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Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.
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Resistencia a Medicamentos Antineoplásicos , Melanoma , Biogênese de Organelas , Inibidores de Proteínas Quinases , Sirtuínas , Melanoma/metabolismo , Melanoma/patologia , Melanoma/genética , Melanoma/tratamento farmacológico , Humanos , Sirtuínas/metabolismo , Sirtuínas/genética , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/tratamento farmacológico , Camundongos Nus , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidoresRESUMO
DHH/DHHA1 family proteins have been proposed to play critical roles in bacterial resistance to environmental stresses. Members of the most radioresistant bacteria genus, Deinococcus, possess two DHH/DHHA1 family proteins, RecJ and RecJ-like. While the functions of Deinococcus radiodurans RecJ (DrRecJ) in DNA damage resistance have been well characterized, the role and biochemical activities of D. radiodurans RecJ-like (DrRecJ-like) remain unclear. Phenotypic and transcriptomic analyses suggest that, beyond DNA repair, DrRecJ is implicated in cell growth and division. Additionally, DrRecJ-like not only affects stress response, cell growth, and division but also correlates with the folding/stability of intracellular proteins, as well as the formation and stability of cell membranes/walls. DrRecJ-like exhibits a preferred catalytic activity towards short single-stranded RNA/DNA oligos and c-di-AMP. In contrast, DrRecJ shows no activity against RNA and c-di-AMP. Moreover, a crystal structure of DrRecJ-like, with Mg2+ bound in an open conformation at a resolution of 1.97 Å, has been resolved. Subsequent mutational analysis was conducted to pinpoint the crucial residues essential for metal cation and substrate binding, along with the dimerization state, necessary for DrRecJ-like's function. This finding could potentially extend to all NrnA-like proteins, considering their conserved amino acid sequence and comparable dimerization forms.
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Proteínas de Bactérias , Deinococcus , Deinococcus/genética , Deinococcus/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Modelos Moleculares , Cristalografia por Raios X , Sequência de Aminoácidos , Reparo do DNARESUMO
Vitiligo is a hypopigmented skin disease characterized by the loss of melanin. The progressive nature and widespread incidence of vitiligo necessitate timely and accurate detection. Usually, a single diagnostic test often falls short of providing definitive confirmation of the condition, necessitating the assessment by dermatologists who specialize in vitiligo. However, the current scarcity of such specialized medical professionals presents a significant challenge. To mitigate this issue and enhance diagnostic accuracy, it is essential to build deep learning models that can support and expedite the detection process. This study endeavors to establish a deep learning framework to enhance the diagnostic accuracy of vitiligo. To this end, a comparative analysis of five models including ResNet (ResNet34, ResNet50, and ResNet101 models) and Swin Transformer series (Swin Transformer Base, and Swin Transformer Large models), were conducted under the uniform condition to identify the model with superior classification capabilities. Moreover, the study sought to augment the interpretability of these models by selecting one that not only provides accurate diagnostic outcomes but also offers visual cues highlighting the regions pertinent to vitiligo. The empirical findings reveal that the Swin Transformer Large model achieved the best performance in classification, whose AUC, accuracy, sensitivity, and specificity are 0.94, 93.82%, 94.02%, and 93.5%, respectively. In terms of interpretability, the highlighted regions in the class activation map correspond to the lesion regions of the vitiligo images, which shows that it effectively indicates the specific category regions associated with the decision-making of dermatological diagnosis. Additionally, the visualization of feature maps generated in the middle layer of the deep learning model provides insights into the internal mechanisms of the model, which is valuable for improving the interpretability of the model, tuning performance, and enhancing clinical applicability. The outcomes of this study underscore the significant potential of deep learning models to revolutionize medical diagnosis by improving diagnostic accuracy and operational efficiency. The research highlights the necessity for ongoing exploration in this domain to fully leverage the capabilities of deep learning technologies in medical diagnostics.
