Most recent publications
Alzheimer’s disease and amyloid beta: The new functional hypothesis
On the basis of the new functional hypothesis recently published by Roberta Ricciarelli and Ernesto Fedele in a prestigious scientific journal*, it may turn out that memory deficits in Alzheimer’s disease (AD) are caused (at least in part) by a loss of function of Aβ peptides. The Authors also suggest that Aβ accumulation, generally considered the main culprit of AD, might instead represent a compensatory neuronal response to the peptide loss of function.
This picture could explain why pharmacological strategies aimed at clearing Aβ from the brain of AD patients have been unsuccessful to date, leading pharma giants like Pfizer and Merck to pull out of research into AD.
Interestingly enough, to increase Aβ levels and ameliorate memory, experimental animal models have been treated with a PDE inhibitor better known as Viagra®.
Very recently, the same research group has identified the protein Rab5 as crucially involved in the neuronal effect of the drug**.
*Ricciarelli R, Fedele E. cAMP, cGMP and Amyloid β: Three Ideal Partners for Memory Formation. Trends Neurosci. 2018, 41(5):255-266.
**Caudano F, Montalto G, Passalacqua M, Pronzato MA, Fedele E, Ricciarelli R. cGMP favors the interaction between APP and BACE1 by inhibiting Rab5 GTPase activity. Sci. Rep. 2020 Jan 28;10(1):1358.
An innovative method in order to improve the effectiveness of chemotherapy
The efficacy of many clinically-used chemotherapeutic drugs, including etoposide, is limited by the reduced bioavailability, the induction of toxic effects that limit the dosage and the metabolic inactivation. In the study recently published in Antioxidants* it has been demonstrated that the use of dendrimeric nanoparticles able of encapsulating etoposide can be a promising strategy in order to improve the effectiveness of chemiotherapeutic drugs. The relevance of this study, which arises from the collaboration between Cinzia Domenicotti’s group and Silvana Alfei (DIFAR), is based on the demonstration that the dendrimeric nanoparticles, acting in synergy with etoposide, increase ROS-mediated cytotoxic action of the drug in a time-dependent manner. These in vitro studies suggest that this new nanoformulation, capable of limiting the degradation of etoposide and promoting its controlled release, could be an effective therapeutic tool in anticancer treatment.
*Alfei S, Marengo B, Domenicotti C. Polyester-Based Dendrimer Nanoparticles Combined with Etoposide Have an Improved Cytotoxic and Pro-Oxidant Effect on Human Neuroblastoma Cells. Antioxidants (Basel). 2020 Jan 6;9(1). pii: E50. doi: 10.3390/antiox9010050.
**Falone S, Lisanti MP, Domenicotti C. Oxidative Stress and Reprogramming of Mitochondrial Function and Dynamics as Targets to Modulate Cancer Cell Behavior and Chemoresistance. Oxid Med Cell Longev. 2019 Nov 15;2019:4647807. doi:10.1155/2019/4647807.
Role of Heme oxygenase 1 in melanoma progression
Heme oxygenase 1 (HO-1) plays a crucial role in favouring cell survival. In cancer cells this can lead to the resistance to therapy and favour cancer progression. In a recent paper published on Internaltional Journal of Cancer * in collaboration with the laboratory of Clinical Immunology at Policlinico Ospedale San Martino in Genoa (Prof. Pietra), Prof. Nitti’s group provided evidence that HO-1 induction increases BRAFv600 melanoma cell resistance to Vemurafenib (the drug commonly used to treat this neoplasia), reducing cancer cell recognition by Natural Killer cells. Therefore, pharmacological HO-1 inhibition can improve melanoma therapy, reducing relapses. Moreover, HO-1 could be involved in other aspects of cancer progression such as angiogenesis, due to the important role played in endothelial cells biology, recently reviewed on Frontiers in Physiology**.
*Furfaro AL, Ottonello S, Loi G, Cossu I, Piras S, Spagnolo F, Queirolo P, Marinari UM, Moretta L, Pronzato MA, Mingari MC, Pietra G, Nitti M. HO-1 downregulation favors BRAF(V600) melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition. Int J Cancer. 2020 Aprn1;146(7):1950-1962. doi: 10.1002/ijc.32611. Epub 2019 Aug 24.
**Nitti M, Furfaro AL, Mann GE. Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment? Front Physiol. 2020 Jan 29;11:23. doi:n10.3389/fphys.2020.00023. eCollection 2020.
