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BACKGROUND: Based on current research, it is known that the gastrointestinal tract microbiota and its genome play a crucial role in mental illnesses. Studies indicate a direct correlation between gastrointestinal tract microbiota and the onset of dementia, mediated by metabolic diseases and low-grade inflammation. The association between various gastrointestinal symptoms and neurodegenerative diseases has been recently discussed. However, there is a lack of research regarding the comparative effects of different surgical procedures on neurodegenerative diseases. Therefore, this study primarily focuses on comparing the association between various gastrointestinal surgeries and dementia, aiming to provide guidance for future clinical practice. METHOD: A nationwide study using the Taiwanese National Health Insurance Research Database included 26 059 patients diagnosed with dementia or Alzheimer's disease and 104 236 controls without diseases. Primary exposures were defined as alimentary surgeries, encompassing cholecystectomy, gastrectomy, bowel resection, and appendectomy. Conditional logistic regression was used to examine the odds ratio and 95% confidence interval for prior alimentary surgery between cases and controls. RESULTS: The results showed that individuals with dementia had a higher rate of gastrectomy. Additionally, individuals with dementia seemed to exhibit a reduced rate of cholecystectomy and appendectomy. Regarding Alzheimer's disease, all four alimentary surgeries showed comparable trends to those observed with dementia. No significant interaction was observed between alimentary surgery and dementia among the four types of surgery evaluated. CONCLUSION: Our study demonstrates that gastrectomy is associated with an elevated risk of dementia. We aim to uncover more direct evidence in future experiments.
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The Cystine-xCT transporter-Glutathione (GSH)-GPX4 axis is the canonical pathway to protect against ferroptosis. While not required for ferroptosis-inducing compounds (FINs) targeting GPX4, FINs targeting the xCT transporter require mitochondria and its lipid peroxidation to trigger ferroptosis. However, the mechanism underlying the difference between these FINs is still unknown. Given that cysteine is also required for coenzyme A (CoA) biosynthesis, here we show that CoA supplementation specifically prevents ferroptosis induced by xCT inhibitors but not GPX4 inhibitors. We find that, auranofin, a thioredoxin reductase inhibitor, abolishes the protective effect of CoA. We also find that CoA availability determines the enzymatic activity of thioredoxin reductase, but not thioredoxin. Importantly, the mitochondrial thioredoxin system, but not the cytosolic thioredoxin system, determines CoA-mediated ferroptosis inhibition. Our data show that the CoA regulates the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolishes its in vitro enzymatic activity and ability to protect cells from ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2, an effect that was rescued by CoA supplementation. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrate increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis leads to an oxidized thioredoxin system, mitochondrial lipid peroxidation, and loss in cell viability, which were all rescued by ferrostatin-1. These findings identify CoA-mediated post-translation modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.
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Quistes , Recurrencia , Humanos , Quistes/cirugía , Hepatopatías/cirugía , Masculino , Gastrostomía/métodos , Drenaje/métodos , Femenino , Persona de Mediana EdadRESUMEN
After reading the article written by Wang et al., we have encountered several concerns that may compromise the credibility of the article. There are some factors, such as changes in sleep patterns, glucose tolerance status, and the use of hypnotics, which may interfere with the research results. Additionally, the design of the sleep pattern could lead to biased outcomes. Therefore, we are writing this letter to recommend that further research should take these concerns into consideration.
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Enfermedades Cardiovasculares , Intolerancia a la Glucosa , Sueño , Humanos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/epidemiología , Sueño/fisiología , Glucemia/análisis , Factores de Riesgo , Factores de Riesgo de Enfermedad Cardiaca , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/epidemiologíaRESUMEN
Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis remains unknown. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that NINJ1-mediated ferroptosis protection can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhanced cystine uptake, and contributed to elevated CoA and GSH levels, collectively contributing to ferroptosis protection. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.
