Altered vitamin B12 metabolism in the central nervous system is associated with the modification of ribosomal gene expression: new insights from comparative RNA dataset analysis

Recent studies have confirmed the direct role of vitamin B12 (VitB12) in the central nervous system (CNS) homeostasis; nevertheless, the detailed mechanisms are poorly understood. By analyzing RNA-Seq and microarray datasets obtained from databanks, this study aims to identify possible basic mechanisms, related to the brain, involved in altering the gene expression under VitB12 deficiency mimicking conditions. The database inquiry returned datasets generated from distinctly heterogeneous experimental sets and considering the quality and relevance requirements, two datasets from mouse and one from rat models were selected. The analyses of individual datasets highlighted a change in ribosomal gene expression in VitB12 deficiency mimicking conditions within each system. Specifically, a divergent regulation was observed depending on the animal model: mice showed a down regulation of the ribosomal gene expression, while rats an upregulation. Interestingly, E2f1 was significantly upregulated under VitB12 deficiency mimicking conditions in the animal models, with a greater upregulation in rats. The rat model also revealed putative E2F1 Transcription Factor Binding Sites (TFBSs) in the promoter of the differently regulated genes involved in ribosomal gene expression. This suggested the possibility that E2F1, being greater expressed in rats, could activate the ribosomal genes having E2F1 TFBSs, thus giving a plausible explication to the divergent regulation observed in animal models. Despite the great diversity of the experimental sets used to generate the datasets considered, a common alteration of the ribosomes exists, thereby indicating a possible basic and conserved response to VitB12 deficiency. Moreover, these findings could provide new insights on E2F1 and its association with CNS homeostasis and VitB12 deficiency

The leucine catabolite and dietary supplement β-hydroxy-β-methyl butyrate (Hmb) as an epigenetic regulator in muscle progenitor cells

β-Hydroxy-β-Methyl Butyrate (HMB) is a natural catabolite of leucine deemed to play a role in amino acid signaling and the maintenance of lean muscle mass. Accordingly, HMB is used as a dietary supplement by sportsmen and has shown some clinical effectiveness in preventing muscle wasting in cancer and chronic lung disease, as well as in age-dependent sarcopenia. However, the molecular cascades underlying these beneficial effects are largely unknown. HMB bears a significant structural similarity with Butyrate and β-Hydroxybutyrate (βHB), two compounds recognized for important epigenetic and histone-marking activities in multiple cell types including muscle cells. We asked whether similar chromatin-modifying actions could be assigned to HMB as well. Exposure of murine C2C12 myoblasts to millimolar concentrations of HMB led to an increase in global histone acetylation, as monitored by anti-acetylated lysine immunoblotting, while preventing myotube differentiation. In these effects, HMB resembled, although with less potency, the histone deacetylase (HDAC) inhibitor Sodium Butyrate. However, initial studies did not confirm a direct inhibitory effect of HMB on HDACs in vitro. β-Hydroxybutyrate, a ketone body produced by the liver during starvation or intense exercise, has a modest effect on histone acetylation of C2C12 cells or in vitro HDAC inhibitor activities, and, unlike Butyrate and HMB, did not interfere with myotube formation in a myoblast differentiation assay. Instead, βHB dramatically increased lysine β-hydroxybutyrylation (Kbhb) of histone tails, an epigenetic mark associated with fasting responses and muscle catabolic states. However, when C2C12 cells were exposed to βHB in the presence of equimolar HMB this chromatin modification was drastically reduced, pointing to a role for HMB in attenuating ketosis-associated muscle wasting. In conclusion, while their mechanistic underpinnings remain to be clarified, these preliminary observations highlight novel and potentially important activities of HMB as an epigenetic regulator and βHB antagonist in muscle precursor cells, to be further explored in their biomedical implications

