Accumulation Kinetics and Biological Action of Doxorubicin in Rabbit Intervertebral Discs.

Doxorubicin (DOX) is widely used for the treatment of several tumors, but considerable dose-dependent side effects on many normal tissues, including bones, have been reported. The aim of the present study was to follow for the first time the kinetics of DOX accumulation/clearance in the non-vascularized intervertebral disc (IVD), as well as to assess the drug's biological action in the annulus fibrosus (AF) and nucleus pulposus (NP) IVD cells and tissues. DOX was administered intravenously to rabbits before the isolation of IVDs, in which DOX quantification was performed using a highly sensitive LC-HRMS/MS analytical method.

Molecular and Environmental Modulators of Aging: Interplay Between Inflammation, Epigenetics, and RNA Stability.

Aging is a complex biological process characterized by the progressive accumulation of cellular and molecular damage, leading to functional decline and increased susceptibility to age-related diseases. Central to this process is cellular senescence, a state of irreversible cell cycle arrest that acts as both a protective mechanism against tumorigenesis and a contributor to tissue degeneration. Herein, we explore the genetic and molecular mechanisms underlying aging, with a focus on telomere dynamics, the gene, angiotensin-converting enzyme (ACE), and the NF-κB pathway.

Screening of a Plant Extract Library from the Greek Flora for Biological Activities Related to Anti-Aging Applications.

Characteristic manifestations of skin aging, due to either intrinsic or extrinsic factors, such as ultraviolet (UV) radiation and oxidative stress, include cell senescence, alterations in collagen and elastin networks, and melanogenesis disorders. Natural products are considered a rich source of anti-aging molecules. Accordingly, the screening of a plant extract library from the Greek flora for a panel of biological activities related to skin aging is presented herein.

The effect of copper on the antifungal activity of polyethyleneimines against quiescent conidia and germlings of Aspergillus nidulans.

The increase in the number of immunocompromised individuals combined with the severity of fungal infections in the general population has contributed to a significant increase in opportunistic fungal infections, which are often associated with high mortality rates. Although effective, existing antifungal drugs operate via a narrow range of mechanisms, leading to the rapid development of resistance and they primarily target growing host cells. Therefore, the need to develop next-generation antifungal agents that function via a broad range of mechanisms and/or target dormant/quiescent cells is highly important.

Copper-Chelated Hyperbranched Polyethyleneimines with Antifungal Activity against quiescent conidia and germlings of the opportunistic fungal pathogen Aspergillus nidulans.

The rising number of immunocompromised individuals, combined with the severity of fungal infections in the general population, has contributed to a significant increase in opportunistic fungal infections, which are often associated with high mortality rates. Existing antifungal drugs, although effective, operate via a narrow range of mechanisms, leading to the rapid development of resistance, while they also primarily target growing host cells. Therefore, the need to develop next-generation antifungal agents that function via a broad range of mechanisms and/or to target dormant/quiescent cells is of great importance.

Natural Product-Derived Senotherapeutics: Extraction and Biological Evaluation Techniques.

Selective targeting of senescent cells has been thus far considered a widespread preventive strategy, as well as a main or adjuvant therapy for age-associated diseases, fueling the research on the discovery of senotherapeutics (i.e., senolytic or senomorphic compounds).

TGF-β induces cholesterol accumulation to regulate the secretion of tumor-derived extracellular vesicles.

Background: Cancer cells are avid extracellular vesicle (EV) producers. EVs transport transforming growth factor-β (TGF-β), which is commonly activated under late stages of cancer progression. Nevertheless, whether TGF-β signaling coordinates EV biogenesis is a relevant topic that remains minimally explored.

Stimulation of IRES-Dependent Translation by Rocaglamide A Increases the Replication and Virulence of Cricket Paralysis Virus in Lepidopteran Insect Cells.

