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Steviol glycosides (SGs) are noncaloric natural sweeteners found in the leaves of stevia ( Stevia rebaudiana ). These diterpene glycosides are biosynthesized by attaching varying numbers of monosaccharides, primarily glucose, to steviol aglycone. Rebaudioside (Reb) D and Reb M are highly glucosylated SGs that are valued for their superior sweetness and organoleptic properties, yet they are present in limited quantities in stevia leaves. This study aims to improve the substrate preference and catalytic efficiency of UDP-sugar-dependent glycosyltransferase UGT91D2 from stevia, which acts as a bottleneck in the biosynthesis of Reb D and Reb M. We modeled the structure of UGT91D2 and substituted two amino acid residues, Y134 and V155, which are located near the glycosyl acceptor and donor, respectively. Expression of the UGT91D2 V155T in budding yeast significantly enhanced the production of Reb D and Reb M. Furthermore, transient expression in Nicotiana benthamiana revealed that the V155T substitution improved the glucosylation activity of UGT91D2, suggesting that this substitution enhances UDP-glucose binding and reduces side reactions involving nonglucose donors. By coexpressing multiple stevia UGT genes in N. benthamiana , we successfully produced highly glucosylated SGs from steviol. Our results provide insights into the substrate specificity of UGT91D2 and contribute to the engineering of SG biosynthesis.

Obesity is associated with mild chronic inflammation, frequently observed along with increased platelet and white blood cell (WBC) levels in adults. We aimed to clarify the relationship between peripheral blood cell count, body mass index standard deviation score (BMI-SDS), and adipocytokine levels in obese adolescents. Participants included 31 patients with obesity (age: 13.1 ± 3.1 yr) and 28 normal-weight controls (age: 13.3 ± 1.9 yr). Obesity was defined as a percentage of overweight ≥ 20%; patients with type 2 diabetes were excluded. As sex differences were observed in blood cell counts, the analysis was performed after adjusting for sex differences. The obese group has significantly higher WBC, red blood cell, and platelet counts, as well as high serum leptin levels and Homeostasis Model Assessment of insulin resistance (HOMA-IR) scores compared with those of the control group. In all participants, BMI-SDS significantly correlated with WBC and platelet counts. Platelet count correlated with serum leptin and glucose levels, whereas WBC count correlated with serum leptin, insulin, HOMA-IR, and glucose levels. Statistical analysis showed that serum leptin level significantly influenced the platelet count and HOMA-IR score affected WBC count. Increased platelet and WBC counts in adolescents with obesity may increase the risk of thrombosis., Competing Interests: None of the authors has any potential conflicts of interest associated with this research., (2024©The Japanese Society for Pediatric Endocrinology.)

New Ru-Pd heterobimetallic complexes were synthesized and structurally characterized utilizing 6,6″-bis(phosphino)-2,2':6',2″-terpyridine as a scaffold for the metal-metal bond. The dicationic Ru-Pd complex was found to exhibit high catalytic activity as a photocatalyst for photochemical reduction of CO 2 to CO under visible light irradiation. This study established a new design of transition metal catalysts that tune photoredox catalysis with metalloligands.

