RESUMEN
Because speciation might have been promoted by ancient introgression from an extinct lineage, it is important to detect the existence of 'ghost introgression' in focal taxa and examine its contribution to their diversification. In this study, we examined possible ghost introgression and its contributions to the diversification of ricefishes of the genus Adrianichthys in Lake Poso, an ancient lake on Sulawesi Island, in which some extinctions are known to have occurred. Population-genomic analysis revealed that two extant Adrianichthys species, A. oophorus and A. poptae are reproductively isolated from each other. Comparisons of demographic models demonstrated that introgression from a ghost population, which diverged from the common ancestor of A. oophorus and A. poptae, is essential for reconstructing the demographic history of Adrianichthys. The best model estimated that the divergence of the ghost population greatly predated the divergence between A. oophorus and A. poptae, and that the ghost population secondarily contacted the two extant species within Lake Poso more recently. Genome scans and simulations detected a greatly divergent locus, which cannot be explained without ghost introgression. This locus was also completely segregated between A. oophorus and A. poptae. These findings suggest that variants that came from a ghost population have contributed to the divergence between A. oophorus and A. poptae, but the large time-lag between their divergence and ghost introgression indicates that the contribution of introgression may be restricted.
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Lagos , FilogeniaRESUMEN
Modes of reproduction in animals are diverse, with different modes having evolved independently in multiple lineages across a variety of taxa. However, an understanding of the genomic change driving the transition between different modes of reproduction is limited. Several ricefishes (Adrianichthyidae) on the island of Sulawesi have a unique mode of reproduction called "pelvic-fin brooding," wherein females carry externally fertilized eggs until hatching using their pelvic fins. Phylogenomic analysis demonstrated pelvic-fin brooders to have evolved at least twice in two distant clades of the Adrianichthyidae. We investigated the genetic architecture of the evolution of this unique mode of reproduction. Morphological analyses and laboratory observations revealed that females of pelvic-fin brooders have longer pelvic fins and a deeper abdominal concavity, and that they can carry an egg clutch for longer than nonbrooding adrianichthyids, suggesting that these traits play important roles in this reproductive mode. Quantitative trait locus mapping using a cross between a pelvic-fin brooder Oryzias eversi and a nonbrooding O. dopingdopingensis reveals different traits involved in pelvic-fin brooding to be controlled by different loci on different chromosomes. Genomic analyses of admixture detected no signatures of introgression between two lineages with pelvic-fin brooders, indicating that introgression is unlikely to be responsible for repeated evolution of pelvic-fin brooding. These findings suggest that multiple independent mutations may have contributed to the convergent evolution of this novel mode of reproduction.
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Peces , Reproducción , Aletas de Animales/anatomía & histología , Animales , Femenino , Peces/genética , Genoma , Fenotipo , Filogenia , Reproducción/genéticaRESUMEN
Sympatric speciation is considered to be difficult without the coupling between ecological traits that allow resource partitioning and reproductive traits that allow assortative mating. Such "magic traits" are known to be involved in most of the compelling examples of sympatric speciation. In this study, we report a possible case of sympatric speciation without magic traits. Three species of ricefish (genus Oryzias) are suggested to have diverged sympatrically within Lake Poso, an ancient lake in Sulawesi. An analysis of genome-wide single-nucleotide polymorphisms showed that these three species are reproductively isolated from each other throughout the lake. Stable isotope analyses revealed that the three species use different food resources, which reflect differences in their feeding morphologies (gill rakers and digestive tracts) and feeding sites. Field and laboratory observations showed that O. nebulosus and O. orthognathus share a mating habitat of cobbles, where they scatter fertilized eggs, whereas this site is never used by O. nigrimas, indicating that assortative mating is partly achieved by spatial isolation. The small, less-adhesive eggs of O. nebulosus and O. orthognathus probably reflect their adaptation to spawning on cobble beaches. Laboratory mating experiments showed strong prezygotic isolation between O. nebulosus and O. orthognathus, which is achieved by strong species recognition presumably by both sexes based on species-specific mating dances and nuptial coloration. In summary, the assortative mating of O. nebulosus and O. orthognathus is probably not coupled to resource partitioning. We discussed how sympatric speciation among these species might have been achieved even without magic traits.
