Sensitization to alloxan-induced diabetes and pancreatic cell apoptosis in acatalasemic mice

AbstractHuman acatalasemia may be a risk factor for the development of diabetes mellitus. However, the mechanism by which diabetes is induced is still poorly understood. The impact of catalase deficiency on the onset of diabetes has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of diabetogenic alloxan. The incidence of diabetes was higher in acatalasemic mice treated with a high dose (180 mg/kg body weight) of alloxan. A higher dose of alloxan accelerated severe atrophy of pancreatic islets and induced pancreatic β cell apoptosis in acatalasemic mice in comparison to wild-type mice. Catalase activity remained low in the acatalasemic pancreas without the significant compensatory up-regulation of glutathione peroxidase or superoxide dismutase. Furthermore, daily intraperitoneal injection of angiotensin II type 1 (AT1) receptor antagonist telmisartan (0.1 mg/kg body weight) prevented the development of alloxan-induced hyperglycemia in acatalasemic mice. This study suggests that catalase plays a crucial role in the defense against oxidative-stress-mediated pancreatic β cell death in an alloxan-induced diabetes mouse model. Treatment with telmisartan may prevent the onset of alloxan-induced diabetes even under acatalasemic conditions

Expression and Localization of Mitochondrial Ferritin mRNA in Alzheimer's Disease Cerebral Cortex

Mitochondrial ferritin (MtF) has been identified as a novel ferritin encoded by an intron-lacking gene with specific mitochondrial localization located on chromosome 5q23.1. MtF has been associated with neurodegenerative disorders such as Friedreich ataxia and restless leg syndrome. However, little information is available about MtF in Alzheimer's disease (AD). In this study, therefore, we investigated the expression and localization of MtF messenger RNA (mRNA) in the cerebral cortex of AD and control cases using real-time polymerase chain reaction (PCR) as well as in situ hybridization histochemistry. We also examined protein expression using western-blot assay. In addition, we used in vitro methods to further explore the effect of oxidative stress and β-amyloid peptide (Aβ) on MtF expression. To do this we examined MtF mRNA and protein expression changes in the human neuroblastoma cell line, IMR-32, after treatment with Aβ, H2O2, or both. The neuroprotective effect of MtF on oxidative stress induced by H2O2 was measured by MTT assay. The in situ hybridization studies revealed that MtF mRNA was detected mainly in neurons to a lesser degree in glial cells in the cerebral cortex. The staining intensity and the number of positive cells were increased in the cerebral cortex of AD patients. Real-time PCR and western-blot confirmed that MtF expression levels in the cerebral cortex were significantly higher in AD cases than that in control cases at both the mRNA and the protein level. Cell culture experiments demonstrated that the expression of both MtF mRNA and protein were increased by treatment with H2O2 or a combination of Aβ and H2O2, but not with Aβ alone. Finally, MtF expression showed a significant neuroprotective effect against H2O2-induced oxidative stress (p<0.05). The present study suggests that MtF is involved in the pathology of AD and may play a neuroprotective role against oxidative stress

成長ホルモン・アンチセンスDNA導入トランスジェニックラットにおける繁殖性の検討

In homozygous transgenic rats harboring an antisense RNA transgene targeted to the rat growth hormone (GH) gene, the suppression of rat GH gene expression lowers the plasma GH concentration and retards growth. We determined the effects of suppressed endogenous rat GH gene expression on the reproductive ability of homozygous transgenic rats. Compared with nontransgenic females, the number of young at the first parturition from homozygous transgenic females significantly decreased lower (p＜0.01) despite the genetic background of mated males. We assessed ovarian physiology by means of sequential studies of ovulation efficiency, follicular growth and the fertilizing ability of oocytes in homozygous transgenic females. Natural ovulation efficiency was significantly reduced by 48％ ( p＜0.01) in homozygous transgenic females compared with those of nontransgenic females. The ovaries of homozygous transgenic rats responded to exogenous gonadotropin in a similar manner to those of nontransgenic rats. The number of eggs in homozygous transgenic females, injected with 7.5 and 15 IU pregnant mare\u27s serum gonadotropin (PMSG) followed 55 hr later with 15 IU human chronic gonadotropin (hCG) and in controls, did not significantly differ. In addition, there was no difference between the fertilizing ability of oocytes from homozygous transgenic and nontransgenic female rats. These results indicated that rat ovarian physiology, especially follicular development and/or ovulation, is mediated by GH. We also demonstrated that GH action on the ovarian function might not be directly related to those of gonadotropins. Therefore, the dwarf transgenic rat is a useful animal model with which to study the biological relevance of GH in ovarian physiology. （和文）　成長ホルモン(GH)を標的にしてアンチセンスDNAをラットに導入したトランスジェニックラットでは、導入遺伝子由来のアンチセンスRNAにより内在性ラット成長ホルモン遺伝子の発現が特異的に抑制されていることが明らかになっている。そのため、このトランスジェニックラットでは、正常ラットに比較して血漿成長ホルモン量が30～40％減少し、体重も30～50％減少していた。また、妊性はあるものの、ホモ接合体のトランスジェニックラット同士の交配では、産子数が正常ラットに比較して低下していることが観察された。　本研究では、この原因を探るためにトランスジェニックラットの繁殖性について検討を加えた。正常ラットとトランスジェニックラットの相互交配によって、トランスジェニック雌ラットにその要因があることが認められた。さらに排卵卵子数、性腺刺激ホルモンに対する感受性、排卵卵子の正常性を検討したところ、産子数の低下は排卵卵子数に起因すること、また性腺刺激ホルモンに対する卵巣の感受性が低いことが明らかになった。このことは、成長ホルモンが卵巣機能とくに卵胞発育に対して何らかの関与をしていることを示しており、今後成長ホルモンが卵巣機能に及ぼす影響を調べる上で、このトランスジェニックラットは有効であることが示唆された。継続後誌:近畿大学先端技術総合研究所紀要 = Memoirs of Institute of Advanced Technology, Kinki Universit

