RESUMEN
Sexual dimorphism affects various biological functions, including immune responses. However, the mechanisms by which sex alters immunity remain largely unknown. Using Caenorhabditis elegans as a model species, we showed that males exhibit enhanced immunity against various pathogenic bacteria through the upregulation of HLH-30 (Helix Loop Helix 30/TFEB (transcription factor EB)), a transcription factor crucial for macroautophagy/autophagy. Compared with hermaphroditic C. elegans, males displayed increased activity of HLH-30/TFEB, which contributed to enhanced antibacterial immunity. atg-2 (AuTophaGy (yeast Atg homolog) 2) upregulated by HLH-30/TFEB mediated increased immunity in male C. elegans. Thus, the males appear to be equipped with enhanced HLH-30/TFEB-mediated autophagy, which increases pathogen resistance, and this may functionally prolong mate-searching ability with reduced risk of infection.Abbreviations: atg-2: AuTophaGy (yeast Atg homolog) 2; FUDR: 5-fluoro-2'-deoxyuridine; GSEA: gene set enrichment analysis; HLH-30: Helix Loop Helix 30; LC3: microtubule associated protein 1 light chain 3; NGM: nematode growth media; RNA-seq: RNA sequencing; SEM: standard error of the mean; TFEB: transcription factor EB; WT: wild-type.
RESUMEN
Importance: Vitiligo is a multifactorial, depigmenting skin disorder characterized by selective loss of melanocytes. Large-scale studies are lacking to determine the risk of vitiligo in transplant recipients with graft-vs-host disease (GVHD). Objective: To investigate the incidence rates and risk of vitiligo in patients who had received solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) overall and by HSCT graft type and concomitant GVHD. Design, Setting, and Participants: This population-based cohort study included data from the National Health Insurance Service database of Korea for patients aged 20 years or older who had received a transplant (SOT or HSCT) between January 2010 and December 2017, with follow-up until December 2019. A cohort of age- and sex-matched (1:5) control individuals who did not receive a transplant was included for comparison. Data were analyzed from July 2021 to December 2021. Exposure: Transplant (SOT or HSCT) and GVHD. Main Outcomes and Measures: The main outcome was risk of vitiligo, assessed using multivariable Cox proportional hazards regression analyses adjusting for potential confounding factors. Results: The study included 23â¯829 patients who had undergone SOT or HSCT (62.78% male; mean [SD] age, 49.58 [11.59] years) and 119â¯145 age- and sex-matched controls. Patients who had undergone transplant had a significantly higher risk of vitiligo compared with controls (adjusted hazard ratio [AHR], 1.73; 95% CI, 1.35-2.22). Risk of vitiligo was also slightly higher in kidney transplant recipients and liver transplant recipients compared with the controls but was highest in HSCT recipients (AHR, 12.69; 95% CI, 5.11-31.50). Patients who had received allogeneic grafts (AHR, 14.43; 95% CI, 5.61-37.15), those who had received autologous grafts (AHR, 5.71; 95% CI, 1.20-3.18), those with comorbid GVHD (AHR, 24.09; 95% CI, 9.16-63.35), and those without GVHD (AHR, 8.21; 95% CI, 3.08-21.87) had a higher risk of vitiligo compared with controls. Conclusion and Relevance: In this study, risk of vitiligo was significantly higher in transplant recipients, especially in HSCT recipients and those with allogeneic grafts or comorbid GVHD. These findings provide new insights into the association between the risk of vitiligo and transplant and GVHD. Clinicians should be aware of these risks, implementing a multidisciplinary approach for monitoring.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Vitíligo , Humanos , Masculino , Persona de Mediana Edad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Vitíligo/epidemiología , Vitíligo/etiología , Estudios de Cohortes , Receptores de Trasplantes , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Estudios RetrospectivosRESUMEN
Eccrine angiomatous hamartoma (EAH) is a benign skin nodule characterized by the proliferation of eccrine glands and vascular structures in the dermis. It usually presents as a single papule or nodule on the extremities, and usually arises at birth or in early childhood, but several cases which appeared in adulthood have been reported. A 52-year-old female presented with a tender subungual nodule on the right great toenail for 3 months. Skin biopsy from the lesion showed proliferation of eccrine glands and capillaries in the dermis, and immunohistochemistry confirmed the diagnosis of EAH. We excised it as a treatment, and at the 3-month follow-up, pain by her lesion has resolved without any adverse effects. Our presented case is an adult-onset EAH that occurred as a subungual lesion. Unlike the previous cases, it did not cause any nail deformity or destruction and initially was misinterpreted as some other subungual tender nodule. To the best of our knowledge, we report the first case of adult-onset subungual EAH without nail deformity.
