Enhanced Anti-Melanoma Activity of Nutlin-3a Delivered via Ethosomes: Targeting p53-Mediated Apoptosis in HT144 Cells.

This study evaluated ethosomes as a novel nanodelivery system for nutlin-3a, a known MDM2 inhibitor and activator of the p53 pathway, to improve nutlin-3a's poor solubility, limiting its bio-distribution and therapeutic efficacy. The potential of nutlin-3a-loaded ethosomes was investigated on two in vitro models of melanoma: the HT144 cell line p53 and the SK-MEL-28 cell line p53. Nutlin-3a-loaded ethosomes were characterized for their physicochemical properties and used to treat melanoma cells at different concentrations, considering nutlin-3a solution and empty ethosomes as controls.

Characterization Methods for Nanoparticle-Skin Interactions: An Overview.

Research progresses have led to the development of different kinds of nanoplatforms to deliver drugs through different biological membranes. Particularly, nanocarriers represent a precious means to treat skin pathologies, due to their capability to solubilize lipophilic and hydrophilic drugs, to control their release, and to promote their permeation through the stratum corneum barrier. A crucial point in the development of nano-delivery systems relies on their characterization, as well as in the assessment of their interaction with tissues, in order to predict their fate under in vivo administration.

Nutlin-3 Loaded Ethosomes and Transethosomes to Prevent UV-Associated Skin Damage.

The skin's protective mechanisms, in some cases, are not able to counteract the destructive effects induced by UV radiations, resulting in dermatological diseases, as well as skin aging. Nutlin-3, a potent drug with antiproliferative activity in keratinocytes, can block UV-induced apoptosis by activation of p53. In the present investigation, ethosomes and transethosomes were designed as delivery systems for nutlin-3, with the aim to protect the skin against UV damage.

Nutrients, herbal bioactive derivatives and commensal microbiota as tools to lower the risk of SARS-CoV-2 infection.

The SARS-CoV-2 outbreak has infected a vast population across the world, causing more than 664 million cases and 6.7 million deaths by January 2023. Vaccination has been effective in reducing the most critical aftermath of this infection, but some issues are still present regarding re-infection prevention, effectiveness against variants, vaccine hesitancy and worldwide accessibility.

Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells.

SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity.

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma.

MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma.

Therapeutic potential of the MDM2 inhibitor Nutlin-3 in counteracting SARS-CoV-2 infection of the eye through p53 activation.

Starting from the beginning of the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) global pandemic, most of the published data has concentrated on the respiratory signs and symptoms of Covid-19 infection, underestimating the presence and importance of ocular manifestations, such as conjunctivitis, usually reported in SARS-CoV-2 infected patients. With the present review we intend to resume the ocular involvement in SARS-CoV-2 infection and the recent discoveries about the different cell types and tissues of the eye that can be directly infected by SARS-CoV-2 and propagate the infection. Moreover, reviewing literature data about p53 expression in normal and diseased eye tissues, we hypothesize that the pleiotropic protein p53 present at high levels in cornea, conjunctiva and tear film might play a protective role against SARS-CoV-2 infection.

Anticancer Activity of Aqueous Extracts from L. Byproduct on Breast Cancer Cells.

Cultivation of asparagus ( L.; Asp) for food and medicinal use has taken place since the early Roman Empire. Today, Asp represents a worldwide diffuse perennial crop.

Overcoming of Microenvironment Protection on Primary Chronic Lymphocytic Leukemia Cells after Treatment with BTK and MDM2 Pharmacological Inhibitors.

In B-chronic lymphocytic leukemia (B-CLL), the interaction between leukemic cells and the microenvironment promotes tumor cell survival. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is one of the first-in-class molecules for the treatment of B-CLL patients; however, the emerging mechanisms of resistance to ibrutinib call for new therapeutic strategies. The purpose of the current study was to investigate the ability of ibrutinib plus the MDM2-inhibitor nutlin-3 to counteract the tumor microenvironment protective effect.

Author Correction: HelixComplex snail mucus exhibits pro-survival, proliferative and pro-migration effects on mammalian fibroblasts.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets?

Ligands and receptors of the tumor necrosis factor (TNF) superfamily regulate immune responses and homeostatic functions with potential diagnostic and therapeutic implications. Kidney disease represents a global public health problem, whose prevalence is rising worldwide, due to the aging of the population and the increasing prevalence of diabetes, hypertension, obesity, and immune disorders. In addition, chronic kidney disease is an independent risk factor for the development of cardiovascular disease, which further increases kidney-related morbidity and mortality.