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Aprendizado Profundo , Vitiligo , Vitiligo/diagnóstico , HumanosRESUMO
Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from the endoplasmic reticulum to the membrane in melanocytes under oxidative stress. To investigate the potential role of CRT in the pathogenesis of vitiligo, we analyzed the correlation between CRT and ROS in serum and lesions of vitiligo, detected CRT and protein kinase RNA-like endoplasmic reticulum kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway and then tested the chemotactic migration of CD8+ T cells or CD11c+ CD86+ cells. Initially, we verified the overexpression of CRT in perilesional epidermis that was positively correlated with the disease severity of vitiligo. Furthermore, the PERK branch of UPR was confirmed to be responsible for the overexpression and membranal translocation of CRT in melanocytes under oxidative stress. We also found that oxidative stress-induced membranal translocation of CRT promoted the activation and migration of CD8+ T cells in vitiligo. In addition, dendritic cells from patients with vitiligo were also prone to maturation with the coincubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes through UPR and might play a role in oxidative stress-triggered CD8+ T-cell response in vitiligo.
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Autoimunidade , Linfócitos T CD8-Positivos , Calreticulina , Melanócitos , Estresse Oxidativo , Resposta a Proteínas não Dobradas , Vitiligo , Vitiligo/imunologia , Vitiligo/metabolismo , Vitiligo/patologia , Humanos , Melanócitos/metabolismo , Melanócitos/imunologia , Estresse Oxidativo/imunologia , Calreticulina/metabolismo , Resposta a Proteínas não Dobradas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Masculino , Adulto , eIF-2 Quinase/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem , Membrana Celular/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/patologiaRESUMO
BACKGROUND: Tumor cells frequently suffer from endoplasmic reticulum (ER) stress. Previous studies have extensively elucidated the role of tumorous unfolded protein response in melanoma cells, whereas the effect on tumor immunology and the underlying mechanism remain elusive. METHODS: Bioinformatics, biochemical assays and pre-clinical mice model were employed to demonstrate the role of tumorous inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) in anti-tumor immunity and the underlying mechanism. RESULTS: We firstly found that IRE1α signaling activation was positively associated with the feature of tumor-infiltrating lymphocytes. Then, pharmacological ER stress induction by HA15 exerted prominent anti-tumor effect in immunocompetent mice and was highly dependent on CD8+T cells, paralleled with the reshape of immune cells in tumor microenvironment via tumorous IRE1α-XBP1 signal. Subsequently, tumorous IRE1α facilitated the expression and secretion of multiple chemokines and cytokines via XBP1-NF-κB axis, leading to increased infiltration and anti-tumor capacity of CD8+T cells. Ultimately, pharmacological induction of tumorous ER stress by HA15 brought potentiated therapeutic effect along with anti-PD-1 antibody on melanoma in vivo. CONCLUSIONS: Tumorous IRE1α facilitates CD8+T cells-dependent anti-tumor immunity and improves immunotherapy efficacy by regulating chemokines and cytokines via XBP1-NF-κB axis. The combination of ER stress inducer and anti-PD-1 antibody could be promising for increasing the efficacy of melanoma immunotherapy.
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Melanoma , Animais , Camundongos , Linfócitos T CD8-Positivos/patologia , Quimiocinas , Citocinas , Endorribonucleases , Melanoma/patologia , NF-kappa B , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/metabolismo , Microambiente TumoralRESUMO
Psoriasis is a common inflammatory skin disease, in which epidermal keratinocytes play a vital role in its pathogenesis by acting both as the responder and as the accelerator to the cutaneous psoriatic immune response. Advanced glycation end products (AGEs) are a class of proinflammatory metabolites that are commonly accumulating in cardiometabolic disorders. Recent studies have also observed the increased level of AGEs in the serum and skin of psoriasis patients, but the role of AGEs in psoriatic inflammation has not been well investigated. In the present study, we initially detected abnormal accumulation of AGEs in epidermal keratinocytes of psoriatic lesions collected from psoriasis patients. Furthermore, AGEs promoted the proliferation of keratinocytes via upregulated Keratin 17 (K17)-mediated p27KIP1 inhibition followed by accelerated cell cycle progression. More importantly, AGEs facilitated the production of interleukin-36 alpha (IL-36α) in keratinocytes, which could enhance T helper 17 (Th17) immune response. In addition, the induction of both K17 and IL-36α by AGEs in keratinocytes was dependent on the activation of signal transducer and activator of transcription 1/3 (STAT1/3) signaling pathways. At last, the effects of AGEs on keratinocytes were mediated by the receptor for AGEs (RAGE). Taken together, these findings support that AGEs potentiate the innate immune function of keratinocytes, which contributes to the formation of psoriatic inflammation. Our study implicates AGEs as a potential pathogenic link between psoriasis and cardiometabolic comorbidities.
