Targeting Metabolic Syndrome Pathways: Carrot microRNAs As Potential Modulators.

Metabolic syndrome is a condition characterized by metabolic alterations that culminate in chronic noncommunicable diseases of high morbidity and mortality, such as cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease, and colon cancer. Developing new therapeutic strategies with a multifactorial approach is important since current therapies focus on only one or two components of the metabolic syndrome. In this sense, plant-based gene regulation represents an innovative strategy to prevent or modulate human metabolic pathologies, including metabolic syndrome. Here, using a computational and systems biology approach, it was found that carrot microRNAs can modulate key BMPs/SMAD signaling members, C/EBPs, and KLFs involved in several aspects associated with metabolic syndrome, including the hsa04350:TGF-beta signaling pathway, hsa04931:insulin resistance, hsa04152:AMPK signaling pathway, hsa04933:AGE-RAGE signaling pathway in diabetic complications, hsa04010:MAPK signaling pathway, hsa04350:TGF-beta signaling pathway, hsa01522:endocrine resistance, and hsa04910:insulin signaling pathway. These data demonstrated the potential applications of carrot microRNAs as effective food-based therapeutics for obesity and associated metabolic diseases.

Docosahexaenoic Acid (DHA), Vitamin D3, and Probiotics Supplementation Improve Memory, Glial Reactivity, and Oxidative Stress Biomarkers in an Aluminum-Induced Cognitive Impairment Rat Model.

Globally, the rise in neurodegenerative issues in tandem with shifts in lifestyle and aging population has prompted a search for effective interventions. Nutraceutical compounds have emerged as promising agents for addressing these challenges. This 60-day study on an aluminum-induced cognitive impairment rat model assessed three compounds and their combinations: probiotics (Prob, Lactobacillus plantarum [5 × 1010 CFU/day], and Lactobacillus acidophilus [5 × 1010 CFU/day]), docosahexaenoic acid (DHA, 23.8 mg/day), and vitamin D3 (VD3, 150 IU/day). Behavioral outcomes were evaluated by using the Morris water maze and novel object recognition tests. Glial activation was assessed through immunofluorescence analysis of GFAP/Iba1, and oxidative stress markers in brain tissue were determined by measuring the levels of Malondialdehyde (MDA) and Superoxide dismutase (SOD). The results demonstrated a progressive improvement in the learning and memory capacity. The aluminum group exhibited the poorest performance in the behavioral test, enhanced GFAP/Iba1 activation, and elevated levels of oxidative stress markers. Conversely, the DHA + Prob + VD3 treatment demonstrated the best performance in the Morris water maze. The combination of DHA + Prob + VD3 exhibited superior performance in the Morris water maze, accompanied by reduced levels of GFAP/Iba1 activation in DG/CA1 brain regions. Furthermore, DHA + Prob supplementation showed lower GFAP/Iba1 activation in the CA3 region and enhanced antioxidant activity. In summary, supplementing various nutraceutical combinations, including DHA, VD3, and Prob, displayed notable benefits against aluminum-induced cognitive impairment. These benefits encompassed memory enhancement, diminished MDA concentration, increased SOD activity, and reduced glial activation, as indicated by GFAP/Iba1 markers.

Biofortified Beverage with Chlorogenic Acid from Stressed Carrots: Anti-Obesogenic, Antioxidant, and Anti-Inflammatory Properties.

Using wounding stress to increase the bioactive phenolic content in fruits and vegetables offers a promising strategy to enhance their health benefits. When wounded, such phenolics accumulate in plants and can provide antioxidant, anti-inflammatory, and anti-obesogenic properties. This study investigates the potential of using wounding stress-treated carrots biofortified with phenolic compounds as a raw material to extract carrot juice with increased nutraceutical properties. Fresh carrots were subjected to wounding stress via slicing and then stored at 15 °C for 48 h to allow phenolic accumulation. These phenolic-enriched slices were blanched, juiced, and blended with orange juice (75:25 ratio) and 15% (w/v) broccoli sprouts before pasteurization. The pasteurized juice was characterized by its physicochemical attributes and bioactive compound content over 28 days of storage at 4 °C. Additionally, its antioxidant, anti-inflammatory, and anti-obesogenic potentials were assessed using in vitro assays, both pre- and post-storage. The results reveal that juice derived from stressed carrots (SJ) possessed 49%, 83%, and 168% elevated levels of total phenolics, chlorogenic acid, and glucosinolates, respectively, compared to the control juice (CJ) (p < 0.05). Both juices reduced lipid accumulation in 3T3-L1 cells and nitric oxide production in Raw 264.7 cells, without significant differences between them. SJ further displayed a 26.4% increase in cellular antioxidant activity. The juice's bioactive characteristics remained stable throughout storage time. In conclusion, the utilization of juice obtained from stressed carrots in a blend with orange juice and broccoli sprouts offers a promising method to produce a beverage enriched in bioactive compounds and antioxidant potential.

