Can a Scaffold Enriched with Mesenchymal Stem Cells Be a Good Treatment for Spinal Cord Injury?

Spinal cord injury (SCI) is a worldwide highly crippling disease that can lead to the loss of motor and sensory neurons. Among the most promising therapies, there are new techniques of tissue engineering based on stem cells that promote neuronal regeneration. Among the different types of stem cells, mesenchymal stem cells (MSCs) seem the most promising. Indeed, MSCs are able to release trophic factors and to differentiate into the cell types that can be found in the spinal cord. Currently, the most common procedure to insert cells in the lesion site is infusion. However, this causes a low rate of survival and engraftment in the lesion site. For these reasons, tissue engineering is focusing on bioresorbable scaffolds to help the cells to stay in situ. Scaffolds do not only have a passive role but become fundamental for the trophic support of cells and the promotion of neuroregeneration. More and more types of materials are being studied as scaffolds to decrease inflammation and increase the engraftment as well as the survival of the cells. Our review aims to highlight how the use of scaffolds made from biomaterials enriched with MSCs gives positive results in in vivo SCI models as well as the first evidence obtained in clinical trials.     

Biomolecular Evaluation of Piceatannol’s Effects in Counteracting the Senescence of Mesenchymal Stromal Cells: A New Candidate for Senotherapeutics?

Several investigations on senescence and its causative role in aging have underscored the importance of developing senotherapeutics, a field focused on killing senescent cells and/or preventing their accumulation within tissues. Using polyphenols in counteracting senescence may facilitate the development of senotherapeutics given their presence in the human diet, their confirmed tolerability and absence of severe side effects, and their role in preventing senescence and inducing the death of senescent cells. Against that background, we evaluated the effect of piceatannol, a natural polyphenol, on the senescence of mesenchymal stromal cells (MSCs), which play a key role in the body’s homeostasis. Among our results, piceatannol reduced the number of senescent cells both after genotoxic stress that induced acute senescence and in senescent replicative cultures. Such senotherapeutics activity, moreover, promoted the recovery of cell proliferation and the stemness properties of MSCs. Altogether, our findings demonstrate piceatannol’s effectiveness in counteracting senescence by targeting its associated pathways and detecting and affecting P53-dependent and P53-independent senescence. Our study thus suggests that, given piceatannol’s various mechanisms to accomplish its pleiotropic activities, it may be able to counteract any senescent phenotypes.     

Potential Roles of Selectins in Periodontal Diseases and Associated Systemic Diseases: Could They Be Targets for Immunotherapy?

Periodontal diseases are predisposing factors to the development of many systemic disorders, which is often initiated via leukocyte infiltration and vascular inflammation. These diseases could significantly affect human health and quality of life. Hence, it is vital to explore effective therapies to prevent disease progression. Periodontitis, which is characterized by gingival bleeding, disruption of the gingival capillary’s integrity, and irreversible destruction of the periodontal supporting bone, appears to be caused by overexpression of selectins in periodontal tissues. Selectins (P-, L-, and E-selectins) are vital members of adhesion molecules regulating inflammatory and immune responses. They are mainly located in platelets, leukocytes, and endothelial cells. Furthermore, selectins are involved in the immunopathogenesis of vascular inflammatory diseases, such as cardiovascular disease, diabetes, cancers, and so on, by mediating leukocyte recruitment, platelet activation, and alteration of endothelial barrier permeability. Therefore, selectins could be new immunotherapeutic targets for periodontal disorders and their associated systemic diseases since they play a crucial role in immune regulation and endothelium dysfunction. However, the research on selectins and their association with periodontal and systemic diseases remains limited. This review aims to discuss the critical roles of selectins in periodontitis and associated systemic disorders and highlights the potential of selectins as therapeutic targets.     

Management of Diabetes Mellitus: Could Simultaneous Targeting of Hyperglycemia and Oxidative Stress Be a Better Panacea?

The primary aim of the current management of diabetes mellitus is to achieve and/or maintain a glycated hemoglobin level of ≤6.5%. However, recent evidence indicates that intensive treatment of hyperglycemia is characterized by increased weight gain, severe hypoglycemia and higher mortality. Besides, evidence suggests that it is difficult to achieve and/or maintain optimal glycemic control in many diabetic patients; and that the benefits of intensively-treated hyperglycemia are restricted to microvascular complications only. In view of these adverse effects and limitations of intensive treatment of hyperglycemia in preventing diabetic complications, which is linked to oxidative stress, this commentary proposes a hypothesis that "simultaneous targeting of hyperglycemia and oxidative stress" could be more effective than "intensive treatment of hyperglycemia" in the management of diabetes mellitus.     

Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?

Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes—pathologic inflammatory, fibrotic changes in the vertebral bone marrow—are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.     

