Home blood pressure measurement days and changes in urinary sodium-to-potassium ratio, estimated salt and potassium intakes and blood pressure: 1-year prospective study.

OBJECTIVE: Current international guidelines recommend home blood pressure (BP) measurement and low sodium and high potassium intakes for the management of hypertension. We hypothesized that increased home BP measurement may result in more effective management of sodium and potassium intakes and BP. METHODS: We examined associations of home BP measurement days with changes in the urinary sodium-to-potassium (Na/K) ratio, estimated salt and potassium intakes and BP. We included 209 healthy participants (mean age, 55.9 years; 56.5% women) from a prospective cohort study. We examined 1-year data on self-measured home BP and spot urine samples. RESULTS: Median (interquartile range) days of home BP measurement was 324 (225-358) over 1-year. Baseline mean (SD) Na/K ratio, salt and potassium intakes, morning and evening SBP, and morning and evening DBP were 3.8 (2.3), 8.5 (1.9) g/day, 1833.5 (416.5) mg/day, 120.4 (14.0) mmHg, 118.2 (14.2) mmHg, 79.2 (10.1) mmHg, and 76.2 (10.1) mmHg, respectively. In multivariable-adjusted linear regression , ß (standard error) per 10 days increase in number of home BP measurement were -0.031 (0.017) for Na/K ratio, -0.036 (0.015) for salt intake, -1.357 (2.797) for potassium intake, -0.178 (0.064) for morning SBP, -0.079 (0.041) for morning DBP, -0.109 (0.067) for evening SBP and -0.099 (0.045) for evening DBP. Additionally, relationships persisted for men and women, but changes in salt intake were more pronounced among participants taking antihypertensive medication (interaction P = 0.002). CONCLUSION: Continuous measurement of home BP may lead not only to self-monitoring of BP, but also to declines in salt intakes and some BP indices.

Successful Cardiac, Lung, and Kidney Transplantation from a Methanol-poisoned Donor.

Massive methanol exposure can lead to severe and detrimental effects that can result in death or brain death. As organs from patients with brain death after methanol ingestion are less likely to be recovered, these patients have been considered marginal donors. We present a case of successful multiple organ transplantation (heart, lungs, and kidneys) from a methanol-poisoned patient. Our experience illustrates that donor death from methanol intoxication does not preclude organ transplantation.

Characteristics and trends of medical malpractice claims in Japan between 2006 and 2021.

Classification and analysis of existing data on medical malpractice lawsuits are useful in identifying the root causes of medical errors and considering measures to prevent recurrence. No study has shown the actual prevalence of all closed malpractice claims in Japan, including the number of cases and their trial results. In this study, we illustrated the recent trends of closed malpractice claims by medical specialty, the effects of the acceptance rates and the settlements and clarified the trends and characteristics. This was a descriptive study of all closed malpractice claims data from the Supreme Court in Japan from 2006-2021. Trends and the characteristics in closed malpractice claims by medical specialty and the outcomes of the claims, including settlements and judgments, were extracted. The total number of closed medical malpractice claims was 13,340 in 16 years, with a high percentage ending in settlement (7,062, 52.9%), and when concluding in judgment (4,734, 35.3%), the medical profession (3,589, 75.8%) was favored. When compared by medical specialty, plastic surgery and obstetrics/gynecology were more likely resolved by settlement. By contrast, psychiatry cases exhibited a lower likelihood of settlement, and the percentage of cases resulting in unfavorable outcomes for patients was notably high. Furthermore, there has been a decline in the number of closed medical malpractice claims in Japan in recent years compared to the figures observed in 2006. In particular, the number of closed medical malpractice claims in obstetrics/gynecology and the number of closed medical malpractice claims per 1,000 physicians decreased significantly compared to other specialties. In conclusion, half of the closed malpractice claims were settled, and a low percentage of patients won their cases. Closed medical malpractice claims in Japan have declined in most medical specialties since 2006. Additionally, obstetrics/gynecology revealed a significant decrease since introducing the Obstetrics/Gynecology Medical Compensation System in 2009.

Associations of indoor and outdoor temperatures and their difference with home blood pressure: The Masuda Study.

