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1.
Medicine (Baltimore) ; 103(40): e39943, 2024 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-39465768

RESUMEN

This study aimed to examine the association between constipation and mild cognitive impairment (MCI); and further elucidate the possible mechanisms involved. A cross-sectional study was conducted among community-dwelling elders (N = 789) in Nanning, China. Trained research staffs collected detailed information through questionnaires and physical examinations. A Bayesian network model was used to explore the hypothesized causal path. Synergistic effects of constipation with infrequent fruit consumption, inactive physical exercise, or history of stroke were observed in the risks of MCI occurrence. The Bayesian network model analyses showed 3 hypothesized causal-association paths leading to MCI occurrence. Among these, constipation, history of stroke, and years of schooling were directly related to the occurrence of MCI. Years of schooling indirectly affected MCI through infrequent fruit consumption and constipation; or through inactive physical exercises and history of stroke. This study demonstrates a direct association between constipation and increased risks of MCI.


Asunto(s)
Disfunción Cognitiva , Estreñimiento , Humanos , Estreñimiento/epidemiología , Estreñimiento/complicaciones , Disfunción Cognitiva/epidemiología , Estudios Transversales , Masculino , Anciano , Femenino , China/epidemiología , Teorema de Bayes , Factores de Riesgo , Vida Independiente/estadística & datos numéricos , Ejercicio Físico , Anciano de 80 o más Años , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/complicaciones , Persona de Mediana Edad , Encuestas y Cuestionarios
2.
Mech Ageing Dev ; 221: 111963, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38986790

RESUMEN

Aging, a complex biological process influenced by genetic, environmental, and pharmacological factors, presents a significant challenge in understanding its underlying mechanisms. In this study, we explored the divergent impacts of metformin treatment on the lifespan and healthspan of young and old C. elegans, demonstrating a intriguing "elixir in youth, poison in elder" phenomenon. By scrutinizing the gene expression changes in response to metformin in young (day 1 of adulthood) and old (days 8) groups, we identified nhr-57 and C46G7.1 as potential modulators of age-specific responses. Notably, nhr-57 and C46G7.1 exhibit contrasting regulation patterns, being up-regulated in young worms but down-regulated in old counterparts following metformin treatment. Functional studies employing knockdown approaches targeting nhr-57, a gene under the control of hif-1 with a documented protective function against pore-forming toxins in C. elegans, and C46G7.1, unveiled their critical roles in modulating lifespan and healthspan, as well as in mediating the biphasic effects of metformin. Furthermore, deletion of hif-1 retarded the influence of metformin, implicating the involvement of hif-1/nhr-57 in age-specific drug responses. These findings underscored the necessity of deciphering the mechanisms governing age-related susceptibility to pharmacological agents to tailor interventions for promoting successful aging.


Asunto(s)
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Longevidad , Metformina , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Metformina/farmacología , Longevidad/efectos de los fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Envejecimiento/efectos de los fármacos , Hipoglucemiantes/farmacología
3.
J Appl Toxicol ; 44(10): 1528-1539, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38840409

RESUMEN

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.


Asunto(s)
Envejecimiento , Antiinflamatorios no Esteroideos , Caenorhabditis elegans , Longevidad , Estrés Oxidativo , Animales , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Antiinflamatorios no Esteroideos/toxicidad , Longevidad/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Acetaminofén/toxicidad , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ibuprofeno/toxicidad , Aspirina/toxicidad , Especies Reactivas de Oxígeno/metabolismo
4.
J Hepatol ; 81(3): 389-403, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38670321

RESUMEN

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/etiología , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Interferón gamma/metabolismo , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/inmunología
5.
Cancer Lett ; 587: 216728, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38431036

RESUMEN

Lysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes' central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.