Significance of the comprehensive geriatric assessment in the administration of chemotherapy to older adults with cancer: Recommendations by the Japanese Geriatric Oncology Guideline Committee

Introduction: The number of older patients with cancer is expected to continue to increase owing to the aging population. Recently, the usefulness of geriatric assessment (GA) conducted by multiple staff members from different medical backgrounds has been reported; however, a consensus on the effectiveness of GA has not yet been achieved. Materials and Methods: We, as the Japanese Geriatric Oncology Guideline Committee for elderly patients with cancer, conducted a literature search of randomized controlled trials published before August 2021 that used GA or comprehensive GA (CGA) as an intervention for patients with cancer undergoing chemotherapy. As the key outcomes for answering the clinical question, we focused on survival benefit, adverse events, and quality of life (QOL). After a systematic review of these studies, the expert panel member developed recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results: For older patients with cancer, GA or CGA is suggested during or before chemotherapy (weakly recommended). Chemotherapy-induced adverse events were significantly reduced by GA/CGA interventions without any adverse effects on survival. Health-related QOL tended to improve with the GA/CGA interventions. Discussion: Although, in our opinion, GA/CGA does require time and resources, it poses no harm patients. Therefore, we suggest expanding the human resources and educating skills of medical providers for clinical implementation of GA/CGA

Japanese Guideline for Atopic Dermatitis 2014

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and coun- termeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the "Guidelines for the Treatment of Atopic Dermatitis 2008" prepared by the Health and Labour Sciences Research and the "Guidelines for the Management of Atopic Dermatitis 2012 (ADGL2012)" prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2013" together with those for other allergic diseases

The Inhibitory Effects of Anti-ERC/Mesothelin Antibody 22A31 on Colorectal Adenocarcinoma Cells, within a Mouse Xenograft Model

The expression of Renal Carcinoma (ERC)/mesothelin is enhanced in a variety of cancers. ERC/mesothelin contributes to cancer progression by modulating cell signals that regulate proliferation and apoptosis. Based on such biological insights, ERC/mesothelin has become a molecular target for the treatment of mesothelioma, pancreatic cancer, and ovarian cancer. Recent studies revealed about 50&ndash;60% of colorectal adenocarcinomas also express ERC/mesothelin. Therefore, colorectal cancer can also be a potential target of the treatment using an anti-ERC/mesothelin antibody. We previously demonstrated an anti-tumor effect of anti-ERC antibody 22A31 against mesothelioma. In this study, we investigated the effect of 22A31 on a colorectal adenocarcinoma cell line, HCT116. The cells were xenografted into BALB/c nu/nu mice. All mice were randomly allocated to either an antibody treatment group with 22A31 or isotype-matched control IgG1&kappa;. We compared the volume of subsequent tumors, and tumors were pathologically assessed by immunohistochemistry. Tumors treated with 22A31 were significantly smaller than those treated with IgG1&kappa; and contained significantly fewer mitotic cells with Ki67 staining. We demonstrated that 22A31 exhibited a growth inhibitory property on HCT116. Our results implied that ERC/mesothelin-targeted therapy might be a promising treatment for colorectal cancer