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1.
J Toxicol Pathol ; 37(4): 151-161, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39359898

RESUMEN

Linalool oxide is frequently used as a flavoring agent, however, data on its toxicity is limited. In this study, we performed a 13-week subchronic toxicity study of linalool oxide (furanoid) in male and female Crl:CD(SD) rats. Doses of 0, 80, 250, and 800 mg/kg body weight (bw) per day were orally administered by gavage, using corn oil as the vehicle. Abnormal gait in both sexes and decreased locomotor activity in males were observed in the 800 mg/kg group. Reduced body weight gain was noted in both sexes at 800 mg/kg and at 250 mg/kg in males. In the 800 mg/kg group, serum biochemistry showed increased γ-glutamyl transpeptidase and decreased glucose in both sexes, increased total protein in males, and increased total cholesterol and phospholipids in females, suggesting that linalool oxide may have adverse effects on the liver. Increased relative and/or absolute liver weights, centrilobular hepatocellular hypertrophy in both sexes, and periportal microvesicular fatty changes in females were observed in the 800 mg/kg group. Increased relative liver weights and decreased serum glucose levels were observed in the 250 mg/kg male and female groups, respectively. Increased serum magnesium levels and relative kidney weights were observed in both sexes in the 800 mg/kg group, suggesting possible adverse effects of linalool oxide. Although histopathology showed accumulation of hyaline droplets in the male kidneys, immunohistochemistry revealed α2u-globulin nephropathy, which was not considered toxicologically significant. These results indicate that the no-observed-adverse-effect level of linalool oxide was 80 mg/kg bw/day for both sexes.

2.
Cancer Sci ; 2024 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-39245467

RESUMEN

Chromosome aberrations (CAs), a genotoxic potential of carcinogens, are believed to contribute to tumorigenesis by chromosomal rearrangements through micronucleus formation. However, there is no direct evidence that proves the involvement of CAs in tumorigenesis in vivo. In the current study, we sought to clarify the involvement of CAs in chemical carcinogenesis using a rat model with a pure CA-inducer hepatocarcinogen, acetamide. Whole-genome analysis indicated that hepatic tumors induced by acetamide treatment for 26-30 weeks showed a broad range of copy number alterations in various chromosomes. In contrast, hepatic tumors induced by a typical mutagen (diethylnitrosamine) followed by a nonmutagen (phenobarbital) did not show such mutational patterns. Additionally, structural alterations such as translocations were observed more frequently in the acetamide-induced tumors. Moreover, most of the acetamide-induced tumors expressed c-Myc and/or MDM2 protein due to the copy number gain of each oncogene. These results suggest the occurrence of chromosomal rearrangements and subsequent oncogene amplification in the acetamide-induced tumors. Taken together, the results indicate that CAs are directly involved in tumorigenesis through chromosomal rearrangements in an acetamide-induced hepatocarcinogenesis rat model.

3.
Ann Surg ; 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39263745

RESUMEN

OBJECTIVE: In living tissue, it has been difficult to make microscopic-level observations without damaging the tissue. SUMMARY BACKGROUND DATA: We have invented a novel intravital fluorescent observation method (IFOM) for real-time tissue observation, combining multi-photon laser scanning microscopy (MPLSM) with curcumin vital staining (CVS-IFOM). The aim of this study was to use CVS-IFOM to analyze the enteric nervous system (ENS) in mice and human patients with hypoganglionosis and Hirschsprung disease. METHODS: In an initial viability study, we compared live ENS images from non-fluorescent C57BL6 mice stained with curcumin (n=5) and GFP mice (n=5) using MPLSM. We then explored CVS-IFOM for the live examination of resected colon tissues from one hypoganglionosis and three Hirschsprung disease patients. RESULTS: In the viability study, detailed ENS histological features were only observed in the curcumin-stained mice. In the hypoganglionosis patient, CVS-IFOM provided ENS details that were not visualized under H&E staining or calretinin immunohistochemistry, allowing the analysis of ENS size, neural bundle number, and neural cell number per plexus. In Hirschsprung disease patients, CVS-IFOM showed a gradual hypoplastic change in the ENS from the oral wedge to the anal wedge, detecting disproportionate changes in the ENS within the same intestinal level, supporting a circumferentially uneven distribution of the intestinal ENS. CONCLUSION: CVS-IFOM may be supportive for intraoperative pathological diagnosis during surgeries in Hirschsprung disease.

