chain reaction with restriction fragment length polymorphism (PCR/RFLP) and electrophoresis was used to genotype genomic DNA from whole blood samples. MMP-2 and MMP-9 serum concentrations were then determined using ELISA. For statistical analysis, Statistica version 13 from TIBCO Software Inc. was utilized with a significance level <0.05. Logistic regression analysis revealed that MMP-2-735CC (OR = 5.39; 95% CI = 0.62–47.17; p = 0.238504) and -735CT genotype (OR = 7.22; 95% CI = 0.78–67.14; p = 0.072836), as well as MMP-9-1562CC (OR = 1.45; 95% CI = 0.31–6.70; p = 0.757914) and -1562CT genotype (OR = 1.60; 95% CI = 0.33–7.83; p = 0.548801) were associated with a higher risk of lung cancer. There were statistically significant differences observed in the MMP-2 concentration between individuals with the -735CC genotype and the -735CT genotype (non-smoking control: 204.04 ng/mL vs. 237.00 ng/mL, respectively, p = 0.041479; adenocarcinoma patients: 157.69 ng/mL vs. 126.37 ng/mL, respectively, p = 0.013222), as well as differences in the MMP-9 concentration between individuals with the -1562CC genotype and the -1562CT genotype (smoking control: 385.67 ng/mL vs. 562.80 ng/mL, respectively, p = 0.000936; patients with other lung neoplasms: 821.64 ng/mL vs. 928.88 ng/mL, respectively p = 0.023315). The role of MMP-2-735C/T and MMP-9 -1562C/T polymorphisms in an increased risk of lung cancer cannot be dismissed. Specific genotypes affect MMP-2 and MMP-9 concentrations in both lung cancer patients and healthy controls, which may thereby increase lung cancer risk, disease aggressiveness, and patient survival outcomes. [ABSTRACT FROM AUTHOR]

Background. The exact association between urinary neutrophil gelatinase-associated lipocalin (uNGAL) and acute kidney injury (AKI) is unknown in a critical care setting, in which the population is heterogeneous and the aetiology of AKI is unclear. Aim of this study is to clarify if uNGAL level is an early diagnostic marker for AKI in patients with sepsis. Materials and methods. The current study was conducted on 86 sepsis patients. The prevalence of AKI was identified among them. The role of uNGAL in predicting AKI development, mortality rate and length of the intensive care unit (ICU) stay were analyzed. Sensitivity and specificity were calculated, and the area under the receiver operating characteristic curve was considered as the optimal uNGAL cut-off level for detecting all classifications of AKI. Results. Most patients belonged to the age group of 51–60 years and their mean age was 54.6 years. Most patients (65.11 %) were males. 26.75 % had both type 2 diabetes mellitus and hypertension. AKI was detected in 89 % of subjects in the current study, as per KDIGO definition. 15.12 % of patients had stage 1 CKD, 15.12 % had stage 2 CKD, and stage 3 CKD was diagnosed in 4.65 % of cases. Mortality rate was 11 %, and 89 % of patients were discharged. The mean ICU length of stay among patients with AKI is 8.9 days. There is significant association between the mean ICU length of stay and AKI presence (p = 0.03). 17.4 % (n = 15) of patients required renal replacement therapy. There is a very significant difference in mean baseline uNGAL in patients with and without AKI: 149.9 and 73.2 ng/ml, respectively (p = 0.0006). This indicated that baseline uNGAL levels predict AKI. The mean uNGAL in people with AKI was 356 ng/ml and in those without AKI, it was 95 ng/ml. There is a very significant difference in mean uNGAL 48 hours after in patients with and without AKI (p < 0.0001). At a cut-off value of 120, there were 69 true positive cases, 9 true negative cases, 0 false positive cases, and 8 false negative cases. Based on these, the sensitivity of uNGAL at baseline in detecting AKI is 89.61 %, specificity is 100 %, and accuracy is 90.70 %. At a cut-off point of 120, there were 77 true positive cases, 8 true negative cases, 1 false positive case, and 0 false negative cases. Based on these, the sensitivity of uNGAL 48 hours after was 100 %, specificity 88.89 %, and accuracy was 98.84 %. There is a significant association between uNGAL levels and the ICU length of stay (p = 0.00). Conclusions. Sensitivity analysis was done in cut-off value of 120 for urinary NGAL in predicting AKI. From these results we conclude that urinary NGAL at the time of ICU admission is a reliable marker of renal function in sepsis patients. There is a significant correlation between AKI presence and urinary NGAL, and the ICU length of stay. We recommend not to use uNGAL alone in predicting AKI. It should be combined with glomerular filtration rate to reliably detect AKI development. Study findings indicate that sepsis patients with elevated uNGAL require proper management with close monitoring of blood pressure, urine output and appropriate doses of diuretics to avoid the development of AKI. [ABSTRACT FROM AUTHOR]

