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1.
Cell ; 184(3): 827-839.e14, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33545036

RESUMEN

Ahmed and colleagues recently described a novel hybrid lymphocyte expressing both a B and T cell receptor, termed double expresser (DE) cells. DE cells in blood of type 1 diabetes (T1D) subjects were present at increased numbers and enriched for a public B cell clonotype. Here, we attempted to reproduce these findings. While we could identify DE cells by flow cytometry, we found no association between DE cell frequency and T1D status. We were unable to identify the reported public B cell clone, or any similar clone, in bulk B cells or sorted DE cells from T1D subjects or controls. We also did not observe increased usage of the public clone VH or DH genes in B cells or in sorted DE cells. Taken together, our findings suggest that DE cells and their alleged public clonotype are not enriched in T1D. This Matters Arising paper is in response to Ahmed et al. (2019), published in Cell. See also the response by Ahmed et al. (2021), published in this issue.


Asunto(s)
Diabetes Mellitus Tipo 1 , Linfocitos B , Células Clonales , Diabetes Mellitus Tipo 1/genética , Citometría de Flujo , Humanos , Receptores de Antígenos de Linfocitos T
2.
Cell ; 173(5): 1123-1134.e11, 2018 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-29775592

RESUMEN

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.


Asunto(s)
Colitis/patología , Dieta , Intestinos/patología , Oxazoles/farmacología , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interleucina-10/metabolismo , Intestinos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/genética , Triptófano/metabolismo
3.
Immunity ; 56(7): 1533-1547.e7, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37354904

RESUMEN

The crosstalk between the immune and neuroendocrine systems is critical for intestinal homeostasis and gut-brain communications. However, it remains unclear how immune cells participate in gut sensation of hormones and neurotransmitters release in response to environmental cues, such as self-lipids and microbial lipids. We show here that lipid-mediated engagement of invariant natural killer T (iNKT) cells with enterochromaffin (EC) cells, a subset of intestinal epithelial cells, promoted peripheral serotonin (5-HT) release via a CD1d-dependent manner, regulating gut motility and hemostasis. We also demonstrated that inhibitory sphingolipids from symbiotic microbe Bacteroides fragilis represses 5-HT release. Mechanistically, CD1d ligation on EC cells transduced a signal and restrained potassium conductance through activation of protein tyrosine kinase Pyk2, leading to calcium influx and 5-HT secretion. Together, our data reveal that by engaging with iNKT cells, gut chemosensory cells selectively perceive lipid antigens via CD1d to control 5-HT release, modulating intestinal and systemic homeostasis.


Asunto(s)
Células T Asesinas Naturales , Serotonina , Serotonina/metabolismo , Lípidos , Antígenos CD1d/metabolismo
4.
Genes Dev ; 38(1-2): 11-30, 2024 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-38182429

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity domain (LCD) of hnRNPA1 can cause splicing changes of thousands of transcripts that collectively are linked to the DNA damage response, cilium organization, and translation. We show that the hnRNPA1 D262V mutant protein binds to new binding sites on differentially spliced transcripts from genes that are linked to ALS. We demonstrate that this ALS-linked hnRNPA1 mutation alters normal RNA-dependent protein-protein interactions. Furthermore, cells expressing this hnRNPA1 mutant exhibit a cell aggregation phenotype, markedly reduced growth rates, changes in stress granule kinetics, and aberrant growth of neuronal processes. This study provides insight into how a single amino acid mutation in a splicing factor can alter RNA splicing networks of genes linked to ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Mutación , Empalme del ARN/genética , Factores de Empalme de ARN/genética
5.
Proc Natl Acad Sci U S A ; 121(34): e2321686121, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39141352

RESUMEN

To broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.