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Doenças Cardiovasculares , Psoríase , Humanos , Pele/patologia , Queratinócitos , Inflamação/metabolismo , Imunidade , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologiaRESUMO
Melanoma is the most lethal skin cancer originating from the malignant transformation of epidermal melanocyte. The dysregulation of cellular metabolism is a hallmark of cancer, including in melanoma. Aberrant branched-chain amino acids (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Herein, we reported that the critical BCAA metabolism enzyme branched-chain amino acid transaminase 2 (BCAT2) is an oncogenic factor in melanoma by activating lipogenesis via the epigenetic regulation of fatty acid synthase (FASN) and ATP-citrate lyase (ACLY) expressions. Firstly, we found that BCAT2 expression was prominently increased in melanoma, and highly associated with clinical stage. Then, it was proved that the deficiency of BCAT2 led to impaired tumor cell proliferation, invasion and migration in vitro, and tumor growth and metastasis in vivo. Further, RNA sequencing technology and a panel of biochemical assays demonstrated that BCAT2 regulated de novo lipogenesis via the regulation of the expressions of both FASN and ACLY. Mechanistically, the inhibition of BCAT2 suppressed the generation of intracellular acetyl-CoA, mitigating P300-dependent histone acetylation at the promoter of FASN and ACLY, and thereby their transcription. Ultimately, zinc finger E-box binding homeobox 1 (ZEB1) was identified as the upstream transcriptional factor responsible for BCAT2 up-regulation in melanoma. Our results demonstrate that BCAT2 promotes melanoma progression by epigenetically regulating FASN and ACLY expressions via P300-dependent histone acetylation. Targeting BCAT2 could be exploited as a promising strategy to restrain tumor progression in melanoma.
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Melanoma , Proteínas da Gravidez , Humanos , Lipogênese/genética , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Histonas/metabolismo , Epigênese Genética , Melanoma/genética , Transaminases/genética , Proteínas da Gravidez/genética , Proteínas da Gravidez/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Ácido Graxo Sintase Tipo I/genéticaRESUMO
The risk of diabetes mellitus (DM) in vitiligo patients is higher than that in non-vitiligo population. Our goal was to explore the influencing factors for DM in vitiligo patients. A matched-pair design of 107 cases with DM and 428 controls without DM was conducted among vitiligo patients in Xijing hospital from January 2010 to October 2021. The baseline characteristics of patients were analysed based on standard descriptive statistics. The vitiligo-associated characteristics were analysed by logistic regression to identify influencing factors of DM. Interaction analysis was performed to explore the additive interactions between vitiligo-associated characteristics and baseline characteristics. After adjustment for the baseline characteristics, the severity of vitiligo [odds ratio (OR) = 2.47, 95% confidence interval (CI): 1.47-4.14] and onset age of vitiligo (OR = 0.98, 95% CI: 0.97-0.99) had a significant correlation with occurrence of DM. The severity of vitiligo had additive interaction with family history of diabetes [relative excess risk due to interaction (RERI) = 132.51 (95% CI: 5.51-1100.20), attributable proportion (AP) = 0.91 (95% CI: 0.17-0.95), synergy index (S) = 11.53 (95% CI: 1.32-100.5)] and with smoking history [RERI = 6.54 (95% CI: 0.67-19.83), AP = 0.64 (95% CI: 0.04-0.80), S = 3.48 (95% CI: 1.17-10.36)]. Earlier onset age of vitiligo and greater BSA involvement might be two independent risk factors for DM in vitiligo patients. Interaction assessment identified the severity of vitiligo as additive interaction factors with diabetes family history and with smoking history for the DM occurrence.