Ambient temperature and blood pressure (BP) are closely related; however, few studies have examined the association of out-of-office BP with indoor or outdoor temperature. The effect of the difference between indoor and outdoor temperatures on BP also remains unknown. Therefore, this study aimed to investigate the association of indoor and outdoor temperatures and their difference with home BP. We studied healthy 352 participants (mean age, 49.8 years; 46.0% women) from a population-based cohort using 2-year data on temperature and self-measured home BP. We measured home BP and indoor temperature at the same time in the morning and evening every day. Outdoor temperature during the same period was based on national data. We observed 82,900 home BP measurements in the morning and 66,420 in the evening. In the mixed-effects model adjusted for age, sex, and possible confounders, indoor temperature was inversely associated with systolic and diastolic BP in the morning and evening. A 1 °C increase in indoor temperature reduced systolic and diastolic BP by 0.37 and 0.22 mmHg, respectively, in the morning and by 0.45 and 0.30 mmHg, respectively, in the evening (all P-values<0.001). The magnitude of associations was stronger for indoor than outdoor temperature. Similarly, a 1 °C increase in indoor temperature above outdoor temperature decreased systolic and diastolic BP by 0.33 and 0.12 mmHg, respectively, in the morning and by 0.45 and 0.26 mmHg, respectively, in the evening independent of outdoor temperature (all P-values <0.001). In conclusion, controlling indoor temperature is important to stabilize home BP levels.

[Tetrodotoxin Intoxications in Nagasaki, Japan: Symptoms of Patients, Tetrodotoxin Levels in Leftover Food and Clinical Urine and Serum Samples].

Incidents of food poisoning associated with tetrodotoxin (TTX) contamination occur every year throughout Japan. Here, we determined TTX levels in leftover foods and serum and urine samples from eight food poisoning incidents associated with TTX contamination in Nagasaki, Japan, from 2011 to 2017.Seven food samples associated with four of these food poisoning incidents were classified as weakly toxic (four samples), moderate-to-strongly toxic (two samples), and strongly toxic (one sample).In comparison with previous reports, TTX was detected at harmful levels in the urine samples, but the grade of poisoning symptoms varied.The patients' time to maximum serum TTX levels (Tmax) was estimated to be 12-24 h after ingestion of TTX-containing foods. Additionally, serum TTX levels of 19.5 ng/mL or higher within 24 h after ingestion indicated Grade 3 poisoning associated with respiratory abnormalities.These conditions were considered indicators of severe symptoms, while TTX levels of 1-3 ng/mL relate to the onset and disappearance of symptoms. A negative correlation was found between the logarithm of serum TTX concentration and the time after ingestion for two patients, indicating that the TTX serum levels decreased logarithmically. Furthermore, the TTX serum half-lives (T1/2) were 17.5 and 23.7 h.The results of this study enhance our understanding of TTX food safety and contribute to TTX risk assessment.

Two independent modes of kidney stone suppression achieved by AIM/CD5L and KIM-1.

The prevalence of kidney stones is increasing and its recurrence rate within the first 5 years is over 50%. No treatments that prevent the occurrence/recurrence of stones have reached the clinic. Here, we show that AIM (also called CD5L) suppresses stone development and improves stone-associated physical damages. The N-terminal domain of AIM associates with calcium oxalate crystals via charge-based interaction to impede the development of stones, whereas the 2nd and C-terminal domains capture the inflammatory DAMPs to promote their phagocytic removal. Accordingly, when stones were induced by glyoxylate in mice, recombinant AIM (rAIM) injection dramatically reduced stone development. Expression of injury molecules and inflammatory cytokines in the kidney and overall renal dysfunction were abrogated by rAIM. Among various negatively charged substances, rAIM was most effective in stone prevention due to its high binding affinity to crystals. Furthermore, only AIM was effective in improving the physical complaints including bodyweight-loss through its DAMPs removal effect. We also found that tubular KIM-1 may remove developed stones. Our results could be the basis for the development of a comprehensive therapy against kidney stone disease.

Amyloid-ß oligomers interact with NMDA receptors containing GluN2B subunits and metabotropic glutamate receptor 1 in primary cortical neurons: Relevance to the synapse pathology of Alzheimer's disease.