4.
J Pharm Sci ; 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39153661

RESUMEN

Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (EC20) was obtained, and the ratio of EC20 values and clinical maximum concentration (Cmax) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels.

5.
J Appl Toxicol ; 44(7): 1084-1103, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38563354

RESUMEN

Although measurements of blood triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels in rodent toxicity studies are useful for detection of antithyroid substances, assays for these measurements are expensive and can show high variability depending on blood sampling conditions. To develop more efficient methods for detecting thyroid disruptors, we compared histopathological and immunohistochemical findings in the thyroid and pituitary glands with blood hormone levels. Six-week-old male and female Sprague-Dawley rats (five rats per group) were treated with multiple doses of the thyroid peroxidase inhibitors propylthiouracil (PTU) and methimazole by gavage for 28 days. Significant decreases in serum T3 and T4 and increases in TSH were observed in the ≥1 mg/kg PTU and ≥3 mg/kg methimazole groups. An increase in TSH was also detected in male rats in the 0.3 mg/kg PTU group. Histopathological and immunohistochemical analyses revealed that follicular cell hypertrophy and decreased T4 and T3 expressions in the thyroid gland were induced at doses lower than doses at which significant changes in serum hormone levels were observed, suggesting that these findings may be more sensitive than blood hormone levels. Significant increases in thyroid weights, Ki67-positive thyroid follicular cell counts, and TSH-positive areas in the pituitary gland were detected at doses comparable with those at which changes in serum T4 and TSH levels were observed, indicating that these parameters may also be useful for evaluation of antithyroid effects. Combining these parameters may be effective for detecting antithyroid substances without relying on hormone measurements.


Asunto(s)
Antitiroideos , Inmunohistoquímica , Metimazol , Hipófisis , Propiltiouracilo , Ratas Sprague-Dawley , Glándula Tiroides , Tirotropina , Tiroxina , Animales , Masculino , Antitiroideos/toxicidad , Femenino , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología , Propiltiouracilo/toxicidad , Ratas , Metimazol/toxicidad , Tirotropina/sangre , Tiroxina/sangre , Hipófisis/efectos de los fármacos , Hipófisis/patología , Yoduro Peroxidasa/antagonistas & inhibidores , Triyodotironina/sangre , Hormonas Tiroideas/sangre , Relación Dosis-Respuesta a Droga
6.
J Toxicol Pathol ; 37(2): 55-67, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38584969

RESUMEN

Renal tubular epithelial cell (TEC) injury is the most common cause of drug-induced kidney injury (DIKI). Although TEC regeneration facilitates renal function and structural recovery following DIKI, maladaptive repair of TECs leads to irreversible fibrosis, resulting in chronic kidney disease (CKD). CD44 is specifically expressed in TECs during maladaptive repair in several types of rat CKD models. In this study, we investigated CD44 expression and its role in renal fibrogenesis in a cyclosporine (CyA) rat model of CKD. Seven-week-old male Sprague-Dawley rats fed a low-salt diet were subcutaneously administered CyA (0, 15, or 30 mg/kg) for 28 days. CD44 was expressed in atrophic, dilated, and hypertrophic TECs in the fibrotic lesions of the CyA groups. These TECs were collected by laser microdissection and evaluated by microarray analysis. Gene ontology analysis suggested that these TECs have a mesenchymal phenotype, and pathway analysis identified CD44 as an upstream regulator of fibrosis-related genes, including fibronectin 1 (Fn1). Immunohistochemistry revealed that epithelial and mesenchymal markers of TECs of fibrotic lesions were downregulated and upregulated, respectively, and that these TECs were surrounded by a thickened basement membrane. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of TECs of fibrotic lesions, whereas fibronectin protein was localized in the stroma surrounding these tubules. Enzyme-linked immunosorbent assay revealed increased serum CD44 levels in CyA-treated rats. Collectively, these findings suggest that CD44 contributes to renal fibrosis by inducing fibronectin secretion in TECs exhibiting partial epithelial-mesenchymal transition and highlight the potential of CD44 as a biomarker of renal fibrosis.