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Lagos , Oryzias , Animales , Femenino , Especiación Genética , Masculino , Fenotipo , Reproducción , SimpatríaRESUMEN
RESEARCH QUESTION: Is natural cycle IVF treatment beneficial to middle-aged women with poor ovarian response? DESIGN: Retrospective investigation of outcomes in women aged 45 years and older, who underwent natural cycle IVF treatment between 2009 and 2018 in a single assisted reproduction clinic with the aim of reporting several successful outcomes. RESULTS: In total, 2408 IVF retrievals in women aged 45 years and older were included in this study. Mean serum FSH level on day 3 was 21.4 ± 12.5 (range: 0.3-93.7) IU/ml. One fresh cleavage-stage embryo was transferred in 37.4% (900/2408) of the initiated cycles. The overall clinical pregnancy rate and live birth rate per fresh embryo transfer were 2.8% (25/900) and 0.8% (7/900), respectively. Natural cycle IVF treatment led to seven successful deliveries during the period. All seven women who successfully delivered were poor ovarian responders who met the diagnostic Bologna criteria and, among them, three had elevated serum FSH levels on day 3 (range: 39.0-47.1 mIU/ml). All seven had full-term delivery, and no congenital abnormalities were observed in their infants. No significant difference was found in serum FSH level on day 3 between those with and without positive beta-HCG test results. CONCLUSIONS: These findings suggest that natural cycle IVF treatment could be an option for older poor responders in countries that do not permit egg donation. Careful counselling is required, however, because of the low probability of live births after IVF in middle-aged women.
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Fertilización In Vitro/estadística & datos numéricos , Ciclo Menstrual/sangre , Índice de Embarazo , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Estudios RetrospectivosRESUMEN
The Indian subcontinent has an origin geologically different from Eurasia, but many terrestrial animal and plant species on it have congeneric or sister species in other parts of Asia, especially in the Southeast. This faunal and floral similarity between India and Southeast Asia is explained by either of the two biogeographic scenarios, 'into-India' or 'out-of-India'. Phylogenies based on complete mitochondrial genomes and five nuclear genes were undertaken for ricefishes (Adrianichthyidae) to examine which of these two biogeographic scenarios fits better. We found that Oryzias setnai, the only adrianichthyid distributed in and endemic to the Western Ghats, a mountain range running parallel to the western coast of the Indian subcontinent, is sister to all other adrianichthyids from eastern India and Southeast-East Asia. Divergence time estimates and ancestral area reconstructions reveal that this western Indian species diverged in the late Mesozoic during the northward drift of the Indian subcontinent. These findings indicate that adrianichthyids dispersed eastward 'out-of-India' after the collision of the Indian subcontinent with Eurasia, and subsequently diversified in Southeast-East Asia. A review of geographic distributions of 'out-of-India' taxa reveals that they may have largely fuelled or modified the biodiversity of Eurasia.
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Oryzias , Animales , Asia Sudoriental , Biodiversidad , India , FilogeniaRESUMEN
Almost all viviparous species possess male external genitalia; for example, the mammalian penis is an intromittent organ. Some live-bearing bony fish use their anal fins to assist in mating and internal fertilization. We previously reported a male-specific asymmetric curvature at the posterior end of the anal fin in Xenotoca eiseni, a viviparous fish of the family Goodeidae. However, three other goodeid species, Xenotoca melanosoma, Zoogoneticus quitzeoensis, and Chapalichthys pardalis, examined in that study possessed lesser anal fin curvature modifications as compared to those in the anal fin of X. eiseni. Here, we report the second case of acute-angled curvature modification of the male anal fin in the family Goodeidae. We obtained a dead specimen of the goodeid species Xenotoca variata from a city zoo in Japan, and the morphological and histological analyses indicated an acute-angled asymmetric curvature of the posterior end of the anal fin in X. variata, similar to that observed in X. eiseni in the previous study. However, in our previous report, obtuse-angled modification was only observed in one other Xenotoca species, X. melanosoma, and two species belonging to other genera, Z. quitzeoensis and C. pardalis. Therefore, our findings suggest that the acute-angled curvature in the male anal fin has been developed in the genus Xenotoca.
