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A pan-cancer analysis summarizing the overall changes in mRNA and protein stability of ADM9, as well as its oncogenic function on immune cell line modulation and checkpoints within the tumor microenvironment (TME), is lacking, despite the fact that ADM9 up-regulation is correlated with the progression of many cancers. Therefore, in this study, we comprehensively analyzed the role of ADAM9 expression and its prognostic value in different cancers to fill this gap. Multiple bioinformatics databases such as Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were used to evaluate the ADAM9 genetic alternation, phosphorylation, and methylation, and indicated highly positive correlated genes that might play a critical interaction with ADAM9 and their molecular function with GO analysis. We also evaluate the effect of higher ADAM9 with prominent immune modulatory genes and immune infiltration especially in liver cancer pathogenesis stimulates lower NK cell effector functions based on its role in MICA shedding and increasing the Tregs infiltration. Immunohistochemistry (IHC) staining from 90 pathologically verified samples proved the positive correlation between ADAM9 and tumor stages and proved the higher expression of ADAM9 correlated genes (SNX9, APP, TNF, CDH1, ITGAV, MAD2L2) in HCC pathogenesis. In conclusion, this pan-cancer study provides a comprehensive understanding of the prognostic value of ADAM9 in various tumors emphasizing its importance to be considered as an innovative treatment approach, especially in tumor immunity shortly., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study investigates the role and mechanisms of ADAM9 as a biomarker and potential therapeutic target in HCC. Utilizing RNA-sequencing data and clinicopathological characteristics from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we conducted survival and meta-analyses, functional enrichment, and immune infiltration studies. Additionally, we evaluated the effects of ADAM9 silencing on HCC cell proliferation, migration, and invasion through in vitro experiments. Our results demonstrate that high ADAM9 expression is associated with poor prognosis and increased immune infiltration in HCC patients. Furthermore, ADAM9 knockdown significantly inhibited tumor cell proliferation and migration. These findings indicate that ADAM9 is a promising prognostic biomarker and potential therapeutic target in HCC. In conclusion, ADAM9 could offer avenues for developing strategies to inhibit tumor progression and improve patient outcomes., (© 2024. The Author(s).)

This research focused on investigating the effects of sevoflurane (Sev) on myocardial autophagy levels after myocardial ischemia reperfusion (I/R) injury via the microRNA-542-3p (miR-542-3p)/ADAM9 axis. Mice underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by echocardiography. Cardiac markers and oxidative stress factors were evaluated by ELISA. Autophagy-associated factors were detected by western blot. Relationship between miR-542-3p and ADAM9 was tested by dual-luciferase reporter gene assay, RT-qPCR, and western blot. Sev treatment ameliorated cardiac dysfunction, myocardial oxidative stress, and histopathological damages, decreased myocardial infarction size and myocardial apoptotic cells after myocardial I/R injury. Sev treatment elevated miR-542-3p expression and decreased ADAM9 expression in myocardial tissues after myocardial I/R injury. miR-542-3p overexpression could enhance the ameliorative effects of Sev on myocardial injury and myocardial autophagy in I/R mice. miR-542-3p targeted and negatively regulated ADAM9 expression. ADAM9 overexpression reversed the ameliorative effects of miR-542-3p up-regulation on myocardial injury and myocardial autophagy in Sev-treated I/R mice. Sev treatment could ameliorate myocardial injury and myocardial autophagy in I/R mice, mediated by mechanisms that include miR-542-3p up-regulation and ADAM9 down-regulation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The effect and molecular regulatory mechanism of A Disintegrin and Metalloproteinase 8 (ADAM8) were explored in alcoholic liver fibrosis (ALF). C57BL/6N male mice were randomly divided into control, alcohol, and ADAM8-sgRNA3 plasmid groups. The control group received control liquid diet, while the alcohol and ADAM8-sgRNA3 plasmid groups were given alcohol liquid feed diet combined with ethanol gavage treatment for 8 weeks to induce ALF modeling. In addition, the ADAM8-sgRNA3 plasmid group was injected with the effective ADAM8-sgRNA3 plasmid, while the alcohol and control group mice were injected with an equivalent amount of physiological saline. LX-2 human hepatic stellate cells were divided into control, alcohol, si-ADAM8-2, and si-ADAM8-NC groups and induced for 48 h for model establishment in vitro. Serological detection, pathological staining, Western blotting, qRT-PCR and CCK8 assay were performed for experiments. Compared with the alcohol group, ADAM8 mRNA, protein and, positive area rate, serological indicators, pathological changes, and the expression of liver fibrosis marker and MAPK signaling pathway-related factors in the ADAM8-sgRNA3 plasmid group significantly decreased in vivo. Compared with the alcohol group, ADAM8 mRNA and protein expression, cell viability, and the expression of liver fibrosis markers and MAPK signaling pathway-related factors (p-ERK1/2, PCNA, Bcl-2, p-c-Jun, TGFβ1, p-p38 MAPK and HSP27) reduced significantly in the si-ADAM8-2 group. Therefore, ADAM8 promotes ALF through the MAPK signaling pathway, a promising target for treating ALF., (© 2024. The Author(s).)

Purpose: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function., Methods: We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent., Results: Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV 0.1 and FVC. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways., Conclusion: Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Atherosclerosis is a chronic inflammatory disease forming plaques in medium and large-sized arteries. ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs-4) is an extracellular-matrix remodelling enzyme involved in the degradation of versican in the arterial wall. Recent reports indicated that increased expression of ADAMTS-4 is associated with plaque progression and vulnerability. Bioactive components of dietary oil, like sesame oil, are reported to have anti-inflammatory and antioxidant properties. Here, we studied the effect of sesame oil on regulating ADAMTS-4 in high-fat diet-induced atherosclerosis rat model. Our results indicated that sesame oil supplementation improved the anti-inflammatory and anti-oxidative status of the body. It also reduced atherosclerotic plaque formation in high-fat diet-fed rats. Our results showed that the sesame oil supplementation significantly down-regulated the expression of ADAMTS-4 in serum and aortic samples. The versican, the large proteoglycan substrate of ADAMTS-4 in the aorta, was downregulated to normal control level on sesame oil supplementation. This study, for the first time, reveals that sesame oil could down-regulate the expression of ADAMTS-4 in high-fat diet-induced atherosclerosis, imparting a new therapeutic potential for sesame oil in the management of atherosclerosis., (Copyright © 2024. Published by Elsevier Inc.)

Background: Hepatocellular carcinoma (HCC) is a prevalent and heterogeneous tumor with limited treatment options and unfavorable prognosis. The crucial role of a disintegrin and metalloprotease (ADAM) gene family in the tumor microenvironment of HCC remains unclear., Methods: This study employed a novel multi-omics integration strategy to investigate the potential roles of ADAM family signals in HCC. A series of single-cell and spatial omics algorithms were utilized to uncover the molecular characteristics of ADAM family genes within HCC. The GSVA package was utilized to compute the scores for ADAM family signals, subsequently stratified into three categories: high, medium, and low ADAM signal levels through unsupervised clustering. Furthermore, we developed and rigorously validated an innovative and robust clinical prognosis assessment model by employing 99 mainstream machine learning algorithms in conjunction with co-expression feature spectra of ADAM family genes. To validate our findings, we conducted PCR and IHC experiments to confirm differential expression patterns within the ADAM family genes., Results: Gene signals from the ADAM family were notably abundant in endothelial cells, liver cells, and monocyte macrophages. Single-cell sequencing and spatial transcriptomics analyses have both revealed the molecular heterogeneity of the ADAM gene family, further emphasizing its significant impact on the development and progression of HCC. In HCC tissues, the expression levels of ADAM9, ADAM10, ADAM15, and ADAM17 were markedly elevated. Elevated ADAM family signal scores were linked to adverse clinical outcomes and disruptions in the immune microenvironment and metabolic reprogramming. An ADAM prognosis signal, developed through the utilization of 99 machine learning algorithms, could accurately forecast the survival duration of HCC, achieving an AUC value of approximately 0.9., Conclusions: This study represented the inaugural report on the deleterious impact and prognostic significance of ADAM family signals within the tumor microenvironment of HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Yuan, Guan, Cui, Fu, Wei and Liu.)

