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1.
Biogerontology ; 25(4): 691-704, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38619669

RESUMO

The skin's protective functions are compromised over time by both endogenous and exogenous aging. Senescence is well-documented in skin phenotypes, such as wrinkling and sagging, a consequence of the senescence-associated secretory phenotype (SASP) that involves the accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling. Although therapeutic approaches for eliminating senescent cells from the skin are available, their efficacy remains unclear. Accordingly, we aimed to examine the effects of dasatinib in combination with quercetin (D + Q) on senescent human skin fibroblasts and aging human skin. Senescence was induced in human dermal fibroblasts (HDFs) using approaches such as long-term passaging, ionizing radiation, and doxorubicin treatment. The generated senescent cells were treated with D + Q or vehicle. Additionally, a mouse-human chimera model was generated by subcutaneously transplanting whole-skin grafts of aged individuals onto nude mice. Mouse models were administered D + Q or vehicle by oral gavage for 30 days. Subsequently, skin samples were harvested and stained for senescence-associated beta-galactosidase. Senescence-associated markers were assessed by western blotting, reverse transcription-quantitative PCR and histological analyses. Herein, D + Q selectively eliminated senescent HDFs in all cellular models of induced senescence. Additionally, D + Q-treated aged human skin grafts exhibited increased collagen density and suppression of the SASP compared with control grafts. No adverse events were observed during the study period. Collectively, D + Q could ameliorate skin aging through selective elimination of senescent dermal fibroblasts and suppression of the SASP. Our findings suggest that D + Q could be developed as an effective therapeutic approach for combating skin aging.


Assuntos
Senescência Celular , Dasatinibe , Fibroblastos , Camundongos Nus , Quercetina , Rejuvenescimento , Envelhecimento da Pele , Pele , Dasatinibe/farmacologia , Quercetina/farmacologia , Quercetina/administração & dosagem , Humanos , Animais , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Camundongos , Rejuvenescimento/fisiologia , Células Cultivadas , Fenótipo Secretor Associado à Senescência , Feminino
2.
Biogerontology ; 25(3): 529-542, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38436793

RESUMO

Aging negatively affects the appearance and texture of the skin owing to the accumulation of senescent fibroblasts within the dermis. Senescent cells undergo abnormal remodeling of collagen and the extracellular matrix through an inflammatory histolytic senescence-associated secretory phenotype (SASP). Therefore, suppression of SASP in senescent cells is essential for the development of effective skin anti-aging therapies. Ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5), an extracellular signaling molecule, has been implicated in vascular aging and apoptosis; however, its role in SASP remains unclear. Therefore, this study aimed to investigate the role of ENPP5 in SASP and skin aging using molecular techniques. We investigated the effects of siRNA-mediated ENPP5 knockdown, human recombinant ENPP5 (rENPP5) treatment, and lentiviral overexpression of ENPP5 on SASP and aging in human skin fibroblasts. Additionally, we investigated the effect of siRNA-mediated ENPP5 knockdown on the skin of C57BL/6 mice. We found that ENPP5 was significantly expressed in replication-aged and otherwise DNA-damaged human skin fibroblasts and that treatment with human rENPP5 and lentiviral overexpression of ENPP5 promoted SASP and senescence. By contrast, siRNA-mediated knockdown of ENPP5 suppressed SASP and the expression of skin aging-related factors. Additionally, ENPP5 knockdown in mouse skin ameliorated the age-related reduction of subcutaneous adipose tissue, the panniculus carnosus muscle layer, and thinning of collagen fibers. Conclusively, these findings suggest that age-related changes may be prevented through the regulation of ENPP5 expression to suppress SASP in aging cells, contributing to the development of anti-aging treatments for the skin.


