Obesity is a global medical issue that can be effectively treated by relieving adipose inflammation and subsequent insulin resistance. Diosgenin (DIOS) has various effects as a steroidal saponin in inflammatory disorders. This study explored the effects and mechanism of DIOS on adipose inflammation and insulin sensitivity, both in silico and in vivo. The high-fat diet-induced obesity model in C57BL/6 mice was divided into five groups: normal chow (NC), high-fat diet (HFD), HFD with atorvastatin 10 mg/kg (AT), HFD with DIOS 100 mg/kg (DIOS 100), and HFD with DIOS 200 mg/kg (DIOS 200). Each group underwent an oral intervention for seven weeks. DIOS significantly suppressed weight gain in the body, liver, and epididymal fat pads. Additionally, it significantly improved fasting glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR), and oral glucose tolerance test results, and reduced the proportion of total and M1 adipose tissue macrophages. Significant changes were shown in mRNA expression of janus kinase 2 (JAK2), insulin receptor (INRS), insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt), all of which exhibited high binding affinity in the in silico. Safety indices, including aspartate aminotransferase (AST), alanine transaminase (ALT), and creatinine level indicated the preventive effects of DIOS. In conclusion, DIOS improves insulin resistance and obesity-associated inflammation via the PI3K/Akt signaling pathway.

Cell-penetrating peptides, such as arginine-rich peptides, encapsulate nucleic acid drugs and deliver them to intracellular compartments. Comprehensive tracking of drug delivery systems (DDSs) provides information about the behavior of the drug as well as the fate of the drug carrier after drug release, which is crucial for minimizing side effects. In this study, we labeled peptides designed to carry plasmid DNA with two types of dyes, traditional dye fluorescein and aggregation-induced emission (AIE) dye tetraphenylethylene, and subsequently tracked the DDS through the complementary ON and OFF fluorescence behaviors of the dyes. Traditional fluorescent dyes are susceptible to aggregation-caused quenching during bioimaging, a problem that is mitigated by using AIE dyes. However, by using both of these contrasting fluorescent labels, we were able to clearly visualize the DDS at different stages of its deployment, from drug transport and delivery to carrier dissociation and migration, demonstrating the feasibility of accurate DDS visualization by complementary fluorescence labeling.

Osteoporosis is induced by an imbalance between osteogenesis and bone resorption, and is treated with osteogenic drugs and/or resorption inhibitors. Resorption inhibitors, such as bisphosphonates, are orally used; however, orally active small molecules with osteogenic activity are not clinically available. We synthesized various types of small molecules and identified a series of diphenylamine and diphenylether derivatives that promoted osteoblast differentiation. Among them, diphenylether derivatives 13a, 13g, and 13h potently promoted osteoblast differentiation (EC₂₀₀ for increasing alkaline phosphatase activity = 11.3, 31.1, and 12.3 nM, respectively) and inhibited cyclin-dependent kinase 8 (CDK8) activity (IC₅₀ = 2.5, 7.8, and 3.9 nM, respectively), suggesting that their osteoblastgenic effects are mediated by the inhibition of CDK8. The ratio of the maximal plasma concentration after oral administration at 10 mg/kg in female rats and EC₂₀₀ for osteoblastogenesis was 148.1 for compound 13a, 53.4 for 13g, and 101.8 for 13h, indicating possible in vivo osteoblastogenic and osteogenic effects. In ovariectomized female rats, 13g and 13h at 10 mg/kg/d for 8 weeks increased plasma bone-type alkaline phosphatase activity, indicating enhanced in vivo osteoblastogenesis. Furthermore, micro-computed tomography (micro-CT) showed that both compounds increased femoral cortical bone volume and mineral contents, which were unaffected by ovariectomy, while having negligible effects on trabecular bone volume and mineral contents, which were markedly reduced by ovariectomy. In conclusion, diphenylamine and diphenylether structures are novel scaffolds for osteoblastogenesis enhancers via the inhibition of CDK8. Among them, 13g and 13h are candidates for anti-osteoporotic drugs with cortical bone-selective osteogenic effects.

