Nrf2 as a potential target for the treatment of epilepsy

Epilepsy is a prevalent chronic brain disorder that is characterized by a persistent predisposition to recurrently generate epileptic seizures and is often associated with cognitive and psychological consequences.Epilepsy affects approximately 65 million individuals,including both males and females of all ages worldwide,and poses a significant burden on patients,their families,and the health system(Vezzani et al.,2019).

Optimization and comparison of two different 3D culture methods to prepare cell aggregates as a bioink for organ printing

The ultimate goal of tissue engineering is to design and fabricate functional human tissues that are similar to natural cells and are capable of regeneration.Preparation of cell aggregates is one of the important steps in 3D tissue engineering technology,particularly in organ printing.Two simple methods,hanging drop(HD)and conical tube(CT)were utilized to prepare cell aggregates.The size and viability of the aggregates obtained at different initial cell densities and pre-culture duration were compared.The proliferative ability of the cell aggregates and their ability to spread in culture plates were also investigated.In both methods,the optimum average size of the aggregates was less than 500μm.CT aggregates were smaller than HD aggregates.5,000 cells per drop HD aggregates showed a marked ability to attach and spread on the culture surface.The proliferative ability reduced when the initial cell density was increased.Comparing these methods,we found that the HD method having better size controlling ability as well as enhanced ability to maintain higher rates of viability,spreading,and proliferation.In conclusion,smaller HD aggregates might be a suitable choice as building blocks for making bioink particles in bioprinting technique.

Natural isothiocyanates of the genus Capparis as potential agonists of apoptosis and antitumor drugs

BACKGROUND Using gas chromatography-mass spectrometry(GC/MS)analysis,we examined the composition of volatile components present in the yellow and green fruits,seeds,and jam of the scrambling shrub Capparis cartilaginea(C.cartilaginea).These plant samples were collected from Kibbutz Yotvata in Israel.In all the tested samples,isothiocyanates were identified.Utilizing the PASS program,we ascertained the biological activity of these isothiocyanates present in the Capparis genus.The study results highlighted that all isothiocyanates could potentially act as apoptosis agonists,making them strong candidates for antitumor drugs.This information holds significant value for the fields of medicinal chemistry,pharmacology,and practical medicine.AIM To investigate the volatile components present in the yellow and green fruits,seeds,and jam of the C.cartilaginea shrub using GC/MS analysis,to detect isothiocyanates in all the analyzed plant samples,and to assess the biological activity of these isothiocyanates utilizing the PASS program.METHODS We utilized two primary methods to analyze the volatile compounds present in the yellow and green fruits,seeds,and jams of the C.cartilaginea,native to Israel.We identified biologically active isothiocyanates in these samples.Their anticipated biological activities were determined using the PASS program,with the most dominant activities being apoptosis agonist,anticarcinogenic,and antineoplastic specifically for genitourinary cancer.RESULTS Fruits,seeds,and jams containing isothiocyanates,which exhibit antineoplastic and anticarcinogenic activities,could be suggested for cancer prevention and management.Specific isothiocyanates,with therapeutic potential in this realm,could be recommended as potent anticancer agents in practical medicine following clinical trials.CONCLUSION The discovery that isothiocyanates exhibit potent antineoplastic and anticarcinogenic activities was unexpected.Additionally,certain isothiocyanates demonstrated antifungal,antiviral(specifically against arbovirus),and antiparasitic properties.

How to Predict AGEs Accumulation Slowdown Effect of a Cosmetic Ingredient? Two Steps <i>In-Vitro</i>System for Evaluating the Anti-AGE Impact of a New Blend

Advanced Glycation End-Products (AGEs), play a crucial part in advancing the process of cellular skin aging and its link to chronological age was re-assessed. AGEs accumulation alters cell structure and function of most types of skin cells, affecting skin’s mechanical and physiological properties, following the molecular transformations. Slowdown AGEs accumulation rate in skin, although a potent anti-aging strategy, is difficult and tricky. The lack of working methods for In-Vitro and In-Vitro measuring AGEs level complicates the evaluation and prediction of active ingredients’ ability to affect cellular AGEs accumulation. A two-step In-Vitro systematic screening method is proposed and three different cosmetic active ingredients were selected for its demonstration, using BSA-Glucose and Collagen-Glucose predicting models. Candidates’ effects on AGEs accumulation were evaluated as standalone, and when formulated in a blend. Additionally, the potency of non-invasive auto-fluorescence in-vivo measurement to detect AGEs levels among subjects of different ages was demonstrated. The results are presented in this work and the potential contribution of the proposed system to assist the desired inhibition of AGEs accumulation in skin is discussed.

