Ritonavir reverses resistance to docetaxel and cabazitaxel in prostate cancer cells with acquired resistance to docetaxel.

Docetaxel is a microtubule-stabilizing drug used for the treatment of several cancers, including prostate cancer. Resistance to docetaxel can either occur through intrinsic resistance or develop under therapeutic pressure, i.e.

Pyroptosis in health and disease.

The field of cell death has witnessed significant advancements since the initial discovery of apoptosis in the 1970s. This review delves into the intricacies of pyroptosis, a more recently identified form of regulated, lytic cell death, and explores the roles of pyroptotic effector molecules, with a strong emphasis on their mechanisms and relevance in various diseases. Pyroptosis, characterized by its proinflammatory nature, is driven by the accumulation of large plasma membrane pores comprised of gasdermin family protein subunits.

Prolonged activity of the transposase helper may raise safety concerns during DNA transposon-based gene therapy.

DNA transposon-based gene delivery vectors represent a promising new branch of randomly integrating vector development for gene therapy. For the side-by-side evaluation of the c and systems-the only DNA transposons currently employed in clinical trials-during therapeutic intervention, we treated the mouse model of tyrosinemia type I with liver-targeted gene delivery using both transposon vectors. For genome-wide mapping of transposon insertion sites we developed a new next-generation sequencing procedure called streptavidin-based enrichment sequencing, which allowed us to identify approximately one million integration sites for both systems.

The E3 Ligase TRIM25 Impairs Apoptotic Cell Death in Colon Carcinoma Cells via Destabilization of Caspase-7 mRNA: A Possible Role of hnRNPH1.

Therapy resistance is still a major reason for treatment failure in colorectal cancer (CRC). Previously, we identified the E3 ubiquitin ligase TRIM25 as a novel suppressor of caspase-2 translation which contributes to the apoptosis resistance of CRC cells towards chemotherapeutic drugs. Here, we report the executioner caspase-7 as being a further target of TRIM25.

Reciprocal abrogation of PKM isoforms: contradictory outcomes and differing impact of splicing signal on CRISPR/Cas9 mediates gene editing in keratinocytes.

The healing of wounded skin is a highly organized process involving a massive cell in- and outflux, proliferation and tissue remodelling. It is well accepted that metabolic constraints such as diabetes mellitus, overweight or anorexia impairs wound healing. Indeed, wound inflammation involves a boost of overall metabolic changes.

The caspase-2 substrate p54nrb exhibits a multifaceted role in tumor cell death susceptibility via gene regulatory functions.

Caspase-2 represents an evolutionary conserved caspase, which plays a role in genotoxic stress-induced apoptosis, ageing-related metabolic changes, and in deleting aneuploid cells in tumors. Genetic deletion of caspase-2 leads to increased tumor susceptibility in vivo. The exact downstream signaling mechanism by which caspase-2 accomplishes its specific tumor suppressor functions is not clear.

A versatile transposon-based technology to generate loss- and gain-of-function phenotypes in the mouse liver.

Background: Understanding the contribution of gene function in distinct organ systems to the pathogenesis of human diseases in biomedical research requires modifying gene expression through the generation of gain- and loss-of-function phenotypes in model organisms, for instance, the mouse. However, methods to modify both germline and somatic genomes have important limitations that prevent easy, strong, and stable expression of transgenes. For instance, while the liver is remarkably easy to target, nucleic acids introduced to modify the genome of hepatocytes are rapidly lost, or the transgene expression they mediate becomes inhibited due to the action of effector pathways for the elimination of exogenous DNA.

Fragmented QRS in inferior leads is associated with non-alcholic fatty liver disease, body-mass index, and interventricular septum thickness in young men.

Objective: Fragmented QRS (fQRS) has been shown to be related to coronary heart disease, heart failure, hypertension, cardiac arrhythmia, and metabolic syndrome. Although fQRS in lateral leads is shown to be associated with a poor outcome in patients with a known cardiac disease, the knowledge about the significance and prevalence of fQRS in inferior leads is scarce. This study aimed to investigate the prevalence and predictors of fQRS in inferior leads in healthy young men.

Application of pseudotyped virus particles to monitor Ebola virus and SARS-CoV-2 viral entry in human cell lines.

Experimental work on highly pathogenic viruses such as Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus-2 requires high-level biosafety facilities. Here, we provide a detailed step-by-step protocol which details the production and application of replication-incompetent murine leukemia virus-based pseudotyped particles to monitor and quantify the viral entry efficiency in human cell lines under biosafety level-2 conditions. We describe the use of viral particles encoding gene and the quantification of transduction efficiency by measuring luciferase activity.

The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection.

Ebola virus (EBOV) is responsible for outbreaks with case fatality rates of up to 90% and for an epidemic in West Africa with more than ten thousand deaths. EBOV glycoprotein (EBOV-GP) is the only viral surface protein and is responsible for viral entry into cells. Here, by employing pseudotyped EBOV-GP viral particles, we uncover a critical role for sphingolipids in inhibiting viral entry.

C6 Ceramide (d18:1/6:0) as a Novel Treatment of Cutaneous T Cell Lymphoma.

Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with a lack of a curative treatment.

Cell death signalling in virus infection.

