Targeting of tumor cells by custom antigen transfer: a novel approach for immunotherapy of cancer.

In the early stages of carcinogenesis, the transformed cells become "invisible" to the immune system. From this moment on, the evolution of the tumor depends essentially on the genotype of the primitive cancer cells and their subsequent genetic drift. The role of the immune system in blocking tumor progression from the earliest stages is largely underestimated because by the time tumors are clinically detectable, the immune system has already completely failed its task. Therefore, a clinical treatment capable of restoring the natural anti-tumor role of the immune system could prove to be the "ultimate weapon" against cancer. Herein, we propose a novel therapeutic approach for the treatment of solid cancer that exploits the capability of activated monocytes to transfer major histocompatibility complex I (MHC-I) molecules bound to antigenic peptides to cancer cells using microvesicles as cargo, making tumor cells target of a "natural" CD8+ T lymphocyte cytotoxic response.

Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer.

Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.

SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis.

5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches.

Differential impact of cold and hot tea extracts on tyrosine phosphatases regulating insulin receptor activity: a focus on PTP1B and LMW-PTP.

PURPOSE: The impact of tea constituents on the insulin-signaling pathway as well as their antidiabetic activity are still debated questions. Previous studies suggested that some tea components act as Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors. However, their nature and mechanism of action remain to be clarified. This study aims to evaluate the effects of both tea extracts and some of their constituents on two main negative regulators of the insulin-signaling pathway, Low-Molecular-Weight Protein Tyrosine Phosphatase (LMW-PTP) and PTP1B. METHODS: The effects of cold and hot tea extracts on the enzyme activity were evaluated through in vitro assays. Active components were identified using gas chromatography-mass spectrometry (GC-MS) analysis. Finally, the impact of both whole tea extracts and specific active tea components on the insulin-signaling pathway was evaluated in liver and muscle cells. RESULTS: We found that both cold and hot tea extracts inhibit LMW-PTP and PTP1B, even if with a different mechanism of action. We identified galloyl moiety-bearing catechins as the tea components responsible for this inhibition. Specifically, kinetic and docking analyses revealed that epigallocatechin gallate (EGCG) is a mixed-type non-competitive inhibitor of PTP1B, showing an IC50 value in the nanomolar range. Finally, in vitro assays confirmed that EGCG acts as an insulin-sensitizing agent and that the chronic treatment of liver cells with tea extracts results in an enhancement of the insulin receptor levels and insulin sensitivity. CONCLUSION: Altogether, our data suggest that tea components are able to regulate both protein levels and activation status of the insulin receptor by modulating the activity of PTP1B.

Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs.

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.

Activated fibroblasts enhance cancer cell migration by microvesicles-mediated transfer of Galectin-1.

Cancer-associated fibroblasts (CAFs) are one of the main components of the stromal compartment in the tumor microenvironment (TME) and the crosstalk between CAFs and cancer cells is essential for tumor progression and aggressiveness. Cancer cells mediate an activation process, converting normal fibroblasts into CAFs, that are characterized by modified expression of many proteins and increased production and release of microvesicles (MVs), extracellular vesicles generated by outwards budding from the cell membrane. Recent evidence underlined that the uptake of CAF-derived MVs changes the overall protein content of tumor cells. In this paper, we demonstrate that tumor activated fibroblasts overexpress Galectin-1 (Gal-1) and consequently release MVs containing increased levels of this protein. The uptake of Gal-1 enriched MVs by tumor cells leads to the upregulation of its intracellular concentration, that strongly affects cancer cell migration, while neither proliferation nor adhesion are altered. Accordingly, tumor cells co-cultured with fibroblasts silenced for Gal-1 have a reduced migratory ability. The present work reveals the key role of an exogenous protein, Gal-1, derived from activated fibroblasts, in cancer progression, and contributes to clarify the importance of MVs-mediated protein trafficking in regulating tumor-stroma crosstalk.

S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset.