The nitrogen-heteroatom single bonds of 1,2-azoles and isoxazolines underwent methylene insertion in the presence of CH 2 I 2 (6 equiv.) and diethylzinc (3 equiv.) to produce a wide variety of the ring-expanded six-membered heterocycles. Density functional theory calculations suggest that the methylene insertion proceeds via cleavage of nitrogen-heteroatom single bonds followed by ring closure., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Formation of borabicyclo[3.2.0]heptadiene derivatives was achieved via boron-insertion into aromatic C-C bonds in the photo-promoted skeletal rearrangement reaction of triarylboranes bearing an ortho-phosphino substituent (ambiphilic phosphine-boranes). The borabicyclo[3.2.0]heptadiene derivatives were fully characterized by NMR and X-ray analyses. The dearomatized products were demonstrated to undergo the reverse reaction in the dark at room temperature, realizing photochemical and thermal interconversion between triarylboranes and boron-doped bicyclic systems. Experimental and theoretical studies revealed that sequential two electrocyclic reactions involving E/Z-isomerization of an alkene moiety proceed via a highly strained trans-borepin intermediate., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Growth Hormone therapy has been shown to induce transient insulin resistance in children, and there is concern regarding the diabetogenic potential of GH therapy in children born small for gestational age (SGA). In this case, female patient born SGA with a weight of 2,750 g (-1.73 standard deviation (SD)) and length of 45.5 cm (-2.6 SD). The patient's father and paternal grandfather were diagnosed with type 2 diabetes mellitus. At 3 years of age, the patient presented with short stature; height and weight were 85 cm (-2.5 SD) and 13 kg (-0.19 SD), respectively. She was placed on GH therapy. At 11 years of age, her fasting blood glucose and hemoglobin A1c levels were 116 mg/dL and 7.4%, respectively. Blood test results were negative for anti-glutamic acid decarboxylase and anti-islet antigen-2 antibodies. The patient discontinued GH therapy and started diet therapy and oral metformin (500 mg/day) administration. Five months later, the hemoglobin A1c level was 5.3% and glycemic control further improved. To our knowledge, family history may be an important risk factor for GH-induced diabetes. So, the GH dosage for patients born SGA with family history of diabetes should be adjusted so as not to be too excessive, and long-term follow-up studies will be required to evaluate fully the effects of GH therapy for them., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Naohiro Nomura et al.)

Purpose: Schools in Japan were closed nationwide from March to May 2020 because of the coronavirus disease 2019 (COVID-19) pandemic. Many suspect that this school closure affected children's mental and physical health. We investigated changes in school-age children's physiques to determine the effects of the COVID-19 lockdown and restrictions on their health., Methods: Data were extracted from a database of school physical examinations in Osaka elementary and junior high schools for 4 consecutive years from 2018 to 2021. The following characteristics were analyzed: short stature, tall stature, underweight, mild obesity, middle grade obesity, and severe obesity. The paired Student t-test was used to compare school examination data in the prepandemic period (2018-2019), pandemic lockdown (2019-2020), and post-lockdown period (2020-2021)., Results: Obesity rates in elementary school students aged 6-12 years, particularly in boys, were significantly higher during the lockdown than they were in 2019. After the pandemic, the tall stature rate continued to rise, while rates of short stature and underweight decreased in both sexes in 2020. In junior high school students aged 12-15 years, rates of obesity and underweight tended to decrease in 2020. However, these rates rebounded and rose in 2021 when the lockdown was lifted., Conclusion: During the COVID-19 pandemic lockdown, elementary school students gained weight, while junior high school students lost weight. The lockdown that was implemented during the COVID-19 pandemic had an unfavorable effect on weight gain, particularly in young school-age children.

Synthesis of arylboronates via borylation of C-C σ-bonds of aryl ketones was achieved by the combined use of photoenergy and a Rh catalyst. The cooperative system enables α-cleavage of photoexcited ketones to generate aroyl radicals via the Norrish type I reaction, which are successively decarbonylated and borylated with the rhodium catalyst. This work establishes a new catalytic cycle merging the Norrish type I reaction and Rh catalysis and demonstrates the new synthetic utility of aryl ketones as aryl sources for intermolecular arylation reactions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objectives: Extracellular vesicles (EVs) are small vesicles released by nearly all types of cells. They deliver different types of substances, including proteins and nucleic acids, to nearby or distant cells and play a role in the mediation of cell-to-cell communication. The aim of this study was to explore the association between EVs and insulin resistance in adolescents with obesity or type 2 diabetes mellitus (DM2)., Methods: The subjects were eight adolescents with DM2 (DM2 group; four males and four females; age: 18.1 ± 2.3 years), 18 adolescents with simple obesity (obesity group; 12 males and six females; age: 12.2 ± 3.4 years), and 20 controls (control group; 10 males and 10 females; age: 13.0 ± 1.4 years). As markers of EVs, serum CD9/CD63 and sonic hedgehog N-terminal (Shh-N) levels were measured using enzyme-linked immunosorbent assay., Results: The CD9/CD63 level in the control group was similar to that in the DM2 group, whereas the obesity group had a significantly higher CD9/CD63 level. In the entire study group, correlations were observed between serum Shh-N level and Homeostasis Model Assessment of insulin resistance (HOMA-IR) score (r=0.371, p=0.0143), Homeostasis Model Assessment-β cell function score (r=0.382, p=0.0115), serum insulin level (r=0.350, p=0.0171), and serum adiponectin level (r=0.367, p=0.0122). Multiple regression analysis revealed that serum Shh-N level was the most significant risk factor for HOMA-IR score and serum insulin level., Conclusions: Shh is correlated with insulin resistance via its association with adiponectin in adolescents., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Bis( o -phosphinophenyl)zinc derivatives were successfully synthesized by the reaction of o -phosphinophenylboronates with dimethylzinc via boron-zinc double transmetallation. The transmetallation was significantly accelerated by the presence of the ortho PR 2 substituent to give diarylzinc selectively. These organozinc compounds act as isolable phenylene-tethered PZnP-pincer ligands, affording PZnP-palladium and ruthenium complexes with a σ-accepting Zn-metalloligand.