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Aletas de Animales/anatomía & histología , Ciprinodontiformes/anatomía & histología , Animales , Masculino , Caracteres SexualesRESUMEN
INTRODUCTION: Mutations of the voltage-gated sodium channel gene (SCN4A), which encodes Nav1.4, cause nondystrophic myotonia that occasionally is associated with severe apnea and laryngospasm. There are case reports of nondystrophic myotonia due to mutations in the C-terminal tail (CTerm) of Nav1.4, but the functional analysis is scarce. METHODS: We present two families with nondystrophic myotonia harboring a novel heterozygous mutation (E1702del) and a known heterozygous mutation (E1702K). RESULTS: The proband with E1702K exhibited repeated rhabdomyolysis, and the daughter showed laryngospasm and cyanosis. Functional analysis of the two mutations as well as another known heterozygous mutation (T1700_E1703del), all located on EF hand-like motif in CTerm, was conducted with whole-cell recording of heterologously expressed channel. All mutations displayed impaired fast inactivation. DISCUSSION: The CTerm of Nav1.4 is vital for regulating fast inactivation. The study highlights the importance of accumulating pathological mutations of Nav1.4 and their functional analysis data.
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Motivos EF Hand/genética , Potenciales de la Membrana/fisiología , Mutación/genética , Trastornos Miotónicos/diagnóstico , Trastornos Miotónicos/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Preescolar , Femenino , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Trastornos Miotónicos/fisiopatología , Adulto JovenRESUMEN
Serum metabolites can reflect the diffusion/export of biochemicals from various organs. They can serve as biomarkers related to diseases and therapeutic efficacy/toxicity. While studies in Caucasians suggested that subject gender and age can affect circulating metabolite profiles, the Japanese population has not been surveyed. Our objective was to delineate gender- and age-associated differences in serum metabolite profiles among Japanese populations. Using a mass spectrometry-based global metabolomics approach, 516 endogenous metabolites were detected in sera from Japanese individuals. The principal component analysis identified gender as the primary component, followed by age, suggesting that these two criteria were key contributors to variations in the dataset. Gender-associated differences were observed in 31 and 25% of metabolites in the young (age 25-35) and old (ages 55-65) populations, respectively, in redox homeostasis, and in steroid and purine nucleotide metabolism pathways. Age-associated differences were observed in 24 and 23% of metabolites in men and women, respectively. No pathway was commonly highlighted. Thus, gender and age impact on metabolite profiles in the Japanese population. Our results provide useful information to explore biomarkers for clinical applications in the Japanese population and to assess the applicability of known biomarkers identified in other populations to the Japanese population.
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Envejecimiento/metabolismo , Metaboloma , Suero/metabolismo , Adulto , Anciano , Envejecimiento/sangre , Pueblo Asiatico , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Caracteres SexualesRESUMEN
Antibody drug is a kind of glycoprotein which molecular weight is over one hundred thousand. The number of pharmaceutical approval of antibody drug has been increasing in recent years. In terms of a working mechanism and pharmacokinetics, antibody drug is markedly different from existing low molecular weight drugs. In prospect, about body kinetics is the same. This paper describes general features of antibody drug mainly about internal kinetics in the first half. In the last half, body kinetics of human anti-RANKL monoclonal antibody called Denosumab and body kinetics changes in special population are outlined.
