Publications by authors named "Masaki Kobayashi"

475 Publications

The effect of sodium-glucose cotransporter 2 inhibitor (tofogliflozin) on renal tubular damage in diabetic patients without albuminuria.

Int Urol Nephrol 2021 Nov 29. Epub 2021 Nov 29.

Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, Ibaraki, 300-0395, Japan.

Purpose: The sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of glucose-lowering drugs for individuals with diabetes. Large-scale clinical trials indicated that SGLT2 inhibitors have both a cardiovascular-protective and renal-protective effects. A reduction in glomerular hyperfiltration and a decrease in albuminuria are suspected as the main causes of SGLT2 inhibitors' renoprotective effect. The effects of SGLT2 inhibitors on tubular damage in non-albuminuric diabetic patients are unclear.

Methods: The SGLT2 inhibitor tofogliflozin (20 mg, 1 × /day) was orally administered to 14 non-albuminuric diabetic patients. Serum and urine samples were collected at baseline (before) and after the start of tofogliflozin treatment. Hemoglobin A1c, hemoglobin, estimated glomerular filtration rate (eGFR), body weight, and blood pressure (BP) were analyzed as clinical parameters at baseline and 1, 3, and 6 months later. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-β-D-glucosaminidase were measured as tubular damage markers and the urinary 8-hidroxydeoxyguanosine (8-OHdG) values were measured as an oxidative stress marker at baseline and at 1 and 3 months.

Results: Compared to baseline, the patients' HbA1c values and body weights were significantly decreased post-tofogliflozin administration, and their eGFR values were decreased at 3 months but recovered at 6 months; the hemoglobin concentrations were significantly increased at 3 and 6 months and the urinary NGAL level tended to be decreased at 3 months. No significant changes in blood urea nitrogen, BP, NAG, urine sodium concentration, or urinary 8-OHdG values occurred. The effect of this SGLT2 inhibitor was not influenced by the use of an angiotensin receptor blocker or dipeptidyl-peptidase 4 inhibitor.

Conclusion: For individuals with non-albuminuric diabetes, tofogliflozin has a good glucose-lowering effect and might have a tubular-protective effect.
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http://dx.doi.org/10.1007/s11255-021-03064-6DOI Listing
November 2021

Variables measured on three-dimensional computed tomography are preferred for predicting the outcomes of shock wave lithotripsy.

World J Urol 2021 Oct 23. Epub 2021 Oct 23.

Department of Urology, Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minami-Ohtsuka, Toshima, Tokyo, 170-8476, Japan.

Purpose: Shock wave lithotripsy (SWL) is used to treat upper urinary tract stones. Recently, some volume analyzers have enabled preoperative assessment using three-dimensional computed tomography (3D-CT). We evaluated the efficacy of 3D-CT variables for predicting the outcomes of SWL.

Methods: The study population included 193 patients who underwent SWL between November 2014 and August 2020. In addition to conventional two-dimensional computed tomography (2D-CT) assessments, 3D-CT assessments of targeted stones were retrospectively performed, and stone size and stone density (SD) were measured. The successful and unsuccessful treatment groups were compared and risk factors for an unsuccessful first SWL session were investigated. The predictive accuracy of variables measured on 3D-CT was evaluated by receiver operating characteristic curves and multivariate analyses.

Results: The success rate of the first SWL session was 73.1%. Stone volume, mean SD and highest SD on 3D-CT were significantly higher in the unsuccessful group than in the successful group. Stone volume showed a higher area under the curve (AUC) than the estimated volumetric stone burden and stone diameter, which were measured on 2D-CT (0.729, 0.683, and 0.672, respectively). The AUCs of the mean SD and highest SD on 3D-CT were higher than those on 2D-CT (0.699, 0.680, 0.617, and 0.627, respectively). Multivariate analyses identified stone volume (≥ 0.29 ml), mean SD on 3D-CT (≥ 421 HU), and absence of hydronephrosis as independent predictive factors for unsuccessful SWL.

Conclusion: 3D-CT variables were promising predictors of the outcomes of SWL. Preoperative 3D-CT assessment is helpful for selecting favorable patients for SWL.
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http://dx.doi.org/10.1007/s00345-021-03861-9DOI Listing
October 2021

Dehydration of Electrochemically Protonated Oxide: SrCoO with Square Spin Tubes.

J Am Chem Soc 2021 Oct 14;143(42):17517-17525. Epub 2021 Oct 14.

Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.

Controlling oxygen deficiencies is essential for the development of novel chemical and physical properties such as high- superconductivity and low-dimensional magnetic phenomena. Among reduction methods, topochemical reactions using metal hydrides (e.g., CaH) are known as the most powerful method to obtain highly reduced oxides including NdSrNiO superconductor, though there are some limitations such as competition with oxyhydrides. Here we demonstrate that electrochemical protonation combined with thermal dehydration can yield highly reduced oxides: SrCoO thin films are converted to SrCoO by dehydration of HSrCoO at 350 °C. SrCoO forms square (or four-legged) spin tubes composed of tetrahedra, in contrast to the conventional infinite-layer structure. Detailed analyses suggest the importance of the destabilization of the SrCoO precursor by electrochemical protonation that can greatly alter reaction energy landscape and its gradual dehydration (HSrCoO) for the SrCoO formation. Given the applicability of electrochemical protonation to a variety of transition metal oxides, this simple process widens possibilities to explore novel functional oxides.
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http://dx.doi.org/10.1021/jacs.1c07043DOI Listing
October 2021

The genome of Shorea leprosula (Dipterocarpaceae) highlights the ecological relevance of drought in aseasonal tropical rainforests.