7.
Artículo en Inglés | MEDLINE | ID: mdl-38432777

RESUMEN

8-Hydroxydeoxyguanosine (8-OHdG) is well known not only as an effective biomarker of oxidative stress but also as a mutagenic DNA modification. Incorporation of dAMP at the opposite site of 8-OHdG induces G>T or A>C transversions. However, in vivo analyses of gene mutations caused by potassium bromate (KBrO3), which can induce 8-OHdG at carcinogenic target sites, showed that G>T was prominent in the small intestines of mice, but not in the kidneys of rats. Because KBrO3 was a much clearer carcinogen in the kidneys of rats, detailed analyses of gene mutations in the kidney DNA of rats treated with KBrO3 could improve our understanding of oxidative stress-mediated carcinogenesis. In the current study, site-specific reporter gene mutation assays were performed in the kidneys of gpt delta rats treated with KBrO3. Groups of 5 gpt delta rats were treated with KBrO3 at concentrations of 0, 125, 250, or 500 ppm in the drinking water for 9 weeks. At necropsy, the kidneys were macroscopically divided into the cortex and medulla. 8-OHdG levels in DNA extracted from the cortex were dramatically elevated at concentrations of 250 ppm and higher compared with those from the medulla. Cortex-specific increases in mutant frequencies in gpt and red/gam genes were found at 500 ppm. Mutation spectrum and sequence analyses of their mutants demonstrated significant elevations in A>T transversions in the gpt gene and single base deletions at guanine or adenine in the gpt or red/gam genes. While A>T transversions and single base deletions of adenine may result from the oxidized modification of adenine, the contribution of 8-OHdG to gene mutations was limited despite possible participation of the 8-OHdG repair process in guanine deletion.


Asunto(s)
Bromatos , ADN , Riñón , Ratas , Ratones , Animales , 8-Hidroxi-2'-Desoxicoguanosina , Mutación , Adenina , Carcinogénesis , Carcinógenos , Guanina
8.
Surg Today ; 54(4): 347-355, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37610628

RESUMEN

PURPOSE: To determine the methylation level of the miR-124 promoter in non-neoplastic rectal mucosa of patients with pediatric-onset ulcerative colitis (UC) to predict UC-associated colorectal cancer (UC-CRC). METHODS: Between 2005 and 2017, non-neoplastic rectal tissue specimens were collected from 86 patients with UC, including 13 patients with UC-CRC; cancer tissues were obtained from the latter group. The methylation status of the miR-124 promoter was quantified using bisulfite pyrosequencing and compared between pediatric- and adult-onset UC patients. RESULTS: Patients with pediatric-onset UC experienced a significantly shorter disease duration than those with adult-onset UC. The levels of miR-124 promoter methylation in non-neoplastic rectal mucosa were positively correlated with the age at the diagnosis and duration of UC. The rate of increase in miR-124 methylation was accelerated in patients with pediatric-onset UC compared to those with adult-onset UC. Furthermore, the miR-124 methylation levels in non-neoplastic rectal mucosa were significantly higher in patients with UC-CRC than in those with UC alone (P = 0.02). A receiver operating characteristic analysis revealed that miR-124 methylation in non-neoplastic tissue discriminated between patients with pediatric-onset UC with or without CRC. CONCLUSION: miR-124 methylation in non-neoplastic rectal mucosa may be a useful biomarker for identifying patients with pediatric-onset UC who face the highest risk of developing UC-CRC.


