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1.
Anal Cell Pathol (Amst) ; 2023: 6985808, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36655117

RESUMO

Proprotein convertase subtilisin/kexin type 9 can mediate the intracellular lysosomal degradation of the low-density lipoprotein receptor protein in hepatocytes and decrease the liver's ability to scavenge low-density lipoprotein cholesterol from circulation, resulting in high levels of cholesterol in the circulatory system. Current studies have primarily focused on the relationship between PCSK9 and blood lipid metabolism; however, the biological function of PCSK9 in hepatocytes is rarely addressed. In this study, we evaluate its effects in the human hepatoma carcinoma cell line HepG2, including proliferation, migration, and free cholesterol transport. PCSK9-D374Y is a gain-of-function mutation that does not affect proliferation but significantly suppresses the migration and cholesterol efflux capacity of these cells. The suppression of the transmembrane outflow of intracellular-free cholesterol regulates small G proteins and the suppression of extracellular signal-regulated kinase. In summary, PCSK9-D374Y affects hepatocyte features, including their migration and free cholesterol transport capabilities.


Assuntos
Hepatócitos , Pró-Proteína Convertase 9 , Humanos , Colesterol/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hepatócitos/metabolismo , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Movimento Celular/genética , Movimento Celular/fisiologia
2.
Proc Natl Acad Sci U S A ; 120(5): e2210361120, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36689652

RESUMO

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a major health problem worldwide. Due to the fast emergence of SARS-CoV-2 variants, understanding the molecular mechanisms of viral pathogenesis and developing novel inhibitors are essential and urgent. Here, we investigated the potential roles of N6,2'-O-dimethyladenosine (m6Am), one of the most abundant modifications of eukaryotic messenger ribonucleic acid (mRNAs), in SARS-CoV-2 infection of human cells. Using genome-wide m6Am-exo-seq, RNA sequencing analysis, and Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing, we demonstrate that phosphorylated C-terminal domain (CTD)-interacting factor 1 (PCIF1), a cap-specific adenine N6-methyltransferase, plays a major role in facilitating infection of primary human lung epithelial cells and cell lines by SARS-CoV-2, variants of concern, and other coronaviruses. We show that PCIF1 promotes infection by sustaining expression of the coronavirus receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) via m6Am-dependent mRNA stabilization. In PCIF1-depleted cells, both ACE2/TMPRSS2 expression and viral infection are rescued by re-expression of wild-type, but not catalytically inactive, PCIF1. These findings suggest a role for PCIF1 and cap m6Am in regulating SARS-CoV-2 susceptibility and identify a potential therapeutic target for prevention of infection.


Assuntos
COVID-19 , Humanos , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2 , RNA Mensageiro/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Serina Endopeptidases
3.
Cell Chem Biol ; 30(1): 97-109.e9, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36626903

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of hepatic LDL receptors (LDLRs). Current therapeutic approaches use antibodies that disrupt PCSK9 binding to LDLR to reduce circulating LDL-C concentrations or siRNA that reduces PCSK9 synthesis and thereby levels in circulation. Recent reports describe small molecules that, like therapeutic antibodies, interfere with PCSK9 binding to LDLR. We report an alternative approach to decrease circulating PCSK9 levels by accelerating PCSK9 clearance and degradation using heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation.


Assuntos
Pró-Proteína Convertase 9 , Serina Endopeptidases , Pró-Proteína Convertase 9/metabolismo , Receptor de Asialoglicoproteína , Serina Endopeptidases/metabolismo , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , LDL-Colesterol , Ligantes
4.
Genes (Basel) ; 14(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36672863

