Development of a novel tocopheryl ester for suppression of lipid accumulation without cytotoxicity by optimization of dicarboxylic ester moiety

Tocopheryl succinate (Tsuc) is a succinic acid ester of the well-known antioxidant α-tocopherol (T). Tsuc exhibits various biological activities, including tumor growth suppression via activation of cell signaling and prevention of lipid accumulation in mouse adipocyte 3T3-L1 cells. The latter findings suggest that Tsuc may be a drug candidate for the treatment of obesity. However, Tsuc was found to induce apoptosis of normal cells (in addition to cancer cells), demonstrating the need to reduce the cytotoxicity of Tsuc without losing the suppression effect on lipid accumulation. Based on our previous findings, we focused on the ester structure of Tsuc for controlling cytotoxicity. Herein, we examined the cytotoxicity and lipid accumulation suppression effect of various T ester derivatives. We found that the terminal carboxylic group is necessary for suppression of lipid accumulation. We synthesized tocopheryl glutarate (Tglu) and tocopheryl adipate (Tadi) by elongation of carbon atoms 1 and 2 of the dicarboxylic moiety, respectively. Tglu and Tadi did not show any cytotoxicity, and both esters suppressed lipid accumulation, although their suppression activities were weaker than that of Tsuc. Tadi showed a more potent lipid accumulation inhibitory effect than Tglu. Although Tadi inhibited lipogenesis and promoted lipolysis, lipolysis was induced at lower concentrations than inhibition of lipogenesis, suggesting that Tadi mainly affects lipolysis. Taken together, we succeeded in the reduction of cytotoxicity, without loss of the suppression effect on lipid accumulation, by elongation of the dicarboxylic moiety of Tsuc. Tadi may be a promising candidate as an anti-obesity drug

Comparison of Internal Fixations for Distal Clavicular Fractures Based on Loading Tests and Finite Element Analyses

It is difficult to apply strong and stable internal fixation to a fracture of the distal end of the clavicle because it is unstable, the distal clavicle fragment is small, and the fractured region is near the acromioclavicular joint. In this study, to identify a superior internal fixation method for unstable distal clavicular fracture, we compared three types of internal fixation (tension band wiring, scorpion, and LCP clavicle hook plate). Firstly, loading tests were performed, in which fixations were evaluated using bending stiffness and torsional stiffness as indices, followed by finite element analysis to evaluate fixability using the stress and strain as indices. The bending and torsional stiffness were significantly higher in the artificial clavicles fixed with the two types of plate than in that fixed by tension band wiring (P<0.05). No marked stress concentration on the clavicle was noted in the scorpion because the arm plate did not interfere with the acromioclavicular joint, suggesting that favorable shoulder joint function can be achieved. The stability of fixation with the LCP clavicle hook plate and the scorpion was similar, and plate fixations were stronger than fixation by tension band wiring

Correlation between the Bone Mineral Density and Stress on Femur around a Duetto SI Stem

In cementless stem fixation, BMD reduction around the stem is of concern because it may cause loosening. This BMD reduction is assumed to be caused by stem implantation-induced alteration of the physiological feedback system, which may cause stress shielding and result in loosening, but the causal relationship has not been clarified. In this study, using a Duetto SI stem, we investigated the correlation between the postoperative BMD around the stem and stress. In patients who underwent their first THA at the orthopedic department of our university, the BMD was measured using DEXA, and FEA was performed with an equivalent time course. Time-course changes in the BMD, von Mises stress, and triaxial stress in Gruen zones 1 through 7 were calculated from those measured at 2 weeks and 5 months after surgery. The BMD and von Mises stress showed a bidirectional correlation when Gruen’s classification was plotted on the horizontal axis. An increase in stress loaded on bone was assumed to be a factor increasing the BMD. The Duetto SI stem was fixed on the distal side, suggesting its stable fixation. BMD measurement and FEA were useful for quantification of the bone dynamics around the stem from an early phase

Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness

Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs

Combination of genetic analysis and ancient literature survey reveals the divergence of traditional Brassica rapa varieties from Kyoto, Japan

京の伝統野菜ミブナの育種の歴史を解明. 京都大学プレスリリース. 2021-06-02.Since ancient times, humans have bred several plants that we rely on today. However, little is known about the divergence of most of these plants. In the present study, we investigated the divergence of Mibuna (Brassica rapa L. subsp. nipposinica L. H. Bailey), a traditional leafy vegetable in Kyoto (Japan), by combining genetic analysis and a survey of ancient literature. Mibuna is considered to have been bred 200 years ago from Mizuna, another traditional leafy vegetable in Kyoto. Mibuna has simple spatulate leaves, whereas Mizuna has characteristic serrated leaves. The quantitative trait loci (QTL) and gene expression analyses suggested that the downregulation of BrTCP15 expression contributed to the change in the leaf shape from serrated to simple spatulate. Interestingly, the SNP analysis indicated that the genomic region containing the BrTCP15 locus was transferred to Mibuna by introgression. Furthermore, we conducted a survey of ancient literature to reveal the divergence of Mibuna and found that hybridization between Mizuna and a simple-leaved turnip might have occurred in the past. Indeed, the genomic analysis of multiple turnip cultivars showed that one of the cultivars, Murasakihime, has almost the same sequence in the BrTCP15 region as Mibuna. These results suggest that the hybridization between Mizuna and turnip has resulted in the establishment of Mibuna

