Betula pendula Leaf Extract Targets the Interplay between Brain Oxidative Stress, Inflammation, and NFkB Pathways in Amyloid Aß1-42-Treated Rats.

Alzheimer's disease (AD) is known as the primary and most common cause of dementia in the middle-aged and elderly population worldwide. Chemical analyses of B. pendula leaf extract (BPE), performed using spectrophotometric and chromatographic methods (LC/MS), revealed high amounts of polyphenol carboxylic acids (gallic, chlorogenic, caffeic, trans-p-coumaric, ferulic, and salicylic acids), as well as flavonoids (apigenin, luteolin, luteolin-7-O-glucoside, naringenin, hyperoside, quercetin, and quercitrin). Four groups of Wistar rats were used in this experiment (n = 7/group): control (untreated), Aß1-42 (2 µg/rat intracerebroventricular (i.c.v.), Aß1-42 + BPE (200 mg/Kg b.w.), and DMSO (10 µL/rat). On the first day, one dose of Aß1-42 was intracerebroventricularly administered to animals in groups 2 and 3. Subsequently, BPE was orally administered for the next 15 days to group 3. On the 16th day, behavioral tests were performed. Biomarkers of brain oxidative stress Malondialdehyde (MDA), (Peroxidase (PRx), Catalase (CAT), and Superoxid dismutase (SOD) and inflammation (cytokines: tumor necrosis factor -α (TNF-α), Interleukin 1ß (IL-1ß), and cyclooxygenase-2 (COX 2)) in plasma and hippocampus homogenates were assessed. Various protein expressions (Phospho-Tau (Ser404) (pTau Ser 404), Phospho-Tau (Ser396) (pTau Ser 396), synaptophysin, and the Nuclear factor kappa B (NFkB) signaling pathway) were analyzed using Western blot and immunohistochemistry in the hippocampus. The results show that BPE diminished lipid peroxidation and neuroinflammation, modulated specific protein expression, enhanced the antioxidant capacity, and improved spontaneous alternation behavior, suggesting that it has beneficial effects in AD.

The Utility of Noninvasive Urinary Biomarkers for the Evaluation of Vesicoureteral Reflux in Children.

Vesicoureteral reflux (VUR) is one of the most important disorders encountered in pediatric nephrology due to its frequency and potential evolution to chronic kidney disease (CKD). The aim of our study was to identify noninvasive and easy-to-determine urinary markers to facilitate the diagnosis and staging of VUR. We performed a cross-section study including 39 patients with VUR followed over three years (August 2021-September 2023) and 39 children without urinary disorder (the control group). We measured the urinary concentration of interleukin-6 (IL-6), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in VUR and healthy controls. Moreover, we analyzed the correlation between these biomarkers and the presence of renal scars (RS), reflux nephropathy (RN), and CKD. The NGAL concentrations were significantly higher in patients with VUR than in the controls (p = 0.02). Regarding the severity of the reflux, NGAL/creatinine and LL-37/creatinine were positively correlated with severe reflux (p = 0.04, respectively, p = 0.02). In patients with VUR and RS, LL-37/creatinine was significantly lower (p = 0.01). LL-37/creatinine with an AUC of 0.71 and NGAL/creatinine with an AUC of 0.72 could be acceptable diagnostic tests for severe VUR. In conclusion, urinary IL-6, NGAL, and LL-37 could serve as valuable markers for diagnosing and predicting outcomes in patients with VUR and RN.

Sleep Deprivation-Induced Oxidative Stress in Rat Models: A Scoping Systematic Review.

Sleep deprivation is highly prevalent in the modern world, possibly reaching epidemic proportions. While multiple theories regarding the roles of sleep exist (inactivity, energy conservation, restoration, brain plasticity and antioxidant), multiple unknowns still remain regarding the proposed antioxidant roles of sleep. The existing experimental evidence is often contradicting, with studies pointing both toward and against the presence of oxidative stress after sleep deprivation. The main goals of this review were to analyze the existing experimental data regarding the relationship between sleep deprivation and oxidative stress, to attempt to further clarify multiple aspects surrounding this relationship and to identify current knowledge gaps. Systematic searches were conducted in three major online databases for experimental studies performed on rat models with oxidative stress measurements, published between 2015 and 2022. A total of 54 studies were included in the review. Most results seem to point to changes in oxidative stress parameters after sleep deprivation, further suggesting an antioxidant role of sleep. Alterations in these parameters were observed in both paradoxical and total sleep deprivation protocols and in multiple rat strains. Furthermore, the effects of sleep deprivation seem to extend beyond the central nervous system, affecting multiple other body sites in the periphery. Sleep recovery seems to be characterized by an increased variability, with the presence of both normalizations in some parameters and long-lasting changes after sleep deprivation. Surprisingly, most studies revealed the presence of a stress response following sleep deprivation. However, the origin and the impact of the stress response during sleep deprivation remain somewhat unclear. While a definitive exclusion of the influence of the sleep deprivation protocol on the stress response is not possible, the available data seem to suggest that the observed stress response may be determined by sleep deprivation itself as opposed to the experimental conditions. Due to this fact, the observed oxidative changes could be attributed directly to sleep deprivation.