RESUMO

To explore the impact of omecamtiv mecarbil (OM) on the gene expression profile in adult male rats. Fourteen male Wistar rats were randomly assigned to a single OM (1.2 mg/kg/h; n = 6) or placebo (n = 8) 30-min infusion. Echocardiography was performed before and after OM infusion. Seven days after infusion, rats were euthanized, and left ventricular (LV) tissues were removed for real-time quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic Bax-to-Bcl2 ratio was decreased, with increased Bcl2 and similar Bax gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase (Gsr) and superoxide dismutases (Sod1/Sod2), remained unchanged, whereas the expression of antioxidant glutathione peroxidase (Gpx) increased. While LV gene expression of key energy sensors, peroxisome proliferator activator (Ppar) α and γ, AMP-activated protein kinase (Ampk), and carnitine palmitoyltransferase 1 (Cpt1) remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 (Pdk4) increased. The LV expression of the major myocardial glucose transporter Glut1 decreased, with no changes in Glut4 expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 (Olr1) and arachidonate 15-lipoxygenase (Alox15) increased, with no changes in fatty acid transporter Cd36. An increased LV expression of angiotensin II receptors AT1 and AT2 was observed, with no changes in angiotensin I-converting enzyme expression. The Kalikrein-bradykinin system was upregulated with increased LV expression of kallikrein-related peptidases Klk8, Klk1c2, and Klk1c12 and bradykinin receptors B1 and B2 (Bdkrb1 and Bdkrb2), whereas the LV expression of inducible nitric oxide synthase 2 (Nos2) increased. LV expression in major molecular determinants involved in calcium-dependent myocardial contraction remained unchanged, except for an increased LV expression of calcium/calmodulin-dependent protein kinase II delta (Cacna1c) in response to OM. A single intravenous infusion of OM, in adult healthy rats, resulted in significant changes in the LV expression of genes regulating apoptosis, oxidative stress, metabolism, and cardiac contractility.


Assuntos
Cálcio , Miosinas , Ratos , Masculino , Animais , Cálcio/metabolismo , Proteína X Associada a bcl-2/metabolismo , Ratos Wistar , Miosinas/metabolismo , Expressão Gênica , Canais de Cálcio Tipo L , Serina Endopeptidases/metabolismo
5.
J Pediatr Hematol Oncol ; 45(1): e109-e118, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36598965

RESUMO

Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in the TMPRSS6 gene, which impair iron homeostasis. We reported a 4-year-old girl who presented with a 1-year history of iron deficiency anemia. Her hemoglobin level increased from 6.5 g/dL to 12.6 g/dL with a prolonged duration of therapeutic dose oral iron therapy (5 mg/kg/d), and the level remained quite stable during the therapy. Genetic analysis of the TMPRSS6 gene revealed compound heterozygotes of 2 novel pathogenic variants: c.811C> T (NM_153609.3) in exon 7 (NP_705837: p.R271Ter) and c.1254C> G in exon 11 (p.Y418Ter). The results highlight the significance of genetic investigation and long-term iron therapy in iron-refractory iron deficiency anemia patients.


Assuntos
Anemia Ferropriva , Pré-Escolar , Feminino , Humanos , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/genética , Ferro , Proteínas de Membrana/genética , Mutação , Serina Endopeptidases/genética
6.
J Agric Food Chem ; 71(1): 603-614, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36577515

RESUMO

Collagen oligopeptides have wide applications in foods, pharmaceuticals, cosmetics, and others due to their high bioactivities and bioavailability. The S8 family is the second-largest family of serine proteases. Several collagenolytic proteases from this family have been reported to have good potential in the preparation of collagen oligopeptides, however, the underlying mechanism remains unknown. A4095 was the most abundant S8 protease secreted by the protease-producing bacterium Anoxybacillus caldiproteolyticus 1A02591. Here, we characterized A4095 as an S8 collagenolytic protease and illustrated its structural basis to produce collagen oligopeptides. Protease A4095 preferentially hydrolyzed the Y-Gly peptide bonds in denatured bovine bone collagen, leading to high production (62.48% <1000 Da) of collagen oligopeptides. Structural and mutational analyses indicated that A4095 has a unique S1' substrate-binding pocket to preferentially bind Gly, which is the structural determinant for the high production of collagen oligopeptides. This study provides mechanistic insight into the advantage of the S8 collagenolytic proteases in preparing collagen oligopeptides.