Asunto(s)
Colitis Ulcerosa , Neoplasias Asociadas a Colitis , Neoplasias Colorrectales , MicroARNs , Adulto , Humanos , Niño , Metilación de ADN , MicroARNs/genética , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/genética , Biomarcadores , Membrana Mucosa , Neoplasias Colorrectales/genética , Mucosa Intestinal
9.
J Appl Toxicol ; 44(3): 455-469, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37876353

RESUMEN

The kidney is a major target organ for the adverse effects of pharmaceuticals; renal tubular epithelial cells (TECs) are particularly vulnerable to drug-induced toxicity. TECs have regenerative capacity; however, maladaptive repair of TECs after injury leads to renal fibrosis, resulting in chronic kidney disease (CKD). We previously reported the specific expression of CD44 in failed-repair TECs of rat CKD model induced by ischemia reperfusion injury. Here, we investigated the pathophysiological role of CD44 in renal fibrogenesis in allopurinol-treated rat CKD model. Dilated or atrophic TECs expressing CD44 in fibrotic areas were collected by laser microdissection and subjected to microarray analysis. Gene ontology showed that extracellular matrix (ECM)-related genes were upregulated and differentiation-related genes were downregulated in dilated/atrophic TECs. Ingenuity Pathway Analysis identified CD44 as an upstream regulator of fibrosis-related genes, including Fn1, which encodes fibronectin. Immunohistochemistry demonstrated that dilated/atrophic TECs expressing CD44 showed decreases in differentiation markers of TECs and clear expression of mesenchymal markers during basement membrane attachment. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of dilated/atrophic TECs, whereas fibronectin was localized in the stroma around these TECs, supporting the production/secretion of ECM by dilated/atrophic TECs. Overall, these data indicated that dilated/atrophic TECs underwent a partial epithelial-mesenchymal transition (pEMT) and that CD44 promoted renal fibrogenesis via induction of ECM production in failed-repair TECs exhibiting pEMT. CD44 was detected in the urine and serum of APL-treated rats, which may reflect the expression of CD44 in the kidney.


Asunto(s)
Fibronectinas , Insuficiencia Renal Crónica , Animales , Ratas , Alopurinol , Células Epiteliales/metabolismo , Fibronectinas/metabolismo , Fibrosis , Receptores de Hialuranos/metabolismo , Riñón , Túbulos Renales/patología , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo
10.
BMC Pediatr ; 23(1): 452, 2023 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-37689624

RESUMEN

BACKGROUND: Tobacco ingestion is widely known to cause nicotine toxicity, which may result in severe symptoms. Two heated tobacco sticks, called TEREA™ and SENTIA™, were launched in 2021 by Philip Morris International (New York, NY, USA), and their ingestion is associated with a risk of bowel injury because they contain a partially pointed metallic susceptor. However, this risk is not well known to the general public or healthcare providers. To increase awareness of this risk, we herein report a case involving extraction of a metallic susceptor after ingestion of the heated tobacco stick TEREA™. CASE PRESENTATION: A 7-month-old girl presented to the emergency department of a nearby hospital because she was suspected to have accidentally swallowed heated tobacco. Although she presented with no symptoms related to nicotine poisoning, abdominal X-ray examination revealed a metal object in her stomach. According to a statement released by the Japan Poison Information Center, the TEREA™ heated tobacco stick contains a metallic susceptor with a rectangular shape and sharp corners. The patient was transferred to our department because of the risk of bowel injury, and upper gastrointestinal endoscopy was performed. No cigarettes were found by endoscopic observation; however, a metallic susceptor was located in the second part of the duodenum. We grasped it with biopsy forceps and carefully removed it using an endoscope with a cap attached to the tip. The post-endoscopic course was uneventful. CONCLUSIONS: Some patients who ingest heated tobacco sticks might be exposed not only to the effects of nicotine but also to physical damage caused by a metallic susceptor. Infants and toddlers especially could swallow these sticks, therefore tobacco companies need to make the problem more public. Clinicians also should alert the problem, and pay attention to this risk in the clinical setting.