The effect of curcumin on reserpine-induced depression-like behaviour in rats.

The aim of this study was to construct an animal model of depression that reproduces the human clinical manifestation, to evaluate the possible benefits of curcumin (CUR) in the treatment of depression and to compare its effect with the effect of a classic antidepressant, escitalopram (ESC). The behavior of depressive-like animals induced by administration of 1.5 mg/kg i. p. reserpine (R), during 10 days (n = 24) was evaluated via the open field test (OFT) and elevated plus maze (EPM) compared to control animals (n = 24) treated with carboxymethylcellulose (CMC) used as a vehicle. On the 11th day, each group was divided into 3 subgroups (n = 8): control (CMC), CMC+CUR, CMC+ESC for group without depression and CMC+R, CMC+R+CUR, CMC+R+ESC for group with depression. CUR (150 mg/kg i.p.) and ESC (20 mg/kg i.p.) were intraperitoneally administrated for 21 days. The improvement in depressive behaviour was assessed by OFT, EPM and biochemical analysis on the 32nd day. The results demonstrated that R induced hypomotility and increased oxidative stress in the brain, but also in the serum of rats. CUR had an antioxidant effect in the brain without significant effect on depressive-like behaviour while ESC improved the hypomotility of the depressive rats.

Vesicoureteral Reflux and Innate Immune System: Physiology, Physiopathology, and Clinical Aspects.

Vesicoureteral reflux represents one of the most concerning topics in pediatric nephrology due to its frequency, clinical expression with the potential to evolve into chronic kidney disease, and last but not least, its socio-economic implications. The presence of vesicoureteral reflux, the occurrence of urinary tract infections, and the development of reflux nephropathy, hypertension, chronic kidney disease, and finally, end-stage renal disease represent a progressive spectrum of a single physiopathological condition. For the proper management of these patients with the best clinical outcomes, and in an attempt to prevent the spread of uropathogens' resistance to antibacterial therapy, we must better understand the physiopathology of urinary tract infections in patients with vesicoureteral reflux, and at the same time, we should acknowledge the implication and response of the innate immune system in this progressive pathological condition. The present paper focuses on theoretical aspects regarding the physiopathology of vesicoureteral reflux and the interconditionality between urinary tract infections and the innate immune system. In addition, we detailed aspects regarding cytokines, interleukins, antimicrobial peptides, and proteins involved in the innate immune response as well as their implications in the physiopathology of reflux nephropathy. New directions of study should focus on using these innate immune system effectors as diagnostic and therapeutic tools in renal pathology.

Magnetic Nanoclusters Stabilized with Poly[3,4-Dihydroxybenzhydrazide] as Efficient Therapeutic Agents for Cancer Cells Destruction.

Magnetic structures exhibiting large magnetic moments are sought after in theranostic approaches that combine magnetic hyperthermia treatment (MH) and diagnostic magnetic resonance imaging in oncology, since they offer an enhanced magnetic response to an external magnetic field. We report on the synthesized production of a core-shell magnetic structure using two types of magnetite nanoclusters (MNC) based on a magnetite core and polymer shell. This was achieved through an in situ solvothermal process, using, for the first time, 3,4-dihydroxybenzhydrazide (DHBH) and poly[3,4-dihydroxybenzhydrazide] (PDHBH) as stabilizers. Transmission electron microscopy (TEM) analysis showed the formation of spherical MNC, X-ray photoelectronic spectroscopy (XPS) and Fourier transformed infrared (FT-IR) analysis proved the existence of the polymer shell. Magnetization measurement showed saturation magnetization values of 50 emu/g for PDHBH@MNC and 60 emu/g for DHBH@MNC with very low coercive field and remanence, indicating that the MNC are in a superparamagnetic state at room temperature and are thus suitable for biomedical applications. MNCs were investigated in vitro, on human normal (dermal fibroblasts-BJ) and tumor (colon adenocarcinoma-CACO2, and melanoma-A375) cell lines, in view of toxicity, antitumor effectiveness and selectivity upon magnetic hyperthermia. MNCs exhibited good biocompatibility and were internalized by all cell lines (TEM), with minimal ultrastructural changes. By means of flowcytometry apoptosis detection, fluorimetry, spectrophotometry for mitochondrial membrane potential, oxidative stress, ELISA-caspases, and Western blot-p53 pathway, we show that MH efficiently induced apoptosis mostly via the membrane pathway and to a lower extent by the mitochondrial pathway, the latter mainly observed in melanoma. Contrarily, the apoptosis rate was above the toxicity limit in fibroblasts. Due to its coating, PDHBH@MNC showed selective antitumor efficacy and can be further used in theranostics since the PDHBH polymer provides multiple reaction sites for the attachment of therapeutic molecules.