Asunto(s)
Antígenos CD1d , Lipidómica , Células T Asesinas Naturales , Receptores de Antígenos de Linfocitos T , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Antígenos CD1d/inmunología , Antígenos CD1d/metabolismo , Animales , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Ratones , Lipidómica/métodos , Humanos , Autoantígenos/inmunología , Autoantígenos/metabolismo , Ceramidas/metabolismo , Ceramidas/inmunología , Lípidos/química , Lípidos/inmunología , Estrés del Retículo Endoplásmico/inmunología
6.
J Neurosci ; 44(13)2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38378273

RESUMEN

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.


Asunto(s)
Dolor Crónico , Ketamina , Humanos , Ratones , Masculino , Animales , Dolor Crónico/metabolismo , Depresión/tratamiento farmacológico , Tálamo , Neuronas/metabolismo , Comorbilidad
7.
J Biol Chem ; 300(9): 107725, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39214300

RESUMEN

Mutations of human TBC1D24 are associated with deafness, epilepsy, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, cognitive disability, and seizures). The causal relationships between TBC1D24 variants and the different clinical phenotypes are not understood. Our hypothesis is that phenotypic heterogeneity of missense mutations of TBC1D24 results, in part, from perturbed binding of different protein partners. To discover novel protein partners of TBC1D24, we conducted yeast two-hybrid (Y2H) screen using mouse full-length TBC1D24 as bait. Kidney and brain protein (KIBRA), a scaffold protein encoded by Wwc1, was identified as a partner of TBC1D24. KIBRA functions in the Hippo signaling pathway and is important for human cognition and memory. The TBC1D24 TLDc domain binds to KIBRA full-length and to its C2 domain, confirmed by Y2H assays. No interaction was detected with Y2H assays between the KIBRA C2 domain and TLDc domains of NCOA7, MEAK7, and OXR1. Moreover, the C2 domains of other WWC family proteins do not interact with the TLDc domain of TBC1D24, demonstrating specificity. The mRNAs encoding TBC1D24 and KIBRA proteins in mouse are coexpressed at least in a subset of hippocampal cells indicating availability to interact in vivo. As two epilepsy-associated recessive variants (Gly511Arg and Ala515Val) in the TLDc domain of human TBC1D24 disrupt the interaction with the human KIBRA C2 domain, this study reveals a pathogenic mechanism of TBC1D24-associated epilepsy, linking the TBC1D24 and KIBRA pathways. The interaction of TBC1D24-KIBRA is physiologically meaningful and necessary to reduce the risk of epilepsy.


Asunto(s)
Epilepsia , Proteínas Activadoras de GTPasa , Péptidos y Proteínas de Señalización Intracelular , Mutación Missense , Animales , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Ratones , Humanos , Epilepsia/genética , Epilepsia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Dominios Proteicos , Células HEK293 , Unión Proteica , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/metabolismo , Técnicas del Sistema de Dos Híbridos , Pérdida Auditiva Sensorineural , Discapacidad Intelectual , Uñas Malformadas , Anomalías Craneofaciales
8.
J Biol Chem ; 300(8): 107561, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39002674

RESUMEN

Protein phosphatase 1D (PPM1D, Wip1) is induced by the tumor suppressor p53 during DNA damage response signaling and acts as an oncoprotein in several human cancers. Although PPM1D is a potential therapeutic target, insights into its atomic structure were challenging due to flexible regions unique to this family member. Here, we report the first crystal structure of the PPM1D catalytic domain to 1.8 Å resolution. The structure reveals the active site with two Mg2+ ions bound, similar to other structures. The flap subdomain and B-loop, which are crucial for substrate recognition and catalysis, were also resolved, with the flap forming two short helices and three short ß-strands that are followed by an irregular loop. Unexpectedly, a nitrogen-oxygen-sulfur bridge was identified in the catalytic domain. Molecular dynamics simulations and kinetic studies provided further mechanistic insights into the regulation of PPM1D catalytic activity. In particular, the kinetic experiments demonstrated a magnesium concentration-dependent lag in PPM1D attaining steady-state velocity, a feature of hysteretic enzymes that show slow transitions compared with catalytic turnover. All combined, these results advance the understanding of PPM1D function and will support the development of PPM1D-targeted therapeutics.


