Two Olea europea extracts reduce deleterious effects in a model of neurotoxicity: involvement of the endoplasmic reticulum.

Prolonged exposure to lead has been recognized as harmful to human health as it may cause neurotoxic effects including mitochondrial damage, apoptosis, excitotoxicity, and myelin formation alterations, among others. Numerous data have shown that consuming olive oil and its valuable components could reduce neurotoxicity and degenerative conditions. Olive oil is traditionally obtained from olive trees; this plant (Olea europaea L.) is an evergreen fruit tree. In this manuscript two extracts have been used and compared: the extract from the leaves of Olea europaea L., (OE), and the extract derived from OE but with a further sonication process (s-OE). Therefore, the objectives of this experimental work were as follows: 1) To generate an innovative extract; 2) To test both extracts on a model of neurotoxicity of human neurons induced following lead exposure; and 3) To study the mechanisms behind lead-induced neurotoxicity. The results showed that the mechanism involved in the neurotoxicity of lead included dysfunction of the cellular endoplasmic reticulum, which suffered oxidative damage. In addition, in all experiments s-OE was more effective than OE, having greater and better effects against lead-induced damage, and being dissolved in a smaller amount of EtOH that promotes its sustainability.

Circulating miRNAs as Novel Clinical Biomarkers in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) represents the most common form of refractory focal epilepsy. The identification of innovative clinical biomarkers capable of categorizing patients with TLE, allowing for improved treatment and outcomes, still represents an unmet need. Circulating microRNAs (c-miRNAs) are short non-coding RNAs detectable in body fluids, which play crucial roles in the regulation of gene expression. Their characteristics, including extracellular stability, detectability through non-invasive methods, and responsiveness to pathological changes and/or therapeutic interventions, make them promising candidate biomarkers in various disease settings. Recent research has investigated c-miRNAs in various bodily fluids, including serum, plasma, and cerebrospinal fluid, of TLE patients. Despite some discrepancies in methodologies, cohort composition, and normalization strategies, a common dysregulated signature of c-miRNAs has emerged across different studies, providing the basis for using c-miRNAs as novel biomarkers for TLE patient management.

The dangerous "West Coast Swing" by hyperglycaemia and chronic stress in the mouse hippocampus: Role of kynurenine catabolism.

Growing epidemiological studies highlight a bi-directional relationship between depressive symptoms and diabetes mellitus. However, the detrimental impact of their co-existence on mental health suggests the need to treat this comorbidity as a separate entity rather than the two different pathologies. Herein, we characterized the peculiar mechanisms activated in mouse hippocampus from the concurrent development of hyperglycaemia, characterizing the different diabetes subtypes, and chronic stress, recognized as a possible factor predisposing to major depression. Our work demonstrates that kynurenine overproduction, leading to apoptosis in the hippocampus, is triggered in a different way depending on hyperglycaemia or chronic stress. Indeed, in the former, kynurenine appears produced by infiltered macrophages whereas, in the latter, peripheral kynurenine preferentially promotes resident microglia activation. In this scenario, QA, derived from kynurenine catabolism, appears a key mediator causing glutamatergic synapse dysfunction and apoptosis, thus contributing to brain atrophy. We demonstrated that the coexistence of hyperglycaemia and chronic stress worsened hippocampal damage through alternative mechanisms, such as GLUT-4 and BDNF down-expression, denoting mitochondrial dysfunction and apoptosis on one hand and evoking the compromission of neurogenesis on the other. Overall, in the degeneration of neurovascular unit, hyperglycaemia and chronic stress interacted each other as the partners of a "West Coast Swing" in which the leading role can be assumed alternatively by each partner of the dance. The comprehension of these mechanisms can open novel perspectives in the management of diabetic/depressed patients, but also in the understanding the pathogenesis of other neurodegenerative disease characterized by the compromission of hippocampal function.

Non-essential heavy metal effects in cardiovascular diseases: an overview of systematic reviews.