Comprehensive Review of Nutraceuticals against Cognitive Decline Associated with Alzheimer's Disease.

Nowadays, nutraceuticals are being incorporated into functional foods or used as supplements with nonpharmacological approaches in the prevention and management of several illnesses, including age-related conditions and chronic neurodegenerative diseases. Nutraceuticals are apt for preventing and treating such disorders because of their nontoxic, non-habit-forming, and efficient bioactivities for promoting neurological well-being due to their ability to influence cellular processes such as neurogenesis, synaptogenesis, synaptic transmission, neuro-inflammation, oxidative stress, cell death modulation, and neuronal survival. The capacity of nutraceuticals to modify all of these processes reveals the potential to develop food-based strategies to aid brain development and enhance brain function, prevent and ameliorate neurodegeneration, and possibly reverse the cognitive impairment observed in Alzheimer's disease, the most predominant form of dementia in the elderly. The current review summarizes the experimental evidence of the neuroprotective capacity of nutraceuticals against Alzheimer's disease, describing their mechanisms of action and the in vitro and in vivo models applied to evaluate their neuroprotective potential.

Kinetic Ultrasound-Assisted Extraction as a Sustainable Approach for the Recovery of Phenolics Accumulated through UVA Treatment in Strawberry By-Products.

Ultrasound-assisted extraction (UAE) is an efficient and sustainable method for extracting bioactive compounds from agro-industrial by-products. Moreover, it has been reported that ultraviolet A (UVA) radiation can induce the biosynthesis and accumulation of bioactive phenolic compounds. This study optimized the efficiency of ultrasound-assisted extraction (UAE) for recovering ultraviolet A (UVA)-induced phenolic compounds in strawberry by-products (RF-N). The impact of three factors (solid-liquid ratio, ethanol concentration, and ultrasound power) on total phenolic compound (TPC) kinetics using Peleg's model was investigated. The developed model showed a suitable fit for both RF-N and strawberry by-products treated with UVA (RF-E). The optimal UAE conditions obtained were of a 1:30 ratio, 46% ethanol, and 100% ultrasound power, resulting in an average yield of 13 g total phenolics kg-1. The bioaccessibility of phenolic compounds during in-vitro digestion was 36.5%, with agrimoniin being the predominant compound. UAE combined with UVA treatment increased the bioactivity of RF extracts, displaying significant anti-proliferative effects on HT29 and Caco-2 cancer cell lines, as well as anti-inflammatory potential and cellular antioxidant activity. The ultrasound proved to be a sustainable and effective technique for extracting phenolic compounds from RF, contributing to the valorization of strawberry agro-industrial by-products, and maximizing their nutraceutical potential.

Fish oil and probiotics supplementation through milk chocolate improves spatial learning and memory in male Wistar rats.

Background: Cognition and brain function is critical through childhood and should be improved with balanced diets. Incorporating bioactive ingredients such as omega-3 polyunsaturated fatty acids (ω3 PUFAs) and probiotics into food formulations could be used as an approach to improve cognitive function. This study evaluated the effects on cognitive capacity of complementing rodent diets with chocolate, by itself and in combination with ω3 PUFAs from fish oil and probiotics. Methods: Spatial learning and memory in the rats were determined by the Barnes maze test in short- and long-term memory. Samples from the cecum were obtained to assess microbial counts (Lactobacillus, Bifidobacterium, Enterobacteriaceae, and total bacteria), and brains were recovered to analyze the neural morphology of the tissues. Also, glucose, brain weights, and epididymal tissue were analyzed. Results: The combination of chocolate with fish oil and probiotics improved the memory of rats compared to the result of each bioactive compound when evaluated separately. Treatments did not affect sugar level, epididymal adipose tissue, or brain weight. On the other hand, consuming probiotics alone or in combination with chocolate decreased Enterobacteria counts, while Lactobacillus and Bifidobacteria counts were not affected. Neural morphological analysis showed that combining chocolate with probiotics and ω3 PUFAs increased the number of neurons in the hippocampal CA1 and CA3 regions. Conclusion: Chocolate added with probiotics and ω3 PUFAs improved spatial memory and learning in the studied model.