BACKGROUND: L-Homocysteine (Hcy) is a non-proteinogenic α-amino acid synthesized from dietary methionine. In healthy humans, high Hcy levels are a risk factor for cardiovascular diseases, stroke and type 2 diabetes. A recent study reports that Hcy reacts with Cys10 of transthyretin (TTR), generating a stable covalent adduct. However, to date the effect of S-homocysteinylation on TTR conformational stability remains unknown. METHODS: The effect of Hcy on the conformational properties of wt- and L55P-TTR were analysed using a set of biophysical techniques. The cytotoxicity of S-homocysteinylated L55P-TTR was also evaluated in the HL-1 cardiomyocyte cell line, while the effects of the assemblies on kinematic and dynamics properties of cardiac muscle cells were analysed in cardiomyocyte syncytia. RESULTS: We found that Hcy stabilizes tetrameric wt-TTR, while it destabilizes the tetrameric structure of the L55P mutant, promoting the accumulation of self-assembly-prone monomeric species. CONCLUSIONS: Our study demonstrated that S-homocysteinylation of the L55P-TTR mutant impairs protein stability, favouring the appearance of toxic monomers. Interestingly, S-homocysteinylation affected only mutant, not wt-TTR. Moreover, we also show that assemblies of S-homocysteinylated L55P-TTR impair cardiomyocytes functional parameters. GENERAL SIGNIFICANCE: Our study offers new insights on the negative impact of S-homocysteinylation on L55P-TTR stability, whose aggregation is considered the causative agent of a form of early-onset familial amyloid polyneuropathy and cardiomyopathy. Our results suggest that high homocysteine levels are a further risk factor for TTR cardiomyopathy in patients harbouring the L55P-TTR mutation.

miR-210-3p mediates metabolic adaptation and sustains DNA damage repair of resistant colon cancer cells to treatment with 5-fluorouracil.

Chemoresistance is the primary cause of chemotherapy failure. Compelling evidence shows that micro RNAs (miRNAs) contribute to reprogram cancer cells toward a resistant phenotype. We investigate the role of miRNAs in the response to acute treatment with 5-FU in colon cancer-resistant cells. We performed a global gene expression profile for the entire miRNA genome and found a change in the expression of four miRNAs following acute treatment with 5-FU. Among them, we focused on miR-210-3p, previously described as a key regulator of DNA damage repair mechanisms and mitochondrial metabolism. We show that miR-210-3p downregulation enables resistant cells to counteract the toxic effect of the drug increasing the expression of RAD-52 protein, responsible for DNA damage repair. Moreover, miR-210-3p downregulation enhances oxidative phosphorylation (OXPHOS), increasing the expression levels of succinate dehydrogenase subunits D, decreasing intracellular succinate levels and inhibiting HIF-1α expression. Altogether, these adaptations lead to increased cells survival following drug exposure. These evidence suggest that miR-210-3p downregulation following 5-FU sustains DNA damage repair and metabolic adaptation to counteract drug treatment.

Morin-dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW-PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in an Apc-driven model of colon cancer.

LMW-PTP has been associated with the development of colorectal cancer (CRC) and with the resistance to chemotherapy in cancer cells. To clarify its role in vivo, we studied LMW-PTP expression in Pirc rats (F344/NTac-Apc am1137 ), genetically prone to CRC and resistant to apoptosis. In the morphologically normal mucosa (NM) of Pirc rats, a dramatic over-expression of LMW-PTP was found compared to wt rats (about 60 times higher). Moreover, LMW-PTP levels further increase in spontaneously developed Pirc colon tumors. To understand if and how LMW-PTP affects resistance to apoptosis, we studied CRC cell lines, sensitive (HT29 and HCT-116), or resistant (HT29R, HCT116R) to 5-Fluorouracil (5-FU): resistant cells over-express LMW-PTP. When resistant cells were challenged with morin, a polyphenol inhibiting LMW-PTP, a fast and dose-related down-regulation of LMW-PTP was observed. 5-FU and morin co-treatment dramatically decreased cell viability, increased apoptosis, and significantly impaired self-renewal ability of all the cancer cell lines we have studied. Similarly, we observed that, in Pirc rats, one-week morin administration (50 mg/kg) down-regulated LMW-PTP and restored the apoptotic response to 5-FU in the NM. Finally, administration of morin for a longer period led to a significant reduction in colon precancerous lesions, together with a down-regulation of LMW-PTP. Taken together, these results document the involvement of LMW-PTP in the process of CRC in vitro and in vivo. Morin treatment may be envisaged as a system to increase the sensitivity to chemotherapy and to prevent carcinogenesis.

LMW-PTP modulates glucose metabolism in cancer cells.