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Vaccination has been a game-changer in the long battle against COVID-19. However, waning vaccine-induced immunity and the immune evasion of emerging variants create challenges. The rapid-fire development of bivalent vaccines (BVs), comprising ancestral strains and a new variant, was authorized to prevent COVID-19, but the effectiveness of the updated vaccines remains largely unclear. Electronic databases were searched to investigate the immunogenicity and reactogenicity of BVs in humans. As of March 2023, 20 trials were identified. Compared with monovalent vaccination, the induced immunogenicity against ancestral strains was similar. The BVs demonstrated approximately 33-50% higher immunogenicity values against additional variant strains. An observational cohort study showed the additional clinical effectiveness of the BVs. The adverse events were similar. In conclusion, our systematic review found that the BVs had equal immunogenicity against ancestral strains without safety concerns. Approximately 33-50% increased additional antibody titers and clinical effectiveness against additional variant strains were observed in subjects with a BV vaccine with moderate heterogeneity, especially for BA.1-containing BVs.
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Neoplasias Hepáticas , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Resultado del Tratamiento , Estudios RetrospectivosAsunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Pulmonares , Humanos , Carcinoma de Células Escamosas de Esófago/terapia , Neoplasias Esofágicas/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios de Cohortes , Puntaje de Propensión , Quimioradioterapia , Estudios RetrospectivosRESUMEN
Acute hemorrhagic encephalomyelitis (AHEM) is the most severe form of acute disseminated encephalomyelitis (ADEM). Patients with AHEM usually have unfavorable outcomes with high mortality rate. We reported a middle-aged male, who was diagnosed with AHEM and died 35 days after admission even under intensive immune therapy. Clinical courses were recorded and serial MR images were demonstrated to illustrate the rapidly changes in brain parenchyma. By highlighting these aspects, we hope to provide valuable insights for future studies and potential advancements in the management of AHEM.
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Oral squamous cell carcinoma (OSCC) can arise anywhere in the oral cavity. OSCC's molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic mutations and altered levels of transcripts, proteins, and metabolites. Platinum-based drugs are the first-line treatment for OSCC; however, severe side-effects and resistance are challenging issues. Thus, there is an urgent clinical need to develop novel and/or combinatory therapeutics. In this study, we investigated the cytotoxic effects of pharmacological concentrations of ascorbate on two human oral cell lines, the oral epidermoid carcinoma meng-1 (OECM-1) cell and the Smulow-Glickman (SG) human normal gingival epithelial cell. Our study examined the potential functional impact of pharmacological concentrations of ascorbates on the cell-cycle profiles, mitochondrial-membrane potential, oxidative response, the synergistic effect of cisplatin, and the differential responsiveness between OECM-1 and SG cells. Two forms of ascorbate, free and sodium forms, were applied to examine the cytotoxic effect and it was found that both forms had a similar higher sensitivity to OECM-1 cells than to SG cells. In addition, our study data suggest that the determinant factor of cell density is important for ascorbate-induced cytotoxicity in OECM-1 and SG cells. Our findings further revealed that the cytotoxic effect might be mediated through the induction of mitochondrial reactive oxygen species (ROS) generation and the reduction in cytosolic ROS generation. The combination index supported the agonistic effect between sodium ascorbate and cisplatin in OECM-1 cells, but not in SG cells. In summary, our current findings provide supporting evidence for ascorbate to serve as a sensitizer for platinum-based treatment of OSCC. Hence, our work provides not only repurposing of the drug, ascorbate, but also an opportunity to decrease the side-effects of, and risk of resistance to, platinum-based treatment for OSCC.
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Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de la Boca , Humanos , Cisplatino/farmacología , Especies Reactivas de Oxígeno/metabolismo , Carcinoma de Células Escamosas/patología , Ácido Ascórbico/farmacología , Neoplasias de la Boca/patología , Antineoplásicos/farmacología , Estrés Oxidativo , Línea Celular Tumoral , ApoptosisRESUMEN
MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow-Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Cobre/metabolismo , Cobre/farmacología , Disulfiram/farmacología , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Fosforilación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina/metabolismo , Treonina/metabolismoRESUMEN
Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We explored the potential mechanism behind the cytotoxicity of DSF-Cu+/Cu2+ complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl2 or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu+/Cu2+ induced cell death in OECM-1 cells, but not SG cells. DSF-Cu+/Cu2+ also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu+/Cu2+ in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu+/Cu2+-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu+/Cu2+ induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl2 increased but DSF- Cu2+ impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl2 stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu+/Cu2-treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl2 complex as a repurposed agent for OSCC cancer therapy.