Commun Biol 2021 10 7;4(1):1166. Epub 2021 Oct 7.

Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.

Hyperdiverse tropical rainforests, such as the aseasonal forests in Southeast Asia, are supported by high annual rainfall. Its canopy is dominated by the species-rich tree family of Dipterocarpaceae (Asian dipterocarps), which has both ecological (e.g., supports flora and fauna) and economical (e.g., timber production) importance. Recent ecological studies suggested that rare irregular drought events may be an environmental stress and signal for the tropical trees. We assembled the genome of a widespread but near threatened dipterocarp, Shorea leprosula, and analyzed the transcriptome sequences of ten dipterocarp species representing seven genera. Comparative genomic and molecular dating analyses suggested a whole-genome duplication close to the Cretaceous-Paleogene extinction event followed by the diversification of major dipterocarp lineages (i.e. Dipterocarpoideae). Interestingly, the retained duplicated genes were enriched for genes upregulated by no-irrigation treatment. These findings provide molecular support for the relevance of drought for tropical trees despite the lack of an annual dry season.
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http://dx.doi.org/10.1038/s42003-021-02682-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497594PMC
October 2021

Diclofenac potentiates the antitumor effect of cisplatin in a xenograft mouse model transplanted with cisplatin-resistant cells without enhancing cisplatin-induced nephrotoxicity.

Drug Metab Pharmacokinet 2021 Aug 16;41:100417. Epub 2021 Aug 16.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan. Electronic address:

Cisplatin (CDDP) is a well-known anticancer agent, and CDDP-induced nephrotoxicity (CIN) is one of the most serious adverse effects. Previously, we revealed that while celecoxib reduces CIN, diclofenac does not appear to enhance it. Furthermore, we reported that diclofenac additively enhances the cytotoxic effect of CDDP on CDDP-resistant A549 cells (A549/DDP cells) and their spheroids. In addition, celecoxib reduces the cytotoxic effect of CDDP on A549/DDP cells while demonstrating an anticancer effect; however, it enhanced the effect of CDDP cytotoxicity on spheroids. Therefore, we evaluated the effects of diclofenac or celecoxib on CIN and the antitumor effect of CDDP in a xenograft mouse model transplanted with A549/DDP cells. Although CDDP did not decrease tumor size and tumor weight, these parameters were significantly reduced following co-administration with diclofenac when compared with the control group. Conversely, celecoxib marginally suppressed the antitumor effect of CDDP. Moreover, CDDP increased the mRNA levels of kidney injury molecule 1 (Kim-1), a renal disorder marker, in the kidneys of xenograft mice; treatment with celecoxib and diclofenac did not impact Kim-1 mRNA levels increased by CDDP. In conclusion, diclofenac potentiated the antitumor effect of CDDP without enhancing CIN.
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http://dx.doi.org/10.1016/j.dmpk.2021.100417DOI Listing
August 2021

Measurement of Plasma Glucagon Levels Using Mass Spectrometry in Patients with Type 2 Diabetes on Maintenance Hemodialysis.

Kidney Blood Press Res 2021 17;46(5):652-656. Epub 2021 Aug 17.

Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Recently, attention has been focused on the effect of glucagon on blood glucose variability. The dynamics of glucagon have attracted attention as a new target in the treatment of diabetes patients. However, the dynamics of glucagon in hemodialysis (HD) patients with type 2 diabetes mellitus (T2DM) remain unclear.

Objectives: The aim of this study was to assess the dynamics of glucagon in HD patients with T2DM.

Materials And Methods: We measured plasma glucagon in HD patients with T2DM by liquid chromatography-high-resolution mass spectrometry (LC-HRMS), sandwich enzyme-linked immunosorbent assay (ELISA), and radioimmunoassay (RIA). The glucagon levels measured by each method were compared. We used the glucagon levels determined by our developed LC-HRMS method as the standard in this study.

Results: Plasma glucagon levels measured by LC-HRMS before HD were significantly higher than those measured after HD. Plasma glucagon levels measured using sandwich ELISA had a significantly higher correlation with those measured using LC-HRMS compared with RIA.

Conclusions: This was the first study to assess glucagon levels in HD patients with T2DM using LC-HRMS, which is considered a highly accurate method. Sandwich ELISA was shown to measure glucagon levels accurately as well.
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http://dx.doi.org/10.1159/000518027DOI Listing
August 2021

Noise Robust Projection Rule for Klein Hopfield Neural Networks.

