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Signal Transduction and Targeted Therapy Jun 2024CD8 T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is...
CD8 T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8 T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8 T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8 T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8 T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8 T cells. Intriguingly, inhibition of ADAM17 in CD8 T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8 T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.
Topics: ADAM17 Protein; CD8-Positive T-Lymphocytes; Animals; Mice; Humans; Cell Differentiation; Neoplasms
PubMed: 38918390
DOI: 10.1038/s41392-024-01873-6 -
Journal of Orthopaedic Surgery and... Feb 2022Epidemiological studies have reported a positive association between hypercholesterolemia and shoulder disease. Previous studies have focused on the effect of...
BACKGROUND
Epidemiological studies have reported a positive association between hypercholesterolemia and shoulder disease. Previous studies have focused on the effect of hypercholesterolemia on tendinopathy. Moreover, hypercholesterolemia has also been linked to joint pathology in the knee and hand. However, the effect of hyperlipidemia on glenohumeral joint remain unclear. A hypercholesterolemic condition has been reported to alter levels of A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAMTSs) and matrix metalloproteases (MMPs) in synovium of the knee joint. Here, we evaluated the mRNA expression of ADAMTSs and MMPs in the glenohumeral synovium of patients with and without hypercholesterolemia.
METHODS
Study participants were 73 patients who underwent arthroscopic rotator cuff repair for degenerative rotator cuff tears. They were divided into two groups according to total cholesterol (TC) and triglyceride levels. Synovial membrane samples were harvested at the rotator interval during surgery, and mRNA expression levels of the aggrecanases ADAM-TS4 and ADAM-TS5 and MMPs (MMP-1, 3, 9, and 13) were analyzed quantitatively.
RESULTS
ADAM-TS5 and MMP1 mRNA levels were significantly higher in the high TC group than in the low TC group (P = 0.023 and P = 0.025, respectively). In contrast, no significant differences were observed in ADAMTS4 or MMPs 3, 9, and 13 (ADAMTS4, P = 0.547; MMP3, P = 0.55; MMP9, P = 0.521; and MMP13, P = 0.785).
CONCLUSION
Hypercholesterolemia may alter MMP1 and ADAMTS5 expression in the synovium of the glenohumeral joint.
Topics: ADAMTS5 Protein; Adult; Aged; Female; Humans; Hypercholesterolemia; Male; Matrix Metalloproteinase 1; Middle Aged; RNA, Messenger; Rotator Cuff Injuries; Synovial Fluid
PubMed: 35168639
DOI: 10.1186/s13018-022-02998-6 -
Toxins May 2023Functional urology involves a large scale of lower urinary tract dysfunctions (LUTDs), including bladder dysfunctions and bladder outlet dysfunctions [...].
Functional urology involves a large scale of lower urinary tract dysfunctions (LUTDs), including bladder dysfunctions and bladder outlet dysfunctions [...].
Topics: Humans; Botulinum Toxins; Urology; Urologic Diseases; Urinary Bladder; Botulinum Toxins, Type A
PubMed: 37235356
DOI: 10.3390/toxins15050321 -
Nature Microbiology Jan 2024Bacterial toxins are well-studied virulence factors; however, recent studies have revealed their importance in bacterial niche adaptation. Enterotoxigenic Bacteroides...
Bacterial toxins are well-studied virulence factors; however, recent studies have revealed their importance in bacterial niche adaptation. Enterotoxigenic Bacteroides fragilis (ETBF) expresses B. fragilis toxin (BFT) that we hypothesized may contribute to both colonic epithelial injury and niche acquisition. We developed a vertical transmission model for ETBF in mice that showed that BFT enabled ETBF to access a lamina propria (LP) niche during colonic microbiome development that was inaccessible to non-toxigenic B. fragilis. LP entry by ETBF required BFT metalloprotease activity, and showed temporal restriction to the pre-weaning period, dependent on goblet-cell-associated passages. In situ single-cell analysis showed bft expression at the apical epithelial surface and within the LP. BFT expression increased goblet cell number and goblet-cell-associated passage formation. These findings define a paradigm by which bacterial toxin expression specifies developmental niche acquisition, suggesting that a selective advantage conferred by a toxin may impact long-term host health.