Hepatic and renal extracellular matrix (ECM) turnover associated with diabetes and potential beneficial effects of yellow lupin extract (YLE) need further investigations. The aim of this study was to explore the effect of yellow Lupinus luteus extract (YLE) on renal and hepatic ECM under diabetes. Composition of YLE performed by LC‐ESI‐MS. Diabetes (DM) was induced in rats by alloxan (250 mg/kg, ip). Normal and diabetic rats received 100 mg/kg of YLE for 1 month. ECM was assessed by ELISA. Gelatinases and collagenases were analyzed by a colorimetric assay. Histology was performed on sections of liver and kidney. In the liver, diabetes increases collagen, laminin, and fibronectin contents, respectively, by 49% (p <.01), 56% (p <.01), and 67% (p <.05) compared to control rats. In the kidney, total collagen and laminin contents were increased by 91% (p <.01) and 35% (p <.01) in the DM group, while fibronectin content in diabetic animals and those treated with YLE remains similar to the control group. Collagenases and gelatinases activities were significantly increased by diabetes in liver and kidney. While YLE treatment abrogates diabetes‐enhanced MMPs activities in liver. In diabetic rats, the liver shows signs of diffuse dilatation of the sinusoid veins and steatosis. However, the liver of diabetic rats treated with yellow lupine extract showed a normal histological aspect similar to controls. Diabetes causes hepatic and renal ECM turnover. YLE can be useful to partially improve tissue disorders induced by diabetes. [ABSTRACT FROM AUTHOR]

Purpose: To examine the effect of grape seed extract (GSE) pretreatment on the reduction of active gelatinases when using universal adhesives in etch-and-rinse mode. Materials and Methods: Fifty extracted non-carious human teeth were used in this study. Dentin powder was prepared for analysis of active MMP-2 by ELISA. Resin-dentin slices were prepared for in situ zymography in order to localize active gelatinases by quenched fluorescein-conjugated gelatin under a confocal microscope. Fluorescence intensity was analyzed quantitatively. Specimens were allocated into 6 groups: a non-treated control, phosphoric acid etched (PA), PA followed by Single Bond Universal (SBU, 3M Oral Care) or G-Premio Bond (GPB, GC), and PA followed by GSE for 1 min prior to SBU or GPB. The data were analyzed with one-way ANOVA and Bonferroni's test at a significance level of 0.05. Results: Application of the universal adhesives SBU and GPB in etch-and-rinse mode reduced active MMP-2 in dentin matrices. However, the only further significant reduction was found in GPB pre-treated with GSE, as analyzed by ELISA. In situ zymography demonstrated the location of active gelatinases, and fluorescence intensity analysis confirmed significant reduction of active gelatinases in the hybrid layer of GPB pre-teated with GSE compared to GPB alone. Conclusion: The present study demonstrated the potential advantage of applying GSE to reduce active gelatinases especially at the hybrid layer, with greater benefit achieved for hydrophobic adhesives. Nevertheless, the mechanism of action, analysis of bond strength, and long-term efficacy require further study. [ABSTRACT FROM AUTHOR]