Assuntos
Fibroblastos , Camundongos Endogâmicos C57BL , Envelhecimento da Pele , Animais , Envelhecimento da Pele/fisiologia , Humanos , Fibroblastos/metabolismo , Camundongos , Fenótipo Secretor Associado à Senescência , Senescência Celular/fisiologia , Pele/metabolismo , Pele/patologia , Diester Fosfórico Hidrolases/metabolismo , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Pirofosfatases/metabolismo , Células Cultivadas , Masculino
3.
Biogerontology ; 25(1): 161-175, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37736858

RESUMO

Accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling due to aging-related secretory phenotypes have been hypothesized to cause age-related skin aging, which results in wrinkles and loss of skin elasticity, thus compromising appearance attractiveness. However, the rejuvenating effects of removing senescent cells from the human skin and the efficacy of related therapeutic agents remain unclear. Here, we investigated the effects of fisetin, a potential anti-aging component found in various edible fruits and vegetables, on senescent human dermal fibroblasts (HDFs) and aging human skin. Senescence was induced in primary HDFs using long-term passaging and treatment with ionizing radiation, and cell viability was assessed after treatment with fisetin and a control component. A mouse/human chimeric model was established by subcutaneously transplanting whole skin grafts from aged individuals into nude mice, which were treated intraperitoneally with fisetin or control a component for 30 d. Skin samples were obtained and subjected to senescence-associated-beta-galactosidase staining; the extent of aging was evaluated using western blotting, reverse transcription-quantitative PCR, and histological analysis. Fisetin selectively eliminated senescent dermal fibroblasts in both senescence-induced cellular models; this effect is attributable to cell death induction by caspases 3, 8, and 9-mediated endogenous and exogenous apoptosis. Fisetin-treated senescent human skin grafts showed increased collagen density and decreased senescence-associated secretory phenotypes (SASP), including matrix metalloproteinases and interleukins. No apparent adverse events were observed. Thus, fisetin could improve skin aging through selective removal of senescent dermal fibroblasts and SASP inhibition, indicating its potential as an effective novel therapeutic agent for combating skin aging.


Assuntos
Senescência Celular , Flavonóis , Rejuvenescimento , Animais , Camundongos , Humanos , Idoso , Senescência Celular/fisiologia , Camundongos Nus , Fibroblastos , Colágeno/metabolismo , Colágeno/farmacologia , Derme/metabolismo
4.
Clin Anat ; 37(3): 321-328, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37732501

RESUMO

Deeply etched forehead creases indicate aging. Various treatments such as filler injections, fat grafting, and facelift surgery are used to remove them. However, knowledge of the anatomical structures associated with subcutaneous tissue changes and the superficial musculoaponeurotic system is lacking, and there is no consensus about the appropriate treatment. We have investigated the subcutaneous structures involved in forehead creases; this will help to establish selection criteria for improved treatment. The forehead sections of five unfixed adult Asian cadavers were obtained. Tissues containing forehead creases were removed from the periosteum and were examined using gross observation, radiography, histology, and nano-computed tomography. All methods revealed that the dermis in the skin crease area, namely the fold visible from the body surface, was bound to the frontalis muscle by a three-dimensional fibrous structure between the fatty septa. This structure was dense near the skin folds and sparse and thin in other areas. In particular, it was tightly bound to the dermis immediately below the crease, with collagen fibers traversing toward the epidermis. In addition, there were fewer skin appendages near the crease than in the normal area, or they were absent altogether; the epidermis was thicker, and the dermal papillae were more developed. It is thought that the density and firmness of the fibrous fatty septal structures between the dermis-frontalis muscle and the specific structures of the epidermis and dermis immediately below the crease account for the characteristic plastic forehead creases.


Assuntos
Ritidoplastia , Sistema Musculoaponeurótico Superficial , Adulto , Humanos , Testa , Pele , Ritidoplastia/métodos , Envelhecimento
5.
Biogerontology ; 24(6): 889-900, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37395866

RESUMO

Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin. A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.