Authors:
Masaki Kobayashi

Neural Comput 2021 05;33(6):1698-1716

Mathematical Science Center, University of Yamanashi, Kofu, Yamanashi 400-8511, Japan

Multistate Hopfield models, such as complex-valued Hopfield neural networks (CHNNs), have been used as multistate neural associative memories. Quaternion-valued Hopfield neural networks (QHNNs) reduce the number of weight parameters of CHNNs. The CHNNs and QHNNs have weak noise tolerance by the inherent property of rotational invariance. Klein Hopfield neural networks (KHNNs) improve the noise tolerance by resolving rotational invariance. However, the KHNNs have another disadvantage of self-feedback, a major factor of deterioration in noise tolerance. In this work, the stability conditions of KHNNs are extended. Moreover, the projection rule for KHNNs is modified using the extended conditions. The proposed projection rule improves the noise tolerance by a reduction in self-feedback. Computer simulations support that the proposed projection rule improves the noise tolerance of KHNNs.
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http://dx.doi.org/10.1162/neco_a_01385DOI Listing
May 2021

Pharmacological Inhibition of MCT4 Reduces 4-Hydroxytamoxifen Sensitivity by Increasing HIF-1α Protein Expression in ER-Positive MCF-7 Breast Cancer Cells.

Biol Pharm Bull 2021 ;44(9):1247-1253

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University.

The rate of glycolysis in cancer cells is higher than that of normal cells owing to high energy demands, which results in the production of excess lactate. Monocarboxylate transporters (MCTs), especially MCT1 and MCT4, play a critical role in maintaining an appropriate pH environment through lactate transport, and their high expression is associated with poor prognosis in breast cancer. Thus, we hypothesized that inhibition of MCTs is a promising therapeutic target for adjuvant breast cancer treatment. We investigated the effect of MCT inhibition in combination with 4-hydroxytamoxifen (4-OHT), an active metabolite of tamoxifen, using two estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. Lactate transport was investigated in cellular uptake studies. The cytotoxicity of 4-OHT was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In both cell lines evaluated, MCT1 and MCT4 were constitutively expressed at the mRNA and protein levels. [C]-L-lactate uptake by both cells was significantly inhibited by bindarit, a selective MCT4 inhibitor, but weakly affected by 5-oxoploline (5-OP), a selective MCT1 inhibitor. The results of the MTT assay showed that combination with bindarit, but not 5-OP, decreased 4-OHT sensitivity. Bindarit significantly increased the levels of hypoxia-inducible factor-1α (HIF-1α) in MCF-7 cells. Moreover, HIF-1α knockdown significantly increased 4-OHT sensitivity, whereas induction of HIF-1α by hypoxia decreased 4-OHT sensitivity in MCF-7 cells. In conclusion, pharmacological MCT4 inhibition confers resistance to 4-OHT rather than sensitivity, by increasing HIF-1α protein levels. In addition, HIF-1α inhibition represents a potential therapeutic strategy for enhancing 4-OHT sensitivity.
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http://dx.doi.org/10.1248/bpb.b21-00030DOI Listing
January 2021

Prolonged caloric restriction ameliorates age-related atrophy in slow and fast muscle fibers of rat soleus muscle.

Exp Gerontol 2021 10 17;154:111519. Epub 2021 Aug 17.

Laboratory of Molecular Pathology & Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan. Electronic address:

Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats. The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers. However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.
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http://dx.doi.org/10.1016/j.exger.2021.111519DOI Listing
October 2021

and evaluation of organic anion-transporting polypeptide 2B1-mediated pharmacokinetic interactions by apple polyphenols.

Xenobiotica 2021 Nov 24;51(11):1318-1325. Epub 2021 Aug 24.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

Organic anion-transporting polypeptide (OATP) 2B1 plays a critical role in the intestinal absorption of substrate drugs. Apple juice reportedly interacts with OATP2B1 substrate drugs. The purpose of this study was to investigate the effect of two apple polyphenols, phloretin and phloridzin, on OATP2B1-mediated substrate transport and to evaluate the effect of phloretin on rosuvastatin pharmacokinetics in rats. studies revealed that both polyphenols inhibited OATP2B1-mediated uptake of estrone-3-sulfate. Despite preincubation with phloretin and subsequent washing, the inhibitory effect was retained. Phloretin markedly decreased OATP2B1-mediated rosuvastatin uptake, with an IC value of 3.6 μM.On coadministering rosuvastatin and phloretin in rats, the plasma concentration of rosuvastatin 10 min after oral administration was significantly lower than that in the vehicle group. The area under the plasma concentration-time curve of rosuvastatin was not significant, showing a tendency to decrease in the phloretin group when compared with the vehicle group. The rat intestinal loop study revealed the inhibitory effect of phloretin on rosuvastatin absorption.Phloretin has potent and long-lasting inhibitory effects on OATP2B1 . Phloretin may inhibit OATP2B1-mediated intestinal absorption of rosuvastatin; however, it failed to significantly impact the systemic exposure of rosuvastatin in rats.
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http://dx.doi.org/10.1080/00498254.2021.1969480DOI Listing
November 2021

Computer-aided diagnosis with a convolutional neural network algorithm for automated detection of urinary tract stones on plain X-ray.