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8/9/15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8/15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8/9/15 high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8/9/15 high patient samples. High ADAM8/9/15 expression correlated with high Ki67 and high ADAM8/15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8/9/15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8/9/15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling., (© 2024. The Author(s).)

Background: Osteoarthritis (OA) is a prevalent degenerative disease. We explored the role and regulatory mechanisms of lncRNA-FAS-AS1 in OA progression., Methods: We exposed human immortalized chondrocytes to IL-1β for 24 h to induce an OA cell model. The target molecule levels were assessed using western blot and quantitative real-time PCR (RT-qPCR). Cell viability and apoptosis were measured using CCK-8 and flow cytometry. The m6A modification of FAS-AS1 was determined using MeRIP. We examined the binding relationships between FAS-AS1, Fragile X mental retardation 1 (FMR1), and A disintegrin and metalloproteinase 8 (ADAM8) using RIP and RNA pull-down. The OA animal model was established by separating the medial collateral ligament and medial meniscus. Safranin-O staining and Mankin's scale were employed to evaluate pathological changes within the cartilage., Results: FAS-AS1, METTL14, and ADAM8 were upregulated, and the JAK/STAT3 signaling pathway was activated in OA mice and IL-1β-induced chondrocytes. FAS-AS1 knockdown inhibited extracellular matrix degradation in IL-1β-induced chondrocytes; however, ADAM8 overexpression reversed this effect. FAS-AS1 maintained the stability of ADAM8 mRNA by recruiting FMR1. METTL14 knockdown repressed FAS-AS1 expression in an m6A-dependent manner. FAS-AS1 overexpression reversed the inhibitory effects of METTL14 knockdown on JAK/STAT3 signaling and cartilage damage in the OA model both in vitro and in vivo., Conclusion: METTL14-mediated FAS-AS1 promotes OA progression through the FMR1/ADAM8/JAK/STAT3 axis., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

As a member of the family of A Disintegrin And Metalloproteinases (ADAM) ADAM8 is preferentially expressed in lymphatic organs, immune cells, and tumor cells. The substrate spectrum for ADAM8 proteolytic activity is not exclusive but is related to effectors of inflammation and signaling in the tumor microenvironment. In addition, complexes of ADAM8 with extracellular binding partners such as integrin β-1 cause an extensive intracellular signaling in tumor cells, thereby activating kinase pathways with STAT3, ERK1/2, and Akt signaling, which causes increased cell survival and enhanced motility. The cytoplasmic domain of ADAM8 harbors five SRC homology-3 (SH3) domains that can potentially interact with several proteins involved in actin dynamics and cell motility, including Myosin 1F (MYO1F), which is essential for neutrophil motility. The concept of ADAM8 thus involves immune cell recruitment, in most cases leading to an enhancement of inflammatory (asthma, COPD) and tumor (including pancreatic and breast cancers) pathologies. In this review, we report on available studies that qualify ADAM8 as a therapeutic target in different pathologies. As a signaling hub, ADAM8 controls extracellular, intracellular, and intercellular communication, the latter one mainly mediated by the release of extracellular vesicles with ADAM8 as cargo. Here, we will dissect the contribution of different domains to these distinct ways of communication in several pathologies. We conclude that therapeutic targeting attempts for ADAM8 should consider blocking more than a single domain and that this requires a thorough evaluation of potent molecules targeting ADAM8 in an in vivo setting., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15 -/- mice developed the same degree of cardiac hypertrophy, dilation, and dysfunction as the parallel female wild-type (WT) mice at 6 wk post-TAC. To determine if this is due to the protective effects of estrogen, which could mask the negative impact of Adam15 loss, WT and Adam15 - / - mice underwent ovariectomy (OVx) 2 wk before TAC. Cardiac structure and function analyses were performed at 6 wk post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15 - / - mice; however, this increase was not reflected in the total-to-phospho-NFAT levels. Integrin-α 7 expression, which was upstream of Cn activation in male Adam15 - / - -TAC mice, remained unchanged in female mice. However, activation of the mitogen-activated protein kinases (ERK, JNK, P38) was greater in Adam15 - / - -OVx-TAC than in WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15 - / - -TAC mice. OVx increased the perivascular fibrosis more in Adam15 - / - compared with WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15 - / - mice post-TAC. As ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding. NEW & NOTEWORTHY Loss of ADAM15 in female mice, unlike the male mice, does not worsen the cardiomyopathy following cardiac pressure overload. Ovariectomy does not worsen the post-TAC cardiomyopathy in female Adam15 - / - mice compared with female WT mice. Lack of deleterious impact of Adam15 deficiency in female mice is not because of the protective effects of ovarian hormones but could be due to a less prominent role of ADAM15 in cardiac response to post-TAC remodeling in female mice.

Objective: To investigate the role of NEAT1 targeted regulation of miR-125/ADAM9 mediated NF-κB pathway in inflammatory response in rosacea., Method: HaCaT cell rosacea phenotype was induced by LL37. The connection targeted by NEAT1 and miR-125a-5p was confirmed by Double-Luciferase report analysis. qPCR was employed to assess the levels of expression for NEAT1, miR-125a-5p, and ADAM9 genes. The levels of expression for ADAM9/TLR2/NF-κB P65 pathway proteins in each batch of cells were determined by Western blotting. The levels of expression for inflammatory factors, including TNF-α, IL-1β, IL-6, and IL-18, were measured through ELISA experimentation., Results: LL37 could successfully induce HaCaT cells to exhibit rosacea phenotype. The luciferase report experiment confirmed that NEAT1 could target and bind miR-125a-5p and inhibit its expression. ADAM9 exhibited increased expression in LL37-induced HaCaT cells, showing a positive association with NEAT1 expression and inverse relationship with miR-125a-5p activation. LL37 treatment promoted the expression of ADAM9/TLR2/NF-κB P65 pathway proteins. Silencing ADAM9 can inhibit the inflammatory signaling pathway and reduce the level of TNF-α, IL-1β, IL-6, and IL-18 in HaCaT cells., Conclusion: NEAT1 can suppress the production of miR-125a-5p and activate the TLR2/NF-κB inflammatory pathway mediated by ADAM9, thereby promoting the inflammatory response in rosacea., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

We present a case of a child with congenital thrombotic thrombocytopenic purpura found to have a compound heterozygous variant in the ADAMTS13 gene with a novel variant resulting in a large duplication of exons 9-11 of ADAMTS13 This variant was identified through additional molecular testing via a chromosomal microarray analysis. To our knowledge, this assay had not previously been utilised to identify an ADAMTS13 variant and the additional testing was possible through the involvement of a genetic counsellor., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis., (© 2024. The Author(s).)

Background: Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear., Methods: Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice., Results: The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment., Conclusions: Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice., (© 2024. The Author(s).)

