L-aspartate ameliorates diet-induced obesity by increasing adipocyte energy expenditure.

Aims: Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment.

Design and Synthesis of Bouchardatine Derivatives as a Novel AMP-Activated Protein Kinase Activator for the Treatment of Colorectal Cancer.

Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, , modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC).

Design, Synthesis, and Evaluation of New Sugar-Substituted Imidazole Derivatives as Selective Transcription Repressors Targeting the Promoter G-Quadruplex.

is a key driver of tumorigenesis. Repressing the transcription of by stabilizing the G-quadruplex (G4) structure with small molecules is a potential strategy for cancer therapy. Herein, we designed and synthesized 49 new derivatives by introducing carbohydrates to our previously developed G4 ligand .

Discovery of a Novel G-Quadruplex and Histone Deacetylase (HDAC) Dual-Targeting Agent for the Treatment of Triple-Negative Breast Cancer.

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (). Among the new compounds, with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and in TNBC cells.

Discovery, enantioselective synthesis of myrtucommulone E analogues as tyrosyl-DNA phosphodiesterase 2 inhibitors and their biological activities.

As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2) can specifically repair topoisomerase 2 (TOP2)-mediated DNA damage, resulting in cancer cell resistance to TOP2 inhibitors. Its inhibitors can enhance the anticancer efficacy of TOP2 inhibitors. In this work, we report the discovery of natural product myrtucommulone E as selective TDP2 inhibitor and its first enantioselective total synthesis through a pivotal CPA-catalyzed Michael addition reaction.

A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation.

Background And Purpose: Non-alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH.

Experimental Approach: The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin-immunoprecipitation sequencing.

Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors.

DNA damage response (DDR) pathways are crucial for the survival of cancer cells and are attractive targets for cancer therapy. Bloom syndrome protein (BLM) is a DNA helicase that performs important roles in DDR pathways. Our previous study discovered an effective new BLM inhibitor with a quinazolinone scaffold by a screening assay.

Discovery of a promising agent IQZ23 for the treatment of obesity and related metabolic disorders.

Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel β-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies.

Magnetic Resonance Imaging of Stroke in the Rat.

Magnetic resonance imaging (MRI) is now a routine neuroimaging tool in the clinic. Throughout all phases of stroke from acute to chronic, MRI plays an important role to diagnose, evaluate and monitor the cerebral tissue undergoing stroke. This review provides a description of various MRI methods and an overview of selected MRI studies, with an embolic stroke model of rat, performed in the MRI laboratory of Department of Neurology, Henry Ford Hospital, Detroit, Michigan, US.

MRI detects brain reorganization after human umbilical tissue-derived cells (hUTC) treatment of stroke in rat.

Human umbilical tissue-derived cells (hUTC) represent an attractive cell source and a potential technology for neurorestoration and improvement of functional outcomes following stroke. Male Wistar rats were subjected to a transient middle cerebral artery occlusion (tMCAo) and were intravenously administered hUTC (N = 11) or vehicle (N = 10) 48 hrs after stroke. White matter and vascular reorganization was monitored over a 12-week period using MRI and histopathology.

MRI measurement of angiogenesis and the therapeutic effect of acute marrow stromal cell administration on traumatic brain injury.

Using magnetic resonance imaging (MRI), the present study was undertaken to investigate the therapeutic effect of acute administration of human bone marrow stromal cells (hMSCs) on traumatic brain injury (TBI) and to measure the temporal profile of angiogenesis after the injury with or without cell intervention. Male Wistar rats (300 to 350 g, n=18) subjected to controlled cortical impact TBI were intravenously injected with 1 mL of saline (n=9) or hMSCs in suspension (n=9, 3 × 10(6) hMSCs) 6 hours after TBI. In-vivo MRI acquisitions of T2-weighted imaging, cerebral blood flow (CBF), three-dimensional (3D) gradient echo imaging, and blood-to-brain transfer constant (Ki) of contrast agent were performed on all animals 2 days after injury and weekly for 6 weeks.

Transplantation of marrow stromal cells restores cerebral blood flow and reduces cerebral atrophy in rats with traumatic brain injury: in vivo MRI study.

Cell therapy promotes brain remodeling and improves functional recovery after various central nervous system disorders, including traumatic brain injury (TBI). We tested the hypothesis that treatment of TBI with intravenous administration of human marrow stromal cells (hMSCs) provides therapeutic benefit in modifying hemodynamic and structural abnormalities, which are detectable by in vivo MRI. hMSCs were labeled with superparamagnetic iron oxide (SPIO) nanoparticles.

Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI.

Using MRI, we investigated dynamic changes of brain angiogenesis after neural progenitor cell transplantation in the living adult rat subjected to embolic stroke. Neural progenitor cells isolated from the subventricular zone (SVZ) of the adult rat were labeled by superparamagnetic particles and intracisternally transplanted into the adult rat 48 h after stroke (n = 8). Before and after the transplantation, an array of MRI parameters were measured, including high resolution 3D MRI and quantitative T1, T1sat (T1 in the presence of an off-resonance irradiation of the macromolecules of brain), T2, the inverse of the apparent forward transfer rate for magnetization transfer (kinv), cerebral blood flow (CBF), cerebral blood volume (CBV), and blood-to-brain transfer constant (Ki) of Gd-DTPA.

Quantitative evaluation of BBB permeability after embolic stroke in rat using MRI.

We sought to identify magnetic resonance imaging (MRI) parameters that can identify as well as predict disruption of the blood-brain barrier (BBB) after embolic stroke in the rat. Rats subjected to embolic stroke with (n=13) and without (n=13) rt-PA treatment were followed with MRI using quantitative permeability-related parameters, consisting of: transfer constant (K(i)) of Gd- DTPA, the distribution volume (V(p)) of the mobile protons, and the inverse of the apparent forward transfer rate for magnetization transfer (k(inv)), as well as the apparent diffusion coefficient of water (ADC(w)), T2, and cerebral cerebral blood flow (CBF). Tissue progressing to fibrin leakage resulting from BBB disruption and adjacent tissue were then analyzed to identify MRI markers that characterize BBB disruption.

MRI evaluation of treatment of embolic stroke in rat with intra-arterial and intravenous rt-PA.

Using magnetic resonance imaging (MRI), we investigated treatment of a rat model of embolic stroke with rt-PA via intra-arterial (IA) and intravenous (IV) routes of administration. Rats were treated with rt-PA by either IA (n = 13) or IV (n = 13) routes at 3 h after stroke induction. Diffusion, perfusion, T2, and magnetization transfer MRI were performed prior to and at 1-3 and at 24 h after embolization.

Magnetic resonance imaging characterization of hemorrhagic transformation of embolic stroke in the rat.

Intracranial hemorrhage is a critical factor when considering efficacy and safety of thrombolytic intervention after thromboembolic stroke. This study tested whether magnetic resonance imaging could identify tissue for hemorrhagic transformation after the onset of embolic stroke. Rats subjected to embolic stroke with and without recombinant tissue-type plasmogen activator (rt-PA) treatment were followed-up with magnetic resonance imaging using the inverse of the apparent forward transfer rate for magnetization transfer (k(inv)), gadolinium-chelate contrast-enhanced magnetic resonance imaging, and diffusion-, perfusion-, and T2-weighted imaging.