Introduction: Cardiovascular diseases (CVDs) are the most important cause of premature death and disability worldwide. Environmental degradation and cardiovascular diseases are two keys to health challenges, characterized by a constant evolution in an industrialized world that exploits natural resources regardless of the consequences for health. The etiological risk factors of CVDs are widely known and include dyslipidemia, obesity, diabetes, and chronic cigarette consumption. However, one component that is often underestimated is exposure to heavy metals. The biological perspective explains that different metals play different roles. They are therefore classified into essential heavy metals, which are present in organisms where they perform important vital functions, especially in various physiological processes, or non-essential heavy metals, with a no biological role but, nonetheless, remain in the environment in which they are absorbed. Although both types of metal ions are many times chemically similar and can bind to the same biological ligands, the attention given today to nonessential metals in several eukaryotic species is starting to raise strong concerns due to an exponential increase in their concentrations. The aim of this systematic review was to assess possible correlations between exposure to nonessential heavy metals and increased incidence of cardiovascular disease, reporting the results of studies published in the last 5 years through March 2023. Methods: The studies includes reviews retrieved from PubMed, Medline, Embase, and Web of Science databases, in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and following the PICO (Population Intervention Comparison Outcome Population) framework. Results: Eight reviews, including a total of 153 studies, were identified. Seven of these review enlighted the association between CVDs and non-essential heavy metals chronic exposure. Discussion: It is evident that exposure to heavy metals represent a risk factor for CVDs onset. However, further studies are needed to better understand the effects caused by these metals.

Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease.

Alzheimer's disease (AD) is a major global health problem today and is the most common form of dementia. AD is characterized by the formation of ß-amyloid (Aß) plaques and neurofibrillary clusters, leading to decreased brain acetylcholine levels in the brain. Another mechanism underlying the pathogenesis of AD is the abnormal phosphorylation of tau protein that accumulates at the level of neurofibrillary aggregates, and the areas most affected by this pathological process are usually the cholinergic neurons in cortical, subcortical, and hippocampal areas. These effects result in decreased cognitive function, brain atrophy, and neuronal death. Malnutrition and weight loss are the most frequent manifestations of AD, and these are also associated with greater cognitive decline. Several studies have confirmed that a balanced low-calorie diet and proper nutritional intake may be considered important factors in counteracting or slowing the progression of AD, whereas a high-fat or hypercholesterolemic diet predisposes to an increased risk of developing AD. Especially, fruits, vegetables, antioxidants, vitamins, polyunsaturated fatty acids, and micronutrients supplementation exert positive effects on aging-related changes in the brain due to their antioxidant, anti-inflammatory, and radical scavenging properties. The purpose of this review is to summarize some possible nutritional factors that may contribute to the progression or prevention of AD, understand the role that nutrition plays in the formation of Aß plaques typical of this neurodegenerative disease, to identify some potential therapeutic strategies that may involve some natural compounds, in delaying the progression of the disease.

The protective effect of Bergamot Polyphenolic Fraction on reno-cardiac damage induced by DOCA-salt and unilateral renal artery ligation in rats.

To date, the complex pathological interactions between renal and cardiovascular systems represent a real global epidemic in both developed and developing countries. In this context, renovascular hypertension (RVH) remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation. Adult male Wistar rats underwent unilateral renal artery ligation and treatment with deoxycorticosterone acetate (DOCA) (20 mg/kg, s.c.), twice a week for a period of 4 weeks, and 1% sodium chloride (NaCl) water (n = 10). A subgroup of hypertensive rats received BPF (100 mg/kg/day for 28 consecutive days, n = 10) by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (that served as control, n = 8). Unilateral renal artery ligation followed by treatment with DOCA and 1% NaCl water resulted in a significant increase in mean arterial blood pressure (MAP; p< 0.05. vs CTRL) which strongly increased the resistive index (RI; p<0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p<0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion when compared to CTRL group, as shown by the increased time-to-peak (T2P; p<0.05) and the decreased whole peak capacity (Pk; p<0.01) in displacement and strain rate (p<0.05, respectively) in longitudinal motion. Consequently, the hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) when compared to CTRL group (p<0.05 in displacement and p <0.01 in strain rate). Furthermore, a significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p< 0.05 for IL-12(40), p< 0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p< 0.001) was observed compared to CTRL group. Interestingly, this pathological condition is prevented by BPF treatment. In particular, BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats (p< 0.05) and exerts a protective effect on the volume of the contralateral kidney (p <0.01). Moreover, BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p <0.01) and reducing the T2P in strain rate motion (p<0.05). These latter effects significantly improve MOWD (p <0.05) preventing the overt dyssynchrony in cardiac wall motion. Finally, the reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of some pro-inflammatory cytokines and chemokines (p<0.05 for KC and IL-12(40), p<0.01 for GM-CSF, IL-13, and TNF- α) restoring physiological levels of renal neutrophil gelatinase-associated lipocalin (NGAL, p<0.05) protein of the tethered kidney. In conclusion, the present results show, for the first time, that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage. Overall, these data point to a potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome.

