Targeting NEK Kinases in Gastrointestinal Cancers: Insights into Gene Expression, Function, and Inhibitors.

Gastrointestinal (GI) cancers, which mainly include malignancies of the esophagus, stomach, intestine, pancreas, liver, gallbladder, and bile duct, pose a significant global health burden. Unfortunately, the prognosis for most GI cancers remains poor, particularly in advanced stages. Current treatment options, including targeted and immunotherapies, are less effective compared to those for other cancer types, highlighting an urgent need for novel molecular targets.

Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression.

Self-Guided Molecular Simulation to Enhance Concerted Motion.

Self-guided (SG) molecular simulation methods, namely self-guided molecular dynamics (SGMD) and self-guided Langevin dynamics (SGLD), enhance conformational search by promoting low-frequency motion. A simple local time averaging scheme is used to extract low-frequency properties with little overhead in computing costs. For molecular processes to form ordered structures like ligand binding and protein folding, it is believed that concerted motions play crucial roles.

Mitoregulin Promotes Cell Cycle Progression in Non-Small Cell Lung Cancer Cells.

Mitoregulin (MTLN) is a 56-amino-acid mitochondrial microprotein known to modulate mitochondrial energetics. MTLN gene expression is elevated broadly across most cancers and has been proposed as a prognostic biomarker for non-small cell lung cancer (NSCLC). In addition, lower MTLN expression in lung adenocarcinoma (LUAD) correlates with significantly improved patient survival.

Purinergic Receptor Activation Protects Glomerular Microvasculature from Increased Mechanical Stress in Angiotensin II-Induced Hypertension: A Modeling Study.

Angiotensin II (Ang II)-induced hypertension increases afferent (AA) and efferent (EA) arteriole resistances via the actions of Ang II on the AT1 receptor. In addition to the increased interstitial levels of Ang II, the increased arterial pressure increases interstitial ATP concentrations. In turn, ATP acts on the purinergic receptors P2X1 and P2X7 to constrict the AA, preventing increases in plasma flow and single-nephron GFR (SNGFR).

Tumor Regulatory Effect of 15-Hydroxyprostaglandin Dehydrogenase (HPGD) in Triple-Negative Breast Cancer.

Prostaglandin regulation is known to play a pivotal role in tumorigenesis; however, the contributions of the prostaglandin-metabolizing enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) to cancer development remain poorly understood. In this study, we investigate the effects of HPGD on cell viability, proliferation, anchorage-independent growth, and migration in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer. Overexpression of HPGD in human TNBC cells resulted in both positive and negative regulation of cell proliferation and colony formation, with these effects occurring independent of prostaglandin E2 (PGE).

A Two-Hour Fetal Glucagon Infusion Stimulates Hepatic Catabolism of Amino Acids in Fetal Sheep.

Postnatally, glucagon acutely lowers plasma amino acid (AA) concentrations by stimulating hepatic AA catabolism, but its fetal actions remain unclear. This study tested whether a 2 h fetal glucagon infusion would stimulate hepatic AA catabolism and inhibit placental AA transfer. Late-gestation pregnant sheep (0.

Sex-Specific Improvements in Myocardial Function and Angiogenesis with SGLT-2 Inhibitor Canagliflozin in a Swine Model of Metabolic Syndrome.

There is a significant body of literature to suggest that coronary artery disease (CAD) is a highly sex-specific disease. The study of sex-specific therapeutics and sex-specific responses to treatment for CAD remains underreported in the literature. Sodium-glucose transporter 2 (SGLT2) inhibitors are of growing interest in the treatment of ischemic heart disease and heart failure; however, the sex-specific response to SGLT2 inhibitors is unknown.

Increased Kindlin-2 via SMURF1 Inhibition Attenuates Endothelial Permeability and Acute Lung Injury.

Integrin β4 (ITGB4) mediates lung endothelial cell (EC) inflammation attenuated by simvastatin, an HMG CoA-reductase inhibitor. The cytoplasmic domain of ITGB4 is predicted to bind kindlin-2. Kindlin-2 expression is mediated by SMURF1, an E3 ubiquitin ligase that promotes kindlin-2 ubiquitination and degradation.

C/EBP Homologous Protein Expression in Retinal Ganglion Cells Induces Neurodegeneration in Mice.

The progressive loss of retinal ganglion cell (RGC) axons leading to irreversible loss of vision is the pathological hallmark of glaucoma. However, the pathological mechanisms of RGC degeneration are not completely understood. Here, we investigated the role of chronic endoplasmic reticulum (ER) stress in glaucomatous neurodegeneration.