Approximations to Diagnosis and Therapy of COVID-19 in Nervous Systems Using Extracellular Vesicles.

The SARS-CoV-2 virus was first identified at the end of December 2019, causing the disease known as COVID-19, which, due to the high degree of contagion, was declared a global pandemic as of 2020. The end of the isolation was in 2022, thanks to the global multidisciplinary work of the massive vaccination campaigns. Even with the current knowledge about this virus and the COVID-19 disease, there are many questions and challenges regarding diagnosis and therapy in the fight against this virus. One of the big problems is the so-called "long COVID", prolonged symptomatology characterized as a multiorgan disorder manifested as brain fog, fatigue, and shortness of breath, which persist chronically after the disease resolution. Therefore, this review proposes using extracellular vesicles (EVs) as a therapeutic or diagnostic option to confront the sequelae of the disease at the central nervous system level. Development: the review of updated knowledge about SARS-CoV-2 and COVID-19 is generally addressed as well as the current classification of extracellular vesicles and their proposed use in therapy and diagnosis. Through an analysis of examples, extracellular vesicles are highlighted to learn what happens in the central nervous system during and after COVID-19 and as a therapeutic option. Conclusions: even though there are limitations in the knowledge of the neurological manifestations of COVID-19, it is possible to observe the potential use of extracellular vesicles in therapy or as a diagnostic method and even the importance of their study for the knowledge of the pathophysiology of the disease.

Exosomes and Biomaterials: In Search of a New Therapeutic Strategy for Multiple Sclerosis.

Current efforts to find novel treatments that counteract multiple sclerosis (MS) have pointed toward immunomodulation and remyelination. Currently, cell therapy has shown promising potential to achieve this purpose. However, disadvantages such as poor survival, differentiation, and integration into the target tissue have limited its application. A series of recent studies have focused on the cell secretome, showing it to provide the most benefits of cell therapy. Exosomes are a key component of the cell secretome, participating in the transfer of bioactive molecules. These nano-sized vesicles offer many therapeutical advantages, such as the capacity to cross the blood-brain barrier, an enrichable cargo, and a customizable membrane. Moreover, integrating of biomaterials into exosome therapy could lead to new tissue-specific therapeutic strategies. In this work, the use of exosomes and their integration with biomaterials is presented as a novel strategy in the treatment of MS.

Presenilin mutations and their impact on neuronal differentiation in Alzheimer's disease.

The presenilin genes (PSEN1 and PSEN2) are mainly responsible for causing early-onset familial Alzheimer's disease, harboring ~300 causative mutations, and representing ~90% of all mutations associated with a very aggressive disease form. Presenilin 1 is the catalytic core of the γ-secretase complex that conducts the intramembranous proteolytic excision of multiple transmembrane proteins like the amyloid precursor protein, Notch-1, N- and E-cadherin, LRP, Syndecan, Delta, Jagged, CD44, ErbB4, and Nectin1a. Presenilin 1 plays an essential role in neural progenitor maintenance, neurogenesis, neurite outgrowth, synaptic function, neuronal function, myelination, and plasticity. Therefore, an imbalance caused by mutations in presenilin 1/γ-secretase might cause aberrant signaling, synaptic dysfunction, memory impairment, and increased Aß42/Aß40 ratio, contributing to neurodegeneration during the initial stages of Alzheimer's disease pathogenesis. This review focuses on the neuronal differentiation dysregulation mediated by PSEN1 mutations in Alzheimer's disease. Furthermore, we emphasize the importance of Alzheimer's disease-induced pluripotent stem cells models in analyzing PSEN1 mutations implication over the early stages of the Alzheimer's disease pathogenesis throughout neuronal differentiation impairment.

Intranasal Administration of Undifferentiated Oligodendrocyte Lineage Cells as a Potential Approach to Deliver Oligodendrocyte Precursor Cells into Brain.

Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.

A Three-Dimensional Alzheimer's Disease Cell Culture Model Using iPSC-Derived Neurons Carrying A246E Mutation in PSEN1.

