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Iron Overload Mediates the Differential Cell Fate of Astrocytes from Neurons and Its Regulatory Mechanisms in Ischemic Stroke.

Iron accumulation and ferroptosis occur in the brain following ischemic stroke. However, the relationship between iron overload and cell type-specific fates remains largely unclear. Here, iron deposition and neuronal loss are reported within the perilesional cortex of three patients with ischemic stroke at both acute and subacute stages. It is identified that ischemia/reperfusion-induced iron overload triggers ferroptosis predominantly in neurons and to a lesser extent in astrocytes, whereas most astrocytes undergo reactive proliferation. Mechanistically, the reduced or elevated Nrf2/GPX4 and

A divergent Pseudomonas aeruginosa palmitoyltransferase essential for cystic fibrosis-specific lipid A.

Strains of Pseudomonas aeruginosa (PA) isolated from the airways of cystic fibrosis patients constitutively add palmitate to lipid A, the membrane anchor of lipopolysaccharide. The PhoPQ regulated enzyme PagP is responsible for the transfer of palmitate from outer membrane phospholipids to lipid A. This enzyme had previously been identified in many pathogenic Gram-negative bacteria, but in PA had remained elusive, despite abundant evidence that its lipid A contains palmitate. Using a combined genetic and biochemical approach, we identified PA1343 as the PA gene encoding PagP. Although PA1343 l

Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription.

The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By explor

The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics.

OBJECTIVE: Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ). APPROACH AND RESULTS: Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenerg

Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway.

Apolipoprotein E (apoE) is the major cholesterol transport protein in the brain. Among the three human APOE alleles (APOE2, APOE3, and APOE4), APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease (AD). The accumulation of amyloid-β (Aβ) is a central event in AD pathogenesis. Increasing evidence demonstrates that apoE isoforms differentially regulate AD-related pathways through both Aβ-dependent and -independent mechanisms; therefore, modulating apoE secretion, lipidation, and function might be an attractive approach for AD therapy. We performed a drug screen for compound

S-palmitoylation and s-oleoylation of rabbit and pig sarcolipin.

Sarcolipin (SLN) is a regulatory peptide present in sarcoplasmic reticulum (SR) from skeletal muscle of animals. We find that native rabbit SLN is modified by a fatty acid anchor on Cys-9 with a palmitic acid in about 60% and, surprisingly, an oleic acid in the remaining 40%. SLN used for co-crystallization with SERCA1a (Winther, A. M., Bublitz, M., Karlsen, J. L., Moller, J. V., Hansen, J. B., Nissen, P., and Buch-Pedersen, M. J. (2013) Nature 495, 265-2691; Ref. 1) is also palmitoylated/oleoylated, but is not visible in crystal structures, probably due to disorder. Treatment with 1 m hydroxy

Identification of a novel cuproptosis-related gene signature for multiple myeloma diagnosis.

BackgroundMultiple myeloma (MM) ranks second among the most prevalent hematological malignancies. Recent studies have unearthed the promise of cuproptosis as a novel therapeutic intervention for cancer. However, no research has unveiled the particular roles of cuproptosis-related genes (CRGs) in the prediction of MM diagnosis.MethodsMicroarray data and clinical characteristics of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed gene analysis, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature e

Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11DS) is associated with learning and cognitive dysfunctions and a high risk of developing schizophrenia. It has become increasingly clear that dendritic spine plasticity is tightly linked to cognition. Thus, understanding how genes involved in cognitive disorders affect synaptic networks is a major challenge of modern biology. Several studies have pointed to a spine density deficit in 22q11DS transgenic mice models. Using the LgDel mouse model, we first quantified spine deficit at different stages using electron microscopy. Next we performed repetitive confocal i

Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).

Cisplatin resistance remains a primary obstacle in oncology, leading to therapeutic failure and disease recurrence. While resistance mechanisms are multifactorial, metabolic reprogramming has emerged as a critical adaptive strategy for cancer cells to evade cisplatin-induced cytotoxicity. This review synthesizes current evidence on how altered metabolism drives cisplatin resistance, with a particular emphasis on the pivotal role of pyruvate dehydrogenase kinases (PDKs). PDKs act as metabolic gatekeepers by inhibiting the pyruvate dehydrogenase complex (PDHC), diverting glucose flux away from m

The palmitoylation state of PMP22 modulates epithelial cell morphology and migration.

PMP22 (peripheral myelin protein 22), also known as GAS 3 (growth-arrest-specific protein 3), is a disease-linked tetraspan glycoprotein of peripheral nerve myelin and constituent of intercellular junctions in epithelia. To date, our knowledge of the post-translational modification of PMP22 is limited. Using the CSS-Palm 2.0 software we predicted that C85 (cysteine 85), a highly conserved amino acid located between the second and third transmembrane domains, is a potential site for palmitoylation. To test this, we mutated C85S (C85 to serine) and established stable cells lines expressing the W

M-current preservation contributes to anticonvulsant effects of valproic acid.