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BACKGROUND: The activation of CD8+ T cells and their trafficking to the skin through JAK-STAT signaling play a central role in the development of vitiligo. Thus, targeting this key disease pathway with innovative drugs is an effective strategy for treating vitiligo. Natural products isolated from medicinal herbs are a useful source of novel therapeutics. Demethylzeylasteral (T-96), extracted from Tripterygium wilfordii Hook F, possesses immunosuppressive and anti-inflammatory properties. METHODS: The efficacy of T-96 was tested in our mouse model of vitiligo, and the numbers of CD8+ T cells infiltration and melanocytes remaining in the epidermis were quantified using whole-mount tail staining. Immune regulation of T-96 in CD8+ T cells was evaluated using flow cytometry. Pull-down assay, mass spectrum analysis, molecular docking, knockdown and overexpression approaches were utilized to identify the target proteins of T-96 in CD8+ T cells and keratinocytes. RESULTS: Here, we found that T-96 reduced CD8+ T cell infiltration in the epidermis using whole-mount tail staining and alleviated the extent of depigmentation to a comparable degree of tofacitinib (Tofa) in our vitiligo mouse model. In vitro, T-96 decreased the proliferation, CD69 membrane expression, and IFN-γ, granzyme B, (GzmB), and perforin (PRF) levels in CD8+ T cells isolated from patients with vitiligo. Pull-down assays combined with mass spectrum analysis and molecular docking showed that T-96 interacted with JAK3 in CD8+ T cell lysates. Furthermore, T-96 reduced JAK3 and STAT5 phosphorylation following IL-2 treatment. T-96 could not further reduce IFN-γ, GzmB and PRF expression following JAK3 knockdown or inhibit increased immune effectors expression upon JAK3 overexpression. Additionally, T-96 interacted with JAK2 in IFN-γ-stimulated keratinocytes, inhibiting the activation of JAK2, decreasing the total and phosphorylated protein levels of STAT1, and reducing the production and secretion of CXCL9 and CXCL10. T-96 did not significantly inhibit STAT1 and CXCL9/10 expression following JAK2 knockdown, nor did it suppress upregulated STAT1-CXCL9/10 signaling upon JAK2 overexpression. Finally, T-96 reduced the membrane expression of CXCR3, and the culture supernatants pretreated with T-96 under IFN-γ stressed keratinocytes markedly blocked the migration of CXCR3+CD8+ T cells, similarly to Tofa in vitro. CONCLUSION: Our findings demonstrated that T-96 might have positive therapeutic responses to vitiligo by pharmacologically inhibiting the effector functions and skin trafficking of CD8+ T cells through JAK-STAT signaling.
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Vitiligo , Animais , Camundongos , Vitiligo/tratamento farmacológico , Vitiligo/metabolismo , Linfócitos T CD8-Positivos , Simulação de Acoplamento Molecular , Pele/metabolismoRESUMO
The dysregulation of branched-chain amino acid (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Here, we explored the role of the BCAA metabolism enzyme BCKDHA in melanoma pathogenesis and elucidated the underlying mechanisms. In vitro cell biology experiments and in vivo pre-clinical mice model experiments were performed to investigate the role of BCKDHA in melanoma progression. RNA sequencing, immunohistochemical/immunofluorescence staining and bioinformatics analysis were used to examine the underlying mechanism. BCKDHA expression was prominently increased in both melanoma tissues and cell lines. The up-regulation of BCKDHA promoted long-term tumour cell proliferation, invasion and migration in vitro and tumour growth in vivo. Through RNA-sequencing technology, it was found that BCKDHA regulated the expressions of lipogenic fatty acid synthase (FASN) and ATP-citrate lyase (ACLY), which was thereafter proved to mediate the oncogenic role of BCKDHA in melanoma. Our results demonstrate that BCKDHA promotes melanoma progression by regulating FASN and ACLY expressions. Targeting BCKDHA could be exploited as a promising strategy to restrain tumour progression in melanoma.