Alzheimer's disease (AD) is a chronic brain disorder characterized by progressive intellectual decline and memory and neuronal loss, caused mainly by extracellular deposition of amyloid-ß (Aß) and intracellular accumulation of hyperphosphorylated tau protein, primarily in areas implicated in memory and learning as prefrontal cortex and hippocampus. There are two forms of AD, a late-onset form that affects people over 65 years old, and the early-onset form, which is hereditable and affect people at early ages ~45 years. To date, there is no cure for the disease; consequently, it is essential to develop new tools for the study of processes implicated in the disease. Currently, in vitro AD three-dimensional (3D) models using induced pluripotent stem cells (iPSC)-derived neurons have broadened the horizon for in vitro disease modeling and gained interest for mechanistic studies and preclinical drug discovery due to their potential advantages in providing a better physiologically relevant information and more predictive data for in vivo tests. Therefore, this study aimed to establish a 3D cell culture model of AD in vitro using iPSCs carrying the A246E mutation. We generated human iPSCs from fibroblasts from a patient with AD harboring the A246E mutation in the PSEN1 gene. Cell reprogramming was performed using lentiviral vectors with Yamanaka's factors (OSKM: Oct4, Sox2, Klf4, and c-Myc). The resulting iPSCs expressed pluripotency genes (such as Nanog and Oct4), alkaline phosphatase activity, and pluripotency stem cell marker expression, such as OCT4, SOX2, TRA-1-60, and SSEA4. iPSCs exhibited the ability to differentiate into neuronal lineage in a 3D environment through dual SMAD inhibition as confirmed by Nestin, MAP2, and Tuj1 neural marker expression. These iPSC-derived neurons harbored Aß oligomers confirmed by Western Blot (WB) and immunostaining. With human iPSC-derived neurons able to produce Aß oligomers, we established a novel human hydrogel-based 3D cell culture model that recapitulates Aß aggregation without the need for mutation induction or synthetic Aß exposure. This model will allow the study of processes implicated in disease spread throughout the brain, the screening of molecules or compounds with therapeutic potential, and the development of personalized therapeutic strategies.

Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer's disease.

Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment. The purpose of this study was to investigate the effects of mesenchymal stem cell-derived exosomes on neurogenesis and cognitive capacity in a mouse model of Alzheimer's disease. Alzheimer's disease mouse models were established by injection of beta amyloid 1-42 aggregates into dentate gyrus bilaterally. Morris water maze and novel object recognition tests were performed to evaluate mouse cognitive deficits at 14 and 28 days after administration. Afterwards, neurogenesis in the subventricular zone was determined by immunofluorescence using doublecortin and PSA-NCAM antibodies. Results showed that mesenchymal stem cells-derived exosomes stimulated neurogenesis in the subventricular zone and alleviated beta amyloid 1-42-induced cognitive impairment, and these effects are similar to those shown in the mesenchymal stem cells. These findings provide evidence to validate the possibility of developing cell-free therapeutic strategies for Alzheimer's disease. All procedures and experiments were approved by Institutional Animal Care and Use Committee (CICUAL) (approval No. CICUAL 2016-011) on April 25, 2016.

Potential Effects of MSC-Derived Exosomes in Neuroplasticity in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia affecting regions of the central nervous system that exhibit synaptic plasticity and are involved in higher brain functions such as learning and memory. AD is characterized by progressive cognitive dysfunction, memory loss and behavioral disturbances of synaptic plasticity and energy metabolism. Cell therapy has emerged as an alternative treatment of AD. The use of adult stem cells, such as neural stem cells and Mesenchymal Stem Cells (MSCs) from bone marrow and adipose tissue, have the potential to decrease cognitive deficits, possibly by reducing neuronal loss through blocking apoptosis, increasing neurogenesis, synaptogenesis and angiogenesis. These processes are mediated primarily by the secretion of many growth factors, anti-inflammatory proteins, membrane receptors, microRNAs (miRNA) and exosomes. Exosomes encapsulate and transfer several functional molecules like proteins, lipids and regulatory RNA which can modify cell metabolism. In the proteomic characterization of the content of MSC-derived exosomes, more than 730 proteins have been identified, some of which are specific cell type markers and others are involved in the regulation of binding and fusion of exosomes with adjacent cells. Furthermore, some factors were found that promote the recruitment, proliferation and differentiation of other cells like neural stem cells. Moreover, within exosomal cargo, a wide range of miRNAs were found, which can control functions related to neural remodeling as well as angiogenic and neurogenic processes. Taking this into consideration, the use of exosomes could be part of a strategy to promote neuroplasticity, improve cognitive impairment and neural replacement in AD. In this review, we describe how exosomes are involved in AD pathology and discuss the therapeutic potential of MSC-derived exosomes mediated by miRNA and protein cargo.