While the U.S. Food and Drug Administration and the European Medicines Evaluation Agency have recently approved new drugs to treat spinal muscular atrophy 1 (SMA1) in young patients, they are mostly ...ineffective in older patients since many motor neurons have already been lost. Therefore, understanding nervous system (NS) physiology in SMA patients is essential. Consequently, studying neural stem cells (NSCs) from SMA patients is of significant interest in searching for new treatment targets that will enable researchers to identify new pharmacological approaches. However, studying NSCs in these patients is challenging since their isolation damages the NS, making it impossible with living patients. Nevertheless, it is possible to study NSCs from animal models or create them by differentiating induced pluripotent stem cells obtained from SMA patient peripheral tissues. On the other hand, therapeutic interventions such as NSCs transplantation could ameliorate SMA condition. This review summarizes current knowledge on the physiological properties of NSCs from animals and human cellular models with an SMA background converging on the molecular and neuronal circuit formation alterations of SMA fetuses and is not focused on the treatment of SMA. By understanding how SMA alters NSC physiology, we can identify new and promising interventions that could help support affected patients.
The production of induced pluripotent stem cells (iPSCs) represent a breakthrough in regenerative medicine, providing new opportunities for understanding basic molecular mechanisms of human ...development and molecular aspects of degenerative diseases. In contrast to human embryonic stem cells (ESCs), iPSCs do not raise any ethical concerns regarding the onset of human personhood. Still, they present some technical issues related to immune rejection after transplantation and potential tumorigenicity, indicating that more steps forward must be completed to use iPSCs as a viable tool for in vivo tissue regeneration. On the other hand, cell source origin may be pivotal to iPSC generation since residual epigenetic memory could influence the iPSC phenotype and transplantation outcome. In this paper, we first review the impact of reprogramming methods and the choice of the tissue of origin on the epigenetic memory of the iPSCs or their differentiated cells. Next, we describe the importance of induction methods to determine the reprogramming efficiency and avoid integration in the host genome that could alter gene expression. Finally, we compare the significance of the tissue of origin and the inter-individual genetic variation modification that has been lightly evaluated so far, but which significantly impacts reprogramming.
This study is a randomized, placebo-controlled, double-blinded trial performed to investigate the effects of a dietary supplement containing a mixture of Boswellia serrata Roxb., chlorophyll, green ...tea extract, glucosamine, chondroitin sulfate, hyaluronic acid, and further in the manuscript: non-hydrolised type II collagen in dogs with osteoarthritis (OA). A total of 40 dogs were enrolled in the study, they were randomly divided in control (CTR) and treatment (TRT) groups. The TRT group received the dietary supplement for 60 days. The CTR group received a placebo for the same number of days. All the subjects had veterinary evaluations during the trial and owners were requested to fill in questionnaires on chronic pain using the Helsinki Chronic Pain Index. The product was easy to administer and no side effects were reported. Combining results from veterinarian and owner evaluations, the tested product proved to be significantly beneficial in alleviating pain and in reducing the clinical signs in dogs with OA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the pro-tumorigenic ...activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not rely only on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV pro-tumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behaviour of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2 dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockage of NOTCH activation by b-Secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the pro-tumorigenic role of EV in MM as well as other tumors.
Both astronauts and patients affected by chronic movement-limiting pathologies face impairment in muscle and/or brain performance. Increased patient survival expectations and the expected longer ...stays in space by astronauts may result in prolonged motor deprivation and consequent pathological effects. Severe movement limitation can influence not only the motor and metabolic systems but also the nervous system, altering neurogenesis and the interaction between motoneurons and muscle cells. Little information is yet available about the effect of prolonged muscle disuse on neural stem cells characteristics. Our
study aims to fill this gap by focusing on the biological and molecular properties of neural stem cells (NSCs). Our analysis shows that NSCs derived from the SVZ of HU mice had shown a reduced proliferation capability and an altered cell cycle. Furthermore, NSCs obtained from HU animals present an incomplete differentiation/maturation. The overall results support the existence of a link between reduction of exercise and muscle disuse and metabolism in the brain and thus represent valuable new information that could clarify how circumstances such as the absence of load and the lack of movement that occurs in people with some neurological diseases, may affect the properties of NSCs and contribute to the negative manifestations of these conditions.
