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Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The inhibitors of histone deacetylases (HDACs) enzymes are an emerging class of drugs proposed for the treatment of several tumors. Despite a general antineoplastic effectiveness, HDACs inhibitors showed conflicting results concerning their effects on the nervous system. Such a discrepancy could be ascribable to the different actions of the HDACs and to drug selectivity. In this review, we analyzed the role of the main HDACs within the nervous system to better understand the effect of their inhibition, with the aim of identifying the most promising candidate to become an effective antineoplastic drug with a limited neurotoxic profile. Histone deacetylases (HDACs) are a group of enzymes that modify gene expression through the lysine acetylation of both histone and non-histone proteins, leading to a broad range of effects on various biological pathways. New insights on this topic broadened the knowledge on their biological activity and even more questions arose from those discoveries. The action of HDACs is versatile in biological pathways and, for this reason, inhibitors of HDACs (HDACis) have been proposed as a way to interfere with HDACs' involvement in tumorigenesis. In 2006, the first HDACi was approved by FDA for the treatment of cutaneous T-cell lymphoma; however, more selective HDACis were recently approved. In this review, we will consider new information on HDACs' expression and their regulation for the treatment of central and peripheral nervous system diseases. [ABSTRACT FROM AUTHOR]

Cellular communication and the transfer of information from one cell to another is crucial for cell viability and homeostasis. During the last decade, tunneling nanotubes (TNTs) have attracted scientific attention, not only as a means of direct intercellular communication, but also as a possible system to transport biological cargo between distant cells. Peculiar TNT characteristics make them both able to increase cellular survival capacities, as well as a potential target of neurodegenerative disease progression. Despite TNT formation having been documented in a number of cell types, the exact mechanisms triggering their formation are still not completely known. In this review, we will summarize and highlight those studies focusing on TNT formation in the nervous system, as well as their role in neurodegenerative diseases. Moreover, we aim to stress some possible mechanisms and important proteins probably involved in TNT formation in the nervous system. [ABSTRACT FROM AUTHOR]

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN) is a frequent adverse event of colorectal cancer treatment. OIPN encompasses a chronic and an acute syndrome. The latter consists of transient axonal hyperexcitability, due to unbalance in Na+ voltage-operated channels (Na+VOC). This leads to sustained depolarisation which can activate the reverse mode of the Na+/Ca2+ exchanger 2 (NCX2), resulting in toxic Ca2+ accumulation and axonal damage (ADa). We explored the role of NCX2 in in vitro and in vivo settings. Embryonic rat Dorsal Root Ganglia (DRG) organotypic cultures treated with SEA0400 (SEA), a NCX inhibitor, were used to assess neuroprotection in a proof-of-concept and pilot study to exploit NCX modulation to prevent ADa. In vivo, OHP treated mice (7 mg/Kg, i.v., once a week for 8 weeks) were compared with a vehicle-treated group (n = 12 each). Neurophysiological and behavioural testing were performed to characterise acute and chronic OIPN, and morphological analyses were performed to detect ADa. Immunohistochemistry, immunofluorescence, and western blotting (WB) analyses were also performed to demonstrate changes in NCX2 immunoreactivity and protein expression. In vitro, NCX inhibition was matched by ADa mitigation. In the in vivo part, after verifyingboth acute and chronic OIPN had ensued, we confirmed via immunohistochemistry, immunofluorescence, and WB that a significant NCX2 alteration had ensued in the OHP group. Our data suggest NCX2 involvement in ADa development, paving the way to a new line of research to prevent OIPN. [ABSTRACT FROM AUTHOR]

Neurons are permanent cells whose key feature is information transmission via chemical and electrical signals. Therefore, a finely tuned homeostasis is necessary to maintain function and preserve neuronal lifelong survival. The cytoskeleton, and in particular microtubules, are far from being inert actors in the maintenance of this complex cellular equilibrium, and they participate in the mobilization of molecular cargos and organelles, thus influencing neuronal migration, neuritis growth and synaptic transmission. Notably, alterations of cytoskeletal dynamics have been linked to alterations of neuronal excitability. In this review, we discuss the characteristics of the neuronal cytoskeleton and provide insights into alterations of this component leading to human diseases, addressing how these might affect excitability/synaptic activity, as well as neuronal functioning. We also provide an overview of the microscopic approaches to visualize and assess the cytoskeleton, with a specific focus on mitochondrial trafficking. [ABSTRACT FROM AUTHOR]

