RESUMO
Although research conducted in East Asia has uncovered parasite eggs from ancient toilets or cesspits, data accumulated to date needs to be supplemented by more archaeoparasitological studies. We examined a total of 21 soil samples from a toilet-like structure at the Hwajisan site, a Baekje-period royal villa, in present-day Korea. At least 4 species of helminth eggs, i.e., Trichuris trichiura, Ascaris lumbricoides, Clonorchis sinensis, and Trichuris sp. (or Trichuris vulpis) were detected in 3 sediment samples of the structure that was likely a toilet used by Baekje nobles. The eggs of T. trichiura were found in all 3 samples (no. 1, 4, and 5); and A. lumbricoides eggs were detected in 2 samples (no. 4 and 5). C. sinensis and T. vulpis-like eggs were found in no. 5 sample. From the findings of this study, we can suppose that the soil-transmitted helminths were prevalent in ancient Korean people, including the nobles of Baekje Kingdom during the 5th to 7th century.
Assuntos
Aparelho Sanitário , Helmintos , Animais , Ascaris lumbricoides , Humanos , República da Coreia , Solo , TrichurisRESUMO
Many diseases, especially cancers, result from aberrant or overexpression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but these are limited mainly to enzymes. An alternative approach that may have utility in drug development relies on selective degradation of pathogenic proteins via small chimeric molecules linking an E3 ubiquitin ligase to the targeted protein for proteasomal degradation. To this end, we recently developed a protein knockdown system based on hybrid small molecule SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers) that recruit inhibitor of the apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins. Here, we extend our previous study to show a proof of concept of the SNIPER technology in vivo By incorporating a high affinity IAP ligand, we developed a novel SNIPER against estrogen receptor α (ERα), SNIPER(ER)-87, that has a potent protein knockdown activity. The SNIPER(ER) reduced ERα levels in tumor xenografts and suppressed the growth of ERα-positive breast tumors in mice. Mechanistically, it preferentially recruits X-linked IAP (XIAP) rather than cellular IAP1, to degrade ERα via the ubiquitin-proteasome pathway. With this IAP ligand, potent SNIPERs against other pathogenic proteins, BCR-ABL, bromodomain-containing protein 4 (BRD4), and phosphodiesterase-4 (PDE4) could also be developed. These results indicate that forced ubiquitylation by SNIPERs is a useful method to achieve efficient protein knockdown with potential therapeutic activities and could also be applied to study the role of ubiquitylation in many cellular processes.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Descoberta de Drogas , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Complexo de Endopeptidases do Proteassoma/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitinação/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23-36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20â¯kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.
Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Peptídeo YY/química , Polietilenoglicóis/química , Alquilação , Sequência de Aminoácidos , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Cães , Eméticos/química , Eméticos/uso terapêutico , Eméticos/toxicidade , Meia-Vida , Infusões Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/patologia , Peptídeo YY/farmacocinética , Peptídeo YY/uso terapêutico , Receptores de Neuropeptídeo Y/agonistas , Receptores de Neuropeptídeo Y/metabolismo , Vômito/etiologiaRESUMO
Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.
Assuntos
Depressores do Apetite/metabolismo , Peptídeos/metabolismo , Receptores de Neurotransmissores/metabolismo , Alquilação , Sequência de Aminoácidos , Animais , Depressores do Apetite/química , Depressores do Apetite/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/agonistas , Receptores de Neurotransmissores/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.
Assuntos
Androgênios/química , Androgênios/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Androgênicos/metabolismo , Anabolizantes/química , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Androgênios/farmacocinética , Animais , Eunuquismo/tratamento farmacológico , Eunuquismo/metabolismo , Humanos , Masculino , Modelos Moleculares , Músculos/efeitos dos fármacos , Músculos/metabolismo , Nitrilas/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Pirrolidinas/farmacocinética , RatosRESUMO
Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use.
Assuntos
Fármacos Antiobesidade/farmacologia , Neuropeptídeos/farmacologia , Polietilenoglicóis/química , Animais , Fármacos Antiobesidade/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/química , Neuropeptídeos/farmacocinética , Suínos , Redução de Peso/efeitos dos fármacosRESUMO
We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.
Assuntos
Androgênios/farmacologia , Descoberta de Drogas , Nitrilas/farmacologia , Receptores Androgênicos/metabolismo , Androgênios/síntese química , Androgênios/química , Animais , Células COS , Chlorocebus aethiops , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Masculino , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Validation of biomarker assays is crucial for effective drug development and clinical applications. Interlaboratory reproducibility is vital for reliable comparison and combination of data from different centers. This review summarizes interlaboratory studies of quantitative LC-MS-based biomarker assays using reference standards for calibration curves. The following points are discussed: trends in reports, reference and internal standards, evaluation of analytical validation parameters, study sample analysis and normalization of biomarker assay data. Full evaluation of these parameters in interlaboratory studies is limited, necessitating further research. Some reports suggest methods to address variations in biomarker assay data among laboratories, facilitating organized studies and data combination. Method validation across laboratories is crucial for reducing interlaboratory differences and reflecting target biomarker responses.
Assuntos
Espectrometria de Massa com Cromatografia Líquida , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes , Padrões de ReferênciaRESUMO
In the past decade, experts have conducted parasitological research on archaeological specimens in Korea to collect historical parasite infection data. In these studies, parasitologists successfully described the infection pattern of each parasite species in history. However, in the first half of the 20th century, archaeoparasitological reports have been scant. In 2021, we conducted a parasitological examination of a toilet-like structure that emerged in the early 20th century. This structure was built by stacking 2 wooden barrels; and in the study samples, we found ancient Trichuris trichiura, Ascaris lumbricoides (unfertilized), and Taenia spp. eggs and therefore proposed a higher possibility that the barrels could have been used as a toilet at the time. To understand how the antihelminthic campaign since the 1960s helped reduce parasite infection rates in Korea, more research should focus on early-20th-century toilet ruins.
Assuntos
Aparelho Sanitário , Helmintíase , Enteropatias Parasitárias , Animais , Humanos , Ascaris lumbricoides , Aparelho Sanitário/história , População do Leste Asiático , República da Coreia/epidemiologia , Óvulo , Taenia , Trichuris , História do Século XX , Helmintíase/epidemiologia , Enteropatias Parasitárias/epidemiologiaRESUMO
Background: Although the fit-for-purpose approach has been proposed for biomarker assay validation, practical data should be compiled to facilitate the predetermination of acceptance criteria. Methods: Immunoaffinity LC-MS was used to analyze glucagon-like peptide-1 as a model biomarker in six laboratories. Calibration curve, carryover, parallelism, precision, relative accuracy and processed sample stability were evaluated, and their robustness among laboratories was assessed. The rat glucagon-like peptide-1 concentrations in four blinded samples were also compared. Results: The obtained results and determined concentrations in the blinded samples at all laboratories were similar, with a few exceptions, and robust, despite the difference in optimization techniques among laboratories. Conclusion: The results provide insights into the predefinition of the acceptance criteria of immunoaffinity LC-MS-based biomarker assays.
Assuntos
Laboratórios , Espectrometria de Massas em Tandem , Ratos , Animais , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Peptídeo 1 Semelhante ao Glucagon , BiomarcadoresRESUMO
OBJECTIVE: The aims of this study were to examine the number of missing teeth in the people of the Edo period (or number of remaining teeth) and to contribute to the 8020 movement proposed in Japan to help people retain 20 or more of their own teeth until the age of 80. BACKGROUND: The study of dentition in ancient skeletal remains of our ancestors from multiple perspectives can yield information that can contribute to the study of physical anthropology and the leading edge of modern dental research. MATERIALS AND METHODS: The materials were 82 excavated individuals (52 males and 30 females) from 1603 to 1868 whose maxillas and mandibles were both examinable. The age and sex were estimated by anthropological methods, and the individuals were divided into five groups. The status of missing teeth was compared between groups, and a chi-square test was used to test significant differences between groups. The rates of tooth loss were examined in the maxillas and mandibles. RESULTS: In the people of the Edo period, many teeth remained in good condition until early to late middle age. There were more remaining teeth in these individuals than in modern-day individuals. However, the Edo people clearly showed increased tooth loss with age. There were no differences in tooth loss by sex. The tooth type with a high rate of tooth loss was posterior teeth, but incisor loss also occurred with ageing. Mandibular canines were most likely to be remaining. CONCLUSION: The Edo people had more remaining teeth than modern-day society. This finding was unexpected. The notion that "people of long past ages lost more teeth more quickly" does not seem to apply to people in the Edo period in Japan.
Assuntos
Perda de Dente/história , Adulto , Fatores Etários , Feminino , História do Século XVII , História do Século XVIII , História do Século XIX , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
Background: Many bioanalytical methods for antisense oligonucleotides (ASOs) using LC-MS have been reported. However, no data have been available on the reproducibility and robustness of a single bioanalytical method for ASOs. As such, in the current study, we evaluated the reproducibility and robustness of LC-MS-based bioanalytical methods for ASOs in multiple laboratories. Methods/Results: Seven independent laboratories were included in this study. Mipomersen was measured by ion-pairing LC-MS (IP-LC-MS) as a model ASO using different LC-MS. The validation results of calibration curve, accuracy, precision and selectivity met the criteria of conventional bioanalytical method validation guidelines using LC/GC-MS for drugs in all laboratories. Meanwhile, carryover (>20%) was detected in three laboratories. Conclusion: We first demonstrated the multicenter-validated IP-LC-MS bioanalytical method for ASOs. Our data showed that the method was sensitive, robust and reproducible. However, the occurrence of carryover should be carefully monitored in its future application.
