RESUMEN
Low sperm motility is a significant contributor to male infertility. beta-defensins have been implicated in host defence and the acquisition of sperm motility; however, the regulatory mechanisms governing their gene expression patterns and functions remain poorly understood. In this study, we performed single-cell RNA and spatial transcriptome sequencing to investigate the cellular composition of testicular and epididymal tissues and examined their gene expression characteristics. In the epididymis, we found that epididymal epithelial cells display a region specificity of gene expression in different epididymal segments, including the beta-defensin family genes. In particular, Defb15, Defb18, Defb20, Defb25 and Defb48 are specific to the caput; Defb22, Defb23 and Defb26 to the corpus; Defb2 and Defb9 to the cauda of the epididymis. To confirm this, we performed mRNA fluorescence in situ hybridisation (FISH) targeting certain exon region of beta-defensin genes, and found some of their expression matched the sequencing results and displayed a close connection with epididimosome marker gene Cd63. In addition, we paid attention to the Sertoli cells and Leydig cells in the testis, along with fibroblasts and smooth muscle cells in the epididymis, by demonstrating their gene expression profile and spatial information. Our study provides a single-cell and spatial landscape for analysing the gene expression characteristics of testicular and epididymal environments and has important implications for the study of spermatogenesis and sperm maturation.
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Epidídimo , Análisis de la Célula Individual , Maduración del Esperma , Transcriptoma , beta-Defensinas , Masculino , Animales , beta-Defensinas/genética , beta-Defensinas/metabolismo , Ratones , Transcriptoma/genética , Maduración del Esperma/genética , Epidídimo/metabolismo , Espermatozoides/metabolismo , Familia de Multigenes , Ratones Endogámicos C57BL , Testículo/metabolismoRESUMEN
BACKGROUND: Men with prediabetes often exhibit concomitant low-quality sperm production or even infertility, problems which urgently require improved therapeutic options. In this study, we have established a sheep model of diet-induced prediabetes that is associated with spermatogenic defects and have explored the possible underlying metabolic causes. RESULTS: We compared male sheep fed a normal diet with those in which prediabetes was induced by a rich diet and with a third group in which the rich diet was supplemented by melatonin. Only the rich diet group had symptoms of prediabetes, and in these sheep, we found impaired spermatogenesis characterized by a block in the development of round spermatids and an increased quantity of testicular apoptotic cells. Comparing the gut microbiomes and intestinal digest metabolomes of the three groups revealed a distinctive difference in the taxonomic composition of the microbiota in prediabetic sheep, and an altered metabolome, whose most significant feature was altered sphingosine metabolism; elevated sphingosine was also found in blood and testes. Administration of melatonin alleviated the symptoms of prediabetes, including those of impaired spermatogenesis, while restoring a more normal microbiota and metabolic levels of sphingosine. Fecal microbiota transplantation from prediabetic sheep induced elevated sphingosine levels and impaired spermatogenesis in recipient mice, indicating a causal role of gut microbiota in these phenotypes. CONCLUSIONS: Our results point to a key role of sphingosine in the disruption of spermatogenesis in prediabetic sheep and suggest it could be a useful disease marker; furthermore, melatonin represents a potential prebiotic agent for the treatment of male infertility caused by prediabetes.
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Microbioma Gastrointestinal , Melatonina , Estado Prediabético , Animales , Apoptosis , Humanos , Masculino , Ratones , Estado Prediabético/complicaciones , Ovinos , Esfingosina , TestículoRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and athletes. ACM has strong genetic determinants, and genetic variants in more than 25 genes have been identified to be associated with ACM, accounting for approximately 60% of ACM cases. Genetic studies of ACM in vertebrate animal models such as zebrafish (Danio rerio), which are highly amenable to large-scale genetic and drug screenings, offer unique opportunities to identify and functionally assess new genetic variants associated with ACM and to dissect the underlying molecular and cellular mechanisms at the whole-organism level. Here, we summarize key genes implicated in ACM. We discuss the use of zebrafish models, categorized according to gene manipulation approaches, such as gene knockdown, gene knock-out, transgenic overexpression, and CRISPR/Cas9-mediated knock-in, to study the genetic underpinning and mechanism of ACM. Information gained from genetic and pharmacogenomic studies in such animal models can not only increase our understanding of the pathophysiology of disease progression, but also guide disease diagnosis, prognosis, and the development of innovative therapeutic strategies.