Asunto(s)
Hierro , Neoplasias , Humanos , Muerte Celular , Hierro/metabolismo , Ferritinas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Lisosomas/metabolismo
6.
Rice (N Y) ; 17(1): 14, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38351214

RESUMEN

Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most devastating diseases for rice crops, significantly affecting crop yield and quality. During the infection process, M. oryzae secretes effector proteins that help in hijacking the host's immune responses to establish infection. However, little is known about the interaction between the effector protein AvrPik-D and the host protein Pikh, and how AvrPik-D increases disease severity to promote infection. In this study, we show that the M. oryzae effector AvrPik-D interacts with the zinc finger-type transcription factor WG7 in the nucleus and promotes its transcriptional activity. Genetic removal (knockout) of the gene WG7 in transgenic rice enhances resistance to M. oryzae and also results in an increased burst of reactive oxygen species after treatments with chitin. In addition, the hormone level of SA and JA, is increased and decreased respectively in WG7 KO plants, indicating that WG7 may negatively mediate resistance through salicylic acid pathway. Conversely, WG7 overexpression lines reduce resistance to M. oryzae. However, WG7 is not required for the Pikh-mediated resistance against rice blast. In conclusion, our results revealed that the M. oryzae effector AvrPik-D targets and promotes transcriptional activity of WG7 to suppress rice innate immunity to facilitate infection.

7.
Appl Microbiol Biotechnol ; 108(1): 228, 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38386129

RESUMEN

Fusarium verticillioides is one of the most important fungal pathogens causing maize ear and stalk rots, thereby undermining global food security. Infected seeds are usually unhealthy for consumption due to contamination with fumonisin B1 (FB1) mycotoxin produced by the fungus as a virulence factor. Unveiling the molecular factors that determine fungal development and pathogenesis will help in the control and management of the diseases. Kex2 is a kexin-like Golgi-resident proprotein convertase that is involved in the activation of some important proproteins. Herein, we identified and functionally characterized FvKex2 in relation to F. verticillioides development and virulence by bioinformatics and functional genomics approaches. We found that FvKex2 is required for the fungal normal vegetative growth, because the growth of the ∆Fvkex2 mutant was significantly reduced on culture media compared to the wild-type and complemented strains. The mutant also produced very few conidia with morphologically abnormal shapes when compared with those from the wild type. However, the kexin-like protein was dispensable for the male role in sexual reproduction in F. verticillioides. In contrast, pathogenicity was nearly abolished on wounded maize stalks and sugarcane leaves in the absence of FvKEX2 gene, suggesting an essential role of Fvkex2 in the virulence of F. verticillioides. Furthermore, high-performance liquid chromatography analysis revealed that the ∆Fvkex2 mutant produced a significantly lower level of FB1 mycotoxin compared to the wild-type and complemented strains, consistent with the loss of virulence observed in the mutant. Taken together, our results indicate that FvKex2 is critical for vegetative growth, FB1 biosynthesis, and virulence, but dispensable for sexual reproduction in F. verticillioides. The study presents the kexin-like protein as a potential drug target for the management of the devastating maize ear and stalk rot diseases. Further studies should aim at uncovering the link between FvKex2 activity and FB1 biosynthesis genes. KEY POINTS: •The kexin-like protein FvKex2 contributes significantly to the vegetative growth of Fusarium verticillioides. •The conserved protein is required for fungal conidiation and conidial morphology, but dispensable for sexual reproduction. •Deletion of FvKEX2 greatly attenuates the virulence and mycotoxin production potential of F. verticillioides.