Topics: Animals; Mice; Bacterial Toxins; Metalloendopeptidases; Bacteria; Colon; Bacteroides fragilis
PubMed: 38168616
DOI: 10.1038/s41564-023-01559-9 -
The Journal of International Medical... Nov 2022Acute volume overload (AVO) induces early ischemia-like changes in intramyocardial arteries. We investigated whether the Factor Xa (FXa) inhibitor apixaban interacts...
OBJECTIVE
Acute volume overload (AVO) induces early ischemia-like changes in intramyocardial arteries. We investigated whether the Factor Xa (FXa) inhibitor apixaban interacts with the myocardium early after AVO.
METHODS
Fifty-five syngeneic Fisher rats underwent surgical abdominal aortocaval fistula to induce AVO. Among them, 17 rats were treated with apixaban (10 mg/kg/day). The myocardial outcome was studied using histological analysis and by measuring atrial natriuretic peptide (ANP) and matrix metalloprotease 9 (MMP9) gene expression.
RESULTS
After 3 days, the total number of intramyocardial arteries was significantly increased in the +apixaban (AVO+A) group compared with that in the AVO group (12.0 ± 1.2 and 10.2 ± 1.5, point score units, respectively). In the AVO+A group, there were significantly more edematous nuclei in myocardial arteries in the right and left ventricle compared with that in the AVO group. ANP and MMP9 expression levels continued to increase significantly in the AVO+A group compared with those in the AVO group.
CONCLUSION
Apixaban interacts with intramyocardial arteries in the left and right ventricles after AVO and ANP and MMP9 expression levels increased. Thus, the myocardial effect of Factor Xa inhibition needs to be monitored after AVO.
Topics: Rats; Animals; Atrial Natriuretic Factor; Matrix Metalloproteinase 9; Factor Xa; Myocardium; Heart Failure; Water-Electrolyte Imbalance
PubMed: 36397004
DOI: 10.1177/03000605221137474 -
Toxins Oct 2022Increasing concern about the use of animal models has stimulated the development of in vitro cell culture models for analysis of the biological effects of snake venoms.... (Review)
Review
Increasing concern about the use of animal models has stimulated the development of in vitro cell culture models for analysis of the biological effects of snake venoms. However, the complexity of animal venoms and the extreme synergy of the venom components during envenomation calls for critical review and analysis. The epithelium is a primary target for injected viper venom's toxic substances, and therefore, is a focus in modern toxinology. We used the Vero epithelial cell line as a model to compare the actions of a crude (Levantine viper) venom with the actions of the same venom with two key enzymatic components inhibited (specifically, phospholipase A2 (PLA2) and metalloproteinases) in the bioenergetic cellular response, i.e., oxygen uptake and reactive oxygen species generation. In addition to the rate of free-radical oxidation and lipid peroxidation, we measured real-time mitochondrial respiration (based on the oxygen consumption rate) and glycolysis (based on the extracellular acidification rate) using a Seahorse analyzer. Our data show that viper venom drives an increase in both glycolysis and respiration in Vero cells, while the blockage of PLA2 or/and metalloproteinases affects only the rates of the oxidative phosphorylation. PLA2-blocking in venom also increases cytotoxic activity and the overproduction of reactive oxygen species. These data show that certain components of the venom may have a different effect within the venom cocktail other than the purified enzymes due to the synergy of the venom components.