The discovery that infections of viruses are pervasive among insects has considerable potential for future applications, such as new strategies for pest control through the manipulation of virus-host interactions. However, few studies can be found that aim to minimize (for beneficial insects) or maximize (for pests) virus impact or virulence. Viruses generally employ molecular mechanisms that deviate from the cells' to increase their replication efficiency and to avoid the immune response.

A subset of human dermal fibroblasts overexpressing Cockayne syndrome group B protein resist UVB radiation-mediated premature senescence.

Ultraviolet B (UVB) radiation is a major contributor to skin photoaging. Although mainly absorbed by the epidermis, UVB photons managing to penetrate the upper dermis affect human dermal fibroblasts (HDFs), leading, among others, to the accumulation of senescent cells. In vitro studies have shown that repeated exposures to subcytotoxic UVB radiation doses provoke HDFs' premature senescence shortly after the end of the treatment period.

Design and Synthesis of Novel Antioxidant 2-Substituted-5,7,8-Trimethyl-1,4-Benzoxazine Hybrids: Effects on Young and Senescent Fibroblasts.

The exponential growth of the aged population worldwide is followed by an increase in the prevalence of age-related disorders. Oxidative stress plays central role in damage accumulation during ageing and cell senescence. Thus, a major target of today's anti-ageing research has been focused on antioxidants counteracting senescence.

Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy.

Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours.

Biological Activities of Citrus-Derived Extracellular Vesicles on Human Cells: The Role of Preservation.

Extracellular vesicles (EVs) have been identified as important mediators for cell-to-cell communication. Citrus-based EVs in particular offer an excellent platform for nutraceutical delivery systems, as their endemic cargo includes micronutrients (e.g.

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging.

Chronic low back pain, a major cause of disability with a great global socioeconomic impact, has been inextricably associated with intervertebral disc degeneration. On the other hand, an enhanced number of senescent cells has been identified in aged and degenerated intervertebral discs and their senescence-associated secretory phenotype (SASP) has been connected with qualitative/quantitative alterations in the extracellular matrix and ultimately with the disturbance of tissue homeostasis. Given that selective elimination of senescent cells (by the so-called senolytics) or amendment of their secretome towards a less catabolic/inflammatory phenotype (by molecules known as senomorphics) has been reported to alleviate symptoms of several age-associated diseases and to improve tissue quality during aging, here we will review the emerging role of senolytic and senomorphic agents derived from plants and natural products against intervertebral disc degeneration.

New long-standing metabolites of 17α-methyltestosterone are detected in HepG2 cell in vitro metabolic model and in human urine.

Novel metabolites of the anabolic androgenic steroid 17α-methyltestosterone have been detected in HepG2 cell in vitro metabolic model and in human urine. Their detection was accomplished through targeted gas chromatography-(tandem) mass spectrometry analysis that has been based on microscale synthesized standards. The related synthesis and the gas chromatography-(tandem) mass spectrometry characterization of the analytical standards are described.

Synthesis, cytotoxic activity evaluation and mechanistic investigation of novel 3,7-diarylsubstituted 6-azaindoles.

A number of new disubstituted 6-azaindoles have been designed and synthesized bearing a crucial structural modification in respect to an analogous antiproliferative hit compound. The synthesis was performed using 2-amino-3-nitro-4-picoline, that was suitably modified and converted to 7-chloro-3-iodo-6-azaindole and this central scaffold was used for successive Suzuki-type couplings, to result in the target compounds. The evaluation of the cytotoxic activity was performed against four human cancer cell lines, as well as a normal human fibroblast strain.

Biological Activities of Pod and Seed Extracts: A Comparative Analysis of Two Cretan Cultivars.

L., commonly known as the carob tree, appears in most Mediterranean countries, often cultivated for the collection of its fruits to be used as food for humans and animals. This study was aimed at the phytochemical characterization of two common Cretan cultivars and the biological evaluation of deseeded pod and seed extracts regarding their putative use in cosmetics.

A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer.

