N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor.

α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABA) receptor-coupled Ca2.

Nonlinear dynamic separation characteristics of friction pair and experimental analysis.

This paper aims to reduce friction pair erosion of the clutch in the case of continuous shift; the dynamic separation process of the friction pair is investigated. The temperature of the friction pair, friction torque, and separation speed in the separation process are taken as the research objects, and the dynamics simulation model and finite element thermal coupling simulation model of the clutch separation process are established. The nonlinear dynamic separation characteristics of the friction pair are investigated by comparing and analyzing the effects of control parameters such as rotational speed difference, damping ratio, and lubricant viscosity on the friction torque, friction pair separation speed, separation gap, and contact stress during the separation process.

In vivo CRISPR/Cas9 screening identifies Pbrm1 as a regulator of myeloid leukemia development in mice.

CRISPR/Cas9 screening approaches are powerful tool for identifying in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which the sequential acquisition of somatic mutations generates clonal diversity. Over time, additional cooperating mutations may drive disease progression.

Aloe-emodin alleviates doxorubicin-induced cardiotoxicity via inhibition of ferroptosis.

Aloe-emodin (AE), a novel ferroptosis inhibitor, alleviates the doxorubicin (DOX)-induced cardiotoxicity in H9c2 rat cardiomyocytes. The inhibition of ferroptosis and the protective effect against cardiotoxicity were evaluated via MTT assay in H9c2 cells. The molecular mechanism of action (MOA) of nuclear factor erythroid 2-related factor 2 (Nrf2) activation, including transactivation of multiple downstream cytoprotective genes, were further assessed by Western blot, luciferase reporter assay and qRT-PCR analyses.

Synthesis and evaluation of Piperine analogs as thioredoxin reductase inhibitors to cause oxidative stress-induced cancer cell apoptosis.

Inhibiting thioredoxin reductase (TrxR) to disrupt the redox equilibrium and induce tumor cell apoptosis is a significant tumor therapeutic strategy. Piperine, a natural product from black pepper, has been demonstrated to suppress tumor cell proliferation by enhancing reactive oxygen species (ROS), subsequently leading to cell death. However, the development of Piperine as an active molecule is hampered by its weak cytotoxicity.

Design, syntheses and biological evaluation of natural product aiphanol derivatives and analogues: Discovery of potent anticancer agents.

The natural product aiphanol (1) is one of the substances with anticancer biological activity isolated from traditional Chinese medicines (TCM) Smilax glabra Roxb. (Tufuling). Our recent research found that aiphanol could suppress angiogenesis and tumor growth by dual-blocking VEGF/VEGFRs and COX2 signal pathway.

Thioredoxin Signaling Pathways in Cancer.

Thioredoxin (Trx) is a powerful antioxidant that reduces protein disulfides to maintain redox stability in cells and is involved in regulating multiple redox-dependent signaling pathways. The current accumulation of findings suggests that Trx participates in signaling pathways that interact with various proteins to manipulate their dynamic regulation of structure and function. These network pathways are critical for cancer pathogenesis and therapy.

Mapping the evolving landscape of super-enhancers during cell differentiation.

Background: Super-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in static cell types. How super-enhancers are established during cell differentiation remains obscure.

The 4-hook anchor coaxial needle with scaled suture is superior to the double spring coil for preoperative localization.

Background: Preoperative localization of small size pulmonary nodules is challenging, but it is necessary for surgical resection of early lung cancer. As a new device for preoperative localization, the 4-hook-anchor coaxial needle with scaled suture was tentatively applied in our department to improve the effect of preoperative localization. However, double spring coil, as a proven positioning technology, used to be our preferred method in the past.

Enhancer dependence of cell-type-specific gene expression increases with developmental age.

How overall principles of cell-type-specific gene regulation (the "logic") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy.

aYAP modRNA reduces cardiac inflammation and hypertrophy in a murine ischemia-reperfusion model.

Myocardial recovery from ischemia-reperfusion (IR) is shaped by the interaction of many signaling pathways and tissue repair processes, including the innate immune response. We and others previously showed that sustained expression of the transcriptional co-activator yes-associated protein (YAP) improves survival and myocardial outcome after myocardial infarction. Here, we asked whether transient YAP expression would improve myocardial outcome after IR injury.

Dissecting super-enhancer hierarchy based on chromatin interactions.

Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants.