Topics: Animals; Chlorocebus aethiops; Viper Venoms; Vero Cells; Reactive Oxygen Species; Viperidae; Phospholipases A2; Metalloproteases; Lipid Peroxidation
PubMed: 36355974
DOI: 10.3390/toxins14110724 -
Molecules (Basel, Switzerland) Jul 2019Scorpions, a characteristic group of arthropods, are among the earliest diverging arachnids, dating back almost 440 million years. One of the many interesting aspects of... (Review)
Review
Scorpions, a characteristic group of arthropods, are among the earliest diverging arachnids, dating back almost 440 million years. One of the many interesting aspects of scorpions is that they have venom arsenals for capturing prey and defending against predators, which may play a critical role in their evolutionary success. Unfortunately, however, scorpion envenomation represents a serious health problem in several countries, including Iran. Iran is acknowledged as an area with a high richness of scorpion species and families. The diversity of the scorpion fauna in Iran is the subject of this review, in which we report a total of 78 species and subspecies in 19 genera and four families. We also list some of the toxins or genes studied from five species, including , and , in the Buthidae and Hemiscorpiidae families. Lastly, we review the diverse functions of typical toxins from the Iranian scorpion species, including their medical applications.
Topics: Animals; Antimicrobial Cationic Peptides; Antineoplastic Agents; Arthropod Proteins; Drug Discovery; Gene Expression; Humans; Ion Channels; Iran; Metalloproteases; Phospholipases A2; Phylogeny; Scorpion Stings; Scorpion Venoms; Scorpions; Serine Proteinase Inhibitors; Species Specificity
PubMed: 31340554
DOI: 10.3390/molecules24142670 -
Theriogenology Sep 2020An increasing number of studies have shown that prostaglandins (PGs) exert multiple regulatory actions in the processes associated to tissue remodeling and fibrosis....
An increasing number of studies have shown that prostaglandins (PGs) exert multiple regulatory actions in the processes associated to tissue remodeling and fibrosis. Extracellular matrix (ECM) turnover is mediated by matrix metallopeptidases (MMPs). The knowledge about the regulation of their expression in mare endometrium is still limited. Thus, the aim of this study was to investigate whether: (i) profibrotic transforming growth factor (TGF)-β1 modulates PG production in equine endometrium; and (ii) PGE and PGF modulate MMPs, their tissue inhibitors (TIMPs), and collagen 1 (COL1) expression. In experiment 1, the effect of TGF-β1 (5 ng/mL) on PG secretion and PG synthases mRNA transcription, after 24 and 48 h treatment of mare endometrial fibroblast and epithelial cells was investigated using ELISA and qPCR. In experiment 2, the effects of PGE and PGF in doses 10M and 10M on secretion and MMP1, 2, 9, 13, TIMP1, 2, and COL1A1 mRNA transcription in mare endometrial fibroblasts were assessed. Transforming growth factor-β1 treatment decreased secretion of PGF by endometrial fibroblasts (P < 0.05) and PGF and PGE by endometrial epithelial cells (P < 0.05). Prostaglandin E increased MMP-2 and MMP-9, and decreased MMP-13 secretion by endometrial fibroblasts (P < 0.05). Additionally, PGF treatment increased MMP-2, MMP-13 and COL1, but decreased MMP-1 secretion by endometrial fibroblasts (P < 0.05). Prostaglandins may be involved in the processes associated to pathological endometrial remodeling by their effect on MMP expression. The effect of PGF on COL1 secretion from fibroblasts suggests its profibrotic role in pathological endometrial remodeling.
Topics: Animals; Collagen; Dinoprostone; Endometrium; Female; Fibroblasts; Gene Expression Regulation; Horses; Metalloendopeptidases; Metalloproteases; Prostaglandins; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta1
PubMed: 32442743
DOI: 10.1016/j.theriogenology.2020.04.040 -
F&S Science Feb 2022To study the cyclic fertilin peptide effects on preimplantation human embryogenesis. Cyclic fertilin peptide reproduces the structure of the binding site of the sperm...
OBJECTIVE
To study the cyclic fertilin peptide effects on preimplantation human embryogenesis. Cyclic fertilin peptide reproduces the structure of the binding site of the sperm Fertilin β (also named A Disintegrin and Metalloprotease 2: ADAM2) disintegrin domain. It binds to the oocyte membrane and increases sperm-oocyte fusion index in human and fertilization rate in mouse, providing healthy pups. It also improves human oocyte maturation and chromosome segregation in meiosis I and binds to human embryo blastomeres, suggesting that it has a membrane receptor.