BMC Urol 2021 Aug 5;21(1):102. Epub 2021 Aug 5.

Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Recent increased use of medical images induces further burden of their interpretation for physicians. A plain X-ray is a low-cost examination that has low-dose radiation exposure and high availability, although diagnosing urolithiasis using this method is not always easy. Since the advent of a convolutional neural network via deep learning in the 2000s, computer-aided diagnosis (CAD) has had a great impact on automatic image analysis in the urological field. The objective of our study was to develop a CAD system with deep learning architecture to detect urinary tract stones on a plain X-ray and to evaluate the model's accuracy.

Methods: We collected plain X-ray images of 1017 patients with a radio-opaque upper urinary tract stone. X-ray images (n = 827 and 190) were used as the training and test data, respectively. We used a 17-layer Residual Network as a convolutional neural network architecture for patch-wise training. The training data were repeatedly used until the best model accuracy was achieved within 300 runs. The F score, which is a harmonic mean of the sensitivity and positive predictive value (PPV) and represents the balance of the accuracy, was measured to evaluate the model's accuracy.

Results: Using deep learning, we developed a CAD model that needed 110 ms to provide an answer for each X-ray image. The best F score was 0.752, and the sensitivity and PPV were 0.872 and 0.662, respectively. When limited to a proximal ureter stone, the sensitivity and PPV were 0.925 and 0.876, respectively, and they were the lowest at mid-ureter.

Conclusion: CAD of a plain X-ray may be a promising method to detect radio-opaque urinary tract stones with satisfactory sensitivity although the PPV could still be improved. The CAD model detects urinary tract stones quickly and automatically and has the potential to become a helpful screening modality especially for primary care physicians for diagnosing urolithiasis. Further study using a higher volume of data would improve the diagnostic performance of CAD models to detect urinary tract stones on a plain X-ray.
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http://dx.doi.org/10.1186/s12894-021-00874-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340490PMC
August 2021

Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats.

Eur J Pharmacol 2021 Oct 29;909:174395. Epub 2021 Jul 29.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharma sciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan; Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan. Electronic address:

Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics.
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http://dx.doi.org/10.1016/j.ejphar.2021.174395DOI Listing
October 2021

Storage Capacity of Quaternion-Valued Hopfield Neural Networks With Dual Connections.

Authors:
Masaki Kobayashi

Neural Comput 2021 07;33(8):2226-2240

Mathematical Science Center, University of Yamanashi, Kofu, Yamanashi 400-8511, Japan

A complex-valued Hopfield neural network (CHNN) is a multistate Hopfield model. A quaternion-valued Hopfield neural network (QHNN) with a twin-multistate activation function was proposed to reduce the number of weight parameters of CHNN. Dual connections (DCs) are introduced to the QHNNs to improve the noise tolerance. The DCs take advantage of the noncommutativity of quaternions and consist of two weights between neurons. A QHNN with DCs provides much better noise tolerance than a CHNN. Although a CHNN and a QHNN with DCs have the samenumber of weight parameters, the storage capacity of projection rule for QHNNs with DCs is half of that for CHNNs and equals that of conventional QHNNs. The small storage capacity of QHNNs with DCs is caused by projection rule, not the architecture. In this work, the ebbian rule is introduced and proved by stochastic analysis that the storage capacity of a QHNN with DCs is 0.8 times as many as that of a CHNN.
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http://dx.doi.org/10.1162/neco_a_01405DOI Listing
July 2021

The effect of a multimodal comprehensive care methodology for family caregivers of people with dementia.

BMC Geriatr 2021 07 22;21(1):434. Epub 2021 Jul 22.

Department of Geriatric Medicine, National Hospital Organization Tokyo Medical Center, 2-5-1, Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan.

Background: Caregivers experience social, physical and psychological burdens in caring for people with dementia. A study was conducted to assess the efficacy of a multimodal comprehensive care methodology training programme for the family caregivers of people with dementia.

Methods: This research was an intervention trial with a quasi-experimental design. A total of 148 family caregivers of people with dementia participated in a multimodal comprehensive care methodology training programme for 6 hours (three times for 2 hours) in 3 months, which was followed by weekly delivery of information via postcard. The care burden of the caregivers was evaluated by the Japanese short version of the Zarit Burden Interview (J-ZBI) before the training, 1 month post-training and 3 months post-training (primary outcome). Each caregiver assessed the symptoms of the people with dementia for whom they provided care with the Behavioral Pathology in Alzheimer's Disease (Behave-AD) (secondary outcome).

Results: A total of 117 family caregivers (79%) were assessed 3 months after training. Over the course of the programme, the care burden significantly decreased from pre-training to 3 months post-training (P < 0.001). The mean care burden scores before, 1 month after, and 3 months after the intervention were 13.3, 10.9 and 10.6, respectively. The mean Behave-AD score of 101 people with dementia (68%) 3 months post-training was lower than that at pre-training, but the difference was not statistically significant (from 13.6 to 11.8, P = 0.005).