Apoptosis, necroptosis and pyroptosis represent three major regulated cell death modalities. Apoptosis features cell shrinkage, nuclear fragmentation and cytoplasm-blebbing. Necroptosis and pyroptosis exhibit osmotic imbalances in the cell accompanied by early membrane ruptures, which morphologically resembles necrosis.

The involvement of regulated cell death forms in modulating the bacterial and viral pathogenesis.

Apoptosis, necroptosis and pyroptosis represent three distinct types of regulated cell death forms, which play significant roles in response to viral and bacterial infections. Whereas apoptosis is characterized by cell shrinkage, nuclear condensation, bleb formation and retained membrane integrity, necroptosis and pyroptosis exhibit osmotic imbalance driven cytoplasmic swelling and early membrane damage. These three cell death forms exert distinct immune stimulatory potential.

Role of efflux transporters in the absorption, distribution and elimination in rodents of a novel PDE4 inhibitor, CHF6001.

CHF6001 is a new and potent PDE4 inhibitor for the treatment of human lung diseases, designed for topical administration by inhalation. In preclinical assessment CHF6001 appeared safe and devoid of emetic effect, which is typical side effect of PDE4 inhibitors in humans. CHF6001 absorption, distribution and excretion were evaluated in rats by PO and IV administration of [14C]CHF6001; additionally the role of transporters was investigated by using transfected cells expressing either human transporters or MDR1 and BCRP KO mice.

Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2.

Caspases are key enzymes responsible for mediating apoptotic cell death. Across species, caspase-2 is the most conserved caspase and stands out due to unique features. Apart from cell death, caspase-2 also regulates autophagy, genomic stability and ageing.

Investigating ABCB1-Mediated Drug-Drug Interactions: Considerations for In vitro and In vivo Assay Design.

Background: ABCB1 is a key ABC efflux transporter modulating the pharmacokinetics of a large percentage of drugs. ABCB1 is also a site of transporter mediated drug-drug interactions (tDDI). It is the transporter most frequently tested for tDDIs both in vitro and in the clinic.

Attenuation of the ELAV1-like protein HuR sensitizes adenocarcinoma cells to the intrinsic apoptotic pathway by increasing the translation of caspase-2L.

Caspase-2 represents the most conserved member of the caspase family, which exhibits features of both initiator and effector caspases. Using ribonucleoprotein (RNP)-immunoprecipitation assay, we identified the proapoptotic caspase-2L encoding mRNA as a novel target of the ubiquitous RNA-binding protein HuR in DLD-1 colon carcinoma cells. Unexpectedly, crosslinking-RNP and RNA probe pull-down experiments revealed that HuR binds exclusively to the caspase-2-5' untranslated region (UTR) despite that the 3' UTR of the mRNA bears several adenylate- and uridylate-rich elements representing the prototypical HuR binding sites.

Screen3D: a novel fully flexible high-throughput shape-similarity search method.

3D shape- or volume-based virtual screening is a broadly used approach in drug discovery. In recent years a large number of publications have appeared in which these tools were compared not only to competitive methods but to docking studies as well. Studies often showed that the effectiveness of docking could be highly variable due to a large number of possible confounding factors, while ligand-based, shape-based approaches were more consistent.

Relationship between increased serum resistin level and severity of coronary artery disease.

Resistin, which is derived from the gene of RSTN, belongs to a family of cysteine-rich secretory proteins called resistin-like molecules (RELMs). Increased serum resistin levels are associated with coronary artery disease (CAD) and the risk of cardiovascular death. Patients (n = 214) with an initial diagnosis of stable angina pectoris, unstable angina pectoris, and myocardial infarction without ST-segment elevation and referred to catheter laboratory for coronary angiography were enrolled in the study.

Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cells.

For a long time necrosis was thought to be an uncontrolled process but evidences recently have revealed that necrosis can also occur in a regulated manner. Necroptosis, a type of programmed necrosis is defined as a death receptor-initiated process under caspase-compromised conditions. The process requires the kinase activity of receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) and mixed lineage kinase domain-like protein (MLKL), as a substrate of RIPK3.

Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis.

Bacterial pathogens modulate host cell apoptosis to establish a successful infection. Pore-forming toxins (PFTs) secreted by pathogenic bacteria are major virulence factors and have been shown to induce various forms of cell death in infected cells. Here we demonstrate that the highly conserved caspase-2 is required for PFT-mediated apoptosis.

Ripoptosome: a novel IAP-regulated cell death-signalling platform.

Recent studies have revealed that cell death stimuli can trigger programmed necrosis, necroptosis. Receptor-interacting serine-threonine kinase family RIP plays a crucial role in regulating the switch between apoptosis and necroptosis. Two studies now describe a novel RIP1 containing ~2 MDa 'Ripoptosome' complex assembled in the cytosol to mediate both apoptosis and necroptosis in response to genotoxic stress and TLR3 stimulation.

The preclinical properties of a novel group II metabotropic glutamate receptor agonist LY379268.

Activation of group II metabotropic glutamate (mGlu2/3) receptors reduces excessive glutamate release that is often associated with neurodegenerative and psychiatric disorders. This finding encouraged the search for potent and selective agonists as potential therapeutic agents. The search led to the discovery of LY379268 {(-)-2-oxa-4-aminobicyclo[3.