Asunto(s)
Dominio Catalítico , Proteína Fosfatasa 2C , Proteína Fosfatasa 2C/metabolismo , Proteína Fosfatasa 2C/química , Proteína Fosfatasa 2C/genética , Humanos , Cristalografía por Rayos X , Magnesio/metabolismo , Magnesio/química , Simulación de Dinámica Molecular , Cinética , Fosfoproteínas Fosfatasas/química , Fosfoproteínas Fosfatasas/metabolismo , Fosfoproteínas Fosfatasas/genética
9.
Genes Cells ; 29(5): 380-396, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38454557

RESUMEN

Left-right (LR) asymmetry is crucial for animal development, particularly in Drosophila where LR-asymmetric morphogenesis of organs hinges on cellular-level chirality, termed cell chirality. In this species, two class I myosins, Myosin1D (Myo1D), and Myosin1C (Myo1C), respectively determine dextral (wild type) and sinistral (mirror image) cell chirality. Previous studies demonstrated Myo1D's ability to propel F-actin in leftward circles during in vitro gliding assays, suggesting its mechanochemical role in defining dextral chirality. Conversely, Myo1C propels F-actin without exhibiting LR-directional preference in this assay, suggesting at other properties governing sinistral chirality. Given the interaction of Myo1D and Myo1C with the membrane, we hypothesized that differences in their membrane behaviors might be critical in dictating their dextral or sinistral activities. In this study, employing single-molecule imaging analyses, we investigated the dynamic behaviors of Myo1D and Myo1C on the plasma membrane. Our findings revealed that Myo1C exhibits a significantly greater proportion of slow-diffusing population compared to Myo1D. Importantly, this characteristic was contingent upon both head and tail domains of Myo1C. The distinct diffusion patterns of Myo1D and Myo1C did not exert mutual influence on each other. This divergence in membrane diffusion between Myo1D and Myo1C may be crucial for dictating cell and organ chirality.


Asunto(s)
Membrana Celular , Proteínas de Drosophila , Macrófagos , Miosina Tipo I , Animales , Membrana Celular/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Miosina Tipo I/metabolismo , Miosina Tipo I/genética , Macrófagos/metabolismo , Drosophila melanogaster/metabolismo , Actinas/metabolismo , Imagen Individual de Molécula , Drosophila/metabolismo
10.
Brief Bioinform ; 24(1)2023 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-36528806

RESUMEN

Determining the pathogenicity and functional impact (i.e. gain-of-function; GOF or loss-of-function; LOF) of a variant is vital for unraveling the genetic level mechanisms of human diseases. To provide a 'one-stop' framework for the accurate identification of pathogenicity and functional impact of variants, we developed a two-stage deep-learning-based computational solution, termed VPatho, which was trained using a total of 9619 pathogenic GOF/LOF and 138 026 neutral variants curated from various databases. A total number of 138 variant-level, 262 protein-level and 103 genome-level features were extracted for constructing the models of VPatho. The development of VPatho consists of two stages: (i) a random under-sampling multi-scale residual neural network (ResNet) with a newly defined weighted-loss function (RUS-Wg-MSResNet) was proposed to predict variants' pathogenicity on the gnomAD_NV + GOF/LOF dataset; and (ii) an XGBOD model was constructed to predict the functional impact of the given variants. Benchmarking experiments demonstrated that RUS-Wg-MSResNet achieved the highest prediction performance with the weights calculated based on the ratios of neutral versus pathogenic variants. Independent tests showed that both RUS-Wg-MSResNet and XGBOD achieved outstanding performance. Moreover, assessed using variants from the CAGI6 competition, RUS-Wg-MSResNet achieved superior performance compared to state-of-the-art predictors. The fine-trained XGBOD models were further used to blind test the whole LOF data downloaded from gnomAD and accordingly, we identified 31 nonLOF variants that were previously labeled as LOF/uncertain variants. As an implementation of the developed approach, a webserver of VPatho is made publicly available at http://csbio.njust.edu.cn/bioinf/vpatho/ to facilitate community-wide efforts for profiling and prioritizing the query variants with respect to their pathogenicity and functional impact.