Biochemical and cellular evidence of the benefit of a combination of cerium oxide nanoparticles and selenium to diabetic rats

AIM: To study the combinative effects of nanocerium and selenium in a murine model of diabetes. METHODS: Cerium oxide (CeO2) nanoparticles (60 mg/kg per day) and sodium selenite (5 μmol/kg per day) aloneor in combination, or the metal form of CeO2 (60 mg/kg) were administered for 2 wk by intraperitoneal injection to streptozotocin-induced diabetic rats. At the end of treatment blood was collected, liver tissue dissected and then oxidative stress markers, extent of energy depletion and lipid prof ile were evaluated.RESULTS: Antioxidant enzymes and high density lipoprotein decreased whereas oxidative stress, adenosine diphosphate/adenosine triphospahte levels, cholesterol, triglyceride and low density lipoprotein increased on induction of diabetes. All were improved by a combination of nanocerium and sodium selenite. There was a relative amelioration by CeO2 nanoparticles or sodium selenite alone, but the metal form of CeO2 showed no signif icant improvement. CONCLUSION: The combination of nanocerium and sodium selenite is more effective than either alone in improving diabetes-induced oxidative stress.

A proposed modulatory role of the endocannabinoid system on adipose tissue metabolism and appetite in periparturient dairy cows

To sustain the nutrient demands of rapid fetal growth,parturition,and milk synthesis,periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis.This process induces an inflammatory response within AT that is resolved as lactation progresses;however,excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases.The suppression of lipolytic action and inflammation,along with amplification of adipogenesis and lipogenesis,serve as prospective therapeutic targets for improving the health of periparturient dairy cows.Generally,the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis,suppresses lipolysis,and increases appetite in mammals.These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows’health,although much is still to be revealed in this context.This review summarizes the current knowledge surrounding the components of the endocannabinoid system,elaborates on the metabolic effects of its activation,and explores the potential to modulate its activity in periparturient dairy cows.

Specifc inflammatory osteoclast precursors induced during chronic inflammation give rise to highly active osteoclasts associated with inflammatory bone loss

Elevated osteoclast(OC)activity is a major contributor to inflammatory bone loss(IBL)during chronic inflammatory diseases.However,the specific OC precursors(OCPs)responding to inflammatory cues and the underlying mechanisms leading to IBL are poorly understood.We identified two distinct OCP subsets:Ly6C^(hi)CD11b^(hi) inflammatory OCPs(iOCPs)induced during chronic inflammation,and homeostatic Ly6C^(hi)CD11b^(lo)OCPs(hOCPs)which remained unchanged.Functional and proteomic characterization revealed that while iOCPs were rare and displayed low osteoclastogenic potential under normal conditions,they expanded during chronic inflammation and generated OCs with enhanced activity.In contrast,hOCPs were abundant and manifested high osteoclastogenic potential under normal conditions but generated OCs with low activity and were unresponsive to the inflammatory environment.Osteoclasts derived from iOCPs expressed higher levels of resorptive and metabolic proteins than those generated from hOCPs,highlighting that different osteoclast populations are formed by distinct precursors.We further identified the TNF-αand S100A8/A9 proteins as key regulators that control the iOCP response during chronic inflammation.Furthermore,we demonstrated that the response of iOCPs but not that of hOCPs was abrogated in tnf-α^(-/-)mice,in correlation with attenuated IBL.Our findings suggest a central role for iOCPs in IBL induction.iOCPs can serve as potential biomarkers for IBL detection and possibly as new therapeutic targets to combat IBL in a wide range of inflammatory conditions.

Overcoming the Bell‐Shaped Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose-response was observed, which limits its clinical use. In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the Cannabis sativa L., clone 202, which is highly enriched in CBD and hardly contains any psychoactive ingredients. In stark contrast to purified CBD, the clone 202 extract, when given either intraperitoneally or orally, provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses. The clone 202 extract reduced zymosan-induced paw swelling and pain in mice, and prevented TNFα production in vivo. It is likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD. We therefore propose that Cannabis clone 202 (Avidekel) extract is superior over CBD for the treatment of inflammatory conditions.