Assuntos
Senescência Celular , Senoterapia , Masculino , Humanos , Animais , Camundongos , Senescência Celular/fisiologia , Rejuvenescimento , Envelhecimento
6.
Int J Mol Sci ; 24(6)2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36982931

RESUMO

Senescent cells accumulate in aging skin, causing age-related changes and a decline in functional efficiency. Therefore, senolysis, a treatment that specifically removes senescent cells and rejuvenates the skin, should be explored. We targeted apolipoprotein D (ApoD), a previously identified marker expressed on senescent dermal fibroblasts, and investigated a novel senolysis approach using a monoclonal antibody against this antigen and a secondary antibody conjugated with the cytotoxic drug pyrrolobenzodiazepine. Observations using fluorescently labeled antibodies revealed that ApoD functions as a surface marker of senescent cells and that the antibody is taken up and internalized only by such cells. The concurrent administration of the antibody with the PBD-conjugated secondary antibody specifically eliminated only senescent cells without harming young cells. The antibody-drug conjugate treatment of aging mice combined with the administration of antibodies reduced the number of senescent cells in the dermis of mice and improved the senescent skin phenotype. These results provide a proof-of-principle evaluation of a novel approach to specifically eliminate senescent cells using antibody-drug conjugates against senescent cell marker proteins. This approach is a potential candidate for clinical applications to treat pathological skin aging and related diseases via the removal of senescent cells.


Assuntos
Senescência Celular , Imunoconjugados , Senescência Celular/fisiologia , Rejuvenescimento , Apolipoproteínas D , Anticorpos Monoclonais , Fibroblastos
7.
Int J Mol Sci ; 24(21)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37958685

RESUMO

Dermal fibroblasts maintain the skin homeostasis by interacting with the epidermis and extracellular matrix. Their senescence contributes to functional defects in the skin related to aging. Therefore, there is an urgent need for novel therapeutic agents that could inhibit fibroblast senescence. In this study, we investigated the effects of Cistanche deserticola polysaccharide (CDP), a natural anti-inflammatory component, on the progression of senescence in human dermal fibroblasts. Normal human dermal fibroblasts (NHDFs) were cultured in passages, and highly senescent cells were selected as senescent cells. CDP treatment increased the cell proliferation in senescent NHDFs and decreased the proportion of senescence-associated-ß-galactosidase-positive cells. The treatment suppressed the senescence-related secretory phenotype, and reactive oxygen species (ROS) production was reduced, alleviating H2O2-induced oxidative stress. CDP mitigated ROS formation via the nuclear factor erythroid 2-related factor/heme oxygenase-1 pathway in senescent cells and was involved in the suppression of upstream p-extracellular signal-regulated kinase. These results indicate that CDP is an antioxidant that can alleviate age-related inflammation and may be a useful compound for skin anti-aging.


Assuntos
Cistanche , Fator 2 Relacionado a NF-E2 , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Cistanche/metabolismo , Senescência Celular , Peróxido de Hidrogênio/metabolismo , Envelhecimento , Fenótipo , Fibroblastos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/metabolismo , Células Cultivadas
8.
Int J Mol Sci ; 23(12)2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35742971

RESUMO

The accumulation of senescent cells in aging tissues is associated with age-related diseases and functional decline. Thus, senolysis, a therapy aimed at rejuvenation by removing senescent cells from the body, is being developed. However, this therapy requires the identification of membrane surface antigens that are specifically expressed on senescent cells for their selective elimination. We showed that atypical chemokine receptor 3 (ACKR3), a receptor of the CXC motif chemokine 12 (CXCL12) implicated in cancer, inflammation, and cardiovascular disorders, is selectively expressed on the surface of senescent human fibroblasts but not on proliferating cells. Importantly, the differential presence of ACKR3 enabled the isolation of senescent cells by flow cytometry using anti-ACKR3 antibodies. Furthermore, antibody-dependent cellular cytotoxicity assays revealed that cell surface ACKR3 preferentially sensitizes senescent but not dividing fibroblasts to cell injury by natural killer cells. Conclusively, the selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells. These results might contribute to the future development of novel senolysis approaches.