BACKGROUND: Low Molecular Weight Phosphotyrosine Protein Phosphatase (LMW-PTP) is an enzyme involved not only in tumor onset and progression but also in type 2 diabetes. A recent review shows that LMW-PTP acts on several RTK (receptor tyrosine kinase) such as PDGFR, EGFR, EphA2, Insulin receptor. It is well described also its interaction with cSrc. It is noteworthy that most of these conclusions are based on the use of cell lines expressing low levels of LMW-PTP. The aim of the present study was to discover new LMW-PTP substrates in aggressive human tumors where the over-expression of this phosphatase is a common feature. METHODS: We investigated, by proteomic analysis, the protein phosphorylation pattern of A375 human melanoma cells silenced for LMW-PTP. Two-dimensional electrophoresis (2-DE) analysis, followed by western blot was performed using anti-phosphotyrosine antibodies, in order to identify differentially phosphorylated proteins. RESULTS: Proteomic analysis pointed out that most of the identified proteins belong to the glycolytic metabolism, such as α-enolase, pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase and triosephosphate isomerase, suggesting an involvement of LMW-PTP in glucose metabolism. Assessment of lactate production and oxygen consumption demonstrated that LMW-PTP silencing enhances glycolytic flux and slow down the oxidative metabolism. In particular, LMW-PTP expression affects PKM2 tyrosine-phosphorylation and nuclear localization, modulating its activity. CONCLUSION: All these findings propose that tumor cells are subjected to metabolic reprogramming after LMW-PTP silencing, enhancing glycolytic flux, probably to compensate the inhibition of mitochondrial metabolism. GENERAL SIGNIFICANCE: Our results highlight the involvement of LMW-PTP in regulating glucose metabolism in A375 melanoma cells.

Targeting LMW-PTP to sensitize melanoma cancer cells toward chemo- and radiotherapy.

Tumor resistance to apoptosis is one the main causes of anticancer treatment failure. Previous studies showed that LMW-PTP overexpression enhances resistance of cancer cells to traditional anticancer drugs. Today, the role of LMW-PTP in inducing resistance to apoptosis in melanoma cells remains to be elucidated. Experimental setting include MTT assay, Annexin V/Pi method, and colony assay to assess whether silencing of LMW-PTP improves the sensitivity of A375 to dacarbazine, 5-FU, and radiotherapy. Pharmacological targeting of LMW-PTP was obtained using Morin, a LMW-PTP inhibitor. The ability of Morin to improve the effectiveness of anticancer drugs and radiotherapy was also studied. Moreover, PC3 cells were used as an alternative cellular model to confirm the data obtained with melanoma cells. We found that LMW-PTP silencing improves the effectiveness of dacarbazine, 5-FU, and radiotherapy. Identical results were obtained in vivo when Morin was used to target LMW-PTP. We demonstrated that Morin synergizes with dacarbazine, improving its cytotoxic activity. However, we showed that the combined treatment, Morin-anticancer drug, does not affect the viability of noncancerous cells. Knockdown of LMW-PTP sensitizes also PC3 cells to docetaxel and radiotherapy. In conclusion, we showed that LMW-PTP targeting improves effectiveness of anticancer drugs used for treatment of melanoma. Moreover, our results suggest that Morin could be used as adjuvant to improve the outcome of patients affected by metastatic melanoma.

Potency Biomarker Signature Genes from Multiparametric Osteogenesis Assays: Will cGMP Human Bone Marrow Mesenchymal Stromal Cells Make Bone?

In skeletal regeneration approaches using human bone marrow derived mesenchymal stromal cells (hBM-MSC), functional evaluation before implantation has traditionally used biomarkers identified using fetal bovine serum-based osteogenic induction media and time courses of at least two weeks. However, emerging pre-clinical evidence indicates donor-dependent discrepancies between these ex vivo measurements and the ability to form bone, calling for improved tests. Therefore, we adopted a multiparametric approach aiming to generate an osteogenic potency assay with improved correlation. hBM-MSC populations from six donors, each expanded under clinical-grade (cGMP) conditions, showed heterogeneity for ex vivo growth response, mineralization and bone-forming ability in a murine xenograft assay. A subset of literature-based biomarker genes was reproducibly upregulated to a significant extent across all populations as cells responded to two different osteogenic induction media. These 12 biomarkers were also measurable in a one-week assay, befitting clinical cell expansion time frames and cGMP growth conditions. They were selected for further challenge using a combinatorial approach aimed at determining ex vivo and in vivo consistency. We identified five globally relevant osteogenic signature genes, notably TGF-ß1 pathway interactors; ALPL, COL1A2, DCN, ELN and RUNX2. Used in agglomerative cluster analysis, they correctly grouped the bone-forming cell populations as distinct. Although donor #6 cells were correlation slope outliers, they contrastingly formed bone without showing ex vivo mineralization. Mathematical expression level normalization of the most discrepantly upregulated signature gene COL1A2, sufficed to cluster donor #6 with the bone-forming classification. Moreover, attenuating factors causing genuine COL1A2 gene down-regulation, restored ex vivo mineralization. This suggested that the signature gene had an osteogenically influential role; nonetheless no single biomarker was fully deterministic whereas all five signature genes together led to accurate cluster analysis. We show proof of principle for an osteogenic potency assay providing early characterization of primary cGMP-hBM-MSC cultures according to their donor-specific bone-forming potential.