New perspective in glaucoma therapy
Glaucoma is a progressive and chronic optic neuropathy characterized by typical visual field defects*. Four main classes of topical drugs are currently available on the market: beta-blockers, prostaglandins, alpha2-agonists and topical carbonic anhydrase inhibitors for the treatment of intraocular pressure (IOP). The purpose of this research is to outline the efficacy of timolol which has few topical side effects, while it has important systemic side effects on the cardiac and respiratory system. The interesting fact of this research is that the use of timolol 0.1% without preservatives is able to control IOP similarly with other beta-blockers at higher concentrations, and is better tolerated by patients who reduced the symptoms of dry eye **. When medical treatment is not enough, surgery can help to decrease intraocular pressure. Many different surgical options are available and some are so called “mini invasive”. The aim of the research is to evaluate the risks and the efficacy of these new techniques***.
*Valente C, D’Alessandro E, Iester M. Classification and Statistical Trend Analysis in Detecting Glaucomatous Visual Field Progression. J Ophthalmol 2019 May 28;2019:1583260. doi: 10.1155/2019/1583260.
**Ferreras A, Figus M, Fogagnolo P, Iester M, Frezzotti P. Managing Side Effects on Ocular Surface Caused by Glaucoma Eye Drops. Curr Med Chem. 2019;26(22):4223-4224. doi: 10.2174/092986732622190920092210.
***Olivari S, Cutolo CA, Negri L, Cappelli F, Testa V, Iester M, Traverso CE. XEN Implant Fracture During Needling Procedure. J Glaucoma. 2019 Dec;28(12):1086-1089. doi: 10.1097/IJG.0000000000001360.
Unraveling molecular mechanisms underlying the chemoresistance
Drug resistance is the major obstacle in successfully treating high-risk neuroblastoma. This study recently published on Scientific Reports* shows that chronic treatment with etoposide of a high-risk neuroblastoma cell line induces a monoallelic deletion of the 13q14.3 locus with a marked down-regulation of P53 inducible miRNA-15a/16-1 levels. This leads to the up-regulation of BMI-1 oncoprotein that causes a metabolic adaptation of drug-resistant cancer cells.
The importance of this multidisciplinary study of Prof Cinzia Domenicotti’s group is to highlight the potential role of these miRNAs as markers of drug resistance and also as therapeutic targets.
*Marengo B, Monti P, Miele M, Menichini P, Ottaggio L, Foggetti G, Pulliero A, Izzotti A, Speciale A, Garbarino O, Traverso N, Fronza G, Domenicotti C. Etoposide-resistance in a neuroblastoma model cell line is associated with 13q14.3 mono-allelic deletion and miRNA-15a/16-1 down-regulation. Sci Rep. 2018, 8(1):13762.
Usefulness of carbonyl and glycoxidative stress markers in cat renal failure
Cats are commonly affected by chronic kidney disease (CKD). Many reactive carbonyl intermediates and end products originating from the oxidative stress pathways are recognised as uraemic toxins and may play a role in CKD progression. The aim of the present study* is to confirm whether carbonyl end-product formation is higher in cats affected by CKD and to assess whether an angiotensin-converting enzyme inhibitor (ACEi) might affect these hallmarks. Significantly high concentrations of both intermediate and end products of carbonyl/oxidative stress were detected in CKD cats. This is the first study to have concurrently taken into account several uraemic toxins and biochemicalparameters in cats affected by CKD. The study seems to indicate that there is no important effect of ACEi on the glycoxidative damage parameters evaluated.
* Valle E, Prola L, Vergnano D, Borghi R, Monacelli F, Traverso N, Bruni N, Bovero A, Schiavone A, Nery J, Bergero D, Odetti P. Investigation of hallmarks of carbonyl stress and formation of end products in feline chronic kidney disease as markers of uraemic toxins. Feline Med Surg. 2018 Jul 1:1098612X18783858. doi: 10.1177/1098612X18783858.
Cell adaptation to stress. A crucial role for HO-1 in neuronal-like cells
Neuronal cell ability to counteract oxidative stress is fundamental to cell survival. However, cell adaptability decreases during ageing while generally increases in tumor cells and favors cell resistance to therapy. Dr. Nitti’s group demonstrated that neuronal cell resistance to redox imbalance involves the up-regulation of HO-1. In neuroblastoma cells exposed to oxidative stress HO-1 induction depends on the expression of microRNA-494, as recently published on Frontiers in Oncology* highlighting new molecular targets for neuroblastoma therapy. Moreover, the role played by HO-1 in nervous system during ageing and neurodegenerative diseases seems to be highly complex and related to the extent of its activation and to the cell types mainly involved, as recently reviewed on International Journal of Molecular Sciences**.
*Piras S, Furfaro AL, Caggiano R, Brondolo L, Garibaldi S, Ivaldo C, Marinari UM, Pronzato MA, Faraonio R, Nitti M. microRNA-494 Favors HO-1 Expression in Neuroblastoma Cells Exposed to Oxidative Stress in a Bach1-Independent Way. Front Oncol. 2018, 8:199.
**Nitti M, Piras S, Brondolo L, Marinari UM, Pronzato MA, Furfaro AL. Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration? Int J Mol Sci. 2018, 19(8).