Publications by authors named "Takahiro Ishikawa"

171 Publications

The D-mannose/L-galactose pathway is the dominant ascorbate biosynthetic route in the moss Physicomitrium patens.

Plant J 2021 Jul 10. Epub 2021 Jul 10.

Faculty of Life and Environmental Science, Shimane University, 1060 Nishikawatsu, Matsue, Shimane, 690-8504, Japan.

Ascorbate is an abundant and indispensable redox compound in plants. Genetic and biochemical studies have established the D-mannose/L-galactose (D-Man/L-Gal) pathway as the predominant ascorbate biosynthetic pathway in streptophyte, while the D-galacturonate (D-GalUA) pathway is distributed in parasinophytes and euglenoids. Based on the presence of the complete set of genes encoding enzymes involved in the D-Man/L-Gal pathway and an orthologous gene encoding aldonolactonae (ALase) - a key enzyme for the D-GalUA pathway - Physicomitrium patens may possess both pathways. Here, we have characterized the moss ALase as a functional lactonase and evaluated the ascorbate biosynthesis capability of the two pathways using knockout mutants. P. patens expresses two ALase paralogs, namely PpALase1 and PpALase2. Kinetic analyses with recombinant enzymes indicated that PpALase1 is a functional enzyme catalyzing the conversion of L-galactonic acid to the final precursor L-galactono-1,4-lactone and that it also reacts with dehydroascorbate as a substrate. Interestingly, mutants lacking PpALase1 (Δal1) showed 1.2-fold higher total ascorbate content than the wild type, and their dehydroascorbate content was increased by 50% compared with that of the wild type. In contrast, the total ascorbate content of mutants lacking PpVTC2-1 (Δvtc2-1) or PpVTC2-2 (Δvtc2-2), which encodes the rate-limiting enzyme GDP-L-Gal phosphorylase in the D-Man/L-Gal pathway, markedly was decreased to 46% and 17%, respectively, compared with that of the wild type. Taken together, the dominant ascorbate biosynthestic pathway in P.patens is the D-Man/L-Gal pathway, not the D-GalUA pathway and PpALase1 may play a significant role in ascorbate metabolism by facilitating dehydroascorbate degradation rather than ascorbate biosynthesis.
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http://dx.doi.org/10.1111/tpj.15413DOI Listing
July 2021

Index for the appropriate vancomycin dosing in premature neonates and infants.

Pediatr Int 2021 Jul 1. Epub 2021 Jul 1.

Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan.

Background: In neonates, vancomycin (VCM) is used to treat gram-positive bacterial infections. However, VCM blood concentrations are affected by gestational age (GA), body weight (BW), and renal function. Therefore, the initial VCM dose adjustment can be difficult, and few reports have evaluated this issue. In this study, we investigated the factors determining the appropriate VCM dosing schedule in neonates, especially premature infants.

Methods: The VCM dosage and trough concentrations were retrospectively investigated from the initial treatment to maintenance therapy in NICU patients who underwent therapeutic drug monitoring (TDM). We examined the average single-administration VCM dosage during maintenance therapy. We then compared the actual VCM dose with that calculated using an index comprising six items that influence the VCM daily dose (postnatal age, GA, BW, serum creatinine level, urine output, and lactate level).

Results: Twenty premature infants were included. The average BW of patients at the initial VCM administration was 975 g. During maintenance therapy, the average VCM dose was 8.4 mg/kg, and the median trough concentration was 12.4 μg/mL. When we applied the six-item index, 18 of 20 patients (90%) had concordant results between the actual VCM dosing schedule and the calculated using the index.

Conclusions: The average VCM dose and six-item index can facilitate the transition from the initial VCM dose to an appropriate dose in many cases and contribute to early treatment in low-birth-weight infants with more variable BW, distribution volumes, and renal function. In conclusion, our six-item index may help standardize VCM administration in premature infants.
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http://dx.doi.org/10.1111/ped.14905DOI Listing
July 2021

Evaluating the long-term effect of space radiation on the reproductive normality of mammalian sperm preserved on the International Space Station.

Sci Adv 2021 Jun 11;7(24). Epub 2021 Jun 11.

Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan.

Space radiation may cause DNA damage to cells and concern for the inheritance of mutations in offspring after deep space exploration. However, there is no way to study the long-term effects of space radiation using biological materials. Here, we developed a method to evaluate the biological effect of space radiation and examined the reproductive potential of mouse freeze-dried spermatozoa stored on the International Space Station (ISS) for the longest period in biological research. The space radiation did not affect sperm DNA or fertility after preservation on ISS, and many genetically normal offspring were obtained without reducing the success rate compared to the ground-preserved control. The results of ground x-ray experiments showed that sperm can be stored for more than 200 years in space. These results suggest that the effect of deep space radiation on mammalian reproduction can be evaluated using spermatozoa, even without being monitored by astronauts in Gateway.
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http://dx.doi.org/10.1126/sciadv.abg5554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195474PMC
June 2021

Cooperation of chloroplast ascorbate peroxidases and proton gradient regulation 5 is critical for protecting Arabidopsis plants from photo-oxidative stress.

Plant J 2021 May 24. Epub 2021 May 24.

Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu, Matsue, Shimane, 690-8504, Japan.

