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Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.
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Mangiferin(MGF) exhibits crucial biological roles, including antioxidant and anti-inflammatory functions. However, how to clearly elucidate the functioning mechanism of MGF for inhibiting cisplatin-induced hearing loss requires in-depth investigation. In this work, we aimed at gaining insight into how MGF functions as the protective agent against cisplatin-triggered ototoxicity using various assays. The variation for reactive oxygen species (ROS) concentrations was determined with MitoSOX-Red and 2',7'-Dichlorodihydrofluorescein diacetate staining (DCFH-DA). The protective function and corresponding mechanism of MGF in hair cell survival in the House Ear Institute-Organ of Corti (HEI-OC1) cell line were assessed using RNA sequencing (RNA-Seq). Our findings demonstrated that MGF significantly alleviated cisplatin-induced injury to hair cells in vitro, encompassing cell lines and cochlear explants, as well as in vivo models, including C57BL/6â¯J mice and zebrafish larvae. Mechanistic studies revealed that MGF reversed the increased accumulation of ROS and inhibited cell apoptosis through mitochondrial-mediated intrinsic pathway. Moreover, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting data indicated MGF protected against cisplatin-mediated ototoxicity via the mitogen-activated protein kinase pathway (MAPK). These findings demonstrated MGF has significant potential promise in combating cisplatin-induced ototoxicity, offering a foundation for expanded investigation into therapeutic approaches for auditory protection.
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Apoptosis , Cisplatino , Células Ciliadas Auditivas , Pérdida Auditiva Sensorineural , Ratones Endogámicos C57BL , Ototoxicidad , Especies Reactivas de Oxígeno , Xantonas , Pez Cebra , Cisplatino/toxicidad , Cisplatino/efectos adversos , Animales , Ototoxicidad/prevención & control , Especies Reactivas de Oxígeno/metabolismo , Ratones , Pérdida Auditiva Sensorineural/inducido químicamente , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/prevención & control , Pérdida Auditiva Sensorineural/patología , Apoptosis/efectos de los fármacos , Xantonas/farmacología , Xantonas/uso terapéutico , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Antioxidantes/farmacologíaRESUMEN
Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.
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Depresión Posparto , Neuronas , Obesidad , Canales Catiónicos TRPC , Animales , Femenino , Ratones , Obesidad/metabolismo , Obesidad/genética , Masculino , Humanos , Canales Catiónicos TRPC/metabolismo , Canales Catiónicos TRPC/genética , Depresión Posparto/metabolismo , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Ratones Endogámicos C57BL , Oxitocina/metabolismo , Conducta MaternaRESUMEN
OBJECTIVE: Obesity-induced kidney injury contributes to the development of diabetic nephropathy (DN). Here, we identified the functions of ubiquitin-specific peptidase 19 (USP19) in HK-2 cells exposed to a combination of high glucose (HG) and free fatty acid (FFA) and determined its association with TGF-beta-activated kinase 1 (TAK1). METHODS: HK-2 cells were exposed to a combination of HG and FFA. USP19 mRNA expression was detected by quantitative RT-PCR (qRT-PCR), and protein analysis was performed by immunoblotting (IB). Cell growth was assessed by Cell Counting Kit-8 (CCK-8) viability and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Cell cycle distribution and apoptosis were detected by flow cytometry. The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation (Co-IP) assays and IB. RESULTS: In HG+FFA-challenged HK-2 cells, USP19 was highly expressed. USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells. Moreover, USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1 (PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species (ROS) generation in HK-2 cells. Mechanistically, USP19 stabilized the TAK1 protein through deubiquitination. Importantly, increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells. CONCLUSION: The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1, providing a potential therapeutic strategy for combating DN.