Mesenchymal Stem Cells (MSCs) are adult multipotent cells able to increase sensory neuron survival: direct co-culture of MSCs with neurons is pivotal to observe a neuronal survival increase. Despite the identification of some mechanisms of action, little is known about how MSCs physically interact with neurons. The aim of this paper was to investigate and characterize the main mechanisms of interaction between MSCs and neurons. Morphological analysis showed the presence of gap junctions and tunneling nanotubes between MSCs and neurons only in direct co-cultures. Using a diffusible dye, we observed a flow from MSCs to neurons and further analysis demonstrated that MSCs donated mitochondria to neurons. Treatment of co-cultures with the gap junction blocker Carbenoxolone decreased neuronal survival, thus demonstrating the importance of gap junctions and, more in general, of cell communication for the MSC positive effect. We also investigated the role of extracellular vesicles; administration of direct co-cultures-derived vesicles was able to increase neuronal survival. In conclusion, our study demonstrates the presence and the importance of multiple routes of communication between MSCs and neurons. Such knowledge will allow a better understanding of the potential of MSCs and how to maximize their positive effect, with the final aim to provide the best protective treatment. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neurotoxicity ( CIPN) is a potentially dose-limiting side effect of the treatment of several cancers. CIPN is predominantly or exclusively sensory, and it is frequently associated with unpleasant symptoms, overall referred to as 'pain.' However, given the markedly different clinical presentation and course of CIPN depending on the antineoplastic drug used, the broad term 'pain' in the specific context of CIPN needs to be reconsidered and refined. In fact, a precise identification of the features of CIPN has relevant implication in the design of rational-based clinical trials and in the selection of possible active drugs. [ABSTRACT FROM AUTHOR]

The article focuses on the potential use of Histone deacetylases inhibitors (HDACi) to overcome chemotherapy-induced peripheral neuropathy (CIPN) by enhancing the antineoplastic effect of anticancer drugs and reducing their neurotoxicity, particularly through the inhibition of HDAC6.

The clinical usability of pancreatic islet transplantation for the treatment of type I diabetes, despite some encouraging results, is currently hampered by the short lifespan of the transplanted tissue. In vivo studies have demonstrated that co-transplantation of Mesenchymal Stem Cells (MSCs) with transplanted pancreatic islets is more effective with respect to pancreatic islets alone in ensuring glycemia control in diabetic rats, but the molecular mechanisms of this action are still unclear. The aim of this study was to elucidate the molecular mechanisms of the positive effect of MSCs on pancreatic islet functionality by setting up direct, indirect and mixed co-cultures. MSCs were both able to prolong the survival of pancreatic islets, and to directly differentiate into an “insulin-releasing” phenotype. Two distinct mechanisms mediated these effects: i) the survival increase was observed in pancreatic islets indirectly co-cultured with MSCs, probably mediated by the trophic factors released by MSCs; ii) MSCs in direct contact with pancreatic islets started to express Pdx1, a pivotal gene of insulin production, and then differentiated into insulin releasing cells. These results demonstrate that MSCs may be useful for potentiating pancreatic islets' functionality and feasibility. [ABSTRACT FROM AUTHOR]