Assuntos
Colágeno , Peptídeo Hidrolases , Animais , Bovinos , Colágeno/química , Oligopeptídeos/metabolismo , Serina Endopeptidases/genética , Bactérias/metabolismo
7.
Otol Neurotol ; 44(1): 21-25, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36509434

RESUMO

OBJECTIVE: Investigate hearing preservation and spatial hearing outcomes in children with TMPRSS3 mutations who received bilateral cochlear implantation. STUDY DESIGN AND METHODS: Longitudinal case series report. Two siblings (ages, 7 and 4 yr) with TMPRSS3 mutations with down-sloping audiograms received sequential bilateral cochlear implantation with hearing preservation with low-frequency acoustic amplification and high-frequency electrical stimulation. Spatial hearing, including speech perception and localization, was assessed at three time points: preoperative, postoperative of first and second cochlear implant (CI). RESULTS: Both children showed low-frequency hearing preservation in unaided, acoustic-only audiograms. Both children demonstrated improvements in speech perception in both quiet and noise after CI activations. The emergence of spatial hearing was observed. Each child's overall speech perception and spatial hearing when listening with bilateral CIs were within the range or better than published group data from children with bilateral CIs of other etiology. CONCLUSION: Bilateral cochlear implantation with hearing preservation is a viable option for managing hearing loss for pediatric patients with TMPRSS3 mutations.


Assuntos
Implante Coclear , Implantes Cocleares , Surdez , Percepção da Fala , Humanos , Criança , Percepção da Fala/fisiologia , Audição/genética , Surdez/reabilitação , Proteínas de Membrana , Proteínas de Neoplasias , Serina Endopeptidases/genética
8.
Proc Natl Acad Sci U S A ; 120(1): e2209815120, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36574660

RESUMO

The cellular prion protein (PrPC) converts to alternatively folded pathogenic conformations (PrPSc) in prion infections and binds neurotoxic oligomers formed by amyloid-ß α-synuclein, and tau. ß-Endoproteolysis, which splits PrPC into N- and C-terminal fragments (N2 and C2, respectively), is of interest because a protease-resistant, C2-sized fragment (C2Sc) accumulates in the brain during prion infections, seemingly comprising the majority of PrPSc at disease endpoint in mice. However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in vivo. Here, a cell-based screen of protease inhibitors unexpectedly linked type II membrane proteins of the S9B serine peptidase subfamily to PrPC ß-cleavage. Overexpression experiments in cells and assays with recombinant proteins confirmed that fibroblast activation protein (FAP) and its paralog, dipeptidyl peptidase-4 (DPP4), cleave directly at multiple sites within PrPC's N-terminal domain. For wild-type mouse and human PrPC substrates expressed in cells, the rank orders of activity were human FAP ~ mouse FAP > mouse DPP4 > human DPP4 and human FAP > mouse FAP > mouse DPP4 >> human DPP4, respectively. C2 levels relative to total PrPC were reduced in several tissues from FAP-null mice, and, while knockout of DPP4 lacked an analogous effect, the combined DPP4/FAP inhibitor linagliptin, but not the FAP-specific inhibitor SP-13786, reduced C2Sc and total PrPSc levels in two murine cell-based models of prion infections. Thus, the net activity of the S9B peptidases FAP and DPP4 and their cognate inhibitors/modulators affect the physiology and pathogenic potential of PrPC.


Assuntos
Proteínas PrPC , Doenças Priônicas , Príons , Camundongos , Animais , Humanos , Proteínas Priônicas/genética , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Príons/química , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Peptídeo Hidrolases , Fibroblastos/metabolismo , Doenças Priônicas/metabolismo , Proteínas PrPC/química
9.
Insect Biochem Mol Biol ; 152: 103895, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538995

RESUMO

Endoparasitoid wasps inject venom proteins into the hemocoel of host insects to ensure survival, growth, and development of their progenies by blocking host immunity. We previously identified ten serine protease inhibitors of the serpin superfamily in venom of the endoparasitoid wasp, Microplitis mediator, but it is unclear how these inhibitors may interact with host immune serine proteases. In this study, we investigated the functions of two serpins, MmvSPN-1 and MmvSPN-2, in the regulation of humoral immune responses in two hosts, the oriental armyworm Pseudaletia separate and the cotton bollworm Helicoverpa armigera, by dsRNA knockdown and biochemical assays using recombinant proteins. Knockdown of the two serpins resulted in increases in prophenoloxidase (PPO) activation and antimicrobial peptide (AMP) production in the hosts. After injection into the host hemocoel, the recombinant serpins inhibited PPO activation and AMP transcription. Mass spectrometry analysis of the pull-downs and in vitro reconstitution experiments revealed that HacSP29, a clip-domain serine protease in H. armigera, is the target of these two serpins. Therefore, these two inhibitors in the wasp venom may protect eggs from attacks by melanization and AMPs in the host insects.