Background: Urinary tract infection (UTI) is the commonest bacterial infection in children . Urine culture is the gold standard for diagnosing UTI, but difficulty in urine collection or improperly collected specimen may lead to false positive results of urine culture . the results of urinalysis, such as the presence of leukocyturia, nitrite and leukocyte esterase are used to diagnose UTI in clinical practice, but low sensitivity and specificity of this analysis is an issue . New data show that serum neutrophil gelatinase-associated lipocalin (s NGAL) and urinary NGAL assay can be used for prediction of urinary tract infection (UTI). this study aimed to investigate the relation between urine and serum neutrophil gelatinase-associated lipocalin and UTI in infants in Zagazig University hospitals . . Methods: A case control study carried out in Pediatric nephrology unit, Faculty of Medicine, Zagazig University Hospitals through a duration of six month starting at august 2018. the study included 48 children between 6 and 12 years divided into three groups arranged as cases with febrile UTI, nonfebrile UTI and healthy control. all patient were investigated for s NGAL, u NGAL, c-reactive protein, procalcitonin, white blood cell count, urine analysis, urine culture and pelvis-abdominal ultra sound. also, all patient had full detailed history and full examination . Patient with other infections, manifestations of chronic renal failure, manifestations of liver cell failure, evidence of obstructive nephropathy and with vesicoureteral reflux were excluded. Results: the study showed that, there was significant increase in level of serum NGAL in patients with febrile and non-febrile UTI in comparison to healthy control group with mean sensitivity 100%, specificity 75%, positive predictive value 66.7%, negative predictive value 100% and cutoff of serum NGAL in prediction of presence of febrile UTI in the studied patients is ≥ 140(pg/ml) with area under curve 0.906 .There was significant increase in level of urine NGAL in patients with febrile UTI in comparison to patients with nonfebrile UTI and healthy control group with sensitivity 81.2%, specificity 50%, positive predictive value 76.5%, negative predictive value 57.1% and cutoff of urine NGAL in prediction of presence of febrile UTI in the studied patients is ≥ 129(pg/ml) with area under curve 0.774 . Conclusions: Serum NGAL had sensitivity and specificity in prediction of UTI in studied patients more than urine NGAL.. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to examine the Neutrophil gelatinase-associated lipocalin" (NGAL) hormone level and some biochemical parameters in a group of (45) males' patients with urinary tract inflammation and (25) males as control. Material and method: The study included measuring the lipocalin hormone and biochemical assays; urea, albumin concentrations as well as creatinine and total proteins. Statistics and Result: The results of the study showed a significant increase (P ≤ 0.05) of (NGAL), urea concentrations and creatinine concentration in patients' group while the results of the study indicated a significant decrease (P ≤ 0.05) in the levels of both total proteins and albumin. [ABSTRACT FROM AUTHOR]

Introduction: Gelatinases, namely MMP2 and MMP9, are involved in the natural turnover of articular cartilage, as well as the loss of the cartilage matrix in osteoarthritis (OA). Studies have reported that fibroblast growth factor 8 (FGF8) promoted the degradation of cartilage in OA. In the present study, we predicted that FGF8 promoted chondrocyte expression and secretion of gelatinases by activating NF-κB p65 signaling. Materials and methods: Primary chondrocytes from C57 mice were cultured with recombinant FGF8. RNA sequencing was employed to explore the gene expression changes of gelatinases. Gelatin zymography was used to determine the activation of gelatinases. Western blot was used to investigate the expression of the gelatinases and NF-κB p65 signaling pathways, and immunofluorescence staining and NF-κB inhibitor assays were performed to confirm the activation of NF-κB p65 signaling. Results: FGF8 could increase the expression and activity of gelatinases in primary chondrocytes. And FGF8-induced expression of gelatinases was regulated through activation of NF-κB signaling with acetylated p65 accumulating in the cell nucleus. We further found that the NF-κB inhibitor, BAY 11-7082, could suppress up-regulation of gelatinase induced by FGF8. Conclusion: FGF8 enhanced the expression and activity of MMP2 and MMP9 in chondrocytes via NF-κB p65 signaling. [ABSTRACT FROM AUTHOR]

The increasing industrial use of vanadium (V), as well as its recent medical use in various pathologies has intensified its environmental release, making it an emerging pollutant. The sea urchin embryo has long been used to study the effects induced by metals, including V. In this study we used an integrated approach that correlates the biological effects on embryo development with proteolytic activities of gelatinases that could better reflect any metal-induced imbalances. V-exposure caused morphological/morphometric aberrations, mainly concerning the correct distribution of embryonic cells, the development of the skeleton, and the embryo volume. Moreover, V induced a concentration change in all the gelatinases expressed during embryo development and a reduction in their total proteolytic activity. The presence of three MMP-like gelatinases (MMP-2, -9, and -14) was also demonstrated and their levels depended on V-concentration. In particular, the MMP-14-like protein modified its expression level during embryo development in a time- and dose-dependent manner. This enzyme also showed a specific localization on filopodia, suggesting that primary mesenchyme cells (PMCs) could be responsible for its synthesis. In conclusion, these results indicate that an integrated study among morphology/morphometry, proteolytic activity, and MMP-14 expression constitutes an important response profile to V-action. [ABSTRACT FROM AUTHOR]