Conclusions: The multimodal comprehensive care methodology training was associated with a reduction in the care burden of family caregivers. These findings suggest that randomized controlled trials with larger sample sizes are needed.

Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000043245 . Registered 4 February 2021 - Retrospectively registered.
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http://dx.doi.org/10.1186/s12877-021-02373-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296621PMC
July 2021

Effects of valproate, an HDAC inhibitor, on the expression of folate carriers and folate metabolism-related genes in the placenta of rats.

Drug Metab Pharmacokinet 2021 Oct 7;40:100409. Epub 2021 Jun 7.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University. Electronic address:

Valproate (VPA), an antiepileptic drug, is known to inhibit histone deacetylases (HDACs). Exposure to VPA during pregnancy increases several fetal risks. The maintenance of folate level during pregnancy is essential for adequate fetal development, and the placenta plays a critical role in supplying nutrients to the fetus. The aim of this study was to elucidate the effects of VPA on the gene expression of folate carriers and metabolizing enzymes in the rat placenta at both mid and late gestation periods. Pregnant rats were orally administered VPA on a single day or 4 days (repeated administration). Gene expression of folate carriers (Folr1, Slc19a1, Slc46a1) and metabolizing enzymes (Cth, Mtr, Mtrr, Mthfr, Dhfr) was assessed in the placenta on gestational day (GD) 13 or GD20. In the control rats, the expression of Folr1, Slc46a1, Cth, and Mthfr tended to be upregulated, whereas that of Mtrr and Dhfr was downregulated during gestation; the expression of Slc19a1 and Mtr did not change. Repeated VPA administration reduced the placental expression of Folr1and Mtr on GD20 and increased the expression of Dhfr on GD13 compared with the control. These findings indicate that administration of VPA alters the placental gene expression of folate carriers and metabolism-related enzymes.
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http://dx.doi.org/10.1016/j.dmpk.2021.100409DOI Listing
October 2021

Kinetic analysis of cystine uptake and inhibition pattern of sulfasalazine in A549 cells.

Biopharm Drug Dispos 2021 Sep 29;42(8):389-392. Epub 2021 Jul 29.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

Cystine/glutamate transporter (xCT) is an antiporter involved in cystine uptake and glutamate efflux. However, there are very few reports regarding the kinetic analysis of xCT for cystine uptake using cancer cell lines, as well as the inhibition pattern of sulfasalazine, an inhibitor of xCT, for cystine uptake. Therefore, the purpose of this study was to clarify the kinetics of xCT in A549 cells, human lung cancer cells, and to reveal the inhibition pattern of sulfasalazine. Cystine uptake occurred in a time-dependent manner, with linear cystine uptake observed for 5 min. Additionally, sulfasalazine inhibited cystine uptake in a concentration-dependent manner, presenting an IC value of 24.7 ± 5.6 μM. Cystine uptake was saturated with increasing concentration, demonstrating K and V values of 179.4 ± 26.7 μM and 30.4 ± 2.3 nmol/min/mg protein, respectively. Moreover, during cystine uptake with sulfasalazine, K and V were >300 μM and 8.0 ± 1.5 nmol/min/mg protein, respectively, suggesting that sulfasalazine might demonstrate a mixed inhibition pattern. Furthermore, xCT siRNA decreased the xCT mRNA level and reduced cystine uptake. In conclusion, xCT was involved in the cystine uptake in A549 cells and sulfasalazine showed a mixed inhibition pattern to xCT.
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http://dx.doi.org/10.1002/bdd.2298DOI Listing
September 2021

Ferromagnetism and giant magnetoresistance in zinc-blende FeAs monolayers embedded in semiconductor structures.

Nat Commun 2021 Jul 7;12(1):4201. Epub 2021 Jul 7.

Dept. of Electrical Engineering and Information Systems, The University of Tokyo, Tokyo, Japan.

Material structures containing tetrahedral FeAs bonds, depending on their density and geometrical distribution, can host several competing quantum ground states ranging from superconductivity to ferromagnetism. Here we examine structures of quasi two-dimensional (2D) layers of tetrahedral Fe-As bonds embedded with a regular interval in a semiconductor InAs matrix, which resembles the crystal structure of Fe-based superconductors. Contrary to the case of Fe-based pnictides, these FeAs/InAs superlattices (SLs) exhibit ferromagnetism, whose Curie temperature (T) increases rapidly with decreasing the InAs interval thickness t (T ∝ t), and an extremely large magnetoresistance up to 500% that is tunable by a gate voltage. Our first principles calculations reveal the important role of disordered positions of Fe atoms in the establishment of ferromagnetism in these quasi-2D FeAs-based SLs. These unique features mark the FeAs/InAs SLs as promising structures for spintronic applications.
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http://dx.doi.org/10.1038/s41467-021-24190-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263727PMC
July 2021

Risk factor analysis for taxane-associated acute pain syndrome under the dexamethasone prophylaxis.

Support Care Cancer 2021 Dec 6;29(12):8059-8067. Epub 2021 Jul 6.

Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan.

Purpose: Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration.

Methods: In total, 143 patients with breast cancer who received docetaxel (75 mg/m) or paclitaxel (175 mg/m)-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of ≥ G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated.

Results: Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of ≥ G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of ≥ G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of ≥ G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences.

Conclusion: Pegfilgrastim co-administration is an independent risk factor for ≥ G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.
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http://dx.doi.org/10.1007/s00520-021-06342-2DOI Listing
December 2021

Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue.

Int J Mol Sci 2021 Jun 2;22(11). Epub 2021 Jun 2.

Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.
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http://dx.doi.org/10.3390/ijms22116025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199692PMC
June 2021

Disordered branched chain amino acid catabolism in pancreatic islets is associated with postprandial hypersecretion of glucagon in diabetic mice.

J Nutr Biochem 2021 11 28;97:108811. Epub 2021 Jun 28.

Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan. Electronic address:

Dysregulation of glucagon is associated with the pathophysiology of type 2 diabetes. We previously reported that postprandial hyperglucagonemia is more obvious than fasting hyperglucagonemia in type 2 diabetes patients. However, which nutrient stimulates glucagon secretion in the diabetic state and the underlying mechanism after nutrient intake are unclear. To answer these questions, we measured plasma glucagon levels in diabetic mice after oral administration of various nutrients. The effects of nutrients on glucagon secretion were assessed using islets isolated from diabetic mice and palmitate-treated islets. In addition, we analyzed the expression levels of branched chain amino acid (BCAA) catabolism-related enzymes and their metabolites in diabetic islets. We found that protein, but not carbohydrate or lipid, increased plasma glucagon levels in diabetic mice. Among amino acids, BCAAs, but not the other essential or nonessential amino acids, increased plasma glucagon levels. BCAAs also directly increased the intracellular calcium concentration in α cells. When BCAAs transport was suppressed by an inhibitor of system L-amino acid transporters, glucagon secretion was reduced even in the presence of BCAAs. We also found that the expression levels of BCAA catabolism-related enzymes and their metabolite contents were altered in diabetic islets and palmitate-treated islets compared to control islets, indicating disordered BCAA catabolism in diabetic islets. Furthermore, BCKDK inhibitor BT2 suppressed BCAA-induced hypersecretion of glucagon in diabetic islets and palmitate-treated islets. Taken together, postprandial hypersecretion of glucagon in the diabetic state is attributable to disordered BCAA catabolism in pancreatic islet cells.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108811DOI Listing
November 2021

Preexisting autoimmune disease is a risk factor for immune-related adverse events: a meta-analysis.

Support Care Cancer 2021 Dec 23;29(12):7747-7753. Epub 2021 Jun 23.

Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.

Purpose: Patients with preexisting autoimmune disease (PAD) are often excluded from clinical trials assessing immune checkpoint inhibitors (ICIs). Therefore, the safety of ICI therapy in patients with PAD remains unclear. Herein, we evaluated the incidence of immune-related adverse events (irAEs) in patients with PAD when compared with non-PAD patients.

Methods: We searched MEDLINE/PubMed, Web of Science, and Google Scholar for eligible studies from inception to January 2021. Observational studies reporting the incidence of irAEs in patients with and without PAD were included. We then performed a meta-analysis of eligible studies using forest plots. The primary endpoint of this study was the incidence rate of irAEs between patients with and without PAD.

Results: We identified three prospective and three retrospective studies involving 206 patients with PAD and 3078 patients without PAD. In the meta-analysis, 128 patients with PAD (62.1%) experienced irAEs, which occurred in 51.9% of non-PAD patients, resulting in an odds ratio (OR) of 2.14 (95% confidence interval [CI] 1.58-2.89). In the subgroup analysis, the incidence of irAEs was significantly higher in patients with PAD (OR = 2.19, 95% CI [1.55-3.08]). Furthermore, no significant heterogeneity or publication bias was detected, indicating that our meta-analysis could be generalized to clinical settings.

Conclusion: This meta-analysis demonstrated that PAD was a risk factor for irAE incidence. These results suggest that monitoring the occurrence of irAEs in patients with PAD is required to manage irAEs appropriately.
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http://dx.doi.org/10.1007/s00520-021-06359-7DOI Listing
December 2021

The effect of multimodal comprehensive care methodology training on oral health care professionals' empathy for patients with dementia.

BMC Med Educ 2021 Jun 3;21(1):315. Epub 2021 Jun 3.

Department of Geriatric Medicine, National Hospital Organization Tokyo Medical Center, Meguro-ku, Tokyo, 152-8902, Japan.

Background: The prevalence of oral diseases in people with dementia has increased, and patients with dementia have worse oral health than people without dementia. However, in the provision of oral care, these patients often exhibit care-resistant behaviours. Empathy is important for health care professionals who provide dental care for people with dementia. A study was conducted to assess whether a multimodal comprehensive care methodology training programme, Humanitude™, was associated with an improvement in empathy for people with dementia among oral health care professionals.