Recent evidence suggests that soluble amyloid-ß oligomers (AßOs) act as a key factor in the pathogenetic mechanism of Alzheimer's disease (AD). AßOs induce neurotoxic and synaptotoxic effects probably through binding to certain receptors, however it remains unclarified which receptors are most critically involved. In addition, dysregulation in glutamatergic signaling is implicated in AD. In this study, we used a rat primary cortical neuron model to investigate AßO-induced aberrations of synaptic proteins and binding of extracellular AßOs to candidate receptors in the glutamatergic system. Immunocytochemical analyses showed that both presynaptic (SNAP-25, synapsin I) and postsynaptic (spinophilin, homer 1b/c) proteins appeared to aberrantly dislocate from synapses upon AßO treatment. Double immunofluorescence staining of AßO-treated neurons without permeabilization pretreatment revealed that extracellular AßOs exist over neuronal soma and neurites and clearly colocalized with GluN1 and GluN2B subunits of NMDA receptors and metabotropic glutamate receptor 1 (mGluR1), but not with NMDA GluN2A subunits and mGluR5. AßO treatment altered neither total protein levels nor intracellular localizations of these receptors. These results suggest that extracellular AßOs specifically bind to both NMDA receptors containing GluN2B subunits and mGluR1. It is likely that binding of AßOs to these receptors induces various pathological responses, consequently leading to synaptic disruptions. Our study thus highlights the important roles of GluN2B-containing NMDA receptors and mGluR1 receptors in the synapse pathology in AD.

AIM/CD5L attenuates DAMPs in the injured brain and thereby ameliorates ischemic stroke.

The sterile inflammation caused by damage-associated molecular patterns (DAMPs) worsens the prognosis following primary injury such as ischemic stroke. However, there are no effective treatments to regulate DAMPs. Here, we report that AIM (or CD5L) protein reduces sterile inflammation by attenuating DAMPs and that AIM administration ameliorates the deleterious effects of ischemic stroke. AIM binds to DAMPs via charge-based interactions and disulfide bond formation. This AIM association promotes the phagocytic removal of DAMPs and neutralizes DAMPs by impeding their binding to inflammatory receptors. In experimental stroke, AIM-deficient mice exhibit severe neurological damage and higher mortality with greater levels of DAMPs and associated inflammation in the brain than wild-type mice, in which brain AIM levels increase following stroke onset. Recombinant AIM administration reduces sterile inflammation in the infarcted region, leading to a profound reduction of animal mortality. Our findings provide a basis for the therapies targeting DAMPs to improve ischemic stroke.

Relationship between insomnia with alcohol drinking before sleep (Ne-Zake) or in the morning (Mukae-Zake) among Japanese farmers.

BACKGROUND: Ne-Zake is the drinking of alcohol before sleeping for helping to fall asleep and sleep well, and Mukae-Zake is the drinking of alcohol in the morning for "calming down" or "curing hangovers". OBJECTIVE: We sought to examine the relationship of insomnia with Ne-Zake and Mukae-Zake among healthy middle-aged Japanese farmers. METHODS: In a cross-sectional study of 746 participants (mean age, 59.5 years; women, 25.9%), Ne-Zake and Mukae-Zake were defined based on a self-administered questionnaire. Insomnia was defined as the Athens Insomnia Scale Japanese version ≥6 or usage of sleeping pills in the previous year. Logistic regression was used to calculate odds ratio (OR) of insomnia related to Ne-Zake and Mukae-Zake adjusting for sex, age, presence of sleep-related disorders, frequency of alcohol consumption, and quantity of alcohol consumed per one occasion. RESULTS: We observed insomnia, Ne-Zake, and Mukae-Zake in 174 (23.3%), 140 (18.8%), and 37 (5.0%) participants, respectively. After adjustment for demographic and confounding factors, participants with Ne-Zake had a significantly higher prevalence of insomnia (OR 2.00 [95% confidence interval, 1.27-3.16]), compared to those without Ne-Zake. Mukae-Zake was also independently associated with a higher prevalence of insomnia among men (OR 3.26 [1.55-6.87]). Participants with both Ne-Zake and Mukae-Zake had a highly significant association with insomnia (OR 4.77 [2.01-11.3]) than those with neither Ne-Zake nor Mukae-Zake. Additionally, for insomnia, the association of Mukae-Zake was more pronounced than that of Ne-Zake (OR 4.09, 95% CI 1.14-14.7, p = 0.031; and OR 1.81, 95% CI 1.08-3.06, p = 0.026, respectively). CONCLUSION: Ne-Zake and Mukae-Zake were associated with insomnia independent of the quantity and frequency of alcohol consumption among Japanese farmers. This finding can be used for stratifying individuals with insomnia not only to improve sleep hygiene but also to prevent alcohol dependence by informing the general population that alcohol has a negative effect on sleep, contrary to popular beliefs.