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Displasia Ventricular Derecha Arritmogénica , Pez Cebra , Animales , Displasia Ventricular Derecha Arritmogénica/genética , Modelos Animales , Arritmias Cardíacas , Muerte Súbita CardíacaRESUMEN
OBJECTIVE: Effects of the diet-induced gut microbiota dysbiosis reach far beyond the gut. We aim to uncover the direct evidence involving the gut-testis axis in the aetiology of impaired spermatogenesis. DESIGN: An excessive-energy diet-induced metabolic syndrome (MetS) sheep model was established. The testicular samples, host metabolomes and gut microbiome were analysed. Faecal microbiota transplantation (FMT) confirmed the linkage between gut microbiota and spermatogenesis. RESULTS: We demonstrated that the number of arrested spermatogonia was markedly elevated by using 10× single-cell RNA-seq in the MetS model. Furthermore, through using metabolomics profiling and 16S rDNA-seq, we discovered that the absorption of vitamin A in the gut was abolished due to a notable reduction of bile acid levels, which was significantly associated with reduced abundance of Ruminococcaceae_NK4A214_group. Notably, the abnormal metabolic effects of vitamin A were transferable to the testicular cells through the circulating blood, which contributed to abnormal spermatogenesis, as confirmed by FMT. CONCLUSION: These findings define a starting point for linking the testicular function and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of male infertility in MetS.
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Microbioma Gastrointestinal/fisiología , Síndrome Metabólico/fisiopatología , Espermatogénesis/fisiología , Testículo/fisiología , Vitamina A/metabolismo , Animales , Ácidos y Sales Biliares/metabolismo , Modelos Animales de Enfermedad , Disbiosis/fisiopatología , Masculino , Metaboloma , OvinosRESUMEN
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.
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Aminoácidos/genética , Predisposición Genética a la Enfermedad/genética , Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Polimorfismo de Nucleótido Simple , Enfermedad de Still del Adulto/genética , Adulto , Alelos , Pueblo Asiatico/genética , China , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Cadenas alfa de HLA-DQ/química , Cadenas HLA-DRB1/química , Haplotipos , Humanos , Desequilibrio de Ligamiento , Modelos Moleculares , Conformación Proteica , Enfermedad de Still del Adulto/etnologíaRESUMEN
A new type of turn-on fluorescent probe CF-AC for the detection of Cys was firstly reported. The probe exhibited an excellent response to Cys with high selectively and sensitivity. In the presence of Cys, two fluorescence emission peaks at 525 nm and 650 nm appeared accompanied by the fluorescence color change from blue to red. Morever, the probe had good biocompatibility and could be successfully used for fluorescence imaging of Cys in MCF-7 cells.
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Cumarinas/química , Cisteína/análisis , Fluoresceína/química , Colorantes Fluorescentes/química , Cisteína/química , Colorantes Fluorescentes/toxicidad , Humanos , Células MCF-7 , Espectrometría de FluorescenciaRESUMEN
In this paper, a new type of ratiometric fluorescent probe HBT-TCF with large emission shift (up to 200 nm) has been developed for sensing HSO3- based on Michael-type addition reaction. The probe could fast recognize of HSO3- within 3 min in PBS buffer solution. The detection limit of the probe for HSO3- is as low as 101 nM. Meanwhile, the sensing mechanism is confirmed by NMR, LCMS. In addition, the probe can be applied to detect HSO3- in living cells.