Actively targeted nanocarriers for drug delivery to cancer cells.

Introduction: Progressive breakthroughs in nanomedicine have been instrumental for the clinical translation of actively targeted drug-delivery approaches. Besides storing large payloads of drugs within the nanoparticle core, the conjugation of targeting moieties confers specific targeting ability to the nanoplatforms. In this respect, clinical results suggest that actively targeted nanocarriers can exhibit an overall improved antitumor efficacy, minimizing off-target toxicity.

HelixComplex snail mucus exhibits pro-survival, proliferative and pro-migration effects on mammalian fibroblasts.

Snail mucus is a mixture of active substances commonly thought to have healthy properties for the treatment of skin disorders. Although snail mucus is an ingredient of several cosmetic and para-pharmaceutic products, a comprehensive characterization of chemical composition and biological effects is still missing. Crude purified extracts from Helix aspersa muller mucus (HelixComplex) were prepared and, after chemical characterization, tested on in vitro experimental models.

Relationship between low levels of circulating TRAIL and atheromatosis progression in patients with chronic kidney disease.

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients.

Changes in expression profiles of internal jugular vein wall and plasma protein levels in multiple sclerosis.

Background: Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disorder of the central nervous system (CNS). Several observations support interactions between vascular and neurodegenerative mechanisms in multiple sclerosis (MS). To investigate the contribution of the extracranial venous compartment, we analysed expression profiles of internal jugular vein (IJV), which drains blood from CNS, and related plasma protein levels.

Coagulation Factor XII Levels and Intrinsic Thrombin Generation in Multiple Sclerosis.

Background: Factor XII (FXII) activation initiates the intrinsic (contact) coagulation pathway. It has been recently suggested that FXII could act as an autoimmunity mediator in multiple sclerosis (MS). FXII depositions nearby dentritic cells were detected in the central nervous system of MS patients and increased FXII activity has been reported in plasma of relapsing remitting and secondary progressive MS patients.

The γ-secretase inhibitors enhance the anti-leukemic activity of ibrutinib in B-CLL cells.

Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-to-microenvironment interactions. Ibrutinib plays a key role in the management of B-CLL and is recommended for first line treatment of high-risk CLL patients with 17p deletion. Therefore, elucidating the factors governing sensitivity/resistance to Ibrutinib represents a relevant issue.

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.

The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed.

Redox signaling and oxidative stress: Cross talk with TNF-related apoptosis inducing ligand activity.

Redox regulation plays a key role in several physiopathological contexts and free radicals, from nitric oxide and superoxide anion up to other forms of reactive oxygen species (ROS), have been demonstrated to be involved in different biological and regulatory processes. The data reported in the current literature describe a link between ROS, inflammation and programmed cell death that is attracting interest as new pathways to be explored and targeted for therapeutic purposes. In this light, there is also growing attention to the involvement of this link in the activity of the TNF-related apoptosis inducing ligand (TRAIL).

Ibrutinib synergizes with MDM-2 inhibitors in promoting cytotoxicity in B chronic lymphocytic leukemia.

Objective: The aim of this study was to investigate the anti-leukemic activity of the Bruton tyrosine kinase inhibitor Ibrutinib in combination with the small molecule MDM-2 inhibitor Nutlin-3 in preclinical models.

Methods: The potential efficacy of the Ibrutinib/Nutlin-3 combination was evaluated in vitro in a panel of B leukemic cell lines (EHEB, JVM-2, JVM-3, MEC-1, MEC-2) and in primary B-chronic lymphocytic leukemia (B-CLL) patient samples, by assessing cell viability, cell cycle profile, apoptosis and intracellular pathway modulations. Validation of the combination therapy was assessed in a B leukemic xenograft mouse model.

Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells.

It is unknown whether components present in heart failure (HF) patients' serum provide an angiogenic stimulus. We sought to determine whether serum from HF patients affects angiogenesis and its major modulator, the Notch pathway, in human umbilical vein endothelial cells (HUVECs). In cells treated with serum from healthy subjects or from patients at different HF stage we determined: (1) Sprouting angiogenesis, by measuring cells network (closed tubes) in collagen gel.