BMP3 Alone and Together with TGF-β Promote the Differentiation of Human Mesenchymal Stem Cells into a Nucleus Pulposus-Like Phenotype

Human mesenchymal stem cells (MSCs) have the potential to differentiate into nucleus pulposus (NP)-like cells under specific stimulatory conditions. Thus far, the effects of bone morphogenetic protein 3 (BMP3) and the cocktail effects of BMP3 and transforming growth factor (TGF)-β on MSC proliferation and differentiation remain obscure. Therefore, this study was designed to clarify these unknowns. MSCs were cultured with various gradients of BMP3 and BMP3/TGF-β, and compared with cultures in basal and TGF-β media. Cell proliferation, glycosaminoglycan (GAG) content, gene expression, and signaling proteins were measured to assess the effects of BMP3 and BMP3/TGF-β on MSCs. Cell number and GAG content increased upon the addition of BMP3 in a dose-dependent manner. The expression of COL2A1, ACAN, SOX9, and KRT19 increased following induction with BMP3 and TGF-β, in contrast to that of COL1A1, ALP, OPN, and COMP. Smad3 phosphorylation was upregulated by BMP3 and TGF-β, but BMP3 did not affect the phosphorylation of extracellular-signal regulated kinase (ERK) 1/2 or c-Jun N-terminal kinase (JNK). Our results reveal that BMP3 enhances MSC proliferation and differentiation into NP-like cells, as indicated by increased cell numbers and specific gene expressions, and may also cooperate with TGF-β induced positive effects. These actions are likely related to the activation of TGF-β signaling pathway.     

30 Hz,Could It Be Part of a Window Frequency for Cellular Response?

Many exogenous and endogenous risk factors have been proposed as precursors of brain tumors, including the exposure to non-ionizing electromagnetic fields. Nevertheless, there is still a debate among the scientific community about the hazard of the effects produced by non-ionizing radiation (NIR) because conflicting results have been found (number of articles reviewed >50). For that reason, to provide new evidence on the possible effects produced by exposure to NIR, we performed different studies with several combinations of extremely low frequencies, times, and field intensities in tumoral and non-tumoral cells. The results of our studies showed that cell viability was frequency dependent in glioblastoma cells. In fact, our results revealed that a frequency of 30 Hz—or even other frequencies close to 30 Hz—could constitute a window frequency determinant of the cellular response in tumoral and non-tumoral cells.     

Clinical Relevancy of Circulating Tumor Cells in Breast Cancer: Epithelial or Mesenchymal Characteristics,Single Cells or Clusters?

Metastatic breast cancer (MBC) is typically an incurable disease with high mortality rates; thus, early identification of metastatic features and disease recurrence through precise biomarkers is crucial. Circulating tumor cells (CTCs) consisting of heterogeneous subpopulations with different morphology and genetic, epigenetic, and gene expression profiles represent promising candidate biomarkers for metastatic potential. The experimentally verified role of epithelial-to-mesenchymal transition in cancer dissemination has not been clearly described in BC patients, but the stemness features of CTCs strongly contributes to metastatic potency. Single CTCs have been shown to be protected in the bloodstream against recognition by the immune system through impaired interactions with T lymphocytes and NK cells, while associations of heterotypic CTC clusters with platelets, leucocytes, neutrophils, tumor-associated macrophages, and fibroblasts improve their tumorigenic behavior. In addition to single CTC and CTC cluster characteristics, we reviewed CTC evaluation methods and clinical studies in early and metastatic BCs. The variable CTC tests were developed based on specific principles and strategies. However, CTC count and the presence of CTC clusters were shown to be most clinically relevant in existing clinical trials. Despite the known progress in CTC research and sampling of BC patients, implementation of CTCs and CTC clusters in routine diagnostic and treatment strategies still requires improvement in detection sensitivity and precise molecular characterizations, focused predominantly on the role of CTC clusters for their higher metastatic potency.     

Neurodegenerative Diseases: Can Caffeine Be a Powerful Ally to Weaken Neuroinflammation?

In recent years, there has been considerable research showing that coffee consumption seems to be beneficial to human health, as it contains a mixture of different bioactive compounds such as chlorogenic acids, caffeic acid, alkaloids, diterpenes and polyphenols. Neurodegenerative diseases (NDs) are debilitating, and non-curable diseases associated with impaired central, peripheral and muscle nervous systems. Several studies demonstrate that neuroinflammation mediated by glial cells—such as microglia and astrocytes—is a critical factor contributing to neurodegeneration that causes the dysfunction of brain homeostasis, resulting in a progressive loss of structure, function, and number of neuronal cells. This happens over time and leads to brain damage and physical impairment. The most known chronic NDs are represented by Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). According to epidemiological studies, regular coffee consumption is associated with a lower risk of neurodegenerative diseases. In this review, we summarize the latest research about the potential effects of caffeine in neurodegenerative disorders prevention and discuss the role of controlled caffeine delivery systems in maintaining high plasma caffeine concentrations for an extended time.     

Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function?

Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of MSC in the treatment of ovarian degenerative disease. However, the evidence for the optimal number of cells for the developing stem cell therapeutics is insufficient. The objective of this study was to evaluate the efficacy in ovarian dysfunction, depends on cell dose. By intraovarian transplantation of low (1 × 10⁵) and high (5 × 10⁵) doses of placenta-derived mesenchymal stem cells (PD-MSCs) into thioacetamide (TAA)-injured rats, we compared the levels of apoptosis and oxidative stress that depend on different cell doses. Apoptosis and oxidative stress were significantly decreased in the transplanted (Tx) group compared to the non-transplanted (NTx) group in ovarian tissues from TAA-injured rats (* p < 0.05). In addition, we confirmed that follicular development was significantly increased in the Tx groups compared to the NTx group (* p < 0.05). However, there were no significant differences in the apoptosis, antioxidant or follicular development of injured ovarian tissues between the low and high doses PD-MSCs group. These findings provide new insights into the understanding and evidence obtained from clinical trials for stem cell therapy in reproductive systems.     

Gut Microbiota,Metabolic Disorders and Breast Cancer: Could Berberine Turn Out to Be a Transversal Nutraceutical Tool? A Narrative Analysis

Metabolic disorders, mainly characterized as the marked alteration of the lipid and carbohydrate profile, in addition to the clinical presence of the direct consequences of these alterations, are pathological conditions that have considerably increased in prevalence in recent years. They are directly linked to the onset of various pathologies, including cancer, particularly breast cancer, and are hormone-responsive. Alongside the known conditions responsible for this scenario, such as nutrition and lifestyle in general, the importance of both the colonic microbiota and the various organs and systems is becoming increasingly evident. In fact, it is now evident that microbial dysbiosis plays a fundamental role in the onset of these metabolic disorders, and therefore how these conditions are indirectly responsible for the onset and progression of neoplasms. Indirect mechanisms such as an altered Firmicutes/Bacteroidetes ratio; the formation of metabolites such as short-chain fatty acids (SCFAs), in particular, butyrate, which is capable of acting as a tumor suppressor; and the glucuronidase activity of estroboloma (bacteria responsible for estrogen metabolism) are just some of the most important mechanisms that contribute to the history of breast cancer. It is therefore understandable that in clinical terms, it is essential to associate the modulation of metabolic disorders and the microbial conditions that contribute to generating them with common therapies, preferably using compounds and solutions that are effective and acceptable for the patient without side effects. Nutraceuticals such as berberine (active both in metabolic scenarios and in the microbiota) and interventions modulating the microbial structure such as the use of probiotics and prebiotics seem to be ideal solutions for these preventive and no-longer-ignorable strategies in the light of numerous data now present in the literature.     

Hypoxia as a Stimulus for the Maturation of Meniscal Cells: Highway to Novel Tissue Engineering Strategies?

The meniscus possesses low self-healing properties. A perfect regenerative technique for this tissue has not yet been developed. This work aims to evaluate the role of hypoxia in meniscal development in vitro. Menisci from neonatal pigs (day 0) were harvested and cultured under two different atmospheric conditions: hypoxia (1% O₂) and normoxia (21% O₂) for up to 14 days. Samples were analysed at 0, 7 and 14 days by histochemical (Safranin-O staining), immunofluorescence and RT-PCR (in both methods for SOX-9, HIF-1α, collagen I and II), and biochemical (DNA, GAGs, DNA/GAGs ratio) techniques to record any possible differences in the maturation of meniscal cells. Safranin-O staining showed increments in matrix deposition and round-shape “fibro-chondrocytic” cells in hypoxia-cultured menisci compared with controls under normal atmospheric conditions. The same maturation shifting was observed by immunofluorescence and RT-PCR analysis: SOX-9 and collagen II increased from day zero up to 14 days under a hypoxic environment. An increment of DNA/GAGs ratio typical of mature meniscal tissue (characterized by fewer cells and more GAGs) was observed by biochemical analysis. This study shows that hypoxia can be considered as a booster to achieve meniscal cell maturation, and opens new opportunities in the field of meniscus tissue engineering.     

Exfoliated Kidney Cells from Urine for Early Diagnosis and Prognostication of CKD: The Way of the Future?