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Benzotiazoles/química , Colorimetría/métodos , Colorantes Fluorescentes/química , Fenoles/química , Espectrometría de Fluorescencia/métodos , Espectroscopía Infrarroja Corta/métodos , Sulfitos/análisis , Humanos , Límite de Detección , Células MCF-7Asunto(s)
Genes MHC Clase II/genética , Genes MHC Clase I/genética , Enfermedad de Still del Adulto/genética , Adulto , Pueblo Asiatico/genética , China , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Insulin is a protein secreted by pancreatic ß-cells, which plays an important role in the regulation of ovarian function. However, the specific molecular mechanism of its function remains largely unknown. This study aimed to assess the effect of insulin on mouse folliculogenesis using an in vitro ovary-culture model. The results demonstrated that insulin promoted the proliferation of ovarian granulosa cells in vitro, and thereby accelerated the progress of folliculogenesis (the percentage of oocytes in cysts declined from 42.6% to 29.3%); however, the percentage of apoptotic oocytes increased after insulin treatment. Further investigation indicated that apoptosis occurred mainly in germ-cell cysts. After 3 days of insulin treatment, oestrogen in the culture medium of mouse ovaries significantly increased (P<0.01), while the lower dose of oestrogen promoted primordial-follicle assembly in vitro. In conclusion, insulin promoted folliculogenesis by facilitating germ-cell apoptosis within the cysts and upregulating oestrogen levels.
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Apoptosis/efectos de los fármacos , Estradiol/análisis , Células Germinativas/efectos de los fármacos , Insulina/farmacología , Folículo Ovárico/efectos de los fármacos , Animales , Medios de Cultivo/química , Femenino , Células Germinativas/metabolismo , Ratones , Técnicas de Cultivo de Órganos , Folículo Ovárico/metabolismo , Ovario/efectos de los fármacos , Ovario/metabolismoRESUMEN
A silver film perforated with two subwavelength uniform slits is proposed for dichroic directional excitation of surface plasmon polaritons (SPPs). Under backside oblique illumination, the SPPs for two work wavelengths can propagate along the two opposite directions or in the same direction. Based on SPP interference, an integer-programming model is established for dichroic directional excitation of SPPs. The branch and bound method is introduced to find the optimal solutions for the integer-programming model, and therefore, the parameters of the structure and illumination angles can be obtained. The field distribution of the structure is investigated by using the finite-difference time-domain method (FDTD) to verify our design. Our theoretical model can achieve dichroic directional excitation of SPPs, simultaneously.
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Ferroptosis is a form of controlled cell death that was first described relatively recently and that is dependent on the formation and accumulation of lipid free radicals through an iron-mediated mechanism. A growing body of evidence supports the close relationship between pathogenic infections and ferroptotic cell death, particularly for viral infections. Ferroptosis is also closely tied to the pathogenic development of hepatic steatosis and other forms of liver disease. Fowl adenovirus serotype 4 (FAdV-4) is a hepatotropic aviadenovirus causing hydropericardium syndrome (HPS) that is capable of impacting fat metabolism. However, it remains uncertain as to what role, if any, ferroptotic death plays in the context of FAdV-4 infection. Here, FAdV-4 was found to promote ferroptosis via the p53-SLC7A11-GPX4 axis, while ferrostain-1 was capable of inhibiting this FAdV-4-mediated ferroptotic death through marked reductions in lipid peroxidation. The incidence of FAdV-4-induced fatty liver was also found to be associated with the activation of ferroptotic activity. Together, these results offer novel insights regarding potential approaches to treating HPS.
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Ferroptosis , Metabolismo de los Lípidos , Animales , Peroxidación de Lípido , Pollos , Aviadenovirus/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Línea Celular , Hígado Graso/veterinaria , Hígado Graso/metabolismo , Infecciones por Adenoviridae/veterinaria , Infecciones por Adenoviridae/virología , Infecciones por Adenoviridae/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Enfermedades de las Aves de Corral/virologíaRESUMEN
Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.