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor.

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (- and -) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, , which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC = 0.035 μM against human URAT1 for vs.

Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity.

Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment.

Expression of Heat Shock Protein 27 in Benign Prostatic Hyperplasia with Chronic Inflammation.

Background: Heat shock protein 27 (HSP 27) is known as a mediator in immune response and has been recently found to be expressed in prostate cancer. This study aimed to investigate the role of HSP27 in inflammatory BPH.

Material And Methods: Hospitalized BPH patients who received TURP were divided into 4 groups by the presence and degrees of chronic inflammation: non-inflammatory BPH (NI BPH), mild-inflammatory BPH (MI BPH), moderate-inflammatory BPH (MOI BPH), and severe-inflammatory BPH (SI BPH).

ABL-N may induce apoptosis of human prostate cancer cells through suppression of KLF5, ICAM-1 and Stat5b, and upregulation of Bax/Bcl-2 ratio: An in vitro and in vivo study.

Identification of novel botanicals that can selectively induce apoptosis and arrest growth of cancer cells without producing cytotoxic effects is highly appreciable for cancer therapy. The present study aimed to investigate the possibility of acetylbritannilactone (ABL) derivative 5-(5-(ethylperoxy)pentan-2-yl)-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a‑hexahydroben-zofuran-4-yl2-(6-methoxynaphthalen-2-yl) propanoate (ABL-N) as a therapeutic agent in human prostate cancer and potential mechanisms. Human prostate cancer cells were treated with ABL-N of different concentrations (0, 5, 10, 20, 30 and 40 µmol/l).

Epicardial FSTL1 reconstitution regenerates the adult mammalian heart.

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression.

Developmental origin of age-related coronary artery disease.

Aim: Age and injury cause structural and functional changes in coronary artery smooth muscle cells (caSMCs) that influence the pathogenesis of coronary artery disease. Although paracrine signalling is widely believed to drive phenotypic changes in caSMCs, here we show that developmental origin within the fetal epicardium can have a profound effect as well.

Methods And Results: Fluorescent dye and transgene pulse-labelling techniques in mice revealed that the majority of caSMCs are derived from Wt1(+), Gata5-Cre(+) cells that migrate before E12.

Cholesterol-derived glucocorticoids control early fate specification in embryonic stem cells.

Aside from its role in cell membrane integrity, cholesterol is a key component in steroid hormone production. The vital functions of steroid hormones such as estrogen, testosterone, glucocorticoids (Gcrts) and mineralocorticoids (Mnrts) in perinatal and adult life are well understood; however, their role during early embryonic development remains largely unexplored. Here we show that siRNA-mediated perturbation of steroid hormone production during mesoderm formation has important consequences on cardiac differentiation in mouse embryonic stem cells (mESC).

Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history.

Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment.

A critical but molecularly uncharacterized step in heart formation and regeneration is the process that commits progenitor cells to differentiate into cardiomyocytes. Here, we show that the endoderm-derived dual Nodal/bone morphogenetic protein (BMP) antagonist Cerberus-1 (Cer1) in embryonic stem cell cultures orchestrates two signaling pathways that direct the SWI/SNF chromatin remodeling complex to cardiomyogenic loci in multipotent (KDR/Flk1+) progenitors, activating lineage-specific transcription. Transient inhibition of Nodal by Cer1 induces Brahma-associated factor 60c (Baf60c), one of three Baf60 variants (a, b, and c) that are mutually exclusively assembled into SWI/SNF.

Preparation of infertile male rabbits by local electron beam irradiation for intratesticular transplantation of autologous bone marrow stem cells.

Purpose: To explore an efficient and safe protocol for the preparation of infertile male rabbits from which bone marrow stem cells (BMSCs) could be isolated and cultured.

Methods: Autologous BMSCs could be used for intratesticular transplantation and male infertility research. For this model, various doses (e.

A Nodal-to-TGFβ cascade exerts biphasic control over cardiopoiesis.

Rationale: The transforming growth factor-β (TGFβ) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGFβ family proteins for myocardial remodeling and regeneration.

Objective: To determine the function(s) of TGFβ family members during stem cell cardiogenesis.

Methods And Results: Murine embryonic stem cells were engineered with a constitutively active human type I Nodal receptor (caACVR1b) to mimic activation by Nodal and found to secrete a paracrine signal that promotes cardiogenesis.