Age-Related Sarcopenia: Diabetes of the Muscle?

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Vitamin B12 Deficiency and the Nervous System: Beyond Metabolic Decompensation—Comparing Biological Models and Gaining New Insights into Molecular and Cellular Mechanisms

Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets

Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells

Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and a poor clinical outcome; however, the primary cellular and/or microenvironmental targets of this agent remain elusive. We report here that Fn directly targets putative colorectal cancer stem cells (CR-CSCs), a tumor cell subset endowed with cancer re-initiating capacity after surgery and chemotherapy. A patient-derived CSC line, highly enriched (70%) for the stem marker CD133, was expanded as tumor spheroids, dissociated, and exposed in vitro to varying amounts (range 100-500 MOI) of Fn. We found that Fn stably adheres to CSCs, likely by multiple interactions involving the tumor-associated Gal-GalNac disaccharide and the Fn-docking protein CEA-family cell adhesion molecule 1 (CEACAM-1), robustly expressed on CSCs. Importantly, Fn elicited innate immune responses in CSCs and triggered a growth factor-like, protein tyrosine phosphorylation cascade largely dependent on CEACAM-1 and culminating in the activation of p42/44 MAP kinase. Thus, the direct stimulation of CSCs by Fn may contribute to microbiota-driven colorectal carcinogenesis and represent a target for innovative therapies

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

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

Effects of Anti-NMDA Antibodies on Functional Recovery and Synaptic Rearrangement Following Hemicerebellectomy

The compensation that follows cerebellar lesions is based on synaptic modifications in many cortical and subcortical regions, although its cellular mechanisms are still unclear. Changes in glutamatergic receptor expression may represent the synaptic basis of the compensated state. We analyzed in rats the involvement of glutamatergic system of the cerebello-frontal network in the compensation following a right hemicerebellectomy. We evaluated motor performances, spatial competencies and molecular correlates in compensated hemicerebellectomized rats which in the frontal cortex contralateral to the hemicerebellectomy side received injections of anti-NMDA antibodies from patients affected by anti-NMDA encephalitis. In the compensated hemicerebellectomized rats, the frontal injections of anti-NMDA antibodies elicited a marked decompensation state characterized by slight worsening of the motor symptoms as well as severe impairment of spatial mnesic and procedural performances. Conversely, in the sham-operated group the frontal injections of anti-NMDA antibodies elicited slight motor and spatial impairment. The molecular analyses indicated that cerebellar compensatory processes were related to a relevant rearrangement of glutamatergic synapses (NMDA and AMPA receptors and other glutamatergic components) along the entire cortico-cerebellar network. The long-term maintenance of the rearranged glutamatergic activity plays a crucial role in the maintenance of recovered function.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nutrients, neurogenesis and brain ageing: From disease mechanisms to therapeutic opportunities

Appreciation of the physiological relevance of mammalian adult neurogenesis has in recent years rapidly expanded from a phenomenon of homeostatic cell replacement and brain repair to the current view of a complex process involved in high order cognitive functions. In parallel, an array of endogenous or exogenous triggers of neurogenesis has also been identified, among which metabolic and nutritional cues have drawn significant attention. Converging evidence from animal and in vitro studies points to nutrient sensing and energy metabolism as major physiological determinants of neural stem cell fate, and modulators of the whole neurogenic process. While the cellular and molecular circuitries underlying metabolic regulation of neurogenesis are still incompletely understood, the key role of mitochondrial activity and dynamics, and the importance of autophagy have begun to be fully appreciated; moreover, nutrient-sensitive pathways and transducers such as the insulin-IGF cascade, the AMPK/mTOR axis and the transcription regulators CREB and Sirt-1 have been included, beside more established \ue2\u80\u9cdevelopmental\ue2\u80\u9d signals like Notch and Wnt, in the molecular networks that dictate neural-stem-cell self-renewal, migration and differentiation in response to local and systemic inputs. Many of these nutrient-related cascades are deregulated in the contest of metabolic diseases and in ageing, and may contribute to impaired neurogenesis and thus to cognition defects observed in these conditions. Importantly, accumulating knowledge on the metabolic control of neurogenesis provides a theoretical framework for the trial of new or repurposed drugs capable of interfering with nutrient sensing as enhancers of neurogenesis in the context of neurodegeneration and brain senescence

Insulin Receptor beta-Subunit Haploinsufficiency Impairs Hippocampal Late-Phase LTP and Recognition Memory

The insulin receptor (IR) is a protein tyrosine kinase playing a pivotal role in the regulation of peripheral glucose metabolism and energy homoeostasis. IRs are also abundantly distributed in the cerebral cortex and hippocampus, where they regulate synaptic activity required for learning and memory. As the major anabolic hormone in mammals, insulin stimulates protein synthesis partially through the activation of the PI3K/Akt/mTOR pathway, playing fundamental roles in neuronal development, synaptic plasticity and memory. Here, by means of a multidisciplinary approach, we report that long-term synaptic plasticity and recognition memory are impaired in IR beta-subunit heterozygous mice. Since IR expression is diminished in type-2 diabetes as well as in Alzheimer's disease (AD) patients, these data may provide a mechanistic link between insulin resistance, impaired synaptic transmission and cognitive decline in humans with metabolic disorders

A new transgenic mouse model for studying the neurotoxicity of spermine oxidase dosage in the response to excitotoxic injury

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