Retina-Targeted 17β-Estradiol by the DHED Prodrug Rescues Visual Function and Actuates Neuroprotective Protein Networks After Optic Nerve Crush in a Rat Model of Surgical Menopause.

The association between 17β-estradiol (E2) deprivation, seen in menopause, and a risk for developing glaucoma has been shown. Thus, exogenous supplementation of E2 may protect against retinal ganglion cell (RGC) degradation and vision loss. Here, we investigated the utility of topical 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a prodrug of E2 that selectively produces the neuroprotective hormone in the retina, on visual function after optic nerve crush (ONC) and ovariectomy (OVX).

Noninvasive Detection of Oxidative Stress in a Mouse Model of 4R Tauopathy via Positron Emission Tomography with [F]ROStrace.

Oxidative stress, defined as the excessive production of reactive oxygen species (ROS), is a crucial factor in the pathogenesis of various neurodegenerative diseases, including the 4-repeat (4R) tauopathies. Collectively, the 4R tauopathies are characterized by the progressive aggregation of tau protein isoforms with four microtubule-binding domains in and around brain cells. The cyclical relationship between oxidative stress and 4R tau aggregation suggests that a means of imaging ROS noninvasively could be a valuable tool for the study and treatment of 4R tauopathy in both humans and animal models.

Alpha4 Na,K-ATPase Localization and Expression Are Dynamic Aspects of Spermatogenesis and in Sperm Incubated Under Capacitating Conditions.

Utilizing high-resolution microscopy in conjunction with a new antibody highly specific for rat alpha4 Na,K-ATPase, we describe changes in alpha4 expression during spermatogenesis and in sperm incubated under capacitating and noncapacitating conditions. Immunohistochemical analyses showed alpha4 expression at low levels in spermatogonia and in pachytene spermatocytes. Alpha4 then becomes highly expressed on round spermatids and the midpiece of elongated spermatozoa within the seminiferous tubules.

Expression Results in Secretion-Mediated, SOX9-Dependent Suppression of Adipogenesis: Implications for the Regulatory Role of Newly Identified CTHRC1/PDGFR-Alpha Stromal Cells of Adipose.

Adipogenesis is regulated by the coordinated activity of adipogenic transcription factors including PPAR-gamma and C/EBP alpha, while dysregulated adipogenesis can predispose adipose tissues to adipocyte hypertrophy and hyperplasia. We have previously reported that -null mice have increased adiposity compared to wildtype mice, supporting the notion that CTHRC1 regulates body composition. Herein, we derived conditioned medium from 3T3-L1 cells expressing human and investigated its anti-adipogenic activity.

Sub-Immunosuppressive Tacrolimus Ameliorates Amyloid-Beta and Tau Pathology in 3xTg-AD Mice.

Tacrolimus (TAC) has emerged as a potential therapy for Alzheimer's disease (AD), with the challenge of balancing its therapeutic benefits against its immunosuppressive effects. This study explores the efficacy of a sub-immunosuppressive TAC dosing regimen to ameliorate AD-related pathologies. TAC was administered daily for 14 days, with drug concentrations measured via liquid chromatography tandem mass spectrometry (LC-MS/MS) in whole blood and hippocampal tissue from C57BL6J mice, while immunofluorescence analyses and Western blotting (performed on hippocampal extracts) were conducted in 10-12 month old 3xTg-AD mice to evaluate levels of tau and amyloid-beta (Aβ) proteins.

Polysaccharides with Arabinose: Key Players in Reducing Chronic Inflammation and Enhancing Immune Health in Aging.

Aging is associated with a decline in physiological performance leading to increased inflammation and impaired immune function. Polysaccharides (PLs) found in plants, fruits, and fungi are emerging as potential targets for therapeutic intervention, but little is known about their effects on chronic inflammation and aging. This review aims to highlight the current advances related to the use of PLs, with the presence of arabinose, to attenuate oxidative stress and chronic and acute inflammation, and their immunomodulatory effects associated with antioxidant status in monocytes, macrophages, and neutrophil infiltration, and leukocyte rolling adhesion in neutrophils.

The Ligand Binding Domain of the Cell Wall Protein SraP Modulates Macrophage Apoptosis and Inflammatory Responses in Infections.

