RESUMEN
The use of immunosuppressive medications to treat rheumatoid arthritis may trigger the activation of latent mycobacteria, leading to infection. These infections can lead to reactive arthritis. Conversely, both reactive and rheumatoid arthritis may be encountered in the geriatric population. When such complications arise, the treatment process becomes more complicated, necessitating careful consideration of elaborate therapeutic approaches. An 83-year-old man presented to our hospital with subacute back pain and arthralgia of the extremities. The patient was diagnosed with rheumatoid arthritis combined with mycobacterial arthritis. We approached the treatment cautiously by concurrently managing tuberculosis and non-tuberculous mycobacteria (NTM), and administering methotrexate and prednisolone for rheumatoid arthritis. This treatment resulted in remission of both conditions. When treating arthritis in older adults, it is important to consider the possibility of reactive arthritis secondary to mycobacterial infection and rule out latent tuberculosis. Moreover, when rheumatoid arthritis is complicated by mycobacterial infection and during the management of rheumatoid arthritis, the possibility of arthritis exacerbation due to mycobacteria should be considered. Hence, in situations where there is a likelihood of extrapulmonary lesions stemming from Mycobacterium infection, a proactive treatment approach targeting both Mycobacterium spp. and rheumatoid arthritis is indispensable.
RESUMEN
Streptomyces albulus NBRC14147 produces a homopoly(amino acid), ε-poly-L-lysine (ε-PL). Due to its antibiotic activity, thermostability, biodegradability, and non-toxicity to humans, ε-PL is used as a food preservative. In this study, homology searches of diaminopimelate (DAP) pathway genes (dapB and dapE), in an S. albulus genome database, were shown to encode predicted enzymes using dapB or dapE in Escherichia coli strain complementation assays. We observed that dapB and dapE transcriptional levels were weak during ε-PL production stages. Therefore, we strengthened this expression using an ermE constitutive promoter. Engineered strains generated faster growth and ε-PL production rates when compared with the control strain. Moreover, maximum ε-PL yields in S. albulus, where dapB was constitutively expressed, were approximately 14% higher when compared with the control strain. These findings showed that enhanced lysine biosynthetic gene expression generated faster and higher ε-PL production levels.
Asunto(s)
Polilisina , Streptomyces , Humanos , Fermentación , Expresión Génica , Polilisina/genética , Polilisina/metabolismo , Streptomyces/metabolismo , Ácido Diaminopimélico/metabolismoRESUMEN
DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-L-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , Epigénesis Genética , Animales , Humanos , Ratones , Transformación Celular Neoplásica/genética , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Metilasas de Modificación del ADN/metabolismo , ADN Metiltransferasa 3BRESUMEN
BACKGROUND: Common cold is among the main reasons patients visit a medical facility. However, few studies have investigated whether prescriptions for common cold in Japan comply with domestic and international evidence. OBJECTIVE: To determine whether prescriptions for common cold complied with domestic and international evidence. METHODS: This cross-sectional study was conducted between October 22, 2020, and January 16, 2021. Patients with cold symptoms who visited the two dispensing pharmacies and met the eligibility criteria were interviewed. MAIN OUTCOME MEASURE: The pharmacists at each store and a physician classified the patients into two groups: the potentially inappropriate prescribing group and the appropriate prescribing group. RESULTS: Of the 150 selected patients, 14 were excluded and 136 were included in the analysis. Males accounted for 44.9% of the total study population, and the median patient age was 34 years (interquartile range [IQR], 27-42). The prevalence rates of potentially inappropriate prescriptions and appropriate prescriptions were 89.0% and 11.0%, respectively and the median drug costs were 602.0 yen (IQR, 479.7-839.2) [$5.2 (IQR, 4.2-7.3)] and 406.7 yen (IQR, 194.5-537.2) [$3.5 (IQR, 1.7-4.7)], respectively. The most common potentially inappropriate prescriptions were the prescription of oral cephem antibacterial agents to patients who did not have symptoms of bacterial infections (50.4%) and ß2 stimulants to those who did not have respiratory symptoms due to underlying disease or history (33.9%). CONCLUSIONS: Approximately 90% of prescriptions for common cold symptoms in the area were potentially inappropriate. Our findings could contribute to the monitoring of the use of medicines for the treatment of common cold symptoms.