High-light (HL) stress enhances the production of H O from the photosynthetic electron transport chain in chloroplasts, potentially causing photo-oxidative damage. Although stromal and thylakoid membrane-bound ascorbate peroxidases (sAPX and tAPX, respectively) are major H O -scavenging enzymes in chloroplasts, their knockout mutants do not exhibit a visible phenotype under HL stress. Trans-thylakoid proton gradient (∆pH)-dependent mechanisms exist for controlling H O production from photosynthesis, such as thermal dissipation of light energy and downregulation of electron transfer between photosystems II and I, and these may compensate for the lack of APXs. To test this hypothesis, we focused on a proton gradient regulation 5 (pgr5) mutant, wherein both ∆pH-dependent mechanisms are impaired, and an Arabidopsis sapx tapx double mutant was crossed with the pgr5 single mutant. The sapx tapx pgr5 triple mutant exhibited extreme sensitivity to HL compared with its parental lines. This phenotype was consistent with cellular redox perturbations and enhanced expression of many oxidative stress-responsive genes. These findings demonstrate that the PGR5-dependent mechanisms compensate for chloroplast APXs, and vice versa. An intriguing finding was that the failure of induction of non-photochemical quenching in pgr5 (because of the limitation in ∆pH formation) was partially recovered in sapx tapx pgr5. Further genetic studies suggested that this recovery was dependent on the NADH dehydrogenase-like complex-dependent pathway for cyclic electron flow around photosystem I. Together with data from the sapx tapx npq4 mutant, we discuss the interrelationship between APXs and ∆pH-dependent mechanisms under HL stress.
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http://dx.doi.org/10.1111/tpj.15352DOI Listing
May 2021

Porphyrin accumulation in humans with common dysfunctional variants of ABCG2, a porphyrin transporter: potential association with acquired photosensitivity.

Hum Cell 2021 Jul 19;34(4):1082-1086. Epub 2021 May 19.

Department of Dermatology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.

Photosensitivity is a skin reaction disorder mediated by phototoxic and/or photoallergic mechanisms. The accumulation of porphyrins is generally considered to induce phototoxicity. ATP-binding cassette subfamily G member 2 (ABCG2) has been identified as a transporter of porphyrins and its common variants-p.Gln126Ter (rs72552713) and p.Gln141Lys (rs2231142)-reportedly decrease the function of porphyrin transport in vitro; however, the physiological importance of ABCG2 as a porphyrin transporter remains to be fully elucidated. We herein investigated whether ABCG2 dysfunction could lead to porphyrin accumulation and photosensitivity in Japanese subjects, and found it to be significantly correlated with erythrocyte protoporphyrin levels (P = 0.012). This appears to be the first clinical finding of ABCG2 dysfunction-associated protoporphyrin accumulation in humans. We divided the patients into a chronic actinic dermatosis (CAD) group and a non-CAD group. CAD was diagnosed based on the criteria of reduced minimal erythema doses to ultraviolet B (UVB) and/or ultraviolet A (UVA). The non-CAD group was composed of patients who exhibited normal reactions to UVB and UVA on phototesting, but had histories of recurrent erythema/papules on sun-exposed areas. Estimated ABCG2 function according to ABCG2 genotypes in the non-CAD group was significantly lower than in the general Japanese population (P = 0.045). In contrast, no difference was found in ABCG2 function between the CAD group and the general population, suggesting that ABCG2 dysfunction might be a genetic factor in non-CAD patients with clinical photosensitivity. In this context, genetic dysfunction of ABCG2 might be an overlooked pathological etiology of "photosensitivity of unknown cause."
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http://dx.doi.org/10.1007/s13577-021-00534-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197704PMC
July 2021

A novel podocyte protein, R3h domain containing-like, inhibits TGF-β-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane.

J Mol Med (Berl) 2021 Jun 23;99(6):859-876. Epub 2021 Feb 23.

Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan.

Not only in kidney glomerular physiological function but also glomerular pathology especially in diabetic condition, glomerular podocytes play pivotal roles. Therefore, it is important to increase our knowledge about the genes and proteins expressed in podocytes. Recently, we have identified a novel podocyte-expressed gene, R3h domain containing-like (R3hdml) and analyzed its function in vivo as well as in vitro. Transforming growth factor-β (TGF-β) signaling regulated the expression of R3hdml. And R3hdml inhibited p38 mitogen-activated protein kinase phosphorylation, which was induced by TGF-β, leading to the amelioration of podocyte apoptosis. Furthermore, a lack of R3hdml in mice significantly worsened glomerular function in streptozotocin (STZ)-induced diabetes, while overexpression of R3hdml ameliorated albuminuria in STZ-induced diabetes. Our results surmise that the functional analyses of R3hdml may lead to the development of novel therapeutic strategies for diabetic nephropathy in the future. KEY MESSAGES: • A novel podocyte expressed protein R3h domain containing-like was identified. • R3HDML inhibits podocyte apoptosis by inhibiting TGF-β-mediated p38 MAPK signaling. • Overexpression of R3HDML ameliorates albuminuria in STZ-induced diabetes mice. • R3HDML may prove to be a novel therapeutic strategy for diabetic nephropathy.
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http://dx.doi.org/10.1007/s00109-021-02050-wDOI Listing
June 2021

Generalized pruritic erythema with neutrophils in a patient with relapsing polychondritis.

J Dermatol 2021 Apr 18;48(4):e153-e154. Epub 2021 Feb 18.

Department of Dermatology, National Defense Medical College, Tokorozawa, Japan.

