Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 235
Filtrar
1.
J Gene Med ; 26(3): e3667, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38442944

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of esophageal cancer with relatively high mortality worldwide. Serine peptidase inhibitor Kazal-type 5 (SPINK5) is reported to be downregulated in ESCC. However, its explicit role in ESCC remains further investigation. METHODS: The tumor tissues and adjacent non-cancerous tissues were obtained from 196 patients with ESCC for the determination of SPINK5 mRNA levels. Additionally, the relationship between SPINK5 mRNA levels and clinicopathological features of ESCC patients was explored. The effects of SPINK5 on the invasion and migration of ESCC cells were assessed using Transwell assays. Furthermore, SPINK5 mRNA and LEKTI protein were measured in ESCC cell lines after treatment with poly (I:C), lipopolysaccharide (LPS) or unmethylated CpG DNA. Moreover, the correlation between expression of SPINK5 and nuclear factor-kappa B (NF-κB) signaling pathway-related genes was analyzed in the TCGA-ESCC cohort, and the effects of SPINK5 on NF-κB transcription was analyzed using a luciferase reporter gene assay. Finally, the correlations between SPINK5 and infiltration of immune cells, immune scores, stromal scores and ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) scores were explored. RESULTS: SPINK5 mRNA levels were downregulated in tumor tissues, which was significantly correlated with higher lymph node metastases. Overexpressed SPINK5 inhibited cell invasion and migration in ESCC cell lines. Mechanistically, LPS-induced activation of Toll-like receptor 4 (TLR4) decreased SPINK5 mRNA and LEKTI in KYSE150 and KYSE70 cells. Spearman correlation analysis revealed that SPINK5 mRNA was significantly negatively correlated with a total of seven NF-κB signaling pathway-related genes in TCGA-ESCC patients. Moreover, downregulation of SPINK5 increased and upregulation of SPINK5 decreased the activity of the NF-κB promoter in HEK293T cells. Finally, immune cells infiltration analysis revealed that SPINK5 was significantly correlated with the infiltration of various immune cells, stromal scores, immune scores and ESTIMATE scores. CONCLUSIONS: SPINK5 plays critical roles in the TLR4/NF-κB pathway and immune cells infiltration, which might contribute to the ESCC metastasis. The findings of the present study may provide a promising biomarker for the diagnosis and treatment of esophageal squamous cell carcinoma.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Inibidor de Serinopeptidase do Tipo Kazal 5 , Humanos , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Células HEK293 , Lipopolissacarídeos , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Receptor 4 Toll-Like/metabolismo
2.
Commun Biol ; 7(1): 152, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316920

RESUMO

Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and the lack of efficacious treatments call for a better understanding of NS mechanisms. Here we describe a novel and viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. By combining transcriptomics and proteomics, we determine a disease molecular profile common to mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. Systemic inflammation in Spink5 cKO mice correlates with disease severity and is associated with thymic atrophy and enlargement of lymph nodes and spleen. This systemic inflammation phenotype is marked by neutrophils and IL-17/IL-22 signaling, does not involve primary T cell immunodeficiency and is independent of bacterial infection. By comparing skin transcriptomes and proteomes, we uncover several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. Our study thus provides a conserved molecular framework for NS and reveals a KLK/IL-36 signaling axis, adding new insights into the disease mechanisms and therapeutic targets.


Assuntos
Síndrome de Netherton , Inibidor de Serinopeptidase do Tipo Kazal 5 , Animais , Humanos , Camundongos , Inflamação , Interleucina-17/genética , Camundongos Knockout , Síndrome de Netherton/genética , Síndrome de Netherton/metabolismo , Síndrome de Netherton/patologia , Peptídeo Hidrolases , Inibidor de Serinopeptidase do Tipo Kazal 5/genética
3.
Mol Biotechnol ; 66(2): 208-221, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37071303

