Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model.

The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRß, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRß-specific agonist. We aimed to examine whether OBG specifically affects LXRß in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (-) group, and (IV) OBG (+) group. All groups' rats were intraperitoneally administered L-NAME. The L-NAME/OBG group's rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) group's rats were administered OBG, while the OBG (-) group's rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRß-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.

Structure-Activity Relationship of Anti-malarial Allylpyrocatechol Isolated from Piper betle.

Malaria disease remains a serious worldwide health problem. In South-East Asia, one of the malaria infection "hot-spots," medicinal plants such as Piper betle have traditionally been used for the treatment of malaria, and allylpyrocatechol (1), a constituent of P. betle, has been shown to exhibit anti-malarial activities. In this study, we verified that 1 showed in vivo anti-malarial activity through not only intraperitoneal (i.p.) but also peroral (p.o.) administration. Additionally, some analogs of 1 were synthesized and the structure-activity relationship was analyzed to disclose the crucial sub-structures for the potent activity.

Synthesis of 5-Aryl-3(2 H)-furanones Using Intramolecular Cyclization of Sulfonium Salts.

Base-induced intramolecular cyclization of novel (4-aryl-2,4-dioxobutyl)methylphenylsulfonium salts prepared from the commercially available 1-arylethanone by a cost-effective process is described in this paper. The reaction was completed within 10 min to produce a family of 2-unsubstituted 5-aryl-3(2 H)-furanones in excellent yield. This procedure is simple, and can be carried out under mild conditions and an ambient atmosphere.

Inhibitor for FcεRI expression on mast cell from Verbasucum thapsus L.

We found out 2',3'-dihydroxypuberulin from South American medicinal plant, V. thapsus L., as a candidate of an anti-allergic lead which inhibits the expression of high-affinity receptor of IgE (FcεRI) on the surface of mast cells. Furthermore, the analysis of structure-activity relationship by using synthesized 2',3'-dihydroxypuberulin analogs revealed that both hydroxy groups in the side chain and both of methyl moieties on phenolic hydroxy groups were crucial for potent activity, but absolute configuration of C-3' position wasn't. The active principle, 2',3'-dihydroxypuberulin, was disclosed to down-regulate the mRNA level of ß-chain of FcεRI, different from previous reported active natural product reducing γ-chain level.

N-Alkylation Using Sodium Triacetoxyborohydride with Carboxylic Acids as Alkyl Sources.

A versatile N-alkylation was performed using sodium triacetoxyborohydride and carboxylic acid as an alkyl source. The combination of these reagents furnished products different from those given previously by a similar reaction. Moreover, the mild conditions of our method allowed some functional groups to remain through the reaction, whereas they would react and be converted into other moieties in the similar reductive N-alkylation reported previously. Herein, we provide a new procedure for the preparation of various compounds containing nitrogen atoms.

Synthesis of 4-Halo-3(2H)-furanones Using Intramolecular Cyclization of Sulfonium Salts.

A simple and efficient synthesis of 4-halo-3(2H)-furanones by halogenative intramolecular cyclization of sulfonium salts is described, which can expedite the production of a variety of 4-bromo- or 4-iodo-3(2H)-furanones, useful synthetic building blocks, in good to high yield under mild conditions.

Does Pelvic Sagittal Inclination in the Supine and Standing Positions Change Over 10 Years of Follow-Up After Total Hip Arthroplasty?

BACKGROUND: Functional anteversion and inclination of the cup change as the pelvic sagittal inclination (PSI) changes. The purposes of this study were to investigate the chronological changes of PSI during a 10-year follow-up period after total hip arthroplasty (THA) and to report the characteristics of patients who showed a greater than 10° change in the PSI from the supine to the standing position. METHODS: The subjects were 70 patients who were followed up for 10 years after THA. PSI values in the supine and standing positions were measured by 2D-3D matching using computed tomography images and pelvic radiographs. PSI values before THA and 1, 5, and 10 years after THA were compared in both the supine and standing positions. RESULTS: Supine PSI showed less than 5° of change, whereas standing PSI showed a significant decrease with time over the 10-year period. Although 43% of patients with less than 10° of difference in the PSI between the supine and standing positions before THA increased PSI posteriorly (reclining) more than 10° in standing from the supine position at 10 years, no late dislocation was observed. CONCLUSION: Supine PSI showed no significant change, but standing PSI showed a significant increase posteriorly with time over a 10-year period. However, this PSI change did not reach the level that it caused negative consequences such as late dislocation. The pelvic position in the supine position might still be a good functional reference position of the pelvis for aiming to achieve proper cup alignment at 10 years.

Functional importance of the sugar moiety of jasmonic acid glucoside for bioactivity and target affinity.