Asunto(s)
Deglución , Nicotina , Femenino , Lactante , Humanos , Duodeno , Servicio de Urgencia en Hospital , Ingestión de Alimentos
11.
Arch Toxicol ; 97(12): 3197-3207, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37773275

RESUMEN

Although aromatic amines are widely used as raw materials for dyes, some, such as o-toluidine and o-anisidine, have shown concerning results regarding carcinogenicity in the urinary bladder. We have recently developed a short-term detection method for bladder carcinogens using immunohistochemistry for γ-H2AX, a DNA damage marker. Here, using this method, we evaluated aromatic amines with structures similar to o-toluidine and o-anisidine for bladder mucosal damage and potential carcinogenicity. In total, 17 aromatic amines were orally administered to male F344 rats for 28 days, and histopathological examination and γ-H2AX immunostaining of the urinary bladder were performed. Histopathological analysis revealed that seven aromatic amines, including 4-chloro-o-toluidine (4-CT), o-aminoazotoluene, 2-aminobenzyl alcohol (ABA), o-acetotoluidine (o-AT), 3,3'-dimethoxybenzidine, 4-aminoazobenzene (AAB), and 4,4'-methylenedianiline (MDA), induced various bladder lesions, such as hemorrhage, necrosis, and urothelial hyperplasia. The morphological characteristics of mucosal damage induced by these substances were divided into two major types: those resembling o-toluidine and those resembling o-anisidine. Six of these aromatic amines, excluding MDA, also caused significant increases in γ-H2AX formation in the bladder urothelium. Interestingly, 4-CT did not cause mucosal damage or γ-H2AX formation at the lower dose applied in previous carcinogenicity studies. These results showed for the first time that o-AT and ABA, metabolites of o-toluidine, as well as AAB caused damage to the bladder mucosa and suggested that they may be bladder carcinogens. In addition, 4-CT, which was thought to be a noncarcinogen, was found to exhibit bladder toxicity upon exposure to high doses, indicating that this compound may contribute to bladder carcinogenesis.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Vejiga Urinaria , Ratas , Animales , Masculino , Ratas Endogámicas F344 , Aminas/toxicidad , Neoplasias de la Vejiga Urinaria/patología , Carcinógenos/toxicidad , Histonas/metabolismo , Fosfoproteínas/metabolismo
12.
J Toxicol Sci ; 48(6): 323-332, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37258237

RESUMEN

We have developed an early detection method for bladder carcinogens with high sensitivity and specificity using immunohistochemistry of γ-H2AX, a well-known marker of DNA damage. To investigate the potential application of γ-H2AX as a biomarker for early detection of hepatocarcinogens, we examined γ-H2AX formation in the liver of rats treated with several different chemicals for 28 days. Six-week-old male F344 rats were orally treated for 28 days with five hepatocarcinogens: N-nitrosodiethylamine (DEN), di(2-ethylhexyl) phthalate, 1,4-dioxane (DO), 3,3'-dimethylbenzidine dihydrochloride, or thioacetamide (TAA), or with two non-hepatocarcinogens: 4-chloro-o-phenylenediamine and N-ethyl-N-nitrosourea. At the end of the treatment period, immunohistochemistry for γ-H2AX and Ki67 and expression analysis of DNA repair-related genes were performed. Significant increases in γ-H2AX-positive hepatocytes with upregulation of Rad51 mRNA expression were induced by three of five hepatocarcinogens (DEN, DO, and TAA), whereas no changes were seen for the other two hepatocarcinogens and the two non-hepatocarcinogens. Significant increases in Ki67 expression with upregulation of Brip1, Xrcc5, and Lig4 were observed in rats treated with TAA, a nongenotoxic hepatocarcinogen, suggesting that both direct DNA damage and secondary DNA damage due to cell replication stress may be associated with γ-H2AX formation. These results suggest that γ-H2AX immunostaining has potential value for early detection of hepatocarcinogens, but examination of the effects of more chemicals is needed, as is whether γ-H2AX immunostaining should be combined with other markers to increase sensitivity. γ-H2AX immunostaining using formalin-fixed paraffin-embedded specimens can be easily incorporated into existing 28-day repeated-dose toxicity studies, and further improvements in this method are expected.