Tyrosol Reduces Amyloid-ß Oligomer Neurotoxicity and Alleviates Synaptic, Oxidative, and Cognitive Disturbances in Alzheimer's Disease Model Mice.

Soluble amyloid-ß (Aß) oligomers (AßOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer's disease (AD). Since AßOs are a key therapeutic target, we attempted to identify natural agents that reduce AßO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AßOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AßO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aß accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AßO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.

TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid ß-Protein Generation in Neurons.

Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid ß-protein (Aß) generation in neurons. TFEB was overexpressed in mature rat primary cortical neurons via recombinant adenoviruses, without (basal conditions) or with co-overexpression of wild-type amyloid precursor protein (APP) or its ß-C-terminal fragment (ß-CTF). We confirmed that TFEB overexpression upregulated the lysosomal proteins, cathepsin D and LAMP-1. In TFEB-expressing neurons, protein levels of ADAM10 were profoundly increased, whereas those of APP, BACE1, or γ-secretase complex proteins were unaffected. However, TFEB did not affect ADAM10 mRNA levels. TFEB overexpression had different effects on Aß production depending on the expression level of APP or ß-CTF: TFEB slightly decreased Aß secretion under basal conditions; clearly increased α-CTF levels and marginally increased ß-CTF levels with modest increases in secreted Aß in APP-expressing neurons; and caused a remarkable increase in ß-CTF levels with a significant increase in secreted Aß in ß-CTF-expressing neurons. Inhibition of proteasomes, but not lysosomes, markedly increased ß-CTF levels in ß-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aß production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting ß-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aß production in neurons.

Two new coumarins and a new xanthone from the leaves of Rhizophora mucronata.

Two new coumarins (1, 2) and a new xanthone (3), together with 14 known compounds-eight coumarins (4, 5, 9, 10, 12-15), three xanthones (11, 16, 17), a benzoic acid (6) and two flavonones (7, 8)-were isolated from the leaves of Rhizophora mucronata. The structures of the compounds were elucidated by spectroscopic (IR, MS, and NMR) analyses. The isolated compounds were tested for cytotoxicity against human cancer cell lines HL-60 and HeLa. Among these compounds, only compound 16 inhibited the growth of both HeLa (IC50 = 4.8 µM) and HL-60 (IC50 = 1.0 µM) cells. Compounds 4, 7, 10, and 12 exhibited moderate activity against HeLa cells (IC50 = 3.8-8.3 µM). Compounds 5, 9, 11, and 17 showed moderate activity against HL-60 cells (IC50 = 2.2-6.3 µM). Higher selectivity against HL-60 cell lines was observed for compounds 5, 9, 11, and 16 with SI values (NIH 3T3/HL-60) of 8.6, 19.2, 9.4, and 10.2, respectively.

The neurotoxicity of amyloid ß-protein oligomers is reversible in a primary neuron model.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid ß-protein (Aß) and intracellular hyperphosphorylated tau proteins. Recent evidence suggests that soluble Aß oligomers elicit neurotoxicity and synaptotoxicity, including tau abnormalities, and play an initiating role in the development of AD pathology. In this study, we focused on the unclarified issue of whether the neurotoxicity of Aß oligomers is a reversible process. Using a primary neuron culture model, we examined whether the neurotoxic effects induced by 2-day treatment with Aß42 oligomers (Aß-O) are reversible during a subsequent 2-day withdrawal period. Aß-O treatment resulted in activation of caspase-3 and eIF2α, effects that were considerably attenuated following Aß-O removal. Immunocytochemical analyses revealed that Aß-O induced aberrant phosphorylation and caspase-mediated cleavage of tau, both of which were mostly reversed by Aß-O removal. Furthermore, Aß-O caused intraneuronal dislocation of ß-catenin protein and a reduction in its levels, and these alterations were partially reversed upon Aß-O withdrawal. The dislocation of ß-catenin appeared to reflect synaptic disorganization. These findings indicate that removal of extracellular Aß-O can fully or partially reverse Aß-O-induced neurotoxic alterations in our neuron model. Accordingly, we propose that the induction of neurotoxicity by Aß oligomers is a reversible process, which has important implications for the development of AD therapies.