RESUMO

Serine protease inhibitor Kazal-type 5 (SPINK5) has been revealed as a significant prognostic biomarker in oral squamous cell carcinoma (OSCC). However, there is little information regarding the detailed epigenetics mechanism underlying its dysregulation in OSCC. Using the Gene Expression Omnibus database, we identified SPINK5 as a significantly downregulated gene in OSCC tissues. Moreover, SPINK5 inhibited the malignant aggressiveness of HSC3 and squamous cell carcinomas (SCC)9 cells, whereas depletion of SPINK5 using shRNAs led to the opposite trend. The euchromatic histone lysine methyltransferase 2 (EHMT2) was found to bind to the SPINK5 promoter, and EHMT2 repressed the SPINK5 expression. SPINK5 reversed the stimulating effects of EHMT2 on the aggressiveness of HSC3 and SCC9 cells by impairing the Wnt/ß-catenin pathway. Wnt/ß-catenin inhibitor IWR-1 treatment reverted the malignant phenotype of OSCC cells in the presence of short hairpin RNA (sh)-SPINK5. Silencing of EHMT2 inhibited tumor growth and blocked the Wnt/ß-catenin signaling in OSCC, which was reversed by SPINK5 knockdown. Our study shows that SPINK5, mediated by the loss of EHMT2, can inhibit the development of OSCC by inhibiting Wnt/ß-catenin signaling and may serve as a treatment target for OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/genética , beta Catenina/genética , beta Catenina/metabolismo , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Linhagem Celular Tumoral , Genes Supressores de Tumor , RNA Interferente Pequeno/genética , Proliferação de Células/genética , Neoplasias de Cabeça e Pescoço/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo
4.
Genes (Basel) ; 14(5)2023 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-37239440

RESUMO

Netherton syndrome (NS) is a rare autosomal recessive disorder caused by SPINK5 mutations, resulting in a deficiency in its processed protein LEKTI. It is clinically characterized by the triad of congenital ichthyosis, atopic diathesis, and hair shaft abnormalities. The SPINK5 (NM_006846.4): c.1258A>G polymorphism (rs2303067) shows a significant association with atopy and atopic dermatitis (AD), which share several clinical features with NS. We describe an NS patient, initially misdiagnosed with severe AD, who carried the heterozygous frameshift (null) mutation (NM_006846.4): c.957_960dup combined with homozygous rs2303067 in the SPINK5 gene. Histopathological examination confirmed the diagnosis, whereas an immunohistochemical study showed normal epidermal expression of LEKTI, despite the genetic findings. Our results corroborate the hypothesis that haploinsufficiency of SPINK5, in the presence of a SPINK5 null heterozygous mutation in combination with homozygous SPINK5 rs2303067 polymorphism, can be causative of an NS phenotype, impairing the function of LEKTI despite its normal expression. Due to the clinical overlap between NS and AD, we suggest performing SPINK5 genetic testing to search for the SPINK5 (NM_006846.4): c.1258A>G polymorphism (rs2303067) and ensure a correct diagnosis, mainly in doubtful cases.


Assuntos
Dermatite Atópica , Eritrodermia Ictiosiforme Congênita , Síndrome de Netherton , Humanos , Mutação da Fase de Leitura , Síndrome de Netherton/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Mutação , Eritrodermia Ictiosiforme Congênita/genética , Dermatite Atópica/genética
5.
Pediatr Allergy Immunol ; 34(4): e13937, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37102386

RESUMO

OBJECTIVE: Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss-of-function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). MATERIAL, METHODS AND RESULTS: Here, we describe NS clinical and genetic features of homogenous patient group: 9 individuals from 7 families with similar ethnic background and who have the same SPINK5 variant (NM_006846.4: c.1048C > T, p.(Arg350*)) in homozygous or compound heterozygous states, suggesting that it is a common founder variant in Latvian population. Indeed, we were able to show that the variant is common in general Latvian population, and it shares the same haplotype among the NS individual. It is estimated that the variant arose >1000 years ago. Clinically, all nine patients exhibited typical NS skin changes (scaly erythroderma, ichthyosis linearis circumflexa, itchy skin), except for one patient who has a different skin manifestation-epidermodysplasia. Additionally, we show that developmental delay, previously underrecognized in NS, is a common feature among these patients. CONCLUSIONS: This study shows that the phenotype of NS individuals with the same genotype is highly homogeneous.


Assuntos
Síndrome de Netherton , Humanos , Síndrome de Netherton/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Letônia , Mutação , Pele
7.
J Dermatol ; 50(4): 494-499, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36419401

RESUMO

Netherton syndrome (NS) is a rare disorder of cornification associated with high morbidity. It is caused by bi-allelic mutations in SPINK5 encoding the serine protease inhibitor LEKTI. Previous studies have shown Th17 skewing with IL-23 upregulation in NS, raising the possibility that targeting these inflammatory pathways may alleviate disease manifestations. We ascertained the therapeutic efficacy of six doses of ustekinumab administered to three patients with NS over a period of 13 months using the Ichthyosis Area and Severity Index (IASI), the Dermatology Life Quality Index (DLQI), a visual analogue scale (VAS) for itch and the peak-pruritus numeric rating scale (PP-NRS). Histopathology analysis including CD3, CD4, CD8 and interleukin 17 (IL-17) immunostaining, was performed at baseline and 4 weeks following the last ustekinumab dose. Total IASI scores were reduced by 28% in two patients at week 16 with sustained response by week 56. No consistent improvement in DLQI, VAS for itch and PP-NRS scores was observed. The inflammatory infiltrate and the degree of acanthosis were slightly reduced at week 56 as compared to baseline. No significant change in immunostaining of the various inflammatory markers was observed at week 56. In conclusion, this case series did not demonstrate a significant therapeutic effect of ustekinumab in NS.


Assuntos
Ictiose , Síndrome de Netherton , Humanos , Síndrome de Netherton/tratamento farmacológico , Síndrome de Netherton/genética , Ustekinumab/uso terapêutico , Ictiose/genética , Mutação , Inibidor de Serinopeptidase do Tipo Kazal 5/genética
8.
Exp Dermatol ; 32(2): 177-185, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36321871

RESUMO

Skin surface pH has been identified as a key regulator of the epidermal homeostasis through its action on serine protease activity. These enzymes, like kallikreins (KLK), are responsible for the degradation of corneodesmosomes, the protein structures linking together corneocytes, and are regulated by Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI). KLK activity increases at pH levels higher than physiological. An increase in skin surface pH has been observed in patients suffering from skin diseases characterized by impaired barrier function, like atopic dermatitis. In this work, we introduce an agent-based model of the epidermis to study the impact of a change in skin surface pH on the structural and physiological properties of the epidermis, through the LEKTI-KLK mechanism. We demonstrate that a less acidic pH, compared to the slightly acidic pH observed in healthy skin, is sufficient to significantly affect the water loss at the surface and the amount of irritant permeating through the epidermis. This weakening of the skin barrier function eventually results in a more intense skin inflammation following exposure to an external irritant. This work provides additional evidence that skin surface pH and serine proteases can be therapeutic targets to improve skin barrier integrity.


Assuntos
Epiderme , Irritantes , Humanos , Epiderme/metabolismo , Calicreínas/metabolismo , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Inflamação/metabolismo , Concentração de Íons de Hidrogênio , Homeostase , Simulação por Computador
9.
Sci Transl Med ; 14(675): eabp9159, 2022 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-36516271

RESUMO

The epidermis is a barrier that prevents water loss while keeping harmful substances from penetrating the host. The impermeable cornified layer of the stratum corneum is maintained by balancing continuous turnover driven by epidermal basal cell proliferation, suprabasal cell differentiation, and corneal shedding. The epidermal desquamation process is tightly regulated by balance of the activities of serine proteases of the Kallikrein-related peptidases (KLK) family and their cognate inhibitor lymphoepithelial Kazal type-related inhibitor (LEKTI), which is encoded by the serine peptidase inhibitor Kazal type 5 gene. Imbalance of proteolytic activity caused by a deficiency of LEKTI leads to excessive desquamation due to increased activities of KLK5, KLK7, and KLK14 and results in Netherton syndrome (NS), a debilitating condition with an unmet clinical need. Increased activity of KLKs may also be pathological in other dermatoses such as atopic dermatitis (AD). Here, we describe the discovery of inhibitory antibodies against murine KLK5 and KLK7 that could compensate for the deficiency of LEKTI in NS. These antibodies are protective in mouse models of NS and AD and, when combined, promote improved skin barrier integrity and reduced inflammation. To translate these findings, we engineered a humanized bispecific antibody capable of potent inhibition of human KLK5 and KLK7. A crystal structure of KLK5 bound to the inhibitory Fab revealed that the antibody binds distal to its active site and uses a relatively unappreciated allosteric inhibition mechanism. Treatment with the bispecific anti-KLK5/7 antibody represents a promising therapy for clinical development in NS and other inflammatory dermatoses.