Assuntos
Proteínas de Membrana , Receptores CXCR/metabolismo , Senescência Celular , Quimiocina CXCL12/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Humanos , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/genética
9.
Int J Mol Sci ; 23(13)2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35806092

RESUMO

Adult mammalian wounds leave visible scars, whereas skin wounds in developing mouse fetuses are scarless until a certain point in development when complete regeneration occurs, including the structure of the dermis and skin appendages. Analysis of the molecular mechanisms at this transition will provide clues for achieving scarless wound healing. The fibroblast growth factor (FGF) family is a key regulator of inflammation and fibrosis during wound healing. We aimed to determine the expression and role of FGF family members in fetal wound healing. ICR mouse fetuses were surgically wounded at embryonic day 13 (E13), E15, and E17. Expression of FGF family members and FGF receptor (FGFR) in tissue samples from these fetuses was evaluated using in situ hybridization and reverse transcription-quantitative polymerase chain reaction. Fgfr1 was downregulated in E15 and E17 wounds, and its ligand Fgf7 was upregulated in E13 and downregulated in E15 and E17. Recombinant FGF7 administration in E15 wounds suppressed fibrosis and promoted epithelialization at the wound site. Therefore, the expression level of Fgf7 may correlate with scar formation in late mouse embryos, and external administration of FGF7 may represent a therapeutic option to suppress fibrosis and reduce scarring.


Assuntos
Fator 7 de Crescimento de Fibroblastos/metabolismo , Cicatrização , Animais , Cicatriz/patologia , Feto/metabolismo , Fibrose , Mamíferos , Camundongos , Camundongos Endogâmicos ICR , Pele/metabolismo
10.
Br J Neurosurg ; 35(1): 27-31, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32216589

RESUMO

BACKGROUND: Gorham-Stout disease (GSD) is a rare and idiopathic bone disorder, characterized by massive osteolysis. To date, there is no established treatment strategy for GSD. We empirically treated two patients, who had presented to us with cranial lesions of GSD. Here, we propose a novel algorithm for the management of Gorham's disease based on our experience and review the literature published to date. METHODS: We reviewed all existing literature on GSD describing the pathophysiology and suggested treatment methods, up to 2018. RESULTS: We found 13 papers with 14 reported cases; an inclusion of our two cases brings the total count up to just 16 recorded cases of GSD involving the skull. Of these, the base of the skull was affected in eight cases, while the remaining eight cases showed cranial involvement. The patients with skull-base involvement were managed conservatively, using medications or radiotherapy. The patients with cranial osteolysis were managed surgically, with an excision of the osteolytic portion, followed by cranioplasty. Of the latter group, the pericranium was not removed in one patient, in whom a very slight progression of the osteolytic process was later observed. CONCLUSIONS: The pathogenesis of GSD remains poorly understood. Further study is required to determine an optimum management strategy. A long-term follow-up will also be necessary to establish the effectiveness of the treatment process. The untreated patients show a progressive resorption of the affected bones of the skull. A painful, vanishing skull deformity is an alarming sign of GSD. Early diagnosis and treatment are necessary to arrest disease progression and to prevent complications.


Assuntos
Osteólise Essencial , Osteólise , Progressão da Doença , Humanos , Osteólise/diagnóstico por imagem , Osteólise/cirurgia , Osteólise Essencial/diagnóstico por imagem , Osteólise Essencial/cirurgia , Osso Parietal , Base do Crânio
11.
Adv Biol (Weinh) ; : e2300434, 2024 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-38183407

RESUMO

Senescent cells accumulate with age and contribute to age-related diseases and organ dysfunctions. Early evidence suggests that removal of senescent cells using senolytic drugs improves the aging phenotype in mice and may improve the health of individuals with chronic diseases. Signs of skin aging, including wrinkles, and sagging, occur largely due to the accumulation of senescent fibroblasts within the dermis; However, there is currently no skin treatment that eliminates senescent cells. In this study, human fibroblasts subjected to replicative aging and ionizing radiation exposure are used to screen plant extracts for potential senescent cell-destructive and/or senescent cell-forming activities. Angelica acutiloba-a traditional Chinese herbal medicine-selectively kills senescent cells without affecting the proliferating cells. Among the major components of this herb, ligustilide shows promising senescent cell-destructive properties, and selectively eliminates senescent cells by inducing an apoptosis. Moreover, ligustilide markedly inhibits senescence-associated secretory phenotypes. Administration of ligustilide to mouse skin eliminates senescent cells and increases dermal collagen density and subcutaneous adipose tissue content; it selectively promotes death of senescent cells without affecting non-senescent cells. These results provide evidence that a natural compound-ligustilide-may exhibit therapeutic effects on the skin aging phenotype by specifically inducing apoptosis in senescent cells.