• The gelatinases, MMP2 and MMP9, share similarities in their structure, expression pattern and ECM substrates. • MMP2−/−/MMP9−/− double KO was characterized by analyzing the structural, histological and mechanical properties of long and flat bones. • A specific role for each gelatinase in bone development was demonstrated; MMP2 is exclusively required for intramembranous ossification while MMP9 is uniquely required for endochondral ossification. • Full transcriptome analysis of different skeletal components across the various genotypes, support their distinct and non-redundant roles via mechanistic pathways of MMP2 or MMP9 inactivation. The gelatinases, a subgroup of the matrix metalloproteinases (MMPs) superfamily are composed of two members; MMP2 and MMP9. They are known to degrade gelatin among other components of the extracellular matrix. Recently, the two gelatinases were found to be necessary for neural crest cell migration and to compensate for each other loss in these cells. To characterize their involvement in the skeletal system, and to better reveal their individual or common roles, we have generated double knockout (dKO) mice, lacking both MMP2 and MMP9. Comprehensive analysis of the skeleton morphological and mechanical parameters at postnatal day (P) 0, P21, 3 months (M) and 8M of age, revealed an unexpected distinct role for each gelatinase; MMP2 was found to be involved merely in intramembranous ossification which led to a smaller skull and inferior cortical parameters upon its loss, while MMP9 was found to affect only the endochondral ossification process, which led to shorter long-bones in its absence. Importantly, the dKO mice demonstrated a combination of both the skull and long bone phenotypes as found in the single-KOs, and not a severer additive phenotype. Transcriptome analysis on the cortical bone, the growth plate and the skull frontal bone, found many genes that were differentially expressed as a direct or indirect result of MMP-loss, and reinforced the specific and distinct role of each gelatinase in each bone type. Altogether, these results suggest that although both gelatinases share the same substrates and are highly expressed in flat and long bones, they are indispensable and control separately the development of different bones. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?The aim was to characterize Zucker diabetic fatty [ZDF (fa/fa)] rats and two control strains [Wistar and lean ZDF (fa/+) rats] during ageing.What is the main finding and its importance?Zucker diabetic fatty (fa/fa) rats with lower glycaemia have higher body and left ventricular weights and lower plasma gelatinase activity compared with hyperglycaemic rats. Given that type 2 diabetes is a heterogeneous metabolic disorder, the inhomogeneity of ZDF (fa/fa) rats might be beneficial in the study of its different aspects. Our experiments might promote a discussion regarding suitable normoglycaemic control animals for aged ZDF (fa/fa) rats, especially in experiments focused on myocardial tissue. Zucker diabetic fatty [ZDF (fa/fa)] rats, which are an animal model for the study of type 2 diabetes, are considered as a uniform group in most experimental studies; however, there are indications of their increasing inhomogeneity over time. The main objective of our study was to monitor biometric and biochemical parameters of ZDF (fa/fa) rats during their development of type 2 diabetes and compare them with two control strains [Wistar and lean ZDF (fa/+) rats]. According to fasting glycaemia, ZDF (fa/fa) rats were split arbitrarily into two phenotypes: obese, ZDF (fa/fa) FAT; and diabetic, ZDF (fa/fa) DIA. Glycaemia increased progressively only in the ZDF (fa/fa) DIA animals, which also exhibited higher cholesterol levels compared with ZDF (fa/fa) FAT animals. In addition, ZDF (fa/fa) FAT rats revealed more pronounced left ventricular hypertrophy and higher body weight, differentiating them from ZDF (fa/fa) DIA rats. We also investigated the activity of matrix metalloproteinases (MMPs), which are multifunctional enzymes involved in tissue remodelling. Rats in the ZDF (fa/fa) FAT group revealed lower plasma MMP2 and MMP9 activity compared with the ZDF (fa/fa) DIA group. However, increased myocardial MMP2 activity indicated left ventricular remodelling in both ZDF phenotypes. Given that type 2 diabetes in humans is a heterogeneous metabolic disorder, the heterogeneity of ZDF (fa/fa) rats might be beneficial in the study of different aspects of this pathology. Moreover, Wistar rats could serve as a more appropriate control for aged ZDF (fa/fa) rats than the commonly used ZDF fa/+ rats, which showed an increase in left ventricular weight, carbonyl stress markers in the left myocardium and MMP2 activity in both ventricles, indicating heart remodelling processes compared with the Wistar control group. [ABSTRACT FROM AUTHOR]