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Denosumab/farmacocinética , Ligando RANK/inmunología , Envejecimiento , Peso Corporal/efectos de los fármacos , Denosumab/administración & dosificación , Denosumab/efectos adversos , Humanos , Enfermedades RenalesRESUMEN
Empty follicle syndrome (EFS) has been defined as a condition where no oocytes can be retrieved for in vitro fertilization (IVF) even though ultrasound findings and estradiol (E2) levels suggest the presence of potential follicles. The EFS is a rare condition with an incidence of 0.5-7 % of women undergoing IVF treatments. Although there are many hypotheses as to the cause of EFS, including advanced ovarian age, drug-related problems, and dysfunctional folliculogenesis, its cause remains unknown. A 37-year-old woman with endometriosis and a 5-year history of primary infertility underwent IVF treatment for 4 cycles. No oocytes were retrieved in 2 cycles and no fertilized eggs were obtained in the other 2 cycles. We assumed that endometriosis adversely affected folliculogenesis and fertilization. Aspiration of an endometrial cyst in the right ovary and subsequent administration of oral contraceptives resulted in successful folliculogenesis and fertilization. Thereafter, she conceived and delivered a 2,662 g female infant at 38 weeks of gestation. Here, we report a case of EFS who conceived in the 5th IVF cycle after aspiration of an endometrial cyst. We assumed that endometriosis might have been involved in the dysfunction of folliculogenesis and EFS.
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The kangaroo endogenous retrovirus (KERV) was previously reported to have undergone a rapid copy number increase in the red-necked wallaby; however, the mode of amplification was left to be clarified. The present study revealed that the long terminal repeat (LTR) (0.6 kb) and internal region (2.0 kb) of a provirus are repeated alternately, forming megasatellite DNA which we named kervRep. This repetition pattern was the same as that observed for walbRep, megasatellite DNA originating from another endogenous retrovirus. Their formation process can be explained using a simple model: pairing slippage followed by homologous recombination. This model features that the initial step is triggered by the presence of two identical sequences within a short distance; the possession of LTRs by endogenous retroviruses fulfills this condition. The discovery of two cases suggests that formation of this type of satellite DNA is one of non-negligible effects of endogenous retroviruses on their host genomes.
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Retrovirus Endógenos , Animales , Retrovirus Endógenos/genética , Provirus/genética , Macropodidae/genética , ADN , Secuencias Repetidas TerminalesRESUMEN
Mutual attachment between mother and pup is important to enable the mother to care for her pup and for the pup to receive care from its mother. Pups eventually leave their mothers, which is also very important to their growth. The mechanism of preference by which pups transfer attachment from their mother to others remains unknown. In this study, we assessed mother/novel dam preferences and examined the brain regions associated with the regulation of this preference in C57BL/6 mice pups. We found that C57BL/6 mice pups had variety in their mother/novel dam preferences at 16 days old. This variety was not related to the sex of the pups, their weight, or the litter size. In order to clarify the brain mechanisms responsible for this variety, we examined the relationship between mother/novel dam preference and neuronal activation induced by contact with the mother. We found that pups exhibiting novel dam preference had higher neural activity in the anterior cingulate cortex (ACC) and bed nucleus of the stria terminalis (BNST) when exposed to their mother. These results suggest that ACC and/or BNST neural activity may be associated with mother/novel dam preferences in infant mice.
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Conducta Materna , Madres , Animales , Encéfalo , Femenino , Humanos , Conducta Materna/fisiología , Ratones , Ratones Endogámicos C57BL , NeuronasRESUMEN
Excessive dietary phosphorus may increase cardiovascular risk in healthy individuals as well as in patients with chronic kidney disease, but the mechanisms underlying this risk are not completely understood. To determine whether postprandial hyperphosphatemia may promote endothelial dysfunction, we investigated the acute effect of phosphorus loading on endothelial function in vitro and in vivo. Exposing bovine aortic endothelial cells to a phosphorus load increased production of reactive oxygen species, which depended on phosphorus influx via sodium-dependent phosphate transporters, and decreased nitric oxide production via inhibitory phosphorylation of endothelial nitric oxide synthase. Phosphorus loading inhibited endothelium-dependent vasodilation of rat aortic rings. In 11 healthy men, we alternately served meals containing 400 mg or 1200 mg of phosphorus in a double-blind crossover study and measured flow-mediated dilation of the brachial artery before and 2 h after the meals. The high dietary phosphorus load increased serum phosphorus at 2 h and significantly decreased flow-mediated dilation. Flow-mediated dilation correlated inversely with serum phosphorus. Taken together, these findings suggest that endothelial dysfunction mediated by acute postprandial hyperphosphatemia may contribute to the relationship between serum phosphorus level and the risk for cardiovascular morbidity and mortality.