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Apoptosis , Glucosa , Quinasas Quinasa Quinasa PAM , Humanos , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Glucosa/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Ácidos Grasos no Esterificados/metabolismo , Ácidos Grasos no Esterificados/farmacología , Ácidos Grasos no Esterificados/efectos adversos , Proliferación Celular/efectos de los fármacos , Ubiquitinación/efectos de los fármacos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genética , Endopeptidasas/metabolismo , Endopeptidasas/genética , Proteínas QuinasasRESUMEN
BACKGROUND: Cepharanthine, a bioactive constituent of Stephania japonica (Thunb.) Miers, is known for its potent anti-tumor properties. Nevertheless, the precise impact of this substance on bladder cancer remains poorly comprehended. The aim of this study was to demonstrate the effect and mechanism of cepharanthine on the metastasis of human bladder cancer cells. METHODS: The application of network pharmacology was utilized to ascertain the possible targets and signaling pathways of cepharanthine in the treatment of bladder cancer. The antiproliferative effects of cepharanthine were evaluated using Cell Counting Kit-8 and colony formation assays. The migration and invasion capabilities were assessed using Transwell assays and wound healing experiments. Proteins related to the Rap1 signaling pathway, cellular migration, cellular invasion, and Epithelial-Mesenchymal Transition (EMT) were quantified by western blotting. RESULTS: Through database screening, 313 cepharanthine-acting targets, 277 candidate disease targets in bladder cancer, 22 intersecting targets, and 12 core targets were confirmed. The involvement of the Rap1 signaling system was revealed by the Kyoto Encyclopedia of Genes and Genomes' pathway enrichment study. Cepharanthine was shown to decrease bladder cancer cell proliferation, migration, and invasion in vitro. Cepharanthine activated the Rap1 signaling pathway by upregulating Epac1 and downregulating E-cadherin and C3G protein expression, leading to increased expression of Rap1 GTP protein and decreased expression of protein kinase D1 and integrin α5. Rap1 signalling pathway activation resulted in the downregulation of migration and invasion-related proteins, matrix metallopeptidase MMP2, MMP9, as well as EMT-related proteins, N-cadherin and Snail, without affecting vimentin expression. CONCLUSION: Cepharanthine inhibits migration, invasion, and EMT of bladder cancer cells by activating the Rap1 signalling pathway. The results offer helpful insights regarding the possible therapeutic use of cepharanthine for treating bladder cancer.
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Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia.
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Enfermedad de Alzheimer , Memoria , Ratones Transgénicos , Plasticidad Neuronal , Receptor de Serotonina 5-HT2C , Animales , Humanos , Receptor de Serotonina 5-HT2C/metabolismo , Receptor de Serotonina 5-HT2C/genética , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Plasticidad Neuronal/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Serotonina/metabolismo , Modelos Animales de Enfermedad , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacologíaRESUMEN
Background: With a variety of active ingredients, Hedyotis Diffusa (H. diffusa) can treat a variety of tumors. The purpose of our study is based on real-world data and experimental level, to double demonstrate the efficacy and possible molecular mechanism of H. diffusa in the treatment of lung adenocarcinom (LUAD). Methods: Phenotype-genotype and herbal-target associations were extracted from the SymMap database. Disease-gene associations were extracted from the MalaCards database. A molecular network-based correlation analysis was further conducted on the collection of genes associated with TCM and the collection of genes associated with diseases and symptoms. Then, the network separation SAB metrics were applied to evaluate the network proximity relationship between TCM and symptoms. Finally, cell apoptosis experiment, Western blot, and Real-time PCR were used for biological experimental level validation analysis. Results: Included in the study were 85,437 electronic medical records (318 patients with LUAD). The proportion of prescriptions containing H. diffusa in the LUAD group was much higher than that in the non-LUAD group (p < 0.005). We counted the symptom relief of patients in the group and the group without the use of H. diffusa: except for symptoms such as fatigue, palpitations, and dizziness, the improvement rate of symptoms in the user group was higher than that in the non-use group. We selected the five most frequently occurring symptoms in the use group, namely, cough, expectoration, fatigue, chest tightness and wheezing. We combined the above five symptom genes into one group. The overlapping genes obtained were CTNNB1, STAT3, CASP8, and APC. The selection of CTNNB1 target for biological experiments showed that the proliferation rate of LUAD A549 cells in the drug intervention group was significantly lower than that in the control group, and it was concentration-dependent. H. diffusa can promote the apoptosis of A549 cells, and the apoptosis rate of the high-concentration drug group is significantly higher than that of the low-concentration drug group. The transcription and expression level of CTNNB1 gene in the drug intervention group were significantly decreased. Conclusion: H. diffusa inhibits the proliferation and promotes apoptosis of LUAD A549 cells, which may be related to the fact that H. diffusa can regulate the expression of CTNNB1.
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Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHbâ5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.
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Conducta Alimentaria , Habénula , Luz , Animales , Masculino , Ratones , Habénula/fisiología , Conducta Alimentaria/fisiología , Núcleo Dorsal del Rafe/fisiología , Humanos , Ratones Endogámicos C57BL , Ingestión de Alimentos/fisiología , Vías Nerviosas/fisiología , Ratas , Neuronas Serotoninérgicas/fisiología , Red Nerviosa/fisiología , OscuridadRESUMEN
Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.
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Apoptosis , Factor de Transcripción STAT3 , Animales , Masculino , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/efectos de los fármacos , Línea Celular , Etanol/toxicidad , Etanol/administración & dosificación , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/prevención & control , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genéticaRESUMEN
Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRNâarcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.