Background: Prostate cancer is a major cause of cancer morbidity and mortality in men worldwide. Androgen deprivation therapy (ADT) has proven effective in early-stage androgen-sensitive disease, but prostate cancer gradually develops into an androgen-resistant metastatic state in the vast majority of patients. According to our oncogene-induced model for cancer development, senescence is a major tumor progression barrier.

Senescence-associated alterations in the extracellular matrix: deciphering their role in the regulation of cellular function.

The extracellular matrix (ECM) is a dynamic structural network that provides a physical scaffolding, as well as biochemical factors that maintain normal tissue homeostasis and thus its disruption is implicated in many pathological conditions. On the other hand, senescent cells express a particular secretory phenotype, affecting the composition and organization of the surrounding ECM and modulating their microenvironment. As accumulation of senescent cells may be linked to the manifestation of several age-related conditions, senescence-associated ECM alterations may serve as targets for novel anti-aging treatment modalities.

Heterogeneity of Cellular Senescence: Cell Type-Specific and Senescence Stimulus-Dependent Epigenetic Alterations.

The aim of the present study was to provide a comprehensive characterization of whole genome DNA methylation patterns in replicative and ionizing irradiation- or doxorubicin-induced premature senescence, exhaustively exploring epigenetic modifications in three different human cell types: in somatic diploid skin fibroblasts and in bone marrow- and adipose-derived mesenchymal stem cells. With CpG-wise differential analysis, three epigenetic signatures were identified: (a) cell type- and treatment-specific signature; (b) cell type-specific senescence-related signature; and (c) cell type-transversal replicative senescence-related signature. Cluster analysis revealed that only replicative senescent cells created a distinct group reflecting notable alterations in the DNA methylation patterns accompanying this cellular state.

A Novel Experimental Rat Model for the Assessment of Myocardial Ischemia Based on Single Photon Emission Computed Tomography.

Background/aim: Myocardial infarction, an acute medical situation with a high mortality rate worldwide, has been extensively studied in modern cardiovascular research, using different experimental models. However, a deep understanding of myocardial activity loss has not been fully investigated. We have developed a novel experimental rat model for noninvasive assessment of myocardial ischemia based on single photon emission computed tomography (SPECT/CT), in order to further understand and evaluate myocardial activity before and after surgical induction of myocardial ischemia.

Identification of Novel Circular RNAs of the Human Protein Arginine Methyltransferase 1 () Gene, Expressed in Breast Cancer Cells.

Circular RNAs (circRNAs) constitute a type of RNA formed through back-splicing. In breast cancer, circRNAs are implicated in tumor onset and progression. Although histone methylation by PRMT1 is largely involved in breast cancer development and metastasis, the effect of circular transcripts deriving from this gene has not been examined.

Activation of the JNKs/ATM-p53 axis is indispensable for the cytoprotection of dermal fibroblasts exposed to UVB radiation.

Although UVB radiation is mainly absorbed by the epidermis, ~5-10% of its photons reach and affect the upper part of the dermis. Physiologically relevant UVB doses, able to provoke erythema, induce apoptosis in human dermal fibroblasts in vitro, as well as in the dermis of SKH-1 mice. Given the sparse and even contradictory existing information on the effect of UVB radiation on dermal fibroblasts' viability, aim of this work was to unravel the crucial signaling pathways regulating the survival of UVB-treated human dermal fibroblasts.

Cytotoxicity and estrogenicity of a novel 3-dimensional printed orthodontic aligner.

Introduction: Orthodontic aligners printed with in-office 3-dimensional (3D) procedures have been described, but no data on their biocompatibility exist. This study investigates the cytotoxicity and estrogenicity of a 3D-printed orthodontic aligner by assessing its biological and behavioral effects.

Methods: Ten sets of 1 type of aligner were immersed in sterile deionized water for 14 days, and the cytotoxicity and estrogenicity of released factors were assessed via MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assays on human gingival fibroblasts and the estrogen-sensitive MCF-7 and the estrogen-insensitive MDA-MB-231 breast cancer cell lines.