Low molecular weight protein tyrosine phosphatase: Multifaceted functions of an evolutionarily conserved enzyme.

Originally identified as a low molecular weight acid phosphatase, LMW-PTP is actually a protein tyrosine phosphatase that acts on many phosphotyrosine-containing cellular proteins that are primarily involved in signal transduction. Differences in sequence, structure, and substrate recognition as well as in subcellular localization in different organisms enable LMW-PTP to exert many different functions. In fact, during evolution, the LMW-PTP structure adapted to perform different catalytic actions depending on the organism type. In bacteria, this enzyme is involved in the biosynthesis of group 1 and 4 capsules, but it is also a virulence factor in pathogenic strains. In yeast, LMW-PTPs dephosphorylate immunophilin Fpr3, a peptidyl-prolyl-cis-trans isomerase member of the protein chaperone family. In humans, LMW-PTP is encoded by the ACP1 gene, which is composed of three different alleles, each encoding two active enzymes produced by alternative RNA splicing. In animals, LMW-PTP dephosphorylates a number of growth factor receptors and modulates their signalling processes. The involvement of LMW-PTP in cancer progression and in insulin receptor regulation as well as its actions as a virulence factor in a number of pathogenic bacterial strains may promote the search for potent, selective and bioavailable LMW-PTP inhibitors.

PAMP Activity of Cerato-Platanin during Plant Interaction: An -Omic Approach.

Cerato-platanin (CP) is the founder of a fungal protein family consisting in non-catalytic secreted proteins, which work as virulence factors and/or as elicitors of defense responses and systemic resistance, thus acting as PAMPs (pathogen-associated molecular patterns). Moreover, CP has been defined an expansin-like protein showing the ability to weaken cellulose aggregates, like the canonical plant expansins do. Here, we deepen the knowledge on CP PAMP activity by the use of a multi-disciplinary approach: proteomic analysis, VOC (volatile organic compound) measurements, and gas exchange determination. The treatment of Arabidopsis with CP induces a differential profile either in protein expression or in VOC emission, as well changes in photosynthetic activity. In agreement with its role of defense activator, CP treatment induces down-expression of enzymes related to primary metabolism, such as RuBisCO, triosephosphate isomerase, and ATP-synthase, and reduces the photosynthesis rate. Conversely, CP increases expression of defense-related proteins and emission of some VOCs. Interestingly, CP exposure triggered the increase in enzymes involved in GSH metabolism and redox homeostasis (glutathione S-transferase, thioredoxin, Cys-peroxiredoxin, catalase) and in enzymes related to the "glucosinolate-myrosinase" system, which are the premise for synthesis of defence compounds, such as camalexin and some VOCs, respectively. The presented results are in agreement with the accepted role of CP as a PAMP and greatly increase the knowledge of plant primary defences induced by a purified fungal elicitor.

Morin: A Promising Natural Drug.

Morin is a natural polyphenol, originally isolated from members of the Moraceae family that can be extracted from leaves, fruits, stems and branches of numerous plants. Several evidence have demonstrated that Morin could have a beneficial effect on several human diseases. In fact, Morin exerts antioxidant, antidiabetic, anti-inflammatory, antitumoral, antihypertensive, antibacterial, hypouricemic, and neuroprotective effects, by modulating the activity of many enzymes. In some cases, Morin shows a systemic protective action, reducing negative side effects of several drugs, without interfering with their functions. In addition, in vitro and in vivo studies demonstrated that Morin exhibits very low toxicity levels and its chronic administration is well tolerated. All these findings suggest that Morin could be used, either alone or in combination with other drugs, to prevent many human pathologies.

5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.

Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stem-like phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer.

Cancer associated fibroblasts transfer lipids and proteins to cancer cells through cargo vesicles supporting tumor growth.