Cenobamate enhances the anticonvulsant effect of other antiseizure medications in the DBA/2 mouse model of reflex epilepsy.

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures. The effects of this adjunctive treatment on motor performance, body temperature, and brain levels of ASMs were also evaluated. CNB was able to antagonize seizures in DBA/2 mice. CNB, at 5 mg/kg, enhanced the antiseizure activity of ASMs, such as diazepam, clobazam, levetiracetam, perampanel, phenobarbital, topiramate, and valproate. No synergistic effects were observed when CNB was co-administered with some Na+ channel blockers. The increase in antiseizure activity was associated with a comparable intensification in motor impairment; however, the therapeutic index of combined treatment of ASMs with CNB was more favorable than the combination with vehicle except for carbamazepine, phenytoin, and oxcarbazepine. Since CNB did not significantly influence the brain levels of the ASMs studied, we suggest that pharmacokinetic interactions seem not probable. Overall, this study shows the ability of CNB to counteract generalized reflex seizures in mice. Moreover, our data documented an evident synergistic antiseizure effect for the combination of CNB with ASMs including phenobarbital, benzodiazepines, valproate, perampanel, topiramate, and levetiracetam.

Audiogenic epileptic DBA/2 mice strain as a model of genetic reflex seizures and SUDEP.

Epilepsy is a chronic neurological disease characterized by abnormal brain activity, which results in repeated spontaneous seizures. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related premature death, particularly in drug-resistant epilepsy patients. The etiology of SUDEP is a structural injury to the brain that is not fully understood, but it is frequently associated with poorly controlled and repeated generalized tonic-clonic seizures (GTCSs) that cause cardiorespiratory and autonomic dysfunctions, indicating the involvement of the brainstem. Both respiratory and cardiac abnormalities have been observed in SUDEP, but not much progress has been made in their prevention. Owing to the complexity of SUDEP, experimental animal models have been used to investigate cardiac and/or respiratory dysregulation due to or associated with epileptic seizures that may contribute to death in humans. Numerous rodent models, especially mouse models, have been developed to better understand epilepsy and SUDEP physiopathology. This review synthesizes the current knowledge about dilute brown agouti coat color (DBA/2) mice as a possible SUDEP model because respiratory arrest (RA) and sudden death induced by audiogenic generalized seizures (AGSs) have been observed in these animals. Respiratory/cardiac dysfunction, brainstem arousal system dysfunction, and alteration of the neurotransmitter systems, which are observed in human SUDEP, have also been observed in these mice. In particular, serotonin (5-HT) alteration and adenosine neurotransmission appear to contribute to not only the pathophysiological mechanisms of medication but also seizure-related respiratory dysfunctions in this animal model. These neurotransmitter systems could be the relevant targets for medication development for chronic epilepsy and SUDEP prevention. We reviewed data on AGSs in DBA/2 mice and the relevance of this model of generalized tonic-clonic epilepsy to human SUDEP. Furthermore, the advantages of using this strain prone to AGSs for the identification of possible new therapeutic targets and treatment options have also been assessed.

Salvia rosmarinus Spenn. (Lamiaceae) Hydroalcoholic Extract: Phytochemical Analysis, Antioxidant Activity and In Vitro Evaluation of Fatty Acid Accumulation.

Salvia rosmarinus Spenn. is a native Mediterranean shrub belonging to the Lamiaceae family and is well-known as a flavoring and spicing agent. In addition to its classical use, it has drawn attention because its biological activities, due particularly to the presence of polyphenols, including carnosic acid and rosmarinic acid, and phenolic diterpenes as carnosol. In this study, the aerial part of rosemary was extracted with a hydroalcoholic solution through maceration, followed by ultrasound sonication, to obtain a terpenoids-rich Salvia rosmarinus extract (TRSrE) and a polyphenols-rich Salvia rosmarinus extract (PRSrE). After phytochemical characterization, both extracts were investigated for their antioxidant activity through a classical assay and with electron paramagnetic resonance (EPR) for their DPPH and hydroxyl radicals scavenging. Finally, their potential beneficial effects to reduce lipid accumulation in an in vitro model of NAFLD were evaluated.