Objective: During the progression of chronic idiopathic pulmonary fibrosis (IPF), maladaptive tissue remodeling including excessive extracellular matrix (ECM) deposition occurs, which eventually leads to architectural distortion and loss of organ function in organ fibrosis. ADAM15, which is highly expressed in the developing lungs and kidneys, is a transmembrane-anchored multidomain protein belonging to the family of metalloproteinases. Compared to the extensive studies about functions of matrix metalloproteinases (MMPs), less are discussed about ADAM15, particularly in function and mechanism involving fibrogenesis. Our study aims to fill in this gap., Methods: We identified ADAM15 as a novel antifibrotic mediator in lung fibrosis. We found that ADAM15 has cross-talks with transforming growth factor-β1 (TGF-β1), which is the most potent profibrotic mediator. We provided molecular and translational evidence that knockdown of ADAM15 accelerated fibrogenic response induced by TGF-β1 and upregulation of ADAM15 rescued TGF-β1-induced myofibroblast activation in part., Results: Overexpression of ADAM15 ameliorates fibrotic changes and ADAM15 deficiency exacerbates changes from fibroblast to myofibroblast in NIH/3T3. Results were also presented and identified by the intuitive immunofluorescence staining., Conclusion: In this study, we uncover a new molecular mechanism of tissue fibrogenesis and identify ADAM15 as a potential therapeutic target in the treatment of fibrotic diseases., (© 2024 by the Association of Clinical Scientists, Inc.)

Sperm proteins undergo post-translational modifications during sperm transit through the epididymis to acquire fertilizing ability. We previously reported that the genomic region coding Pate family genes is key to the proteolytic processing of the sperm membrane protein ADAM3 and male fertility. This region contains nine Pate family genes (Pate5-13), and two protein-coding genes (Gm27235 and Gm5916), with a domain structure similar to Pate family genes. Therefore, in this study, we aimed to identify key factors by narrowing the genomic region. We generated three knockout (KO) mouse lines using CRISPR/Cas9: single KO mice of Pate10 expressed in the caput epididymis; deletion KO mice of six caput epididymis-enriched genes (Pate5-7, 13, Gm27235, and Gm5916) (Pate7-Gm5916 KO); and deletion KO mice of four genes expressed in the placenta and epididymis (Pate8, 9, 11, and 12) (Pate8-12 KO). We observed that the fertility of only Pate7-Gm5916 KO males was reduced, whereas the rest remained unaffected. Furthermore, when the caput epididymis-enriched genes, Pate8 and Pate10 remained in Pate7-Gm5916 KO mice were independently deleted, both KO males displayed more severe subfertility due to a decrease in mature ADAM3 and a defect in sperm migration to the oviduct. Thus, our data showed that multiple caput epididymis-enriched genes within the region coding Pate5-13 cooperatively function to ensure male fertility in mice., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nasopharyngeal carcinoma (NPC) is a type of epithelial malignancy known for its high likelihood of metastasizing to distant organs, which remains the primary obstacle in the treatment of NPC. The present study aimed to identify potential intervention target for NPC metastasis., Methods: The differentially expressed genes (DEGs) were firstly analyzed and intersected across various NPC related datasets in the Gene Expression Omnibus database. Subsequently, various techniques including quantitative polymerase chain reaction (qPCR), western blotting, immunohistochemistry, migration and invasion assays, in conjunction with bioinformatics and prognostic modeling, were utilized to elucidate the role of candidate genes in NPC metastasis., Results: We discerned the gene a disintegrin and metalloprotease 22 (ADAM22) as a distinct and significant factor in the progression and metastasis of NPC through five datasets. The elevated expression of ADAM22 was observed in clinical tissue and plasma samples with advanced NPC, as well as in high metastatic cells. Furthermore, we highlighted its essential role in a prognostic model that demonstrated strong prediction performance for NPC. Notably, overexpression of ADAM22 was found to enhance the aggressiveness and epithelial-mesenchymal transition (EMT) of low metastatic NPC cells, whereas the downregulation of ADAM22 resulted in suppressed effect in high metastatic cells. Delving into the mechanism, ADAM22 activated the PI3K/Akt signaling pathway through the mediation of Rac Family Small GTPase 2 (RAC2), thereby facilitating EMT and metastasis in NPC., Conclusions: The study provided pioneering insights that ADAM22 had the potential to act as an oncogene by promoting EMT and metastasis of NPC through the RAC2-mediated PI3K/Akt signaling pathway. Thus, ADAM22 could serve as a novel prognostic indicator in NPC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Abnormalities of DNA modifications are closely related to the pathogenesis and prognosis of pancreatic cancer. The development of third-generation sequencing technology has brought opportunities for the study of new epigenetic modification in cancer. Here, we screened the N6-methyladenine (6mA) and 5-methylcytosine (5mC) modification in pancreatic cancer based on Oxford Nanopore Technologies sequencing. The 6mA levels were lower compared with 5mC and upregulated in pancreatic cancer. We developed a novel method to define differentially methylated deficient region (DMDR), which overlapped 1319 protein-coding genes in pancreatic cancer. Genes screened by DMDRs were more significantly enriched in the cancer genes compared with the traditional differential methylation method (P < 0.001 versus P = 0.21, hypergeometric test). We then identified a survival-related signature based on DMDRs (DMDRSig) that stratified patients into high- and low-risk groups. Functional enrichment analysis indicated that 891 genes were closely related to alternative splicing. Multi-omics data from the cancer genome atlas showed that these genes were frequently altered in cancer samples. Survival analysis indicated that seven genes with high expression (ADAM9, ADAM10, EPS8, FAM83A, FAM111B, LAMA3 and TES) were significantly associated with poor prognosis. In addition, the distinction for pancreatic cancer subtypes was determined using 46 subtype-specific genes and unsupervised clustering. Overall, our study is the first to explore the molecular characteristics of 6mA modifications in pancreatic cancer, indicating that 6mA has the potential to be a target for future clinical treatment., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Asthma is a complex chronic respiratory disease characterized by airway hyperresponsiveness, inflammation, and obstruction. Many genes have been identified as associated with asthma but none with such substantial significance as the ADAM33 gene due to its role in airway remodeling and bronchial hyperresponsiveness. This review summarizes the current knowledge on the genetic and functional aspects of ADAM33 in asthma pathogenesis. We highlight its genetic variants associated with asthma susceptibility and severity, as well as the functional effects of ADAM33 on airway remodeling, smooth muscle cell proliferation, and its interplay with environmental factors. Additionally, we discuss the potential clinical implications of ADAM33 as a therapeutic target for asthma management.

Epigenetic analysis is a fundamental part of understanding pathophysiological processes with potential applications in diagnosis, prognosis, and assessment of disease susceptibility. Epigenetic changes have been widely studied in chronic obstructive pulmonary disease (COPD), but currently, there is no molecular marker used to improve the treatment of patients. Furthermore, this progressive disease is a risk factor for the development of more severe COVID-19. Methylation-specific polymerase chain reaction (MSP-PCR) plays an important role in the analysis of DNA methylation profiles, and it is one of the most widely used techniques. In this context, the combination of MSP-PCR with emerging PCR technologies, such as digital PCR (dPCR), results in more accurate analyses of the DNA methylation profile of the genes under study. In this study, we propose the application of the MSP-dPCR technique to evaluate the methylation profile of the ADAM33 gene from saliva samples and lung tissue biopsies of patients with COPD and COVID-19. MSP-dPCR generated a measurable prediction of gene methylation rate, with the potential application of this combined technology for diagnostic and prognostic purposes. It has also proven to be a powerful tool for liquid biopsy applications., (© 2024 the author(s), published by De Gruyter.)

