BRAF-Mutated Melanoma Cell Lines Develop Distinct Molecular Signatures After Prolonged Exposure to AZ628 or Dabrafenib: Potential Benefits of the Antiretroviral Treatments Cabotegravir or Doravirine on BRAF-Inhibitor-Resistant Cells.

Melanoma is an aggressive cancer characterized by rapid growth, early metastasis, and poor prognosis, with resistance to current therapies being a significant issue. BRAF mutations drive uncontrolled cell division by activating the MAPK pathway. In this study, A375 and FO-1, BRAF-mutated melanoma cell lines, were treated for 4-5 months with RAF inhibitor dabrafenib or AZ628, leading to drug resistance over time.

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines.

This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals-lamivudine, doravirine, and cabotegravir-in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells.

Hyperforin Enhances Heme Oxygenase-1 Expression Triggering Lipid Peroxidation in BRAF-Mutated Melanoma Cells and Hampers the Expression of Pro-Metastatic Markers.

Hyperforin (HPF) is an acylphloroglucinol compound found abundantly in extract which exhibits antidepressant, anti-inflammatory, antimicrobial, and antitumor activities. Our recent study revealed a potent antimelanoma effect of HPF, which hinders melanoma cell proliferation, motility, colony formation, and induces apoptosis. Furthermore, we have identified glutathione peroxidase-4 (GPX-4), a key enzyme involved in cellular protection against iron-induced lipid peroxidation, as one of the molecular targets of HPF.

Protein Oligomerization.

Protein self-association is a biologically remarkable event that involves and affects the structural and functional properties of proteins [...

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism.

Hyperforin (HPF), the main component responsible for the antidepressant action of , displays additional beneficial properties including anti-inflammatory, antimicrobic, and antitumor activities. Among its antitumor effects, HPF activity on melanoma is poorly documented. Melanoma, especially BRAF-mutated melanoma, is still a high-mortality tumor type and the currently available therapies do not provide solutions.

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation.

Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma incidence and survival. Thus, we explored the effects of testosterone and 17β-estradiol on RNASEL and miR-146a expression in LM-20 and A375 melanoma cell lines.

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections.

The majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly regulated process. Onconase (ONC) is an amphibian ribonuclease known for cytotoxicity against tumors and antiviral activity.

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins.

Onconase (ONC) is an amphibian secretory ribonuclease displaying cytostatic and cytotoxic activities against many mammalian tumors, including melanoma. ONC principally damages tRNA species, but also other non-coding RNAs, although its precise targets are not known. We investigated the ONC ability to modulate the expression of 16 onco-suppressor microRNAs (miRNAs) in the A375 BRAF-mutated melanoma cell line.

Salviolone from Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation.

Melanoma is a highly malignant solid tumor characterized by an elevated growth and propagation rate. Since, often, melanoma treatment cannot prevent recurrences and the appearance of metastasis, new anti-melanoma agents need to be discovered. roots are a source of diterpenoid derivatives, natural compounds with several biological activities, including antiproliferative and anticancer effects.

The crystal structure of the domain-swapped dimer of onconase highlights some catalytic and antitumor activity features of the enzyme.

Onconase (ONC) is a monomeric amphibian "pancreatic-type" RNase endowed with remarkable anticancer activity. ONC spontaneously forms traces of a dimer (ONC-D) in solution, while larger amounts can be formed when ONC is lyophilized from mildly acidic solutions. Here, we report the crystal structure of ONC-D and analyze its catalytic and antitumor activities in comparison to ONC.

RNase A Domain-Swapped Dimers Produced Through Different Methods: Structure-Catalytic Properties and Antitumor Activity.

Upon oligomerization, RNase A can acquire important properties, such as cytotoxicity against leukemic cells. When lyophilized from 40% acetic acid solutions, the enzyme self-associates through the so-called three-dimensional domain swapping (3D-DS) mechanism involving both N- and/or C-terminals. The same species are formed if the enzyme is subjected to thermal incubation in various solvents, especially in 40% ethanol.

Anti-Tumor Activity of L. and Hyperforin through Modulation of Inflammatory Signaling, ROS Generation and Proton Dynamics.

In this paper we review the mechanisms of the antitumor effects of L. (St. John's wort, SJW) and its main active component hyperforin (HPF).

Protective Role of St. John's Wort and Its Components Hyperforin and Hypericin against Diabetes through Inhibition of Inflammatory Signaling: Evidence from In Vitro and In Vivo Studies.

Diabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of L.

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production.

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs.

Ribonucleases (RNases) are a large number of enzymes gathered into different bacterial or eukaryotic superfamilies. Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family. In physiological conditions, most RNases secreted in the extracellular space counteract the undesired effects of extracellular RNAs and become protective against infections.

Onconase Restores Cytotoxicity in Dabrafenib-Resistant A375 Human Melanoma Cells and Affects Cell Migration, Invasion and Colony Formation Capability.

Melanoma is a lethal tumor because of its severe metastatic potential, and serine/threonine-protein kinase B-raf inhibitors (BRAFi) are used in patients harboring BRAF-mutation. Unfortunately, BRAFi induce resistance. Therefore, we tested the activity of onconase (ONC), a cytotoxic RNase variant, against BRAFi-resistant cells to re-establish the efficacy of the chemotherapy.

Influence of onconase in the therapeutic potential of PARP inhibitors in A375 malignant melanoma cells.

Human malignant melanoma is one of the most aggressive cancers, accompanied with poor prognosis, metastatic evolution and high mortality. Many strategies have been developed using BRAF and MEK inhibitors in spite of the classic therapy with alkylating agents, but failure related to the ability of the tumor to activate alternative proliferation pathways occurred after promising initial successes. Poly(ADP-ribose) polymerase (PARP) enzymes are well known to be crucial for DNA damage response, and PARP inhibition results in the accumulation of DNA strand breaks that induce cell injury.

The beclomethasone anti-inflammatory effect occurs in cell/mediator-dependent manner and is additively enhanced by formoterol: NFkB, p38, PKA analysis.

Aims: Beclomethasone/formoterol (BDP/FOR) has been reported to be more effective than its separate components in airway disease control and in airway inflammation improvement. However, BDP/FOR effects on cytokine-induced inflammation in structural cells have not been described and whether these effects occur in a cell- and mediator-dependent manner has not been fully elucidated. We sought to evaluate BDP and/or FOR effects on endothelial ICAM-1, E-selectin, IL-8 and on bronchial epithelial ICAM-1 and IL-8.

Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach.

Asthma is a chronic lung disease affecting people of all ages worldwide, and it frequently begins in childhood. Because of its chronic nature, it is characterized by pathological manifestations, including airway inflammation, remodeling, and goblet cell hyperplasia. Current therapies for asthma, including corticosteroids and beta-2 adrenergic agonists, are directed toward relieving the symptoms of the asthmatic response, with poor effectiveness against the underlying causes of the disease.

Phosphorylation of pyridoxal 5'-phosphate enzymes: an intriguing and neglected topic.

Pyridoxal 5'-phosphate (PLP)-dependent enzymes catalyze a wide range of reactions of amino acids and amines, with the exception of glycogen phosphorylase which exhibits peculiar both substrate preference and chemical mechanism. They represent about 4% of the gene products in eukaryotic cells. Although structure-function investigations regarding these enzymes are copious, their regulation by post-translational modifications is largely unknown.

Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic β cells treated with St John's wort and its component hyperforin.

Objectives: St John's wort extract (SJW) and its component hyperforin (HPF) were shown to potently inhibit cytokine-induced STAT-1 and NF-κB activation in pancreatic β cells and protect them against injury. This study aimed at exploring the time course of STAT-1 inhibition afforded by these natural compounds in the β-cell line INS-1E.

Methods: INS-1E cells were pre-incubated with SJW extract (2-5 μg/ml) or HPF (0.

St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells.

The extract of the herbaceous plant St. John's wort (SJW) and its phloroglucinol component hyperforin (HPF) were previously shown to inhibit cytokine-induced STAT-1 and NF-κB activation and prevent damage in pancreatic β cells. To further clarify the mechanisms underlying their protective effects, we evaluated the phosphorylation state of various factors of cytokine signaling pathways and the expression of target genes involved in β-cell function, inflammatory response and apoptosis induction.

PARP inhibition treatment in a nonconventional experimental mouse model of chronic asthma.

Allergic asthma is an immunological disease that occurs as a consequence of aeroallergen exposure. Inhibition of poly(ADP-ribose) polymerases (PARPs) in conventional models of asthma-like reaction has emerged as an effective anti-inflammatory and airway remodeling intervention. In a house dust mite (HDM) exposure mouse model, we investigated the impact of PARP inhibition on allergic airway inflammation, sensitization, and remodeling.