12-O-ß-D-Glucopyranosyljasmonic acid (JAG, 1) induces nyctinastic leaf-folding of Samanea saman. The SAR studies of 1 revealed the unique role of its glycone moiety. Biological activity and the target affinity of 1 were affected by the stereochemistry of the glycone moiety. JAG belongs to a unique class of ligands in which the structure of the glycone moiety is involved in the molecular recognition by the target protein.

[Duodenal gastrointestinal stromal tumor (GIST) with deletion in exon 11 of c-kit treated with emergency pancreaticoduodenectomy due to massive bleeding: a case report].

A Japanese woman in her 50s presented with coffee-ground vomiting at a local clinic and was referred to our hospital for further investigation. Esophagogastroduodenoscopy demonstrated a submucosal tumor in the descending part of the duodenum, and she was diagnosed with a gastrointestinal stromal tumor (GIST) by other imaging studies. Elective surgery of the tumor was initially planned. However, on the 13th day of hospitalization, emergency pancreaticoduodenectomy was performed because of massive hematemesis with hemorrhagic shock. Genetic analysis demonstrated a deletion in exon 11 of the c-kit gene, which could dramatically alter the clinical course. Although duodenal GIST with active bleeding is comparatively rare, we have to assume that it is the cause of gastrointestinal bleeding and treat such cases with a minimally invasive surgical procedure and neoadjuvant/adjuvant chemotherapy. It is necessary to accumulate more cases with duodenal GIST to establish an evidence-based therapeutic strategy.

Spinal factors influencing change in pelvic sagittal inclination from supine position to standing position in patients before total hip arthroplasty.

In some atypical patients, pelvic sagittal inclination (PSI) changes posteriorly by >10° from supine to standing position before total hip arthroplasty (THA). Several studies have suggested PSI in standing position is related to lumbar degeneration. The purpose of this study was to investigate spinal factors influencing changes in PSI from supine to standing position before THA. Participants comprised 163 consecutive patients who had undergone THA. Presence of compression fractures, presence of lumbar spondylolisthesis, thoracic kyphosis angle, lumbar lordosis angle, S1 anterior tilt angle and T4 plumb line position were investigated as spinal factors. Presence of compression fractures, age, presence of lumbar spondylolisthesis and small S1 anterior tilt angle were independently associated with posterior change in PSI from supine to standing position in patients before THA.

Proposal for structure revision of pinofuranoxin A through total syntheses of stereoisomers.

The relative configuration of the epoxide functionality in pinofuranoxin A (1), α-alkylidene-ß-hydroxy-γ-methyl-γ-butyrolactone with trans-epoxy side chain isolated by Evidente et al. in 2021, was revised by DFT-based spectral reinvestigations and stereo-controlled synthesis. The present investigation demonstrates the difficulty of the configurational elucidation of the stereogenic centers on the conformationally flexible acyclic side-chains. Sharpless's enantioselective epoxidations and dihydroxylations were quite effective in the reinvestigations of the configurations. As our syntheses made all diastereomers available, these would be quite effective in the next structure-biological activity relationship studies.

Triazoyl-phenyl linker system enhancing the aqueous solubility of a molecular probe and its efficiency in affinity labeling of a target protein for jasmonate glucoside.

In methods employing molecular probes to explore the targets of bioactive small molecules, long or rigid linker moieties are thought to be critical factors for efficient tagging of target protein. We previously reported the synthesis of a jasmonate glucoside probe with a highly rigid linker consisting of a triazoyl-phenyl (TAzP) moiety, and this probe demonstrated effective target tagging. Here we compare the TAzP probe with other rigid or flexible probes with respect to target tagging efficiency, hydrophobic parameters, aqueous solubility, and dihedral angles around the biaryl linkage by a combination of empirical and calculation methods. The rigid biaryl linkage of the TAzP probe has a skewed conformation that influences its aqueous solubility. Such features that include rigidness and good aqueous solubility resulted in highly efficient target tagging. These findings provide a promising guideline toward designing of better linkers for improving molecular probe performance.

Three-dimensional topographical variation of femoral cartilage T2 in healthy volunteer knees.

OBJECTIVE: Quantitative knee cartilage T2 assessment on limited two-dimensional midsagittal or midcoronal planes may be insufficient to assess variations in normal cartilage composition. The purpose of this work was to reveal characteristic 3D distribution of T2 values in femoral cartilage in healthy volunteer knees. MATERIALS AND METHODS: Sixteen volunteers were enrolled in this study. One knee joint in each volunteer was imaged using a 3D fast image employing steady-state acquisition cycled phases (FIESTA-C) sequence for modeling distal femoral morphology, as well as a sagittal T2 mapping of cartilage. 3D distribution of cartilage T2 values was generated for the femoral condyles. At each medial and lateral condyle, four regions of interest (ROI) were manually defined based on the cartilage covered by the 3D surface model of the medial and lateral menisci. RESULTS: The 3D maps showed a relatively inhomogeneous distribution of cartilage T2 on the medial and lateral condyles. Cartilage T2 values in the internal half of the weight-bearing zone were significantly higher than those in all other zones on both lateral and medial condyles. CONCLUSIONS: Analysis of 3D distribution of femoral cartilage T2 may be valuable in determining the site-specific normal range of cartilage T2 in the healthy knee joint.