RESUMEN
Since a mixed state of environmental contaminants, including microplastics (MPs), heavy metals, pharmaceuticals, and personal care products (PPCPs), exists in aquatic ecosystems, it is necessary to evaluate not only the adverse effects of exposure to a single stressor but to combined stressors. In this study, we exposed the freshwater water flea Daphnia magna to 2⯵m MPs and triclosan (TCS), one of PPCPs, for 48â¯h to investigate the synergistic toxic consequences of simultaneous exposure to both pollutants. We measured in vivo endpoints, antioxidant responses, multixenobiotic resistance (MXR) activity, and autophagy-related protein expression via the PI3K/Akt/mTOR and MAPK signaling pathways. While MPs single exposure did not show toxic effects in water fleas, simultaneous exposure to TCS and MPs was associated with significantly greater deleterious effects in the form of increased mortality and alterations in antioxidant enzymatic activities compared with water fleas exposed to TCS alone. In addition, MXR inhibition was confirmed by measurement of the expression of P-glycoproteins and multidrug-resistance proteins in MPs-exposed groups, which led to the accumulation of TCS. Overall, these results suggest that simultaneous exposure to MPs and TCS resulted in higher TCS accumulation via MXR inhibition, leading to synergistic toxic effects such as autophagy in D. magna.
Asunto(s)
Cladóceros , Triclosán , Contaminantes Químicos del Agua , Animales , Microplásticos/toxicidad , Daphnia , Plásticos/metabolismo , Triclosán/metabolismo , Ecosistema , Antioxidantes/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Agua Dulce , Contaminantes Químicos del Agua/análisisRESUMEN
Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.
Asunto(s)
Aconitato Hidratasa , Caenorhabditis elegans , Humanos , Animales , Aconitato Hidratasa/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Ácido Oxaloacético , Oxaloacetatos , Respuesta de Proteína Desplegada , Mamíferos/metabolismoRESUMEN
Aging is associated with changes in a variety of biological processes at the transcriptomic level, including gene expression. Two types of aging occur during a lifetime: chronological and physiological aging. However, dissecting the difference between chronological and physiological ages at the transcriptomic level has been a challenge because of its complexity. We analyzed the transcriptomic features associated with physiological and chronological aging using Caenorhabditis elegans as a model. Many structural and functional transcript elements, such as noncoding RNAs and intron-derived transcripts, were up-regulated with chronological aging. In contrast, mRNAs with many biological functions, including RNA processing, were down-regulated with physiological aging. We also identified an age-dependent increase in the usage of distal 3' splice sites in mRNA transcripts as a biomarker of physiological aging. Our study provides crucial information for dissecting chronological and physiological aging at the transcriptomic level.
Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Envejecimiento/genética , Envejecimiento/metabolismo , Perfilación de la Expresión Génica , Proteínas de Caenorhabditis elegans/genética , TranscriptomaRESUMEN
Treatment options for Bowen's disease (BD) include surgical excision, cryotherapy, curettage with cautery, topical 5-fluorouracil or imiquimod, and photodynamic therapy. However, it is not clear which treatment is the most effective due to lack of studies. We reviewed the electronic medical records of 158 patients who were diagnosed with BD and treated at Seoul St. Mary's Hospital from January 2011 to December 2020. Treatment modalities were surgical excision, cryotherapy, photodynamic therapy, and imiquimod. A total of 121 patients was enrolled in this study. The average treatment period was longest for cryotherapy, followed by imiquimod, PDT, and excision (119.53, 87.75, 68.50, and 1 day, respectively). The therapeutic efficacy was highest in the surgical excision group (100%) and lowest in the PDT group (62.5%). The recurrence rate was highest in the imiquimod group (33.33%). Surprisingly, only in patients treated with cryotherapy, satellite lesions developed in 9.09% of them during follow-up. Surgical excision exhibited the highest clearance rate and the lowest recurrence rate, and its treatment period was the shortest, confirming that it remains the gold standard. In contrast, since cryotherapy demonstrated a relatively high recurrence rate including development of satellite lesions, careful monitoring is required when performing cryotherapy for treatment of BD.
RESUMEN
BACKGROUND/AIM: Pyruvate kinase M2 (PKM2) functions as an important rate-limiting enzyme in aerobic glycolysis and is involved in tumor initiation and progression. However, there are few studies on the correlation between PKM2 expression and its role in glioma. MATERIALS AND METHODS: PKM2 expression was immunohistochemically examined in human brain tumor samples. Furthermore, we studied the effects of two PKM2 inhibitors (shikonin and compound 3K) on the U87MG glioma cell line. RESULTS: PKM2 was overexpressed in most glioma tissues when compared to controls. Interestingly, glioma-adjacent tissues from showed slight PKM2 overexpression. This suggests that PKM2 overexpression maybe an important trigger factor for glioma tumorigenesis. We found that the PKM2 inhibitor shikonin was effective against U87MG cells at a relatively low dose and was largely dependent on low cellular density compared to the effects of the anticancer drug vincristine. Shikonin highly increased late-apoptosis of U87MG cells. We also demonstrated that autophagy was involved in the increase in late-apoptosis levels caused by shikonin. Although vincristine treatment led to a high level of G2-phase arrest in U87MG cells, shikonin did not increase G2 arrest. Co-treatment with two PKM2 inhibitors, shikonin and compound 3K, increased the inhibitory effects. CONCLUSION: Combination therapy with PKM2 inhibitors together might be more effective than combination therapy with anticancer drugs. Our findings encourage the application of PKM2-targeting in gliomas, and lay the foundation for the development of PKM2 inhibitors as promising antitumor agents for glioma.
Asunto(s)
Antineoplásicos , Proteínas Portadoras , Glioma , Proteínas de la Membrana , Hormonas Tiroideas , Antineoplásicos/farmacología , Apoptosis/genética , Proteínas Portadoras/biosíntesis , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Proteínas de la Membrana/biosíntesis , Inhibidores de Proteínas Quinasas/farmacología , Piruvato Quinasa/metabolismo , Piruvato Quinasa/farmacología , Hormonas Tiroideas/biosíntesis , Proteínas de Unión a Hormona TiroideRESUMEN
Metabolic syndrome (MetS) is associated with psoriasis, but it remains unclear whether risk of psoriasis remains in patients whose MetS diagnosis changes. To assess the relationship between risk of psoriasis and changes in MetS components. We obtained data from the National Health Insurance Service of Korea and divided the participants into four groups: individuals without MetS (control); individuals with MetS in 2009, but without MetS in 2012 (pre-MetS); individuals without MetS in 2009, but with newly diagnosed MetS in 2012 (post-MetS); and individuals with MetS during the 2009-2012, period (continuous-MetS). We calculated the risk of psoriasis for each group. Risk of psoriasis was similar in the control and pre-MetS groups but was significantly higher in the post-MetS group (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.04-1.12) and in the continuous-MetS group (HR, 1.11; 95% CI, 1.07-1.15) than in the control group. Among MetS components, waist circumference showed the strongest association with psoriasis, followed by high-density lipoprotein and triglyceride levels. Risk of psoriasis was higher in patients with continuous- or post-MetS than in those with pre-MetS (regardless of prior MetS status).