Assuntos
Dermatite Atópica , Síndrome de Netherton , Dermatopatias , Camundongos , Humanos , Animais , Síndrome de Netherton/genética , Síndrome de Netherton/metabolismo , Síndrome de Netherton/patologia , Dermatite Atópica/patologia , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Epiderme/patologia , Dermatopatias/metabolismo , Anticorpos/metabolismo , Calicreínas/metabolismo
11.
Eur J Dermatol ; 32(4): 459-463, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36301754

RESUMO

Background: Netherton syndrome is a rare but severe autosomal recessive disorder with dominant impaired skin barrier function, caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene, which encodes LEKTI (lymphoepithelial Kazal-type-related inhibitor). Objectives: To establish a murine model of Netherton syndrome based on CRISPR/Cas9 gene editing technology. Materials & Methods: Spink5-sgRNA was designed to target exon 3 of the mouse Spink5 gene. Cas9 mRNA and sgRNA were microinjected into the zygotes of C57BL/6J mice. Spink5 homozygous knockout mice were born from a heterozygous intercross, and the phenotype of these mice was compared with wild-type regarding gross morphology, histopathology and immunofluorescent detection of LEKTI. Results: Following microinjection of zygotes using the CRISPR/Cas9 system, sequencing demonstrated a 22-bp deletion at exon 3 of the mouse Spink5 gene. Histological investigation revealed complete detachment of the stratum corneum from the underlying granular layer and an absence of LEKTI in skin from Spink5 homozygous knockout mice. Conclusion: The 22-bp deleted Spink5 transgenic mouse model demonstrates the clinical phenotype and genotype of human Netherton syndrome, representing a useful tool for future gene correction and skin barrier/inflammation studies.


Assuntos
Dermatite , Síndrome de Netherton , Animais , Humanos , Camundongos , Sistemas CRISPR-Cas , Dermatite/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Netherton/genética , Síndrome de Netherton/patologia , Proteínas Secretadas Inibidoras de Proteinases/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética
12.
Int J Mol Sci ; 23(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35955819

RESUMO

The skin acts as a mechanical barrier that protects the body from the exterior environment, and skin barrier function is attributed to the stratum corneum (SC), which is composed of keratinocytes and skin lipids. Skin barrier homeostasis is maintained by a delicate balance between the differentiation and exfoliation of keratinocytes, and keratinocyte desquamation is regulated by members of the serine protease kalikrein (KLK) family and their endogenous inhibitor SPINK5/LEKTI (serine protease inhibitor Kazal type 5/lympho-epithelial Kazal-type-related inhibitor). Furthermore, SPINK5/LEKTI deficiency is involved in impaired skin barrier function caused by KLK over-activation. We sought to determine whether increased SPINK5/LEKTI expression ameliorates atopic dermatitis (AD) by strengthening skin barrier function using the ethanol extract of Lobelia chinensis (LCE) and its active compound, diosmetin, by treating human keratinocytes with UVB and using a DNCB-induced murine model of atopic dermatitis. LCE or diosmetin dose-dependently increased the transcriptional activation of SPINK5 promoter and prevented DNCB-induced skin barrier damage by modulating events downstream of SPINK5, that is, KLK, PAR2 (protease activated receptor 2), and TSLP (thymic stromal lymphopoietin). LCE or diosmetin normalized immune response in DNCB treated SKH-1 hairless mice as determined by reductions in serum immunoglobulin E and interleukin-4 levels and numbers of lesion-infiltrating mast cells. Our results suggest that LCE and diosmetin are good candidates for the treatment of skin barrier-disrupting diseases such as Netherton syndrome or AD, and that they do so by regulating SPINK5/LEKTI.