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Resfriado Común , Prescripción Inadecuada , Adulto , Resfriado Común/tratamiento farmacológico , Resfriado Común/epidemiología , Estudios Transversales , Prescripciones de Medicamentos , Humanos , Japón/epidemiología , Masculino , FarmacéuticosRESUMEN
Thermogenic adipocytes that are distinct from classical brown adipocytes (beige adipocytes) were identified in 2012. Beige adipocytes are also called inducible brown adipocytes because their differentiation is induced by a number of physiological stimuli, including adrenaline or myokines. PPARγ is the master regulator of adipogenesis and promotes thermogenic adipocyte differentiation. A PPARγ agonist also promotes thermogenic adipocyte differentiation in mouse white adipose tissues. The vitamin E analog α-tocopherol promotes PPARγ expression and induces mRNA expression of target genes. This study investigated the effects of vitamin E analogs on thermogenic adipocyte differentiation in mouse preadipocytes and rat white adipose tissues. We determined the effects of vitamin E analogs (α-tocopherol and γ-tocopherol) on PPARγ, PGC-1α, and uncoupling protein 1 (UCP1) gene expression in 3T3-L1 cells. UCP1 expression and the mitochondrial contents were confirmed in the cells using immunofluorescence. In an in vivo study, male SD-IGS rats were fed a high-fat diet (HFD), α-tocopherol-enriched HFD, or γ-tocopherol-enriched HFD for 8 weeks before the analysis of PPARγ, PGC-1α, UCP1, and CD137 gene expression, and pathological examinations of white adipose tissues. The expression of PPARγ, PGC-1α, and UCP1 increased in 3T3-L1 cells following α-tocopherol treatment in a concentration-dependent manner. UCP1 expression and mitochondrial content also increased in α-tocopherol-treated cells. According to the histopathological examinations of rat white adipose tissues, multilocular cells were observed in the α-tocopherol intake group. Furthermore, the gene expression levels of PGC-1α, UCP1, and CD137 increased in the α-tocopherol intake group. Our results suggest that α-tocopherol promotes thermogenic adipocyte differentiation in mammalian white adipose tissues.
Asunto(s)
Adipocitos Beige/citología , Adipocitos Beige/efectos de los fármacos , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , alfa-Tocoferol/farmacología , Células 3T3-L1 , Animales , Peso Corporal/efectos de los fármacos , Células Cultivadas , Dieta Alta en Grasa , Relación Dosis-Respuesta a Droga , Masculino , Ratones , PPAR gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Proteína Desacopladora 1/genética , alfa-Tocoferol/administración & dosificaciónRESUMEN
Cadmium fluoride (CdF2, CdF for short) is the most lethal and hepatotoxic of all Cd-containing compounds. The toxic effects of CdF appear to depend on its detoxification and elimination. This study was designed to determine the early dynamics of the absorption, systemic distribution, and metabolism of CdF. The kinetics of cadmium and fluoride were investigated in the blood, bile, and urine of rats as a model of accidental occupational exposure to CdF. The serum concentration-time profiles measured after intravenous CdF (1.34, 2.67 or 4.01 mg/ per kg body weight) administration were analyzed by compartmental modeling using the WinNonlin program. Bile and urine were collected for 300 min after the administration. The kinetic profiles indicate that the clearance of Cd was diminished in the 2.67 and 4.01 mg/kg groups, leading to a persistently high serum Cd level. The mean total biliary excretions of Cd in the 2.67 and 4.01 mg/kg groups were significantly higher than that in the 1.34 mg/kg group. The abnormal kinetics of Cd was attributable to severe hepatic injury that diminished the capacity for Cd accumulation. The elimination of serum F was delayed in the 4.01 mg/kg group. The mean urinary F excretion amount was not significantly higher in the 4.01 mg/kg group than in the 2.67 mg/kg group. The abnormal kinetics of F was attributable to nephrotoxicity that diminished its elimination from the kidney.