Silencing expression with short interfering RNA (siRNA) is a rapid and cost-effective way to analyze the involvement of target genes in a range of biological processes. Here we describe isolation of primary human monocytes from peripheral blood and their in vitro differentiation to macrophages, followed by electroporation with siRNA to silence expression of a disintegrin and metalloproteinase 17 (ADAM17). This enables evaluation of ADAM17's role in cleaving transmembrane proteins, such as its prototypic substrate tumor necrosis factor (TNF), by enzyme-linked immunosorbent assay (ELISA), flow cytometry, or immunoblotting., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Muscle-invasive and metastatic bladder cancer indicates extra worse prognosis. Accumulating evidence roots for the prominent role of circular RNAs(circRNAs) in bladder cancer, while the mechanisms linking circRNAs and bladder cancer metastasis remain limitedly investigated. Here, we identified a significantly upregulated circRNA candidate, hsa&#95;circ&#95;0001583, from online datasets. Validated by qRT-PCR, PCR, sanger sequencing, actinomycin D and RNase R digestion experiments, hsa&#95;circ&#95;0001583 was proved to be a genuine circular RNA with higher expression levels in bladder cancer tissue. Through gain and loss of function experiments, hsa&#95;circ&#95;0001583 exhibited potent migration and invasion powers both in vitro and in vivo. The staphylococcal nuclease and Tudor domain containing 1 (SND1) was identified as an authentic binding partner for hsa&#95;circ&#95;0001583 through RNA pulldown and RIP experiments. Elevated levels of hsa&#95;circ&#95;0001583 could bind more to SND1 and protect the latter from degradation. Rescue experiments demonstrated that such interaction-induced increased in SND1 levels in bladder cancer cells enabled the protein to pump its endonuclease activity, leading to the degradation of tumor-suppressing MicroRNAs (miRNAs) including miR-126-3p, the suppressor of Disintegrin And Metalloproteinase Domain-Containing Protein 9 (ADAM9), ultimately driving cells into a highly migrative and invasive state. In summary, our study is the first to highlight the upregulation of hsa&#95;circ&#95;0001583 in bladder cancer and its role in downregulating miR-126-3p by binding to and stabilizing the SND1 protein, thereby promoting bladder cancer cell migration and invasion. This study adds hsa&#95;circ&#95;0001583 to the pool of bladder cancer metastasis biomarkers and therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor-promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell-cell and cell-extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15-knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15-deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen-presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15-derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 ( 1.9q34.2 ) in the patient's ADAMTS13 gene. One mutation was a non-synonymous mutation ( exon 5: c.A530G: p.Y177C ), while the other was a nonsense mutation ( exon 21: c.G2651A: p.W884X ). Both mutations were found to be heterozygous. The patient's parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient's father was a heterozygote for the nonsense mutation of the ADAMTS13 gene ( exon 21: c.G2651A: p.W884X ), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C ). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C , and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.

Proven by publications, long non-coding RNAs (lncRNAs) play critical roles in the development of clear cell renal cell carcinoma (ccRCC). Although lncRNA LINC00565 has been implicated in the progression of various cancers, its biological effects on ccRCC remain unknown. This study aimed to investigate the biological functions of LINC00565, as well as its potential mechanism in ccRCC. Here, the expression data of mature microRNAs (miRNAs) (normal: 71, tumor: 545), messenger RNAs (mRNAs), and lncRNAs (normal: 72, tumor: 539) of ccRCC were acquired from The Cancer Genome Atlas (TCGA) database and subjected to differential expression analysis. Quantitative reverse transcriptase polymerase chain reaction analyzed the expression levels of LINC00565, miR-532-3p, and ADAM19 mRNA. TCGA database, dual-luciferase report detection, and Argonaute 2 RNA immunoprecipitation were utilized to confirm the relationships between LINC00565 and miR-532-3p and between miR-532-3p and ADAM19, respectively. The progression of ccRCC cells was determined via CCK-8, colony formation, scratch healing, and transwell assays. Western blot was applied to detect the protein levels of epithelial-mesenchymal transition markers and ADAM19. We herein suggested that LINC00565 was prominently upregulated in ccRCC tissues and cells. Knockdown of LINC00565 repressed cell progression. We further predicted and validated miR-532-3p as a target of LINC00565, and miR-532-3p could target ADAM19. Knockdown of LINC00565 resulted in ADAM19 level downregulation in ccRCC cells and suppressed miR-532-3p could restore ADAM19 level. Thus, the three RNAs constructed a ceRNA network. Overexpressed ADAM19 could eliminate the anticancer effects caused by knocking down LINC00565 on ccRCC cells. In conclusion, LINC00565 upregulated ADAM19 via absorbing miR-532-3p, thereby facilitating the progression of ccRCC cells., Competing Interests: None

Background: Investigation of biomarkers may facilitate understanding the mechanisms of primary open-angle glaucoma (POAG) and developing therapeutic targets. This study aimed to identify potential genes based on competing endogenous RNA (ceRNA) network for POAG., Methods: Based on long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) from the Gene Expression Omnibus (GEO) database, we identified differential expressed lncRNAs (DELs), differential expressed miRNAs (DEMis) and differential expressed mRNAs (DEMs) and then constructed a ceRNA network. Through weighted gene co-expression network analysis (WGCNA), we identified gender-specific genes for gender-associated ceRNA network construction, followed by the protein-protein interaction (PPI) network and functional enrichment analysis to screen hub genes and reveal their functions. The expression levels of hub genes were measured in steroid-induced ocular hypertension (SIOH) mice., Results: A total of 175 DELs, 727 DEMs and 45 DEMis were screened between control and POAG samples. Seven modules were identified through WGCNA and one module was associated with gender of POAG patients. We discovered 41 gender-specific genes for gender-associated ceRNA construction and then identified 8 genes (NAV3, C1QB, RXRB, P2RY4, ADAM15, VAV3, ZNF207 and TOP1), which were enriched in cell cycle-related pathways and immune-related pathways. C1QB, RXRB, Top1 and ZNF207 were highly interacted with other proteins. The expression levels of NAV3 and C1QB were downregulated in SIOH, while the levels of RXRB, P2RY4, ADAM15, VAV3, ZNF207 and TOP1 were upregulated in SIOH., Conclusion: This study identifies hub genes associated with the pathogenesis of gender-specific POAG and provides potential biomarkers for POAG., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment.