Asunto(s)
Aprendizaje Profundo , Humanos , Mutación con Ganancia de Función , Genoma
11.
Methods ; 231: 26-36, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39270885

RESUMEN

Interactions of biological molecules in organisms are considered to be primary factors for the lifecycle of that organism. Various important biological functions are dependent on such interactions and among different kinds of interactions, the protein DNA interactions are very important for the processes of transcription, regulation of gene expression, DNA repairing and packaging. Thus, keeping the knowledge of such interactions and the sites of those interactions is necessary to study the mechanism of various biological processes. As experimental identification through biological assays is quite resource-demanding, costly and error-prone, scientists opt for the computational methods for efficient and accurate identification of such DNA-protein interaction sites. Thus, herein, we propose a novel and accurate method namely DeepDBS for the identification of DNA-binding sites in proteins, using primary amino acid sequences of proteins under study. From protein sequences, deep representations were computed through a one-dimensional convolution neural network (1D-CNN), recurrent neural network (RNN) and long short-term memory (LSTM) network and were further used to train a Random Forest classifier. Random Forest with LSTM-based features outperformed the other models, as well as the existing state-of-the-art methods with an accuracy score of 0.99 for self-consistency test, 10-fold cross-validation, 5-fold cross-validation, and jackknife validation while 0.92 for independent dataset testing. It is concluded based on results that the DeepDBS can help accurate and efficient identification of DNA binding sites (DBS) in proteins.

12.
J Allergy Clin Immunol ; 153(4): 913-923, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38365015

RESUMEN

The immune system classically consists of 2 lines of defense, innate and adaptive, both of which interact with one another effectively to protect us against any pathogenic threats. Importantly, there is a diverse subset of cells known as innate-like T cells that act as a bridge between the innate and adaptive immune systems and are pivotal players in eliciting inflammatory immune responses. A growing body of evidence has demonstrated the regulatory impact of these innate-like T cells in central nervous system (CNS) diseases and that such immune cells can traffic into the brain in multiple pathological conditions, which can be typically attributed to the breakdown of the blood-brain barrier. However, until now, it has been poorly understood whether innate-like T cells have direct protective or causative properties, particularly in CNS diseases. Therefore, in this review, our attention is focused on discussing the critical roles of 3 unique subsets of unconventional T cells, namely, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells, in the context of CNS diseases, disorders, and injuries and how the interplay of these immune cells modulates CNS pathology, in an attempt to gain a better understanding of their complex functions.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Células T Invariantes Asociadas a Mucosa , Células T Asesinas Naturales , Humanos , Enfermedades del Sistema Nervioso Central/metabolismo , Inmunidad Innata
13.
Nano Lett ; 24(15): 4633-4640, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38568864

RESUMEN

The glycerol oxidation reaction (GOR) run with photoelectrochemical cells (PECs) is one of the most promising ways to upgrade biomass because it is thermodynamically favorable, while irreversible overoxidation leads to unsatisfactory product selectivities. Herein, a tunable one-dimensional nanoconfined environment was introduced into the GOR process, which accelerated mass transfer of glycerol via the microscale fluid effect and changed the main oxidation product from formic acid (FA) to glyceraldehyde (GLD), which led to retention of the heavier multicarbon products. The rate of glycerol diffusion in the nanochannels increased by a factor of 4.92 with decreasing inner diameters. The main product from the PEC-selective oxidation of glycerol changed from the C1 product FA to the C3 product GLD with a great selectivity of 60.7%. This work provides a favorable approach for inhibiting further oxidation of multicarbon products and illustrates the importance of microenvironmental regulation in biomass oxidation.

