Pharmacological targeting of caspase-8/c-FLIP heterodimer enhances complex II assembly and elimination of pancreatic cancer cells.

Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIP, in the caspase-8/c-FLIP heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis.

Aminomethylmorpholino Nucleosides as Novel Inhibitors of PARP1 and PARP2: Experimental and Molecular Modeling Analyses of Their Selectivity and Mechanism of Action.

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play a key role in DNA repair. As major sensors of DNA damage, they are activated to produce poly(ADP-ribose). PARP1/PARP2 inhibitors have emerged as effective drugs for the treatment of cancers with BRCA deficiencies.

Design of Ctenophore Ca-Regulated Photoprotein Berovin Capable of Being Converted into Active Protein Under Physiological Conditions: Computational and Experimental Approaches.

Here, we describe (1) the AlphaFold-based structural modeling approach to identify amino acids of the photoprotein berovin that are crucial for coelenterazine binding, and (2) the production and characterization of berovin mutants with substitutions of the identified residues regarding their effects on the ability to form an active photoprotein under physiological conditions and stability to light irradiation. The combination of mutations K90M, N107S, and W103F is demonstrated to cause a shift of optimal conditions for the conversion of apo-berovin into active photoprotein towards near-neutral pH and low ionic strength, and to reduce the sensitivity of active berovin to light. According to the berovin spatial structure model, these residues are found in close proximity to the 6-(-hydroxy)-phenyl group of the coelenterazine peroxyanion.

Proteome-wide CETSA reveals new step in apoptosis control.

Apoptosis, a well-established program of cell death, is fundamental to all multicellular organisms. Recent studies of apoptosis initiation events using proteome-wide cellular thermal shift assay (CETSA) have revealed a novel regulatory mechanism involving the cleavage of nuclear substrates. This finding suggests a previously unrecognized amplification step in apoptosis occurring within the nucleus.

Targeting caspase-8/c-FLIP heterodimer in complex II promotes DL-mediated cell death.

Death receptor (DR) networks are controlled by the assembly of the Death-Inducing Signaling Complex (DISC) and complex II. The family of small molecules FLIPins (FLIP interactors) were developed to target the caspase-8/c-FLIP heterodimer. FLIPin compounds were shown to promote apoptosis and caspase-8 activation at the DISC upon stimulation with death ligands (DLs) such as CD95L and TRAIL.

Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions.

Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the h2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface.

Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks.

Procaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by the PRMT5/RIOK1/WD45 methylosome complex.

Modulation of extrinsic apoptotic pathway by intracellular glycosylation.

The importance of post-translational modifications (PTMs), particularly O-GlcNAcylation, of cytoplasmic proteins in apoptosis has been neglected for quite a while. Modification of cytoplasmic proteins by a single N-acetylglucosamine sugar is a dynamic and reversible PTM exhibiting properties more like phosphorylation than classical O- and N-linked glycosylation. Due to the sparse information existing, we have only limited understanding of how GlcNAcylation affects cell death.

Prioritization of potential pharmacological targets for the development of anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway: the reconstruction and analysis of associative gene networks help.

Hepatocellular carcinoma (HCC) is a common severe type of liver cancer characterized by an extremely aggressive course and low survival rates. It is known that disruptions in the regulation of apoptosis activation are some of the key features inherent in most cancer cells, which determines the pharmacological induction of apoptosis as an important strategy for cancer therapy. The computer design of chemical compounds capable of specifically regulating the external signaling pathway of apoptosis induction represents a promising approach for creating new effective ways of therapy for liver cancer and other oncological diseases.

RL2 Enhances the Elimination of Breast Cancer Cells by Doxorubicin.

RL2 (recombinant lactaptin 2), a recombinant analogon of the human milk protein Κ-Casein, induces mitophagy and cell death in breast carcinoma cells. Furthermore, RL2 was shown to enhance extrinsic apoptosis upon long-term treatment while inhibiting it upon short-term stimulation. However, the effects of RL2 on the action of chemotherapeutic drugs that induce the intrinsic apoptotic pathway have not been investigated to date.

A cytosolic mutp53(E285K) variant confers chemoresistance of malignant melanoma.

Malignant melanoma (MM) is known to be intrinsically chemoresistant, even though only ~20% of MM carry mutations of the tumor suppressor p53. Despite improvement of systemic therapy the mortality rate of patients suffering from metastatic MM is still ~70%, highlighting the need for alternative treatment options or for the re-establishment of conventional therapeutic approaches, including chemotherapy. Screening the p53 mutation status in a cohort of 19 patient-derived melanoma samples, we identified one rarely described missense mutation of p53 leading to E285K amino acid exchange (mutp53(E285K)).