Methods: This research was a pre-post prospective study. A total of 45 dentists and dental hygienists participated in a 7-h multimodal comprehensive care methodology training programme. Participants' empathy for their patients was evaluated with the Jefferson Scale of Physician Empathy-Health Professionals Version (JSPE-HP) before the training and 1 month after the training (primary outcome). Each participant listed 3 patients with poor oral health due to the refusal of usual oral care or dental treatment from his or her clinical practice. The oral health of the 3 care-resistant patients listed by each participant was evaluated by the Oral Health Assessment Tool (OHAT) before the training and 1 month after the training (secondary outcome).

Results: The post-training response rate was 87% (21 dentists and 18 dental hygienists). From pre-training to post-training, the multimodal comprehensive care methodology training significantly increased the mean empathy score (from 113.97 to 122.95, P < 0.05, effect size = 0.9). Regardless of gender, profession and years of clinical experience, all post-training subgroup scores were higher than the pre-training subgroup scores. The tongue, natural teeth, and oral hygiene scores of patients with dementia who resisted usual oral care or dental treatment, as assessed by the OHAT, were significantly improved compared with those before the training.

Conclusions: The multimodal comprehensive care methodology training was associated with an improvement in oral health professionals' empathy for patients with dementia. These findings suggest that randomized controlled trials with large sample sizes will be needed.

Trial Registration: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000041687 . Registered 4 September 2020 - Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047586.
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http://dx.doi.org/10.1186/s12909-021-02760-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176594PMC
June 2021

LMX1B-associated nephropathy that showed myelin figures on electron microscopy.

CEN Case Rep 2021 11 2;10(4):588-591. Epub 2021 Jun 2.

Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo Ami, Inashiki, Ibaraki, 300-0395, Japan.

The mutation of LIM homeodomain transcription factor LMX1B gene leads to nail-patella syndrome (NPS), which is characterized by dysplastic nails, hypoplastic patellae, iliac horns and nephropathy. The characteristic renal histological finding of NPS nephropathy is irregular thickening of the glomerular basement membrane with patchy lucent areas, including deposits of bundles of type III collagen fibrils revealed by electron microscopy (EM). Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A activity, and the characteristic EM finding is a lamellated membrane structure (myelin figures). We present the case of a male with LMX1B-associated nephropathy (LAN) who showed focal segmental glomerulosclerosis (FSGS) on light microscopy, and myelin figures and slight deposits of collagen fibrils on EM, without findings of glomerular basement membrane abnormality suggestive for NPS. A 21-year-old Japanese-Brazilian man was admitted to hospital for an investigation of the cause of proteinuria and decreased renal function. A renal biopsy was performed to investigate the cause of renal damage. Fabry disease was initially considered, based on the presence of myelin figures on EM, but since he had normal α-galactosidase A activity, this initial diagnosis was denied, and the patient was subsequently diagnosed with FSGS. At 22 years after that renal biopsy, the patient was incidentally diagnosed with LAN when NM_002316:3c.746G > A:p.(Arg249Gln) LMX1B variant was identified in his older brother by a pre-transplantation examination, and the same mutation was confirmed in the patient. Myelin figures revealed by EM might become one of the clues for the diagnosis of LAN.
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http://dx.doi.org/10.1007/s13730-021-00612-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494852PMC
November 2021

Exosomal CD47 Plays an Essential Role in Immune Evasion in Ovarian Cancer.

Mol Cancer Res 2021 09 20;19(9):1583-1595. Epub 2021 May 20.

Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Ovarian cancer is largely diagnosed at advanced stages upon detection of multiple peritoneal dissemination, resulting in poor outcomes. CD47 is overexpressed in tumors, facilitates tumor immune evasion, and is located on exosomes. We aimed to investigate the role of exosomal CD47 in ovarian cancer progression. Prognostic significance of CD47 expression in ovarian cancer was examined using a public database including 1,435 patients and validated with 26 patients at our institution. CD47 expression was associated with poor progression-free survival and inversely correlated with macrophage infiltration in ovarian cancer tissues. Exosomes were collected from ovarian cancer cell lines, and CD47 expression on exosomes was confirmed via flow cytometry. Inhibition of exosome secretion with GW4869 and exosome uptake with 5-(N-ethyl-N-isopropyl)-amiloride inhibited the surface CD47 expression on ovarian cancer cells and promoted phagocytosis by macrophages. (a key regulator of exosome release) knockdown inhibited exosome secretion and led to CD47 downregulation in ovarian cancer cells. In a xenograft mouse model, suppression of the release of tumor-derived exosomes by GW4869 or knockdown suppressed tumor progression and enhanced M1 macrophage phagocytosis in cancer tissues. Collectively, CD47 expression was correlated with poor prognoses in patients with ovarian cancer, suggesting the importance of immune evasion. CD47 was expressed on exosomes and the inhibition of exosome secretion and/or uptake enhanced cancer cell phagocytosis by macrophages, and thus, suppressed peritoneal dissemination. This suggests the potential of a novel immune checkpoint therapeutic agent that focuses on exosomes. IMPLICATIONS: Mechanistic insight from the current study suggests that exosomal CD47 may be an advantageous therapeutic target in ovarian cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0956DOI Listing
September 2021

Oxygen Release and Storage Property of Fe-Al Spinel Compounds: A Three-Way Catalytic Reaction over a Supported Rh Catalyst.