Oxidative stress is common in several human and veterinary conditions and it is associated to alteration of the glutathione peroxidase (GPx) level. GPx is an enzyme present in erythrocytes, kidney, ...and liver and it has a role in protecting against oxidative damage. In this randomised double-blinded control trial on healthy dogs, we present findings indicating that the administration for a total of 35 days of a supplement containing S-acetyl-glutathione (SAG) alongside other antioxidant natural ingredients, leads to an increase in the GPx level. Furthermore, the supplement positively changes liver blood parameters, even in healthy dogs. These preliminary results hold promise for conducting new studies using the same supplement on dogs affected by liver conditions, thereby confirming its antioxidant effects and the potential improvement of altered blood parameters.HIGHLIGHTSOxidative stress characterises several conditions in dogs and the use of antioxidants can improve their health.The administration of a new supplement containing S-acetyl-glutathione (SAG) together with other antioxidant natural ingredients, increased the level of glutathione peroxidase (GPx).No adverse events were reported after the supplement administration.
Objectives: The beneficial effects of many substances have been discovered because of regular dietary consumption. This is also the case with curcumin, whose effects have been known for more than ...4,000 years in Eastern countries such as China and India. A curcumin-rich diet has been known to counteract many human diseases, including cancer and diabetes, and has been shown to reduce inflammation. The effect of a curcumin treatment for neurological diseases, such as spinal muscular atrophy; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; multiple sclerosis; and others, has only recently been brought to the attention of researchers and the wider population.
Methods: In this paper, we summarise the studies on this natural product, from its isolation two centuries ago to its characterisation a century later.
Results: We describe its role in the treatment of neurological diseases, including its cellular and common molecular mechanisms, and we report on the clinical trials of curcumin with healthy people and patients.
Discussion: Commenting on the different approaches adopted by the efforts made to increase its bioavailability.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS ...malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.
Needle biopsy samples were taken from vastus lateralis muscle (VL) of five male body builders (BB, age 27.4 ± 0.93 years;
mean ± s.e.m. ), who had being performing hypertrophic heavy resistance ...exercise (HHRE) for at least 2 years, and from five male active,
but untrained control subjects (CTRL, age 29.9 ± 2.01 years). The following determinations were performed: anatomical cross-sectional
area and volume of the quadriceps and VL muscles in vivo by magnetic resonance imaging (MRI); myosin heavy chain isoform (MHC) distribution of the whole biopsy samples by SDS-PAGE;
cross-sectional area (CSA), force ( P o ), specific force ( P o /CSA) and maximum shortening velocity ( V o ) of a large population ( n = 524) of single skinned muscle fibres classified on the basis of MHC isoform composition by SDS-PAGE; actin sliding velocity
( V f ) on pure myosin isoforms by in vitro motility assays. In BB a preferential hypertrophy of fast and especially type 2X fibres was observed. The very large hypertrophy
of VL in vivo could not be fully accounted for by single muscle fibre hypertrophy. CSA of VL in vivo was, in fact, 54% larger in BB than in CTRL, whereas mean fibre area was only 14% larger in BB than in CTRL. MHC isoform
distribution was shifted towards 2X fibres in BB. P o /CSA was significantly lower in type 1 fibres from BB than in type 1 fibres from CTRL whereas both type 2A and type 2X fibres
were significantly stronger in BB than in CTRL. V o of type 1 fibres and V f of myosin 1 were significantly lower in BB than in CTRL, whereas no difference was observed among fast fibres and myosin
2A. The findings indicate that skeletal muscle of BB was markedly adapted to HHRE through extreme hypertrophy, a shift towards
the stronger and more powerful fibre types and an increase in specific force of muscle fibres. Such adaptations could not
be fully accounted for by well known mechanisms of muscle plasticity, i.e. by the hypertrophy of single muscle fibre (quantitative
mechanism) and by a regulation of contractile properties of muscle fibres based on MHC isoform content (qualitative mechanism).
Two BB subjects took anabolic steroids and three BB subjects did not. The former BB differed from the latter BB mostly for
the size of their muscles and muscle fibres.
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