Reconstruction of the regulatory hypermethylation network controlling hepatocellular carcinoma development during hepatitis C viral infection.

Hepatocellular carcinoma (HCC) has been associated with hepatitis C viral (HCV) infection as a potential risk factor. Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC genes through regulatory pathways.

[Mathematical model for assessing the level of cross-immunity between strains of influenza virus subtype HN].

Introduction: The WHO regularly updates influenza vaccine recommendations to maximize their match with circulating strains. Nevertheless, the effectiveness of the influenza A vaccine, specifically its H3N2 component, has been low for several seasons. The aim of the study is to develop a mathematical model of cross-immunity based on the array of published WHO hemagglutination inhibition assay (HAI) data.

Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks.

The extrinsic pathway is mediated by death receptors (DRs), including CD95 (APO-1/Fas) or TRAILR-1/2. Defects in apoptosis regulation lead to cancer and other malignancies. The master regulator of the DR networks is the cellular FLICE inhibitory protein (c-FLIP).

Impact of human CD95 mutations on cell death and autoimmunity: a model.

CD95/Fas/APO-1 can trigger apoptotic as well as nonapoptotic pathways in immune cells. CD95 signaling in humans can be inhibited by several mechanisms, including mutations in the gene encoding CD95. CD95 mutations lead to autoimmune disorders, such as autoimmune lymphoproliferative syndrome (ALPS).

Computer analysis of the relation between hydrogen bond stability in SOD1 mutants and the survival time of amyotrophic lateral sclerosis patients.

Background And Objective: Mutations in the SOD1 protein can lead to the death of motor neurons, which, in turn, causes an incurable disease called amyotrophic lateral sclerosis (ALS). At the same time, the mechanism of the onset and development of this disease is not fully understood and is often contradictory.

Methods: Accelerated Molecular Dynamics as implemented in the OpenMM library, principal component analysis, regression analysis, random forest method.

Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients.

This work compares the metabolic profiles of plasma and the cerebrospinal fluid (CSF) of the patients with high-grade (III and IV) gliomas and the conditionally healthy controls using the wide-range targeted screening of low molecular metabolites by HPLC-MS/MS. The obtained data were analyzed using robust linear regression with Huber's M-estimates, and a number of metabolites with correlated content in plasma and CSF was identified. The statistical analysis shows a significant correlation of metabolite content in plasma and CSF samples for the majority of metabolites.

Pharmacological targeting of c-FLIP and Bcl-2 family members promotes apoptosis in CD95L-resistant cells.

The development of efficient combinatorial treatments is one of the key tasks in modern anti-cancer therapies. An apoptotic signal can either be induced by activation of death receptors (DR) (extrinsic pathway) or via the mitochondria (intrinsic pathway). Cancer cells are characterized by deregulation of both pathways.

Mathematical Modeling Reveals the Importance of the DED Filament Composition in the Effects of Small Molecules Targeting Caspase-8/c-FLIP Heterodimer.

Procaspase-8 activation at the death-inducing signaling complex (DISC) triggers extrinsic apoptotic pathway. Procaspase-8 activation takes place in the death effector domain (DED) filaments and is regulated by c-FLIP proteins, in particular, by the long isoform c-FLIP. Recently, the first-in-class chemical probe targeting the caspase-8/c-FLIP heterodimer was reported.

The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications.

The current pandemic of novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) poses a significant global public health threat. While urgent regulatory measures in control of the rapid spread of this virus are essential, scientists around the world have quickly engaged in this battle by studying the molecular mechanisms and searching for effective therapeutic strategies against this deadly disease. At present, the exact mechanisms of programmed cell death upon SARS-CoV-2 infection remain to be elucidated, though there is increasing evidence suggesting that cell death pathways play a key role in SARS-CoV-2 infection.

ANDDigest: a new web-based module of ANDSystem for the search of knowledge in the scientific literature.

Background: The rapid growth of scientific literature has rendered the task of finding relevant information one of the critical problems in almost any research. Search engines, like Google Scholar, Web of Knowledge, PubMed, Scopus, and others, are highly effective in document search; however, they do not allow knowledge extraction. In contrast to the search engines, text-mining systems provide extraction of knowledge with representations in the form of semantic networks.