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1.
Future Oncol ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652217

RESUMO

Aim: To describe the treatment landscape and associated economic burden for myelodysplastic syndrome in Japan. Methods: We studied nationwide retrospective claims data from 2008 to 2019. The study cohort was categorized into patients receiving transfusion, erythropoiesis-stimulating agent, erythropoiesis-stimulating agent + transfusion, azacitidine, azacitidine + transfusion and others. Results: Our study found that the azacitidine + transfusion group had the highest medical cost and severity of disease compared with the other groups. In those patients, healthcare resource utilization and the costs of transfusions, including iron chelation therapy, increased medical costs. Conclusion: Our retrospective analysis provides a current snapshot of real-world treatment patterns and associated incremental economic costs of iron chelation therapy with the presence of transfusions that drive an increase in total costs.

2.
Hepatol Commun ; 5(9): 1555-1570, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34510840

RESUMO

How liver tolerance is disrupted in immune-mediated liver injury is currently unclear. There is also insufficient information available regarding susceptibility, precipitation, escalation, and perpetuation of autoimmune hepatitis. To explore how dietary fiber influences hepatic damage, we applied the concanavalin A (ConA)-induced acute immune-mediated liver injury model in mice fed a diet supplemented with 6.8% inulin, a water-soluble fermentable fiber. Twelve hours after ConA administration, inulin-supplemented diet-fed mice demonstrated significantly alleviated hepatic damage histologically and serologically, with down-regulation of hepatic interferon-γ and tumor necrosis factor and reduced myeloperoxidase (MPO)-producing neutrophil infiltration. Preconditioning with an inulin-supplemented diet for 2 weeks significantly reduced hepatic adenosine triphosphate (ATP) content; suramin, a purinergic P2 receptor antagonist, abolished the protective effect. Of note, the portal plasma derived from mice fed the inulin-supplemented diet significantly alleviated ConA-induced immune-mediated liver injury. Mechanistically, increased portal short-chain fatty acid (SCFA) levels, such as those of acetate and butyrate, by inulin supplementation leads to up-regulation of hepatic γ-type peroxisome proliferator-activated receptor (Pparg) and uncoupling protein 2 (Ucp2), which uncouples mitochondrial ATP synthesis downstream of PPARγ. Pparg down-regulating small interfering RNA cancelled the protective effect of inulin supplementation against MPO-producing neutrophil infiltration and the subsequent immune-mediated liver injury, suggesting that the SCFA-PPARγ-UCP2 axis plays a key role in the protective effect by inulin supplementation. Moreover, significant changes in the gut microbiota, including increased operational taxonomic units in genera Akkermansia and Allobaculum, also characterized the protective effect of the inulin-supplemented diet. Conclusion: There is a possible unraveled etiopathophysiological link between the maintenance of liver tolerance and dietary fiber. The SCFA-PPARγ-UCP2 axis may provide therapeutic targets for immune-mediated liver injury in the future.

3.
J Clin Monit Comput ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468914

RESUMO

PURPOSE: The aim of the study was to evaluate the plasma rocuronium concentration in autologous blood transfusion obtained from the cell salvage (CS) system following cardiac surgery with cardiopulmonary bypass (CPB). METHODS: This prospective observational study was conducted in a university teaching hospital from July to November 2020. Patients undergoing general anesthesia for cardiac surgery with CPB were enrolled in the study. After separation from CPB, residual blood remaining in the extracorporeal system was collected as the control sample. The second sample (CS blood) was collected from the autologous blood transfusion obtained after completion of the CS system with Cell Saver® Elite®. Hematocrit values of both samples were also examined. RESULTS: Ten subjects (aged 57-86 years) were enrolled in this study. Plasma rocuronium concentrations (ng/ml) were significantly lower in the CS blood (94.0 ± 77.5) compared to the control (2950 ± 812.2) (p = 0.002). Hematocrit values (%) were significantly higher in the CS blood (75.2 ± 11.3) compared to the control (40.2 ± 10.2) (p = 0.002). CONCLUSION: Autologous blood transfusion obtained from CS system following cardiac surgery with CPB, only retained a small amount of plasma rocuronium concentration, therefore, the risk of autologous blood transfusion contributing to clinically relevant residual neuromuscular blockade postoperatively should be considered to be low. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network under registration number UMIN000040877 (registration date; June 24, 2020).

4.
BMC Infect Dis ; 21(1): 960, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530739

RESUMO

BACKGROUND: Entamoeba histolytica (E. histolytica) is rarely identified as a cause of amebic pericarditis. We report a case of amebic pericarditis complicated by cardiac tamponade, in which the diagnosis was missed initially and was made retrospectively by polymerase chain reaction (PCR) testing of a stored sample of pericardial fluid. Furthermore, we performed a systematic review of the literature on amebic pericarditis. CASE PRESENTATION: A 71-year-old Japanese man who had a history of sexual intercourse with several commercial sex workers 4 months previously, presented to our hospital with left chest pain and cough. He was admitted on suspicion of pericarditis. On hospital day 7, he developed cardiac tamponade requiring urgent pericardiocentesis. The patient's symptoms temporarily improved, but 1 month later, he returned with fever and abdominal pain, and multiple liver lesions were found in the right lobe. Polymerase chain reaction of the aspiration fluid of the liver lesion and pericardial and pleural fluid stored from the previous hospitalization were all positive for E. histolytica. Together with the positive serum antibody for E. histolytica, a diagnosis of amebic pericarditis was made. Notably, the diagnosis was missed initially and was made retrospectively by performing PCR testing. The patient improved with metronidazole 750 mg thrice daily for 14 days, followed by paromomycin 500 mg thrice daily for 10 days. CONCLUSIONS: This case suggests that, although only 122 cases of amebic pericarditis have been reported, clinicians should be aware of E. histolytica as a potential causative pathogen. The polymerase chain reaction method was used to detect E. histolytica in the pericardial effusion and was found to be useful for the diagnosis of amebic pericarditis in addition to the positive results for the serum antibody testing for E. histolytica. Because of the high mortality associated with delayed treatment, prompt diagnosis should be made.


Assuntos
Amebíase , Entamoeba histolytica , Derrame Pericárdico , Idoso , Entamoeba histolytica/genética , Humanos , Masculino , Derrame Pericárdico/diagnóstico , Reação em Cadeia da Polimerase , Estudos Retrospectivos
5.
Exp Dermatol ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587317

RESUMO

It has long been known that there is a special affinity of psoriasis for the scalp: Here, it occurs most frequently, lesions terminate sharply in frontal skin beyond the hair line and are difficult to treat. Yet, surprisingly, scalp psoriasis only rarely causes alopecia, even though the pilosebaceous unit clearly is affected. Here, we systematically explore the peculiar, insufficiently investigated connection between psoriasis and growing (anagen) terminal scalp hair follicles (HFs), with emphasis on shared regulatory mechanism and therapeutic targets. Interestingly, several drugs and stressors that can trigger/aggravate psoriasis can inhibit hair growth (e.g. beta-blockers, chloroquine, carbamazepine, interferon-alpha, perceived stress). Instead, several anti-psoriatic agents can stimulate hair growth (e.g., cyclosporine, glucocorticoids, dithranol, UV irradiation), while skin/HF trauma (Köbner phenomenon/depilation) favors the development of psoriatic lesions and induces anagen in "quiescent" (telogen) HFs. On this basis, we propose two interconnected working models: a) the existence of a bidirectional "hair follicle-psoriasis axis", along which keratinocytes of anagen scalp HFs secrete signals that favor the development and maintenance of psoriatic scalp lesions and respond to signals from these lesions, and b) that anagen induction and psoriatic lesions share molecular "switch-on" mechanisms, which invite pharmacological targeting, once identified. Therefore, we advocate a novel, cross-fertilizing and integrative approach to psoriasis and hair research that systematically characterizes the "HF-psoriasis axis", focused on identification and therapeutic targeting of selected, shared signaling pathways in the future management of both, psoriasis and hair growth disorders.

6.
Anaerobe ; 72: 102459, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34555513

RESUMO

Infective endocarditis caused by Parvimonas micra is rare. Its clinical features are presented in this systematic review. We also describe the case of an 82-year-old man with infective endocarditis and pacemaker infection due to P. micra. There are some reports of recurrence during antimicrobial therapy; hence, careful follow-up is necessary.

7.
Intern Med ; 60(15): 2419-2424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334591

RESUMO

A 65-year-old woman with a history of treatment for splenic marginal zone B-cell lymphoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma underwent esophagogastroduodenoscopy. A reddish elevated lesion was found in the fundus of the stomach. On image-enhanced endoscopy, several findings, such as glandular structures of varying sizes suggesting well-differentiated adenocarcinoma, pruned blood vessels, and dilated blood vessels in deeper mucosa suggesting MALT lymphoma, were observed. The final pathological diagnosis after surgical resection was collision tumors of well-differentiated adenocarcinoma and MALT lymphoma. The features of both tumors could be observed simultaneously with image-enhanced endoscopy.


Assuntos
Adenocarcinoma , Infecções por Helicobacter , Helicobacter pylori , Linfoma de Zona Marginal Tipo Células B , Neoplasias Gástricas , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Idoso , Endoscopia do Sistema Digestório , Feminino , Mucosa Gástrica , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico por imagem , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/cirurgia
8.
Physiol Rep ; 9(17): e15003, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34435451

RESUMO

Myosin, the most abundant myofibrillar protein in skeletal muscle, functions as a motor protein in muscle contraction. Myosin polymerizes into the thick filaments in the sarcomere where approximately 50% of embryonic myosin (Myh3) are replaced within 3 h (Ojima K, Ichimura E, Yasukawa Y, Wakamatsu J, Nishimura T, Am J Physiol Cell Physiol 309: C669-C679, 2015). The sarcomere structure including the thick filament is maintained by a balance between protein biosynthesis and degradation. However, the involvement of a protein degradation system in the myosin replacement process remains unclear. Here, we show that the muscle-specific ubiquitin ligase Ozz regulates replacement rate of Myh3. To examine the direct effect of Ozz on myosin replacement, eGFP-Myh3 replacement rate was measured in myotubes overexpressing Ozz by fluorescence recovery after photobleaching. Ozz overexpression significantly decreased the replacement rate of eGFP-Myh3 in the myofibrils, whereas it had no effect on other myosin isoforms. It is likely that ectopic Ozz promoted myosin degradation through increment of ubiquitinated myosin, and decreased myosin supply for replacement, thereby reducing myosin replacement rate. Intriguingly, treatment with a proteasome inhibitor MG132 also decreased myosin replacement rate, although MG132 enhanced the accumulation of ubiquitinated myosin in the cytosol where replaceable myosin is pooled, suggesting that ubiquitinated myosin is not replaced by myosin in the myofibril. Collectively, our findings showed that Myh3 replacement rate was reduced in the presence of overexpressed Ozz probably through enhanced ubiquitination and degradation of Myh3 by Ozz.

9.
Intern Emerg Med ; 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34363550

RESUMO

Various scoring systems have been developed to predict the need for endoscopic treatment in patients with non-variceal upper gastrointestinal bleeding (NVUGIB). However, they have rarely been applied in clinical practice because the processes are complicated. The aim of this study was to establish a simple scoring system that predicts the need for endoscopic intervention in patients with NVUGIB. We retrospectively enrolled 509 consecutive patients with suspected NVUGIB who underwent emergency endoscopy. In the development cohort (from January 2016 to December 2018), risk factors that predict the need for endoscopic intervention were determined from 349 patients' data by multivariate logistic regression analysis. This led to the development of a novel scoring system named the Nagoya University score (N score). In the validation cohort (from January 2019 to September 2020), we evaluated the diagnostic value of the N score, the Hirosaki score, and the Glasgow-Blatchford scores (GBS) by receiver operating characteristic (ROC) curves using another 160 patients' data. Multivariate logistic regression analysis revealed syncope, hematemesis, blood urea nitrogen (BUN), and BUN/Cr as significant predictive factors for endoscopic intervention. In the validation study, the N score was superior to the GBS and equal to the Hirosaki score in predicting the endoscopic intervention (AUC, N score 0.776 [95% CI 0.702-0.851] vs. GBS 0.615 [0.523-0.708], Hirosaki 0.719 [0.636-0.803]). The N score revealed a sensitivity of 84.5% and a specificity of 61.8%. Our N score, which is consisted of only four factors, would select patients who require endoscopic intervention with high probability.

10.
Science ; 373(6552)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34437124

RESUMO

Oocytes mature in a specialized fluid-filled sac, the ovarian follicle, which provides signals needed for meiosis and germ cell growth. Methods have been developed to generate functional oocytes from pluripotent stem cell-derived primordial germ cell-like cells (PGCLCs) when placed in culture with embryonic ovarian somatic cells. In this study, we developed culture conditions to recreate the stepwise differentiation process from pluripotent cells to fetal ovarian somatic cell-like cells (FOSLCs). When FOSLCs were aggregated with PGCLCs derived from mouse embryonic stem cells, the PGCLCs entered meiosis to generate functional oocytes capable of fertilization and development to live offspring. Generating functional mouse oocytes in a reconstituted ovarian environment provides a method for in vitro oocyte production and follicle generation for a better understanding of mammalian reproduction.


Assuntos
Células-Tronco Embrionárias Murinas/fisiologia , Oócitos/fisiologia , Oogênese , Folículo Ovariano/citologia , Animais , Técnicas de Cultura de Células , Diferenciação Celular , Desenvolvimento Embrionário , Feminino , Fertilização In Vitro , Masculino , Mesoderma/citologia , Mesoderma/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Células-Tronco Embrionárias Murinas/citologia , Oócitos/citologia , Folículo Ovariano/embriologia , Folículo Ovariano/fisiologia , RNA-Seq , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Transcriptoma
11.
Intern Med ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433718

RESUMO

Hemolytic anemia and pure red cell aplasia are rare hematological complications of hepatitis B virus infection. We herein report a 24-year-old man who was diagnosed with hemolytic anemia and possible transient pure red cell anemia eight weeks after a severe episode of acute hepatitis B virus infection. Rapid recovery was observed with conservative management. Hemoglobin returned to baseline within three months. As the clinical features of hemolytic anemia associated with hepatitis B virus have not yet been elucidated, we conducted a systematic review and present an analysis of the 20 reported cases, including our present case.

12.
Chemosphere ; 286(Pt 1): 131676, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34346340

RESUMO

Recently, a new sustainable anionic surfactant called bio-based internal olefin sulfonate (Bio IOS) has been developed. This surfactant enables excellent water solubility and high surface activity. It has a unique structure of long hydrophobic alkyl chains (C16 to C18) with two types of hydrophilic groups in its midsection, which distinguish it from other conventional anionic surfactants. However, the effects of the specific structural features of the surfactant on its environmental properties and the consequent effects on the environment remain unclear. In this study, we investigated the environmental fate and ecotoxicity of Bio IOS and the effects of the types and positions of hydrophilic groups on biodegradability and ecotoxicity. Biodegradation studies demonstrated that Bio IOS was readily biodegradable with >99.5% removal in wastewater treatment activated sludge (test concentration: 1 mg/L) and a fast half-life of 5.8 h in river water (test concentration: 10 µg/L); the excellent biodegradability was likely due to the high water solubility attributed to the internal hydrophilic groups. Meanwhile, moderately toxic effects were observed, whereby the 50% lethal and effect concentrations of the three freshwater species were above 1 mg/L. Ecotoxicity studies with different types and positions of hydrophilic groups revealed that hydroxyalkane sulfonate was less toxic and that toxicity was reduced in the presence of more internally located hydrophilic groups. These findings suggest that the hydroxyl group and the internal positions of hydrophilic groups that constitute the molecular configuration resembling two separate shorter alkyl chains may reduce the adverse effects on organisms despite the long alkyl chains.

13.
Nat Commun ; 12(1): 4474, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294714

RESUMO

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103-CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Estreladas do Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transferência Adotiva , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células Estreladas do Fígado/imunologia , Humanos , Memória Imunológica , Interleucina-15/imunologia , Cirrose Hepática/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/terapia , Receptores CCR5/imunologia , Adulto Jovem
14.
Sci Rep ; 11(1): 13690, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34211048

RESUMO

Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.

15.
J Chem Phys ; 154(17): 174303, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34241073

RESUMO

Photodissociation of [Ar-N2]+ induced by a near-IR (800 nm) femtosecond laser pulse is investigated using ion-trap time-of-flight mass spectrometry. The intra-complex charge transfer proceeding in the course of the decomposition of the electronically excited Ar+(2P3/2)⋯N2(X1Σg +), prepared by the photoexcitation of the electronic ground Ar(1S0)⋯N2 +(X2Σg +), is probed by the ion yields of Ar+ and N2 +. The yield ratio γ of N2 + with respect to the sum of the yields of Ar+ and N2 + is determined to be γ = 0.62, which is much larger than γ ∼ 0.2 determined before when the photodissociation is induced by a nano-second laser pulse in the shorter wavelength region between 270 and 650 nm. This enhancement of γ at 800 nm and the dependence of γ on the excitation wavelength are interpreted by numerical simulations, in which the adiabatic population transfer from Ar+(2P3/2)⋯N2(X1Σg +) to Ar(1S0)⋯N2 +(X2Σg +) at the avoided crossings is accompanied by the vibrational excitation in the N2 +(X2Σg +) moiety followed by the intra-complex vibrational energy transfer from the N2 +(X2Σg +) moiety to the intra-complex vibrational mode leading to the dissociation.

16.
Gene ; 799: 145811, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224829

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. α-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linné (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of α-synuclein and promoted the dissociation of α-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant α-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated α-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in the eye of A30P fly PD model. Saffron had a cytoprotective effect on a human neuronal cell line with α-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.


Assuntos
Carotenoides/farmacologia , Crocus/química , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/etiologia , Degeneração Retiniana/tratamento farmacológico , Vitamina A/análogos & derivados , Animais , Animais Geneticamente Modificados , Linhagem Celular , Modelos Animais de Doenças , Drosophila melanogaster/genética , Feminino , Humanos , Longevidade/efeitos dos fármacos , Masculino , Mutação , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Degeneração Retiniana/etiologia , Degeneração Retiniana/fisiopatologia , Vitamina A/farmacologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade
17.
Eur J Clin Pharmacol ; 77(7): 971-978, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059932

RESUMO

BACKGROUND: Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. METHODS: Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. RESULTS: Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). CONCLUSION: Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.

18.
J Mol Biol ; 433(15): 167046, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-33971210

RESUMO

The ribosomal stalk protein plays a crucial role in functional interactions with translational GTPase factors. It has been shown that the archaeal stalk aP1 binds to both GDP- and GTP-bound conformations of aEF1A through its C-terminal region in two different modes. To obtain an insight into how the aP1•aEF1A binding mode changes during the process of nucleotide exchange from GDP to GTP on aEF1A, we have analyzed structural changes in aEF1A upon binding of the nucleotide exchange factor aEF1B. The isolated archaeal aEF1B has nucleotide exchange ability in the presence of aa-tRNA but not deacylated tRNA, and increases activity of polyphenylalanine synthesis 4-fold. The aEF1B mutation, R90A, results in loss of its original nucleotide exchange activity but retains a remarkable ability to enhance polyphenylalanine synthesis. These results suggest an additional functional role for aEF1B other than in nucleotide exchange. The crystal structure of the aEF1A•aEF1B complex, resolved at 2.0 Å resolution, shows marked rotational movement of domain 1 of aEF1A compared to the structure of aEF1A•GDP•aP1, and this conformational change results in disruption of the original aP1 binding site between domains 1 and 3 of aEF1A. The loss of aP1 binding to the aEF1A•aEF1B complex was confirmed by native gel analysis. The results suggest that aEF1B plays a role in switching off the interaction between aP1 and aEF1A•GDP, as well as in nucleotide exchange, and promote translation elongation.


Assuntos
Archaea/metabolismo , Fatores de Alongamento de Peptídeos/química , Fatores de Alongamento de Peptídeos/metabolismo , Archaea/química , Archaea/genética , Proteínas Arqueais/química , Proteínas Arqueais/genética , Proteínas Arqueais/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Modelos Moleculares , Mutação , Fatores de Alongamento de Peptídeos/genética , Conformação Proteica , Domínios Proteicos
19.
Artigo em Inglês | MEDLINE | ID: mdl-33990424

RESUMO

The dropping of glass vials based on negligence or accidental events that occur during the preparation or mixing of injectable drugs are examples of instances of occupational exposures occurring in a clinical setting. To reduce such risks, several types of glass vial packaging have been developed. We herein compared the resistance of base- and cup-type packaged vials to breakage and scattering of contents during falls with control vials. The falling heights at which test products were dropped were set to 70, 135, and 180 cm. Compared with the control group, appearance changes were inhibited in the cup-type groups. Significant differences were found between the cup-type and control groups at heights of 135 and 180 cm. Next, resistance of packaging to spilling and scattering of solution from the vial was determined. There was no scattering in any types of vials at a height of 70 cm because they were not broken. However, at heights of 135 and 180 cm, the mean scattering distance in the control groups were 50 and 70.6 cm, respectively. At these heights, some vials in the base-type and cup-type group were also cracked, but the solution stayed completely inside the covering packaging, indicating an obvious antiscattering ability. Vials packed in cup- and base-type packaging would lower the risk of the exposure of hazardous drugs during vial breakages. Because the base-type packaging did not show significant antibreakage effects, the cup-type packaging is more suited for hazardous drug packaging. However, cup-type packaging requires equipment investments from pharmaceutical manufacturers. Thus, cost-effectiveness and the target drug profile should be evaluated, and the use of cup- and base-type packaging, as well as control, forms should be selected accordingly.

20.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925862

RESUMO

Resident myogenic stem cells (satellite cells) are attracting attention for their novel roles in myofiber type regulation. In the myogenic differentiation phase, satellite cells from soleus muscle (slow fiber-abundant) synthesize and secrete higher levels of semaphorin 3A (Sema3A, a multifunctional modulator) than those derived from extensor digitorum longus (EDL; fast fiber-abundant), suggesting the role of Sema3A in forming slow-twitch myofibers. However, the regulatory mechanisms underlying fast-twitch myotube commitment remain unclear. Herein, we focused on netrin family members (netrin-1, -3, and -4) that compete with Sema3A in neurogenesis and osteogenesis. We examined whether netrins affect fast-twitch myotube generation by evaluating their expression in primary satellite cell cultures. Initially, netrins are upregulated during myogenic differentiation. Next, we compared the expression levels of netrins and their cell membrane receptors between soleus- and EDL-derived satellite cells; only netrin-1 showed higher expression in EDL-derived satellite cells than in soleus-derived satellite cells. We also performed netrin-1 knockdown experiments and additional experiments with recombinant netrin-1 in differentiated satellite cell-derived myoblasts. Netrin-1 knockdown in myoblasts substantially reduced fast-type myosin heavy chain (MyHC) expression; exogenous netrin-1 upregulated fast-type MyHC in satellite cells. Thus, netrin-1 synthesized in EDL-derived satellite cells may promote myofiber type commitment of fast muscles.


Assuntos
Fibras Musculares Esqueléticas/metabolismo , Mioblastos/metabolismo , Netrina-1/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares de Contração Rápida/citologia , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/citologia , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/citologia , Cadeias Pesadas de Miosina/metabolismo , Cultura Primária de Células/métodos , Células Satélites de Músculo Esquelético/metabolismo , Semaforina-3A/metabolismo
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