DESIGN
Thawed human embryos at the 3 to 4 cells stage were randomly included in a dose-response study with cyclic fertilin peptide. Inner cell mass (ICM), trophectoderm (TE), and total cell numbers were evaluated in top- and good-quality blastocysts.
SETTING
The study was performed in an academic hospital and research laboratory.
PATIENT(S)
Human embryos donated for research. This project was approved by the French "Agence de la Biomédecine."
INTERVENTION(S)
Immunofluorescence and tissue-specific gene expression analysis, using Clariom D microarrays, were performed to study its mechanism of action.
MAIN OUTCOME MEASURE(S)
Cyclic fertilin peptide improves blastocyst formation by almost 20%, the concentration of 1 μM being the lowest most efficient concentration. It significantly increases twice the TE cell number, without modifying the ICM. It increases the in vitro hatching rate from 14% to 45%.
RESULT(S)
Cyclic fertilin peptide stimulates TE growth. In the ICM, it induces transcriptional activation of intracellular protein and vesicle-mediated transport.
CONCLUSION(S)
Cyclic fertilin peptide dramatically improves human embryo development potential. It could be used to supplement culture medium and improve the in vitro human embryo development. Starting supplementation immediately after fertilization, instead of day 2, could significantly upgrade assisted reproductive technology outcome.
Topics: ADAM Proteins; Disintegrins; Embryonic Development; Fertilins; Humans; Membrane Glycoproteins; Peptides, Cyclic
PubMed: 35559995
DOI: 10.1016/j.xfss.2021.12.002 -
Journal of Dentistry Jan 2021To evaluate the incorporation of doxycycline (DOX) into a commercial dental adhesive regarding physicochemical properties, microtensile bond strength (μTBS),...
OBJECTIVES
To evaluate the incorporation of doxycycline (DOX) into a commercial dental adhesive regarding physicochemical properties, microtensile bond strength (μTBS), nanoleakage (NL), nanohardness (NH) and Young's modulus (YM), metalloproteinases (MMP) inhibition, and antibiofilm activity.
METHODS
DOX was incorporated into the adhesive at 0.05, 0.1, 0.5, and 1 wt%. Restored teeth were evaluated for μTBS, NL, NH, and YM after 24 -hs and 1-year of water storage. Biofilms of Streptococcus mutans were grown on top of these adhesives and determined for bacterial viability and amount of biomass. The inhibitory effect on MMP was analyzed by in situ zymography under confocal microscopy.
RESULTS
Adhesives with 0.5 and 1 wt% of DOX presented reduced pH and degree of conversion. The incorporation of DOX did not affect μTBS and hybrid layer YM. The control group (no DOX) had a decrease in μTBS and the densest silver nitrate areas after 1-year storage. Hybrid layer NH values increased with 0.1 wt% DOX compared to control and 1 wt% DOX groups, at 24 -hs. After 1-year storage, NH of 1 wt% DOX adhesive decreased compared to the control group. The 0.5 and 1 wt% concentrations of DOX decreased the bacterial viability and the biofilm biomass. Confocal images suggest an increased MMP inhibition proportional to the percentage of DOX.
CONCLUSION
At any concentration, DOX-doped dental adhesives were able to inhibit MMP activity, diminish nanoleakage, and maintain the resin-dentin bond-strength after 1 year of artificial aging.
CLINICAL SIGNIFICANCE
Doxycycline-doped dental adhesive inhibited metalloproteinases activity and preserved interface bond strength. This formulation has a potential to improve adhesive restorations clinical longevity.
Topics: Biofilms; Dental Bonding; Dental Cements; Dentin; Dentin-Bonding Agents; Doxycycline; Humans; In Vitro Techniques; Materials Testing; Metalloproteases; Molar; Resin Cements; Tensile Strength
PubMed: 33276081
DOI: 10.1016/j.jdent.2020.103550