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http://dx.doi.org/10.1111/1346-8138.15755DOI Listing
April 2021

Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan.

Aging (Albany NY) 2020 12 29;12(24):24940-24956. Epub 2020 Dec 29.

Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.
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http://dx.doi.org/10.18632/aging.202441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803551PMC
December 2020

Alterations of retinal thickness measured by optical coherence tomography correlate with neurophysiological measures in diabetic polyneuropathy.

J Diabetes Investig 2020 Dec 10. Epub 2020 Dec 10.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: Diabetic polyneuropathy (DPN) and diabetic retinopathy (DR) are traditionally regarded as microvascular complications. However, these complications may share similar neurodegenerative pathologies. Here we evaluate the correlations in the severity of DPN and changes in the thickness of neuroretinal layers to elucidate whether these complications exist at similar stages of progression.

Materials And Methods: A total of 43 patients with type 2 diabetes underwent a nerve conduction study (NCS), a macular optical coherence tomography, and a carotid artery ultrasound scan. Diabetic polyneuropathy was classified according to Baba's classification using NCS. The retina was automatically segmented into four layers; ganglion cell complex (GCC), inner nuclear layer/outer plexiform layer (INL/OPL), outer nuclear layer/photoreceptor inner and outer segments, and retinal pigment epithelium (RPE). The thickness of each retinal layer was separately analyzed for the fovea and the parafovea.

Results: Fourteen patients were classified as having moderate to severe diabetic polyneuropathy. The thicknesses of the foveal and parafoveal INL/OPL increased in patients with diabetic polyneuropathy compared with patients without. The thickness of the parafoveal retinal pigment epithelium decreased in patients with diabetic polyneuropathy. The thinning of parafoveal ganglion cell complex and foveal and parafoveal retinal pigment epithelium were positively correlated with deterioration of nerve functions in the nerve conduction study, but the thickening of INL/OPL was positively correlated with the nerve function deterioration. The thinning of parafoveal ganglion cell complex and foveal retinal pigment epithelium were positively correlated with the thickening of the carotid intima-media.

Conclusions: Depending on the progression of diabetic polyneuropathy, the ganglion cell complex and retinal pigment epithelium became thinner and the INL/OPL became thicker. These retinal changes might be noteworthy for pathological investigations and for the assessment of diabetic polyneuropathy and diabetic retinopathy.
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http://dx.doi.org/10.1111/jdi.13476DOI Listing
December 2020

Neuroretinal dysfunction revealed by a flicker electroretinogram correlated with peripheral nerve dysfunction and parameters of atherosclerosis in patients with diabetes.

J Diabetes Investig 2021 Jul 18;12(7):1236-1243. Epub 2020 Dec 18.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: Diabetic polyneuropathy (DPN) develops in the early stage of diabetes. However, no common diagnostic protocol has yet been established. Here, to verify that the flicker electroretinogram using a hand-held device can detect the early dysfunction of the peripheral nervous system in patients with diabetes, we investigated the correlation between the progression of DPN and neuroretinal dysfunction.

Materials And Methods: In total, 184 participants with type 1 or 2 diabetes underwent a flicker electroretinogram (ERG) using a hand-held device RETeval™ and nerve conduction study. Participants were also evaluated for intima-media thickness, ankle-brachial index, toe brachial index and brachial-ankle pulse wave velocity. Parameters of the nerve conduction study were used to diagnose the severity according to Baba's classification. A multiple regression analysis was used to examine the associations of ERG parameters with the severity of DPN categorized by Baba's classification. Diagnostic properties of the device in DPN were evaluated using a receiver operating characteristic curve.

Results: A multiple regression model to predict the severity of DPN was generated using ERG. In the model, moderate-to-severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.692, sensitivity 56.5%, specificity 78.3%, positive predictive value 70.6%, negative predictive value 66.1%, positive likelihood ratio 2.60, negative likelihood ratio 0.56). In the patients without diabetic retinopathy, the implicit time and amplitude in ERG significantly correlated with the parameters of the nerve conduction study, brachial-ankle pulse wave velocity and intima-media thickness.

Conclusions: Electroretinogram parameters obtained by the hand-held device successfully predict the severity of DPN. The device might be useful to evaluate DPN.
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http://dx.doi.org/10.1111/jdi.13465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264400PMC
July 2021

Comparison of Visceral Fat Reduction by Ipragliflozin and Metformin in Elderly Type 2 Diabetes Patients: Sub-Analysis of a Randomized-Controlled Study.

Diabetes Ther 2021 Jan 24;12(1):183-196. Epub 2020 Oct 24.

Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8677, Japan.

Introduction: To compare the effects of ipragliflozin, a sodium-glucose transporter 2 inhibitor, with those of metformin on visceral fat (as well as muscles and bones) in Japanese elderly patients with type 2 diabetes (T2D), we conducted a sub-analysis of a prospective, multicenter, blinded-endpoint randomized-controlled study.

Methods: In total, 103 patients with T2D (body mass index ≥ 22 kg/m; glycated hemoglobin, 7-10%) and being treated with sitagliptin (a dipeptidyl peptidase-4 inhibitor) were included and randomized to receive ipragliflozin or metformin. The primary outcome was the change in visceral fat area measured using computed tomography 24 weeks following treatment. The secondary outcomes included changes in subcutaneous and total fat area, muscle volume, bone density measured using computed tomography, handgrip strength, bone markers, plasma glucose, insulin, homeostasis model assessment (HOMA)2-beta, HOMA2-R, glycated hemoglobin, lipid panel, uric acid, blood pressure, adiponectin, and high-sensitivity C-reactive protein. All patients aged 65-74 years were selected for sub-analysis.