Asunto(s)
Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Psoriasis/epidemiología , Psoriasis/etiología , Adulto , Anciano , Anciano de 80 o más Años , Susceptibilidad a Enfermedades , Femenino , Humanos , Incidencia , Masculino , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Vigilancia de la Población , Modelos de Riesgos Proporcionales , Sistema de Registros , República de Corea , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Y RNA is a conserved small non-coding RNA whose functions in aging remain unknown. Here, we sought to determine the role of C. elegans Y RNA homologs, CeY RNA (CeY) and stem-bulge RNAs (sbRNAs), in aging. We found that the levels of CeY and sbRNAs generally increased during aging. We showed that CeY was downregulated by oxidative and thermal stresses, whereas several sbRNAs were upregulated by oxidative stress. We did not observe lifespan phenotypes by mutations in CeY-coding yrn-1. Future research under various genetic and environmental conditions is required to further evaluate the role of Y RNA in C. elegans aging.
RESUMEN
Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in numerous species. In Caenorhabditis elegans, mutations in the daf-2/insulin/IGF-1 receptor dramatically increase lifespan and immunity, but generally impair motility, growth, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in insulin/IGF-1 signaling pathway remains unknown. Through performing a mutagenesis screen, we identified a missense mutation daf-18(yh1) that alters a cysteine to tyrosine in DAF-18/PTEN phosphatase, which maintained the long lifespan and enhanced immunity, while improving the reduced motility in adult daf-2 mutants. We showed that the daf-18(yh1) mutation decreased the lipid phosphatase activity of DAF-18/PTEN, while retaining a partial protein tyrosine phosphatase activity. We found that daf-18(yh1) maintained the partial activity of DAF-16/FOXO but restricted the detrimental upregulation of SKN-1/NRF2, contributing to beneficial physiological traits in daf-2 mutants. Our work provides important insights into how one evolutionarily conserved component, PTEN, can coordinate animal health and longevity.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Longevidad/genética , Mutación , Fosfohidrolasa PTEN/genética , Receptor IGF Tipo 1/genética , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Aptitud Genética/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Microscopía Fluorescente/métodos , Fosfohidrolasa PTEN/metabolismo , RNA-Seq/métodos , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismoRESUMEN
A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, including Caenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age in C. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(-) animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.
Asunto(s)
Envejecimiento/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Insulina/metabolismo , Transducción de Señal/fisiología , Animales , Caenorhabditis elegans/metabolismo , Regulación hacia Abajo/fisiología , Factores de Transcripción Forkhead/metabolismo , Longevidad/fisiología , Receptor de Insulina/metabolismo , Activación Transcripcional/fisiología , Regulación hacia Arriba/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Dietary restriction extends lifespan in various organisms by reducing the levels of both nutrients and non-nutritional food-derived cues. However, the identity of specific food-derived chemical cues that alter lifespan remains unclear. Here, we identified several volatile attractants that decreased the longevity on food deprivation, a dietary restriction regimen in Caenorhabditis elegans. In particular, we found that the odor of diacetyl decreased the activity of DAF-16/FOXO, a life-extending transcription factor acting downstream of insulin/IGF-1 signaling. We then demonstrated that the odor of lactic acid bacteria, which produce diacetyl, reduced the nuclear accumulation of DAF-16/FOXO. Unexpectedly, we showed that the odor of diacetyl decreased longevity independently of two established diacetyl receptors, ODR-10 and SRI-14, in sensory neurons. Thus, diacetyl, a food-derived odorant, may shorten food deprivation-induced longevity via decreasing the activity of DAF-16/FOXO through binding to unidentified receptors.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Diacetil/efectos adversos , Factores de Transcripción Forkhead/metabolismo , Odorantes/análisis , Animales , Dietoterapia , Regulación hacia Abajo , LongevidadRESUMEN
Nonsense-mediated mRNA decay (NMD) is a biological surveillance mechanism that eliminates mRNA transcripts with premature termination codons. In Caenorhabditis elegans, NMD contributes to longevity by enhancing RNA quality. Here, we aimed at identifying NMD-modulating factors that are crucial for longevity in C. elegans by performing genetic screens. We showed that knocking down each of algn-2/asparagine-linked glycosylation protein, zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule increased the transcript levels of NMD targets. Among these, algn-2 exhibited an age-dependent decrease in its expression and was required for maintaining normal lifespan and for longevity caused by various genetic interventions. We further demonstrated that upregulation of ALGN-2 by inhibition of daf-2/insulin/IGF-1 receptor contributed to longevity in an NMD-dependent manner. Thus, algn-2, a positive regulator of NMD, plays a crucial role in longevity in C. elegans, likely by enhancing RNA surveillance. Our study will help understand how NMD-mediated mRNA quality control extends animal lifespan.
