Effect of fentanyl and remifentanil on neuron damage and oxidative stress during induction neurotoxicity.

Opioids can be used for medical and non-medical purposes. Chronic pain such as cancer, as well as the frequent use of such drugs in places such as operating rooms and intensive care units, and in non-medical areas like drug abuse the effects and side effects of these drugs need to be examined in more detail. For this purpose, the effects of fentanyl and remifentanil drugs on neuroinflammation, oxidative stress and cholinesterase metabolism were investigated. Neuron cells (CRL-10742) were used for the evaluation of the toxicity of fentanyl and remifentanil. MTT, PON1 activity and total thiol levels for its effect on oxidative stress, AChE and BChE activities for its effect on the cholinergic system, and TNF, IL-8 and IL-10 gene levels for its neuroinflammation effect were determined. The highest neurotoxic dose of fentanyl and remifentanil was determined as 10 µg/mL. It was observed that the rate of neuron cells in this dose has decreased by up to 61.80% and 56.89%, respectively. The IL-8 gene expression level in both opioids was down-regulated while IL 10 gene level was up-regulated in a dose-dependent manner compared to the control. In our results, the TNF gene expression level differs between the two opioids. In the fentanyl group, it was seen to be up-regulated in a dose-dependent manner compared to the control. Fentanyl and remifentanil showed an inhibitory effect against PON1, while remifentanil showed an increase in total thiol levels. PON1, BChE and total thiol activities showed similarity with MTT.

Analyzing the impact of synthetic and natural steroids: a study of cytochrome P450 metabolism, morphological alterations through metabolomics, and histopathological Examination.

This study focuses on the comparative metabolic profiling and effects of two steroid types: natural and synthetic, specifically 17α-methyl testosterone (17α-MT) at varying concentrations (1.5, 2, and 3 mg/kg) in rainbow trout (Oncorhynchus mykiss). Over a 75-day feeding trial, growth metrics, such as feed efficiency, daily specific growth, live weight gain, total weight gain, and survival rate were systematically monitored every 15 days. At the end of the feeding trial, histopathology, immunohistochemistry, and metabolome analyses were performed in the high-concentration groups (3 mg/kg natural and 3 mg/kg synthetic), in which the lowest survival rate was determined. Key findings reveal that the type of hormone significantly influences growth parameters. While some natural steroids enhanced certain growth aspects, synthetic variants often yielded better results. The metabolomic analysis highlighted significant shifts in the metabolism of tryptophan, purine, folate, primary bile acids, phosphonates, phosphinates, and xenobiotics via cytochrome P450 pathways. Histopathologically, the natural hormone groups showed similar testicular, hepatic, muscular, gill, cerebral, renal, and intestinal tissue structures to the control, with minor DNA damage and apoptosis observed through immunohistochemistry. Conversely, the synthetic hormone groups exhibited moderate DNA damage and mild degenerative and necrotic changes in histopathology.

Glioblastoma cell-derived exosomes induce cell death and oxidative stress in primary cultures of olfactory neurons. Role of redox stress.

BACKGROUND: Glioblastoma multiforme, described as glioblastoma, is a malignancy originating from glial progenitors in the central nervous system and is the most malignant subtype of brain tumors which attracted researcher's attention due to their high recurrence and mortality despite optimal treatments. In the study, we aimed to research whether glioblastoma-originated exosomes play a role in olfactory nerve cell toxicity. METHODS AND RESULTS: For this aim, exosomes obtained from U373 and T98G cells were applied to olfactory nerve cell culture at distinct doses. Then, glutathione (GSH), lactate dehydrogenase (LDH), total antioxidant capacity (TAC), 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT), total oxidant status (TOS) and Immunofluorescence analyzes were performed. We found that both glioblastoma-derived exosomes decreased cell viability in olfactory neurons with increasing doses. According to the obtained data, the olfactory neuron vitality rate was 71% in T98G-exosome, but the decrease in U373-exosome was more obvious (48%). In particular, the 100 µg/ml dose exacerbated oxidative stress by increasing TOS. It also increased cellular apoptosis compared to the control group due to LDH leakage. However, the results of GSH and TAS showed that antioxidant levels were significantly reduced. CONCLUSION: In the microenvironment of olfactory neurons, GBM-derived exosomes increased oxidative stress-induced toxicity by reducing TAC and GSH levels. Therefore, glioblastoma cells by induction of exosome-based stress support malignant growth.