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We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %-51.09 %), 12.50 % (2.66 %-32.36 %), 50.00 % (29.12 %-70.88 %), and 41.67 % (22.11 %-63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12-760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73-1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28-1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35-5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67-10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27-14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82-3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64-7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66-4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18-49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra Rotavirus , Vacunas de Productos Inactivados , Humanos , Adulto , Método Doble Ciego , Masculino , Femenino , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Persona de Mediana Edad , Adulto Joven , Adolescente , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversos , Vacunas contra Rotavirus/inmunología , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/efectos adversos , China , Inmunogenicidad Vacunal , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/inmunología , Rotavirus/inmunología , Voluntarios Sanos , Pruebas de NeutralizaciónRESUMEN
Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.
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Asma , Receptores Quiméricos de Antígenos , Animales , Asma/inmunología , Asma/terapia , Ratones , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Inmunoterapia Adoptiva/métodos , Linfocitos T/inmunología , Interleucina-5/inmunología , Interleucina-5/metabolismo , Modelos Animales de Enfermedad , Humanos , Interleucina-4/inmunología , Interleucina-4/metabolismo , Ratones Endogámicos C57BL , Eosinófilos/inmunología , Femenino , Interleucina-13/metabolismo , Interleucina-13/inmunologíaRESUMEN
Accurate identification of single nucleotide variants (SNVs) in key driver genes holds a significant value for disease diagnosis and treatment. Fluorescent probes exhibit tremendous potential in specific, high-resolution, and rapid detection of SNVs. However, additional steps are required in most post-PCR assays to convert double-stranded DNA (dsDNA) products into single-stranded DNA (ssDNA), enabling them to possess hybridization activity to trigger subsequent reactions. This process not only prolongs the complexity of the experiment but also introduces the risk of losing target information. In this study, we proposed two strategies for enriching active double-stranded DNA, involving PCR based on obstructive groups and cleavable units. Building upon this, we explored the impact of modified units on the strand displacement reaction (SDR) and assessed their discriminatory efficacy for mutations. The results showed that detection of low variant allele frequencies (VAF) as low as 0.1% can be achieved. The proposed strategy allowed orthogonal identification of 45 clinical colorectal cancer tissue samples with 100% specificity, and the results were generally consistent with sequencing results. Compared to existing methods for enriching active targets, our approach offers a more diverse set of enrichment strategies, characterized by the advantage of being simple and fast and preserving original information to the maximum extent. The objective of this study is to offer an effective solution for the swift and facile acquisition of active double-stranded DNA. We anticipate that our work will facilitate the practical applications of SDR based on dsDNA.
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ADN , Polimorfismo de Nucleótido Simple , Polimorfismo de Nucleótido Simple/genética , Humanos , ADN/genética , ADN/química , Neoplasias Colorrectales/genética , Reacción en Cadena de la Polimerasa , Colorantes Fluorescentes/química , ADN de Cadena Simple/genética , ADN de Cadena Simple/químicaRESUMEN
Microplastics (MPs) occurrence in marine ecosystems is well known, but their accumulation in seaweeds and subsequent human exposure remain understudied. This research quantifies MPs presence in two commonly consumed seaweeds, kelp (Saccharina japonica) and nori (Pyropia yezoensis), in East Asia, revealing widespread contamination dominated by microfibers (<500 µm). Based on dietary patterns, human uptake through seaweed consumption was estimated and quantified. Notably, Chinese people consume an estimated 17,034 MPs/person/year through seaweed consumption, representing 13.1% of their total annual MPs intake. This seaweeds-derived exposure surpasses all other dietary sources, contributing up to 45.5% of overall MPs intake. The highest intake was in South Korea, followed by North Korea, China, and Japan. This research identifies seaweeds as a major, previously overlooked route of dietary MPs exposure. These findings are crucial for comprehensive risk assessments of seaweed consumption and the development of mitigation strategies, particularly for populations in East Asian countries.