Neurotoxicity of Bisphenol A and the Impact of Melatonin Administration on Oxidative Stress, ERK/NF-kB Signaling Pathway, and Behavior in Rats.

Bisphenol A (BPA) exposure can be associated with neurodevelopmental disorders due to impairment of cell proliferation and synaptic development. Our study evaluated the effects of melatonin (MEL) on ambulatory activity, lipid peroxidation, cytokines, ERK/NF-kB signaling pathway in the hippocampus and frontal lobe, and histopathological changes in the hippocampus of the BPA-treated rats. The animals were divided into 4 groups: control, BPA, BPA + MEL I, and BPA + MEL II. MEL I (20 mg/kg b.w.) and MEL II (40 mg/kg b.w.) were orally administered for 28 days. On the 29th day, BPA (1 mg/kg b.w.) was intraperitoneally administered, and, after 24 h, an open field test (OFT) and an elevated plus maze (EPM) were conducted. The results showed that the MEL II group made significantly more entries in the open arms of EPM, traveled significantly greater distance, and spent more time in the central part of OFT. Malondialdehyde levels were diminished by MEL II in the hippocampus and by MEL I in the frontal lobe. In the hippocampus, the MAPK level was significantly lowered by both doses of MEL (p < 0.05) while in the frontal lobe, only MEL II reduced the MAPK activation. MEL I and II significantly decreased the γH2AX and upregulated the NFkB and pNFkB expressions in the hippocampus while MEL II downregulated the MCP1 expression. Both doses of MEL attenuated the BPA-evoked histopathological alterations in the hippocampus. These data indicate that MEL can mediate the neuroprotection against BPA-induced neurotoxicity and improves behavioral changes suggesting a real potential as a protective agent in brain toxicity.

Time to Sleep?-A Review of the Impact of the COVID-19 Pandemic on Sleep and Mental Health.

Sleep is intrinsically tied to mental and overall health. Short sleep duration accompanies the modern lifestyle, possibly reaching epidemic proportions. The pandemic and subsequent lockdowns determined a fundamental shift in the modern lifestyle and had profound effects on sleep and mental health. This paper aims to provide an overview of the relationship between sleep, mental health and COVID-19. Contrasting outcomes on sleep health have been highlighted by most reports during the pandemic in the general population. Consequently, while longer sleep durations have been reported, this change was accompanied by decreases in sleep quality and altered sleep timing. Furthermore, an increased impact of sleep deficiencies and mental health burden was generally reported in health care workers as compared with the adult general population. Although not among the most frequent symptoms during the acute or persistent phase, an increased prevalence of sleep deficiencies has been reported in patients with acute and long COVID. The importance of sleep in immune regulation is well known. Consequently, sleep deficiencies may influence multiple aspects of COVID-19, such as the risk, severity, and prognosis of the infection and even vaccine response.

Oxidative Stress and DNA Lesion Reduction of a Polyphenolic Enriched Extract of Thymus marschallianus Willd. in Endothelial Vascular Cells Exposed to Hyperglycemia.