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Cardiotoxicidad , Doxorrubicina , Lapatinib , Sistema de Señalización de MAP Quinasas , Pez Cebra , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Pez Cebra/embriología , Doxorrubicina/toxicidad , Doxorrubicina/efectos adversos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Cardiotoxicidad/etiología , Lapatinib/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estrés Oxidativo/efectos de los fármacos , FemeninoRESUMEN
BACKGROUND: Paragonimiasis, primarily caused by Paragonimus westermani and P. skrjabini in China, is a common food-borne parasitic zoonosis. However, the national distribution of Paragonimus spp. infection and its associated environmental determinants remain poorly understood. In this paper, we summarize the infection of P. westermani and P. skrjabini and describe key biogeographical characteristics of the endemic areas in China. METHODS: Data on Paragonimus infection in humans and animal hosts were extracted from eight electronic databases, including CNKI, CWFD, Chongqing VIP, SinoMed, Medline, Embase, PubMed, and Web of Science. A random-effects meta-analysis model was used to estimate the pooled prevalence. All survey locations were georeferenced and plotted on China map, and scatter plots were used to illustrate the biogeographical characteristics of regions reporting Paragonimus infection. RESULTS: A total of 28,948 cases of human paragonimiasis have been documented, with 2,401 cases reported after 2010. Among the 11,443 cases with reported ages, 88.05% were children or adolescents. The pooled prevalence of P. skrjabini is 0.45% (95% CI: 0.27-0.66%) in snails, 31.10% (95% CI: 24.77-37.80%) in the second intermediate host, and 20.31% (95% CI: 9.69-33.38%) in animal reservoirs. For P. westermani, the pooled prevalence is 0.06% (95% CI: 0.01-0.13%) in snails, 52.07% (95% CI: 43.56-60.52%) in the second intermediate host, and 21.40% (95% CI: 7.82-38.99%) in animal reservoirs. Paragonimus are primarily distributed in regions with low altitude, high temperature, and high precipitation. In northeastern China, only P. westermani infections have been documented, while in more southern areas, infections of both P. westermani and P. skrjabini have been reported. CONCLUSIONS: Paragonimiasis remains prevalent in China, particularly among children and adolescents. Variations exist in the intermediate hosts and geographical distribution of P. westermani and P. skrjabini. Additionally, altitude, temperature, and precipitation may influence the distribution of Paragonimus.
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Paragonimiasis , Paragonimus , Animales , Paragonimiasis/epidemiología , Paragonimiasis/parasitología , Humanos , China/epidemiología , Paragonimus/aislamiento & purificación , Paragonimus/clasificación , Paragonimus/genética , Zoonosis/parasitología , Zoonosis/epidemiología , Prevalencia , NiñoRESUMEN
BACKGROUND: Many laboratories have described the in vitro isolation of multipotent cells with stem cell properties from the skin of various species termed skin-derived stem cells (SDSCs). However, the cellular origin of these cells and their capability to give rise, among various cell types, to male germ cells, remain largely unexplored. METHODS: SDSCs were isolated from newborn mice skin, and then differentiated into primordial germ cell-like cells (PGCLCs) in vitro. Single-cell RNA sequencing (scRNA-seq) was then applied to dissect the cellular origin of SDSCs using cells isolated from newborn mouse skin and SDSC colonies. Based on an optimized culture strategy, we successfully generated spermatogonial stem cell-like cells (SSCLCs) in vitro. RESULTS: Here, using scRNA-seq and analyzing the profile of 7543 single-cell transcriptomes from newborn mouse skin and SDSCs, we discovered that they mainly consist of multipotent papillary dermal fibroblast progenitors (pDFPs) residing in the dermal layer. Moreover, we found that epidermal growth factor (EGF) signaling is pivotal for the capability of these progenitors to proliferate and form large colonies in vitro. Finally, we optimized the protocol to efficiently generate PGCLCs from SDSCs. Furthermore, PGCLCs were induced into SSCLCs and these SSCLCs showed meiotic potential when cultured with testicular organoids. CONCLUSIONS: Our findings here identify pDFPs as SDSCs derived from newborn skin and show for the first time that such precursors can be induced to generate cells of the male germline.