14.
Dev Dyn ; 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38822685

RESUMEN

BACKGROUND: Approximately 7% of the males exhibit reduced fertility; however, the regulatory genes and pathways involved remain largely unknown. TBC1 domain family member 21 (TBC1D21) contains a conserved RabGAP catalytic domain that induces GDP/GTP exchange to inactivate Rabs by interacting with microtubules. We previously reported that Tbc1d21-null mice exhibit severe sperm tail defects with a disrupted axoneme, and that TBC1D21 interacts with RAB10. However, the pathological mechanisms underlying the Tbc1d21 loss-induced sperm tail defects remain unknown. RESULTS: Murine sperm from wild-type and Tbc1d21-null mice were comparatively analyzed using proteomic assays. Over 1600 proteins were identified, of which 15 were significantly up-regulated in Tbc1d21-null sperm. Notably, several tektin (TEKT) family proteins, belonging to a type of intermediate filament critical for stabilizing the microtubular structure of cilia and flagella, were significantly up-regulated in Tbc1d21-/- sperm. We also found that TBC1D21 interacts with TEKT1. In addition, TEKT1 co-localized with RAB10 during sperm tail formation. Finally, we found Tbc1d21-null sperm exhibited abnormal accumulation of TEKT1 in the midpiece region, accompanied by disrupted axonemal structures. CONCLUSIONS: These results reveal that TBC1D21 modulates TEKTs protein localization in the axonemal transport system during sperm tail formation.

15.
Artículo en Inglés | MEDLINE | ID: mdl-39236286

RESUMEN

The role of circRNAs in sepsis-induced lung injury is not clear. This study investigated the role and molecular mechanism of a novel circRNA in sepsis-induced lung injury and explored its prognostic value in sepsis patients. In this study, aberrant circRNA expression profiling in lung tissues from mice with sepsis-induced lung injury was analyzed using high-throughput sequencing. CircRNA-Cacna1d was verified by quantitative real-time polymerase chain reaction, and its biological function in sepsis-induced lung injury was validated in vitro and in vivo. The interactions among circRNA-Cacna1d, miRNAs, and their downstream genes were verified. Furthermore, the clinical value of circRNA-Cacna1d in peripheral blood from sepsis patients was also evaluated. We found that circRNA-Cacna1d expression was significantly increased in lung tissues of sepsis mice and microvascular endothelial cells after lipopolysaccharide (LPS) challenge. CircRNA-Cacna1d knockdown alleviated inflammatory response and ameliorated the permeability of vascular endothelium, thereby mitigating sepsis-induced lung injury and significantly improving the survival rate of sepsis mice. Mechanistically, circRNA-Cacna1d directly interacted with miRNA-185-5p and functioned as a miRNA sponge to regulate the RhoA/ROCK1 signaling pathway. The expression level of circRNA-Cacna1d in patients with early sepsis was significantly higher than that in the healthy controls. Higher levels of circRNA-Cacna1d in sepsis patients were associated with increased disease severity and poorer outcomes. In conclusions, circRNA-Cacna1d may play a role in sepsis-induced lung injury by regulating the RhoA/ROCK1 axis by acting as miRNA-185-5p sponge. CircRNA-Cacna1d is a potential therapeutic target for sepsis-induced lung injury and a prognostic biomarker in sepsis.