ACS Appl Mater Interfaces 2021 Jun 20;13(21):24615-24623. Epub 2021 May 20.

Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyotodaigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.

We evaluated the catalytic performance of the Rh-Fe/AlO catalyst during a three-way catalytic reaction and found, by chance, that a part of Fe species was dissolved into the γ-AlO support and worked as an oxygen storage material, which adjusts the oxygen concentration around the catalytically active sites to a suitable level for three-way catalysis. In this study, we demonstrated that the Fe-doped γ-AlO can reversibly store and release oxygen by the redox of Fe/Fe at the tetrahedral (T) site of the spinel structure without its structure deformation. The finding that a spinel-structured metal oxide, Fe-doped γ-AlO, could work as an oxygen storage material suggested a new opportunity for the development of oxygen storage materials without rare metals.
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http://dx.doi.org/10.1021/acsami.1c01486DOI Listing
June 2021

Characterization of deoxyribonucleoside transport mediated by concentrative nucleoside transporters.

Biochem Biophys Res Commun 2021 06 25;558:120-125. Epub 2021 Apr 25.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharma Sciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.

Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize CNT-subtype specificity to understand the systemic disposition of deoxyribonucleosides (dNs) and their analogs, the involvement of CNTs in transporting dNs is not fully understood. In this study, using COS-7 cells that transiently expressed CNT1, CNT2, or CNT3, we investigated if CNTs could transport not only ribonucleosides but also dNs, i.e., 2'-deoxyadenosine (dAdo), 2'-deoxyguanosine (dGuo), and 2'-deoxycytidine (dCyd). The cellular uptake study demonstrated that dAdo and dGuo were taken up by CNT2 but not by CNT1. Although dCyd was taken up by CNT1, no significant uptake was detected in COS-7 cells expressing CNT2. Similarly, these dNs were transported by CNT3. The apparent K values of their uptake were as follows: CNT1, K = 141 μM for dCyd; CNT2, K = 62.4 μM and 54.9 μM for dAdo and dGuo, respectively; CNT3, K = 14.7 μM and 34.4 μM for dGuo and dCyd, respectively. These results demonstrate that CNTs contribute not only to ribonucleoside transport but also to the transport of dNs. Moreover, our data indicated that CNT1 and CNT2 selectively transported pyrimidine and purine dNs, respectively, and CNT3 was shown to transport both pyrimidine and purine dNs.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.075DOI Listing
June 2021

Transport function, regulation, and biology of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4).

Pharmacol Ther 2021 10 22;226:107862. Epub 2021 Apr 22.

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

Human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4) are involved in the proton-dependent transport of monocarboxylates such as L-lactate, which play an essential role in cellular metabolism and pH regulation. hMCT1 and 4 are overexpressed in a number of cancers, and polymorphisms in hMCT1 have been reported to be associated with the prognosis of some cancers. Accordingly, recent advances have focused on the inhibition of these transporters as a novel therapeutic strategy in cancers. To screen for MCT inhibitors for clinical application, it is important to study MCT function and regulation, and the effect of compounds on them, using human-derived cells. In this review, we focus on the transport function, regulation, and biology of hMCT1 and hMCT4, and the effects of genetic variation in these transporters in humans.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107862DOI Listing
October 2021

Erratum to "Imaging of ultraweak photon emission for evaluating the oxidative stress of human skin" [J. Photochem. Photobiol. B: Biol. 198 (2019) 1-6/111562].

J Photochem Photobiol B 2021 May 22;218:112187. Epub 2021 Apr 22.

Graduate Department of Electronics, Tohoku Institute of Technology, Sendai, Japan.

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http://dx.doi.org/10.1016/j.jphotobiol.2021.112187DOI Listing
May 2021

Mitochondrial Unfolded Protein Responses in White Adipose Tissue: Lipoatrophy, Whole-Body Metabolism and Lifespan.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

The mitochondrial unfolded protein response (UPR) is a stress response mediated by the expression of genes such as chaperones, proteases, and mitokines to maintain mitochondrial proteostasis. Certain genetically modified mice, which defect mitochondrial proteins specifically in adipocytes, developed atrophy of the white adipose tissue, resisted diet-induced obesity, and had altered whole-body metabolism. UPR, which has beneficial functions for living organisms, is termed "mitohormesis", but its specific characteristics and detailed regulatory mechanism have not been elucidated to date. In this review, we discuss the function of UPR in adipose atrophy (lipoatrophy), whole-body metabolism, and lifespan based on the concept of mitohormesis.
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http://dx.doi.org/10.3390/ijms22062854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998111PMC
March 2021
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