Antiseizure Medications in Alzheimer's Disease from Preclinical to Clinical Evidence.

Alzheimer's disease (AD) and epilepsy are common neurological disorders in the elderly. A bi-directional link between these neurological diseases has been reported, with patients with either condition carrying almost a two-fold risk of contracting the other compared to healthy subjects. AD/epilepsy adversely affects patients' quality of life and represents a severe public health problem. Thus, identifying the relationship between epilepsy and AD represents an ongoing challenge and continuing need. Seizures in AD patients are often unrecognized because they are often nonconvulsive and sometimes mimic some behavioral symptoms of AD. Regarding this, it has been hypothesized that epileptogenesis and neurodegeneration share common underlying mechanisms. Targeted treatment to decrease epileptiform activity could represent a valuable strategy for delaying the neurodegenerative process and related cognitive impairment. Several preclinical studies have shown that some antiseizure medications (ASMs) targeting abnormal network hyperexcitability may change the natural progression of AD. However, to date, no guidelines are available for managing seizures in AD patients because of the paucity of randomized clinical trials sufficient for answering the correlated questions. Future AD clinical studies are mandatory to update clinicians about the symptomatic treatment of seizures in AD patients and recognize whether ASM therapy could change the natural progression of the disease, thereby rescuing cognitive performance.

The Effects of Andrographis paniculata (Burm.F.) Wall. Ex Nees and Andrographolide on Neuroinflammation in the Treatment of Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) affect millions of people worldwide, and to date, Alzheimer's and Parkinson's diseases are the most common NDs. Of the many risk factors for neurodegeneration, the aging process has the most significant impact, to the extent that it is tempting to consider neurodegenerative disease as a manifestation of accelerated aging. However, genetic and environmental factors determine the course of neurodegenerative disease progression. It has been proposed that environmental stimuli influence neuroplasticity. Some clinical studies have shown that healthy lifestyles and the administration of nutraceuticals containing bioactive molecules possessing antioxidant and anti-inflammatory properties have a preventive impact or mitigate symptoms in previously diagnosed patients. Despite ongoing research efforts, the therapies currently used for the treatment of NDs provide only marginal therapeutic benefits; therefore, the focus is now directly on the search for natural products that could be valuable tools in combating these diseases, including the natural compound Andrographis paniculata (Ap) and its main constituent, andrographolide (Andro). Preclinical studies have shown that the aqueous extract of Ap can modulate neuroinflammatory and neurodegenerative responses, reducing inflammatory markers and oxidative stress in various NDs. Therefore, in this review, we will focus on the molecular mechanisms by which Ap and Andro can modulate the processes of neurodegeneration and neuroinflammation, which are significant causes of neuronal death and cognitive decline.

An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists.

BACKGROUND: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. METHODS: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. RESULTS: In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. CONCLUSIONS: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

Protective Role of an Extract Waste Product from Citrus bergamia in an In Vitro Model of Neurodegeneration.

A balanced diet, rich in fruits and vegetables and ensuring the intake of natural products, has been shown to reduce or prevent the occurrence of many chronic diseases. However, the choice to consume large quantities of fruits and vegetables leads to an increase in the amount of waste, which can cause an alteration in environmental sustainability. To date, the concept of a "byproduct" has evolved, now being understood as a waste product from which it is still possible obtain useful compounds. Byproducts in the agricultural sector are a rich source of bioactive compounds, capable of possessing a second life, decreasing the amount of waste products, the disposal costs, and environmental pollution. A promising and well-known citrus of the Mediterranean diet is the bergamot (Citrus bergamia, Risso et Poiteau). The composition of bergamot is known, and the rich presence of phenolic compounds and essential oils has justified the countless beneficial properties found, including anti-inflammatory, antioxidant, anti-cholesterolemic, and protective activity for the immune system, heart failure, and coronary heart diseases. The industrial processing of bergamot fruits leads to the formation of bergamot juice and bergamot oil. The solid residues, referred to as "pastazzo", are normally used as feed for livestock or pectin production. The fiber of bergamot (BF) can be obtained from pastazzo and could exert an interesting effect thanks to its content of polyphenols. The aims of this work were twofold: (a) to have more information (composition, polyphenol and flavonoid content, antioxidant activity, etc.) on BF powder and (b) to verify the effects of BF on an in vitro model of neurotoxicity induced by treatment with amyloid beta protein (Aß). In particular, a study of cell lines was carried out on both neurons and oligodendrocytes, to measure the involvement of the glia and compare it with that of the neurons. The results obtained showed that BF powder contains polyphenols and flavonoids and that it is able to exercise an antioxidant property. Moreover, BF exerts a protective action on the damage induced by treatment with Aß, and this defense is found in experiments on the cell viability, on the accumulation of reactive oxygen species, on the involvement of the expression of caspase-3, and on necrotic or apoptotic death. In all these results, oligodendrocytes were always more sensitive and fragile than neurons. Further experiments are needed, and if this trend is confirmed, BF could be used in AD; at the same time, it could help to avoid the accumulation of waste products.

