Valeria Consoli

Bio: Valeria Consoli is an academic researcher from University of Catania. The author has contributed to research in topics: Medicine & Heme oxygenase. The author has an hindex of 2, co-authored 6 publications receiving 11 citations.

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions.

Abstract: Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

Abstract: The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study’s purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO’s effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO’s implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO’s contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.

Nanomedicine Strategies for Management of Drug Resistance in Lung Cancer

Abstract: Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge, as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and the encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer, presents novel nanomedicine therapeutics aimed at improving the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for the clinical application of nanomedicine in the management of LC resistance.

Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation.

Abstract: In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents.

Heme Oxygenase-1: An Anti-Inflammatory Effector in Cardiovascular, Lung, and Related Metabolic Disorders

Abstract: The heme oxygenase (HO) enzyme system catabolizes heme to carbon monoxide (CO), ferrous iron, and biliverdin-IXα (BV), which is reduced to bilirubin-IXα (BR) by biliverdin reductase (BVR). HO activity is represented by two distinct isozymes, the inducible form, HO-1, and a constitutive form, HO-2, encoded by distinct genes (HMOX1, HMOX2, respectively). HO-1 responds to transcriptional activation in response to a wide variety of chemical and physical stimuli, including its natural substrate heme, oxidants, and phytochemical antioxidants. The expression of HO-1 is regulated by NF-E2-related factor-2 and counter-regulated by Bach-1, in a heme-sensitive manner. Additionally, HMOX1 promoter polymorphisms have been associated with human disease. The induction of HO-1 can confer protection in inflammatory conditions through removal of heme, a pro-oxidant and potential catalyst of lipid peroxidation, whereas iron released from HO activity may trigger ferritin synthesis or ferroptosis. The production of heme-derived reaction products (i.e., BV, BR) may contribute to HO-dependent cytoprotection via antioxidant and immunomodulatory effects. Additionally, BVR and BR have newly recognized roles in lipid regulation. CO may alter mitochondrial function leading to modulation of downstream signaling pathways that culminate in anti-apoptotic, anti-inflammatory, anti-proliferative and immunomodulatory effects. This review will present evidence for beneficial effects of HO-1 and its reaction products in human diseases, including cardiovascular disease (CVD), metabolic conditions, including diabetes and obesity, as well as acute and chronic diseases of the liver, kidney, or lung. Strategies targeting the HO-1 pathway, including genetic or chemical modulation of HO-1 expression, or application of BR, CO gas, or CO donor compounds show therapeutic potential in inflammatory conditions, including organ ischemia/reperfusion injury. Evidence from human studies indicate that HO-1 expression may represent a biomarker of oxidative stress in various clinical conditions, while increases in serum BR levels have been correlated inversely to risk of CVD and metabolic disease. Ongoing human clinical trials investigate the potential of CO as a therapeutic in human disease.

Analytical profile and antioxidant and anti-inflammatory activities of the enriched polyphenol fractions isolated from bergamot fruit and leave

Abstract: The aim of the study is to compare the qualitative and semi-quantitative profile of the polyphenol fraction purified from the leaf (BLPF) and fruit (BFPF) of bergamot (Citrus bergamia), and to evaluate their antioxidant and anti-inflammatory activity. The analytical qualitative profile was carried out by LC-ESI/MS using three different approaches: targeted (searching analytes already reported in bergamot extract), semi-targeted (a selective search of 3-hydroxy-3-methylglutarate [HMG] derivatives involved in the cholesterol reducing activity of BPF) and untargeted. A total number of 108 compounds were identified by using the three approaches, 100 of which are present in both the extracts thus demonstrating a good qualitative overlapping of polyphenols between the two extracts. The antioxidant activity was higher for BLPF in respect to BFPF but when normalized in respect to the polyphenol content they were almost overlapping. Both the extracts were found to dose dependently inhibit cell inflammation stimulated with IL-1α. In conclusion, the comparison of the qualitative and quantitative profile of polyphenols as well as of the antioxidant and anti-inflammatory activity of bergamot leaf and fruit well indicates that leaf is a valid source of bergamot polyphenol extraction and an even richer source of polyphenol in respect to the fruit.

RONS and Oxidative Stress: An Overview of Basic Concepts

Abstract: Oxidative stress (OS) has greatly interested the research community in understanding damaging processes occurring in cells. OS is triggered by an imbalance between reactive oxygen species (ROS) production and their elimination by the antioxidant system; however, ROS function as second messengers under physiological conditions. ROS are produced from endogenous and exogenous sources. Endogenous sources involve mitochondria, nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), oxidases (NOXs), endoplasmic reticulum (ER), xanthine oxidases (XO), endothelial nitric oxide synthase (eNOs), and others. In contrast, exogenous ROS might be generated through ultraviolet (UV) light, ionizing radiation (IR), contaminants, and heavy metals, among others. It can damage DNA, lipids, and proteins if OS is not controlled. To avoid oxidative damage, antioxidant systems are activated. In the present review, we focus on the basic concepts of OS, highlighting the production of reactive oxygen and nitrogen species (RONS) derived from internal and external sources and the last elimination. Moreover, we include the cellular antioxidant system regulation and their ability to decrease OS. External antioxidants are also proposed as alternatives to ameliorate OS. Finally, we review diseases involving OS and their mechanisms.

Molecular Mechanisms of Iron and Heme Metabolism.

Abstract: An abundant metal in the human body, iron is essential for key biological pathways including oxygen transport, DNA metabolism, and mitochondrial function. Most iron is bound to heme but it can also be incorporated into iron-sulfur clusters or bind directly to proteins. Iron's capacity to cycle between Fe2+ and Fe3+ contributes to its biological utility but also renders it toxic in excess. Heme is an iron-containing tetrapyrrole essential for diverse biological functions including gas transport and sensing, oxidative metabolism, and xenobiotic detoxification. Like iron, heme is essential yet toxic in excess. As such, both iron and heme homeostasis are tightly regulated. Here we discuss molecular and physiologic aspects of iron and heme metabolism. We focus on dietary absorption; cellular import; utilization; and export, recycling, and elimination, emphasizing studies published in recent years. We end with a discussion on current challenges and needs in the field of iron and heme biology. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson’s Disease

Abstract: Parkinson's disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress have been implicated in the pathogenesis of PD. Genetic and environmental factors can produce oxidative stress which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrate activation of multiple protective genes, including Heme oxygenase-1(HO-1), through which protects cells from oxidative stress.Nrf2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. Recently, a series of studies have reported different bioactive compounds were shown to be able to activate Nrf2/ARE can ameliorate PD-associated neurotoxin, both in animal models as well as in tissue culture.In this review, we briefly overview the sources of oxidative stress and the association between oxidative stress and the pathogenesis of PD. Then, we provided a concise overview of Nrf2/ARE pathway, and delineated the role played by activation of Nrf2/HO-1 in PD. At last, we expand our discussion to the neuroprotective effects of pharmacological modulation of Nrf2/HO-1 by bioactive compounds and the potential application of Nrf2 activators for the treatment of PD. This review suggest that pharmacological modulation of Nrf2/HO-1 signalling pathway by bioactive compounds as a therapeutic target of PD.