Fibroblasts are the most abundant cells in connective tissue and, with fibrillar extracellular matrix, form the structural scaffolding of organs. In solid tumors, interaction with cancer cells induces fibroblasts transdifferentiation into an activated form, which become a fundamental part of the tumor stroma. Within tumor microenvironment stromal and cancer cells engage a crosstalk that is mediated by soluble factors, cellcell contacts and extracellular vesicles trafficlking. Here we report that fibroblasts have the ability to transfer a remarkable amount of proteins and lipids to neighboring cells, in an ectosome-dependent fashion, identifying a novel and native property of these cells. Cancer-associated fibroblasts show an enhanced production and delivering of ectc:Jsomes to cancer cells compared to normal fibroblasts. As a consequence of this phenomenon, tumor cells increase their proliferation rate, indicating that ectosome-mediated trafficking could be a relevant mechanism mediating the trophic function of activated connective tissue on tumor cells.

Comparative proteomic analysis of two distinct stem-cell populations from human amniotic fluid.

Human amniotic fluid (AF) contains a variety of stem cells of embryonic and extra-embryonic origins. We characterized two distinct types of stem cells isolated from residual AF material derived from prenatal diagnostic amniocentesis. The two types of cells differed in their morphology and growth kinetics, showing fast (fast human amniotic stem cells; fHASCs) or slow (slow human amniotic stem cells; sHASCs) population-doubling times. Both fHASCs and sHASCs expressed pluripotent stem-cell markers, yet unlike sHASCs, clonogenic fHASCs would generate embryoid bodies and maintain their original phenotype during prolonged in vitro passaging. fHASCs - but not sHASCs - expressed the KLF4, SSEA-4 and CD117 markers. Differential proteomic analysis allowed us to identify the protein patterns specific for either cell type as potentially contributing to their distinct phenotypes. We found thirty-six proteins that were differentially expressed by the two cell types, and those proteins were classified according to their biological and molecular functions. Bioinformatic cluster analysis revealed differential occurrence of cytoskeletal proteins, such as vimentin, F-actin-binding protein, and chloride intracellular channel protein 1. Selected proteins differentially expressed by fHASCs and sHASCs were further characterized by Western blot analysis and confocal microscopy.

A peculiar molecular profile of umbilical cord-mesenchymal stromal cells drives their inhibitory effects on multiple myeloma cell growth and tumor progression.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are under intensive investigation in preclinical models of cytotherapies against cancer, including multiple myeloma (MM). However, the therapeutic use of stromal progenitors holds critical safety concerns due to their potential MM-supporting activity in vivo. Here, we explored whether MSCs from sources other than BM, such as adipose tissue (AD-MSCs) and umbilical cord (UC-MSCs), affect MM cell growth in comparison to either normal (nBM-MSCs) or myelomatous marrow MSCs (MM-BM-MSCs). Results from both proliferation and clonogenic assays indicated that, in contrast to nBM- and MM-BM-MSCs, both AD and particularly UC-MSCs significantly inhibit MM cell clonogenicity and growth in vitro. Furthermore, when co-injected with UC-MSCs into mice, RPMI-8226 MM cells formed smaller subcutaneous tumor masses, while peritumoral injections of the same MSC subtype significantly delayed the tumor burden growing in subcutaneous plasmocytoma-bearing mice. Finally, both microarrays and ELISA revealed different expression of several genes and soluble factors in UC-MSCs as compared with other MSCs. Our data suggest that UC-MSCs have a distinct molecular profile that correlates with their intrinsic anti-MM activity and emphasize the UCs as ideal sources of MSCs for future cell-based therapies against MM.

Effect of natural compounds on insulin signaling.

Results of several epidemiological studies have indicated that diabetes mellitus will become a global epidemic in the next decades, being more than 400 million the human subjects in the world affected by this disease in the 2030. Most of these subjects will be affected by type 2 diabetes mellitus (T2DM) whose diffusion is mainly related to excessive caloric upload, sedentary life and obesity. Typically, the treatment for T2DM is diet, weight control, physical activity or hypoglycaemic and/or lipid-lowering drugs. Unfortunately, these drugs often show low effectiveness or adverse side effects, thereby forcing patient to discontinue medical treatment. Nevertheless traditional medicine suggests the use of several formulations or medicinal foods to treat T2DM. Most of them are characterized by safety, low cost, effectiveness, and good availability. Before the advent of modern pharmacology, these remedies were used to treat diabetes and obesity or prevent their onset. Today, we know that their effectiveness is due to the presence of several bioactive compounds able to influence insulin signaling pathway and cellular metabolism. In the last decades, many efforts have been carried out to clarify their action mechanism. Here we provide a classification of the natural compounds that stimulate the insulin pathway, highlighting their effectiveness in controlling glycaemia on diabetic animal models or improving insulin signaling in cellular systems.