Background: Coronavirus Disease of 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients had varying clinical symptoms and disease severity (mild, moderate, severe, and critical). Several risk factors, including genetic polymorphisms, have been reported to be associated with disease risk and severity. This study aimed to investigate the association of two polymorphisms in the orosomucoid1-like 3 (ORMDL3) and a disintegrin and metalloprotease 33 (ADAM33) asthma-related genes with the severity of COVID-19., Material and Methods: The study included 116 COVID-19 patients with a positive polymerase chain reaction (PCR) test for the SARS-CoV-2 Delta variant. 58 patients with moderate symptoms, 28 patients with severe symptoms, and 30 outpatients with mild symptoms. Genotyping of rs7216389 in the ORMDL3 and rs2280091 in ADAM33 genes was performed by polymerase chain reaction-restriction fragment length polymorphism. Furthermore, records of patients were studied for hematological profiles and biochemical markers., Results: No significant association was found between rs7216389 and rs2280091 and the severity of COVID-19 between different groups of COVID-19 patients. The serum levels of RBC and neutrophil-to-lymphocyte ratio were significantly increased; the erythrocyte sedimentation rate (ESR), and Aspartate transaminase (SGOT) were significantly decreased during treatment in intensive care unit (ICU) patients. The serum levels of red blood cells, Platelets, Urea, Alkaline phosphatase, ESR, Alanine transaminase (SGPT), and SGOT were significantly increased during treatment in hospitalized patients. The serum levels of inflammatory factors, including C-reactive protein (CRP), D-dimer, and Ferritin at the time of admission, were significantly higher in patients admitted to the ICU patients compared to the other group of patients., Conclusion: The two polymorphisms studied in this research are not suitable markers for predicting the severity of COVID-19. However, there are significant differences in the amounts of some blood factors in different groups of COVID-19 patients (P < 0.05) and these factors can be used as a marker for the disease severity prediction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Comorbidity exists between amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), but the role of genetic factors is unclear., Objective: We aim to investigate genetic correlation, causal relationship, and comorbid genes between ALS and PD., Methods: Leveraging the largest genome-wide association study data (ALS: 27,205 cases, 110,881 controls; PDG: 33,674 cases, 449,056 controls), we used linkage disequilibrium score regression and Mendelian randomization analysis for genetic correlation and causal inference. We performed genome-wide cross-trait analysis via Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association to identify specific single-nucleotide polymorphisms, followed by functional mapping and annotation. Integrating expression quantitative trait loci data from 13 brain regions, we conducted a transcriptome-wide association study via functional summary-based imputation and joint-tissue imputation to explore comorbid genes, followed by pathway enrichment analysis., Results: We found that PD positively correlates with ALS (r g  = 0.144, P = 0.026) and confers a causal effect (odds ratio = 1.09, 95% confidence interval: 1.03-1.15, P = 3.00 × 10 -3 ). We identified nine single-nucleotide polymorphisms (eight new), associating with three risk loci (chromosomes 4, 10, and 17) and seven genes (TMEM175, MAPT, NSF, LRRC37A2, ARHGAP27, GAK, and FGFRL1). In transcriptome-wide association study analysis, we showed six previously unreported pleiotropic genes (KANSL1, ARL17B, EFNA1, WNT3, ERCC8, and ADAM15), and we found these candidate genes are mainly enriched in negative regulation of neuron projection development (GO:0010977)., Conclusions: Our work demonstrates shared genetic architecture between ALS and PD, reports new pleiotropic genes, and sheds light on the comorbid mechanism. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Fabry disease (FD) is an X-linked lysosomal rare disease due to a deficiency of α-galactosidase A activity. The accumulation of glycosphingolipids mainly affects the kidney, heart, and central nervous system, considerably reducing life expectancy. Although the accumulation of undegraded substrate is considered the primary cause of FD, it is established that secondary dysfunctions at the cellular, tissue, and organ levels ultimately give rise to the clinical phenotype. To parse this biological complexity, a large-scale deep plasma targeted proteomic profiling has been performed. We analyzed the plasma protein profiles of FD deeply phenotyped patients (n = 55) compared to controls (n = 30) using next-generation plasma proteomics including 1463 proteins. Systems biology and machine learning approaches have been used. The analysis enabled the identification of proteomic profiles that unambiguously separated FD patients from controls (615 differentially expressed proteins, 476 upregulated, and 139 downregulated) and 365 proteins are newly reported. We observed functional remodeling of several processes, such as cytokine-mediated pathways, extracellular matrix, and vacuolar/lysosomal proteome. Using network strategies, we probed patient-specific tissue metabolic remodeling and described a robust predictive consensus protein signature including 17 proteins CD200, SPINT1, CD34, FGFR2, GRN, ERBB4, AXL, ADAM15, PTPRM, IL13RA1, NBL1, NOTCH1, VASN, ROR1, AMBP, CCN3, and HAVCR2. Our findings highlight the pro-inflammatory cytokines' involvement in FD pathogenesis along with extracellular matrix remodeling. The study shows a tissue-wide metabolic remodeling connection to plasma proteomics in FD. These results will facilitate further studies to understand the molecular mechanisms in FD to pave the way for better diagnostics and therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS) are secreted, multi-domain matrix-related zinc endopeptidases that play a role in organogenesis, assembly and degradation of extracellular matrix (ECM), cancer and inflammation. Genome-wide identification and analysis of the bovine ADAMTS gene family has not yet been carried out. In this study, 19 ADAMTS family genes were identified in Bos taurus by genome-wide bioinformatics analysis, and they were unevenly distributed on 12 chromosomes. Phylogenetic analysis shows that the Bos taurus ADAMTS are divided into eight subfamilies, with highly consistent gene structures and motifs within the same subfamily. Collinearity analysis showed that the Bos taurus ADAMTS gene family is homologous to other bovine subfamily species, and many ADAMTS genes may be derived from tandem replication and segmental replication. In addition, based on the analysis of RNA-seq data, we found the expression pattern of ADAMTS gene in different tissues. Meanwhile, we also analyzed the expression profile of ADAMTS gene in the inflammatory response of bovine mammary epithelial cells (BMECs) stimulated by LPS by qRT-PCR. The results can provide ideas for understanding the evolutionary relationship and expression pattern of ADAMTS gene in Bovidae, and clarify the theoretical basis of the function of ADAMTS in inflammation., Competing Interests: Declaration of competing interest Authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: ADAMTS13 is a circulating metalloprotease that cleaves von Willebrand factor (VWF) in a shear-dependent manner. ADAMTS13 is secreted as an active protease but has a long half-life, suggesting that it is resistant to circulating protease inhibitors. These zymogen-like properties indicate that ADAMTS13 exists as a latent protease that is activated by its substrate., Objectives: To investigate the mechanism of ADAMTS13 latency and resistance to metalloprotease inhibitors., Methods: Probe the active site of ADAMTS13 and variants using alpha-2 macroglobulin (A2M), tissue inhibitors of metalloproteases (TIMPs), and Marimastat., Results: ADAMTS13 and C-terminal deletion mutants are not inhibited by A2M, TIMPs, or Marimastat, but cleave FRETS-VWF73, suggesting that the metalloprotease domain is latent in the absence of substrate. Within the metalloprotease domain, mutating the gatekeeper triad (R193, D217, D252) or substituting the calcium-binding (R180-R193) or the variable (G236-S263) loops with corresponding features from ADAMTS5 did not sensitize MDTCS to inhibition. However, substituting the calcium-binding loop and an extended variable loop (G236-S263) corresponding to the S1-S1' pockets with those from ADAMTS5, resulted in MDTCS-GVC5 inhibition by Marimastat, but not by A2M or TIMP3. Substituting the MD domains of ADAMTS5 into full-length ADAMTS13 resulted in a 50-fold reduction in activity compared with the substitution into MDTCS. However, both chimeras were susceptible to inhibition, suggesting that the closed conformation does not contribute to the latency of the metalloprotease domain., Conclusion: The metalloprotease domain protects ADAMTS13 from inhibitors and exists in a latent state that is partially maintained by loops flanking the S1 and S1' specificity pockets., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Thyroid cancer is the most prevalent endocrine malignancy globally; however, its underlying pathogenesis remains unclarified. Reportedly, alternative splicing is involved in processes such as embryonic stem and precursor cell differentiation, cell lineage reprogramming, and epithelial-mesenchymal transitions. ADAM33-n, an alternative splicing isoform of ADAM33, encodes a small protein containing 138 amino acids of the N-terminal of full-length ADAM33, which constructs a chaperone-like domain that was previously reported to bind and block the proteolysis activity of ADAM33. In this study, we reported for the first time that ADAM33-n was downregulated in thyroid cancer. The results of cell counting kit-8 and colony formation assays showed that ectopic ADAM33-n in papillary thyroid cancer cell lines restricted cell proliferation and colony formation. Moreover, we demonstrated that ectopic ADAM33-n reversed the oncogenic function of full-length ADAM33 in cell growth and colony formation in the MDA-T32 and BCPAP cells. These findings indicate the tumor suppressor ability of ADAM33-n. Altogether, our study findings present a potential explanatory model of how the downregulation of the oncogenic gene ADAM33 promotes the pathogenesis of thyroid cancer., (© 2023. The Author(s).)