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Inhibidores del Acetaldehído Deshidrogenasa/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cobre/uso terapéutico , Disulfiram/uso terapéutico , Neoplasias de la Boca/tratamiento farmacológico , Inhibidores del Acetaldehído Deshidrogenasa/química , Inhibidores del Acetaldehído Deshidrogenasa/farmacología , Carcinoma de Células Escamosas/metabolismo , Cobre/química , Disulfiram/química , Disulfiram/farmacología , Reposicionamiento de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mitocondrias/efectos de los fármacos , Neoplasias de la Boca/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
Mesenchymal stem cells (MSCs) play an important role as immune modulator through interaction with several immune cells, including macrophages. In this study, the immunomodulatory potency of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) was demonstrated in the in vivo middle cerebral artery occlusion (MCAo)-induced brain injury rat model and in vitro THP-1-derived macrophages model. At 24 h after induction of MCAo, hUC-MSCs was administered via tail vein as a single dose. Remarkably, hUC-MSCs could inhibit M1 polarization and promote M2 polarization of microglia in vivo after 14 days induction of MCAo. Compared with THP-1-derived macrophages which had been stimulated by lipopolysaccharide, the secretion of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ inducible protein (IP-10), were significantly reduced in the presence of hUC-MSCs. Moreover, the secretion of anti-inflammatory cytokine, interleukin-10 (IL-10), was significantly increased after cocultured with hUC-MSCs. Prostaglandins E2 (PGE2), secreted by hUC-MSCs, is one of the crucial immunomodulatory factors and could be inhibited in the presence of COX2 inhibitor, NS-398. PGE2 inhibition suppressed hUC-MSCs immunomodulatory capability, which was restored after addition of synthetic PGE2, establishing the minimum amount of PGE2 required for immunomodulation. In conclusion, our data suggested that PGE2 is a crucial potency marker involved in the therapeutic activity of hUC-MSCs through macrophages immune response modulation and cytokines regulation. This study provides the model for the development of a surrogate quantitative potency assay of immunomodulation in stem cells production.
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Isquemia Encefálica/terapia , Dinoprostona/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Animales , Isquemia Encefálica/metabolismo , Diferenciación Celular/inmunología , Técnicas de Cocultivo/métodos , Citocinas/metabolismo , Dinoprostona/inmunología , Femenino , Sangre Fetal/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Humanos , Inmunidad/efectos de los fármacos , Inmunomodulación/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Microglía/metabolismo , Prostaglandinas E/inmunología , Prostaglandinas E/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismo , Cordón Umbilical/citologíaRESUMEN
In recent years, L-ascorbic acid (L-AA), or vitamin C, has been attracting attention as a potential anticancer drug that mediates hydrogen peroxide-induced oxidation and ten-eleven translocation 2-catalyzed DNA demethylation. However, the precise mechanism by which L-AA acts remains unclear. We examined the cytotoxic effects of L-AA or sodium ascorbate in human cervical carcinoma cells by assessing cell viability, expression of cell cycle-related mRNAs and proteins, and mitochondrial functions, and by performing flow cytometric analyses of cell cycle profiles, apoptosis, cell proliferation, and production of reactive oxygen species (ROS). We later tested the effects of ascorbates in combination with two first-line chemotherapeutic drugs, cisplatin, and doxorubicin. At pharmacological concentrations (1-10 mM), L-AA increased ROS levels; decreased levels of several cell cycle-related proteins, including p53, p21, cyclin D1, and phosphorylated histone 3 at serine residue 10; induced DNA damage, as indicated by changes in γH2A.x; decreased levels of the anti-oxidative transcription factor Nrf2; and increased levels of catalase, superoxide dismutase 1, and endoplasmic reticulum stress-related indicators, such as the p-eIF2α/eIF2α ratio and CHOP levels. L-AA also promoted cell proliferation and induced apoptosis and mitochondrial dysfunction. Finally, L-AA increased the susceptibility of HeLa cells to cisplatin and doxorubicin. These findings provide insight into how the adjustment of the cellular ROS status through L-ascorbate (L-AA or sodium ascorbate) administration could potentially synergistically enhance the efficacy of cancer therapies.