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Células Germinativas , Células Madre Hematopoyéticas , Animales , Ratones , Células Germinativas/metabolismo , Diferenciación Celular , Células Madre Multipotentes , Células Cultivadas , FibroblastosRESUMEN
Background: Dedifferentiated fat cells (DFATs) are highly homogeneous and multipotent compared with adipose-derived stromal cells (SCs). Infrapatellar fat pad (IFP)-SCs have advanced chondrogenic potency; however, whether IFP-DFATs could serve as better cell material remains unclear. Here, we aimed to examine the influence of age and body mass index (BMI) on the features of IFPs and IFP-derived cells (IFP-SCs and IFP-DFATs) with exploration of the clinical utilization of IFP-DFATs. Methods: We collected IFPs with isolation of paired IFP-SCs and IFP-DFATs from individuals aged 65 years and older with distinct body weights who underwent total knee replacement for osteoarthritis (OA). Flow cytometry was used to characterize the cellular immunophenotypes. Adipogenesis and chondrogenesis were performed in vitro. Real-time qPCR, western blotting, and Oil Red O or Alcian blue staining were performed to evaluate inflammation, adipogenesis, and chondrogenesis. RNA sequencing and Seahorse analyses were conducted to explore the underlying mechanisms. Results: We found that IFPs from old or normal-weight individuals with knee OA were pro-inflammatory, and that interleukin-6 (IL-6) signaling was associated with multiple immune-related molecules, whereas IFP-derived cells could escape the inflammatory properties. Aging plays an important role in diminishing the chondrogenic and adipogenic abilities of IFP-SCs; however, this effect was avoided in IFP-DFATs. Generally, IFP-DFATs presented a steady state of chondrogenesis (less influenced by age) and consistently enhanced adipogenesis compared to paired IFP-SCs in different age or BMI groups. RNA sequencing and Seahorse analysis suggested that the downregulation of eukaryotic initiation factor 2 (EIF2) signaling and enhanced mitochondrial function may contribute to the improved cellular biology of IFP-DFATs. Conclusions: Our data indicate that IFP-DFATs are superior cell material compared to IFP-SCs for cartilage differentiation and adipogenesis, particularly in advanced aging patients with knee OA. The translational potential of this article: These results provide a novel concept and supportive evidence for the use of IFP-DFATs for cell therapy or tissue engineering in patients with knee OA. Using Ingenuity Pathway Analysis (IPA) of RNA-seq data and Seahorse analysis of mitochondrial metabolic parameters, we highlighted that some molecules, signaling pathways, and mitochondrial functions are likely to be jointly coordinated to determine the enhanced biological function in IFP-DFATs.
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Controllable and visible delivery of therapeutic agents is critical for tumor precise therapy. Tumor targeting and deep penetration of therapeutic agents are still challenging issues for controllable delivery. Visible drug delivery with imaging navigation can optimize the treatment window for personalized medicine. Herein, a biomimetic platelet intelligent vehicle with navigation (IRDNP-PLT) was developed to achieve controllable and visible delivery with a navigation system, a driving system, and a loading system. The platelets acted as engines and drug repositories to exert the target driving and delivery functions. The fluorescent photothermal agent IR-820 was introduced in the platform to offer an imaging navigation for the intelligent platelet vehicle in addition to photothermal therapy. The nanodrug-loaded platelets enabled efficient drug loading and controlled release of the therapeutic payload by encapsulating photothermal-/pH-sensitive chemotherapeutic nanoparticles (PDA@Dox NPs). In in vivo experiments on 4T1 tumor-bearing mice models, IRDNP-PLT performed well in tumor targeting and showed excellent therapeutic efficacy and tumor recurrence prevention ability. The intelligent platelet vehicle achieved the functions of tumor targeting and deep penetration, fluorescence imaging guidance, photocontrolled drug release, and chemo-photothermal combination therapy, suggesting the advancement for tumor precise delivery and efficient therapy.