Covalent inhibitors of enzymes are increasingly appreciated as pharmaceutical seeds, yet discovering non-cysteine-targeting inhibitors remains challenging. Herein, we report an intriguing experience during our activity-based proteomic screening of 1601 reactive small molecules, in which we monitored the ability of library molecules to compete with a cysteine-reactive iodoacetamide probe. One epoxide molecule, F8, exhibited unexpected enhancement of the probe reactivity for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-limiting glycolysis enzyme. In-depth mechanistic analysis suggests that F8 forms a covalent adduct with an aspartic acid in the active site to displace NAD + , a cofactor of the enzyme, with concomitant enhancement of the probe reaction with the catalytic cysteine. The mechanistic underpinning permitted the identification of an optimized aspartate-reactive GAPDH inhibitor. Our findings exemplify that activity-based proteomic screening with a cysteine-reactive probe can be used for discovering covalent inhibitors that react with non-cysteine residues.

Background: With the revision of the Japanese School Health and Safety Law in 2016, the use of growth and obesity curves has been recommended. This study aimed to determine the prevalence of growth and obesity curve creation in elementary and junior high schools using government-issued software in Japan between 2016 and 2019., Methods: A questionnaire survey was conducted with school nursing teachers in elementary and junior high schools in Osaka, Japan. The questionnaire was distributed and collected by e-mail between 1 and 31 March 2020., Results: The survey response rate was 87.1%. In total, 78.5% of the elementary schools, and 75.0% of the junior high schools had the software for creating the growth curves. The rate of adoption of growth curve creation using the software increased in elementary schools (from 16.2% in 2016 to 40.5% in 2019 and in junior high schools from 6.0% in 2016 to 33.6% in 2019. The detection rates of growth abnormalities also increased over the 4 years in elementary and junior high schools, as follows: short stature (2.48- and 3.81-fold, respectively), tall stature (2.77- and 4.77-fold, respectively), emaciation (2.62 and 4.85-fold, respectively), mild obesity (2.66 and 5.15-fold, respectively), moderate obesity (2.71- and 4.14-fold, respectively), and severe obesity (2.45- and 3.32-fold, respectively). The rates of receiving a recommendation slip and going on to consult a specialist for each growth abnormality were low., Conclusions: By utilizing these curves, the detection rate of physical development abnormalities increased, but the rate of recommending a specialist consultation and the rate of actual consultation with a specialist were still low., (© 2022 Japan Pediatric Society.)

Prenatal malnutrition is known to affect the phenotype of the offspring through changes in epigenetic regulation. Growing evidence suggests that epigenetics is one of the mechanisms by which nutrients and minerals affect metabolic traits. Although the perinatal period is the time of highest phenotypic plasticity, which contributes largely to developmental programming, there is evidence of nutritional influence on epigenetic regulation during adulthood. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. This brief review aims to identify the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in the offspring. Those findings demonstrate that maternal Ca deficiency during pregnancy may affect the epigenetic regulation of gene expression and thereby induce different metabolic phenotypes. We aim to address the need for Ca during pregnancy and propose the scaling-up of clinical and public health approaches that improved pregnancy outcomes.