12.
Plast Reconstr Surg Glob Open ; 12(3): e5675, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38515557

RESUMO

This case series aimed to describe a new technique for correcting contractures and deformities that reliably addresses lacrimal punctum deviation and severe cicatricial lower eyelid ectropion. This was a technical description and a retrospective interventional case series. Eyelid ectropion and lacrimal punctum deviation were treated surgically by grafting the fascia lata and suturing the tarsus-Horner muscle. In total, three patients underwent this surgery: one for burns, one for lower eyelid tumor resection, and the other for an orbital floor fracture following a motorcycle accident, all resulting in ectropion. All patients previously had failed ectropion correction procedures, including scar revision, skin grafting, auricular cartilage grafting, and lateral tarsal strips. The mean follow-up was 15.8 (12.5-18.5) months. Furthermore, all patients showed resolution of lower eyelid ectropion and significant improvement in lower eyelid contracture, with a mean increase of 4.0 (2.5-5) mm. No severe complications were observed, and they reported a significant improvement in ocular surface symptoms. Our study shows that tacking of the tarsus and Horner muscles in combination with fascia lata grafting is effective in correcting refractory cicatricial lower eyelid ectropion with deviation of the tear punctum.

13.
Sci Rep ; 14(1): 10854, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740788

RESUMO

Unlike adult mammalian wounds, early embryonic mouse skin wounds completely regenerate and heal without scars. Analysis of the underlying molecular mechanism will provide insights into scarless wound healing. Twist2 is an important regulator of hair follicle formation and biological patterning; however, it is unclear whether it plays a role in skin or skin appendage regeneration. Here, we aimed to elucidate Twist2 expression and its role in fetal wound healing. ICR mouse fetuses were surgically wounded on embryonic day 13 (E13), E15, and E17, and Twist2 expression in tissue samples from these fetuses was evaluated via in situ hybridization, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction. Twist2 expression was upregulated in the dermis of E13 wound margins but downregulated in E15 and E17 wounds. Twist2 knockdown on E13 left visible marks at the wound site, inhibited regeneration, and resulted in defective follicle formation. Twist2-knockdown dermal fibroblasts lacked the ability to undifferentiate. Furthermore, Twist2 hetero knockout mice (Twist + /-) formed visible scars, even on E13, when all skin structures should regenerate. Thus, Twist2 expression correlated with skin texture formation and hair follicle defects in late mouse embryos. These findings may help develop a therapeutic strategy to reduce scarring and promote hair follicle regeneration.


Assuntos
Feto , Folículo Piloso , Regeneração , Pele , Proteína 2 Relacionada a Twist , Cicatrização , Animais , Folículo Piloso/metabolismo , Camundongos , Cicatrização/genética , Cicatrização/fisiologia , Feto/metabolismo , Pele/metabolismo , Proteína 2 Relacionada a Twist/metabolismo , Proteína 2 Relacionada a Twist/genética , Camundongos Knockout , Camundongos Endogâmicos ICR , Feminino , Fibroblastos/metabolismo , Proteínas Repressoras , Proteína 1 Relacionada a Twist
14.
Rejuvenation Res ; 26(2): 42-50, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36571249