Adipocytes’ biology and the mechanisms that control adipogenesis have gained importance because of the need to develop therapeutic strategies to control obesity and the related pathologies. Human mesenchymal stem cells (hMSCs), undifferentiated stem cells present in the bone marrow that are physiological precursors of adipocytes, were induced to adipogenic differentiation. The molecular mechanisms on the basis of the adipogenesis were evaluated, focusing on the MAPKinases ERK1 and ERK2, which are involved in many biological and cellular processes. ERK1 and ERK2 phosphorylation was reduced with different timing and intensity for the two isoforms in treated hMSCs in comparison with control cells until day 10 and then at 14–28 days, it reached the level of untreated cultures. The total amount of ERK1 was also decreased up to day 10 and then was induced to the level of untreated cultures, whereas the expression of ERK2 was not changed following adipogenic induction. Treatment with the specific ERK1/2 inhibitor U0126 during the whole differentiation period hampered hMSCs’ adipogenic differentiation, as lipid droplets appeared in very few cells and were reduced in number and size. When U0126 was administered only during the initial phase of differentiation, the number of hMSCs recruited to adipogenesis was reduced while, when it was administered later, hMSCs did not acquire a mature adipocytic phenotype. ERK1 and ERK2 are important for hMSC adipogenic differentiation since any alteration to the correct timing of their phosphorylation affects either the recruitment into the differentiation program and the extent of their maturation. [ABSTRACT FROM PUBLISHER]

Multiple Sclerosis (MS) is a disabling immune-mediated neurological disease, affecting more than 2.5 million people worldwide. Regardless of the broad arena of pharmaceutical strategies against MS, up to now a concrete cure is still missing. The drugs against MS currently used in the clinical practice are mainly biological immunomodulatory therapeutics, which are effective and safe during the short-term treatment. Nevertheless, they are suitable only for systemic administration and fairly expensive, hence academic and industrial environments are still addressing their efforts towards the development of new drugs Chamberlain et al. (2016). Considering that neurodegeneration is a contributory factor in the onset of MS, Sigma 1 Receptor (S1R) could play a crucial role in MS Collina et al. (2013), Peviani et al. (2014). During the years, our interdisciplinary research group identified compound (R)-RC-33, as a new selective S1R agonist with an excellent S1R afinity (Ki= 1.8 nM) along with high selectivity over other receptors, including S2R, and good in vitro metabolic stability Rossi et al. (2010), Rossi et al. (2013), Marra et al. (2016). On the bases of these results, (R)-RC-33 has been selected as lead compound for MS preliminary biological assay. A pilot study was performed to evaluate the effect of the S1R agonist (R)-RC33 on rat Dorsal Root Ganglia (DRG) experimental model. Our encouraging results support the idea that S1R represents a novel appealing target for the treatment of neurodegeneration and a promising protein for the development of new drugs against MS. [ABSTRACT FROM AUTHOR]

Among the different families of intracellular molecules that can be modulated during cell damage and repair, mitogen-activated protein kinases (MAPKs) are particularly interesting because they are involved in several intracellular pathways activated by injury and regeneration signals. Despite most of the studies have been performed in non-neurological models, recently a causal role for MAPKs has been postulated in central nervous system disorders. However, also in some peripheral neuropathies, MAPK changes can occur and these modifications might be relevant in the pathogenesis of the damage as well as during regeneration and repair. In this review, the current knowledge on the role of MAPKs in peripheral neuropathies will be discussed. [ABSTRACT FROM AUTHOR]

Thee article offers information on the positive effects of the Mesenchymal Stem Cell (MSC)-induced neuroprotection on the mitochondrial transfer. It mentions the studies that have investigated the mechanisms of MSC neuroprotective effect, with the identification of multiple mechanisms, potentially involved: from the release of trophic molecules such as growth factors, cytokines, antioxidants, to the secretion of vesicles containing molecules important for tissue repair.

The article presents a study which explores the morphological and functional assessment of NCX2 potential role in axonal damage related to Oxaliplatin. It mentions that Oxaliplatin (OHP) induced peripheral neurotoxicity (OIPN), a potentially persistent sequela of chemotherapy, characterised by a chronic and acute neurotoxicity syndrome.