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Hipertermia Inducida , Nanopartículas , Neoplasias , Ratones , Animales , Fototerapia/métodos , Hipertermia Inducida/métodos , Doxorrubicina , Plaquetas , Liberación de Fármacos , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológicoRESUMEN
Toxicology studies provide a reliable dose range for the use of compounds. Zebrafish show unique advantages in toxicology research. Cinnamaldehyde (Cin) is one of the main active compounds isolated from Cinnamon trees and other species of the genus Cinnamomum. In this study, we investigated the developmental neurotoxicity of cinnamaldehyde in zebrafish and preliminarily explored its underlying mechanism. Cinnamaldehyde causes developmental neurotoxicity in zebrafish, as evidenced by the damage to ventricular structures, eye malformations, shortened body length, trunk curvature, decreased neuronal fluorescence, and pericardial oedema. Moreover, it can induce abnormal behaviour and gene expression in zebrafish. After treatment with the oxidative stress inhibitor astaxanthin, the behaviour and abnormal gene expression were reversed. All of these data demonstrated that the developmental neurotoxicity of cinnamaldehyde might be attributed to oxidative stress. In addition, this study also confirmed that zebrafish is a reliable model for toxicity studies.
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Síndromes de Neurotoxicidad , Pez Cebra , Animales , Pez Cebra/metabolismo , Síndromes de Neurotoxicidad/genética , Estrés Oxidativo , Acroleína/farmacologíaRESUMEN
Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.
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Cardiomiopatías/inducido químicamente , Cardiomiopatías/genética , Doxorrubicina/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Apoptosis , Autofagia , Elementos Transponibles de ADN/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Insuficiencia Cardíaca/fisiopatología , Modelos Biológicos , Músculo Esquelético/metabolismo , Mutación/genética , Miocardio/metabolismo , Miocitos Cardíacos/patología , Polimorfismo de Nucleótido Simple/genética , Agregado de Proteínas , Factores de Riesgo , Estrés FisiológicoRESUMEN
BACKGROUND: Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). METHODS: A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). RESULTS: The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. CONCLUSIONS: The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.
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Antipsicóticos , Clozapina , Neutropenia , Esquizofrenia , Antipsicóticos/efectos adversos , Clozapina/efectos adversos , Estudio de Asociación del Genoma Completo , Humanos , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Neutropenia/genética , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
Duck hepatitis A virus (DHAV) is one of the pathogens that cause fatal duck viral hepatitis (DVH) in ducklings, which is an acute and contagious disease with a high mortality rate. Despite a continuing official duck vaccination program, DHAV infection remains a major threat to the duck industry. Considerable changes were observed in the epidemiology of DHAV-1/-3 in China over time. Therefore, comparing the pathogenicity of different DHAV serotypes can provide a theoretical basis for the diagnosis and prevention of DVH. In this study, we systematically investigated the effects of infection with DHAV-1/-3 field strains on clinical signs, gross lesions, histopathological changes, viral RNA detection, enzymatic systems, and metabolite concentrations. The results demonstrated that the major macroscopic and microscopic lesions in ducks infected with DHAV-1/-3 in the liver, brain, spleen, pancreas, and kidneys exhibited no significant differences. After 24 h of infection, DHAV quickly appeared in blood and major organs. Significant changes in clinical chemical markers together with histopathological lesions and viral RNA detection indicated that the liver is the major target organ for both viruses, resulting in impaired of liver integrity and function. In addition, we found that both viruses were able to invade both central and peripheral immune organs. Also lipase plasma activity was substantially affected by DHAV-1/-3, indicating that the integrity and function of the pancreas was compromised. However, there was no significant difference in pathogenicity between DHAV-1 and -3. The results of this study provide new insights into the pathogenesis of DHAV-1/3, two viruses that cause serious depression, metabolic disorders, and immunosuppression.