16.
Am J Physiol Cell Physiol ; 326(6): C1563-C1572, 2024 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-38586879

RESUMEN

Atherosclerosis is an inflammatory disease of blood vessels involving the immune system. Natural killer T (NKT) cells, as crucial components of the innate and acquired immune systems, play critical roles in the development of atherosclerosis. However, the mechanism and clinical relevance of NKT cells in early atherosclerosis are largely unclear. The study investigated the mechanism influencing NKT cell function in apoE deficiency-induced early atherosclerosis. Our findings demonstrated that there were higher populations of NKT cells and interferon-gamma (IFN-γ)-producing NKT cells in the peripheral blood of patients with hyperlipidemia and in the aorta, blood, spleen, and bone marrow of early atherosclerotic mice compared with the control groups. Moreover, we discovered that the infiltration of CD80+ macrophages and CD1d expression on CD80+ macrophages in atherosclerotic mice climbed remarkably. CD1d expression increased in CD80+ macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) ex vivo and in vitro. Ex vivo coculture of macrophages with NKT cells revealed that ox-LDL-induced CD80+ macrophages presented lipid antigen α-Galcer (alpha-galactosylceramide) to NKT cells via CD1d, enabling NKT cells to express more IFN-γ. Furthermore, a greater proportion of CD1d+ monocytes and CD1d+CD80+ monocytes were found in peripheral blood of hyperlipidemic patients compared with that of healthy donors. Positive correlations were found between CD1d+CD80+ monocytes and NKT cells or IFN-γ+ NKT cells in hyperlipidemic patients. Our findings illustrated that CD80+ macrophages stimulated NKT cells to secrete IFN-γ via CD1d-presenting α-Galcer, which may accelerate the progression of early atherosclerosis. Inhibiting lipid antigen presentation by CD80+ macrophages to NKT cells may be a promising immune target for the treatment of early atherosclerosis.NEW & NOTEWORTHY This work proposed the ox-LDL-CD80+ monocyte/macrophage-CD1d-NKT cell-IFN-γ axis in the progression of atherosclerosis. The proinflammatory IFN-γ+ NKT cells are closely related to CD1d+CD80+ monocytes in hyperlipidemic patients. Inhibiting CD80+ macrophages to present lipid antigens to NKT cells through CD1d blocking may be a new therapeutic target for atherosclerosis.


Asunto(s)
Antígenos CD1d , Aterosclerosis , Antígeno B7-1 , Hiperlipidemias , Lipoproteínas LDL , Macrófagos , Células T Asesinas Naturales , Animales , Humanos , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Antígenos CD1d/metabolismo , Antígenos CD1d/inmunología , Antígenos CD1d/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Antígeno B7-1/metabolismo , Antígeno B7-1/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Ratones Endogámicos C57BL , Femenino , Persona de Mediana Edad
17.
J Cell Mol Med ; 28(19): e70123, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39365143

RESUMEN

Cancer remains a prominent cause to life expectancy, and targeted cancer therapy stands as a pivotal approach in contemporary therapy. Calcium (Ca2+) signalling plays a multifaceted role in cancer progression, such as proliferation, invasion and distant metastasis. Otherwise, it also exerts an important influence on the efficacy of clinical treatment, including cancer therapy resistance. In this review we discuss the role of the L-type calcium channel CaV1.3 (calcium voltage-gated channel subunit alpha1 D) in different types of cancers, highlighting its potential as a therapeutic target for certain cancer types. The development of selective blockers of the CaV1.3 channel has been of great interest and is expected to be a new option for the treatment of cancers such as prostate cancer and endometrial cancer. We present the pharmacological properties of CaV1.3 and the current status of selective blocker development, and analyse the challenges and possible directions for breakthroughs in the development of tailored medicines.


Asunto(s)
Bloqueadores de los Canales de Calcio , Canales de Calcio Tipo L , Neoplasias , Humanos , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/genética , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Animales , Bloqueadores de los Canales de Calcio/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Terapia Molecular Dirigida , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología
18.
J Cell Mol Med ; 28(10): e18360, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38785199

