Novel mono substituted pyridoimidazoisoquinoliniums via a silver-catalyzed intramolecular cyclization and their applications in cellular imaging.

Cationic heterocycles, an important class of organic compounds soluble in polar solvents, have been gaining attention in the construction of fluorescent probes. This paper reports the quick synthesis of novel pyrido[1',2';2,3]imidazo[5,1-a]isoquinoliniums starting from 2-(2-ethynylphenyl)imidazo[1,2-a]pyridines at room temperature via intramolecular cyclization by employing a catalytic amount of silver trifluoromethanesulfonate in addition to lithium trifluoromethanesulfonate and silica gel as the counter anion source and additive, respectively. The designed pyridoimidazoisoquinoliniums consisted of an imidazo[1,2-a]pyridine fused isoquinolinium. The X-ray diffraction results revealed that pyrido[1',2';2,3]imidazo[5,1-a]isoquinolinium trifluoromethanesulfonate contained considerable planar parent skeletons and interacted by π-π stacking with neighbouring molecules. Furthermore, in a methanol solution the designed 6-phenyl derivative exhibited strong fluorescence in the 420-450 nm region in addition to strong mitochondrial specificity in a cell staining assay.

Large-scale preparation of yeast strains expressing condensates derived from a glycolytic enzyme via controlled dissolved oxygen levels under hypoxia.

Under hypoxia, Saccharomyces cerevisiae forms cytoplasmic condensates composed of proteins, including glycolytic enzymes, that are thought to regulate cellular metabolism. However, the hypoxic conditions required for condensate formation remain unclear. In this study, we developed a 300-mL-scale culture method to produce condensate-forming cells by precisely controlling the dissolved oxygen (DO) level in the media. Using enolase as a model, a foci formation rate of more than 50% was achieved at ∼0.1% DO, and the results showed that the DO level affected the foci formation rate. The foci formation rates of the previously reported foci-deficient strains and strains with single amino acid substitutions in the endogenous enolase were examined, and the effect of these amino acid substitutions on glucose consumption and ethanol and glycerol production under hypoxia was evaluated. The results of this study contribute to the investigation of the mechanisms that regulate biomacromolecular condensates under hypoxia.

Renal Dysfunction after Rectal Cancer Surgery: A Long-term Observational Study.

Objectives: Despite the high incidence of urinary dysfunction (UD) after rectal surgery, it remains questionable whether UD causes future chronic kidney disease (CKD). This study aimed to clarify the long-term trends in renal function and risk factors for future CKD after rectal resection. Methods: For comparison, patients who underwent rectal resection (n = 129) and colectomy (n = 127) between 2006 and 2017 were identified. The estimated glomerular filtration rate (eGFR) ratio was calculated as the ratio to the baseline. "eGFR ratio < 0.75 at 3-year" was adopted as a surrogate indicator of future CKD. Results: eGFR ratio significantly decreased in the rectal cohort compared with the colon cohort at 1.5 years (0.9 vs. 0.95, p = 0.008) and at 3 years (0.85 vs. 0.94, p < 0.001). Although the preoperative prevalence of CKD was lower in the rectal than the colon cohort (13.9% vs. 23.6%, p = 0.055), it was similar at 3 years (29.5% vs. 30.7%). In multivariate analysis, females, and cT4 were independent risk factors for future CKD, but UD itself was not. Conclusions: Postoperative eGFR significantly decreased after rectal cancer surgery compared to colectomy. The prevalence of CKD more than doubled at 3 years after rectal resection. The female sex and cT4 tumor, instead of the UD, were independent risk factors for future CKD.

N-of-1 Trial of Electrical Sensory Stimulation Therapy on the Tibial Innervated Area during Gait in a Case of Post-stroke Sensory Disturbance.