Objectives: Bone can act as an endocrine organ through the secretion of bone-specific hormones, i.e., osteokines. Recent research has demonstrated that lipocalin 2 (LCN2) secreted by osteoblasts are part of an important endocrine system that is finely tuned with other organs to ensure homeostatic balance and health. The aim of this study was to explore the association between bone and glucose metabolism in adolescents with obesity and type 2 diabetes mellitus (DM2)., Methods: The participants were 8 adolescents with DM2 (5 males, 3 females; age: 17.0 (14.0-20.0) years, median (interquartile range)), 14 adolescents with simple obesity (9 males, 5 females; age: 13.5 (12.4-15.5) years), and 15 controls (6 males, 9 females; age: 13.3 (11.0-15.0) years). Serum LCN2 and under-carboxylated osteocalcin (un-OC) levels were measured using enzyme-linked immunosorbent assays., Results: The LCN2 levels were higher in patients with DM2 (58.1 (34.2-95.0) ng/mL; median (interquartile range)), but not in those with obesity (30.8 (23.1-38.3) ng/mL), when compared to the controls (18.2 (9.8-25.7) ng/mL). In the whole study group overall, serum LCN2 was positively correlated with the Model Assessment of Insulin Resistance score ( r =0.339, p=0.046) and body mass index ( r =0.580, p<0.0001), and negatively correlated with adiponectin ( r =-0.462, p=0.005). A multiple stepwise regression model showed that serum adiponectin was an independent predictor of serum LCN2., Conclusions: The results of this study indicate that further investigations are warranted to determine whether LCN2 may act as a sensitive indicator of early-stage insulin resistance., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Rpn13 is one of several ubiquitin receptors in the 26S proteasome. Cys88 of Rpn13 has been proposed to be the principal target of RA190, an electrophilic small molecule with interesting anti-cancer activities. Here, we examine the claim that RA190 mediates its cytotoxic effects through engagement with Rpn13. We find no evidence that this is the case. In vitro, RA190 is has no measurable effect on any of the known interactions of Rpn13. In cellulo, we see no physical engagement of Rpn13 by RA190, either on C88 or any other residue. However, chemical proteomics experiments in two different cell lines reveal that dozens of other proteins are heavily engaged by RA190. Finally, increasing or reducing the level of Rpn13 in HeLa and melanoma cells had no effect on the sensitivity of HeLa or melanoma cells to RA190. We conclude that Rpn13 is not the physiologically relevant target of RA190., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Efficient synthesis of o-borylphenols is achieved through the Ru-catalyzed regio- and site-selective sp2 C-H borylation of aryl diphenylphosphinites followed by removal of the phosphorus directing group. A successful application to aryl phosphites enables practical one-pot borylation of phenols, demonstrating high synthetic utility of this protocol.

Recent development in catalytic application of transition metal complexes having an M-E bond (E = main group metal or metalloid element), which is stabilized by a multidentate ligand, is summarized. Main group metal and metalloid supporting ligands furnish unusual electronic and steric environments and molecular functions to transition metals, which are not easily available with standard organic supporting ligands such as phosphines and amines. These characteristics often realize remarkable catalytic activity, unique product selectivity, and new molecular transformations. This perspective demonstrates the promising utility of main group metal and metalloid compounds as a new class of supporting ligands for transition metal catalysts in synthetic chemistry., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