Results: The sub-analysis included 15 and 14 patients in the ipragliflozin and metformin groups, respectively. The patients' backgrounds were well balanced. Visceral fat area reduction was greater in the ipragliflozin group than in the metformin group (- 10.58% vs. - 6.93%; P = 0.034). There were significant differences in the changes in bone absorption markers, uric acid, and total cholesterol levels between the groups.

Conclusion: Ipragliflozin significantly reduced the visceral fat area compared with metformin when added to sitagliptin in elderly patients with T2D. Long-term and large-scale studies are required to elucidate whether ipragliflozin is suitable for elderly patients.

Trial Registration: The study was registered at https://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170).
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http://dx.doi.org/10.1007/s13300-020-00949-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843837PMC
January 2021

A multi-sensory dataset for the activities of daily living.

Data Brief 2020 Oct 2;32:106122. Epub 2020 Aug 2.

Department of Electronics and Electrical Engineering, Keio University, 3-14-1 Hiyoshi, Kohokuku, Yokohama, Kanagawa 223-8522, Japan.

The article describes a multi-sensory dataset related to the Activities of Daily Living (ADL). These are the activities that contribute to an assessment of the overall status of elderly or people with special needs, possibly suffering from mild cognitive impairments. Typical basic ADLs include walking, such postural transitions as getting up or sitting down, as well as behaviours related to feeding, such as drinking or eating with knife and fork, or personal hygiene, e.g., teeth brushing. The collection process adopted for building this dataset considers nine ADL-related activities, which have been performed in different locations and involving the usage of both left and right arms. The dataset acquisition involved 10 volunteers performing 186 ADL instances, for a grand total of over 1860 examples. The dataset contains data from six 9-axis Inertial Measurement Units (IMUs), worn by each volunteer (two for each arm, one on the back and one on the right thigh). The dataset features an accurate data labelling done via manual annotation performed thanks to videos recorded by an RGB camera. The videos recorded during the experiments have been used only for labelling purposes, and they are not published.
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http://dx.doi.org/10.1016/j.dib.2020.106122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452700PMC
October 2020

Point-of-care nerve conduction device predicts the severity of diabetic polyneuropathy: A quantitative, but easy-to-use, prediction model.

J Diabetes Investig 2021 Apr 14;12(4):583-591. Epub 2020 Sep 14.

Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan.

Aims/introduction: A gold standard in the diagnosis of diabetic polyneuropathy (DPN) is a nerve conduction study. However, as a nerve conduction study requires expensive equipment and well-trained technicians, it is largely avoided when diagnosing DPN in clinical settings. Here, we validated a novel diagnostic method for DPN using a point-of-care nerve conduction device as an alternative way of diagnosis using a standard electromyography system.

Materials And Methods: We used a multiple regression analysis to examine associations of nerve conduction parameters obtained from the device, DPNCheck™, with the severity of DPN categorized by the Baba classification among 375 participants with type 2 diabetes. A nerve conduction study using a conventional electromyography system was implemented to differentiate the severity in the Baba classification. The diagnostic properties of the device were evaluated using a receiver operating characteristic curve.

Results: A multiple regression model to predict the severity of DPN was generated using sural nerve conduction data obtained from the device as follows: the severity of DPN = 2.046 + 0.509 × ln(age [years]) - 0.033 × (nerve conduction velocity [m/s]) - 0.622 × ln(amplitude of sensory nerve action potential [µV]), r = 0.649. Using a cut-off value of 1.3065 in the model, moderate-to-severe DPN was effectively diagnosed (area under the receiver operating characteristic curve 0.871, sensitivity 70.1%, specificity 87.7%, positive predictive value 83.0%, negative predictive value 77.3%, positive likelihood ratio 5.67, negative likelihood ratio 0.34).

Conclusions: Nerve conduction parameters in the sural nerve acquired by the handheld device successfully predict the severity of DPN.
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http://dx.doi.org/10.1111/jdi.13386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015817PMC
April 2021

Carotenoid accumulation in the eyespot apparatus required for phototaxis is independent of chloroplast development in Euglena gracilis.

Plant Sci 2020 Sep 15;298:110564. Epub 2020 Jun 15.

Department of Biosciences, School of Science and Engineering, Teikyo University, 1-1 Toyosatodai, Utsunomiya, Tochigi, 320-8551, Japan; Division of Integrated Science and Engineering, Graduate School of Science and Engineering, Teikyo University Graduate Schools, 1-1 Toyosatodai, Utsunomiya, Tochigi, 320-8551, Japan. Electronic address:

Euglena gracilis exhibits photomovements in response to various light stimuli, such as phototactic and photophobic responses. Our recent study revealed that carotenoids in the eyespot apparatus are required for triggering phototaxis in this alga. However, the role of chloroplasts in eyespot formation is not understood. Here, we isolated carotenoid-less (cl) strains of E. gracilis from cells silenced gene expression of phytoene synthase (EgcrtB). Unlike WT, the culture colors of cl1, cl3, and the non-photosynthetic mutant SM-ZK were orange, while that of cl4 was white. Electron microscope observations showed that SM-ZK, cl1, and cl3 had no developed chloroplast and formed a normal eyespot apparatus, similar to that of WT, but this was not the case for cl4. Carotenoids detected in WT were diadinoxanthin, neoxanthin, and β-carotene. However, the most abundant species of SM-ZK, cl1, and cl3 was zeaxanthin, and there was no diadinoxanthin or neoxanthin. Photomovement analysis showed that SM-ZK, cl1, and cl3 exhibited negative phototactic and photophobic responses, similar to those of WT, whereas cl4 lacked negative phototaxis. Taken together, the formation of the eyespot apparatus required for phototaxis is independent of chloroplast development in E. gracilis, suggesting that this property is different from other photosynthetic flagellates.
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http://dx.doi.org/10.1016/j.plantsci.2020.110564DOI Listing
September 2020

Effects of ipragliflozin versus metformin in combination with sitagliptin on bone and muscle in Japanese patients with type 2 diabetes mellitus: Subanalysis of a prospective, randomized, controlled study (PRIME-V study).

J Diabetes Investig 2021 Feb 20;12(2):200-206. Epub 2020 Aug 20.

Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, International University of Health and Welfare, Narita, Japan.

Aims/introduction: Recent randomized clinical trials have suggested that sodium-glucose cotransporter 2 inhibitors might reduce cardiovascular events and heart failure, and have renal protective effects. Despite these remarkable benefits, the effects of sodium-glucose cotransporter 2 inhibitors on bone and muscle are unclear.

Materials And Methods: A subanalysis of a randomized controlled study was carried out to evaluate the effects of the sodium-glucose cotransporter 2 inhibitor, ipragliflozin, versus metformin on bone and muscle in Japanese patients with type 2 diabetes mellitus (baseline body mass index ≥22 kg/m and hemoglobin A1c 7-10%) who were already receiving sitagliptin. These patients were randomly administered ipragliflozin 50 mg or metformin 1,000-1,500 mg daily. The effects of these medications on the bone formation marker, bone alkali phosphatase; the bone resorption marker, tartrate-resistant acid phosphatase 5b (TRACP-5b); handgrip strength; abdominal cross-sectional muscle area; and bone density of the fourth lumbar vertebra were evaluated.

Results: After 24 weeks of treatment, the changes in bone density of the fourth lumbar vertebra, handgrip strength and abdominal cross-sectional muscle area were not significantly different between the two groups. However, TRACP-5b levels increased in patients treated with ipragliflozin compared with patients treated with metformin (median 11.94 vs -10.30%, P < 0.0001), showing that ipragliflozin can promote bone resorption.

Conclusions: There were no adverse effects on bone or muscle when sitagliptin was used in combination with either ipragliflozin or metformin. However, ipragliflozin combination increased the levels of TRACP-5b. A long-term study is required to further understand the effects of this TRACP-5b increase caused by ipragliflozin.
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http://dx.doi.org/10.1111/jdi.13340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858125PMC
February 2021

Zinc Increases ABCA1 by Attenuating Its Clearance Through the Modulation of Calmodulin Activity.

J Atheroscler Thromb 2021 Mar 24;28(3):261-270. Epub 2020 Jun 24.

Food and Nutritional Sciences,Chubu University.

Aim: We previously revealed that Ca-activated calmodulin binds to ABCA1 by the region near the PEST sequence and retards its calpain-mediated degradation to increase HDL biogenesis. Calmodulin activity is reportedly modulated also by other nutritional divalent cations; thus, we attempted to determine whether Zn is involved in the regulation of ABCA1 stability through the modulation of calmodulin activity.

Methods: The effects of Zn on ABCA1 expression was investigated in J774 mouse macrophage cell-line cells and HepG2 human hepatoma cell-line cells.

Results: Zn increased ABCA1 expression, not by increasing the mRNA but by attenuating its decay rate, more prominently in the presence of cAMP. Accordingly, it enhanced cell cholesterol release with extracellular apolipoprotein A-I. Calmodulin binding to ABCA1 was increased by Zn and Ca. Zn suppressed calpain-mediated hydrolysis of the peptide of ABCA1 cytosolic loop, including the PEST sequence and the calmodulin-binding site, in a calmodulin- dependent fashion, in the presence of the minimum amount of Ca to activate calpain, but not calmodulin. Calpain activity was not directly inhibited by Zn at the concentration for enhancing calmodulin binding to ABCA1.

Conclusion: Nutritional divalent cation Zn is involved in the regulation of ABCA1 activity and biogenesis of HDL through the modulation of calmodulin activity. The results were consistent with previous clinical findings that Zn increased plasma HDL in the conditions of sympathetic activation, such as type 2 diabetes and chronic hemodialysis.
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http://dx.doi.org/10.5551/jat.55384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049148PMC
March 2021

The Cerebro-Cerebellum as a Locus of Forward Model: A Review.

Front Syst Neurosci 2020 9;14:19. Epub 2020 Apr 9.

Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

This review surveys physiological, behavioral, and morphological evidence converging to the view of the cerebro-cerebellum as loci of internal forward models. The cerebro-cerebellum, the phylogenetically newest expansion in the cerebellum, receives convergent inputs from cortical, subcortical, and spinal sources, and is thought to perform the predictive computation for both motor control, motor learning, and cognitive functions. This predictive computation is known as an internal forward model. First, we elucidate the theoretical foundations of an internal forward model and its role in motor control and motor learning within the framework of the optimal feedback control model. Then, we discuss a neural mechanism that generates various patterns of outputs from the cerebro-cerebellum. Three lines of supporting evidence for the internal-forward-model hypothesis are presented in detail. First, we provide physiological evidence that the cerebellar outputs (activities of dentate nucleus cells) are predictive for the cerebellar inputs [activities of mossy fibers (MFs)]. Second, we provide behavioral evidence that a component of movement kinematics is predictive for target motion in control subjects but lags behind a target motion in patients with cerebellar ataxia. Third, we provide morphological evidence that the cerebellar cortex and the dentate nucleus receive separate MF projections, a prerequisite for optimal estimation. Finally, we speculate that the predictive computation in the cerebro-cerebellum could be deployed to not only motor control but also to non-motor, cognitive functions. This review concludes that the predictive computation of the internal forward model is the unifying algorithmic principle for understanding diverse functions played by the cerebro-cerebellum.
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http://dx.doi.org/10.3389/fnsys.2020.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160920PMC
April 2020

Pustular psoriasis with severe liver dysfunction: psoriasis-specific immune hepatitis?

Eur J Dermatol 2021 Apr;31(2):277-279

Department of Dermatology, National Defense Medical College, Tokorozawa, Japan.

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http://dx.doi.org/10.1684/ejd.2020.3720DOI Listing
April 2021

Dehydroascorbate Reductases and Glutathione Set a Threshold for High-Light-Induced Ascorbate Accumulation.

Plant Physiol 2020 05 23;183(1):112-122. Epub 2020 Mar 23.

Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Shimane 690-8504, Japan

Plants require a high concentration of ascorbate as a redox buffer for survival under stress conditions, such as high light. Dehydroascorbate reductases (DHARs) are enzymes that catalyze the reduction of DHA to ascorbate using reduced glutathione (GSH) as an electron donor, allowing rapid ascorbate recycling. However, a recent study using an Arabidopsis () triple mutant lacking all three genes (herein called ∆) did not find evidence for their role in ascorbate recycling under oxidative stress. To further study the function of DHARs, we generated ∆ Arabidopsis plants as well as a quadruple mutant line combining ∆ with an additional mutation that causes ascorbate deficiency. Measurements of ascorbate in these mutants under low- or high-light conditions indicated that DHARs have a nonnegligible impact on full ascorbate accumulation under high light, but that they are dispensable when ascorbate concentrations are low to moderate. Because GSH itself can reduce DHA nonenzymatically, we used the mutant that contains ∼30% of the wild-type GSH level. The mutant accumulated ascorbate at a wild-type level under high light; however, when the mutation was combined with ∆, there was near-complete inhibition of high-light-dependent ascorbate accumulation. The lack of ascorbate accumulation was consistent with a marked increase in the ascorbate degradation product threonate. These findings indicate that ascorbate recycling capacity is limited in ∆ plants, and that both DHAR activity and GSH content set a threshold for high-light-induced ascorbate accumulation.
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http://dx.doi.org/10.1104/pp.19.01556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210653PMC
May 2020

Primary small cell carcinoma of the ureter with hydronephrosis: A case report.

Urol Case Rep 2020 Mar 14;29:101099. Epub 2019 Dec 14.

Department of Urology, Oita University Faculty of Medicine, Yuhu, Japan.

Small cell carcinoma in the ureter is extremely rare, with few cases reported in the literature. The current report describes the case of a 63-year-old man who presented with right-side back pain. A mass was identified in the right ureter. A nephroureterectomy was performed. Subsequent microscopic examination revealed that the mass comprised a monotonous population of small cells and that the carcinoma cells were positive for cluster of AE1/AE3 and synaptophysin. The tumor was diagnosed as a ureteral small cell carcinoma. Adjuvant chemotherapy was administered with 80 mg/m intravenous cisplatin on day 1 and 100 mg/m etoposide on days 1-3, every 21 days for 2 cycles. The patient has remained disease-free 6 months after surgery.
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http://dx.doi.org/10.1016/j.eucr.2019.101099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938797PMC
March 2020

Comparative proteomic analysis of mitochondria isolated from Euglena gracilis under aerobic and hypoxic conditions.

PLoS One 2019 31;14(12):e0227226. Epub 2019 Dec 31.

Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, Matsue, Shimane, Japan.

The unicellular microalga Euglena gracilis produces wax esters for ATP acquisition under low-oxygen conditions. The regulatory mechanism of wax ester production is not yet understood. Indeed, our previous transcriptomic analysis showed that transcript levels of genes involved in the wax ester synthesis hardly changed under hypoxic conditions, suggesting contribution of post-transcriptional regulation. In this study, we conducted a proteome analysis of E. gracilis mitochondria, as this organelle employs the fatty-acid synthesis pathway under hypoxic conditions. Mitochondria were isolated from E. gracilis SM-ZK strain treated with both aerobic and hypoxic conditions and used for shotgun proteomic analysis. Three independent proteomic analyses succeeded in identifying a total of 714 non-redundant proteins. Of these, 229 were detected in common to all experiments, and 116 were significantly recognized as differentially expressed proteins. GO enrichment analysis suggested dynamic changes in mitochondrial metabolic pathways and redox reactions under aerobic and hypoxic conditions. Protein levels of bifunctional enzymes isocitrate lyase and malate synthase in glyoxylate cycle were 1.35-fold higher under hypoxic conditions. Abundances of the propionyl-CoA synthetic enzymes, succinyl-CoA synthetase and propionyl-CoA carboxylase, were also 1.35- and 1.47-fold higher, respectively, under hypoxic conditions. Protein levels of pyruvate:NADP+ oxidoreductase, a key enzyme for anaerobic synthesis of acetyl-CoA, which serves as a C2 donor for fatty acids, showed a 1.68-fold increase under hypoxic conditions, whereas those of pyruvate dehydrogenase subunits showed a 0.77-0.81-fold decrease. Protein levels of the fatty-acid synthesis enzymes, 3-ketoacyl-CoA thiolase isoforms (KAT1 and KAT2), 3-hydroxyacyl-CoA dehydrogenases, and acyl-CoA dehydrogenase were up-regulated by 1.20- to 1.42-fold in response to hypoxic treatment. Overall, our proteomic analysis revealed that wax ester synthesis-related enzymes are up-regulated at the protein level post-transcriptionally to promote wax ester production in E. gracilis under low-oxygen conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938325PMC
April 2020