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ATP Citrato (pro-S)-Liase , Melanoma , Animais , Camundongos , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Linhagem Celular , Proliferação de Células , Lipogênese , Melanoma/genéticaRESUMO
Melanoma is the most lethal type of skin cancer, originating from the malignant transformation of melanocyte. While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating the therapeutic effect, the prognosis of patients with melanoma is still suboptimal. During tumor progression, melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment. SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular nicotinamide adenine dinucleotide (NAD+), with versatile biological functions in maintaining cell homeostasis. Nevertheless, whether SIRT7 regulates tumor cell biology and tumor immunology in melanoma under stressful tumor microenvironment remains elusive. Herein, we reported that SIRT7 orchestrates melanoma progression by simultaneously promoting tumor cell survival and immune evasion via the activation of unfolded protein response. We first identified that SIRT7 expression was the most significantly increased one in sirtuins family upon stress. Then, we proved that the deficiency of SIRT7 potentiated tumor cell death under stress in vitro and suppressed melanoma growth in vivo. Mechanistically, SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of tumor-promoting cytokines. SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-ß-SMAD4 signal, which relieved the transcriptional repression on IRE1α and induced the activation of the IRE1α-XBP1 axis. Moreover, SIRT7 up-regulation eradicated anti-tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis. Additionally, the synergized therapeutic effect of SIRT7 suppression and anti-PD-1 immune checkpoint blockade was also investigated. Taken together, SIRT7 can be employed as a promising target to restrain tumor growth and increase the effect of melanoma immunotherapy.
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Melanoma , Sirtuínas , Humanos , Endorribonucleases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Sobrevivência Celular/genética , Evasão da Resposta Imune , Linhagem Celular Tumoral , Melanoma/genética , Microambiente Tumoral , Sirtuínas/genéticaRESUMO
BACKGROUND: Treatment resistance often occurs with BRAF inhibitor (BRAFi) therapy for melanoma, bringing in a great challenge to the treatment of melanoma patients harboring mutant BRAF gene. Recent studies revealed redox vulnerability constitutes a novel opportunity to overcome BRAFi resistance. Previously we found Sestrin2 provided protection to metastatic melanoma cells by detoxifying reactive oxygen species (ROS) induced by anoikis, but its defensive role against redox stimuli elicited by BRAFi was unclear. OBJECTIVE: In-depth explored the role of Sestrin2 in BRAFi-resistant melanoma. METHODS: Vemurafenib-resistant melanoma cells were established using 451Lu and UACC62 cell lines carrying BRAFV600E mutation. Mechanistic studies were subsequently performed by transfection of lentiviral vectors encoding an shRNA against SESN2 or embedded with the coding sequences of SESN2 cDNA. RESULTS: Elevated Sestrin2 expression was found in vemurafenib-resistance melanoma cells. Further mechanistic studies revealed that BRAFi-resistant melanoma cells employ Sestrin2 to adapt to higher oxidative stress under vemurafenib exposure. It was also demonstrated that mTOR signaling was significantly activated following Sestrin2 knockdown. Given the known promoting role of active mTOR signaling in melanoma proliferation and survival, the effects of mTOR blocker and Sestrin2 ablation on BRAFi-resistant melanoma cells were further tested, and the combination was found to result in enhanced inhibition of melanoma cell growth. CONCLUSIONS: Our findings demonstrated the contribution of Sestrin2 to the development of BRAFi resistance and the fact that the combination of mTOR blocker assisted Sestrein2 ablation in eliminating BRAFi resistance of melanoma. Therefore, mTOR and Sestrin2 may be novel combinatorial therapeutic targets to overcome BRAFi resistance of melanoma.