The cell wall protein serine rich adhesin for platelets (SraP) belongs to a large surface glycoprotein family of adhesins. Here, we provide experimental evidence that SraP mediates macrophage functions in a human monocyte-derived macrophage model via its N-terminal L-lectin module (LLM) in the ligand binding region. Our flow cytometry data demonstrated that macrophages infected by the LLM deletion strain profoundly impacted apoptosis, reducing the percentage of apoptotic cells by approximately 50%, whereas LLM overexpression significantly increased the percentage of early-stage apoptotic cells ( < 0.

Development and Validation of Two Cell-Based Reporter-Gene Assays for Determining the Bioactivity of Recombinant Human Thyroid-Stimulating Hormone Pharmaceutical Products.

To develop a cell-based in vitro thyroid-stimulating hormone (TSH) biological activity assay that can simulate in vivo pharmacodynamic mechanisms, we constructed two HEK293-TSHR cell lines based on two main cell signaling pathways (Gαs-cAMP-PKA and Gαq/11-PLC-Ca) that TSH depends on for its in vivo physiological function. These cell lines stably expressed the luciferase reporter driven by the cAMP response element (CRE) and nuclear factor of activated T cells (NFAT) response element, and two reporter-gene assays (RGAs) were correspondingly established and validated. The two transgenic genes could measure signals produced from the simulation of the in vivo effects of TSH from the Gαs-cAMP and Gαq/11-PLC pathways after TSH activation.

Towards Imaging Tau Hyperphosphorylation: Is DYRK1A a Potential Target for Imaging Hyperphosphorylation of Tau? Molecular Modeling Assessment and Synthesis of [I]Radioiodinated DYRK1A Inhibitor.

Dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), a phosphorylation kinase, is localized within the central nervous system and is linked to hyperphosphorylation of Tau. Imaging of DYRK1A may provide an earlier biomarker for Tauopathies, including Alzheimer's disease (AD). We have used Chimera-Autodock to evaluate potential molecules for binding to the binding site of DYRK1A.

Morphological and Genetic Assessments of Coyote Diet in Qualla Boundary, North Carolina, Show Interaction with Humans.

Throughout the 20th century, coyotes () expanded from their historical geographic range west of the Mississippi River to a current range of almost all of North America. Over the course of this expansion, coyotes have demonstrated diverse and variable omnivorous diets that change with the food resources available. This study examined the stomach contents of 25 coyotes in an area where they are relatively new, the Qualla Boundary in North Carolina, to better understand the diets of coyotes in this area.

Granulocyte-Macrophage Colony Stimulating Factor Receptor Contributes to Plexiform Neurofibroma Initiation.

Plexiform neurofibroma (PNF) is an immune cell-rich peripheral nerve sheath tumor that develops primarily in individuals with Neurofibromatosis Type 1 (NF1). Granulocyte-macrophage colony stimulating factor receptor-β (GM-CSFR-β) is a shared component of receptors for the cytokines GM-CSF, IL-3, and IL-5, ligands with immunomodulatory and tumor promoting roles. In the present study, we use genetically engineered mouse model of neurofibroma.

Metabolomic Profiling of Disease Progression Following Radiotherapy for Breast Cancer.

Background: This study aims to explore metabolic biomarkers and pathways in breast cancer prognosis.

Methods: We performed a global post-radiotherapy (RT) urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) patients as the reference and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). UPLC-MS/MS (Metabolon Inc.

ECM Stiffness-Induced Redox Signaling Enhances Stearoyl Gemcitabine Efficacy in Pancreatic Cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to its dense fibrotic stroma that promotes drug resistance and tumor progression. While patient-derived organoids (PDOs) have emerged as promising tools for modeling PDAC and evaluating therapeutic responses, the current PDO models grown in soft matrices fail to replicate the tumor's stiff extracellular matrix (ECM), limiting their predictive value for advanced disease.

Methods: We developed a biomimetic model using gelatin-based matrices of varying stiffness, achieved through modulated transglutaminase crosslinking rates, to better simulate the desmoplastic PDAC microenvironment.

Biosocial Determinants of Health Among Patients with Chronic Liver Disease and Liver Cancer.

Background: Metabolic disorders and chronic liver disease (CLD) play crucial roles in the development and progression of liver cancer (LC). Since the ethnic minority population increasingly suffers from CLD and LC, it is vital to understand the biosocial factors contributing to CLD and LC. The 'All of Us' database, with significant participation from minority populations, provides a valuable tool for studies in different racial/ethnic groups.