Asunto(s)
Carcinogénesis , Carcinógenos , Ratas , Masculino , Animales , Ratas Endogámicas F344 , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Carcinogénesis/metabolismo , Carcinógenos/toxicidad , Hígado/metabolismo , Tioacetamida/toxicidad , Tioacetamida/metabolismo , Histonas/metabolismo , Histonas/farmacología , Fosfoproteínas/metabolismo
13.
Food Chem Toxicol ; 175: 113702, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36871879

RESUMEN

Heme iron (HI) has been widely used as a food additive and supplement to support iron fortification. However, no sufficient toxicological data to evaluate the safety of HI have been reported. In the current study, we performed a 13-week subchronic toxicity study of HI in male and female Crl:CD(SD) rats. Rats were orally administered HI in the diet at concentrations of 0%, 0.8%, 2%, and 5%. Observations of general condition, body weight (bw) and food consumption, urinalysis, hematology, serum biochemistry, and macroscopic and histopathological examination were performed. The results showed that HI had no adverse effects on any of the examined parameters. Therefore, we concluded that the no-observed-adverse-effect level (NOAEL) for HI was estimated to be 5% for both sexes (2,890 mg/kg bw/day for males and 3,840 mg/kg bw/day for females). Since the iron content of HI used in this study was in a range of 2.0-2.6%, iron content at NOAEL for HI was calculated to be 57.8-75.1 mg/kg bw/day for males and 76.8-99.8 mg/kg bw/day for females.


Asunto(s)
Aditivos Alimentarios , Hierro , Ratas , Masculino , Femenino , Animales , Ratas Sprague-Dawley , Pruebas de Toxicidad Subcrónica/métodos , Aditivos Alimentarios/farmacología , Hierro/toxicidad , Hemo/toxicidad , Peso Corporal , Tamaño de los Órganos , Administración Oral
15.
Surg Today ; 53(4): 483-489, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36219246

RESUMEN

PURPOSE: To assess the severity of preoperative myopenia and myosteatosis in pediatric patients with inflammatory bowel disease (IBD) and examine their impact on postoperative complications. METHODS: The subjects of this retrospective study were 30 pediatric patients with IBD (22 with ulcerative colitis (UC) and 8 with Crohn's disease (CD)) and 67 age-matched controls. Preoperative body mass index (BMI), psoas muscle index (PMI), and intramuscular adipose tissue content were compared between the patient groups, to investigate their association with postoperative complications. RESULTS: BMI and PMI were significantly lower in the IBD patients than in the controls (p < 0.0001, p < 0.0001, respectively). CD was associated with significantly lower BMI and PMI (p = 0.01, p = 0.01, respectively) than UC. Intramuscular adipose tissue content was comparable between the IBD patients and the controls and between the UC and CD patients. There were no significant differences among the three indices in relation to the presence or absence of postoperative complications in patients with IBD. When limited to surgical site infection (SSI), only PMI was significantly lower in the patients with SSI than in those without SSI (p = 0.04). CONCLUSIONS: Although BMI and PMI were lower preoperatively in pediatric IBD patients than in controls, only myopenia seemed to affect the development of SSI.


Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Niño , Estudios Retrospectivos , Enfermedades Inflamatorias del Intestino/complicaciones , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/cirugía , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/cirugía , Infección de la Herida Quirúrgica , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología
16.
J Toxicol Sci ; 47(11): 457-466, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36328536

