Contractility assessment using aligned human iPSC-derived cardiomyocytes.

Introduction: Cardiac safety assessment, such as lethal arrhythmias and contractility dysfunction, is critical during drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been shown to be useful in predicting drug-induced proarrhythmic risk through international validation studies. Although cardiac contractility is another key function, fit-for-purpose hiPSC-CMs in evaluating drug-induced contractile dysfunction remain poorly understood.

Oligoarginine-Conjugated Peptide Foldamers Inhibiting Vitamin D Receptor-Mediated Transcription.

The vitamin D receptor (VDR) is a nuclear receptor, which is involved in several physiological processes, including differentiation and bone homeostasis. The VDR is a promising target for the development of drugs against cancer and bone-related diseases. To date, several VDR antagonists, which bind to the ligand binding domain of the VDR and compete with the endogenous agonist 1α,25(OH)D, have been reported.

Effects of cigarette smoke extract derived from heated tobacco products on the proliferation of lung cancer stem cells.

Epidemiological studies have suggested that cigarette smoking can increase a person's risk of developing several types of cancer, including lung cancer. Lung cancer originates from cancer stem cells (CSCs), which constitute a minor cell population in tumors, and contribute to drug resistance and recurrence. Heated tobacco products (HTPs) produce aerosols that contain nicotine and toxic chemicals.

Can a Short-term Daily Oral Administration of Propolis Improve Muscle Fatigue and Recovery?

This study investigated the effect of 1-week oral administration of propolis on muscle fatigue and recovery after performing a fatigue task (total 100 maximal voluntary concentric knee extension repetitions). In this placebo-controlled, double-blind study, 18 young men consumed a formulation with high Brazilian green propolis dose (H-BGP), a formulation with low Brazilian green propolis dose, or a placebo, for 1 week before performing the fatigue task (an interval between each intervention: 1-2 weeks). Maximal voluntary contraction torque, central fatigue (voluntary activation and root mean square values of the surface electromyography amplitude), and peripheral fatigue (potentiated triplet torque) were assessed before, immediately after, and 2 minutes after the fatigue task.

Transforming Growth Factor Beta Promotes the Expansion of Cancer Stem Cells via S1PR3 by Ligand-Independent Notch Activation.

Growing evidence suggests that cancer originates from cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry. However, the regulation of CSC growth is not fully understood. In the present study, we investigated the effects of Transforming Growth Factor-β (TGFβ) in breast CSC expansion.

Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines.

Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists.

1α,25-Dihydroxyvitamin D [1α,25(OH)D, ] is an active form of vitamin D and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, ) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative () is a more potent agonist than 1α,25(OH)D, (), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of with amino acid residues in the VDR ligand-binding pocket.

Relationship Between Drop Jump Training-Induced Changes in Passive Plantar Flexor Stiffness and Explosive Performance.

Passive muscle stiffness is positively associated with explosive performance. Drop jump training may be a strategy to increase passive muscle stiffness in the lower limb muscles. Therefore, the purpose of this study was to examine the effect of 8-week drop jump training on the passive stiffness in the plantar flexor muscles and the association between training-induced changes in passive muscle stiffness and explosive performance.

FTY720 Inhibits Expansion of Breast Cancer Stem Cells via PP2A Activation.

Growing evidence suggests that breast cancer originates from a minor population of cancer cells termed cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry analysis. However, novel therapeutic drugs for the eradication of CSCs have not been discovered yet. Recently, drug repositioning, which finds new medical uses from existing drugs, has been expected to facilitate drug discovery.

Relationship between resting medial gastrocnemius stiffness and drop jump performance.

Although the influence of the series elastic element of the muscle-tendon unit on jump performance has been investigated, the corresponding effect of the parallel elastic element remains unclear. This study examined the relationship between the resting calf muscle stiffness and drop jump performance. Twenty-four healthy men participated in this study.

Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.

Lithocholic acid () was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to . Among the synthesized compounds, bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid () and 3 times more potent than 1α,25-dihydroxyvitamin D ().

Eight-Week Low-Intensity Squat Training at Slow Speed Simultaneously Improves Knee and Hip Flexion and Extension Strength.

Considering that the squat exercise requires flexion and extension of the knee and hip joints, a resistance training program based on squat exercises should efficiently increase the flexion and extension strength of both the knee and hip. To our knowledge, however, no study has simultaneously investigated the effects of squat training on both flexion and extension strength in both the knee and hip. Low-intensity squat exercises at slow speeds can be expected to effectively and safely improve knee and hip flexion and extension strength in a wide range of individuals.

Carbon dioxide hydrate as a recovery tool after fatigue of the plantar flexors.

This study investigated the effects of cooling the triceps surae with carbon dioxide hydrate (CDH), which is a gas hydrate, a crystalline structure belonging to the clathrates, on the recovery from muscle fatigue. Thirty-six healthy young men were equally and randomly assigned to an ICE group, a CDH group, or a non-cooling (NON) group. All participants performed 80 maximal voluntary isometric contractions (MVCs) of the plantar flexors as a fatiguing task.

Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones.

A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera.

Active recovery has a positive and acute effect on recovery from fatigue induced by repeated maximal voluntary contractions of the plantar flexors.

This study investigated the acute effect of active recovery (AR) following fatigue induced by 80 three-second maximal voluntary isometric plantar flexion contractions (MVICs) in 12 young men. AR consisted of a total of 180 voluntary isometric ramp contractions of the plantar flexors (0.75-s contraction/relaxation) targeting 10% of MVIC torque.

Structural Development of Cell-Penetrating Peptides Containing Cationic Proline Derivatives.

We designed and synthesized a series of cell-penetrating peptides containing cationic proline derivatives (Pro) that exhibited responsive changes in their secondary structures to the cellular environment. Effects of the peptide length and steric arrangement of the side chain in cationic proline derivatives [Pro and Pro] on their secondary structures and cell membrane permeability were investigated. Moreover, peptides 3 and 8 exhibited efficient intracellular delivery of plasmid DNA.

Tobacco nitrosamine NNK increases ALDH-positive cells via ROS-Wnt signaling pathway in A549 human lung cancer cells.

Epidemiological studies suggest that lung cancer, which is a major cause of cancer death, has a critical association with cigarette smoking. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoke is a major risk factor for carcinogenesis. However, the mechanisms by which NNK promotes cancer development have not been fully elucidated.

Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells.

Organotin compounds, such as tributyltin (TBT), are well-known endocrine disruptors. TBT is also known to cause various forms of cytotoxicity, including neurotoxicity and immunotoxicity. However, TBT toxicity has not been identified in normal stem cells.

Tributyltin induces G2/M cell cycle arrest via NAD(+)-dependent isocitrate dehydrogenase in human embryonic carcinoma cells.

Organotin compounds, such as tributyltin (TBT), are well-known endocrine-disrupting chemicals (EDCs). We have recently reported that TBT induces growth arrest in the human embryonic carcinoma cell line NT2/D1 at nanomolar levels by inhibiting NAD(+)-dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the irreversible conversion of isocitrate to α-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear.

Nicotine induces mitochondrial fission through mitofusin degradation in human multipotent embryonic carcinoma cells.

Nicotine is considered to contribute to the health risks associated with cigarette smoking. Nicotine exerts its cellular functions by acting on nicotinic acetylcholine receptors (nAChRs), and adversely affects normal embryonic development. However, nicotine toxicity has not been elucidated in human embryonic stage.

Fission Yeast Exo1 and Rqh1-Dna2 Redundantly Contribute to Resection of Uncapped Telomeres.

The uncapping of telomeres induces a DNA damage response. In Schizosaccharomyces pombe, deletion of pot1+ causes telomere uncapping and rapid telomere resection, resulting in chromosome fusion. Using the nmt-pot1-aid strain, we previously reported that Pot1 shut-off causes telomere loss and chromosome fusion in S.

Role and Function of LitR, an Adenosyl B12-Bound Light-Sensitive Regulator of Bacillus megaterium QM B1551, in Regulation of Carotenoid Production.

Unlabelled: The LitR/CarH family of proteins is a light-sensitive MerR family of transcriptional regulators that contain an adenosyl B12 (coenzyme B12 or AdoB12)-binding domain at the C terminus. The genes encoding these proteins are found in phylogenetically diverse bacterial genera; however, the biochemical properties of these proteins from Gram-positive bacteria remain poorly understood. We performed genetic and biochemical analyses of a homolog of the LitR protein from Bacillus megaterium QM B1551, a Gram-positive endospore-forming soil bacterium.

2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP.

Breast cancer is the most common malignancy among women and has poor survival and high recurrence rates for aggressive metastatic disease. Notably, triple-negative breast cancer (TNBC) is a highly aggressive cancer and there is no preferred agent for TNBC therapy. In this study, we show that a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), has ability to inhibit breast cancer cell growth and invasiveness in vitro and in vivo.

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation.

Many tumours originate from cancer stem cells (CSCs), which is a small population of cells that display stem cell properties. However, the molecular mechanisms that regulate CSC frequency remain poorly understood. Here, using microarray screening in aldehyde dehydrogenase (ALDH)-positive CSC model, we identify a fundamental role for a lipid mediator sphingosine-1-phosphate (S1P) in CSC expansion.

Ubiquitin ligase CHIP suppresses cancer stem cell properties in a population of breast cancer cells.

Cancer stem cells (CSCs) have several distinctive characteristics, including high metastatic potential, tumor-initiating potential, and properties that resemble normal stem cells such as self-renewal, differentiation, and drug efflux. Because of these characteristics, CSC is regarded to be responsible for cancer progression and patient prognosis. In our previous study, we showed that a ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein (CHIP) suppressed breast cancer malignancy.