Analysis of CER in X-ALD

X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder associated with peroxisomal dysfunction. Patients with this rare disease accumulate very long-chain fatty acids (VLCFAs) in their bodies because of impairment of peroxisomal VLCFA β-oxidation. Several clinical types of X-ALD, ranging from mild (axonopathy in the spinal cord) to severe (cerebral demyelination), are known. However, the molecular basis for this phenotypic variability remains largely unknown. In this study, we determined plasma ceramide (CER) profile using liquid chromatography-tandem mass spectrometry. We characterized the molecular species profile of CER in the plasma of patients with mild (adrenomyeloneuropathy;AMN) and severe (cerebral) X-ALD. Eleven X-ALD patients (five cerebral, five AMN, and one carrier) and 10 healthy volunteers participated in this study. Elevation of C26:0 CER was found to be a common feature regardless of the clinical types. The level of C26:1 CER was significantly higher in AMN but not in cerebral type, than that in healthy controls. The C26:1 CER level in the cerebral type was significantly lower than that in the AMN type. These results suggest that a high level of C26:0 CER, along with a control level of C26:1 CER, is a characteristic feature of the cerebral type X-ALD

Mental Condition and Treatment of Patients after Disclosure of Cancer Diagnosis

In Japan, historically, doctors had refrained from disclosing a cancer diagnosis to patients, but attitudes regarding disclosure have recently been changing. We investigated the mental condition and treatment of patients after disclosure of cancer. Thirty-seven cancer patients (7 gastric cancer, 23 colorectal cancer, 5 breast cancer, 2 hepatocellular carcinoma) participated in this study. We divided the patients at Week 1 after disclosure of the diagnosis of cancer into two groups according to their score of Hospital Anxiety and Depression Scale (HADS): one group whose HADS was 8 points or more (Group A), and another group whose points were below 8 (Group B) at Week 1 after disclosure. There were 11 (29.7%) patients in Group A, and 26 (70.3%) in Group B. The average HADS differed between the two groups before disclosure, and at Weeks 1 to 5 after disclosure. Group A was treated with paroxetine hydrochloride hydrate (PAX) and about 70% of the patients showed an improvement of anxiety or depression by Week 5. While, there was 0% in HADS of 8 or more in breast cancer patients after disclosure. Some patients felt anxiety and depression unrelated to the stage of cancer. Furthermore, we noted that anxiety and depression were not detected after the cancer disclosure in any of the breast cancer patients, suggesting the possibility that anxiety and depression were alleviated by events such as surgery. It is necessary for medical treatment to advance to new steps in the treatment of cancer, providing enough support to the patients in the future

Natural ligand-nonmimetic inhibitors of the lipid-transfer protein CERT

Lipid transfer proteins mediate inter-organelle transport of membrane lipids at organelle contact sites in cells, playing fundamental roles in the lipidome and membrane biogenesis in eukaryotes. We previously developed a ceramide-mimetic compound as a potent inhibitor of the ceramide transport protein CERT. Here we develop CERT inhibitors with structures unrelated to ceramide. To this aim, we identify a seed compound with no ceramide-like structure but with the capability of forming a hydrogen-bonding network in the ceramide-binding START domain, by virtual screening of ~3 × 106 compounds. We also establish a surface plasmon resonance-based system to directly determine the affinity of compounds for the START domain. Then, we subject the seed compound to a series of in silico docking simulations, efficient chemical synthesis, affinity analysis, protein-ligand co-crystallography, and various in vivo assays. This strategy allows us to obtain ceramide-unrelated compounds that potently inhibited the function of CERT in human cultured cells

Association between preoperative toe perfusion index and maternal core temperature decrease during cesarean delivery under spinal anesthesia: a prospective cohort study

Background: The main mechanism of body temperature decrease during cesarean delivery under spinal anesthesia is core-to-peripheral redistribution of body heat, attributable to vasodilation. Perfusion index (PI) obtained with a pulse oximeter helps to assess peripheral perfusion dynamics by detecting the change in peripheral vascular tone. This study aimed to examine whether preoperative toe PI could predict the decrease in core temperature induced by spinal anesthesia during cesarean delivery.Methods: Parturients undergoing scheduled cesarean delivery under combined spinal-epidural anesthesia from September 2019 to March 2020 were enrolled in this single-center prospective cohort study. All parturients received 0.5% hyperbaric bupivacaine (10 mg) with fentanyl (15 μg) intrathecally. A pulse oximeter probe was placed on the left second toe for continuous PI measurement. The 3 M™ Bair Hugger™ Temperature Monitoring System placed over the right temporal region was used to record core temperature over time. We evaluated the association between the maximum core temperature decrease, which is the primary outcome, and the preoperative toe PI at operating room (OR) admission using a segmented regression model (SRM) and a generalized additive model (GAM). The maximum core temperature decrease was defined as the difference between core temperature at OR admission and minimum intraoperative core temperature.Results: Forty-eight patients were evaluated. In the SRM, the slope for the association between the maximum core temperature decrease and the preoperative toe PI changed from 0.031 to 0.124 after PI = 2.4%. Likewise, with the GAM, there was a small core temperature decrease when preoperative toe PI was greater than 2.0 to 3.0%.Conclusions: Low preoperative toe PI was associated with maternal core temperature decrease during cesarean delivery under spinal anesthesia. Preoperative toe PI is a simple, non-invasive, and effective tool for the early prediction of perioperative core temperature decrease during cesarean delivery.Trial registration: UMIN Clinical Trials Registry (registry number: UMIN000037965)