RESUMEN

Although both o-toluidine and o-anisidine are known as aromatic amines with bladder carcinogenicity, the specific metabolites involved in carcinogenesis are still unclear. Here, we examined the toxicological effects of head-to-tail dimers of o-toluidine and o-anisidine, 2-methyl-N4-(2-methylphenyl) benzene-1,4-diamine (MMBD) and 2-methoxy-N4-(2-methoxyphenyl) benzene-1,4-diamine (MxMxBD), respectively, in rats. Six-week-old male F344 rats were orally administered MMBD, MxMxBD, o-toluidine, and o-anisidine at a dose of 100 mg/kg/day for 28 days. Rats administered 400 mg/kg o-toluidine and 600 mg/kg/day o-anisidine were set as high-dose groups for comparison. Histopathology and immunohistochemistry for γ-H2AX, a DNA damage biomarker, and bladder stem cell markers, including aldehyde dehydrogenase 1A1 (ALDH1A1), were performed. MMBD and MxMxBD caused different toxicities than their monomers, inducing hepatotoxicity such as vacuolar degeneration but not splenic lesions due to methemoglobinemia. Bladder lesions, including urothelial hyperplasia, were observed in the high-dose o-toluidine and o-anisidine groups, whereas no obvious changes were induced in the low-dose groups or their dimers. Although γ-H2AX formation was significantly increased by o-toluidine and o-anisidine treatment, γ-H2AX formation did not differ among the MMBD, MxMxBD, and control groups. Notably, immunohistochemistry revealed marked increases in ALDH1A1 expression in the bladder urothelium of the MMBD and MxMxBD groups and in the o-toluidine and o-anisidine groups, suggesting that the two dimers may contribute to the bladder carcinogenic effects of o-toluidine and o-anisidine to some extent. The degrees of bladder lesions and γ-H2AX formation did not correlate with the amount of unchanged o-toluidine and o-anisidine in urine, indicating the presence of other metabolites responsible for these findings.


Asunto(s)
Benceno , Diaminas , Ratas , Masculino , Animales , Ratas Endogámicas F344 , Administración Oral
17.
Food Chem Toxicol ; 168: 113365, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35970270

RESUMEN

2-Methylfuran (2-MF) exists naturally in foods and is used as a flavoring agent. Furan, the core structure of 2-MF, possesses hepatocarcinogenicity in rodents. Accumulation of toxicological information on furan derivatives is needed to elucidate their carcinogenic mode of action. In the current study, we examined the comprehensive toxicological studies of 2-MF using gpt delta rats. 2-MF was intragastrically administered to groups of 10 male and 10 female Sprague-Dawley gpt delta rats at a dose of 0, 1.2, 6, or 30 mg/kg/day for 13 weeks. Effects of 2-MF on the hepatobiliary system including an increase in serum alkaline phosphatase were observed in the 6 and 30 mg/kg groups, and cholangiofibrosis was found in the 30 mg/kg group. The no observed adverse effect level was set at 1.2 mg/kg/day for both sexes and 1.14 mg/kg/day was determined as the benchmark dose low. The acceptable daily intake was calculated to be 11.4 µg/kg/day. Increases in the number and areas of glutathione S-transferase placental form-positive foci in the 30 mg/kg group were apparent, suggesting the hepatocarcinogenicity of 2-MF in rats. By contrast, the lack of increase in in vivo mutagenicity in the liver implied that 2-MF hepatocarcinogenesis may not involve genotoxic mechanisms.


Asunto(s)
Fosfatasa Alcalina , Aromatizantes , Animales , Carcinógenos/toxicidad , Daño del ADN , Relación Dosis-Respuesta a Droga , Femenino , Aromatizantes/farmacología , Furanos/toxicidad , Glutatión Transferasa , Hígado , Masculino , Pruebas de Mutagenicidad , Placenta , Embarazo , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Ratas Transgénicas
18.
Toxicol Sci ; 189(1): 51-61, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-35771629

RESUMEN

We investigated γ-H2AX formation, a biomarker of DNA damage, and expression of stem cell markers (SCMs), including cytokeratin 14, aldehyde dehydrogenase 1A1 (ALDH1A1), and CD44, in the development of rat bladder tumors induced by short-term administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Histopathological examination showed that diffuse simple hyperplasia of the bladder urothelium induced by BBN recovered to the normal-appearing urothelium after withdrawal, whereas focal proliferative lesions were newly developed and subsequently progressed to benign papilloma and carcinoma. Immunohistochemical analysis revealed that BBN-induced γ-H2AX formation and ALDH1A1 and CD44 expression persisted at higher levels in the normal-appearing urothelium than those in the control group for long periods after withdrawal. Since persistent chronic inflammation was observed even after withdrawal, targeted gene expression analysis of inflammation-related factors revealed 101 genes, including Stat3 and Myc, that showed persistent high expression. Pathway analysis suggested that Stat3 and/or Myc activation may be associated with SCM expression. We focused on hepatocyte growth factor (Hgf), one of the genes predicted in relation to Stat3/Myc, and confirmed that HGF-positive cells increased by BBN persisted in the normal-appearing urothelium after withdrawal and colocalized with γ-H2AX and SCMs. These results suggested that the long-term persistence of γ-H2AX formation and SCM expression, which occurred during the early stages of bladder tumorigenesis, is not a transient response to exposure and might contribute to bladder tumorigenesis. Although further studies are needed, BBN-induced rat bladder tumors may originate from focal hyperplasia arising from SCM-positive cells via activation of the STAT3/MYC pathway after DNA damage involving γ-H2AX formation.