Tobacco smoking is the leading risk factor for many respiratory diseases. Several genes are associated with nicotine addiction, such as CHRNA5 and ADAM33 . This research aims to evaluate the association of the polymorphisms rs16969968 ( CHRNA5 ) and rs3918396 ( ADAM33 ) in patients who developed severe COVID-19. We included 917 COVID-19 patients hospitalized with critical disease and oxygenation impairment. They were divided into two groups, tobacco-smoking ( n = 257) and non-smoker ( n = 660) patients. The genotype and allele frequencies of two single nucleotide variants, the rs16969968 ( CHRNA5 ) and rs3918396 ( ADAM33 ), were evaluated. The rs3918396 in ADAM33 does not show a significative association. We analyzed the study population according to the rs16969968 genotype (GA + AA, n = 180, and GG, n = 737). The erythrocyte sedimentation rate (ESR) shows statistical differences; the GA + AA group had higher values than the GG group ( p = 0.038, 32 vs. 26 mm/h, respectively). The smoking patients and GA or AA genotype carriers had a high positive correlation ( p < 0.001, rho = 0.753) between fibrinogen and C-reactive protein. COVID-19 patients and smokers carriers of one or two copies of the risk allele (rs16969968/A) have high ESR and a positive correlation between fibrinogen and C-reactive protein.

Many reproductive physiological processes, such as folliculogenesis, ovulation, implantation, and fertilization, require the synthesis, remodeling, and degradation of the extracellular matrix (ECM). The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) family genes code for key metalloproteinases in the remodeling process of different ECM. Several genes of this family encode for proteins with important functions in reproductive processes; in particular, ADAMTS1 , 4, 5 and 9 are genes that are differentially expressed in cell types and the physiological stages of reproductive tissues. ADAMTS enzymes degrade proteoglycans in the ECM of the follicles so that the oocytes can be released and regulate follicle development during folliculogenesis, favoring the action of essential growth factors, such as FGF-2, FGF-7 and GDF-9. The transcriptional regulation of ADAMTS1 and 9 in preovulatory follicles occurs because of the gonadotropin surge in preovulatory follicles, via the progesterone/progesterone receptor complex. In addition, in the case of ADAMTS1, pathways involving protein kinase A (PKA), extracellular signal regulated protein kinase (ERK1/2) and the epidermal growth factor receptor (EGFR) might contribute to ECM regulation. Different Omic studies indicate the importance of genes of the ADAMTS family from a reproductive aspect. ADAMTS genes could serve as biomarkers for genetic improvement and contribute to enhance fertility and animal reproduction; however, more research related to these genes, the synthesis of proteins encoded by these genes, and regulation in farm animals is needed.

The modulation of gene expression via DNA methylation modifications is relevant to the pathogenesis of periodontitis. This study aimed at identifying novel biomarkers in gingival tissues from periodontitis by integrally analyzing methylation profiles and gene expression data. Differential gene expressions (DGEs) of dataset GSE106090 were obtained from the Gene Expression Omnibus (GEO) database for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. DNA methylation DGEs (DM-DGEs) were analyzed from dataset GSE173082. After integrating these two datasets, expressions of common genes were validated in gingival tissues from healthy controls and periodontitis patients by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. GO analysis of 748 upregulated and 847 downregulated DEGs from the GSE106090 dataset revealed that immune response-regulating signaling pathway, cell-cell junction and signaling receptor activator activity as the top enriched biological process (BP), cellular component (CC) and molecular function (MF), respectively. DEGs were mainly enriched in cytokine-cytokine receptor interaction, Ras signaling pathway, and chemokine signaling pathway. There was one up-regulated mRNA with hypo-methylated gene [ADAM28 (a disintegrin and metalloproteinase 28)] and one down-regulated mRNA with hyper-methylated gene [ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3)] after integrating GSE106090 and GSE173082 datasets. Increased ADAM28 expression was validated in gingival tissues from periodontitis patients as compared to the healthy controls with decreased ADAMTSL3 expression, which were correlated with disease stage. ADAM28 and ADAMTSL3 may act as novel biomarkers in gingival tissues from periodontitis by a comprehensive analysis of bioinformatics methods and executed validation.

ADAMTS-2 and ADAMTS-3, known as procollagen amino proteases (PNP), are primarily responsible for processing the amino ends of the fibrillar collagen precursors. ADAMTS-2 is a highly expressed gene in type I collagen-rich tissues, such as skin, bones, tendons, and aorta. ADAMTS-3 is mainly expressed in cartilage, where it colocalizes with type II procollagen and in the nervous system. Studies about ADAMTS-2 and ADAMTS-3 enzymes primarily focused on their collagen processing activity. Knowledge about the transcriptional regulations of these genes is rather limited. Here we analyzed the transcriptional regulations of ADAMTS-2 and ADAMTS-3 genes under chemically induced hypoxic conditions in endothelial cell model, HUVECs. We elucidated that hypoxia is the potent positive regulator of ADAMTS-2 and ADAMTS-3 genes. qRT-PCR and western blotting studies revealed that ADAMTS-2 and ADAMTS-3 expressions were increased at mRNA and protein levels under chemically induced hypoxic conditions in HUVECs. In addition, Transient transfection experiments of ADAMTS-2 and ADAMTS-3 promoter-reporter constructs indicated that low oxygen conditions increased ADAMTS-2 and ADAMTS-3 promoter activities. Furthermore, the DNA-protein interaction assay provided evidence of the functional binding of HIF-1α on bioinformatically determined HRE regions on the ADAMTS-2 and ADAMTS-3 promoters., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immunotherapy plus tyrosine kinase inhibitor (IO-TKI) has become the standard first-line therapy for advanced renal cell carcinoma (RCC). However, the modest response rate of IO-TKI therapy and the absence of biomarkers limited the selection of treatment strategies for RCC patients. There were three cohorts enrolled: two from our facility (ZS-MRCC and ZS-HRRCC) and one from a clinical study (JAVELIN-101). By RNA sequencing, the expression of ADAM9 in each sample was measured. By flow cytometry and immunohistochemistry, immune infiltration and T cell function were examined. Primary outcomes were established as treatment response and progression-free survival (PFS). Patients with low-ADAM9 expression had a higher objective response rate (56.5% vs 13.6%, P = 0.01) and longer PFS in both cohorts. In the ZS-HRRCC cohort, the expression of ADAM9 was associated with increased tumor-infiltrating T cells, which was proved by immunohistochemistry (P < 0.05) and flow cytometry (Spearman's ρ = 0.42, P < 0.001). In the high-ADAM9 group, CD8 + and CD4 + T cells revealed an exhausted phenotype with decreased GZMB (Spearman's ρ =  - 0.31, P = 0.05, and Spearman's ρ =  - 0.49, P < 0.001, respectively), and fewer Macrophages were identified. A predictive RFscore was further constructed by random forest approach, involving ADAM9 and immunologic genes. Only in the subgroup with the lower RFscore did IO-TKI outperform TKI monotherapy. High-ADAM9 expression was associated with immunosuppression and IO-TKI resistance. Expression of ADAM9 was also associated with the exhaustion and dysfunction of T cells. ADAM9-based RFscore has the potential to be used as a biomarker to distinguish the optimal patient treatment methods between IO-TKI and TKI monotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