Valproic acid (VPA) has been widely used for decades to treat epilepsy; however, its mechanism of action remains poorly understood. Here, we report that the anticonvulsant effects of nonacute VPA treatment involve preservation of the M-current, a low-threshold noninactivating potassium current, during seizures. In a wide variety of neurons, activation of Gq-coupled receptors, such as the m1 muscarinic acetylcholine receptor, suppresses the M-current and induces hyperexcitability. We demonstrated that VPA treatment disrupts muscarinic suppression of the M-current and prevents resultant agonist-

The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease.

HIP14 is the most highly conserved of 23 human palmitoyl acyltransferases (PATs) that catalyze the post-translational addition of palmitate to proteins, including huntingtin (HTT). HIP14 is dysfunctional in the presence of mutant HTT (mHTT), the causative gene for Huntington disease (HD), and we hypothesize that reduced palmitoylation of HTT and other HIP14 substrates contributes to the pathogenesis of the disease. Here we describe the yeast two-hybrid (Y2H) interactors of HIP14 in the first comprehensive study of interactors of a mammalian PAT. Unexpectedly, we discovered a highly significant

Role of PAX6, TRPA1, BCL11B, MCOLN2, CUX1, EMX1 in colorectal cancer and osteosarcoma.

Colorectal cancer is a cancer that arises from the abnormal growth of cells in the colon or rectum. Osteosarcoma (OS) is a common primary bone tumor with high degree of malignancy. The configuration files for colorectal cancer dataset GSE142279 and OS datasets GSE197158 and GSE206448 were downloaded from Gene Expression Omnibus database using the platforms GPL20795, GPL20301, and GPL24676. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis (WGCNA) was performed. Construction and analysis of protein-protein interactions (PPI) network. Functional

Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review.

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-dru

Immune Checkpoint Inhibitors and Immunomodulators for Cancer Immunotherapy: Insights Into Resistance and Therapeutic Strategies.

Cancer immunotherapy has redefined cancer treatment. However, the molecular and cellular basis of immune evasion and therapeutic resistance remains incompletely understood. Early immune checkpoint inhibitors have delivered significant clinical benefit, but their efficacy and durability remain limited in many patients. These limitations have driven the exploration of next-generation immune checkpoints and additional regulatory pathways that shape tumor-immune interactions. Recent advances have broadened the immune checkpoint landscape and revealed new targets. These targets operate within inter

Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications.

Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling-driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications-plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This mode

Освещение нанотерапевтики с точными глазами: от оптического к радионаностантике.

Рак по-прежнему относится к числу самых смертоносных заболеваний во всем мире, унося много жизней из-за высоких показателей смертности. Химиотерапия, являющаяся одной из основных форм лечения рака, приносит значительные выгоды, однако ей мешают недостатки, которые ставят под угрозу качество жизни пациентов. Таким образом, разработка альтернатив минимально инвазивному лечению по-прежнему представляет собой серьезную проблему. Среди них наноматериалы, легкая фототерапия, включая фотодинамическую терапию, фототермальную терапию и радиотерапию, являются перспективными вариантами, обеспечивающими т

Micronutrient Status and Breast Cancer: A Narrative Review.

Breast cancer is one of the most common cancers worldwide, at the same time being one of the most prevalent causes of women's death. Many factors such as alcohol, weight fluctuations, or hormonal replacement therapy can potentially contribute to breast cancer development and progression. Another important factor in breast cancer onset includes micronutrient status. In this narrative review, we analyzed 23 micronutrients and their possible influence on breast cancer onset and progression. Further, the aim of this study was to investigate the impact of micronutrient status on the prevention of b

Amino acids metabolism: a potential target for cancer treatment.

Metabolic reprogramming of amino acids has been recognized as a significant characteristic in various types of cancers. Numerous studies have indicated that the metabolic reprogramming of amino acids in tumors significantly supports certain malignant behaviors, including tumor proliferation, survival, invasion, and even immune escape. Amino acids can provide biomolecules such as nucleotides and glutathione (GSH) for tumors, and the bioavailability of amino acids influences tumor progression. Meanwhile, as essential metabolites, amino acids are closely associated with immune cell activation and

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… Specifically, high levels of GLDC can maintain mitochondrial protein lipoylation and change glycolysis, glycine/serine metabolism, and pyrimidine metabolism, thus promoting cell malignant transformation and tumor growth [ 215 – 217 ]. …

Cuproptosis related genes in immune infiltration and treatment of osteoporosis by bioinformatic analysis and machine learning methods.

Cuproptosis, a copper-dependent form of cell death, has been implicated in immune function and osteoporosis. However, the specific roles of cuproptosis-related genes (CRGs) in osteoporosis remain unclear. The differentially expressed CRGs from the Gene Expression Omnibus datasets of persons with osteoporosis and healthy individuals were categorized using R software tools in this study. Following that, the CIBERSORT algorithm and the GSVA technique were used to investigate the relationships between the different clusters and immune infiltration characteristics. Based on four machine learning te