Assuntos
Mariposas , Serpinas , Vespas , Animais , Vespas/metabolismo , Serpinas/genética , Serpinas/metabolismo , Serina Endopeptidases , Mariposas/genética , Mariposas/metabolismo , Venenos de Vespas/metabolismo , Serina Proteases/genética , Serina Proteases/metabolismo , Peptídeos Antimicrobianos , Proteínas de Insetos/metabolismo
10.
Biochem Biophys Res Commun ; 641: 102-109, 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36525924

RESUMO

The premature death and degeneration of striatal neurons are typical hallmarks of HtrA2-inactivated motor neuron degeneration 2 (mnd2) mice. Although HtrA2 has been extensively studied in relation to the regulation of apoptosis using mnd2 mice, little is known about the other physiological functions of HtrA2. In this study, we found that the skin color of wild-type (WT) and mnd2 mice was black and pink on postnatal day 32. Using histological and molecular assays (i.e., assessing the activation of MAPK and expression patterns of PCNA), we demonstrated that this differential skin color change is consistent with the delay in the telogen - to - anagen phase of the hair cycle in mnd2 mice. We also examined adipocytes in the subcutaneous skin layer, finding that HtrA2 inactivation leads to the growth retardation of adipocytes, thereby delaying the hair cycle of mnd2 mice. Collectively, these findings show for the first time that HtrA2 plays an essential role in regulating the adipogenesis-associated hair cycle.


Assuntos
Proteínas Mitocondriais , Serina Endopeptidases , Animais , Camundongos , Apoptose , Cabelo/metabolismo , Serina Peptidase 2 de Requerimento de Alta Temperatura A/genética , Proteínas Mitocondriais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
11.
Mol Metab ; 67: 101662, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36566984

RESUMO

OBJECTIVE: The liver-derived circulating PCSK9 enhances the degradation of the LDL receptor (LDLR) in endosomes/lysosomes. PCSK9 inhibition or silencing is presently used in clinics worldwide to reduce LDL-cholesterol, resulting in lower incidence of cardiovascular disease and possibly cancer/metastasis. The mechanism by which the PCSK9-LDLR complex is sorted to degradation compartments is not fully understood. We previously suggested that out of the three M1, M2 and M3 subdomains of the C-terminal Cys/His-rich-domain (CHRD) of PCSK9, only M2 is critical for the activity of extracellular of PCSK9 on cell surface LDLR. This likely implicates the binding of M2 to an unknown membrane-associated "protein X" that would escort the complex to endosomes/lysosomes for degradation. We reported that a nanobody P1.40 binds the M1 and M3 domains of the CHRD and inhibits the function of PCSK9. It was also reported that the cytosolic adenylyl cyclase-associated protein 1 (CAP1) could bind M1 and M3 subdomains and enhance the activity of PCSK9. In this study, we determined the 3-dimensional structure of the CHRD-P1.40 complex to understand the intricate interplay between P1.40, CAP1 and PCSK9 and how they regulate LDLR degradation. METHODS: X-ray diffraction of the CHRD-P1.40 complex was analyzed with a 2.2 Å resolution. The affinity and interaction of PCSK9 or CHRD with P1.40 or CAP1 was analyzed by atomic modeling, site-directed mutagenesis, bio-layer interferometry, expression in hepatic cell lines and immunocytochemistry to monitor LDLR degradation. The CHRD-P1.40 interaction was further analyzed by deep mutational scanning and binding assays to validate the role of predicted critical residues. Conformational changes and atomic models were obtained by small angle X-ray scattering (SAXS). RESULTS: We demonstrate that PCSK9 exists in a closed or open conformation and that P1.40 favors the latter by binding key residues in the M1 and M3 subdomains of the CHRD. Our data show that CAP1 is well secreted by hepatic cells and binds extracellular PCSK9 at distinct residues in the M1 and M3 modules and in the acidic prodomain. CAP1 stabilizes the closed conformation of PCSK9 and prevents P1.40 binding. However, CAP1 siRNA only partially inhibited PCSK9 activity on the LDLR. By modeling the previously reported interaction between M2 and an R-X-E motif in HLA-C, we identified Glu567 and Arg549 as critical M2 residues binding HLA-C. Amazingly, these two residues are also required for the PCSK9-induced LDLR degradation. CONCLUSIONS: The present study reveals that CAP1 enhances the function of PCSK9, likely by twisting the protein into a closed configuration that exposes the M2 subdomain needed for targeting the PCSK9-LDLR complex to degradation compartments. We hypothesize that "protein X", which is expected to guide the LDLR-PCSK9-CAP1 complex to these compartments after endocytosis into clathrin-coated vesicles, is HLA-C or a similar MHC-I family member. This conclusion is supported by the PCSK9 natural loss-of-function Q554E and gain-of-function H553R M2 variants, whose consequences are anticipated by our modeling.