Synthetic studies of cortistatin A analogue from the CD-ring fragment of vitamin D2.

Syntheses of analogue compounds of cortistatin A (1), an anti-angiogenic steroidal alkaloid from Indonesian marine sponge, were investigated by utilizing the CD-ring fragment of vitamin D2. The incidental preparation of a new analogue having CD-cis-fused skeleton and its biological evaluation revealed the importance of the CD-trans-fused structure for the potent and selective antiproliferative activity of 1 against human umbilical vein endothelial cells (HUVECs).

Hybrid stereoisomers of a compact molecular probe based on a jasmonic acid glucoside: syntheses and biological evaluations.

12-O-ß-D-glucopyranosyl jasmonic acid (JAG) shows unique biological activities, including leaf-closing of Samanea saman. It is expected that the mode of action for such regulation is distinct from that of other jasmonates. We developed high-performance compact molecular probes (CMPs) based on JAG that can be used for the FLAG-tagging of JAG target. We synthesized four hybrid-type JAG-CMP stereoisomers (7, ent-7, 8, and ent-8), which are composed of (-)-12-OH-JA (2)/D-galactopyranoside, (-)-2/L-galactopyranoside, (+)-ent-2/d-galactopyranoside, and (+)-ent-2/L-galactopyranoside moieties, respectively, and we examined their biological features, such as the stereospecific induction of shrinkage, rate of the cellular response, and dependence on potassium channel activity. These features of the JAG-CMPs were completely consistent with those of the original JAG. These results indicate the biological equivalence of JAG and the JAG-CMPs. During the course of such biological evaluations, it was revealed that the biological activity of the CMPs is greatly dependent on the d/l-stereochemistry of a glycon moiety. To the best of our knowledge, this is the first study suggesting that the d/l-stereochemistry of the glycon moiety significantly affects the biological activity of the associated glycoside.

Snapping Knee Syndrome of the Sartorius Accompanying Osteoarthritis Cured by Osteophyte Removal During Total Knee Arthroplasty.

Snapping knee syndrome on the medial side is rare. Here, we report the case of a patient with snapping knee syndrome of the sartorius with knee osteoarthritis. A large osteophyte at the posteromedial femoral condyle impinged on the sartorius myotendinous junction, causing painless snapping. The patient was successfully treated with osteophyte removal and total knee arthroplasty while preserving the tendon. Hence, tendon release or resection to treat snapping syndrome is not always necessary if the underlying cause can be eliminated. Furthermore, we found that while tendon tension is important for the occurrence of snapping syndrome, the impingement site determines the occurrence of snapping pain.

In vivo metal-catalyzed SeCT therapy by a proapoptotic peptide.

Selective cell tagging (SeCT) therapy is a strategy for labeling a targeted cell with certain chemical moieties via a catalytic chemical transformation in order to elicit a therapeutic effect. Herein, we report a cancer therapy based on targeted cell surface tagging with proapoptotic peptides (Ac-GGKLFG-X; X = reactive group) that induce apoptosis when attached to the cell surface. Using either Au-catalyzed amidation or Ru-catalyzed alkylation, these proapoptotic peptides showed excellent therapeutic effects both in vitro and in vivo. In particular, co-treatment with proapoptotic peptide and the carrier-Ru complex significantly and synergistically inhibited tumor growth and prolonged survival rate of tumor-bearing mice after only a single injection. This is the first report of Ru catalyst application in vivo, and this approach could be used in SeCT for cancer therapy.

Prenylcoumarin with Rev-export inhibitory activity from Cnidii Monnieris Fructus.

By use of the fission yeast expressing the model fusion protein comprised of GST, SV40 T antigen NLS, GFP, and Rev-NES in the bioassay, the prenylcoumarin osthol (1) was disclosed as the new Rev-export inhibitor from the MeOH extract of Cnidii Monnieris Fructus. Furthermore, 1 was also found to inhibit export the genuine Rev in HeLa cells by indirect fluorescent antibody technique. By the competitive experiment using the biotinylated probe 3, osthol (1) was revealed to inhibit nuclear export of Rev through a NES non-antagonistic mode. Structure-activity relationship analysis of several analogs of 1 clarified that both prenyl side chain and double bond adjacent to the lactone carbonyl residue play an important role in the Rev-export inhibitory potency of 1.