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Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Serina-Treonina Quinases TOR/metabolismo , Mutação , Oxirredução , Linhagem Celular Tumoral , Sestrinas/genética , Sestrinas/metabolismoRESUMO
The dynamic characteristics of facial expressions might affect time perception. Compared with static emotional faces, dynamic emotional faces are more intense, have higher ecological validity, and contain time series information, which may lead to time overestimation. In the present study, we aimed at investigating how dynamic characteristics of angry facial expressions affect time perception, as measured using event-related potentials (ERPs). Dynamic and static angry and neutral faces with different durations (400, 600, 800, 1000, 1200, 1400, and 1600 ms) were presented in the classical temporal bisection paradigm. Participants were asked to judge whether the duration of the presented face was closer to 400 or 1600 ms. The behavioral results showed a significant overestimation effect for dynamic angry faces compared with static faces, both in terms of proportion of long and Bisection Point. The ERP results indicated that the processing mechanisms are significantly different between judging the duration of dynamic and static angry faces. Dynamic angry faces evoked a larger N2 and Late Positive Potential than did static faces, while the static angry faces evoked a larger P2 and Early Posterior Negativity. The Contingent Negative Variation showed a complex change pattern over time. Our results indicate that dynamic angry facial expressions influence time perception differently than do static faces. Static angry faces were processed earlier and were considered to cause an overestimation of time through early emotional arousal and attentional bias, while dynamic angry faces may have caused the overestimation of time through response inhibition and late sustained attention.
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In vitiligo, autoreactive CD8+ T cells have been established as the main culprit considering its pathogenic role in mediating epidermal melanocyte-specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8+ T cells remains ill-defined. In this study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo. Additionally, inhibiting MIF ameliorated the disease progression in vitiligo mice, which manifested as less infiltration of CD8+ T cells and more retention of epidermal melanocytes in the tail skin. More importantly, in vitro experiments indicated that MIF-inhibition suppressed the activation and proliferation of CD8+ T cells from the lymph nodes of vitiligo mice, and the effect extended to CD8+ T cells in peripheral blood mononuclear cells of vitiligo patients. Finally, CD8+ T cells derived from MIF-inhibited vitiligo mice also exhibited an impaired capacity for activation and proliferation. Taken together, our results show that MIF might be clinically targetable in vitiligo treatment, and its inhibition might ameliorate vitiligo progression by suppressing autoreactive CD8+ T cell activation and proliferation. © 2023 The Pathological Society of Great Britain and Ireland.
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Fatores Inibidores da Migração de Macrófagos , Vitiligo , Humanos , Camundongos , Animais , Vitiligo/tratamento farmacológico , Vitiligo/patologia , Linfócitos T CD8-Positivos , Leucócitos Mononucleares/patologia , Melanócitos/patologia , Proliferação de Células , Oxirredutases IntramolecularesRESUMO
PURPOSE: The low objective response of immune checkpoint inhibitors (ICIs) remains a great challenge in advanced melanoma therapy. Interferon-alpha has been proven to be a promising combination regimen with ICI in a phase Ib/II trial. Herein, we evaluated the efficacy and safety of interferon-alpha 1b plus PD-1 monoantibody in a real-world Chinese metastatic melanoma cohort. METHODS: Profiles of patients diagnosed with unresectable stage IV (AJCC 8th Edition) between December 1st, 2018 and February 28th, 2022 from the Department of Dermatology, Xijing Hospital were reviewed. All of them received the combination treatment of interferon-alpha 1b (600 µg every other day) plus PD-1 monoantibody (Pembrolizumab 2 mg/kg or Toripalimab 240 mg or Sintilimab 200 mg, every 3 weeks) for at least 12 weeks. The efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST V1.1). The safety data were identified according to Common Terminology Criteria for Adverse Events (CTC AE) V.5.0. RESULTS: In total, 70 patients were included. 50% were females. 52.9% were with ECOG performance status ≥ 1. The fraction of patients receiving Pembrolizumab, Toripalimab, and Sintilimab was 28.6%, 67.1%, and 4.3%, respectively. Acral and mucosal subtypes accounted for 48.6% and 20%. The median follow-up period is 15.1 months. The objective response rate was 32.8%. The median time of overall survival was 18 months (95% CI 14.2-21.8 months), and the median time of PFS was 5.2 months (95% CI 4.2-6.2 months). The incidence of adverse events (any grade) was 98.6%, but only 8.6% of cases experienced grade 3 or 4 adverse reactions. CONCLUSION: The combination of interferon-alpha 1b and PD-1 monoantibody demonstrated promising anti-tumor effects and acceptable toxicity in Chinese metastatic melanoma patients with cutaneous, acral, and mucosal subtypes.