Assuntos
Terapia Biológica , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes , CalibragemRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid ß, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid ß pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Proteínas tau/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Técnicas de Cultura de Células , Córtex Cerebral/citologia , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Comportamento Exploratório/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mutação/genética , Neurônios/efeitos dos fármacos , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Presenilina-1/genética , Fatores de Tempo , Proteínas tau/genéticaRESUMO
The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists.
Assuntos
Anabolizantes/química , Pirazóis/química , Pirimidinas/química , Receptores de Detecção de Cálcio/antagonistas & inibidores , Administração Oral , Anabolizantes/farmacocinética , Anabolizantes/uso terapêutico , Animais , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Macaca fascicularis , Conformação Molecular , Osteoporose/tratamento farmacológico , Hormônio Paratireóideo/metabolismo , Pirazóis/síntese química , Pirazóis/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Receptores de Detecção de Cálcio/metabolismoRESUMO
A series of novel tetrahydropyrazolopyrimidine derivatives containing an adamantyl group were synthesized and evaluated as potential calcium-sensing receptor (CaSR) antagonists. After chemical modification of 9a, which was identified as a hit compound in a random screening of CaSR antagonist assay, 7,7-dimethyl derivative 16c was found to be the most active compound of this new series (IC(50)=10nM). We report the synthesis of this series and their biological activities and structure-activity relationship.
Assuntos
Pirimidinas/síntese química , Receptores de Detecção de Cálcio/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/farmacologia , Animais , Concentração Inibidora 50 , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Tuberculosis has been recognized in Japan and Korea for more than 500 years in historical medical documents. However, the origin and early existence of tuberculosis is poorly understood in these regions. Very recently, skeletal evidence for tuberculosis from the Bronze Age (or Aneolithic) period was reported from Japan and Korea. This article describes a possible case of spinal tuberculosis from an archeological site in Korea, which was dated to the first century BC. This date corresponds to the Aneolithic (Yayoi) period in Japan. Skeletal evidence for tuberculosis during the Bronze Age period found in both Korea and Japan are, therefore, discussed as evidence of the earliest tuberculosis outbreaks in East Asia and as biological indicators of population movement between Korea and Japan during this period.
Assuntos
Osso e Ossos/patologia , Paleopatologia , Dinâmica Populacional , Tuberculose da Coluna Vertebral/história , Tuberculose da Coluna Vertebral/patologia , Diagnóstico Diferencial , História Antiga , Humanos , Coreia (Geográfico)RESUMO
Over the decades, mummy studies have expanded to reconstruct a multifaceted knowledge about the ancient populations' living conditions, pathologies, and possible cause of death in different spatiotemporal contexts. Mainly due to linguistic barriers, however, the international knowledge of East Asian mummies has remained sketchy until recently. We thus analyse and summarize the outcomes of the studies so far performed in Korea and China in order to provide mummy experts with little-known data on East Asian mummies. In this report, similarities and differences in the mummification processes and funerary rituals in Korea and China are highlighted. Although the historical periods, the region of excavation, and the structures of the graves differ, the cultural aspects, the mechanisms of mummification, and biological evidence appear to be essentially similar to each other. Independently from the way they are called locally, the Korean and Chinese mummies belong to the same group with a shared cultural background.
Assuntos
Múmias , China , História do Século XVI , História do Século XVII , História do Século XVIII , Humanos , Múmias/história , República da CoreiaRESUMO
BACKGROUND AND PURPOSE: Neuromedin U (NmU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both responsible for the NmU-mediated anti-obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor-selective agonists. EXPERIMENTAL APPROACH: Efficacy and safety were assessed in mice with diet-induced obesity (DIO) and those with leptin-deficient diabetes (ob/ob) through repeated peripheral administration of selective agonists to NMU1 (NMU-6102) and NMU2 (NMU-2084), along with non-selective NMU1/2 agonists (NMU-0002 and NMU-6014). We also performed immunohistochemistry for c-Fos protein expression in the brain to probe their mechanisms of action. KEY RESULTS: Although both non-selective NMU1/2 agonists and the NMU2-selective agonist had high efficacy compared with the NMU1-selective agonist, only the NMU2-selective agonist led to relatively low adverse effects, such as diarrhoea, in DIO mice. However, the non-selective NMU1/2 agonist and the NMU1-selective agonist, but not the NMU2-selective agonist, were effective in diabetic ob/ob mice. Mechanistically, NMU2-selective agonists preferentially activate pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus but not in the paraventricular nucleus. CONCLUSIONS AND IMPLICATIONS: These results suggest that an NMU2 receptor-selective agonist may be a well-balanced drug for the treatment of obesity and that an NMU1 receptor-selective agonist may also be beneficial for treating obesity and diabetes once its side effects are minimized.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Receptores de Neurotransmissores/agonistas , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Encéfalo/metabolismo , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia.
Assuntos
Atividade Motora , Orquiectomia , Pirrolidinonas/farmacologia , Receptores Androgênicos/efeitos dos fármacos , Comportamento Sexual Animal , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirrolidinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/fisiologia , Distribuição Tecidual , Transcrição GênicaRESUMO
Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.