Background • The aim of this study was to evaluate the predictive value of urinary neutrophil gelatinaseassociated lipid (uNGAL) for the prediction of sepsisassociated acute kidney injury (SA-AKI). Methods • From September to December 2012, 110 patients were prospectively enrolled from the intensive care units (ICUs) of 3 general hospitals. After being admitted to the ICU, the patients were continuously observed for 72 hours. According to the Kidney Disease Improving Global Outcomes (KDIGO) criteria for the diagnosis of acute kidney injury (AKI), the patients were divided into the AKI group (33 patients) and non-AKI group (77 patients). Per the sepsis diagnostic criteria, the patients were classified as septic (79 patients) and non-septic (31 patients). Serum creatinine and uNGAL of the patients were analyzed daily. The difference in uNGAL in septic and non-septic patients, patients with and without AKI, and septic patients with with and without AKI were compared. In addition, the difference in serum creatinine and uNGAL in patients with and without AKI were recorded and compared, and the sensitivity and specificity of uNGAL and sCr for the diagnosis of AKI in the ICU patients were evaluated using the receiver operating characteristic (ROC) curve. Results • uNGAL levels were all significantly different in septic and non-septic patients (P = .001, P = .028, P = .010, respectively), patients with and without AKI (P = .001, P = .042, P = .001, respectively), septic patients with AKI and septic patients without AKI (P = .003, P = .012, P = .001, respectively) at 24, 48 and 72 hours after being admitted to the ICU, while the difference in sCr was not significant (P = .169) after 24 hours. The area under the ROC curve of uNGAL and sCr in patients admitted to the ICU at 24 hours were 0.828 (95% CI, 0.742 to 0.914) and 0.583 (95% CI, 0.471 to 0.695), respectively. The cutoff value of uNGAL was 170 ng/mL in patients admitted to the ICU at 24 hours, and the sensitivity and specificity were 0.778 and 0.784, respectively. The sensitivity of uNGAL was superior sCr. Conclusion • uNGAL has relatively high sensitivity and specificity in predicting the occurrence of AKI in septic patients, which is superior to sCr and has certain clinical early diagnostic value. uNGAL could be used as an indicator for early diagnosis of AKI in septic patients in the ICU. [ABSTRACT FROM AUTHOR]

Stroke, especially hemorrhagic form, is one of the most serious comorbidity disease of diabetes mellitus, often associated with high mortality, particularly in type 2 DM (T2DM). Therefore, it is relevant the search for drugs with a metabolically justified protective effect. Edaravone (Eda) is widely used for treating ischemic stroke but its biochemical effects in intracerebral hemorrhage (ICH) associated with T2DM is not still confirmed. The aim of the study was to assess the impact of Eda on the markers of oxidative modification of proteins (OMP), such as advanced oxidation protein products (AOPP), neutral and basic carbonyls (PC370 and PC430), advanced glycation end products (AGE) and ischemia modified albumin (IMA) as well as on the activity of matrix metalloproteinases MMP2/MMP9 (gelatinases) in rats with experimental T2DM after collagenase-induced ICH. Metformin was used as a comparative drug. The data obtained indicate that ICH in diabetic rats is accompanied by an increase in AOPP, PC370, AGE, and mature forms of both gelatinases. On the contrary, IMA and proMMP9 were below normal level after ICH. Both studied drugs decreased the OMP markers to the levels of intact rats or lower, and Eda show a more potent effect. Besides, Eda significantly decreased the activity of MMP9 and changed progelatinases activity. We conclude that Eda has a perspective to be useful in the treatment of comorbid brain hemorrhage in T2DM due to inhibiting of oxidative stress and modulation of gelatinases activity.

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF. [ABSTRACT FROM AUTHOR]

Stroke, especially hemorrhagic form, is one of the most serious comorbidity disease of Diabetes Mellitus (DM), often associated with high mortality, particularly in Type 2 DM (T2DM). Therefore, it is relevant the search for drugs with a metabolically justified protective effect. Edaravone (Eda) is widely used for treating ischemic stroke, but its biochemical effects in Intracerebral Hemorrhage (ICH) associated with T2DM are still not confirmed. The aim of the study was to assess the impact of Eda on the markers of Oxidative Modification of Proteins (OMP), such as Advanced Oxidation Protein Products (AOPP), neutral and basic carbonyls (PC370 and PC430), Advanced Glycation End products (AGEs) and Ischemia Modified Albumin (IMA) as well as on the activity of matrix metalloproteinases MMP2/MMP9 (gelatinases) in rats with experimental T2DM after collagenaseinduced ICH. Metformin was used as a comparative drug. The data obtained indicate that ICH in diabetic rats is accompanied by an increase in AOPP, PC370, AGEs, and mature forms of both gelatinases. On the contrary, IMA and proMMP9 were below normal level after ICH. Both studied drugs decreased the OMP markers to the levels of intact rats or lower, and Eda demonstrated a more potent effect. Besides, Eda decreased the activity of MMP9 and changed progelatinases activity. We conclude that Eda has a perspective to be useful in the treatment of comorbid brain hemorrhage in T2DM due to inhibition of oxidative stress and modulation of gelatinases activity. [ABSTRACT FROM AUTHOR]