Assuntos
Dermatite Atópica , Lobelia , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Dinitroclorobenzeno , Flavonoides , Humanos , Lobelia/metabolismo , Camundongos , Proteínas Secretadas Inibidoras de Proteinases/farmacologia
13.
J Dermatol Sci ; 107(1): 2-7, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35817663

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease; the three major factors responsible for AD, i.e., epidermal barrier dysfunction, allergic inflammation, and itching, interact with each other to form a pathological condition. Excessive protease activities are characteristic abnormalities that affect the epidermal barrier in patients with AD. In normal skin, epidermal serine protease activities are controlled by kallikrein-related peptidases (KLKs) and their inhibitors, including lympho-epithelial Kazal-type-related inhibitor (LEKTI). In AD lesions, KLKs are excessively expressed, which results in the enhancement of epidermal serine protease activities and facilitates the invasion by allergens and microorganisms. In addition, some KLKs can activate protease-activated receptor 2 (PAR2) in epidermal keratinocytes and peripheral nerves, resulting in the induction of inflammation and itching. Furthermore, in AD patients with single nucleotide polymorphism (SNP) such as E420K and D386N of SPINK5 which encodes LEKTI, LEKTI function is attenuated, resulting in the activation of KLKs and easy invasion by allergens and microorganisms. Further analysis is needed to elucidate the detailed mechanism underlying the control of serine protease activities, which may lead to the development of new therapeutic and prophylactic agents for AD.


Assuntos
Dermatite Atópica , Serina Endopeptidases , Alérgenos , Dermatite Atópica/enzimologia , Dermatite Atópica/metabolismo , Humanos , Inflamação , Calicreínas , Prurido , Serina Endopeptidases/metabolismo , Inibidor de Serinopeptidase do Tipo Kazal 5
15.
J Healthc Eng ; 2022: 2209979, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35368958

RESUMO

This study aimed to elucidate how SPINK5 affects the malignant phenotypes of NSCLC and the molecular mechanism. NSCLC and adjacent normal tissues were collected to detect the differential level of SPINK5. The influence of SPINK5 on pathological indicators of NSCLC was analyzed. Cellular functions of NSCLC cells overexpressing SPINK5 were assessed by CCK-8, EdU, and transwell assay. By confirming the downstream target of SPINK5, its molecular mechanism on regulating NSCLC was finally explored through rescue experiments. SPINK5 was lowly expressed in NSCLC tissues, and it predicted tumor staging and lymphatic metastasis. In vitro overexpression of SPINK5 declined proliferative and migratory rates in NSCLC cells. PSIP1 was verified as the target gene binding SPINK5, and they displayed a negative correlation in NSCLC tissues. Overexpression of PSIP1 was able to reverse the inhibited proliferative and migratory potentials in NSCLC cells overexpressing SPINK5. SPINK5 level has a close relation to tumor staging and lymphatic metastasis in NSCLC. It serves as a tumor-suppressor gene that inhibits proliferation and migration of NSCLC through negatively regulating PSIP1.


Assuntos
Carcinoma , Movimento Celular , Neoplasias Pulmonares , MicroRNAs , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma/genética , Carcinoma/patologia , Movimento Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Genes Supressores , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , MicroRNAs/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
S D Med ; 75(12): 554-556, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36893349

RESUMO

Netherton syndrome (NS) is a rare autosomal recessive condition caused by mutations in the serine peptidase inhibitor, Kazal type 5 (SPINK5) gene which encodes for a serine protease inhibitor, lymphoepithelial Kazal-typerelated inhibitor (LEKT1). NS is characterized by a triad of ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis with elevated IgE levels. The syndrome typically presents in infancy, where life-threatening complications are frequent, and evolves into a less severe condition with milder clinical symptoms in adulthood. This case report details the clinical history and genetic testing of a mother and two children with clinically symptomatic and genetically proven NS.


Assuntos
Eritrodermia Ictiosiforme Congênita , Síndrome de Netherton , Humanos , Criança , Feminino , Síndrome de Netherton/complicações , Síndrome de Netherton/diagnóstico , Síndrome de Netherton/genética , Mães , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Eritrodermia Ictiosiforme Congênita/genética , Mutação , Inibidores de Serino Proteinase/genética
17.
J Dermatol ; 49(1): 165-167, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34862657

RESUMO

Netherton syndrome (NS) is a rare autosomal recessive genetic disease caused by SPINK5 gene mutation without specific effective therapies available. We report a case of NS confirmed by whole exome sequencing of DNA using peripheral blood, and Sanger sequencing found two new mutations associated with her clinical presentation located at SPINK5 gene c.1220+5G>A from her father and c.1870delA from her mother. The patient was treated with dupilumab (600 mg at week 0, then 300 mg every 2 weeks, s.c.). The clinical manifestation and dermoscopic images of the patient's hair showed remarkable improvement after dupilumab treatment with no adverse effects. We also reviewed previous reports to learn more about the therapeutic effect and adverse reactions of NS treated with dupilumab.