Investigator-initiated clinical study of a functional peptide, SR-0379, for limb ulcers of patients with Werner syndrome as a pilot study.

Geriatr Gerontol Int 2019 Nov;19(11):1118-1123

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Aim: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome.

Methods: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period.

Results: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events.

Conclusion: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123.
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http://dx.doi.org/10.1111/ggi.13782DOI Listing
November 2019

Extracellular transglutaminase 2 induces myotube hypertrophy through G protein-coupled receptor 56.

Biochim Biophys Acta Mol Cell Res 2020 02 27;1867(2):118563. Epub 2019 Oct 27.

Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan. Electronic address:

Skeletal muscle secretes biologically active proteins that contribute to muscle hypertrophy in response to either exercise or dietary intake. The identification of skeletal muscle-secreted proteins that induces hypertrophy can provide critical information regarding skeletal muscle health. Dietary provitamin A, β-carotene, induces hypertrophy of the soleus muscle in mice. Here, we hypothesized that skeletal muscle produces hypertrophy-inducible secretory proteins via dietary β-carotene. Knockdown of retinoic acid receptor (RAR) γ inhibited the β-carotene-induced increase soleus muscle mass in mice. Using RNA sequencing, bioinformatic analyses, and literature searching, we predicted transglutaminase 2 (TG2) to be an all-trans retinoic acid (ATRA)-induced secretory protein in cultured C2C12 myotubes. Tg2 mRNA expression increased in ATRA- or β-carotene-stimulated myotubes and in the soleus muscle of β-carotene-treated mice. Knockdown of RARγ inhibited β-carotene-increased mRNA expression of Tg2 in the soleus muscle. ATRA increased endogenous TG2 levels in conditioned medium from myotubes. Extracellular TG2 promoted the phosphorylation of Akt, mechanistic target of rapamycin (mTOR), and ribosomal p70 S6 kinase (p70S6K), and inhibitors of mTOR, phosphatidylinositol 3-kinase, and Src (rapamycin, LY294002, and Src I1, respectively) inhibited TG2-increased phosphorylation of mTOR and p70S6K. Furthermore, extracellular TG2 promoted protein synthesis and hypertrophy in myotubes. TG2 mutant lacking transglutaminase activity exerted the same effects as wild-type TG2. Knockdown of G protein-coupled receptor 56 (GPR56) inhibited the effects of TG2 on mTOR signaling, protein synthesis, and hypertrophy. These results indicated that TG2 expression was upregulated through ATRA-mediated RARγ and that extracellular TG2 induced myotube hypertrophy by activating mTOR signaling-mediated protein synthesis through GPR56, independent of transglutaminase activity.
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http://dx.doi.org/10.1016/j.bbamcr.2019.118563DOI Listing
February 2020

Intercellular IgA dermatosis aggravated during pregnancy.

Eur J Dermatol 2019 Oct;29(5):551-552

Department of Dermatology, National Defense Medical College, Tokorozawa, Japan.

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http://dx.doi.org/10.1684/ejd.2019.3620DOI Listing
October 2019

R3hdml regulates satellite cell proliferation and differentiation.

EMBO Rep 2019 11 16;20(11):e47957. Epub 2019 Sep 16.

Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.

In this study, we identified a previously uncharacterized skeletal satellite cell-secreted protein, R3h domain containing-like (R3hdml). Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice are lower compared to control mice. Expression levels of cell cycle-related markers, phosphorylation of Akt, and expression of insulin-like growth factor within the skeletal muscle are reduced in R3hdml KO mice compared to control mice. Expression of R3hdml increases during muscle regeneration in response to cardiotoxin (CTX)-induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml. Our results indicate that R3hdml is required for skeletal muscle development, regeneration, and, in particular, satellite cell proliferation and differentiation.
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http://dx.doi.org/10.15252/embr.201947957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832012PMC
November 2019

Multidrug use positively correlates with high-risk prescriptions in the Japanese elderly: a longitudinal study.

J Pharm Health Care Sci 2019 2;5:20. Epub 2019 Sep 2.

1Pharmacy of Chiba University Hospital, Chiba, Japan.

Background: There is a lack of evidence that multidrug use triggers adverse events. Therefore, the main purpose of this study was to clarify the relationship between the total number of drugs and number of high-risk prescriptions administered to Japanese elderly patients.