Asunto(s)
Fumonisinas , Fusarium , Micotoxinas , Masculino , Humanos , Micotoxinas/genética , Virulencia
8.
Int J Biol Macromol ; 261(Pt 2): 129841, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38309401

RESUMEN

The transcription factor FgHtf1 is important for conidiogenesis in Fusarium graminearum and it positively regulates the expression of the sporulation-related gene FgCON7. However, the regulatory mechanism underlying its functions is still unclear. The present study intends to uncover the functional mechanism of FgHtf1 in relation to FgCon7 in F. graminearum. We demonstrated that FgCON7 serves as a target gene for FgHtf1. Interestingly, FgCon7 also binds the promoter region of FgHTF1 to negatively regulate its expression, thus forming a negative-feedback loop. We demonstrated that FgHtf1 and FgCon7 have functional redundancy in fungal development. FgCon7 localizes in the nucleus and has transcriptional activation activity. Deletion of FgCON7 significantly reduces conidia production. 4444 genes were regulated by FgCon7 in ChIP-Seq, and RNA-Seq revealed 4430 differentially expressed genes in FgCON7 deletion mutant, with CCAAT serving as a consensus binding motif of FgCon7 to the target genes. FgCon7 directly binds the promoter regions of FgMSN2, FgABAA, FgVEA and FgSMT3 genes and regulates their expression. These genes were found to be important for conidiogenesis. To our knowledge, this is the first study that unveiled the mutual regulatory functions of FgCON7 and FgHTF1 to form a negative-feedback loop, and how the loop mediates sporulation in F. graminearum.


Asunto(s)
Fusarium , Factores de Transcripción , Retroalimentación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Fusarium/fisiología , Expresión Génica , Regulación Fúngica de la Expresión Génica , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Enfermedades de las Plantas/microbiología
9.
Int J Biol Macromol ; 261(Pt 2): 129793, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38290627

RESUMEN

A water-soluble glycopeptide (named GL-PWQ3) with a molecular weight (Mw) of 2.40 × 104 g/mol was isolated from Ganoderma lucidum fruiting body by hot water extraction, membrane ultrafiltration, and gel column chromatography, which mainly consisted of glucose and galactose. Based on the methylation, FT-IR, 1D, and 2D NMR analysis, the polysaccharide portion of GL-PWQ3 was identified as a glucogalactan, which was comprised of unsubstituted (1,6-α-Galp, 1,6-ß-Glcp, 1,4-ß-Glcp) and monosubstituted (1,2,6-α-Galp and 1,3,6-ß-Glcp) in the backbone and possible branches that at the O-3 position of 1,3-Glcp and T-Glcp, and the O-2 position of T-Fucp, T-Manp or T-Glcp. The chain conformational study by SEC-MALLS-RI and AFM revealed that GL-PWQ3 was identified as a highly branched polysaccharide with a polydispersity index of 1.25, and might have compact sphere structures caused by stacked multiple chains. Moreover, the GL-PWQ3 shows strong anti-oxidative activity in NRK-52E cells. This study provides a theoretical basis for further elucidating the structure-functionality relationships of GL-PWQ3 and its potential application as a natural antioxidant in pharmacotherapy as well as functional food additives.


Asunto(s)
Reishi , Reishi/química , Espectroscopía Infrarroja por Transformada de Fourier , Polisacáridos/química , Glucosa/análisis , Peso Molecular , Agua
10.
Phytomedicine ; 121: 155089, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37738908

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly lethal cancer characterized by dominant driver mutations, including p53. Consequently, there is an urgent need to search for novel therapeutic agents to treat HCC. Andrographolide (Andro), a clinically available anti-inflammatory phytochemical agent, has shown inhibitory effects against various types of cancer, including HCC. However, the underlying molecular mechanisms of its action remain poorly understood. PURPOSE: This study aims to investigate the molecular mechanisms by which p53 and p62 collectively affect Andro-induced HCC cell death, using both in vitro and in vivo models. METHODS: In vitro cellular experiments were conducted to examine the effects of Andro on cell viability and elucidate its mechanisms of action. In vivo xenograft experiments further validated the anti-cancer effects of Andro. RESULTS: Andro induced dose- and time-dependent HCC cell death while sparing normal HL-7702 hepatocytes. Furthermore, Andro caused DNA damage through the generation of reactive oxygen species (ROS), a critical event leading to cell death. Notably, HCC cells expressing p53 exhibited greater resistance to Andro-induced cell death compared to p53-deficient cells, likely due to the ability of p53 to induce G2/M cell cycle arrest. Additionally, Andro-induced p62 aggregation led to the proteasomal degradation of RAD51 and 53BP1, two key proteins involved in DNA damage repair. Consequently, silencing or knocking out p62 facilitated DNA damage repair and protected HCC cells. Importantly, disruption of either p53 or p62 did not affect the expression of the other protein. These findings were further supported by the observation that xenograft tumors formed by p62-knockout HCC cells displayed increased resistance to Andro treatment. CONCLUSION: This study elucidates the mechanistic basis of Andro-induced HCC cell death. It provides valuable insights for repurposing Andro for the treatment of HCC, regardless of the presence of functional p53.