Assuntos
Síndrome de Netherton , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Mutação , Síndrome de Netherton/diagnóstico , Síndrome de Netherton/tratamento farmacológico , Síndrome de Netherton/genética , Proteínas Secretadas Inibidoras de Proteinases/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética
18.
Exp Dermatol ; 31(2): 223-232, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34378233

RESUMO

Skin barrier dysfunction induces skin inflammation. Signal transducer and activator of transcription 3 (STAT3) is known to be involved in Th17-mediated immune responses and barrier integrity in the cornea and intestine; however, its role in the skin barrier remains largely unknown. In this study, we elucidated the potential role of STAT3 in the skin barrier and its effect on kallikrein-related peptidase 5 (KLK5) and serine protease inhibitor Kazal-type 5 (SPINK5) expression using a mouse model with keratinocyte-specific ablation of STAT3. Keratinocyte-specific loss of STAT3 induced a cutaneous inflammatory phenotype with pruritus and intense scratching behaviour in mice. Transcriptomic analysis revealed that the genes associated with impaired skin barrier function, including KLK5, were upregulated. The effect of STAT3 on KLK5 expression in keratinocytes was not only substantiated by the increase in KLK5 expression following treatment with STAT3 siRNA but also by its decreased expression following STAT3 overexpression. Overexpression and IL-17A-mediated stimulation of STAT3 increased the expression of SPINK5, which was blocked by STAT3 siRNA. These results suggest that the expression of SPINK5 and KLK5 in keratinocytes could be dependent on STAT3 and that STAT3 might play an essential role in the maintenance of skin barrier homeostasis.


Assuntos
Calicreínas , Fator de Transcrição STAT3 , Calicreínas/genética , Calicreínas/metabolismo , Queratinócitos/metabolismo , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/metabolismo , Inibidor de Serinopeptidase do Tipo Kazal 5/genética
19.
Anticancer Drugs ; 33(1): e327-e335, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34387602

RESUMO

Serine protease inhibitor Kazal-type 5 (SPINK5) has been indicated to act as a prognostic predictor for patients with head and neck squamous cell carcinoma. However, its specific role in nasopharyngeal carcinoma (NPC), a malignancy that has a high propensity for chemoresistance, remains largely obscure. We, thus, sought to investigate the importance of SPINK5 expression in regulating chemoresistance in NPC. Differentially expressed genes in NPC were screened using the cancer genome atlas-head and neck squamous cell carcinoma database and microarray analysis. SPINK5 was downregulated in NPC tissues and cells. After SPINK5 upregulation, the cells treated with cisplatin showed reduced cell survival and the ability to migrate, invade and metastasize. Mechanistically, the transcription factors regulating SPINK5 were queried through the JASPAR website, followed by dual-luciferase and Chromatin immunoprecipitation assay validation. CCAAT enhancer-binding protein (CEBP) beta (CEBPB) bound to the SPINK5 promoter region in NPC cells. The silencing of CEBPB enhanced the expression of SPINK5. CEBPB overexpression reversed the inhibitory effects of cisplatin on NPC cell malignant phenotype in the presence of SPINK5 overexpression. In conclusion, CEBPB silencing promoted chemoresistance of NPC cells via activating SPINK5, signifying that targeting CEBPB was a new approach to enhance the chemotherapy efficacy in NPC.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Cisplatino/farmacologia , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia
20.
J Allergy Clin Immunol ; 149(4): 1358-1372, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34543653

RESUMO

BACKGROUND: Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). OBJECTIVE: We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. METHODS: We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. RESULTS: Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. CONCLUSIONS: This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.


Assuntos
Hipersensibilidade , Síndrome de Netherton , Dermatopatias , Epiderme/patologia , Humanos , Hipersensibilidade/patologia , Interferon-alfa , Interleucina-17/genética , Síndrome de Netherton/genética , Proteínas Secretadas Inibidoras de Proteinases/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Pele/patologia , Dermatopatias/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...