Effects of omega-3 supplementation on components of the endocannabinoid system and metabolic and inflammatory responses in adipose and liver of peripartum dairy cows

Background:Dietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system(ECS)by decreasing the availability of arachidonic acid,thus lowering endocannabinoids(e CBs)levels.The ECS is a modulator of energy metabolism,stress response and inflammation in mammals,yet there is little information on the roles of the ECS in transition dairy cows.During the periparturient period,the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation;however,exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows'physiology.Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows,by supplementing twenty-eight transition Holstein dairy cows with either saturated fat(CTL)or encapsulated flaxseed oil(FLX).Components of the ECS,metabolic and inflammatory markers were measured in blood,liver,and subcutaneous adipose tissue.Results:FLX supplementation reduced feed intake by 8.1%(P<0.01)and reduced plasma levels of arachidonic acid(by 44.2%;P=0.02)and anandamide(by 49.7%;P=0.03)postpartum compared to CTL.The m RNA transcription levels of the cannabinoid receptor 1(CNR1/CB1)tended to be lower(2.5 folds)in white blood cells of FLX than in CTL(P=0.10),and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL(P=0.04).In adipose tissue,palmitoylethanolamide levels were lower in FLX than in CTL(by 61.5%;P=0.02),relative m RNA transcription of lipogenic genes were higher,and the protein abundance of cannabinoid receptor 2(P=0.08)and monoacylglycerol lipase(P=0.10)tended to be higher in FLX compared to CTL.Hepatic 2-arachidonoylglycerol tended to be higher(by 73.1%;P=0.07),and interlukin-6 m RNA transcription level was 1.5 folds lower in liver of FLX than in CTL(P=0.03).Conclusions:Nutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation,which could be related to lower feed intake.The altered ECS components in blood,adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.

Protective Effects of a Novel Preparation Consists of Concentrated Dead Sea Water and Natural Plants Extracts against Skin Photo-Damage

Background: Exposure to solar UV rays has deleterious effects on skin appearance through physiological and structural alterations that eventually lead to skin photo-damage. Aims: To test the photo-protective effect of a novel preparation, Dead Sea Osmoter Concentrate (DSOC), containing high concentration of Dead Sea water. Methods: Human skin organ culture was used as a model to assess the biological effects of UVB irradiation and the protective effect of topical application of DSOC preparation. Skin pieces were analyzed for mitochondrial activity by Alamar blue (resazurin) assay, for apoptosis by caspase 3 assay, for detoxification by proteasome 20S sub-unit activity and for skin hydration by aquaporin 3 (AQP3) membrane channels expression. Human subjects were tested to evaluate the effect of DSOC Serum, a topical formula for facial skin, on skin hydration by a corneometer. Results: UVB irradiation induced cell apoptosis in the epidermis of skin organ cultures and decreased their proteasome activity and AQP3 expression. Topical application of DSOC significantly attenuated all these effects. In human subjects, an elevation in the intense skin moisture, which was higher relatively to subjects’ regular moisturizer, was observed. Moreover, DSOC Serum boosted the hydration effect together with regular moisturizer. Conclusions: The results clearly demonstrate that DSOC preparation can significantly improve the skin capability in coping with UVB rays stress in different cellular functions such as anti-apoptotic properties as well as detoxification and hydration recovery that can attenuate biological effects of skin photo-damage. Topical application of DSOC Serum had contributed to skin appearance by a strong hydration impact, also as a booster.

Nrf2 Pathway Involvement in the Beneficial Skin Effects of Moderate Ionic Osmotic Stress—The Case of The Dead Sea Water

Objectives: Exposing skin to moderate ionic osmotic stress (MIOS) triggers several biochemical responses. The objective of this work is to reveal the mechanism triggered by MIOS on the skin surface. Furthermore, this work aims to study the involvement of the Nrf2 (nuclear factor erythroid-2-related factor 2) pathway, activated by MIOS, and its beneficial effect in protecting skin against stress via the stimulation of phase II enzymes. Methods: HaCaT cells and human skin organ culture were exposed to Dead Sea Water (DSW) as MIOS inducers and the induction of internal ROS elevation, Nrf2 translocation, mRNA gene expressions of the phase II enzymes, heme-oxygenase 1 (HO1), and Catalase (CAT) were determined. Results: Skin exposure to MIOS increases Nrf2 translocation to the nucleus, leading to increased levels of ROS, HO1, and CAT. Furthermore, exposing skin to MIOS promotes protection against UVB-related risks. This is demonstrated by attenuation of the expression of biomarkers, related to UVB-induced damage, Caspase-3, IL-8, and IL-1β. Conclusions: Skin exposure to MIOS leads to the activation of Nrf2 skin defense pathway and, therefore, could present beneficial advantages to human skin health, as demonstrated on human skin models. The beneficial effects of MIOS, induced by DSW are significantly superior to eq. NaCl brine, suggests that MIOS protection of skin against stress is partially related to specific mineral combinations.