Chronic kidney disease (CKD) is a global health issue, affecting more than 10% of the worldwide population. The current approach for formal diagnosis and prognostication of CKD typically relies on non-invasive serum and urine biomarkers such as serum creatinine and albuminuria. However, histological evidence of tubulointerstitial fibrosis is the ‘gold standard’ marker of the likelihood of disease progression. The development of novel biomedical technologies to evaluate exfoliated kidney cells from urine for non-invasive diagnosis and prognostication of CKD presents opportunities to avoid kidney biopsy for the purpose of prognostication. Efforts to apply these technologies more widely in clinical practice are encouraged, given their potential as a cost-effective approach, and no risk of post-biopsy complications such as bleeding, pain and hospitalization. The identification of biomarkers in exfoliated kidney cells from urine via western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence techniques, measurement of cell and protein-specific messenger ribonucleic acid (mRNA)/micro-RNA and other techniques have been reported. Recent innovations such as multispectral autofluorescence imaging and single-cell RNA sequencing (scRNA-seq) have brought additional dimensions to the clinical application of exfoliated kidney cells from urine. In this review, we discuss the current evidence regarding the utility of exfoliated proximal tubule cells (PTC), podocytes, mesangial cells, extracellular vesicles and stem/progenitor cells as surrogate markers for the early diagnosis and prognostication of CKD. Future directions for development within this research area are also identified.     

Curcumin: A Novel Way to Improve Quality of Life for Colorectal Cancer Patients?

Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women. Treatment of metastatic CRC consists of highly toxic chemotherapeutic drug combinations that often negatively affect patient quality of life (QoL). Moreover, chemotherapy-induced toxicity and chemotherapy resistance are among the most important factors limiting cancer treatment and can lead to the interruption or discontinuation of potentially effective therapy. Several preclinical studies have demonstrated that curcumin acts through multiple cellular pathways and possesses both anti-cancer properties against CRC and the capacity to mitigate chemotherapy-related side effects and overcome drug resistance. In this review article, we suggest that the addition of curcumin to the standard chemotherapeutic treatment for metastatic CRC could reduce associated side-effects and overcome chemotherapy resistance, thereby improving patient QoL.     

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.     

Evaluation of Alternative Risk Stratification Systems in a Large Series of Solitary Fibrous Tumors with Molecular Findings and Ki-67 Index Data: Do They Improve Risk Assessment?

The clinical evolution of solitary fibrous tumors (SFTs) is often uncertain and several risk stratification systems (RSS) have been proposed. The Demicco et al. RSS is the most frequently implemented. In this study we aim to validate two alternative RSS (Sugita et al. and G-Score) using results for the Demicco RSS from a previous study of 97 SFTs. In addition, we aim to determine whether reclassified cases had any distinctive molecular features. As the Sugita et al. system substitutes mitotic count with Ki-67 index we also investigated whether Ki-67 results for tissue microarrays are comparable to those obtained using whole tissue sections. In the present study we detected that many cases classified by Demicco RSS as low-risk were reclassified as intermediate risk using the new system (G-score RSS). Kaplan-Meier survival plots for G-Score RSS showed that the low-risk and intermediate-risk SFTs had a similar evolution that contrasted with the more aggressive high-risk group. Moreover, the similar evolution in both low and intermediate-risk groups occurred despite the G-score system being stricter in classifying low-risk tumors. We observed that Sugita RSS does not provide any better risk stratification in comparison with the Demicco RSS, and testing both RSS in our series produced similar Kaplan-Meier survival data. We found some discordant results when comparing whole sections and the corresponding tissue microarrays samples, finding the hotspot areas easier to locate in whole sections. Forty-one SFTs with initial low-risk assigned by the Demicco RSS were reclassified as intermediate-risk by G-score finding both TP53 and HTER mutations in four cases, only HTER mutation in 11 cases, and only TP53 mutation in 2 cases. All six cases of SFT classified as high-risk by both the Demicco and G-score RSS suffered recurrence/metastasis, and half showed both TP53 and HTER mutations. Five SFTs were categorized as low-risk by both Demicco and G-score, of which 4 cases revealed HTER mutation. Regarding the outcome of these 5 patients, two were lost to follow-up, and one of the remaining three patients suffered recurrence. We believe that although the presence of both TP53 and HTER mutations may confer or be related to poor evolution, the isolated presence of HTER mutation alone would not necessarily be related to poor outcome. The G-score RSS more accurately identified low-risk patients than the other two risk models evaluated in the present series. Late recurrence/metastasis may occasionally be observed even in low-risk SFTs categorized by stricter classification systems such as the G-score RSS. These findings support the possibility that additional, as yet unknown factors may influence the clinical evolution of SFTs. In conclusion, given the possibility of late recurrence, long-term follow-up is recommended for all SFT patients, even in cases classified as low risk by the stricter G-score system. An integration of clinical, radiological, pathological, and molecular findings may improve SFT risk stratification and better predict patient outcome.     

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells

The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence. The adaptive immune system is constituted by two types of lymphocytes, T and B cells, and the function and fitness of these cell populations are affected during ageing. Here, we review the impact of ageing on T and B cells and discuss the approaches that have been described or proposed to modulate and reverse the decline of the ageing adaptive immune system.