Assuntos
Antígenos HLA-C , Pró-Proteína Convertase 9 , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Serina Endopeptidases/metabolismo , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/metabolismo , Espalhamento a Baixo Ângulo , Difração de Raios X , Receptores de LDL/metabolismo
12.
Biomed Res Int ; 2022: 7841969, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457338

RESUMO

The protease produced by the transmembrane serine protease 2 (TMPRSS2) gene enhances viral infections and has been linked to severe acute respiratory syndrome coronavirus 2 pathogenesis. Therefore, this study evaluated the association between TMPRSS2 and coronavirus disease 2019 (COVID-19) mortality. TMPRSS2 rs12329760 polymorphism was genotyped using the tetraprimer amplification refractory mutation system-polymerase chain reaction method in 592 dead and 693 improved patients. In the current study, the frequency of TMPRSS2 rs12329760 CC than TT genotypes was significantly lower in improved patients than in dead patients. According to the findings of the multivariate logistic regression test, higher levels of mean age, creatinine, erythrocyte sedimentation rate, C-reactive protein, aspartate aminotransferase, lower levels of 25-hydroxyvitamin D, uric acid, and real-time PCR Ct values and TMPRSS2 rs12329760 CC genotype were observed to be associated with increased COVID-19 mortality rates. In conclusion, the TMPRSS2 rs12329760 CC genotype was a polymorphism linked to a significantly higher incidence of severe COVID-19. Further studies are required to corroborate the obtained findings.


Assuntos
COVID-19 , Serina Endopeptidases , Humanos , Sedimentação Sanguínea , COVID-19/genética , COVID-19/mortalidade , Genótipo , Polimorfismo Genético , SARS-CoV-2 , Serina Endopeptidases/genética , Fatores de Risco
13.
Science ; 378(6623): 996-1000, 2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36454823

RESUMO

Cells need to detect and degrade faulty membrane proteins to maintain homeostasis. In this study, we identify a previously unknown function of the human signal peptidase complex (SPC)-the enzyme that removes endoplasmic reticulum (ER) signal peptides-as a membrane protein quality control factor. We show that the SPC cleaves membrane proteins that fail to correctly fold or assemble into their native complexes at otherwise hidden cleavage sites, which our study reveals to be abundant in the human membrane proteome. This posttranslocational cleavage synergizes with ER-associated degradation to sustain membrane protein homeostasis and contributes to cellular fitness. Cryptic SPC cleavage sites thus serve as predetermined breaking points that, when exposed, help to target misfolded or surplus proteins for degradation, thereby maintaining a healthy membrane proteome.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Proteínas de Membrana , Serina Endopeptidases , Humanos , Proteínas de Membrana/metabolismo , Proteoma , Proteólise
15.
Curr Hypertens Rev ; 18(2): 130-137, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36508271

RESUMO

BACKGROUND: This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19. METHODS AND RESULTS: Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa. CONCLUSION: Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.