Asunto(s)
Compuestos de Cadmio/farmacocinética , Intoxicación por Cadmio/fisiopatología , Fluoruros/farmacocinética , Animales , Bilis/química , Compuestos de Cadmio/administración & dosificación , Compuestos de Cadmio/análisis , Relación Dosis-Respuesta a Droga , Fluoruros/administración & dosificación , Fluoruros/análisis , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The acute toxicity of hydrofluoric acid (HFA) was investigated in a 24-h lethal dose study of intravenous infusion in rats. The lethal dose lowest (LDLo) and LD50 were 13.1 and 17.4 mg/kg, respectively. Harmful systemic effects were also studied 1 h after acute sublethal exposure to HFA. The maximum dose was set at 9.6 mg/kg (LD5). Rats were injected with HFA (1.6, 3.2, 6.4 or 9.6 mg/kg), saline, sodium fluoride (NaF) or HCl solution. NaF and HCl solution concentrations corresponded to the F- and H+ concentrations of 9.6 mg/kg HFA. Blood urea nitrogen (BUN) and Cr were significantly increased in response to HFA concentrations greater than 3.2mg/kg. Acute glomerular dysfunction also occurred at HFA concentrations greater than 3.2 mg/kg. HCO3- and base excess (BE) were significantly decreased in the 6.4 and 9.6 mg/kg groups. Ca2+ was significantly decreased, and K+ was increased in the 9.6 mg/kg group. BUN was significantly increased in the NaF and HFA groups and was increased in the HFA group compared with that in the NaF group. Cr was significantly increased in the HFA group only. HCO3- and BE were significantly decreased in the NaF and HFA groups and were increased in the HFA group compared with values in the NaF group. Ca2+ was significantly decreased in the NaF and HFA groups, and K+ was significantly increased in the NaF and HFA groups. F- exposure directly affected serum electrolytes. Mortality was thought to be due to cardiac arrhythmia resulting from hypocalcemia and hyperkalemia. Metabolic acidosis and renal failure were more severe in response to HFA exposure than in response to NaF exposure because of more free F-, which has strong cytotoxicity, in the HFA group than in the NaF group. Lethal effects of HFA are promoted by exposure routes such as inhalation that cause rapid absorption into the body. Even low exposure to HFA can cause acute renal dysfunction, electrolyte abnormalities and metabolic acidosis. These complications result in a poor prognosis.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Ácido Fluorhídrico/toxicidad , Hiperpotasemia/inducido químicamente , Hipocalcemia/inducido químicamente , Riñón/lesiones , Hígado/lesiones , Acidosis Tubular Renal/inducido químicamente , Acidosis Respiratoria/inducido químicamente , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Ácido Fluorhídrico/administración & dosificación , Infusiones Intravenosas , Riñón/efectos de los fármacos , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Cadmium fluoride (CdF) is commonly used as an insulator for ulta high speed mass telecommunications equipment, and there is a considerable risk that industrial workers will inhale CdF particles. Despite the possibility that acute exposure can cause harmful systemic effects, there are no studies to date that address the health consequences of acute CdF exposure. This study therefore aimed to determine the acute lethal dose of CdF and its effects on various target organs, including the liver and kidney. We also determined the effect of CdF on serum electrolytes and acid-base balance. The effective lethal dose was determined and dose-response study was conducted after intravenous administration of CdF in rats. The 24 h LD(50) of CdF was determined to be 3.29 mg/kg. The dose-response study used doses of 1.34, 2.67, 4.01 mg/kg CdF. Saline or sodium fluoride solution were used for controles. Severe hepatocellular injury was induced at doses greater than 2.67 mg/kg, as demonstrated by AST and ALT activities greater than 1,500 IU/l in rats injected with a dose of 4.01 mg/kg. Acute renal failure was induced at doses greater than 2.67 mg/kg. Decreased serum Ca, increased serum K and metabolic acidosis were induced at a dose of 4.01 mg/kg. Decreased serum Ca was caused by exposure to ionized F. CdF has the strongest lethal and hepatic toxicity among all Cd containing compounds.