ADAMTS13 (a disintegrin-like metalloprotease domain with thrombospondin type 1 motif, member 13) is a protease of crucial importance in the regulation of the size of von Willebrand factor multimers. Very low ADAMTS13 activity levels result in thrombotic thrombocytopenic purpura, a rare and life-threatening disease. The mechanisms involved can either be acquired (immune-mediated thrombotic thrombocytopenic purpura [iTTP]) or congenital (cTTP, Upshaw-Schulman syndrome) caused by the autosomal recessive inheritance of disease-causing variants (DCVs) located along the ADAMTS13 gene, which is located in chromosome 9q34. Apart from its role in TTP, and as a regulator of microthrombosis, ADAMTS13 has begun to be identified as a prognostic and/or diagnostic marker of other diseases, such as those related to inflammatory processes, liver damage, metastasis of malignancies, sepsis, and different disorders related to angiogenesis. Since its first description almost 100 years ago, the improvement of laboratory tests and the description of novel DCVs along the ADAMTS13 gene have contributed to a better and faster diagnosis of patients under critical conditions. The ability of ADAMTS13 to dissolve platelet aggregates in vitro and its antithrombotic properties makes recombinant human ADAMTS13 treatment a potential therapeutic approach targeting not only patients with cTTP but also other medical conditions., Competing Interests: None declared., (Thieme. All rights reserved.)

The ADAMs (a disintegrin and metalloproteinase) play regulatory roles in cell adhesion, migration and proteolysis. To explore the origin and evolution of ADAMs, this study identified the homologs of adam10 and adam17 in Lampetra morii and Lampetra japonica. Sequence analysis revealed that they share the same genomic structures with their counterparts in jawed vertebrates. The putative proteins possess conserved motifs, including a furin cut site (RXXR) for precursor processing, an enzyme catalytic motif (HEXGEHXXGXXH) for hydrolysis, and a Ca 2+ -binding motif (CGNXXXEXGEXCD) for stabilizing protein structure. In addition, a substrate recognition domain is present at the membrane-proximal region of lamprey ADAM17. The cytoplasmic region of lamprey ADAM10 contains a potential threonine phosphorylation site which has been shown to be activated by protein kinase C (PKC) in mammals. Both the adam10 and adam17 genes were constitutively expressed in the brain, kidney, and gills and were differentially regulated in the primary blood leukocytes by lipopolysaccharide (LPS) and pokeweed mitogen (PWM). Adam10 was induced by LPS but not PWM; conversely, adam17 was induced by PWM but not LPS. Taken together, our results suggest that the activation pathways and functions of ADAM10 and ADAM17 are conserved in agnathans., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: ADAM metallopeptidase domain 12 (ADAM12) is generally upregulated in tissues of various tumors, emerging as a prognostic biomarker. However, the clinical significance of serum ADAM12 in tumors still remains to be fully elucidated. The present study aimed to investigate the expression and prognostic value of serum ADAM12 in tumor patients., Materials and Methods: Serum samples were collected from healthy doners (HDs; n = 87) and patients (n = 238) with a clinical diagnosis of breast, liver, lung, stomach and esophageal (STES) and thyroid cancer. Serum ADAM12 protein and mRNA expression was detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR), respectively. Receiver-operator characteristic (ROC) analysis was performed to explored the prognostic value of serum ADAM12 expression., Results: The expression of serum ADAM12 in breast and liver cancer patients was significantly upregulated compared with HDs. In patients with breast cancer, the levels of serum ADAM12 protein and mRNA were significantly higher in tumor stages than that in HDs (p < 0.05), with AUC value of 0.82. In liver cancer, elevated levels of serum ADAM12 protein were significantly correlated with clinical stage (r = 0.74; p = 6.9e-4) and T stage (r = 0.74, p = 7.6e-4), and attained AUC value of 1. However, the clinical significance of serum ADAM12 expression in lung, STES and thyroid cancer had not been found., Conclusions: Serum ADAM12 expression showed high degree of tumor heterogeneity, and may be a valuable noninvasive diagnostic and prognostic biomarker for breast and liver cancer., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Studies of the genetic regulation of cerebrospinal fluid (CSF) proteins may reveal pathways for treatment of neurological diseases. 398 proteins in CSF were measured in 1,591 participants from the BioFINDER study. Protein quantitative trait loci (pQTL) were identified as associations between genetic variants and proteins, with 176 pQTLs for 145 CSF proteins (P < 1.25 × 10 -10 , 117 cis-pQTLs and 59 trans-pQTLs). Ventricular volume (measured with brain magnetic resonance imaging) was a confounder for several pQTLs. pQTLs for CSF and plasma proteins were overall correlated, but CSF-specific pQTLs were also observed. Mendelian randomization analyses suggested causal roles for several proteins, for example, ApoE, CD33, and GRN in Alzheimer's disease, MMP-10 in preclinical Alzheimer's disease, SIGLEC9 in amyotrophic lateral sclerosis, and CD38, GPNMB, and ADAM15 in Parkinson's disease. CSF levels of GRN, MMP-10, and GPNMB were altered in Alzheimer's disease, preclinical Alzheimer's disease, and Parkinson's disease, respectively. These findings point to pathways to be explored for novel therapies. The novel finding that ventricular volume confounded pQTLs has implications for design of future studies of the genetic regulation of the CSF proteome., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Lots of epidemiological and clinical studies have shown that human cytomegalovirus (HCMV) is related to the pathogenesis of atherosclerosis. Released by inflammatory cells and vascular smooth muscle cell (VSMCs), metalloproteinases are observed in many pathological vessel conditions, including atherosclerosis and restenosis. This study was designed to investigate the effect of HCMV infection on the expression of metalloproteinases and their involvements in the HCMV-induced functional changes of VSMCs. Differential metalloproteinase after HCMV infection was assayed using reverse transcription-polymerase chain reaction (RT-PCR) microarray. The most significant increased a disintegrin and metalloprotease 9 (ADAM9) was chosen to investigate the mechanism of its specific increase after infection using the treatment of UV-irradiated replication-deficient HCMV, HCMV-infected cell lysate filters or Foscarnet. The function of proliferation, migration, production of inflammatoty factors and phenotypic transformation were determined by using cell counting kit-8, transwell, Enzyme-linked immunosorbent assay, RT-quantitative PCR (qPCR) and Western blot, respectively. Moreover, the effect of ADAM9 deficiency on HCMV replication was also determined using RT-qPCR and immunofluorescence. The expression levels of 6 genes were upregulated and 14 genes were downregulated at different time points after HCMV infection. Among these, the expression level of ADAM9 increased most significantly at each time point and the abnormal expression of ADAM9 might be induced by the early gene products of HCMV. Further studies found that ADAM9 promoted the proliferation, the migration, the production of inflammatory factors and the transit from the contractile phenotype (decreased ACTA2 expression) to the synthetic phenotype (increased osteopontin [OPN] expression). Knockdown theADAM9 expression could rescue the decreased ACTA2 expression, but has no effect on OPN expression. ADAM-9 deficiency didn't affect the replication of HCMV. The findings of our study suggest that HCMV infection changed VSMC function through ADAM9 expression, which may contribute to the understanding of the underlying pathological mechanisms of HCMV-induced atherosclerosis., (© 2022 Wiley Periodicals LLC.)