Assuntos
COVID-19 , Hipertensão , Humanos , SARS-CoV-2/metabolismo , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fatores de Risco , Hipertensão/diagnóstico , Sistema Renina-Angiotensina , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
16.
Clin Epigenetics ; 14(1): 191, 2022 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-36581876

RESUMO

BACKGROUND: Stroke is the leading cause of mortality in China. DNA methylation has essential roles in multiple diseases, but its association with stroke was barely studied. We hereby explored the association between blood-based HTRA serine protease 1 (HTRA1) methylation and the risk of stroke. RESULTS: The association was discovered in a hospital-based case-control study (cases/controls = 190:190) and further validated in a prospective nested case-control study including 139 cases who developed stroke within 2 years after recruitment and 144 matched stroke-free controls. We observed stroke-related altered HTRA1 methylation and expression in both case-control study and prospective study. This blood-based HTRA1 methylation was associated with stroke independently from the known risk factors and mostly affected the older population. The prospective results further showed that the altered HTRA1 methylation was detectable 2 years before the clinical determination of stroke and became more robust with increased discriminatory power for stroke along with time when combined with other known stroke-related variables [onset time ≤ 1 year: area under the curve (AUC) = 0.76]. CONCLUSIONS: In our study, altered HTRA1 methylation was associated with stroke at clinical and preclinical stages and thus may provide a potential biomarker in the blood for the risk evaluation and preclinical detection of stroke.


Assuntos
Metilação de DNA , Serina Endopeptidases , Humanos , Estudos Prospectivos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Estudos de Casos e Controles , Biomarcadores/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo
17.
Int J Mol Sci ; 23(23)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36499094

RESUMO

The current global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of COVID-19 has infected hundreds of millions of people, killed millions, and continues to pose a threat. It has become one of the largest epidemics in human history, causing enormous damage to people's lives and economies in the whole world. However, there are still many uncertainties and continued attention to the impact of SARS-CoV-2 on human health. The entry of SARS-CoV-2 into host cells is facilitated by the binding of the spike protein on the virus surface to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). Furthermore, transmembrane protease serine 2 (TMPRSS2) is a host surface protease that cleaves and proteolytically activates its S protein, which is necessary for viral infection. Thus, SARS-CoV-2 uses the ACE2 receptor for cell entry and initiates the S protein using the protease TMPRSS2. Schizophyllum commune (SC) is one of the most widely distributed fungi, often found on the rotten wood of trees that has been found to have various health benefits, including anticancer, antimicrobial activity, antiparasitic, and immunomodulatory function. In this article, SC significantly diminished the expression ACE2 and TMPRSS2 protein in vitro and in vivo without cell damage. In addition, adenosine from SC was also proven in this experiment to reduce the ACE2 and TMPRSS2 expression. Thus, our findings suggest that SC and adenosine exhibit potential for the repression of SARS-CoV-2 infection via the ACE2 and TMPRSS2 axis.


Assuntos
Enzima de Conversão de Angiotensina 2 , Produtos Biológicos , COVID-19 , Schizophyllum , Serina Endopeptidases , Humanos , Adenosina , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2/metabolismo , Schizophyllum/química , Serina Endopeptidases/genética , Produtos Biológicos/farmacologia
18.
Molecules ; 27(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36364238

RESUMO

As a cellular protease, transmembrane serine protease 2 (TMPRSS2) plays roles in various physiological and pathological processes, including cancer and viral entry, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we conducted expression, mutation, and prognostic analyses for the TMPRSS2 gene in pan-cancers as well as in COVID-19-infected lung tissues. The results indicate that TMPRSS2 expression was highest in prostate cancer. A high expression of TMPRSS2 was significantly associated with a short overall survival in breast invasive carcinoma (BRCA), sarcoma (SARC), and uveal melanoma (UVM), while a low expression of TMPRSS2 was significantly associated with a short overall survival in lung adenocarcinoma (LUAD), demonstrating TMPRSS2 roles in cancer patient susceptibility and severity. Additionally, TMPRSS2 expression in COVID-19-infected lung tissues was significantly reduced compared to healthy lung tissues, indicating that a low TMPRSS2 expression may result in COVID-19 severity and death. Importantly, TMPRSS2 mutation frequency was significantly higher in prostate adenocarcinoma (PRAD), and the mutant TMPRSS2 pan-cancer group was significantly associated with long overall, progression-free, disease-specific, and disease-free survival rates compared to the wild-type (WT) TMPRSS2 pan-cancer group, demonstrating loss of functional roles due to mutation. Cancer cell lines were treated with small molecules, including cordycepin (CD), adenosine (AD), thymoquinone (TQ), and TQFL12, to mediate TMPRSS2 expression. Notably, CD, AD, TQ, and TQFL12 inhibited TMPRSS2 expression in cancer cell lines, including the PC3 prostate cancer cell line, implying a therapeutic role for preventing COVID-19 in cancer patients. Together, these findings are the first to demonstrate that small molecules, such as CD, AD, TQ, and TQFL12, inhibit TMPRSS2 expression, providing novel therapeutic strategies for preventing COVID-19 and cancers.