Left ventricular pressure overload (LVPO) can develop from antecedent diseases such as aortic valve stenosis and systemic hypertension and is characterized by accumulation of myocardial extracellular matrix (ECM). Evidence from patient and animal models supports limited reductions in ECM following alleviation of PO, however, mechanisms that control the extent and timing of ECM regression are undefined. LVPO, induced by 4 wk of transverse aortic constriction (TAC) in mice, was alleviated by removal of the band (unTAC). Cardiomyocyte cross-sectional area, collagen volume fraction (CVF), myocardial stiffness, and collagen degradation were assessed for: control, 2-wk TAC, 4-wk TAC, 4-wk TAC + 2-wk unTAC, 4-wk TAC + 4-wk unTAC, and 4-wk TAC + 6-wk unTAC. When compared with 4-wk TAC, 2-wk unTAC resulted in increased reactivity of collagen hybridizing peptide (CHP) (representing initiation of collagen degradation), increased levels of collagenases and gelatinases, decreased levels of collagen cross-linking enzymes, but no change in CVF. When compared with 2-wk unTAC, 4-wk unTAC demonstrated decreased CVF, which did not decline to control values. At 4-wk and 6-wk unTAC, CHP reactivity and mediators of ECM degradation were reduced versus 2-wk unTAC, whereas levels of tissue inhibitor of metalloproteinase (TIMP)-1 increased. ECM homeostasis changed in a timedependent manner after removal of LVPO and is characterized by early increases in collagen degradation, followed by a later dampening of this process. Tempered ECM degradation with time is predicted to contribute to the finding that normalization of hemodynamic overload alone does not completely regress myocardial fibrosis. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are a group of enzymes that are correlated with the degradation of the hybrid layer. This article describes the effect of adhesive systems on the MMPs. A systematic review of the literature was conducted analyzing articles published on PubMed, Google scholar, Scopus, ResearchGate and ScienceDirect between 2011 and 2021, activity of the MMPs was the selected outcome variable. A total of 22 publications were selected, 9 of which were selected for detailed review. Chief question in this article was: which generation of adhesive systems has more effect on MMPs? How does it affect them? Etch-and rinse adhesive systems showed higher level gelatinolytic activity, when compared to Self-etch adhesive systems. Activation of the MMPs is due in most adhesive systems, which is responsible for the degradation of the hybrid layer. Etch-and-rinse adhesive systems showed higher gelatinolytic activity when compared to self-etch adhesive systems, further studies are needed on new chemicals capable of inhibiting MMP activity. Moreover, further studies are needed to check MMP activity in non-vital teeth. [ABSTRACT FROM AUTHOR]

The unique bactericidal mechanism of metal nanoparticles (MNPs) is considered to be an effective strategy to deal with antibiotic resistance, but the oxidative stress damage caused by excessive accumulation of MNPs to normal cells cannot be ignored. Achieving on-demand release of nano-drugs in specific infection environments is highly attractive. Herein, we constructed a "core-shell" nanogel (G@CuS) based on a copper sulfide (CuS) antimicrobial agent and gelatin for targeted drug release and bacterial clearance in a gelatinase infected microenvironment. G@CuS produced heat and reactive oxygen species (ROS) under the irradiation of a laser, which together with the released Cu2+ cause irreversible and efficient physical damage to the bacteria. Moreover, the encapsulation of gelatin not only limits the biotoxicity of CuS nanodots (NDs), but also effectively promotes the proliferation of mammalian cells. Under the synergy of multiple mechanisms, G@CuS eradicated the colonized bacteria in the wound of mice infected with Staphylococcus aureus (S. aureus) and accelerated wound healing. The proposed application strategy of nanogel is expected to provide a new idea for clinical transformation. [ABSTRACT FROM AUTHOR]