An unprecedented photo-promoted skeletal rearrangement reaction of phosphine-borane frustrated Lewis pairs, o-(borylaryl)phosphines, involving cleavage of an unstrained sp 2 C-sp 3 C σ-bond is reported. The reaction realizes an efficient synthesis of cyclic phosphonium borate compounds. The reaction mechanism via a boranorcaradiene intermediate is proposed based on theoretical calculations. This work sheds light on the new photoreactivity of phosphine-borane FLPs., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Rh-catalyzed direct carboxylation of alkenyl C-H bonds was achieved by using pyrazole as a removable directing group. In the presence of 5 mol% RhCl 3  ⋅ 3H 2 O, 6 mol% P(Mes) 3 , and 2 equiv. of AlMe 2 (OMe), the alkenyl C-H bond of various alkenylpyrazoles was directly carboxylated in good yields under CO 2 atmosphere. Furthermore, several useful transformations of the pyrazole moiety of the product were achieved to afford synthetically useful carboxylic acid derivatives in good yields., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: There is limited evidence about the ways in which poverty affects the health and educational environment of schoolchildren. We investigated the impact of family income on the lifestyle and physique of children in Japan., Methods: We mailed a questionnaire to 1,000 fifth-grade elementary school and 1,000 second-grade junior high school students and their parents in Higashi-Osaka City from August to September, 2017. Physique was evaluated based on standard body weight for height., Results: The questionnaire survey recovery rate was 31.3%. Overweight / obesity was confirmed in 8.1% of males and 3.7% of females. The prevalence of overweight / obesity was higher in children of families with incomes under the median than in families with incomes over the median only in females. The number of children with less than 1 h of studying time after school was significantly higher in children of families with incomes under the median, as well as in overweight / obese children. In children of families with incomes under the median, the rates of possessing books, exercise equipment, and their own room were lower than in children of families with incomes over the median, but there was no difference in the rates of possessing smartphones, or video games, based on income., Conclusions: Children of low-income families have an educational handicap, which is one of the risk factors for the "chain of poverty.", (© 2019 Japan Pediatric Society.)

Rhodium complexes with an indium metalloligand were successfully synthesized by utilizing a pyridine-tethered cyclopentadienyl ligand as a support for an In-Rh bond. The indium metalloligand dramatically changes the electronic and redox properties of the rhodium metal, thereby enabling catalysis of sp 2 C-H bond activation., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis and structural analyses of pincer-type iridium complexes having gallyl- and indyl-metalloligands were achieved utilizing 2,5-bis(6-phosphino-2-pyridyl)pyrrolide as a new scaffold for metal-metal bonds. A BH3-coordinated PInP-Ir dihydride complex was also developed as an equivalent to an iridium dihydride complex, which could be a useful catalyst for synthetic reactions.

Iridium complexes having a pincer-type gallylene ligand were successfully synthesized utilizing bis(phosphino)terpyridine as an efficient scaffold for the Ir-Ga I bond. The stabilization of the gallylene moiety by the pincer-type structure enabled various reactions at Ir with keeping the gallylene ligand intact, leading to unique structures and reactivities of PGa I P-Ir complexes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The improved catalytic conditions and detailed reaction mechanism of the visible-light driven hydrocarboxylation of alkenes with CO 2 by the Rh(I) and photoredox dual catalysts were investigated. The use of the benzimidazoline derivative, BI(OH)H, as a sacrificial electron donor was found to increase the yield of the hydrocarboxylated product by accelerating the reduction process. In addition, the incorporation of the cyclometalated Ir(III) complex as a second photosensitizer with [Ru(bpy) 3 ] 2+ photosensitizer also resulted in the promotion of the reduction process, supporting that the catalytic cycle includes two photochemical elementary processes: photoinduced electron and energy transfers.

Dimethyl fumarate (DMF) is a prescribed treatment for multiple sclerosis and has also been used to treat psoriasis. The electrophilicity of DMF suggests that its immunosuppressive activity is related to the covalent modification of cysteine residues in the human proteome. Nonetheless, our understanding of the proteins modified by DMF in human immune cells and the functional consequences of these reactions remains incomplete. In this study, we report that DMF inhibits human plasmacytoid dendritic cell function through a mechanism of action that is independent of the major electrophile sensor NRF2. Using chemical proteomics, we instead identify cysteine 13 of the innate immune kinase IRAK4 as a principal cellular target of DMF. We show that DMF blocks IRAK4-MyD88 interactions and IRAK4-mediated cytokine production in a cysteine 13-dependent manner. Our studies thus identify a proteomic hotspot for DMF action that constitutes a druggable protein-protein interface crucial for initiating innate immune responses., (Copyright © 2019 by The American Association of Immunologists, Inc.)