RESUMO

The current understanding of skin aging is that senescent fibroblasts accumulate within the dermis and subcutaneous fat to cause abnormal tissue remodeling and extracellular matrix dysfunction, triggering a senescence-associated secretory phenotype (SASP). A novel therapeutic approach to prevent skin aging is to specifically eliminate senescent dermal fibroblasts; this requires the identification of specific protein markers for senescent cells. Apolipoprotein D (ApoD) is involved in lipid metabolism and antioxidant responses and is abundantly expressed in tissues affected by age-related diseases such as Alzheimer's disease and atherosclerosis. However, its behavior and role in skin aging remain unclear. In this study, we examined whether ApoD functions as a marker of aging using human dermal fibroblast aging models. In cellular senescence models induced through replicative aging and ionizing radiation exposure, ApoD expression was upregulated at the gene and protein levels and correlated with senescence-associated ß-galactosidase activity and the decreased uptake of the proliferation marker bromodeoxyuridine, which was concomitant with the upregulation of SASP genes. Furthermore, ApoD-positive cells were found to be more abundant in the aging human dermis using fluorescence flow cytometry. These results suggest that ApoD is a potential clinical marker for identifying aging dermal fibroblasts.


Assuntos
Apolipoproteínas D , Envelhecimento da Pele , Humanos , Apolipoproteínas D/metabolismo , Células Cultivadas , Senescência Celular/genética , Fibroblastos/metabolismo , Rejuvenescimento
15.
Geroscience ; 45(1): 427-437, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36057013

RESUMO

Cellular senescence is characterized by cell cycle arrest and the senescence-associated secretory phenotype (SASP) and can be triggered by a variety of stimuli, including deoxyribonucleic acid (DNA) damage, oxidative stress, and telomere exhaustion. Cellular senescence is associated with skin aging, and identification of specific markers of senescent cells is essential for development of targeted therapies. Cathepsin F (CTSF) has been implicated in dermatitis and various cancers and participates in cell immortalization through its association with Bcl family proteins. It is a candidate therapeutic target to specifically label and eliminate human skin fibroblasts and keratinocytes immortalized by aging and achieve skin rejuvenation. In this study, we investigated whether CTSF is associated with senescence in human fibroblasts and keratinocytes. In senescence models, created using replicative aging, ionizing radiation exposure, and the anticancer drug doxorubicin, various senescence markers were observed, such as senescence-associated ß-galactosidase (SA-ß-gal) activity, increased SASP gene expression, and decreased uptake of the proliferation marker BrdU. Furthermore, CTSF expression was elevated at the gene and protein levels. In addition, CTSF-positive cells were abundant in aged human epidermis and in some parts of the dermis. In the population of senescent cells with arrested division, the number of CTSF-positive cells was significantly higher than that in the proliferating cell population. These results suggest that CTSF is a candidate for therapeutic modalities targeting aging fibroblasts and keratinocytes.


Assuntos
Catepsina F , Envelhecimento da Pele , Humanos , Idoso , Catepsina F/metabolismo , Senescência Celular , Queratinócitos/metabolismo , Fibroblastos
16.
Rejuvenation Res ; 26(4): 147-158, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37345689

RESUMO

Abnormal remodeling of collagen and extracellular matrix caused by the accumulation of senescent fibroblasts in the dermis is the most likely cause of skin aging. Therefore, the application of "senolysis," in which only senescent cells are cleared from the body, has a potential in the development of antiaging treatments for skin. However, markers that label senescent fibroblasts only reflect the state of senescence, and it is important to develop markers as therapeutic targets to aid senolysis application. We investigated the potential of serotonin 2A receptor (HTR2A), which is involved in melanin production in response to ultraviolet light, as a senescent cell marker. The results showed that HTR2A is upregulated in aging dermal fibroblasts but is expressed at low levels in proliferating young cells. Flow cytometry demonstrated the presence of many HTR2A-positive cells in the aging cell population and few in the young cells. Furthermore, antibody-dependent cytotoxicity assays revealed that HTR2A preferentially sensitizes senescent fibroblasts and specifically damages only senescent cells by natural killer cells that recognize it. In conclusion, selective labeling of the novel senescent cell marker, HTR2A, could preferentially eliminate senescent cells and may contribute to the future development of novel skin senolysis approaches.