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Exposición Dietética , Contaminación de Alimentos , Microplásticos , Algas Marinas , Algas Marinas/química , Algas Marinas/metabolismo , Humanos , Microplásticos/análisis , Contaminación de Alimentos/análisis , Exposición Dietética/análisis , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/metabolismo , Asia Oriental , Dieta , Kelp/química , Kelp/metabolismoRESUMEN
Sonodynamic therapy (SDT) has been recognized as a promising treatment for cancer due to its advantages of superior specificity, non-invasiveness, and deep tissue penetration. However, the antitumor effect of SDT remains restricted by the limited generation of reactive oxygen species (ROS) due to the lack of highly efficient sonosensitizers. In this work, we developed the novel sonosensitizer Pt/CeO2-xSx by constructing oxygen defects through S doping and Pt loading in situ. Large amounts of oxygen defects have been obtained by S doping, endowing Pt/CeO2-xSx with the ability to suppress electron-hole recombination, further promoting ROS production. Moreover, the introduction of Pt nanoparticles can not only produce oxygen in situ for relieving hypoxia but also form a Schottky heterojunction with CeO2-xSx for further inhibiting electron-hole recombination. In addition, Pt/CeO2-xSx could effectively deplete overexpressed glutathione (GSH) via redox reactions, amplifying oxidative stress in the tumor microenvironment (TME). Combined with the excellent POD-mimetic activity, Pt/CeO2-xSx can achieve highly efficient synergistic therapy of SDT and chemodynamic therapy (CDT). All these findings demonstrated that Pt/CeO2-xSx has great potential for cancer therapy, and this work provides a promising direction for designing and constructing efficient sonosensitizers.
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Antineoplásicos , Cerio , Cerio/química , Cerio/farmacología , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones , Especies Reactivas de Oxígeno/metabolismo , Terapia por Ultrasonido , Platino (Metal)/química , Platino (Metal)/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Tamaño de la Partícula , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Neoplasias/terapiaRESUMEN
Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.
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Menopausia Prematura , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , MicroARNs , Insuficiencia Ovárica Primaria , Animales , Femenino , Ratones , Antígenos CD28 , Interleucina-10/genética , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , Insuficiencia Ovárica Primaria/genética , Insuficiencia Ovárica Primaria/terapia , Insuficiencia Ovárica Primaria/inducido químicamente , Proteínas Proto-Oncogénicas c-aktRESUMEN
Precise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood-brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2-fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging-mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti-inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1-fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.
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Modelos Animales de Enfermedad , Trampas Extracelulares , Accidente Cerebrovascular Isquémico , Microglía , Neutrófilos , Animales , Microglía/metabolismo , Microglía/efectos de los fármacos , Ratones , Trampas Extracelulares/metabolismo , Trampas Extracelulares/efectos de los fármacos , Accidente Cerebrovascular Isquémico/inmunología , Neutrófilos/metabolismo , Neutrófilos/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Masculino , Nanopartículas , Ratones Endogámicos C57BLRESUMEN
Gene expression is regulated at multiple levels, including RNA processing and DNA methylation/demethylation. How these regulations are controlled remains unclear. Here, through analysis of a suppressor for the OsEIN2 over-expressor, we identified an RNA recognition motif protein SUPPRESSOR OF EIN2 (SOE). SOE is localized in nuclear speckles and interacts with several components of the spliceosome. We find SOE associates with hundreds of targets and directly binds to a DNA glycosylase gene DNG701 pre-mRNA for efficient splicing and stabilization, allowing for subsequent DNG701-mediated DNA demethylation of the transgene promoter for proper gene expression. The V81M substitution in the suppressor mutant protein mSOE impaired its protein stability and binding activity to DNG701 pre-mRNA, leading to transgene silencing. SOE mutation enhances grain size and yield. Haplotype analysis in c. 3000 rice accessions reveals that the haplotype 1 (Hap 1) promoter is associated with high 1000-grain weight, and most of the japonica accessions, but not indica ones, have the Hap 1 elite allele. Our study discovers a novel mechanism for the regulation of gene expression and provides an elite allele for the promotion of yield potentials in rice.
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Regulación de la Expresión Génica de las Plantas , Silenciador del Gen , Oryza , Proteínas de Plantas , Transgenes , Oryza/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regiones Promotoras Genéticas/genética , Mutación/genética , Dominios Proteicos , Haplotipos/genética , Metilación de ADN/genética , Unión Proteica , Plantas Modificadas Genéticamente , AlelosRESUMEN
Long-term antitumor efficacy of chimeric antigen receptor (CAR) T cells depends on their functional persistence in vivo. T cells with stem-like properties show better persistence, but factors conferring bona fide stemness to T cells remain to be determined. Here, we demonstrate the induction of CAR T cells into an immortal-like and functional state, termed TIF. The induction of CARTIF cells depends on the repression of two factors, BCOR and ZC3H12A, and requires antigen or CAR tonic signaling. Reprogrammed CARTIF cells possess almost infinite stemness, similar to induced pluripotent stem cells while retaining the functionality of mature T cells, resulting in superior antitumor effects. Following the elimination of target cells, CARTIF cells enter a metabolically dormant state, persisting in vivo with a saturable niche and providing memory protection. TIF represents a novel state of T cells with unprecedented stemness, which confers long-term functional persistence of CAR T cells in vivo and holds broad potential in T cell therapies.