The present study aimed to compare two polyphenolic-enriched extracts obtained from the Thymus marschallianus Willd. (Lamiaceae) species, harvested from culture (TMCE in doses of 0.66 µg GAE/mL and 0.066 µg GAE/mL) and from spontaneous flora (TMSE in doses of 0.94 µg GAE/mL and 0.094 µg GAE/mL) by assessing their biological effects on human umbilical vein endothelial cells (HUVECs) exposed to normoglycemic (137 mmol/L glucose) and hyperglycemic conditions (200 mmol/L glucose). Extracts were obtained by solid phase extraction (SPE) and analyzed by chromatographical (HPLC-DAD) and spectrophotometrical methods. Their effects on hyperglycemia were evaluated by the quantification of oxidative stress and NF-ĸB, pNF-ĸB, HIF-1α, and γ-H2AX expressions. The HPLC-DAD analysis highlighted significant amounts of rosmarinic acid (ranging between 0.18 and 1.81 mg/g dry extract), luteolin (ranging between 2.04 and 17.71 mg/g dry extract), kaempferol (ranging between 1.85 and 7.39 mg/g dry extract), and apigenin (ranging between 4.97 and 65.67 mg/g dry extract). Exposure to hyperglycemia induced oxidative stress and the activation of NF-ĸ increased the expression of HIF-1α and produced DNA lesions. The polyphenolic-enriched extracts proved a significant reduction of oxidative stress and γ-H2AX formation and improved the expression of HIF-1α, suggesting their protective role on endothelial cells in hyperglycemia. The tested extracts reduced the total NF-ĸB expression and diminished its activation in hyperglycemic conditions. The obtained results bring evidence for the use of the polyphenolic-enriched extracts of T. marschallianus as adjuvants in hyperglycemia.

Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress.

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.

Evaluation of Hepatoprotective Activity and Oxidative Stress Reduction of Rosmarinus officinalis L. Shoots Tincture in Rats with Experimentally Induced Hepatotoxicity.

Rosmarinus officinalis L. is a widely known species for its medicinal uses, that is also used as raw material for the food and cosmetic industry. The aim of the present study was to offer a novel perspective on the medicinal product originating from this species and to test its hepatoprotective activity. The tested sample consisted in a tincture obtained from the fresh young shoots. Compounds that are evaluated for this activity are polyphenols and terpenoids, that are identified and quantified by HPLC-UV-MS and GC-MS. Antioxidant activity was assessed in vitro, using the DPPH, FRAP and SO assays. Hepatoprotective activity was tested in rats with experimentally-induced hepatotoxicity. In the chemical composition of the tincture, phenolic diterpenes (carnosic acid, carnosol, rosmanol, rosmadial) and rosmarinic acid were found to be the majority compounds, alongside with 1,8-cineole, camphene, linalool, borneol and terpineol among monoterpenes. In vitro, the tested tincture proved significant antioxidant capacity. Results of the in vivo experiment showed that hepatoprotective activity is based on an antioxidant mechanism. In this way, the present study offers a novel perspective on the medicinal uses of the species, proving significant amounts of polyphenols and terpenes in the composition of the fresh young shoots tincture, that has proved hepatoprotective activity through an antioxidant mechanism.

Targeting Oxidative Stress Reduction and Inhibition of HDAC1, MECP2, and NF-kB Pathways in Rats With Experimentally Induced Hyperglycemia by Administration of Thymus marshallianus Willd. Extracts.

The effects of two lyophilized extracts obtained from the aerial parts of Thymus marschallianus Willd. and harvested from wild flora (TMW) and obtained from culture (TMC) were evaluated in Wistar rats with experimentally induced hyperglycemia. The hyperglycemia was induced by streptozotocin (STZ) administration and the obtained results were evaluated in comparison for TMW and TMC. The polyphenolic composition of extracts was evaluated by spectrophotometrical and LC-MS methods. In vitro antioxidant capacity assays (DPPH, FRAP, EPR) were performed in order to preliminary establish the ability of tested samples to protect against free radical induced damage. Afterwards, the effects of these extracts were assessed in vivo on rats with experimental-induced hyperglycemia. Oxidative stress biomarkers (e.g. malondialdehyde-MDA), phosphorylated transcription factor subunit of nuclear kappaB (NF-kB) p65, methyl CpG binding protein (MECP) 2 and histone deacetylase 1 (HDAC1) expressions in hippocampus and frontal lobe were assessed. Open Field Test (OFT) and Elevated Plus Maze (EPM) were conducted on tested animals. Malondialdehyde (MDA) levels and HDAC1and MeCP2 expressions increased significantly in hippocampus (p<0.05) and frontal lobe (p<0.001) of diabetes group compared to the control group in parallel with decreasing of GSH/GSSG ratio. TMW and TMC administration reduced blood glucose levels and diminished lipid peroxidation, HDAC1 expression and enhanced antioxidant capacity in frontal lobe. TMW improved central locomotion of rats, increased phospho-NFkB p65 and diminished MECP2 expressions in hippocampus. Both tested samples exerted a beneficial effect by increasing the antioxidant defense. Our findings indicate that the administration of these extracts might represent a good option in the treatment of diabetes and its complications.