Chemotherapy-induced peripheral neuropathy (CIPN) is widely recognized as a potentially severe toxicity that often leads to dose reduction or discontinuation of cancer treatment. Symptoms may persist despite discontinuation of chemotherapy and quality of life can be severely compromised. The clinical symptoms of CIPN, and the cellular and molecular targets involved in CIPN, are just as diverse as the wide variety of anticancer agents that cause peripheral neurotoxicity. There is an urgent need for extensive molecular and functional investigations aimed at understanding the mechanisms of CIPN. Furthermore, a reliable human cell culture system that recapitulates the diversity of neuronal modalities found in vivo and the pathophysiological changes that underlie CIPN would serve to advance the understanding of the pathogenesis of CIPN. The demonstration of experimental reproducibility in a human peripheral neuronal cell system will increase confidence that such an in vitro model is clinically useful, ultimately resulting in deeper exploration for the prevention and treatment of CIPN. Herein, we review current in vitro models with a focus on key characteristics and attributes desirable for an ideal human cell culture model relevant for CIPN investigations. [ABSTRACT FROM AUTHOR]

Cell-free therapy using extracellular vesicles (EVs) from adipose-derived mesenchymal stromal/stem cells (ASCs) seems to be a safe and effective therapeutic option to support tissue and organ regeneration. The application of EVs requires particles with a maximum regenerative capability and hypoxic culture conditions as an in vitro preconditioning regimen has been shown to alter the molecular composition of released EVs. Nevertheless, the EV cargo after hypoxic preconditioning has not yet been comprehensively examined. The aim of the present study was the characterization of EVs from hypoxic preconditioned ASCs. We investigated the EV proteome and their effects on renal tubular epithelial cells in vitro. While no effect of hypoxia was observed on the number of released EVs and their protein content, the cargo of the proteins was altered. Proteomic analysis showed 41 increased or decreased proteins, 11 in a statistically significant manner. Furthermore, the uptake of EVs in epithelial cells and a positive effect on oxidative stress in vitro were observed. In conclusion, culture of ASCs under hypoxic conditions was demonstrated to be a promising in vitro preconditioning regimen, which alters the protein cargo and increases the anti-oxidative potential of EVs. These properties may provide new potential therapeutic options for regenerative medicine. [ABSTRACT FROM AUTHOR]

Gliomas, which account for nearly a quarter of all primary CNS tumors, present significant contemporary therapeutic challenges, particularly the highest-grade variant (glioblastoma multiforme), which has an especially poor prognosis. These difficulties are due to the tumor's aggressiveness and the adverse effects of radio/chemotherapy on the brain. Stem cell therapy is an exciting area of research being explored for several medical issues. Neural stem cells, normally present in the subventricular zone and the hippocampus, preferentially migrate to tumor masses. Thus, they have two main advantages: They can minimize the side effects associated with systemic radio/chemotherapy while simultaneously maximizing drug delivery to the tumor site. Another feature of stem cell therapy is the variety of treatment approaches it allows. Stem cells can be genetically engineered into expressing a wide variety of immunomodulatory substances that can inhibit tumor growth. They can also be used as delivery vehicles for oncolytic viral vectors, which can then be used to combat the tumorous mass. An alternative approach would be to combine stem cells with prodrugs, which can subsequently convert them into the active form upon migration to the tumor mass. As with any therapeutic modality still in its infancy, much of the research regarding their use is primarily based upon knowledge gained from animal studies, and a number of ongoing clinical trials are currently investigating their effectiveness in humans. The aim of this review is to highlight the current state of stem cell therapy in the treatment of gliomas, exploring the different mechanistic approaches, clinical applicability, and the existing limitations. [ABSTRACT FROM AUTHOR]

The article informs that oxaliplatin induced peripheral neurotoxicity is a double folded late toxicity comprising a sensory chronic neuropathy and a peculiar acute neurotoxicity syndrome. It is noted that chronic neurotoxicity was assessed via nerve conduction studies, behavioural tests and neuropathology and observed a significant Oxaliplatin-related neurotoxicity reduction related to Sodium-calcium exchanger family inhibition assessing Dorsal Root Ganglianeurite elongation.