Background: Transcutaneous electrical sensory nerve stimulation (TESS) is used to enhance the recovery of sensorimotor function in post-stroke hemiparesis. However, TESS efficacy for post-stroke gait disturbance remains unknown. We hypothesized that TESS on the area innervated by the tibial nerve, targeting the superficial plantar sensation, combined with gait training would improve gait function in patients with gait disturbance caused by severe superficial sensory disturbance after stroke. Case: A 42-year-old man was referred to the convalescent rehabilitation hospital 4 months after a left pontine hemorrhage. He showed severe superficial sensory disturbance without motor paresis in the right lower leg and planta pedis. Gait training with TESS on the tibial nerve innervated area was performed, targeting plantar sensation according to an N-of-1 study design of a single-case ABCAB that included two 10-min sessions of gait training without TESS (phase A), two gait training sessions with TESS targeting the right plantar sensation (phase B), and one session with TESS targeting the upper leg sensation as control (phase C). The patient showed increased gait distance and stride length, improved superficial sensation on the right planta pedis, and improved balance after phase B, but not after phases A and C. Discussion: Gait training with TESS on the tibial nerve innervated area improved gait ability, superficial plantar sensation on the targeted side, and balance function in a post-stroke patient with sensory disturbance. Gait training with TESS may be effective for gait dysfunction caused by sensory disturbance in patients with central nervous system disorders.

Molecular Beacon Imaging System to Discriminate the Differentiation State of Cells from Energy Metabolic Pathways.

Metabolic pathways of energy production play an essential role as a function of cells. It is well recognized that the differentiation state of stem cells is highly associated with their metabolic profile. Therefore, visualization of the energy metabolic pathway makes it possible to discriminate the differentiation state of cells and predict the cell potential for reprogramming and differentiation. However, at present, it is technically difficult to directly assess the metabolic profile of individual living cells. In this study, we developed an imaging system of cationized gelatin nanospheres (cGNS) incorporating molecular beacons (MB) (cGNSMB) to detect intracellular pyruvate dehydrogenase kinase 1 (PDK1) and peroxisome proliferator-activated receptor γ, coactivator-1α (PGC-1α) mRNA of key regulators in the energy metabolism. The prepared cGNSMB was readily internalized into mouse embryonic stem cells, while their pluripotency was maintained. The high level of glycolysis in the undifferentiated state, the increased oxidative phosphorylation over the spontaneous early differentiation, and the lineage-specific neural differentiation were visualized based on the MB fluorescence. The fluorescence intensity corresponded well to the change of extracellular acidification rate and the oxygen consumption rate of representative metabolic indicators. These findings indicate that the cGNSMB imaging system is a promising tool to visually discriminate the differentiation state of cells from energy metabolic pathways.

Neck Hair-Thread Tourniquet Syndrome by Co-sleeping With Family: A Case Report and Literature Review.

Neck hair-thread tourniquet syndrome (NHTTS) is a rare condition that can be a pediatric emergency, occurring when a hair or thread becomes tightly wrapped around a body part, leading to vascular or tissue damage. NHTTS commonly affects infants and young children and can result in severe complications if not promptly diagnosed and treated. The unusual nature of this event, the diffuse petechial hemorrhage on the face, and the presentation of ligature marks extending around the neck led us to admit the child to the general pediatric ward for follow-up and further investigation of the possibility of non-accidental trauma. Co-sleeping is a common cultural practice in Japan where parents sleep in close proximity to their infants. This case report aims to raise awareness among pediatricians and parents about the possibility of NHTTS occurring in infants who co-sleep, particularly when a strand of hair becomes entangled around their neck, about the early detection and appropriate management of NHTTS. And we also summarize the reported NHTTS cases.

Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding.