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Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fósforo Dietético/farmacología , Adulto , Animales , Arteria Braquial/efectos de los fármacos , Arteria Braquial/fisiología , Enfermedades Cardiovasculares/epidemiología , Bovinos , Células Cultivadas , Estudios Cruzados , Modelos Animales de Enfermedad , Método Doble Ciego , Endotelio Vascular/citología , Humanos , Hiperfosfatemia/sangre , Hiperfosfatemia/complicaciones , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fósforo/sangre , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Factores de Riesgo , Vasodilatación/efectos de los fármacosRESUMEN
A 35-year-old Japanese nulliparous woman exhibited rapid weight gain (6 kg/7 days), reduced antithrombin activity and platelet count at 37 weeks of gestation without hypertension or proteinuria, and underwent cesarean section. Postnatally, pulmonary edema developed for 7 days, with transient hypertension and proteinuria, and bodyweight loss (14.6 kg) by 14 days postpartum. Platelet count and antithrombin activity normalized promptly postpartum. Despite a life-threatening clinical condition due to enhanced vascular permeability, neither hypertension nor proteinuria appeared antenatally. Determining antithrombin activity and platelet count may be useful for distinguishing between women with pathological edema and physiological edema.
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Edema/diagnóstico , Preeclampsia/diagnóstico , Adulto , Cesárea , Femenino , Humanos , Embarazo , Proteinuria/diagnósticoRESUMEN
BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe disorder due to a systemic hypersensitivity reaction. We report on a case with DIHS-like symptoms following human herpes virus 6 (HHV-6) infection complicated with encephalopathy. CASE SUMMARY: An 11-month-old girl suffered from a human herpes virus 6 (HHV-6) infection (exanthema subitum) complicated with encephalopathy. We treated the patient with continuous infusion of thiopental, assisted mechanical ventilation, methylprednisolone pulse therapy, and gamma-globulin infusion therapy starting on the fifth day of the illness and started phenobarbital administration on the eleventh day. The patient developed a fever, systemic erythematous exanthema, lymphadenopathy, and eosinophilia two weeks after the start of phenobarbital administration. Steroid therapy, methylprednisolone (4 mg/kg/day) followed by oral prednisolone (1 mg/kg/day), was started on the 28th day and was tapered off on the 72nd day after admission. Serum anti-HHV-6 IgG antibody elevation and the presence of HHV-6 DNA in the peripheral blood detected by polymerase chain reaction (PCR) analysis suggested reactivation of HHV-6 after the primary infection of HHV-6. Lymphocyte transformation test for phenobarbital was positive three weeks after the DIHS crisis. DISCUSSION: HHV-6 reactivation is a unique feature in DIHS. In general one develops DIHS accompanied by reactivation of HHV-6 which has been residing in the body since the initial infection (exanthema subitum) in early childhood. This is the first report of a patient with DIHS-like symptoms which developed immediately following the primary infection of HHV-6.