Pathophysiological Aspects of Muscle Atrophy and Osteopenia Induced by Chronic Constriction Injury (CCI) of the Sciatic Nerve in Rats.

Skeletal muscle atrophy is a condition characterized by a loss of muscle mass and muscle strength caused by an imbalance between protein synthesis and protein degradation. Muscle atrophy is often associated with a loss of bone mass manifesting as osteoporosis. The aim of this study was to evaluate if chronic constriction injury (CCI) of the sciatic nerve in rats can be a valid model to study muscle atrophy and consequent osteoporosis. Body weight and body composition were assessed weekly. Magnetic resonance imaging (MRI) was performed on day zero before ligation and day 28 before sacrifice. Catabolic markers were assessed via Western blot and Quantitative Real-time PCR. After the sacrifice, a morphological analysis of the gastrocnemius muscle and Micro-Computed Tomography (Micro-CT) on the tibia bone were performed. Rats that underwent CCI had a lower body weight increase on day 28 compared to the naive group of rats (p < 0.001). Increases in lean body mass and fat mass were also significantly lower in the CCI group (p < 0.001). The weight of skeletal muscles was found to be significantly lower in the ipsilateral hindlimb compared to that of contralateral muscles; furthermore, the cross-sectional area of muscle fibers decreased significantly in the ipsilateral gastrocnemius. The CCI of the sciatic nerve induced a statistically significant increase in autophagic and UPS (Ubiquitin Proteasome System) markers and a statistically significant increase in Pax-7 (Paired Box-7) expression. Micro-CT showed a statistically significant decrease in the bone parameters of the ipsilateral tibial bone. Chronic nerve constriction appeared to be a valid model for inducing the condition of muscle atrophy, also causing changes in bone microstructure and leading to osteoporosis. Therefore, sciatic nerve constriction could be a valid approach to study muscle-bone crosstalk and to identify new strategies to prevent osteosarcopenia.

From Diabetes Care to Heart Failure Management: A Potential Therapeutic Approach Combining SGLT2 Inhibitors and Plant Extracts.

Diabetes is a complex chronic disease, and among the affected patients, cardiovascular disease (CVD)is the most common cause of death. Consequently, the evidence for the cardiovascular benefit of glycaemic control may reduce long-term CVD rates. Over the years, multiple pharmacological approaches aimed at controlling blood glucose levels were unable to significantly reduce diabetes-related cardiovascular events. In this view, a therapeutic strategy combining SGLT2 inhibitors and plant extracts might represent a promising solution. Indeed, countering the main cardiometabolic risk factor using plant extracts could potentiate the cardioprotective action of SGLT2 inhibitors. This review highlights the main molecular mechanisms underlying these beneficial effects that could contribute to the better management of diabetic patients.

Ferula communis L. (Apiaceae) Root Acetone-Water Extract: Phytochemical Analysis, Cytotoxicity and In Vitro Evaluation of Estrogenic Properties.