G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP), and cholecystokinin (CCK). Although GPR120 signaling in adipose tissue and macrophages has been reported to ameliorate obesity and insulin resistance in a high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in the intestine, we generated intestine-specific GPR120-knockout (GPR120int-/-) mice. In comparison with floxed GPR120 (WT) mice, GPR120int-/- mice exhibited reduced GIP secretion and CCK action without change of insulin, GLP-1, or peptide YY (PYY) secretion after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed a mild reduction of body weight and substantial amelioration of insulin resistance and fatty liver. Moreover, liver and white adipose tissue (WAT) of GPR120int-/-mice exhibited increased Akt phosphorylation and reduced gene expression of suppressor of cytokine signaling (SOCS) 3, which inhibits insulin signaling. In addition, gene expression of inflammatory cytokines in WAT and lipogenic molecules in liver were reduced in GPR120int-/- mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding.NEW & NOTEWORTHY We generated novel intestine-specific GPR120-knockout (GPR120int-/-) mice and investigated the metabolic effect of GPR120 in the intestine. GPR120int-/- mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed mild improvement in obesity and marked amelioration of insulin resistance and hepatic steatosis. Our results indicate an important role of intestinal GPR120 on insulin resistance and hepatic steatosis.

Foci-forming regions of pyruvate kinase and enolase at the molecular surface incorporate proteins into yeast cytoplasmic metabolic enzymes transiently assembling (META) bodies.

Spatial reorganization of metabolic enzymes to form the "metabolic enzymes transiently assembling (META) body" is increasingly recognized as a mechanism contributing to regulation of cellular metabolism in response to environmental changes. A number of META body-forming enzymes, including enolase (Eno2p) and phosphofructokinase, have been shown to contain condensate-forming regions. However, whether all META body-forming enzymes have condensate-forming regions or whether enzymes have multiple condensate-forming regions remains unknown. The condensate-forming regions of META body-forming enzymes have potential utility in the creation of artificial intracellular enzyme assemblies. In the present study, the whole sequence of yeast pyruvate kinase (Cdc19p) was searched for condensate-forming regions. Four peptide fragments comprising 27-42 amino acids were found to form condensates. Together with the fragment previously identified from Eno2p, these peptide regions were collectively termed "META body-forming sequences (METAfos)." METAfos-tagged yeast alcohol dehydrogenase (Adh1p) was found to co-localize with META bodies formed by endogenous Cdc19p under hypoxic conditions. The effect of Adh1p co-localization with META bodies on cell metabolism was further evaluated. Expression of Adh1p fused with a METAfos-tag increased production of ethanol compared to acetic acid, indicating that spatial reorganization of metabolic enzymes affects cell metabolism. These results contribute to understanding of the mechanisms and biological roles of META body formation.

Impact of combined resection of the internal iliac artery on loss of volume of the gluteus muscles after pelvic exenteration.

PURPOSE: To clarify the influence of additional internal iliac artery (IIA) resection on the loss of the gluteus muscle volume after pelvic exenteration (PE). METHODS: The subjects of this retrospective analysis were 78 patients who underwent PE with or without IIA resection (n = 44 and n = 34, respectively) between 2006 and 2018. The areas of gluteal muscles (GMs) and psoas muscles (PSMs) were calculated using CT images before and 6 months after PE, and the difference was compared. RESULTS: The volumes of the GMs and PSMs were significantly reduced after PE (P < 0.001 and P = 0.005, respectively). In the IIA resection group, the GMs were significantly reduced after surgery, but the PSMs were not. The maximum GM (Gmax) was the most atrophied among the GMs. Multivariable analysis revealed that complete IIA resection was an independent promotor of the loss of volume of the Gmax (P = 0.044). In 18 patients with unilateral IIA resection, the downsizing rate of the Gmax was significantly greater on the resected side than on the non-resected side (P = 0.008). CONCLUSIONS: The GMs and PSMs were significantly smaller after PE. Complete IIA resection reduced the Gmax area remarkably. Preservation of the superior gluteus artery is likely to help maintain Gmax size, suggesting a potential preventative measure against secondary sarcopenia.

Current status of transanal total mesorectal excision for rectal cancer and the expanding indications of the transanal approach for extended pelvic surgeries.

Transanal total mesorectal excision (taTME) has been rapidly accepted as a promising surgical approach to the distal rectum. The benefits include ease of access to the bottom of the deep pelvis linearly over a short distance in order to easily visualize the important anatomy. Furthermore, the distal resection margins can be secured under direct vision. Additionally, a two-team approach combining taTME with a transabdominal approach could decrease the operative time and conversion rate. Although taTME was expected to become more rapidly popularized worldwide, enthusiasm for it has stalled due to unfamiliar intraoperative complications, a lack of oncologic evidence from randomized trials, and the widespread use of robotic surgery. While international registries have reported favorable short- and medium-term outcomes from taTME, a Norwegian national study reported a high local recurrence rate of 9.5%. The characteristics of the recurrences included rapid, multifocal growth in the pelvis, which was quite different from recurrences following traditional transabdominal TME; thus, the Norwegian Colorectal Cancer Group reached a consensus for a temporary moratorium on the performance of taTME. To ensure acceptable baseline quality and patient safety, taTME should be performed by well-trained colorectal surgeons. Although the appropriate indications for taTME remain controversial, the transanal approach is extremely important as a means of goal setting in difficult TME cases and as an aid to the transabdominal approach in various types of extended pelvic surgeries. The benefits in transanal lateral lymph node dissection and pelvic exenteration are presented herein.

Triphenylbismuth dichloride inhibits human glyoxalase I and induces cytotoxicity in cultured cancer cell lines.

Organobismuth compounds, i.e., organic-inorganic hybrid molecules composed of an organic structure and bismuth metal, have been reported to induce cytotoxicity in cancer cells; however, the target proteins associated with this cytotoxicity have not been elucidated. Herein, we investigated the inhibitory effect of five organobismuth compounds on human glyoxalase I (hGLO I), a promising target candidate for cancer therapy. Among these compounds, triphenylbismuth dichloride (Bi-05) exerted a strong inhibitory effect on hGLO I. Indeed, Bi-05 inhibited hGLO I in a dose-dependent manner with an IC50 value of 0.18 µM. Bi-05 also induced cytotoxicity in human leukemia HL-60 cells and human lung cancer NCI-H522 cells, both of which exhibit high expression levels of GLO I. However, the hGLO I-inhibiting and cytotoxic effects of Bi-05 disappeared when the bismuth atom was replaced with an antimony or phosphorus atom. Bismuth(III) nitrate had little inhibitory effect on hGLO I activity and only slightly reduced the viability of cancer cells. In the culture medium of Bi-05-treated HL-60 cells, the concentration of the GLO I substrate methylglyoxal was markedly elevated. In addition, Bi-05 treatment more strongly inhibited human lung cancer NCI-H522 cell (exhibiting high GLO I expression) proliferation than human lung cancer NCI-H460 cell (exhibiting low GLO I expression) proliferation. Furthermore, the cytotoxicity of Bi-05 was significantly decreased by pre- and co-treatment with the methylglyoxal scavengers N-acetyl-L-cysteine and aminoguanidine. Overall, these results suggest that Bi-05 treatment leads to the accumulation of methylglyoxal via GLO I inhibition, resulting in cytotoxic effects in cancer cells.

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides.

The development of novel and efficient synthesis methods for 2-substituted benzazole derivatives is of interest as they are biologically active substances. Herein, a simple method for the synthesis of 2-aryl- and 2-alkyl-substituted benzazoles is described. The reaction of 2-aminophenols with thioamides at 60 °C in the presence of triphenylbismuth dichloride in 1,2-dichloroethane as a promoter afforded various 2-aryl- and 2-alkylbenzoxazoles in moderate to excellent yields under mild reaction conditions. This method could also be applied to the synthesis of benzimidazoles and benzothiazoles. This study presents the first use of triphenylbismuth dichloride to produce benzimidoyl chloride from thioamides by desulfurization and chlorination, as well as its application to the synthesis of 2-substituted benzazoles.