RESUMEN
Vaccinia virus-related kinase (VRK) is an evolutionarily conserved nuclear protein kinase. VRK-1, the single Caenorhabditis elegans VRK ortholog, functions in cell division and germline proliferation. However, the role of VRK-1 in postmitotic cells and adult life span remains unknown. Here, we show that VRK-1 increases organismal longevity by activating the cellular energy sensor, AMP-activated protein kinase (AMPK), via direct phosphorylation. We found that overexpression of vrk-1 in the soma of adult C. elegans increased life span and, conversely, inhibition of vrk-1 decreased life span. In addition, vrk-1 was required for longevity conferred by mutations that inhibit C. elegans mitochondrial respiration, which requires AMPK. VRK-1 directly phosphorylated and up-regulated AMPK in both C. elegans and cultured human cells. Thus, our data show that the somatic nuclear kinase, VRK-1, promotes longevity through AMPK activation, and this function appears to be conserved between C. elegans and humans.
RESUMEN
Excessive glucose causes various diseases and decreases lifespan by altering metabolic processes, but underlying mechanisms remain incompletely understood. Here, we show that Lipin 1/LPIN-1, a phosphatidic acid phosphatase and a putative transcriptional coregulator, prevents life-shortening effects of dietary glucose on Caenorhabditis elegans. We found that depletion of lpin-1 decreased overall lipid levels, despite increasing the expression of genes that promote fat synthesis and desaturation, and downregulation of lipolysis. We then showed that knockdown of lpin-1 altered the composition of various fatty acids in the opposite direction of dietary glucose. In particular, the levels of two ω-6 polyunsaturated fatty acids (PUFAs), linoleic acid and arachidonic acid, were increased by knockdown of lpin-1 but decreased by glucose feeding. Importantly, these ω-6 PUFAs attenuated the short lifespan of glucose-fed lpin-1-inhibited animals. Thus, the production of ω-6 PUFAs is crucial for protecting animals from living very short under glucose-rich conditions.
Asunto(s)
Caenorhabditis elegans/enzimología , Ácidos Grasos Insaturados/metabolismo , Glucosa/metabolismo , Fosfatidato Fosfatasa/metabolismo , Animales , Caenorhabditis elegans/metabolismo , Dieta , HumanosRESUMEN
The oligosaccharyl transferase (OST) protein complex mediates the N-linked glycosylation of substrate proteins in the endoplasmic reticulum (ER), which regulates stability, activity, and localization of its substrates. Although many OST substrate proteins have been identified, the physiological role of the OST complex remains incompletely understood. Here we show that the OST complex in C. elegans is crucial for ER protein homeostasis and defense against infection with pathogenic bacteria Pseudomonas aeruginosa (PA14), via immune-regulatory PMK-1/p38 MAP kinase. We found that genetic inhibition of the OST complex impaired protein processing in the ER, which in turn up-regulated ER unfolded protein response (UPRER). We identified vitellogenin VIT-6 as an OST-dependent glycosylated protein, critical for maintaining survival on PA14. We also showed that the OST complex was required for up-regulation of PMK-1 signaling upon infection with PA14. Our study demonstrates that an evolutionarily conserved OST complex, crucial for ER homeostasis, regulates host defense mechanisms against pathogenic bacteria.