RESUMEN

Neuroblastoma (NB), a common solid tumour in young children originating from the sympathetic nervous system during embryonic development, poses challenges despite therapeutic advances like high-dose chemotherapy and immunotherapy. Some survivors still grapple with severe side effects and drug resistance. The role of lncRNA NUTM2A-AS1 has been explored in various cancers, but its function in drug-resistant NB progression is unclear. Our study found that NUTM2A-AS1 expression in cisplatin-resistant NB cells increased in a time- and dose-dependent manner. Knockdown of NUTM2A-AS1 significantly improved NB cell sensitivity to cisplatin and inhibited metastatic abilities. Additionally, we identified B7-H3, an immune checkpoint-related protein, as a NUTM2A-AS1-associated protein in NB cells. NUTM2A-AS1 was shown to inhibit the protein degradation of B7-H3. Moreover, NUTM2A-AS1 modulated immune evasion in cisplatin-resistant NB cells through B7-H3. Furthermore, NUTM2A-AS1 expression in cisplatin-resistant NB cells was transactivated by NR1D1. In summary, our results unveil the molecular or biological relationship within the NR1D1/NUTM2A-AS1/B7-H3 axis in NB cells under cisplatin treatment, providing an intriguing avenue for fundamental research into cisplatin-resistant NB.


Asunto(s)
Antígenos B7 , Cisplatino , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Neuroblastoma , ARN Largo no Codificante , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Resistencia a Antineoplásicos/genética , Antígenos B7/metabolismo , Antígenos B7/genética , ARN Largo no Codificante/genética , Cisplatino/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Evasión Inmune , Animales , Proteolisis/efectos de los fármacos , Ratones
19.
Immunology ; 172(4): 627-640, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38736328

RESUMEN

Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off-the-shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4- subset that has a TH1/cytolytic profile, and a CD4+ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti-tumour effects is not known. Using live cell imaging, we found that CD4- iNKT cells limited growth of CD1d+ Epstein-Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4+ iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4- iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4+ iNKT cells. Immunotherapeutic CD4+ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4+ iNKT cells also had adjuvant-like effects on monocyte-derived DCs and promoted antigen-dependent responses of human T cells in vitro. These results show that allogeneic CD4+ iNKT cellular immunotherapy leads to marked anti-tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen-specific T cells.


Asunto(s)
Antígenos CD1d , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Inmunoterapia Adoptiva , Linfoma de Células B , Células T Asesinas Naturales , Antígenos CD1d/metabolismo , Antígenos CD1d/inmunología , Humanos , Animales , Células T Asesinas Naturales/inmunología , Inmunoterapia Adoptiva/métodos , Herpesvirus Humano 4/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Ratones , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Ratones SCID , Ratones Endogámicos NOD
20.
Int J Cancer ; 155(8): 1487-1499, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-38771720

RESUMEN

Colorectal cancer (CRC) is the third most common cancer and causes high mortality worldwide. Although CRC has been studied widely, the molecular mechanism is not completely known. Eukaryotic translation elongation factor 1 delta (EEF1D) participates in the progression of various tumors, however, the effect of EEF1D on CRC remains unclear. Here, we aimed to identify the potential mechanism of EEF1D in CRC. The expression levels of EEF1D were assessed in CRC samples. Functional analysis of EEF1D in CRC was detected in vitro and in vivo. The regulatory mechanism of EEF1D was identified with RNA immunoprecipitation, RNA pull-down assay, and proteomics analysis. Our findings confirmed that EEF1D was upregulated in human CRC tissues. Functionally, EEF1D overexpression accelerated cell proliferation and metastasis, whereas EEF1D knockdown inhibited cell proliferation and metastasis both in vitro and in vivo CRC models. Furthermore, we showed that EEF1D was upregulated by SRSF9 via binding to 3'UTR of EEF1D mRNA. EEF1D knockdown reversed the malignant phenotype induced by SRSF9 overexpression. These findings demonstrated that EEF1D promotes CRC progression, and EEF1D may be a molecular target against CRC.


Asunto(s)
Proliferación Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Factor 1 de Elongación Peptídica , Factores de Empalme Serina-Arginina , Animales , Femenino , Humanos , Masculino , Ratones , Regiones no Traducidas 3'/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ratones Desnudos , Metástasis de la Neoplasia , Factor 1 de Elongación Peptídica/genética , Factor 1 de Elongación Peptídica/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Factores de Empalme Serina-Arginina/genética , Regulación hacia Arriba
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