As an easy-to-handle reagent for the in situ generation of outstandingly electrophilic Tf₂C=CH₂ (Tf=CF₃SO₂), we have designed and synthesised a novel 4-substituted 2-fluoropyridinium zwitterion, in which a partially fluorinated alkyl group is attached to the pyridinium 4-position. Its zwitterionic nature has been well characterised by quantum chemical bonding analysis. By using this reagent, a wide variety of organic compounds, including commercial bioactive agents, were successfully decorated by the strongly acidic or ionic functionality. Remarkably, the 4-substituted 2-fluoropyridine derivative, which results from the zwitterion with the generation of Tf₂C=CH₂, can be rapidly separated and recovered from the reaction mixture appropriately using distillation, organic solvent extraction, or fluorous solid phase extraction techniques. Such multi-optionality for the purification methods favours in the isolation of the strongly acidic and/or ionic products.

We studied the reaction pathway of our reductive Heck hydroarylation using a palladium catalyst and a hydrosilane. A key question to verify the reaction mechanism was which active species, Ar-Pd^II-I or Si-Pd^II-H, first performs migratory insertion into the alkenes. Identifying this step is crucial to elucidate the reaction mechanism. To address this, we designed a substrate containing two trisubstituted alkenes and tested its product. The results suggest that the migratory insertion of Ar-Pd^II-I into the alkene is the initial step of the reaction. Furthermore, this reaction can construct a quaternary carbon center and give high yields with high functional group tolerance.

N-[(4R)-5,7-Difluoro-2′-(5-methylpyridin-2-yl)-4′-oxo-2,2′,3,4′,5′,7′-hexahydrospiro[1-benzopyran-4,6′-pyrazolo[4,3-c]pyridin]-3′-yl]-2-(methanesulfonyl)acetamide (S-309309) is an anti-obesity drug developed by Shionogi & Co., Ltd. that has a monoacylglycerol acyltransferase 2 inhibitory effect. S-309309 has poor wettability, and the amount of the degradation product (4R)-3′-amino-5,7-difluoro-2′-(5-methylpyridin-2-yl)-2,2′,3,7′-tetrahydrospiro[[1]benzopyran-4,6′-pyrazolo[4,3-c]pyridin]-4′(5′H)-one (compound 8) increases over time under acidic conditions. In this study, we have tried to improve S-309309 wettability and suppress the amount of degradation product increased under acidic conditions. As a result of the study, we found that by mixing with a water-soluble polymer, the wettability of S-309309 and its dissolved concentration in fluid were increased suggesting that its dissolution behavior should be enhanced. In addition, by encapsulating S-309309, the increase of degradation product amount was suppressed under acidic conditions, suggesting that the suppression of degradation product formation would be expected in the stomach after oral dosing. Overall, these results suggest that the drug property issues of S-309309 can be overcome by mixing S-309309 with a water-soluble polymer and encapsulation.

25-Hydroxyvitamin D₃-23,26-lactone (1) and 1α,25-dihydroxyvitamin D₃-23,26-lactone (2) have long been considered as among the end metabolites of vitamin D₃. Recently, however, we found that these lactones exhibit biological activity related to the β-oxidation of fatty acids. We hypothesized that a metabolic pathway might exist to inactivate their physiological activity. Here, by means of metabolic experiments with a variety of cytochrome P450 (CYP) enzymes, we show that CYP3A4 metabolizes the lactones. The metabolites were presumed to be hydroxylated at C4 based on the previous reports showing that metabolism of 25-hydroxyvitamin D₃ by CYP3A4 along with the current LC-MS analysis. To confirm this, we chemically synthesized 4α,25(OH)₂D₃-23,26-lactone (3), 4β,25(OH)₂D₃-23,26-lactone (4), 1α,4α,25(OH)₃D₃-23,26-lactone (5), and 1α,4β,25(OH)₃D₃-23,26-lactone (6). HPLC analysis using these authentic compounds as standards revealed that 1 was metabolized to 3 and 4, while 2 was metabolized exclusively to 6 by CYP3A4. Docking studies suggest that the hydroxyl group at C1 in 2 forms hydrogen bonds with Ser119 and Arg212 of CYP3A4, contributing to the fixation of C4β on heme iron in the CYP, thereby resulting in stereoselective hydroxylation at C4.

We have developed a method for the site-selective hydrogenation of unactivated alkenes using 8-aminoquinoline amide as the directing group. For unactivated alkenes with two C–C double bonds, Daugulis’s 8-aminoquinoline amide facilitated the site-selective hydrogenation of the desired C–C double bond, producing a product in which one C–C double bond was reduced. Site-selective reduction methodologies using intramolecular directing groups are expected to contribute significantly to the synthesis of molecules with multiple reducible functional groups in the future.