Background: Myocardial hypertrophy and dilation are key features of cardiomyopathies and involve several cellular and molecular events. ADAMs (a disintegrin and metalloproteinases) are membrane-bound proteinases with diverse functions whose role in heart disease remains underexplored. ADAM15 is expressed in the heart and is downregulated in the failing human heart. We investigated the role ADAM15 in pressure overload cardiomyopathy., Methods: We assessed ADAM15 levels in myocardial specimens from patients. Its direct role in pressure overload was investigated by subjecting wildtype and Adam15 -deficient mice to transverse aortic constriction (TAC)., Results: ADAM15 levels did not change in patients with concentric hypertrophy, but markedly decreased in eccentric hypertrophy and heart failure. Loss of ADAM15 alone did not cause cardiomyopathy in mice (1 year old). After TAC, Adam15 -/- mice exhibited worsened eccentric hypertrophy and dilation with greater increase in hypertrophy markers (pJNK, pERK1/2; Nppb, Nppa , Myh7 , Acta1 ) compared with wildtype-TAC. Expression of integrin-α7 (but not integrin β1) increased significantly more in Adam15 -/- -TAC hearts, while the interaction of these integrins with basement membrane (laminin), decreased consistent with worsened left ventricle dilation. In vitro, ADAM15 knockdown increased cardiomyocyte hypertrophy in response to mechanical stretch. Adam15 -/- -TAC hearts exhibited increased calcineurin activity and de-phosphorylation of nuclear factor of activated T cells. Calcineurin inhibition (cyclosporin-A) blocked the excess hypertrophy and dilation in Adam15 -/- -TAC mice. Proteome profiling demonstrated the increased abundance of the key proteins linked to worsened DCM in Adam15 -/- -TAC., Conclusion: This is the first report demonstrating that ADAM15 can suppress hypertrophy through regulating the integrin-laminin interaction and the calcineurin pathway.

With approximately 1.4 million men annually diagnosed with prostate cancer (PCa) worldwide, PCa remains a dreaded threat to life and source of devastating morbidity. In recent decades, a significant decrease in age-specific PCa mortality has been achieved by increasing prostate-specific antigen (PSA) screening and improving treatments. Nevertheless, upcoming, augmented recommendations against PSA screening underline an escalating disproportion between the benefit and harm of current diagnosis/prognosis and application of radical treatment standards. Undoubtedly, new potent diagnostic and prognostic tools are urgently needed to alleviate this tensed situation. They should allow a more reliable early assessment of the upcoming threat, in order to enable applying timely adjusted and personalized therapy and monitoring. Here, we present a basic study on an epigenetic screening approach by Methylated DNA Immunoprecipitation (MeDIP). We identified genes associated with hypomethylated CpG islands in three PCa sample cohorts. By adjusting our computational biology analyses to focus on single CpG-enriched 60-nucleotide-long DNA probes, we revealed numerous consistently differential methylated DNA segments in PCa. They were associated among other genes with NOTCH3, CDK2AP1, KLK4, and ADAM15 . These can be used for early discrimination, and might contribute to a new epigenetic tumor classification system of PCa. Our analysis shows that we can dissect short, differential methylated CpG-rich DNA fragments and combinations of them that are consistently present in all tumors. We name them tumor cell-specific differential methylated CpG dinucleotide signatures (TUMS).

Inherited copy number variations (CNVs) can provide valuable information for cancer susceptibility and prognosis. However, their association with oropharynx squamous cell carcinoma (OPSCC) is still poorly studied. Using microarrays analysis, we identified three inherited CNVs associated with OPSCC risk, of which one was validated in 152 OPSCC patients and 155 controls and related to pseudogene-microRNA-mRNA interaction. Individuals with three or more copies of ADAM3A and ADAM5 pseudogenes (8p11.22 chromosome region) were under 6.49-fold increased risk of OPSCC. ADAM5 shared a highly homologous sequence with the ADAM9 3'-UTR, predicted to be a binding site for miR-122b-5p. Individuals carrying more than three copies of ADAM3A and ADAM5 presented higher ADAM9 expression levels. Moreover, patients with total deletion or one copy of pseudogenes and with higher expression of miR-122b-5p presented worse prognoses. Our data suggest, for the first time, that ADAM3A and ADAM5 pseudogene-inherited CNV could modulate OPSCC occurrence and prognosis, possibly through the interaction of ADAM5 pseudogene transcript, miR-122b-5p, and ADAM9 .

Background: Circular RNAs (circRNAs) have critical roles in various types of diseases, including preeclampsia (PE). Circ&#95;0005714 function in PE was explored in this study., Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed for level analysis of circ&#95;0005714, micoRNA-223-3p (miR-223-3p), and a disintegrin and metalloproteinase 9 (ADAM9). Cell Counting Kit-8 (CCK-8) and colony formation assays were used for cell viability and colony formation detection. Cell proliferation was determined by EdU assay. The determination of migration and invasion was conducted by wound healing assay and transwell assay. Tube formation assay was applied to assess angiopoiesis. Target binding analysis was performed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Western blot was used for protein examination., Results: Circ&#95;0005714 was highly expressed in PE placenta tissues. The expression promotion of circ&#95;0005714 reduced proliferation, migration, invasion, and angiopoiesis in trophoblast cells. Furthermore, circ&#95;0005714 acted as a molecular sponge for miR-223-3p and the effects of circ&#95;0005714 on trophoblast cells were achieved by sponging miR-223-3p. Moreover, miR-223-3p could target ADAM9 and knockdown of ADAM9 reversed cell progression inhibition induced by miR-223-3p inhibitor. In addition, circ&#95;0005714 upregulated the ADAM9 expression and inactivated the Wnt/β-catenin pathway through targeting miR-223-3p., Conclusions: All results manifested that circ&#95;0005714 retarded the progression of PE by mediating the miR-223-3p/ADAM9 signal network.

ADAM33 is a zinc-dependent metalloprotease of the ADAM family, which plays a vital biological role as an activator of Th 2 cytokines and growth factors. Moreover, this protein is crucial for the normal development of the lung in the fetus two months after gestation leading to determining lung functions all over life. In this regard, mutations in ADAM33 have been linked with asthma risk factors. Consequently, identifying ADAM33 pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) can be very important in asthma treatment. In the present study, 1055 nsSNPs of human ADAM33 were analyzed using biocomputational software, 31 of which were found to be detrimental mutations. Precise structural and stability analysis revealed D219V, C669G, and C606S as the most destabilizing SNPs. Furthermore, MD simulations disclosed higher overall fluctuation and alteration in intramolecular interactions compared with the wild-type structure. Overall, the results suggest D219V, C669G, and C606S detrimental mutations as a starting point for further case-control studies on the ADAM33 protein as well as an essential source for future targeted mechanisms., Competing Interests: All the authors declare that there are no conflicts of interest., (Copyright © 2022 Milad Mohkam et al.)