The advent of the new revolutionary approach based on regenerative medicine is progressively reshaping the therapeutic scenario of many different diseases, such as cardiovascular diseases and immune diseases, with encouraging results. During the last 10 years, many studies have also proposed the use of mesenchymal stem cells (MSCs), adult stem cells with several interesting properties already used in different experimental models, for the treatment of diabetes, however, reporting conflicting outcomes. These reasons have given rise to a question: are these cells a real trump card for the biomedical field? Are they really able to outclass the traditional therapies, or at least able to give an advantage over them? In this review, we will discuss the most promising results obtained with MSCs for the treatment of diabetes and its complications, we will compare the different therapeutic treatments applied as well as the most likely mechanisms of action, and overall we will give an in-depth overview of the pros and the cons of the use of MSCs for the therapy of both type-1 and type-2 diabetes. [ABSTRACT FROM AUTHOR]

Diabetes is a worldwide disease which actually includes different disorders related to glucose metabolism. According to different epidemiological studies, patients affected by diabetes present a higher risk to develop both acute and chronic pancreatitis, clinical situations which, in turn, increase the risk to develop pancreatic cancer. Current therapies are able to adjust insulin levels according to blood glucose peak, but they only partly reach the goal to abrogate the consequent inflammatory milieu responsible for diabetes-related diseases. In recent years, many studies have investigated the possible use of adult mesenchymal stem cells (MSCs) as alternative therapeutic treatment for diabetes, with promising results due to the manifold properties of these cells. In this review we will critically analyze the many different uses of MSCs for both diabetes treatment and for the reduction of diabetes-related disease development, focusing on their putative molecular mechanisms. [ABSTRACT FROM AUTHOR]

During the last two decades Mesenchymal Stem Cells (MSCs) have been proposed for the treatment of several neurological diseases, such as Alzheimer's disease or Parkinson's Disease [1], initially with the aim to replace the damaged neuronal cells, and later to cure, rather than to replace the neuronal cells. In particular, previous studies demonstrated that MSCs directly co-cultured with sensory neurons were able to strongly increase the neuronal survival, and to protect them from different toxic stimuli [2; 3], thus theoretically being useful to really change the course of all the diseases affecting sensory neurons. Anyway, it is mandatory to understand the mechanisms involved in such an interaction. Aim of this work is to investigate the different interaction manners, and the identification of the molecules used by MSCs and neurons to communicate. In particular, by Immunofluorescence and Electron microscopy analysis, we observed the formation of gap junctions and tunneling nanotubes, cellular structures potentially allowing the flow of cellular stuff (4). In addition, with the diffusible fluorescent dye Calcein, we demonstrated the flux direction from MSCs to neurons. We then analyzed the nature of the exchanged materials, and we observed an involvement of exosome and more in general vesicular structures, and even subcellular components as mitochondria. All these molecules and structures may be used by MSCs to cure neurons. As a proof of concept, we will expose neurons to the putative protective MSC-derived molecules, to determine if they are sufficient to achieve a positive effect. On the basis of the identified interactions and the pivotal molecules exchanged, it will be possible to enhance the MSC protective effect on neurons by exploiting the identified key molecules. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) have been often proposed for the therapy of several neurological diseases, due to their manifold peculiar properties. In particular, since it has been previously demonstrated that these cells are able to increase the survival of untreated sensory neurons [1], in this work we evaluated their possible protective effect on sensory neurons previously exposed to toxic agents. This could be particularly relevant to design a supportive therapy to counteract the peripheralneuropathy, a very common side effect of several chemotherapeutic agents, such asplatinum and taxanes compounds, which often represents their dose limiting factor [2]. Several strategies have been suggested to reduce drug neurotoxicity without affecting the antineoplastic potential, but up to now results were not encouraging [3]. Here we demonstrated that Cisplatin (CDDP) and Paclitaxel treatedsensory neurons are protected by the co-culture with MSCs, but in two different manners: through a direct contact able to block apoptosis for CDDP-treated neurons, and by the release of trophic factors (including glutathione) for Paclitaxel-treated ones. In addition, theMSCs' effectiveness was also verified on cortical neurons, since the recent advances in targeted drug delivery allowed to drive chemotherapeutic drugs also to the central nervous system. We verified that cortical neurons are more vulnerable to thetoxic action of the drugs, and overall that MSCs fail at all to protect them. All these data demonstrated that MSCs are potentially useful to limit the peripheral neuropathy onset for their protective effect on injured-sensory neurons, but they also identified for the first time a different susceptibility of cortical and sensory neurons to MSC action. [ABSTRACT FROM AUTHOR]