Methods: Using hospital electronic medical records (EMR), we evaluated the prescriptions of outpatients aged 65 years or older. We defined prescriptions of potentially inappropriate medications (PIMs) and overlapping prescription of drugs with the same mechanism of action (DSAs) as high-risk prescriptions. We analyzed the relationship among total number of drugs and high-risk prescriptions. In addition, we performed a secondary research to determine whether the hospitalization rate and concomitant medication contents differ depending on the high-risk prescriptions.

Results: Data for 13,630 outpatients were analyzed. A significant positive correlation between the numbers of total drugs and PIMs was found. The prescription frequency of individual PIMs rose as the total number of prescription drugs increased. The odds ratio (OR) of overlapping DSAs was significantly higher in patients using 5 or more drugs. In addition, there were significantly more prescriptions of laxatives among patients with overlapping prescriptions of anticholinergic drugs. The use of almost all PIMs was not an independent risk factor for hospitalization; instead, the number of PIMs was an independent risk factor for hospitalization [OR 1.18 (95% CI, 1.12-1.26)].

Conclusions: The number of PIMs and overlapping DSAs were high in patients receiving multidrug treatment. To avoid adverse events and hospitalization, it might be useful to review prescriptions and consider the number of PIMs and overlapping DSAs.
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http://dx.doi.org/10.1186/s40780-019-0150-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717964PMC
September 2019

Visualizing wax ester fermentation in single cells by Raman microspectroscopy and multivariate curve resolution analysis.

Biotechnol Biofuels 2019 22;12:128. Epub 2019 May 22.

2Faculty of Life and Environmental Science, Shimane University, Matsue, 690-8504 Japan.

Background: Global demand for energy is on the rise at a time when limited natural resources are fast depleting. To address this issue, microalgal biofuels are being recommended as a renewable and eco-friendly substitute for fossil fuels. is one such candidate that has received special interest due to their ability to synthesize wax esters that serve as precursors for production of drop-in jet fuel. However, to realize economic viability and achieve industrial-scale production, development of novel methods to characterize algal cells, evaluate its culture conditions, and construct appropriate genetically modified strains is necessary. Here, we report a Raman microspectroscopy-based method to visualize important metabolites such as paramylon and ester during wax ester fermentation in single cells in a label-free manner.

Results: We measured Raman spectra to obtain intracellular biomolecular information in under anaerobic condition. First, by univariate approach, we identified Raman markers corresponding to paramylon/esters and constructed their time-lapse chemical images. However, univariate analysis is severely limited in its ability to obtain detailed information as several molecules can contribute to a Raman band. Therefore, we further employed multivariate curve resolution analysis to obtain chain length-specific information and their abundance images of the produced esters. Accumulated esters in were particularly identified to be myristyl myristate (C28), a wax ester candidate suitable to prepare drop-in jet fuel. Interestingly, we found accumulation of two different forms of myristyl myristate for the first time in through our exploratory multivariate analysis.

Conclusions: We succeeded in visualizing molecular-specific information in during wax ester fermentation by Raman microspectroscopy. It is obvious from our results that simple univariate approach is insufficient and that multivariate curve resolution analysis is crucial to extract hidden information from Raman spectra. Even though we have not measured any mutants in this study, our approach is directly applicable to other systems and is expected to deepen the knowledge on lipid metabolism in microalgae, which eventually leads to new strategies that will help to enhance biofuel production efficiency in the future.
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http://dx.doi.org/10.1186/s13068-019-1471-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529988PMC
May 2019

Chloroplast development activates the expression of ascorbate biosynthesis-associated genes in Arabidopsis roots.

Plant Sci 2019 Jul 16;284:185-191. Epub 2019 Apr 16.

Department of Life Science and Biotechnology, Faculty of Life and Environmental Science, Shimane University, 1060 Nishikawatsu, Matsue, Shimane, 690-8504, Japan; Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu, Matsue, Shimane, 690-8504, Japan; Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu, Matsue, Shimane, 690-8504, Japan.

Transcriptional activation of ascorbate biosynthesis-associated genes under illumination is one of the important steps in ascorbate pool size regulation in photosynthetic tissues. Several biological processes within chloroplasts such as photosynthesis are required for this activation, suggesting functional chloroplasts to play a key role. We herein found that when grown on agar plate, ascorbate content in Arabidopsis non-photosynthetic tissues, roots, are unexpectedly almost comparable to that in shoots. The high accumulation of ascorbate was particularly observed in root regions closer to the root-hypocotyl junction, in which chloroplast development occurred because of a direct exposure to light. When chloroplast development in roots were further stimulated by shoot removal, the expression of biosynthetic genes, especially VTC2 gene that encodes GDP-l-galactose phosphorylase, was activated, resulting in an increase in ascorbate pool size. These positive effects were canceled when the roots were treated with a photosynthetic inhibitor. A null mutation in the LONG HYPOCOTYL 5 (HY5) gene almost completely inhibited root greening as well as the VTC2 expression. Overall, these findings show that chloroplast development can trigger the expression of ascorbate biosynthesis-associated genes not only in leaves but also in roots.
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http://dx.doi.org/10.1016/j.plantsci.2019.04.012DOI Listing
July 2019

Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

Diabetes Obes Metab 2019 08 8;21(8):1990-1995. Epub 2019 May 8.

Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, Chiba, Japan.

A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%-10%, and body mass index (BMI) ≥ 22 kg/m . Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000-1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12.06% vs. -3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.
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http://dx.doi.org/10.1111/dom.13750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767075PMC
August 2019
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