Assuntos
Receptor 5-HT2A de Serotonina , Pele , Células Cultivadas , Fibroblastos , Senescência Celular
17.
Rejuvenation Res ; 26(1): 9-20, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36324221

RESUMO

Chronic senescence, such as aging, contributes to age-related tissue dysfunction and disease development. The accumulation of senescent fibroblasts and the senescence-associated secretory phenotype is particularly implicated in this process. Removal of senescent cells has been reported to prevent tissue dysfunction and to extend the life span during aging. ABT-263 (navitoclax), which inhibits antiapoptotic proteins, is a leading antiaging drug; however, its role in human skin aging is unclear. This study aimed to determine the rejuvenating effects of ABT-263 on aging skin using a human skin graft mouse model. We assessed the viability of ABT-263-treated skin fibroblasts after inducing senescence. Aged human skin was transplanted under the back skin of nude mice and injected intraperitoneally with the drug or control. Analysis of the skin specimens revealed that ABT-263 induced selective elimination of senescent dermal fibroblasts. Senescent human skin treated with ABT-263 exhibited a decrease in the number of senescent cells and in the expression of aging-related secretory phenotype molecules, such as matrix metalloproteinases and interleukins and an increase in collagen density. Our results indicate that selective removal of senescent skin cells with ABT-263 can improve the aging phenotype of human skin without side effects. ABT-263 is, thus, a novel potential therapeutic agent for skin aging.


Assuntos
Senescência Celular , Pele , Animais , Camundongos , Humanos , Idoso , Camundongos Nus , Fibroblastos
18.
Plast Reconstr Surg Glob Open ; 11(8): e5163, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37547349

RESUMO

The extended latissimus dorsi (ELD) flap is a safe and aesthetically acceptable method to reconstruct small to medium-sized breasts. However, the long time required for flap elevation and intraoperative bleeding contributes to various postoperative complications. We investigated the use of alternative devices, such as the Harmonic ACE+7, which has a long arm that can help simultaneously detach and seal tissues to prevent such complications. Methods: We compared 27 patients who underwent breast reconstruction with the ELD flap using the Harmonic ACE +7 scalpel, and 28 patients who underwent breast reconstruction using an electrocautery scalpel, between May 2019 and March 2022. Data on patient demographics, surgery, and postoperative complications were collected. Surgical outcomes were compared between electrocautery (EC) and Harmonic ACE+7 (HA) groups. Results: The median age of the patients was 50.2 years. The patient demographics between the groups did not show significant differences. Flap necrosis and hematomas did not occur, and seroma was the major postoperative complication (65.7% in the EC group and 70% in the HA group). The time required for flap elevation was significantly shorter in the HA group than in the EC group (286.0 minutes and 179.0 minutes, respectively). Blood loss reduced significantly in the HA and EC groups (138.5 mL and 78.2 mL, respectively). Moreover, decreased drainage was observed for the breast area. There were no significant differences in other end points. Conclusion: In breast reconstruction with ELD flaps, using the Harmonic ACE+7 can help reduce the rate of seroma, operative time, and intraoperative bleeding without further disadvantages.

20.
Biomedicines ; 11(4)2023 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-37189631

RESUMO

Unlike adults, early developing fetuses can completely regenerate tissue, and replicating this could lead to the development of treatments to reduce scarring. Mice epidermal structures, including wound healing patterns, are regenerated until embryonic day (E) 13, leaving visible scars thereafter. These patterns require actin cable formation at the epithelial wound margin through AMP-activated protein kinase (AMPK) activation. We aimed to investigate whether the administration of compound 13 (C13), a recently discovered AMPK activator, to the wound could reproduce this actin remodeling and skin regeneration pattern through its AMPK activating effect. The C13 administration resulted in partial formations of actin cables, which would normally result in scarring, and scar reduction during the healing of full-layer skin defects that occurred in E14 and E15 fetuses. Furthermore, C13 was found to cause AMPK activation in these embryonic mouse epidermal cells. Along with AMPK activation, Rac1 signaling, which is involved in leaflet pseudopodia formation and cell migration, was suppressed in C13-treated wounds, indicating that C13 inhibits epidermal cell migration. This suggests that actin may be mobilized by C13 for cable formation. Administration of C13 to wounds may achieve wound healing similar to regenerative wound healing patterns and may be a potential candidate for new treatments to heal scars.

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