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Anticorpos Monoclonais , Melanoma , Feminino , Humanos , Masculino , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/uso terapêutico , Melanoma/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1 , Estudos RetrospectivosRESUMO
Melanoma is the most lethal form of skin cancer, resulting from the malignant transformation of epidermal melanocytes. Recent revolutionary progress in targeted therapy and immunotherapy has prominently improved the treatment outcome, but the survival of melanoma patients remains suboptimal. Ferroptosis is greatly involved in cancer pathogenesis and can execute the outcome of immunotherapy. However, the detailed regulatory mechanisms of melanoma cell ferroptosis remain elusive. Herein, we report that Wnt/ß-catenin signaling regulates ferroptosis and melanoma immunotherapy efficacy via the regulation of MITF. First of all, we found that Wnt/ß-catenin signaling was prominently suppressed in melanoma cell ferroptosis. Then, we proved that targeting ß-catenin exacerbated melanoma cell ferroptosis by promoting the generation of lipid peroxidation both in vitro and in vivo. Subsequent mechanistic studies revealed that MITF mediated the effect of Wnt/ß-catenin signaling on melanoma cell ferroptosis, and PGC1α and SCD1 were documented as two main effectors downstream of Wnt/ß-catenin-MITF pathway. Ultimately, pharmacological inhibition of ß-catenin or MITF increased the efficacy of anti-PD-1 immunotherapy in preclinical xenograft tumor model by promoting ferroptosis. Taken together, Wnt/ß-catenin signaling deficiency exacerbates ferroptosis in melanoma via the regulation of MITF. Targeting Wnt/ß-catenin-MITF pathway could be a promising strategy to potentiate ferroptosis and increase the efficacy of anti-PD-1 immunotherapy.
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Ferroptose , Melanoma , Humanos , beta Catenina/metabolismo , Proteínas Wnt/metabolismo , Melanoma/patologia , Via de Sinalização Wnt , Imunoterapia , Fator de Transcrição Associado à Microftalmia/metabolismoRESUMO
Multiple myeloma (MM) is an incurable hematological malignancy that lacks effective therapeutic interventions. Ferroptosis is a newly discovered form of cell death that has shown great potential for MM therapy. As a proteasome inhibitor and necroptosis inducer, shikonin (SHK) performs dual functions in MM cells. However, whether SHK inhibits the development of MM via ferroptosis or any other mechanism remains elusive. Here, we provide evidence that SHK treatment was capable of inducing ferroptosis and immunogenic cell death (ICD) in MM. The results showed that SHK treatment induced lactate dehydrogenase release, triggered cell death, evoked oxidative stress, and enhanced ferrous iron and lipid peroxidation levels. Furthermore, treatment with ferroptosis inhibitors reversed SHK-induced cell death, which indicated that ferroptosis contributed to this phenomenon. Meanwhile, ferroptosis was accompanied by the extracellular release of Adenosine 5'-triphosphate (ATP) and High mobility group protein B1 (HMGB1), which are characteristics of ICD. Further investigation showed that glutamic-oxaloacetic transaminase 1 (GOT1) acted as a critical mediator of SHK-induced ferroptosis by promoting ferritinophagy. In conclusion, our findings suggest that SHK exerts ferroptotic effects on MM by regulating GOT1-mediated ferritinophagy. Thus, SHK is a potential therapeutic agent for MM.