The Influence of Gut Microbiota on Neurogenesis: Evidence and Hopes

Adult neurogenesis (i.e., the life-long generation of new neurons from undifferentiated neuronal precursors in the adult brain) may contribute to brain repair after damage, and participates in plasticity-related processes including memory, cognition, mood and sensory functions. Among the many intrinsic (oxidative stress, inflammation, and ageing), and extrinsic (environmental pollution, lifestyle, and diet) factors deemed to impact neurogenesis, significant attention has been recently attracted by the myriad of saprophytic microorganismal communities inhabiting the intestinal ecosystem and collectively referred to as the gut microbiota. A growing body of evidence, mainly from animal studies, reveal the influence of microbiota and its disease-associated imbalances on neural stem cell proliferative and differentiative activities in brain neurogenic niches. On the other hand, the long-claimed pro-neurogenic activity of natural dietary compounds endowed with antioxidants and anti-inflammatory properties (such as polyphenols, polyunsaturated fatty acids, or pro/prebiotics) may be mediated, at least in part, by their action on the intestinal microflora. The purpose of this review is to summarise the available information regarding the influence of the gut microbiota on neurogenesis, analyse the possible underlying mechanisms, and discuss the potential implications of this emerging knowledge for the fight against neurodegeneration and brain ageing

Cannabinoid CB2 receptor (CB2R) stimulation delays rubrospinal mitochondrial-dependent degeneration and improves functional recovery after spinal cord hemisection by ERK1/2 inactivation.

Spinal cord injury (SCI) is a devastating condition of CNS that often results in severe functional impairments for which there are no restorative therapies. As in other CNS injuries, in addition to the effects that are related to the primary site of damage, these impairments are caused by degeneration of distal regions that are connected functionally to the primary lesion site. Modulation of the endocannabinoid system (ECS) counteracts this neurodegeneration, and pharmacological modulation of type-2 cannabinoid receptor (CB2R) is a promising therapeutic target for several CNS pathologies, including SCI. This study examined the effects of CB2R modulation on the fate of axotomized rubrospinal neurons (RSNs) and functional recovery in a model of spinal cord dorsal hemisection (SCH) at the cervical level in rats. SCH induced CB2R expression, severe atrophy, and cell death in contralateral RSNs. Furthermore, SCH affected molecular changes in the apoptotic cascade in RSNs - increased cytochrome c release, apoptosome formation, and caspase-3 activity. CB2R stimulation by its selective agonist JWH-015 significantly increased the bcl-2/bax ratio, reduced cytochrome c release, delayed atrophy and degeneration, and improved spontaneous functional recovery through ERK1/2 inactivation. These findings implicate the ECS, particularly CB2R, as part of the endogenous neuroprotective response that is triggered after SCI. Thus, CB2R modulation might represent a promising therapeutic target that lacks psychotropic effects and can be used to exploit ECS-based approaches to counteract neuronal degeneration

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer’s disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing

Adherence issues related to sublingual immunotherapy as perceived by allergists

Objectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence. Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10. Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists. Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers. © 2010 Scurati et al, publisher and licensee Dove Medical Press Ltd

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion

Adult neurogenesis initiated by neural stem cells (NSCs) contributes to brain homeostasis, damage repair, and cognition. Energy metabolism plays a pivotal role in neurogenic cell fate decisions regarding self-renewal, expansion and multilineage differentiation. NSCs need to fine-tune quiescence and proliferation/commitment to guarantee lifelong neurogenesis and avoid premature exhaustion. Accumulating evidence supports a model whereby calorie restriction or increased energy expenditure reinforce NSC quiescence and promote self-renewal. Conversely, growth/proliferation inputs and anabolic signals, although necessary for neurogenesis, deplete the NSCs pool in the long run. This framework incorporates the emerging neurogenic roles of nutrient-sensing signaling pathways, providing a rationale for the alarming connection between nutritional imbalances, metabolic disorders and accelerated brain aging

Aβ toxicity in Alzheimer's disease

Alzheimer's Disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive cognitive decline, synaptic loss, the formation of extracellular β-amyloid plaques and intracellular neurofibrillary tangles, and neuronal cell death. Despite the massive neuronal loss in the 'late stage' of disease, dendritic spine loss represents the best pathological correlate to the cognitive impairment in AD patients. The 'amyloid hypothesis' of AD recognizes the Aβ peptide as the principal player in the pathological process. Many lines of evidence point out to the neurotoxicity of Aβ, highlighting the correlation between soluble Aβ oligomer accumulation, rather than insoluble Aβ fibrils and disease progression. Pathological increase of Aβ in AD brains, resulting from an imbalance between its production, aggregation and clearance, might target mitochondrial function promoting a progressive synaptic impairment. The knowledge of the exact mechanisms by which Aβ peptide impairs neuronal function will help us to design new pharmacological tools for preventing AD neurodegeneration