Asunto(s)
Nitrosaminas , Neoplasias de la Vejiga Urinaria , Animales , Butilhidroxibutilnitrosamina/metabolismo , Butilhidroxibutilnitrosamina/toxicidad , Carcinogénesis/metabolismo , Histonas/metabolismo , Hiperplasia , Inflamación/metabolismo , Nitrosaminas/toxicidad , Fosfoproteínas/metabolismo , Ratas , Células Madre/metabolismo , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/genética
19.
Oncol Lett ; 23(4): 136, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35317024

RESUMEN

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is upregulated in various tumors, and several studies have demonstrated the role of TPX2 as a prognostic marker in cancer. However, the function of TPX2 in neuroblastoma (NB) has not been completely elucidated. In the present study, the clinical significance and functional role of TPX2 in NB was investigated. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET)-NB dataset was used. A total of 43 patients with NB were enrolled in the present study as the validation set. After evaluating the prognostic role of TPX2, the combined predictive effect of TPX2 and MYCN proto-oncogene bHLH transcription factor (MYCN) gene amplification was assessed. Double immunofluorescence staining for TPX2 and N-Myc was used to analyze colocalization, and multiple cell function tests were performed by means of in vitro experiments to elucidate the functional role of TPX2 using RNA interference technology in NB cell lines. In both the TARGET-NB set and the validation set, it was found that upregulated of TPX2 was significantly associated with poor overall survival (OS) in patients with NB. The expression of TPX2 was higher in NB patients with MYCN gene amplification, and NB patients with high TPX2 expression and MYCN gene amplification had the poorest OS compared with patients with low TPX2 expression or a single copy of MYCN. In vitro experiments indicated that TPX2 positively regulated cell proliferation and the cell cycle, and promoted cell survival by increasing the resistance to apoptosis. The colocalization of TPX2 with N-Myc in NB cells and tissue was observed. The findings of the present study indicate that TPX2 plays an oncogenic role in NB development and may be a potential prognostic indicator in patients with NB.

20.
J Toxicol Pathol ; 34(4): 309-317, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34629732

RESUMEN

2-(l-Menthoxy)ethanol has been frequently employed as a flavoring agent; however, data regarding 2-(l-menthoxy)ethanol toxicity remain limited. We performed a 13-week subchronic toxicity study of 2-(l-menthoxy)ethanol in male and female F344 rats, with doses of 0, 15, 60, or 250 mg/kg body weight (BW)/day orally administered by gavage using corn oil as the vehicle. No significant toxicological changes in general condition, body weight, or food intake were observed in any groups. The hematological assessment showed decreased hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin and increased platelet count in the male 250 mg/kg group. Serum biochemistry revealed elevated total cholesterol in the 250 mg/kg group of male and female rats, reduced triglyceride in the female 250 mg/kg group, and increased total protein in the male 250 mg/kg group, indicating effects on lipid metabolism and protein synthesis. For organ weights, absolute and relative weights of the liver and adrenal glands were increased in the 250 mg/kg group of both sexes and the male 250 mg/kg group, respectively. Histopathological analysis showed chronic nephropathy in the male 15 mg/kg or higher groups, with increased absolute and relative kidney weights, as well as elevated serum creatinine, in the male 60 and 250 mg/kg groups. However, eosinophilic granules containing α2u-globulin were identified in proximal tubules, suggesting α2u-globulin nephropathy specific to male rats and without toxicological significance. These results indicated that the no-observed-adverse-effect level of 2-(l-menthoxy)ethanol was 60 mg/kg BW/day for both sexes.

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