Performance of the accelerated assessment of the European Medicines Agency.

Aims: In Europe, the European Medicines Agency (EMA) has an accelerated pathway to prioritize approval of medicines. Approved drugs are then assessed by Health Technology Assessment (HTA) bodies before being made available to patients. The aim of the study was to evaluate the characteristics of the drugs admitted to the EMA accelerated assessment (AA) and scrutinize the downstream HTA procedures regarding these medicines and the final assessment regarding added therapeutic value (ATV).

The curious case of type I interferon signaling in cancer.

Cytokines are the crucial signaling proteins that mediate the crosstalks between the cells of tumor microenvironment (TME). Interferon-1 (IFN-1) are the important cytokines that are widely known for their tumor suppressive roles comprising of cancer cell intrinsic and extrinsic mechanisms. Despite having known antitumor effects, IFN-1 are also reported to have tumor promoting functions under varying circumstances.

Portable Voltammetry: A Rapid and Efficient Technique for Determining UV Filters in Cosmetics: A Comparative Study with HPLC-PDA and HPLC-MS/MS.

This study addresses the widespread use of UV filters (UVFs) in cosmetic and solar products due to the negative effects of UV radiation, particularly in relation to melanoma risk. While these filters offer protection, their extensive application raises concerns about their environmental and health impacts. Organic UVFs, in particular, have been associated with endocrine disruption in aquatic species and coral reef damage.

Novel NLRP3 inhibitor INF195: Low doses provide effective protection against myocardial ischemia/reperfusion injury.

Background: Several factors contribute to ischemia/reperfusion injury (IRI), including activation of the NLRP3 inflammasome and its byproducts, such as interleukin-1β (IL-1β) and caspase-1. However, NLRP3 may paradoxically exhibit cardioprotective properties. This study aimed to assess the protective effects of the novel NLRP3 inhibitor, INF195, both in vitro and ex vivo.

Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation.

Inspired by the recent advancements in understanding the binding mode of sulfonylurea-based NLRP3 inhibitors to the NLRP3 sensor protein, we developed new NLRP3 inhibitors by replacing the central sulfonylurea moiety with different heterocycles. Computational studies evidenced that some of the designed compounds were able to maintain important interaction within the NACHT domain of the target protein similarly to the most active sulfonylurea-based NLRP3 inhibitors. Among the studied compounds, the 1,3,4-oxadiazol-2-one derivative 5 (INF200) showed the most promising results being able to prevent NLRP3-dependent pyroptosis triggered by LPS/ATP and LPS/MSU by 66.

Evidence-Based Anti-Diabetic Properties of Plant from the Occitan Valleys of the Piedmont Alps.

Data on urban and rural diabetes prevalence ratios show a significantly lower presence of diabetes in rural areas. Several bioactive compounds of plant origin are known to exert anti-diabetic properties. Interestingly, most of them naturally occur in different plants present in mountainous areas and are linked to traditions of herbal use.

Effects of Vanadyl Complexes with Acetylacetonate Derivatives on Non-Tumor and Tumor Cell Lines.

Vanadium has a good therapeutic potential, as several biological effects, but few side effects, have been demonstrated. Evidence suggests that vanadium compounds could represent a new class of non-platinum, metal antitumor agents. In the present study, we aimed to characterize the antiproliferative activities of fluorescent vanadyl complexes with acetylacetonate derivates bearing asymmetric substitutions on the β-dicarbonyl moiety on different cell lines.

Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor.

In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP.

Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3.

Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings.

Analyzing Cysteine Site Neighbors in Proteins to Reveal Dimethyl Fumarate Targets.

This work proposes a novel approach by which to consistently classify cysteine sites in proteins in terms of their reactivity toward dimethyl fumarate (DMF) and fumarate. Dimethyl fumarate-based drug products have been approved for use as oral treatments for psoriasis and relapsing-remitting multiple sclerosis. The adduction of DMF and its (re)active metabolites to certain cysteine residues in proteins is thought to underlie their effects.

Antiproliferative, Proapoptotic, Antioxidant and Antimicrobial Effects of Sinapis nigra L. and Sinapis alba L. Extracts.

High Brassicaceae consumption reduces the risk of developing several cancer types, probably due to high levels of glucosinolates. Extracts from Sinapis nigra L. (S.

EPR and photophysical characterization of six bioactive oxidovanadium(IV) complexes in the conditions of in vitro cell tests.

A number of oxidovanadium(IV) complexes have been reported to display anticancer activity. A theranostic approach, based on the simultaneous observation of both the effect of oxidovanadium(IV) complexes on cell viability and the disclosure of their intracellular fate, is possible by using oxidovanadium(IV) complexes functionalized with fluorescent ligands. In the present study we accomplished the characterization of six oxidovanadium(IV) complexes in conditions close to those employed for in vitro administration.

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations.

BRAF V600E is a determinant of sensitivity to proteasome inhibitors.

A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair-or boost-the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug-genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios.

Synthesis, characterization and cell viability test of six vanadyl complexes with acetylacetonate derivatives.

Vanadium compounds are known to display a number of therapeutic effects, namely insulin-mimetic and cardiovascular effects. Evidence of the antiproliferative and proapoptotic activity of a number of vanadyl complexes, together with their low toxicity, establishes these metal compounds as promising antitumoral therapeutic agents. In the present work, we describe the synthesis and full characterization of six new vanadyl complexes with acetylacetonate derivatives bearing asymmetric substitutions on the β-dicarbonyl moiety: the complexes were characterized in the solid state as well as in solution.

Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug.