Dietary Flavonoids Interaction with CREB-BDNF Pathway: An Unconventional Approach for Comprehensive Management of Epilepsy

cAMP response element binding protein (CREB) is a key transcriptional regulator that regulates the transcription of genes related with neuronal differentiation, synaptic plasticity, learning and memory. Brain derived neurotrophic factor (BDNF), is a CREB dependent gene which plays a pivotal role in the pathogenesis of epilepsy and central comorbid conditions associated with epilepsy. However, the beneficial or detrimental consequences of CREB-BDNF activation on the induction and/or progression of seizures depend specifically on the region of brain involved and the time of activation. The bioactive molecules that alter the activity of CREB in a way to have specialized effects in different brain regions and neural circuits involved could potentially be utilized for therapeutic purposes. Flavonoids are the polyphenolic compounds which lead to phosphorylation of CREB in the hippocampus, followed by increase in extracellular signal regulated kinase (ERK) and BDNF. Several members of flavonoid family have also showed suppression of epileptic seizures via interaction with CREB/BDNF pathway. Moreover, epilepsy is often accompanied by a number of behavioural and psychological comorbid conditions that further gets aggravated by the use of conventional antiepileptic drug therapy. Multiple studies have also supported the beneficial effects of flavonoids in cognitive and memory impairments by upregulation of CREB-BDNF pathway. The current review is an attempt to collate the available preclinical and clinical studies to establish the therapeutic potential of various dietary flavonoids in comprehensive management of epilepsy with relation to CREB-BDNF pathway.

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Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression

Cells ◽

10.3390/cells10092492 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2492

Author(s):

Wing-Shan Yu ◽

So-Hyun Kwon ◽

Stephen Kugbere Agadagba ◽

Leanne-Lai-Hang Chan ◽

Kah-Hui Wong ◽

...

Keyword(s):

Electrical Stimulation ◽

Therapeutic Potential ◽

Brain Regions ◽

Neuroprotective Effects ◽

Transcorneal Electrical Stimulation ◽

Beneficial Effects ◽

Non Invasive ◽

Antidepressant Treatments ◽

Antidepressant Effects ◽

Apoptosis And Inflammation

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

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Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02378-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ali Hassanzadeh ◽

Heshu Sulaiman Rahman ◽

Alexander Markov ◽

Judi Januadi Endjun ◽

Angelina Olegovna Zekiy ◽

...

Keyword(s):

Regenerative Medicine ◽

Messenger Rna ◽

Immune Modulation ◽

Therapeutic Potential ◽

Membrane Vesicles ◽

Bilayer Membrane ◽

Bioactive Molecules ◽

Phenotypic Traits ◽

Bioactive Lipids ◽

Beneficial Effects

AbstractRecently, mesenchymal stem/stromal cells (MSCs) and their widespread biomedical applications have attracted great consideration from the scientific community around the world. However, reports have shown that the main populations of the transplanted MSCs are trapped in the liver, spleen, and lung upon administration, highlighting the importance of the development of cell-free therapies. Concerning rising evidence suggesting that the beneficial effects of MSC therapy are closely linked to MSC-released components, predominantly MSC-derived exosomes, the development of an MSC-based cell-free approach is of paramount importance. The exosomes are nano-sized (30–100 nm) lipid bilayer membrane vesicles, which are typically released by MSCs and are found in different body fluids. They include various bioactive molecules, such as messenger RNA (mRNA), microRNAs, proteins, and bioactive lipids, thus showing pronounced therapeutic competence for tissues recovery through the maintenance of their endogenous stem cells, the enhancement of regenerative phenotypic traits, inhibition of apoptosis concomitant with immune modulation, and stimulation of the angiogenesis. Conversely, the specific roles of MSC exosomes in the treatment of various tumors remain challenging. The development and clinical application of novel MSC-based cell-free strategies can be supported by better understanding their mechanisms, classifying the subpopulation of exosomes, enhancing the conditions of cell culture and isolation, and increasing the production of exosomes along with engineering exosomes to deliver drugs and therapeutic molecules to the target sites. In the current review, we deliver a brief overview of MSC-derived exosome biogenesis, composition, and isolation methods and discuss recent investigation regarding the therapeutic potential of MSC exosomes in regenerative medicine accompanied by their double-edged sword role in cancer.

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Anti-Inflammatory Activity of Exopolysaccharides from Phormidium sp. ETS05, the Most Abundant Cyanobacterium of the Therapeutic Euganean Thermal Muds, Using the Zebrafish Model

Biomolecules ◽

10.3390/biom10040582 ◽

2020 ◽

Vol 10 (4) ◽

pp. 582 ◽

Cited By ~ 4

Author(s):

Raffaella Margherita Zampieri ◽

Alessandra Adessi ◽

Fabrizio Caldara ◽

Alessia Codato ◽

Mattia Furlan ◽

...

Keyword(s):

Therapeutic Potential ◽

Chronic Inflammatory Disease ◽

Bioactive Molecules ◽

In Vitro Tests ◽

Transgenic Zebrafish ◽

Zebrafish Model ◽

Beneficial Effects ◽

Anti Inflammatory

The Euganean Thermal District (Italy) represents the oldest and largest thermal center in Europe, and its therapeutic mud is considered a unique product whose beneficial effects have been documented since Ancient Roman times. Mud properties depend on the heat and electrolytes of the thermal water, as well as on the bioactive molecules produced by its biotic component, mainly represented by cyanobacteria. The investigation of the healing effects of compounds produced by the Euganean cyanobacteria represents an important goal for scientific validation of Euganean mud therapies and for the discovering of new health beneficial biomolecules. In this work, we evaluated the therapeutic potential of exopolysaccharides (EPS) produced by Phormidium sp. ETS05, the most abundant cyanobacterium of the Euganean mud. Specifically, Phormidium EPS resulted in exerting anti-inflammatory and pro-resolution activities in chemical and injury-induced zebrafish inflammation models as demonstrated using specific transgenic zebrafish lines and morphometric and expression analyses. Moreover, in vivo and in vitro tests showed no toxicity at all for the EPS concentrations tested. The results suggest that these EPS, with their combined anti-inflammatory and pro-resolution activities, could be one of the most important therapeutic molecules present in the Euganean mud and confirm the potential of these treatments for chronic inflammatory disease recovery.

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Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

Journal of Functional Morphology and Kinesiology ◽

10.3390/jfmk6020048 ◽

2021 ◽

Vol 6 (2) ◽

pp. 48

Author(s):

Elisa Innocenzi ◽

Ida Cariati ◽

Emanuela De Domenico ◽

Erika Tiberi ◽

Giovanna D’Arcangelo ◽

...

Keyword(s):

Alternative Splicing ◽

Aerobic Exercise ◽

Frontal Cortex ◽

Molecular Mechanisms ◽

Splice Variants ◽

Brain Regions ◽

Synaptic Function ◽

Molecular Changes ◽

Beneficial Effects ◽

The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

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Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode

Molecular Psychiatry ◽

10.1038/s41380-021-01054-9 ◽

2021 ◽

Author(s):

Jonas Hauser ◽

Edoardo Pisa ◽

Alejandro Arias Vásquez ◽

Flavio Tomasi ◽

Alice Traversa ◽

...

Keyword(s):

Cognitive Development ◽

Gut Microbiota ◽

Human Milk ◽

Molecular Mechanisms ◽

Brain Regions ◽

Nervous System Development ◽

Bioactive Molecules ◽

Human Milk Oligosaccharides ◽

Milk Oligosaccharides ◽

Eye Opening

AbstractBreastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1tm2Jxm/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6′SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6′SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6′SL-deficient milk. To test whether lactational 6′SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6′SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6′SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.

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Targeting necroptosis as therapeutic potential in chronic myocardial infarction

Journal of Biomedical Science ◽

10.1186/s12929-021-00722-w ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Chanon Piamsiri ◽

Chayodom Maneechote ◽

Natthaphat Siri-Angkul ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Myocardial Infarction ◽

Therapeutic Potential ◽

Coronary Perfusion ◽

Beneficial Effects ◽

Cell Death Pathways ◽

Threatening Condition ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

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Brain angiotensin system: a new promise in the management of epilepsy?

Clinical Science ◽

10.1042/cs20201296 ◽

2021 ◽

Vol 135 (6) ◽

pp. 725-730

Author(s):

Alberto Javier Ramos

Keyword(s):

Therapeutic Potential ◽

Renin Angiotensin System ◽

B Cell Lymphoma ◽

Ang Ii ◽

Angiotensin System ◽

Beneficial Effects ◽

System A ◽

Pilocarpine Model ◽

Animal Models Of Epilepsy ◽

Future Work

Abstract Epilepsy is a highly prevalent neurological disease and anti-epileptic drugs (AED) are almost the unique clinical treatment option. A disbalanced brain renin–angiotensin system (RAS) has been proposed in epilepsy and several reports have shown that angiotensin II (Ang II) receptor-1 (ATR1) activation is pro-inflammatory and pro-epileptogenic. In agreement, ATR1 blockage with the repurposed drug losartan has shown benefits in animal models of epilepsy. Processing of Ang II by ACE2 enzyme renders Ang-(1-7), a metabolite that activates the mitochondrial assembly (Mas) receptor (MasR) pathway. MasR activation presents beneficial effects, facilitating vasodilatation, increasing anti-inflammatory and antioxidative responses. In a recent paper published in Clinical Science, Gomes and colleagues (Clin. Sci. (Lond.) (2020) 134, 2263–2277) performed intracerebroventricular (icv) infusion of Ang-(1-7) in animals subjected to the pilocarpine model of epilepsy, starting after the first spontaneous motor seizure (SMS). They showed that this approach reduced the frequency of SMS, restored animal anxiety, increased exploration, and augmented the hippocampal expression of protective catalase enzyme and antiapoptotic protein B-cell lymphoma 2 (Bcl-2). Interestingly, but surprisingly, Gomes and colleagues showed that MasR expression and mTor activity were reduced in the hippocampus of the epileptic Ang-(1-7) treated animals. These results show that Ang-(1-7) administration could represent a new avenue for developing strategies for the management of epilepsy in clinical settings. However, future work is necessary to evaluate the levels of RAS metabolites and the activity of key enzymes in these experimental interventions to completely understand the therapeutic potential of the brain RAS manipulation in epilepsy.

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Secretin as a satiation whisperer with the potential to turn into an obesity-curbing knight

Endocrinology ◽

10.1210/endocr/bqab113 ◽

2021 ◽

Author(s):

Katharina Schnabl ◽

Yongguo Li ◽

Mueez U-Din ◽

Martin Klingenspor

Keyword(s):

Bariatric Surgery ◽

Body Weight ◽

Energy Balance ◽

Food Intake ◽

Weight Control ◽

Therapeutic Potential ◽

Physiological Mechanism ◽

Gut Hormones ◽

Metabolic Effects ◽

Beneficial Effects

Abstract The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, it only recently has been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these two entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery as well as chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin’s metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.

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From mesenchymal stem cells and stromal cells - from bench to bedside

Trillium Exctracellular Vesicles ◽

10.47184/tev.2019.01.05 ◽

2019 ◽

Vol 1 (1) ◽

pp. 36-39

Author(s):

Bernd Giebel ◽

Verena Börger ◽

Mario Gimona ◽

Eva Rohde

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

Stromal Cells ◽

Therapeutic Agent ◽

Therapeutic Potential ◽

Therapeutic Effects ◽

Cell Replacement ◽

Beneficial Effects ◽

Promising Tool

Human mesenchymal stem/stromal cells (MSCs) represent a promising tool in regenerative medicine. Until now, almost one thousand NIH-registered clinical trials investigated their immunomodulatory and pro-regenerative therapeutic potential in various diseases. Despite controversial reports regarding the efficacy of MSC-treatments, MSCs appear to exert their beneficial effects in a paracrine manner rather than by cell replacement. In this context, extracellular vesicles (EVs), such as exosomes and microvesicles, seem to induce the MSCs’ therapeutic effects. Here, we briefly illustrate the potential of MSC-EVs as therapeutic agent of the future.

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Resveratrol and cardiac fibrosis prevention and treatment

Current Pharmaceutical Biotechnology ◽

10.2174/1389201022666210212125003 ◽

2021 ◽

Vol 22 ◽

Author(s):

Parinaz Zivarpour ◽

Željko Reiner ◽

Jamal Hallajzadeh ◽

Liaosadat Mirsafaei

Keyword(s):

Cardiovascular Diseases ◽

Cardiac Fibrosis ◽

Therapeutic Potential ◽

Developed Countries ◽

Clinical Results ◽

Matrix Proteins ◽

Protective Effects ◽

Beneficial Effects ◽

Laboratory Models

: Cardiovascular diseases are some of the major causes of morbidity and mortality in developed or developing countries but in developed countries as well. Cardiac fibrosis is one of the most often pathological changes of heart tissues. It occurs as a result of extracellular matrix proteins accumulation at myocardia. Cardiac fibrosis results in impaired cardiac systolic and diastolic functions and is associated with other effects. Therapies with medicines have not been sufficiently successful in treating chronic diseases such as CVD. Therefore, the interest for therapeutic potential of natural compounds and medicinal plants has increased. Plants such as grapes, berries and peanuts contain a polyphenolic compound called "resveratrol" which has been reported to have various therapeutic properties for a variety of diseases. Studies on laboratory models that show that resveratrol has beneficial effects on cardiovascular diseases including myocardial infarction, high blood pressure cardiomyopathy, thrombosis, cardiac fibrosis, and atherosclerosis. In vitro animal models using resveratrol indicated protective effects on the heart by neutralizing reactive oxygen species, preventing inflammation, increasing neoangiogenesis, dilating blood vessels, suppressing apoptosis and delaying atherosclerosis. In this review, we are presenting experimental and clinical results of studies concerning resveratrol effects on cardiac fibrosis as a CVD outcome in humans.

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