Asunto(s)
Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Humanos , Apoptosis , Carcinoma Hepatocelular/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Muerte Celular , Diterpenos/farmacología , Diterpenos/uso terapéutico , Línea Celular Tumoral , Antiinflamatorios/farmacología , Daño del ADN
11.
ACS Chem Neurosci ; 14(17): 2995-3012, 2023 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-37579022

RESUMEN

Ferroptosis is increasingly being recognized as a key element in the pathogenesis of diverse diseases. Recent studies have highlighted the intricate links between iron metabolism and neurodegenerative disorders. Emerging evidence suggests that iron homeostasis, oxidative stress, and neuroinflammation all contribute to the regulation of both ferroptosis and neuronal health. However, the precise molecular mechanisms underlying the involvement of ferroptosis in the pathological processes of neurodegeneration and its impact on neuronal dysfunction remain incompletely understood. In our Review, we provide a comprehensive analysis and summary of the potential molecular mechanisms underlying ferroptosis in neurodegenerative diseases, aiming to elucidate the disease progression of neurodegeneration. Additionally, we discuss potential therapeutic agents that modulate ferroptosis with the goal of identifying novel drug molecules for the treatment of neurodegenerative disorders.


Asunto(s)
Ferroptosis , Enfermedades Neurodegenerativas , Muerte Celular Regulada , Humanos , Progresión de la Enfermedad , Hierro
12.
Toxics ; 11(2)2023 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-36851037

RESUMEN

Microcystin-LR (MCLR) is an aquatic toxin, which could lead to the development of hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are considered important regulatory elements in the occurrence and development of cancer. However, the roles and mechanisms of lncRNAs during the process of HCC, induced by MCLR, remain elusive. Here, we identified a novel lncRNA, namely lnc-GCLC-1 (lncGCLC), which is in close proximity to the chromosome location of glutamate-cysteine ligase catalytic subunit (GCLC). We then investigated the role of lncGCLC in MCLR-induced malignant transformation of WRL68, a human hepatic cell line. During MCLR-induced cell transformation, the expression of lncGCLC and GCLC decreased continuously, accompanied with a consistently high expression of miR-122-5p. Knockdown of lncGCLC promoted cell proliferation, migration and invasion, but reduced cell apoptosis. A xenograft nude mouse model demonstrated that knockdown of lncGCLC promoted tumor growth. Furthermore, knockdown of lncGCLC significantly upregulated miR-122-5p expression, suppressed GCLC expression and GSH levels, and enhanced oxidative DNA damages. More importantly, the expression of lncGCLC in human HCC tissues was significantly downregulated in the high-microcystin exposure group, and positively associated with GCLC level in HCC tissues. Together, these findings suggest that lncGCLC plays an anti-oncogenic role in MCLR-induced malignant transformation by regulating GCLC expression.