RESUMO
A series of functional biomaterials with different sizes and morphologies can be constructed through self-assembly, among which amphiphilic peptide-based materials have received intense attention. One main possible reason is that the short amphiphilic peptides can facilitate the formation of versatile materials and promote their further applications in different fields. Another reason is that the simple structure of amphiphilic peptides can help establish the structure-function relationship. This review highlights the recent advances in the self-assembly of two typical peptide species, surfactant-like peptides (SLPs) and peptides amphiphiles (PAs). These peptides can self-assemble into diverse nanostructures. The formation of these different nanostructures resulted from the delicate balance of varied non-covalent interactions. This review embraced each non-covalent interaction and then listed the typical routes for regulating these non-covalent interactions, then realized the morphologies modulation of the self-assemblies. Finally, their applications in some biomedical fields, such as the stabilization of membrane proteins, templating for nanofabrication and biomineralization, acting as the antibacterial and antitumor agents, hemostasis, and synthesis of melanin have been summarized. Further advances in the self-assembly of SLPs and PAs may focus on the design of functional materials with targeted properties and exploring their improved properties.
Assuntos
Nanoestruturas , Peptídeos , Humanos , Peptídeos/farmacologia , Peptídeos/química , Nanoestruturas/química , Materiais Biocompatíveis/química , Tensoativos/químicaRESUMO
BACKGROUND: Although anti-programmed cell death protein 1 (PD-1) immunotherapy is greatly effective in melanoma treatment, low response rate and treatment resistance significantly hinder its efficacy. Tumor cell ferroptosis triggered by interferon (IFN)-γ that is derived from tumor-infiltrating CD8+ T cells greatly contributes to the effect of immunotherapy. However, the molecular mechanism underlying IFN-γ-mediated ferroptosis and related potentially promising therapeutic strategy warrant further clarification. MicroRNAs (miRNAs) participate in ferroptosis execution and can be delivered systemically by multiple carriers, which have manifested obvious therapeutic effects on cancer. METHODS: MiRNAs expression profile in IFN-γ-driven ferroptosis was obtained by RNA sequencing. Biochemical assays were used to clarify the role of miR-21-3p in IFN-γ-driven ferroptosis and the underlying mechanism. MiR-21-3p-loaded gold nanoparticles were constructed and systemically applied to analyze the role of miR-21-3p in anti-PD-1 immunotherapy in preclinical transplanted tumor model. RESULTS: MiRNAs expression profile of melanoma cells in IFN-γ-driven ferroptosis was first obtained. Then, upregulated miR-21-3p was proved to facilitate IFN-γ-mediated ferroptosis by potentiating lipid peroxidation. miR-21-3p increased the ferroptosis sensitivity by directly targeting thioredoxin reductase 1 (TXNRD1) to enhance lipid reactive oxygen species (ROS) generation. Furthermore, miR-21-3p overexpression in tumor synergized with anti-PD-1 antibody by promoting tumor cell ferroptosis. More importantly, miR-21-3p-loaded gold nanoparticles were constructed, and the systemic delivery of them increased the efficacy of anti-PD-1 antibody without prominent side effects in preclinical mice model. Ultimately, ATF3 was found to promote miR-21-3p transcription in IFN-γ-driven ferroptosis. CONCLUSIONS: MiR-21-3 p upregulation contributes to IFN-γ-driven ferroptosis and synergizes with anti-PD-1 antibody. Nanoparticle delivery of miR-21-3 p is a promising therapeutic approach to increase immunotherapy efficacy without obvious systemic side effects.