Inflammatory and anti-inflammatory states of adipose tissue in transgenic mice bearing a single TCR.

Obesity is accompanied by chronic, low-grade inflammation in adipose tissue, which is associated with insulin resistance and consequent multiple metabolic diseases. In addition to M1 macrophage infiltration, multiple involvements of adipose tissue T lymphocytes in the progression of inflammation have been highlighted recently. Here, we isolated a specific Vα5/Vß8.2 TCR-bearing T cell that accumulated in obese adipose tissue of mice, and generated transgenic mice expressing this TCR. Under lean conditions with a normal chow diet, CD4+FoxP3+ Treg cells and M2 macrophages increased in adipose tissue with ageing in wild-type mice, but not in transgenic mice. However, both mice exhibited no obvious adipose tissue inflammation such as the formation of crown-like structures (CLSs) of infiltrating macrophages. When fed a high-fat diet, the proportion of adipose tissue Treg cells was markedly small at a similar level in transgenic and wild-type mice. Both types of mice exhibited comparable inflammatory states in adipose tissue, including vast formation of macrophage CLSs, accompanied by insulin resistance. Together, our findings suggest that the absence of an increase in Treg cells and M2 macrophages is not sufficient to initiate inflammatory macrophage infiltration in lean adipose tissue and also provide a new view about the involvement of T cells in promoting obesity-associated inflammation.

Autopsy Case of Bilateral Optic Nerve Aplasia with Microphthalmia: Neural Retina Formation Is Required for the Coordinated Development of Ocular Tissues.

Human congenital anomalies provide information that contributes to the understanding of developmental mechanisms. Here we report bilateral optic nerve aplasia (ONA) with microphthalmia in the autopsy of the cadaver of a 70-year-old Japanese female. The gross anatomical inspection of the brain showed a cotton thread-like cord in the presumed location of the optic nerve tract or chiasm. Histologically, no neural retina, optic nerve bundle or retinal central vessels were formed in the eye globe, and the retinal pigment cells formed rosettes. The cornea, iris, and lens were also histologically abnormal. Immunohistochemically, no retinal cells expressed beta III tubulin, and Pax6- immunoreactive cells were present in the ciliary non-pigmented epithelial cells. This case of ONA could be attributed to the agenesis of retinal projection neurons as a sequel to the disruption of neural retina development. The neural retina formation would coordinate the proper development of ocular tissues.

Circulating AIM prevents hepatocellular carcinoma through complement activation.

Hepatocellular carcinoma (HCC) is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM(-/-) mice were highly susceptible to steatosis-associated HCC development, whereas no AIM(+/+) mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM(-/-) mice, and HCC induction by diethylnitrosamine was more prominent in AIM(-/-) than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC.

[Distribution of toxicity in liver of wild pufferfish Takifugu rubripes].

Livers from wild pufferfish, Takifugu rubripes, can be described as having a smooth frontal side and an upper-region that is attached to the hepatic portal vein. Based on this description, the liver can be divided into 10 parts (L1-5 and R1-5), and in this work, the lethal potency of each part was determined by mouse bioassay. Among the raw livers from 58 individuals, all 10 parts of 16 individuals, and some parts of 4 individuals showed mouse lethality, but no toxicity was detected in any part of the liver from 22 individuals. In the livers of 4 individuals that were partially toxic, the lethal potency of the toxic parts was less than 4 mouse units (MU)/g, and no part showed especially high toxicity. The remaining 16 individuals were considered non-toxic based on the assay of only one part. Among 13 frozen livers, all parts of 9 individuals were toxic, while all parts of 4 individuals were non-toxic. Liquid chromatography-mass spectrometry analysis revealed that all parts of a weakly toxic raw liver and a strongly toxic frozen liver had tetrodotoxin as the major toxin. Regarding the 16 raw and 9 frozen livers, whose parts were all toxic, the relative lethal potency of each part to the mean lethal potency of the individual (8.9-709 MU/g) was calculated, and subjected to a two-way analysis of variance with 2 factors (left/right and top/bottom) for each group of livers (raw or frozen). The analysis indicated non-significance among factors and interactions at a significance level of 5% in the frozen livers. However, in the raw livers, although no interaction between the 2 factors was detected, the right-side and the 4th-portion from the top were significantly higher than the left-side and the other portions, respectively. Therefore, we concluded that individual inspection using R4, which is the region that lies below the right-center location of the liver, is suitable for toxicity evaluation of liver to ensure the safe consumption of pufferfish.

Aldose reductase inhibitor fidarestat attenuates leukocyte-endothelial interactions in experimental diabetic rat retina in vivo.

PURPOSE: Dysregulation of the polyol pathway has been implicated as a major cause of diabetic retinopathy. The aldose reductase inhibitor fidarestat was recently reported to prevent retinal oxidative stress and overexpression of vascular endothelial growth factor (VEGF) protein in diabetic rats. In this study, we investigated the effect of fidarestat on leukocyte-endothelial cell interactions in an in vivo experimental model for diabetic retina. MATERIALS AND METHODS: Diabetes was induced in six-week-old male Long-Evans rats by intraperitoneal injection of streptozotocin (STZ) (75 mg/kg). The rats were divided into four experimental groups: non-diabetic control rats, untreated diabetic rats, and diabetic rats treated with a low (4 mg/kg/day) or high (16 mg/kg/day) oral dose of fidarestat. After four weeks of treatment, accumulated leukocytes in the retina were counted in vivo by acridine orange digital fluorography. Intercellular adhesion molecule-1 (ICAM-1) and VEGF-164 mRNA levels in the retina were analyzed using the quantitative reverse transcription-polymerase chain reaction. ICAM-1 protein expression in the retina was investigated by immunohistochemistry. RESULTS: Fidarestat treatment significantly decreased concentrations of sorbitol and fructose in the retinas of STZ-induced diabetic rats. Leukocyte accumulation in the retinas of fidarestat-treated rats was significantly less than in the untreated diabetic group (P < 0.01). Fidarestat treatment significantly reduced the expression ICAM-1 mRNA, but not VEGF-164 mRNA, in the retina of diabetic rats. Immunohistochemical study also revealed the suppressive effect of fidarestat on expression of ICAM-1. CONCLUSIONS: Oral administration of fidarestat attenuated leukocyte accumulation in the retina of STZ induced-diabetic rats, suggesting that fidarestat may have a therapeutic role in preventing the progression of diabetic retinopathy.

The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability.

Insulin secretion and glucose transport are the major mechanisms to balance glucose homeostasis. Recently, we found that the death effector domain-containing DEDD inhibits cyclin-dependent kinase-1 (Cdk1) function, thereby preventing Cdk1-dependent inhibitory phosphorylation of S6 kinase-1 (S6K1), downstream of phosphatidylinositol 3-kinase (PI3K), which overall results in maintenance of S6K1 activity. Here we newly show that DEDD forms a complex with Akt and heat-shock protein 90 (Hsp90), and supports the stability of both proteins. Hence, in DEDD(-/-) mice, Akt protein levels are diminished in skeletal muscles and adipose tissues, which interferes with the translocation of glucose-transporter 4 (GLUT4) upon insulin stimulation, leading to inefficient incorporation of glucose in these organs. Interestingly, as for the activation of S6K1, suppression of Cdk1 is involved in the stabilization of Akt protein by DEDD, since diminishment of Cdk1 in DEDD(-/-) cells via siRNA expression or treatment with a Cdk1-inhibitor, increases both Akt and Hsp90 protein levels. Such multifaceted involvement of DEDD in glucose homeostasis by supporting both insulin secretion (via maintenance of S6K1 activity) and glucose uptake (via stabilizing Akt protein), may suggest an association of DEDD-deficiency with the pathogenesis of type 2 diabetes mellitus.