Naturally occurring Cinchona alkaloids such as quinidine (QD)/cinchonine (CN) and their diastereomers, quinine (QN)/cinchonidine (CD), have been recognized as pseudo-enantiomeric pairs. Utilizing these pseudo-enantiomeric alkaloids as chiral resources provides complementary enantioselectivity in many asymmetric reactions. During the screening of Cinchona alkaloid phase-transfer catalysts (PTCs) in the hydrolytic dynamic kinetic resolution of racemic 3-phenyl-2-oxetanone (1) to tropic acid (2), we found that the introduction of a 4-trifluoromethylphenyl group at the vinyl terminus of BnQN significantly reduced the enantioselectivity to 41% enantiomeric excess (ee). The optimized structure of tetrahedral intermediates (TI, PTC + 1 + OH⁻) of hydrolysis obtained by density functional theory (DFT) calculations shows that the orientation of the quinoline and benzene rings of QD class PTC are nearly parallel to each other and to construct a greatly extended π-electron cloud surface, allowing good π–π interaction with the benzene ring of 1.

The MeOH extract from dried immature fruits of Euonymus sieboldianus (Celastraceae) plants yielded nineteen new β-dihydroagarofuran-type sesquiterpene polyesters. The structures of these compounds were established using NMR, MS spectroscopic analysis and chemical evidence.

Acute kidney injury (AKI) is a commonly encountered critical condition in clinical settings, often resulting from sepsis, infections or ischemia. Astragaloside IV (AS-IV) is the primary active component of Astragalus. The functions of Astragalus are mainly related to AS-IV, showing remarkable therapeutic effects in anti-inflammatory, antioxidant, immune-enhancing, and anti-tumor aspects. This study aimed to explore the role of AS-IV in AKI development. Lipopolysaccharide (LPS) was used to stimulate the HK-2 cells and rats to establish the AKI model in vivo and in vitro. After AS-IV treatment, the cell viability, pyroptosis rate, lactate dehydrogenase (LDH) activity, interleukin (IL)-18 and IL-1β contents, and cleaved-caspase-1, GSDMD-N, SIRT, FOXO3a protein levels were detected. Caspase-1 levels were analyzed by immunofluorescence staining. Additionallly, the acetylation levels of FOXO3a were detected by immunoprecipitation and Western blot assays. AS-IV treatment promoted the cell viability, and inhibited the pyroptosis, LDH activity, caspase-1 levels in the LPS stimulated HK-2 cells. AS-IV treatment decreased the IL-18 and IL-1β contents, cleaved-caspase-1 and GSDMD-N protein levels in both LPS stimulated HK-2 cells and rats. Furthermore, after EX527 treatment, a Sirtuin 1 (SIRT1) inhibitor, the role of AS-IV in the LPS stimulated HK-2 cells were reversed. AS-IV treatment increased the protein levels and decreased the acetylation levels of FOXO3a, which was reversed after EX527 treatment. Co-immunoprecipitation (CO-IP) assay and immunofluorescence staining confirmed that SIRT1 interacted with FOXO3a. In conclusion, this research demonstrated that AS-IV treatment inhibited the pyroptosis occurrence in LPS stimulated HK-2 cells and rats. This may be related to the SIRT1 mediated deacetylation of FOXO3a.

Phosphorus binders are often used in combination to produce synergistic effects. However, the synergistic effect may be affected by the change in pH or concomitant drugs. Nonetheless, the data on the adsorption capacities of these binders when used in combination with other binders are limited. In this study, we evaluated the adsorption capacity of phosphorus binders when used in combination. Precipitated calcium carbonate (CC), ferric citrate hydrate (FC), lanthanum carbonate hydrate (LC), and sucroferric oxyhydroxide (SO) were used as phosphorus binders. SO showed high adsorption capacity in the 1st and 2nd fluid, and the adsorption capacity of SO in combination with other binders was stable. In contrast, the adsorption capacities of CC + FC and FC + LC decreased in the 1st and 2nd fluid compared with that when used alone because of the release of citrate ions that chelate calcium or lanthanum ions. These results suggest that SO is less affected by interactions with other phosphorus binders and changes in pH and may be suitable for patients receiving concomitant drugs.