Enantioselective Construction of Tetrahydroindole Skeletons by Rh-Catalyzed [2+2+2] Cycloaddition of Homopropargyl Enamides with Alkynes.

We have developed the Rh-catalyzed enantioselective [2+2+2] cycloaddition of homopropargyl enamides (tosylamide-tethered 1,6-enynes) with alkynes to construct tetrahydroindole skeletons found in natural alkaloids and pharmaceuticals. This cycloaddition proceeds at room temperature in high yields and regio- and enantioselectivity with a broad substrate scope. The preparative scale reaction followed by substituent conversion on the nitrogen atom and the diastereoselective [4+2] cycloaddition with singlet O affords hexahydroindole-diols bearing three stereogenic centers and variable substituents on the nitrogen.

Pharmacological HIF-1 activation upregulates extracellular vesicle production synergistically with adiponectin through transcriptional induction and protein stabilization of T-cadherin.

Pharmacological activation of hypoxia-inducible factor 1 (HIF-1), a hypoxia-responsive transcription factor, has attracted increasing attention due to its efficacy not only in renal anemia but also in various disease models. Our study demonstrated that a HIF-1 activator enhanced extracellular vesicle (EV) production from cultured endothelial cells synergistically with adiponectin, an adipocyte-derived factor, through both transcriptional induction and posttranscriptional stabilization of an adiponectin binding partner, T-cadherin. Increased EV levels were observed in wild-type mice but not in T-cadherin null mice after consecutive administration of roxadustat.

ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.

Exosomes, extracellular vesicles (EVs) produced within cells, mediate both the disposal of intracellular waste and communication with distant cells, and they are involved in a variety of disease processes. Although disease modifications of exosome cargos have been well studied, it has been poorly investigated how disease processes, such as endoplasmic reticulum (ER) stress, affect EV production. We previously reported that adiponectin, an adipocyte-secreted salutary factor, increases systemic exosome levels through T-cadherin-mediated enhancement of exosome biogenesis.

Chronic hyperadiponectinemia induced by transgenic overexpression increases plasma exosomes without significantly improving glucose and lipid metabolism.

The fat-derived factor, adiponectin, is considered a salutary circulating factor. We recently demonstrated that native adiponectin binds T-cadherin and promotes intracellular biogenesis and secretion of the exosome. Exosomes play important roles in various aspects of homeostasis, including glucose and energy metabolism.

Rhodium-Catalyzed Chemo-, Regio-, Diastereo-, and Enantioselective Intermolecular [2+2+2] Cycloaddition of Three Unsymmetric 2π Components.

We have developed the Rh /H -binap-catalyzed chemo-, regio-, diastereo-, and enantioselective intermolecular [2+2+2] cycloaddition of three unsymmetric 2π components. Thus, two arylacetylenes react with a cis-enamide to yield a protected chiral cyclohexadienylamine. Moreover, replacing one arylacetylene with a silylacetylene enables the [2+2+2] cycloaddition of three distinct unsymmetric 2π components.

Coexistence of Renin-independent Aldosterone Secretion and Multiple Endocrine Neoplasia Type 1 Within a Family.

Primary aldosteronism (PA) is a state of renin-independent aldosterone secretion that can range from subclinical to overt. Some normotensive individuals for whom PA screening is not routinely recommended are reported to fulfill the loading test criterion used for the diagnosis of PA. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the development of various endocrine tumors.

Case of slowly progressive type 1 diabetes mellitus with drastically reduced insulin secretory capacity after immune checkpoint inhibitor treatment for advanced renal cell carcinoma.

We encountered a 55-year-old Japanese man with advanced renal cell carcinoma and slowly progressive type 1 diabetes mellitus (SPT1DM), whose insulin secretory capacity was drastically reduced for a brief period after only one cycle of immune checkpoint inhibitor (ICI) treatment. The patient had been diagnosed with type 2 diabetes at the age of 53 years and was treated using oral hypoglycemic agents. However, 2 years later, he was diagnosed with SPT1DM and autoimmune thyroiditis, based on the presence of anti-glutamic acid decarboxylase antibodies (GADA) and thyroid autoantibodies, which was accompanied by advanced renal cell carcinoma.

Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.

Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency.

Synthetic Methodologies for Perfluoroaryl-Substituted (Diaryl)methylphosphonates, -Phosphinates via SAr Reaction.

The new synthetic methodologies for perfluoroaryl-substituted (diaryl)methylphosphonates, -phosphinates via nucleophilic aromatic substitution (SAr) were developed. Benzylphosphonate and α-fluorobenzylphosphonate reacted with a wide variety of perfluoroarenes via SAr reaction. The reaction took place quickly and gave perfluoroarylated phosphonates in high yields.

Design of Phosphinic Acid Catalysts with the Closest Stereogenicity at the α-Position: Synthesis and Application of α-Stereogenic Perfluoroalkyl Phosphinic Acid Catalysts.

Chiral C-symmetric phosphinic acids were designed based on sterically demanding and helical chiral perfluoroalkyl groups at the closest α-position advancing asymmetric reaction environment and catalytic activity. The perfluoroalkyl catalysts, [(CF)F] and [(CF)F] phosphinic acids, were synthesized via a stereoselective addition/cyclization sequence of methyl phosphinate and deoxofluorination. These new classes of Brønsted acid catalysts were applied to an asymmetric Friedel-Crafts reaction to give up to 89% yield and 82% R-enantioselectivity, which is higher than those obtained with the parent phosphoric acid (42% and 55.

Direct conjugate addition of alkynes with α,β-unsaturated carbonyl compounds catalyzed by NCN-pincer Ru complexes.

NCN-pincer Ru-complexes containing bis(oxazolinyl)phenyl ligands serve as suitable catalysts in the direct conjugate additions of α,β-unsaturated carbonyl compounds, including ketones, esters, and amides, as well as vinylphosphonates, giving various β-alkynyl carbonyl and phosphonate compounds. A bis(oxazolinyl)phenyl (phebox)-Ru complex also catalyzes the asymmetric conjugate addition of an alkyne with a β-substituted, α,β-unsaturated ketone to produce a chiral β-alkynyl ketone.