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Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sulfate led to dose-dependent decreases in HeLa cell viability, along with increases in the subG1 and G2/M populations and corresponding decreases in the G1 population. Copper sulfate also increased the levels of apoptosis, senescence, mitochondrial dysfunction, autophagy, ROS, and the expression of several stress proteins, including ATF3, c-Fos, DEC1 (differentiated embryonic chondrocyte gene 1), p21, p53, and HIF-1α (hypoxia-inducible factor 1 alpha). The suppression of copper-induced ROS generation by the ROS scavenger N-acetyl cysteine verified copper's functional role, while the suppression of copper's effects by the copper chelator disulfiram, confirmed its specificity. Selective induction of HIF-1α, p53, and phosphorylated ERK proteins by copper was blocked by the knockdown of the transcription factor DEC1, suggesting copper's effects are mediated by DEC1. In addition to HeLa cells, copper also exerted cytotoxic effects in human endometrial (HEC-1-A) and lung (A549) adenocarcinoma cells, but not in normal human kidney (HEK293) or bronchial (Beas-2B) epithelial cells. These findings shed new light on the functional roles of copper within cells.
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Sulfato de Cobre/toxicidad , Proteínas Supresoras de Tumor/metabolismo , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Sulfato de Cobre/farmacología , Células HEK293 , Células HeLa , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
Neurodegenerative disorders and brain damage are initiated by excessive production of reactive oxygen species (ROS), which leads to tissue injury, cellular death and inflammation. In cellular anti-oxidant systems, heme oxygenase-1 (HO-1) is an oxidative-sensor protein induced by ROS generation or carbon monoxide (CO) release. CO releasing molecules (CORMs), including CORM-3, exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanisms of CORM-3-induced HO-1 expression and protection against interleukin (IL)-1ß-induced inflammatory responses have not been fully elucidated in rat brain astrocytes (RBA-1). To study the regulation of CORM-3-induced HO-1 expression, signaling pathways, promoter activity, mRNA and protein expression were assessed following treatment with pharmacological inhibitors and gene-specific siRNA knockdown. We found that CORM-3 mediated HO-1 induction via transcritional and translational processes. Furthermore, CORM-3-induced HO-1 expression was mediated by phosphorylation of several protein kinases, such as c-Src, Pyk2, protein kinase Cα (PKCα) and p42/p44 mitogen-activated protein kinase (MAPK), which were inhibited by respective pharmacological inhibitors or by gene-specific knockdown with siRNA transfections. Next, we found that CORM-3 sequentially activated the c-Src/Pyk2/PKCα/p42/p44 MAPK pathway, thereby up-regulating mRNA for the activator protein (AP)-1 components c-Jun and c-Fos; these effects were attenuated by an AP-1 inhibitor (Tanshinone IIA; TSIIA) and other relevant inhibitors. Moreover, CORM-3-induced upregulation of HO-1 attenuated the IL-1ß-induced cell migration and matrix metallopeptidase-9 mRNA expression in RBA-1 cells. These effects were reversed by an matrix metalloproteinase (MMP)2/9 inhibitor or by transfection with HO-1 siRNA.
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Polymeric fluorescent nanoparticles, R6GDARs, containing rhodamine 6G within 1,3-phenylenediamine resin are prepared using the extensive Stöber method. The R6GDAR is capable of sensing intracellular pH in living cells, with the fluorescence intensity increasing upon decreasing the pH values from 8.0 to 3.0. This fluorescence enhancement at low pH is based on the "retro-self-quenching" mechanism, where the protonation of the R6GDAR backbones expands the particle structure, leading to increase in the separation among concentrated R6G molecules as well as their release. Fluorescence time-course measurement shows that even individual R6GDARs have high sensitivity to report the environmental pH at the single particle level. Compared to other existing pH sensors, R6GDARs offer a wider working pH range (5 pH units), higher sensitivity, and greater photostability. R6GDARs have been demonstrated to be sensitive to map local pH values inside MCF7 and MDA-MB-231 cells, with extremely low cell toxicity. R6GDARs serve as an excellent pH sensing probe for cellular microenvironments.