Assuntos
COVID-19 , Neoplasias Pulmonares , Neoplasias da Próstata , Masculino , Humanos , SARS-CoV-2 , COVID-19/genética , Prognóstico , Adenosina , Mutação , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Serina Endopeptidases/genética
19.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430180

RESUMO

Factor-VII-activating protease (FSAP) is involved in the regulation of hemostasis and inflammation. Extracellular histones play a role in inflammation and the conversion of latent pro-FSAP into active FSAP. FSAP has been shown to regulate endothelial permeability, but the mechanisms are not clear. Here, we have investigated the effects of FSAP on endothelial permeability in vitro. A mixture of histones from calf thymus stimulated permeability, and the wild-type (WT) serine protease domain (SPD) of FSAP blocked this effect. WT-SPD-FSAP did not influence permeability on its own, nor that stimulated by thrombin or vascular endothelial growth factor (VEGF)-A165. Histones induced a large-scale rearrangement of the junction proteins VE-cadherin and zona occludens-1 from a clear junctional distribution to a diffuse pattern. The presence of WT-SPD-FSAP inhibited these changes. Permeability changes by histones were blocked by both TLR-2 and TLR4 blocking antibodies. Histones upregulated the expression of TLR-2, but not TLR-4, in HUVEC cells, and WT-SPD-FSAP abolished the upregulation of TLR-2 expression. An inactive variant, Marburg I (MI)-SPD-FSAP, did not have any of these effects. The inhibition of histone-mediated permeability may be an important function of FSAP with relevance to sepsis, trauma, and stroke and the need to be investigated further in in vivo experiments.


Assuntos
Histonas , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 Toll-Like/metabolismo , Serina Endopeptidases/metabolismo , Permeabilidade , Inflamação
20.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430216

RESUMO

Colitis-associated colon cancer (CAC) accompanies the massive infiltration of neutrophils during tumorigenesis and progression of CAC. Depletion of neutrophils in circulation results in significant inhibition of tumor incidence in CAC. However, the underlying mechanisms are largely unclear. In this study, we provide evidence for the crucial involvement of inflammatory neutrophil-activated serine proteases (NSPs) on the dysregulation of the anti-inflammatory and antitumor IGFBP-3/IGFBP-3R signaling axis in CAC using a chronic AOM/DSS mouse model. We also provide preclinical evidence for α1-antitrypsin (AAT) as a preventive and as a therapeutic for CAC. AAT administration not only prevented colitis-associated tumorigenesis but also inhibited established CAC. AOM/DSS treatment results in the significant activation of NSPs, leading to CAC through increased pro-inflammatory cytokines and decreased anti-inflammatory and antitumor IGFBP-3. Collectively, these data suggest that the NSPs proteolyze IGFBP-3, whereas AAT inhibits chronic colonic inflammation-induced NSP activity and subsequently suppresses IGFBP-3 proteolysis. Therefore, the anti-inflammatory and antitumor functions of the IGFBP-3/IGFBP-3R axis are restored. AAT mimicking small peptides also showed their inhibitory effects on NSP-induced IGFBP-3 proteolysis. These results suggest that targeting the NSP-IGFBP-3/IGFBP-3R axis using NSP inhibitors such as AAT and the AAT mimics and IGFBP-3R agonists could lead to novel approaches for the prevention and treatment of CAC.


Assuntos
Neoplasias Associadas a Colite , Deficiência de alfa 1-Antitripsina , Camundongos , Animais , Neutrófilos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Serina Proteases , Proteólise , Sulfato de Dextrana , Carcinogênese , Transformação Celular Neoplásica , Inflamação/tratamento farmacológico , Serina Endopeptidases
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