13.
Autophagy ; 19(7): 2164-2165, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36519332

RESUMEN

Ischemia may be the most common pathological occurrence to restrict nutrient availability and induce macroautophagy/autophagy. As a self-digestive process, autophagy helps sustain nutrient/energy and restrict damages in short-term scenarios, but it switches to a self-destructive process leading to cell death in long-term scenarios. Notably, ischemia has been used as one clinical application to treat cancer, particularly transarterial embolization (TAE) and chemoembolization (TACE) as the first-line treatments of intermediate-stage hepatocellular carcinoma (HCC, the predominant type of liver cancer). Partly due to the induced autophagy together with hypoxia-induced angiogenesis, TAE/TACE is not successful to treat HCC in many cases. Our recent work demonstrated that simultaneous treatments with sorafenib (a first-line therapeutic agent for advanced HCC) can sensitize HCC cells to cell death induced by glucose starvation via impairing mitophagy, a mitochondria-specific form of autophagy. Moreover, we identified SIAH1 as an important E3 ubiquitin ligase for mitophagic induction in HCC cells.


Asunto(s)
Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Mitofagia , Autofagia , Isquemia
14.
Exp Mol Med ; 54(11): 2007-2021, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36385558

RESUMEN

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Sorafenib/farmacología , Sorafenib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Mitofagia , Glucosa , Niacinamida/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
15.
Autophagy ; 18(6): 1240-1255, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-34662529

RESUMEN

Macroautophagy/autophagy is an evolutionarily well-conserved recycling process in response to stress conditions, including a burst of reactive oxygen species (ROS) production. High level of ROS attack key cellular macromolecules. Protein cysteinyl thiols or non-protein thiols as the major redox-sensitive targets thus constitute the first-line defense. Autophagy is unique, because it removes not only oxidized/damaged proteins but also bulky ROS-generating organelles (such as mitochondria and peroxisome) to restrict further ROS production. The oxidative regulations of autophagy occur in all processes of autophagy, from induction, phagophore nucleation, phagophore expansion, autophagosome maturation, cargo delivery to the lysosome, and finally to degradation of the cargo and recycling of the products, as well as autophagy gene transcription. Mechanically, these regulations are achieved through direct or indirect manners. Direct thiol oxidation of key proteins such as ATG4, ATM and TFEB are responsible for specific regulations in phagophore expansion, cargo recognition and autophagy gene transcription, respectively. Meanwhile, oxidation of certain redox-sensitive chaperone-like proteins (e.g. PRDX family members and PARK7) may impair a nonspecifically local reducing environment in the phagophore membrane, and influence BECN1-involved phagophore nucleation and mitophagy recognition. However, ROS do exhibit some inhibitory effects on autophagy through direct oxidation of key autophagy regulators such as ATG3, ATG7 and SENP3 proteins. SQSTM1 provides an alternative antioxidant mechanism when autophagy is unavailable or impaired. However, it is yet to be unraveled how cells evolve to equip proteins with different redox susceptibility and in their correct subcellular positions, and how cells fine-tune autophagy machinery in response to different levels of ROS.Abbreviations: AKT1/PKB: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATM: ATM serine/threonine kinase; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; BH3: BCL2-homology-3; CAV1: caveolin 1; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CTSB: cathepsin B; CTSL: cathepsin L; DAPK: death associated protein kinase; ER: endoplasmic reticulum; ETC: electron transport chain; GSH: glutathione; GSTP1: glutathione S-transferase pi 1; H2O2: hydrogen peroxide; HK2: hexokinase 2; KEAP1: kelch like ECH associated protein 1; MAMs: mitochondria-associated ER membranes; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAPK8/JNK1: mitogen-activated protein kinase 8; MAP3K5/ASK1: mitogen-activated protein kinase kinase kinase 5; MCOLN1: mucolipin 1; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NFKB1: nuclear factor kappa B subunit 1; NOX: NADPH oxidase; O2-: superoxide radical anion; p-Ub: phosphorylated Ub; PARK7/DJ-1: Parkinsonism associated deglycase; PE: phosphatidylethanolamine; PEX5: peroxisomal biogenesis factor 5; PINK1: PTEN induced kinase 1; PPP3CA/calcineurin: protein phosphatase 3 catalytic subunit beta; PRDX: peroxiredoxin; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKD/PKD: protein kinase D; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; ROS: reactive oxygen species; SENP3: SUMO specific peptidase 3; SIRT1: sirtuin 1; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; SUMO: small ubiquitin like modifier; TFEB: transcription factor EB; TRAF6: TNF receptor associated factor 6; TSC2: TSC complex subunit 2; TXN: thioredoxin; TXNRD1: thioredoxin reductase 1; TXNIP: thioredoxin interacting protein; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1.