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Encefalopatías Metabólicas/diagnóstico , Hipersensibilidad a las Drogas/diagnóstico , Exantema Súbito/diagnóstico , Herpesvirus Humano 6/fisiología , Activación Viral , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Encefalopatías Metabólicas/complicaciones , Encefalopatías Metabólicas/tratamiento farmacológico , Encefalopatías Metabólicas/fisiopatología , Diagnóstico Diferencial , Hipersensibilidad a las Drogas/complicaciones , Hipersensibilidad a las Drogas/tratamiento farmacológico , Hipersensibilidad a las Drogas/fisiopatología , Eosinofilia , Exantema Súbito/complicaciones , Exantema Súbito/tratamiento farmacológico , Exantema Súbito/fisiopatología , Femenino , Glucocorticoides/uso terapéutico , Herpesvirus Humano 6/patogenicidad , Humanos , Lactante , Enfermedades Linfáticas , Fenobarbital/administración & dosificación , Fenobarbital/efectos adversos , ConvulsionesRESUMEN
PURPOSE: Acetaminophen (APAP) has hepatotoxic potential when overdosed. Recent studies have reported serum alanine aminotransferase (ALT) elevations that resolve spontaneously with continued use of the drug, referred to as adaptation, in several individuals receiving therapeutic doses of APAP. However, the clinical significance of these ALT elevations remains unclear. This study was performed to investigate the incidence and characteristics of hepatic adaptation to therapeutic doses of APAP in healthy individuals. METHODS: In a randomized, single-blind, placebo-controlled study, 242 healthy Japanese individuals were enrolled. Each person received 3 g/d of APAP (n = 202) or placebo (n = 40) for 28 days. All study participants underwent analysis of genetic polymorphisms of CYP2E1 and UGT1A1; measurements of plasma APAP concentration and urine metabolites (glucuronide, sulfate, cysteine, and mercapturate); liver function monitoring, including ALT, microRNA-122, and high-mobility group box 1. Individuals with ALT levels remaining below the upper limit of normal (ULN; 40 U/L) during the study period were defined as tolerant and those with ALT elevations above the ULN as susceptible. Susceptible individuals who developed ALT elevations exceeding 2 × ULN discontinued use of the study drug for tolerability consideration. Susceptible individuals who had ALT elevations that decreased toward the ULN spontaneously with continued use of the study drug were classified as adaptation. FINDINGS: In the APAP group, 129 individuals (66%) were classified as tolerant and 65 (34%) as susceptible. Among 65 susceptible individuals, 12 (18%) discontinued use of APAP because of ALT elevations (>2 × ULN), whereas 53 (82%) completed 28-day APAP dosing. Thirty of 65 susceptible individuals (46%) had adaptation within 28 days. In the placebo group, no individuals was withdrawn from the study because of elevated ALT levels, 33 individuals (89%) were classified as tolerant, and 4 (11%) were classified as susceptible. None had clinical signs of liver injury. ALT level correlated significantly with microRNA-122 but not with high-mobility group box 1. No association was found between plasma APAP concentrations and ALT levels. Urinary excretion of APAP mercapturate was higher in susceptible than in tolerant individuals (P = 0.018, Wilcoxon or Kruskal-Wallis test). The frequency of homozygotes and compound heterozygotes for UGT1A1∗28 and UGT1A1∗6 (∗28/∗28, ∗6/∗6, and ∗6/∗28) was higher in susceptible than in tolerant individuals (13.9% vs 3.9%; P = 0.011, χ2 test). IMPLICATIONS: These findings indicate that in healthy individuals, APAP at a therapeutic dose can cause transient and self-limiting ALT elevation, reflecting subclinical hepatocellular damage, and these ALT elevations may be associated with the disposition of APAP metabolites and genetic factors. UMIN-CTR identifier: UMIN000019607.
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Acetaminofén/administración & dosificación , Alanina Transaminasa/sangre , Analgésicos no Narcóticos/administración & dosificación , Acetaminofén/sangre , Acetaminofén/farmacocinética , Acetaminofén/orina , Adulto , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/farmacocinética , Analgésicos no Narcóticos/orina , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/orina , Citocromo P-450 CYP2E1/genética , Tolerancia a Medicamentos/genética , Femenino , Glucuronosiltransferasa/genética , Proteína HMGB1 , Voluntarios Sanos , Humanos , Hígado/metabolismo , Masculino , MicroARNs , Método Simple Ciego , Adulto JovenRESUMEN
Drug-induced liver injury (DILI) is a major adverse event caused by drug treatment, which can be categorized into three types: hepatocellular, mixed, and cholestatic. Although nearly every class of drugs can cause DILI, an overall understanding of lipid profiles in DILI patients is lacking. We used lipidomics to analyze the plasma lipid profiles of patients to understand their hepatic pathophysiology and identify DILI biomarkers. We identified 463 lipids and compared their levels between the acute and recovery phases of the three types of DILI patients. Mixed and cholestatic types demonstrated specific plasma lipid alterations between the phases, but the hepatocellular type did not. Moreover, as specific indicators of mixed-type DILI, levels of several ceramides increased in the acute phase, while those of arachidonic acid-containing ether-linked phosphoglycerolipids decreased. In contrast, as specific indicators of cholestatic-type DILI, levels of palmitic acid-containing saturated or monounsaturated phosphatidylcholines increased in the acute phase, while those of arachidonic acid- or docosahexaenoic acid-containing ether-linked phosphoglycerolipids and phosphatidylinositols decreased. We also identified lipids with a relatively high capacity to discriminate the acute phase from the recovery phase and healthy subjects. These findings may help with understanding the pathophysiology of different DILI types and identify candidate biomarkers.