Ferula communis L. (F. communis) belongs to the Apiaceae family and is a herbaceous plant with various pharmaceutical properties, due to the different contents of bioactive compounds extracted mainly from its roots, as well as its leaves and rhizome. To date, this plant extract has demonstrated estrogenic, anti-inflammatory, antiproliferative, cytotoxic, antimicrobial and anti-neoplastic properties. Its estrogenic activity is justified by the presence of ferutinin, an ester of a sesquiterpenic alcohol that acts as an agonist for estrogen receptors, with a chemical formula equal to C22H3O4. The component present in F. communis responsible for the toxicity of the plant is ferulenol, a prenylated coumarin with the chemical formula C24H30O3. This compound is capable of inducing mortality via its strong anti-coagulant properties, leading to a lethal hemorrhagic syndrome, ferulosis, in animals that feed on a chemotype of F. communis containing a high amount of ferulenol. The removal of the component ferulenol makes extracts of Ferula non-toxic. In fact, the remaining prenylated coumarins are not present in concentrations sufficient to induce toxicity. The intake of high concentrations of the extract of this plant leads a double dose-dependent effect that is typical of sesquiterpenes such as ferutinin. Here, we assessed the cytotoxicity and the estrogenic properties of the F. communis phytocomplex obtained through extraction using a mixture of acetone and water. Among the active constituents of F. communis, the identification of ferutinin and ferulenol was performed using HPLC. The effects of the extract were evaluated, following the removal of ferulenol, on three cell lines: human breast cancer MCF-7, human cervical cancer HeLa and human osteoblastic sarcoma Saos-2. The choice of these cell lines was justified by the need to mimic certain processes which may occur in vivo and which are estrogen-dependent. The obtained results demonstrated that F. communis extract, in addition to possessing an estrogenic-like property, showed a dose-dependent effect. Low concentrations (0.1-0.8 µM) demonstrated a hyperproliferative effect, whereas higher concentrations (1.6-50 µM) were toxic. Therefore, this extract could be an excellent candidate to make up for a reduction or lack of estrogen.

The Employment of Genera Vaccinium, Citrus, Olea, and Cynara Polyphenols for the Reduction of Selected Anti-Cancer Drug Side Effects.

Cancer is one of the most widespread diseases globally and one of the leading causes of death. Known cancer treatments are chemotherapy, surgery, radiation therapy, targeted hormonal therapy, or a combination of these methods. Antitumor drugs, with different mechanisms, interfere with cancer growth by destroying cancer cells. However, anticancer drugs are dangerous, as they significantly affect both cancer cells and healthy cells. In addition, there may be the onset of systemic side effects perceived and mutagenicity, teratogenicity, and further carcinogenicity. Many polyphenolic extracts, taken on top of common anti-tumor drugs, can participate in the anti-proliferative effect of drugs and significantly reduce the side effects developed. This review aims to discuss the current scientific knowledge of the protective effects of polyphenols of the genera Vaccinium, Citrus, Olea, and Cynara on the side effects induced by four known chemotherapy, Cisplatin, Doxorubicin, Tamoxifen, and Paclitaxel. In particular, the summarized data will help to understand whether polyphenols can be used as adjuvants in cancer therapy, although further clinical trials will provide crucial information.

The Contribution of Gut Microbiota and Endothelial Dysfunction in the Development of Arterial Hypertension in Animal Models and in Humans.

The maintenance of the physiological values of blood pressure is closely related to unchangeable factors (genetic predisposition or pathological alterations) but also to modifiable factors (dietary fat and salt, sedentary lifestyle, overweight, inappropriate combinations of drugs, alcohol abuse, smoking and use of psychogenic substances). Hypertension is usually characterized by the presence of a chronic increase in systemic blood pressure above the threshold value and is an important risk factor for cardiovascular disease, including myocardial infarction, stroke, micro- and macro-vascular diseases. Hypertension is closely related to functional changes in the endothelium, such as an altered production of vasoconstrictive and vasodilator substances, which lead to an increase in vascular resistance. These alterations make the endothelial tissue unresponsive to autocrine and paracrine stimuli, initially determining an adaptive response, which over time lead to an increase in risk or disease. The gut microbiota is composed of a highly diverse bacterial population of approximately 1014 bacteria. A balanced intestinal microbiota preserves the digestive and absorbent functions of the intestine, protecting from pathogens and toxic metabolites in the circulation and reducing the onset of various diseases. The gut microbiota has been shown to produce unique metabolites potentially important in the generation of hypertension and endothelial dysfunction. This review highlights the close connection between hypertension, endothelial dysfunction and gut microbiota.

N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy.

N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.

MAFLD progression contributes to altered thalamus metabolism and brain structure.

Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p < 0.05 vs NC NW). Our results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance, that is quantifiable by 1H-MRS in vivo, might cause structural damage to brain cells and dysfunctions of neurotransmitter release.