Asunto(s)
Autofagia , Peróxido de Hidrógeno , Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/fisiología , Peróxido de Hidrógeno/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina , Compuestos de Sulfhidrilo/farmacología , Tiorredoxinas/metabolismo , Tiorredoxinas/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinas/metabolismo
16.
Mitochondrial DNA B Resour ; 6(11): 3207-3208, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34676291

RESUMEN

Tripsacum laxum (Guatemalan grass) is a perennial fodder grasses, which is commonly growing in large parts of Africa for a source of livestock feed. It has a high economic value as a forage. In this study, we obtained a complete chloroplast genome of T. laxum by Illumina sequencing. The results showed a circular genome of 140,556 bp, including the large single copy region (LSC, 82,939 bp), the small single-copy region (SSC, 12,573 bp), and a pair of 22,522 bp inverted repeat regions (IRs). The circular genome contained 120 genes, including 74 protein-coding genes, eight ribosomal RNA genes and 38 tRNA genes. Evolutionary relationship analysis indicates that T. laxum is more closely related to previously reported T. dactyloides.

17.
Mol Plant Pathol ; 22(12): 1613-1623, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34459564

RESUMEN

The functions of ubiquitin-conjugating enzymes (E2) in plant immunity are not well understood. In this study, OsUBC26, a rice ubiquitin-conjugating enzyme, was characterized in the defence against Magnaporthe oryzae. The expression of OsUBC26 was induced by M. oryzae inoculation and methyl jasmonate treatment. Both RNA interference lines and CRISPR/Cas9 null mutants of OsUBC26 reduced rice resistance to M. oryzae. WRKY45 was down-regulated in OsUBC26 null mutants. In vitro E2 activity assay indicated that OsUBC26 is an active ubiquitin-conjugating enzyme. Yeast two-hybrid assays using OsUBC26 as bait identified the RING-type E3 ligase UCIP2 as an interacting protein. Coimmunoprecipitation assays confirmed the interaction between OsUBC26 and UCIP2. The CRISPR/Cas9 mutants of UCIP2 also showed compromised resistance to M. oryzae. Yeast two-hybrid screening using UCIP2 as bait revealed that APIP6 is a binding partner of UCIP2. Moreover, OsUBC26 working with APIP6 ubiquitinateds AvrPiz-t, an avirulence effector of M. oryzae, and OsUBC26 null mutation impaired the proteasome degradation of AvrPiz-t in rice cells. In summary, OsUBC26 plays important roles in rice disease resistance by regulating WRKY45 expression and working with E3 ligases such as APIP6 to counteract the effector protein AvrPiz-t from M. oryzae.


Asunto(s)
Resistencia a la Enfermedad/genética , Magnaporthe , Oryza , Enfermedades de las Plantas , Proteínas de Plantas , Enzimas Ubiquitina-Conjugadoras , Ascomicetos , Magnaporthe/patogenicidad , Oryza/enzimología , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Inmunidad de la Planta , Proteínas de Plantas/genética , Enzimas Ubiquitina-Conjugadoras/genética
18.
Front Microbiol ; 12: 646062, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34122360