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Bcl-2 is an intracellular membrane protein that prevents cells from undergoing apoptosis in response to various cell-death signals. It negatively regulates mitochondrial outer membrane permeabilization, which is responsible for the release of apoptogenic factors and the subsequent activation of caspases. A microbial metabolite, aranorosin, was identified as an inhibitor of the anti-apoptotic function of Bcl-2. Based on its structure, a more potent derivative, K050, was synthesized. Apoptosis could be induced in a cell line that overexpressed Bcl-2 when cells were treated with an anti-Fas antibody in addition to K050, at sub-micromolar concentrations. Furthermore, K050 inhibited anti-apoptotic functions regulated by Bcl-2, resulting in a Fas-triggered mitochondrial transmembrane potential loss, the activation of caspase-9, and a morphological change to apoptosis. Inhibition of cell-based function of Bcl-2 and its anti-apoptotic effects could serve as useful pharmacological effects. Thus, a novel aranorosin derivative, K050, could be a potent therapeutic agent against Bcl-2-overexpressing human malignancies.
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Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Núcleo Celular/efectos de los fármacos , Núcleo Celular/ultraestructura , Cicloheximida/farmacología , Furanos/química , Furanos/farmacología , Células HeLa , Humanos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Receptor fas/antagonistas & inhibidoresRESUMEN
Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Japan and other Westernized countries. Over 50% of the ESRD patients die from cardiovascular events. Cardiovascular disease (CVD) in ESRD patients with diabetes mellitus (DM) are implicated in the endothelial dysfunction caused by hyperglycemia, hyperlipidemia, and hypertension, and in the vascular calcification of intimal and medial arterial blood vessels caused by hyperphosphatemia. Therefore, dietary control of hyperglycemia and hyperphosphatemia should play an important role in the management of ESRD patients with DM. Furthermore, recent findings suggest that high concentrations of serum phosphate, even if within the normal range, may be a risk factor for CVD and mortality. An in vivo study using klotho knockout mice and fibroblast growth factor 23 (FGF-23) knockout mice has revealed that correction of hyperphosphatemia and hypervitaminosis D could ameliorate the premature aging-like phenotype. A low glycemic index and low phosphate diet may provide an advantage in the prevention of aging-related diseases in healthy individuals as well as in those with chronic kidney disease.
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Nefropatías Diabéticas/prevención & control , Envejecimiento/sangre , Animales , Factor-23 de Crecimiento de Fibroblastos , Índice Glucémico , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/dietoterapia , Ratones , Ratones Noqueados , Fosfatos/sangre , Fósforo Dietético/administración & dosificaciónRESUMEN
Lipid metabolites in the blood are expected to be biomarker candidates to reflect disease states and responses to therapeutic drugs. However, their profiles are influenced by subject background, which may lead to confounding results. This study aimed to evaluate whether age and gender affect lipid metabolite levels in the plasma of healthy Japanese adults. Comprehensive lipidomic analysis was performed using liquid chromatography-mass spectrometry for overnight fasted volunteers consisting of 4 groups of 15 subjects each: young males (25-35 years), elderly males (55-64 years), young females (25-35 years), and elderly females (55-65 years). Of 326 detected lipids, none showed significant gender-associated differences in the young groups and 3 metabolites showed significant gender-associated differences in the elderly groups, suggesting that age has little impact on plasma lipid levels in Japanese subjects. We found age-associated differences in 111 (34%) and 115 (35%) metabolites in males and females, respectively, indicating that the subjects' age should be considered an important confounding factor for lipid biomarker exploration and validation studies in Japanese populations. These findings provide fundamental information on biomarker discovery, validation, and qualification processes in Japanese populations, and facilitate the evaluation of biomarker candidates found in other populations.