Origanum vulgare ssp. vulgare: Chemical Composition and Biological Studies.

The biological properties and main phenolic compounds of the O. vulgare L. ssp. vulgare extract are described in the present paper. The polyphenolic compounds were analyzed by chromatographic and spectrophotometric techniques. The antioxidant potential was evaluated using several methods: CUPRAC (cupric ion reducing antioxidant capacity), FRAP (ferric reducing ability of plasma), inhibition of lipid peroxidation catalyzed by cytochrome c, and superoxide (SO) scavenging assays. The antimicrobial activity of the oregano extract was evaluated by means of agar-well diffusion assay. The hepatoprotective effect of the O. vulgare extract on CCl4-induced hepatotoxicity was evaluated in rats. Liver injury was estimated by determination of alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), gamma-glutamyl transferase GGT, total protein and albumin concentrations, glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA). These values were improved by the administration of oregano extract. A specific phenolic profile was evidenced by these data, with large amounts of rosmarinic and chlorogenic acids. The oregano extract showed very strong antioxidant activity in good agreement with the phenolic content. Antimicrobial activity was good, especially against Salmonella enteritidis and Aspergillus niger strains. The high hepatoprotective, antioxidant and antimicrobial activity, along with polyphenol-rich content, can support the use of O. vulgare in therapy. We also expect our results to open new research directions for designing important new drug products, using indigenous plant material.

Curcumin Reverses the Diazepam-Induced Cognitive Impairment by Modulation of Oxidative Stress and ERK 1/2/NF-κB Pathway in Brain.

Oxidative stress and inflammation can be involved in cognitive dysfunction associated with neurodegenerative disorders. Diazepam (DZP) administration has been chosen to simulate the memory impairment. The aim of this study was to evaluate the effects of curcumin (CUR) on spatial cognition, ambulatory activity, and blood and brain oxidative stress levels. The ERK/NF-κB signaling pathway and the histopathological changes in the hippocampus and frontal lobe, in diazepam-treated rats, were also analyzed. The animals were divided into 4 groups: control, carboxymethylcellulose (CMC) + CUR, CMC + DZP, and CUR + CMC + DZP. CUR (150 mg/kg b.w.) was orally administered for 28 days. DZP (2 mg/kg b.w.) was intraperitoneally administered 20 minutes before the behavioral tests (open field test, Y-maze, and elevated plus maze). CUR improved the spontaneous alternation behavior, decreased the oxidative stress levels, both in the blood and in the hippocampus, and downregulated the extracellular signal-regulated kinase (ERK 1/2)/nuclear transcription factor- (NF-) κB/pNF-κB pathway in the hippocampus and the iNOS expression in the hippocampus and frontal lobe of the DZP-treated rats. Histopathologically, no microscopic changes were found. The immunohistochemical signal of iNOS decreased in the DZP and CUR-treated group. Thus, our findings suggest that curcumin administration may improve the cognitive performance and may also have an antioxidant effect.

Modulatory effects of caffeine on oxidative stress and anxiety-like behavior in ovariectomized rats.

Menopause is accompanied by enhanced oxidative stress and behavioral changes, effects attenuated by antioxidants. The aim of this study was to evaluate the effects of caffeine on behavior and oxidative stress in an experimental model of menopause. Female rats were divided into the following groups: sham-operated (CON), sham-operated and caffeine-treated (CAF), ovariectomized (OVX), ovariectomized and caffeine-treated (OVX+CAF). Caffeine (6 mg/kg) and vehicle were administered for 21 days (subchronic) and 42 days (chronic), using 2 experimental subsets. Behavioral tests and oxidative stress parameters in the blood, whole brain, and hippocampus were assessed. The subchronic administration of caffeine decreased the lipid peroxidation and improved the antioxidant defense in the blood and brain. The GSH/GGSG ratio in the brain was improved by chronic administration, with reduced activities of antioxidant enzymes and enhanced nitric oxide and malondialdehyde levels. In particular, the lipid peroxidation in the hippocampus decreased in both experiments. The rats became hyperactive after 21 days of treatment, but no effect was observed after chronic administration. In both experimental subsets, caffeine had anxiolytic effects as tested in elevated plus maze. The administration of low doses of caffeine, for a short period of time, may be a new therapeutic approach to modulating the oxidative stress and anxiety in menopause.