RESUMEN

Effector genes play critical roles in the antagonistic interactions between plants and pathogens. However, knowledge of mutation mechanisms and evolutionary processes in effector genes and the contribution of climatic factors to the evolution of effector genes are fragmented but important in sustainable management of plant diseases and securing food supply under changing climates. Here, we used a population genetic approach to explore the evolution of the Avr4 gene in Phytophthora infestans, the causal agent of potato blight. We found that the Avr4 gene exhibited a high genetic diversity generated by point mutation and sequence deletion. Frameshifts caused by a single base-pair deletion at the 194th nucleotide position generate two stop codons, truncating almost the entire C-terminal, which is important for effector function and R4 recognition in all sequences. The effector is under natural selection for adaptation supported by comparative analyses of population differentiation (FST ) and isolation-by-distance between Avr4 sequences and simple sequence repeat marker loci. Furthermore, we found that local air temperature was positively associated with pairwise FST in the Avr4 sequences. These results suggest that the evolution of the effector gene is influenced by local air temperature, and the C-terminal truncation is one of the main mutation mechanisms in the P. infestans effector gene to circumvent the immune response of potato plants. The implication of these results to agricultural and natural sustainability in future climate conditions is discussed.

19.
Int J Biol Sci ; 17(6): 1538-1546, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33907517

RESUMEN

The outbreak of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly evolved into a global pandemic. One major challenge in the battle against this deadly disease is to find effective therapy. Due to the availability and proven clinical record of hydroxychloroquine (HCQ) and chloroquine (CQ) in various human diseases, there have been enormous efforts in repurposing these two drugs as therapeutics for COVID-19. To date, substantial amount of work at cellular, animal models and clinical trials have been performed to verify their therapeutic potential against COVID-19. However, neither lab-based studies nor clinical trials have provided consistent and convincing evidence to support the therapeutic value of HCQ/CQ in the treatment of COVID-19. In this mini review we provide a systematic summary on this important topic and aim to reveal some truth covered by the mystery regarding the therapeutic value of HCQ/CQ in COVID-19.


Asunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Cloroquina/uso terapéutico , Hidroxicloroquina/uso terapéutico , Animales , COVID-19/virología , Modelos Animales de Enfermedad , Endocitosis , Humanos , SARS-CoV-2/aislamiento & purificación
20.
FEMS Microbiol Lett ; 368(6)2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33693611

RESUMEN

Russula griseocarnosa is one of the uncultivable important mycorrhizal edible fungi. Currently, there is a limited insight into the dynamic composition of the microbial communities associated with Russula. Here, the microbiota in the root and mycorrhizosphere from Russula-Fagaceae nature areas of Fujian province were identified by Illumina MiSeq high-throughput sequencing. First, we compared three types of fungal communities associated with Russula-Fagaceae root mycelia-running stage (stage-1), Russula sporocarping stage-2 (stage-2) and Russula-free Fagaceae root (stage-3). Fungal diversity negatively correlated with Russula. Russula, Tomentella and Lactarius were core EcM in Fagaceae roots. A total of eight genera, including Boletus, are likely a positive indicator of Russula sporocarp production in Russula-Fagaceae roots, while Tomentella and Elaphomyces for Russula symbiosis. Secondly, analysis of fungal and bacterial communities within rhizosphere soils from the three stages revealed six genera, including Dacryobolus and Acidocella, as possible indicator species associated with sporocarping in Russula. Elaphomyces, Tomentella, Sorangium, Acidicaldus, Acidobacterium and Haliangium occurred more frequently in the Russula rhizosphere. Furthermore, operational taxonomic unit (OTU) network analysis showed a positive correlation between Russula,Tomentella, Elaphomyces and Sorangium. Overall, our results revealed a relationship between micro-community and Russula, which may provide a new strategy for improving Russula symbiosis and sporocarp production.


Asunto(s)
Basidiomycota , Biodiversidad , Microbiota , Micorrizas , Simbiosis , Bacterias/clasificación , Bacterias/genética , China , Hongos/clasificación , Hongos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Microbiota/fisiología , Micorrizas/clasificación , Micorrizas/genética , Raíces de Plantas/microbiología , Microbiología del Suelo
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