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Intoxicación por Cadmio/fisiopatología , Cadmio/administración & dosificación , Cadmio/farmacología , Electrólitos/análisis , Riñón/lesiones , Hígado/lesiones , Enfermedad Aguda , Animales , Relación Dosis-Respuesta a Droga , Electrólitos/sangre , Japón , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Ammonium citratoperoxotitanate IV (TAS-FINE) is a water-soluble titanium complex used to synthesize a photocatalytic titanium(IV) oxide film. This study was aimed to investigate the LD50, dose-response, time-course response, and renal toxicity of TAS-FINE using an animal model. Serum titanium (S-Ti) and its 24-h urinary excretion (U-Ti) were determined by inductively coupled plasma-argon emission spectrometry (ICPAES) after a single oral TAS-FINE administration to male Wistar rats. The LD50 of TAS-FINE was 7.97 g/kg body weight in 24 h, and its half-life was 3.78+/-1.28 d for S-Ti and 2.19+/-0.09 d for U-Ti. Although TAS-FINE was not easily absorbed in the gastrointestinal tract, it was distributed into the bloodstream in a dose-dependent manner. Within 24 h, 0.189% of administrated Ti was excreted via urine. It was speculated that TAS-FINE formed conjugates with serum constituents that resulted in nephrotoxicity resulting from an allergic reaction. The observed indices in this study were revealed to be good indicators for TAS-FINE exposure. The analytical method and animal model described in this study will help to further elucidate details about human exposure to TAS-FINE, which in recent times has become an occupational and environmental toxicant of concern.
Asunto(s)
Exposición a Riesgos Ambientales , Riñón/efectos de los fármacos , Compuestos Organometálicos/toxicidad , Titanio/análisis , Acetilglucosaminidasa/metabolismo , Acetilglucosaminidasa/orina , alfa-Globulinas/metabolismo , alfa-Globulinas/orina , Animales , Tasa de Filtración Glomerular/efectos de los fármacos , Dosificación Letal Mediana , Masculino , Compuestos Organometálicos/farmacología , Ratas , Ratas Wistar , Factores de Tiempo , Titanio/sangre , Titanio/orinaRESUMEN
Evaluation of yttrium exposure in biological samples has not been fully examined. To evaluate yttrium nephrotoxicity, yttrium chloride was orally administered to male Wistar rats and the urine volume (UV) and N-acetyl-beta-D-glucosaminidase (NAG) and creatinine excretion (Crt) were measured in 24-h urine samples. The urinary yttrium concentration and excretion rate were determined by inductively coupled plasma-argon emission spectrometry (ICP-AES). Large significant decreases of UV (>30%) and Crt (>10%) were observed at yttrium doses of 58.3-116.7 mg per rat, but no significant NAG changes was observed. This response pattern shows that a high yttrium dosage alters glomerular function rather than the proximal convoluted tubules. A urinary yttrium excretion rate of 0.216% and good dose-dependent urinary excretion (r=0.77) were confirmed. These results suggest that urinary yttrium is a suitable indicator of occupational and environmental exposure to this element, an increasingly important health issue because recent technological advances present significant potential risks of exposure to rare earth elements. We propose that the ICP-AES analytical method and animal experimental model described in this study will be a valuable tool for future research on the toxicology of rare earth elements.
Asunto(s)
Riñón/efectos de los fármacos , Itrio/orina , Acetilglucosaminidasa/orina , Animales , Creatinina/orina , Tasa de Filtración Glomerular , Riñón/fisiopatología , Masculino , Ratas , Ratas Wistar , Análisis de Regresión , Reproducibilidad de los Resultados , Itrio/toxicidadRESUMEN
OBJECTIVE: The aim of this study was to establish reference concentrations of urinary strontium by inductively coupled plasma atomic emission spectrometry (ICP-AES). METHODS: For the determination of strontium, urine samples were collected from healthy Japanese (n=146; 115 males, 31 females; mean age, 33±9 years; age range, 18 to 58 years). The urine samples stored at or below -20°C were thawed with incubation at 40°C for 30 min and sediments were dissolved by vigorous shakings. Then, the samples were centrifuged at 3000 g for 5 min, and the supernatant was directly aspired into a P-5200-3600/1200 ICP-AES system from Hitachi Ltd., Tokyo, Japan. RESULTS: A steeper increase in the S/N ratio and a good effective linearity of the calibration line was obtained at 407.771 nm in the range of 0-300 µg/L strontium standard solution. Urine samples having the same background signal as that of 18 MΩ cm ultrapure blank water, a good correspondence of the single peak pattern of the spectra, accuracy and precision of spike recovery were also confirmed. Urinary strontium concentrations showed a log-normal distribution and a geometric mean concentration of 143.9 µg/L, with 5-95% confidential interval of 40.9-505.8 µg/L. CONCLUSION: The results of this study will be useful as guidelines for the biological monitoring of strontium in normal subjects and in individuals therapeutically or environmentally exposed to strontium.