Flavonoid-Rich Sambucus nigra Berry Extract Enhances Nrf2/HO-1 Signaling Pathway Activation and Exerts Antiulcerative Effects In Vivo.

Sambucus nigra (SN) berry extract is characterized by high antioxidant and anti-inflammatory activity. The current study aimed to investigate the effect of SN berry extract against indomethacin (IND)-induced gastric ulcer in rats and the mechanism involved. SN berry extract alleviated IND-induced gastric ulcers, as shown by assessing pathological manifestations in the gastric mucosa. These protective effects are attributed to attenuated oxidative damage to the gastric mucosa, correlated to increased activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), enhanced glutathione (GSH) levels, total antioxidant capacity (TAC), and upregulation of the Nrf2/HO-1 cascade. Moreover, oxidative stress markers, including malondialdehyde (MDA) and total oxidant status (TOS), were downregulated in SN-extract-treated animals. Furthermore, SN berry extract suppressed gastric mucosal inflammation by downregulating interleukin (IL)-33, IL-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) levels, and attenuating myeloperoxidase (MPO) activity. The protective effects of SN berry extract were similar to those exerted by esomeprazole (ESO), an acid-secretion-suppressive drug. In conclusion, SN berry extract has antiulcerative effects, alleviating oxidative stress and inflammation.

The potential effect mechanism of high-fat and high-carbohydrate diet-induced obesity on anxiety and offspring of zebrafish.

Anxiety and obesity are two current phenomena. They are among the important public health problems with increasing prevalence worldwide. Although it is claimed that there are strong relations between them, the mechanism of this relationship has not been fully clarified yet. On the other hand, the effect of this relationship on the offspring has been another research subject. In this study, obese zebrafish were obtained by feeding two different diets, one containing high amount of lipid (HF) and the other containing high amount of carbohydrate (HK), and their anxiety levels were evaluated. To establish a relationship between these two phenomena, in addition to histopathological and immunohistochemical analysis in the brain tissues of fish, the transcription levels of some genes related to lipid and carbohydrate metabolisms were determined. In addition, offspring were taken from obese zebrafish and studied to examine the effect of parental obesity on offspring. As a result, it was observed that the HC diet, causing more weight increase than the HF diet, showed an anxiolytic while the HF diet an anxiogenic effect. It was suggested that the probable cause of this situation may be the regulatory effect on the appetite-related genes depending on the upregulation severity of the PPAR gene family based on the diet content. In addition, it was also suggested that it may have contributed to this process in neuron degenerations caused by oxidative stress. Regarding effects on offspring, it can be concluded that HF diet-induced obesity has more negative effects on the next generation than the HC diet.Level of evidenceNo Level of evidence: animal study.

Effect of betulinic acid administration on TLR-9/NF-κB /IL-18 levels in experimental liver injury

Background/aim: Acetaminophen (APAP), used in the composition of thousands of preparations, is the most commonly used analgesic and antipyretic drug. The present study aimed to investigate the potential protective effects of the betulinic acid (BA) treatment through an APAP-induced hepatotoxicity rat model, using inflammatory, biochemical, and histopathological parameters. Materials and methods: The study consisted of four groups: control group, APAP group, BA group, and APAP+BA group. Experimental studies continued for fifteen days. Serum samples were analysed for glucose, total cholesterol (TChol), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), aspartate amino transferase (AST), malondialdehyde (MDA), toll-like receptor-9 (TLR-9), nuclear factor kappa B (NF-κB), and interleukin-18 (IL-18). Results: TLR9, IL-18, NF-κB, and MDA levels increased significantly in liver injury groups. These increases considerably decreased by the BA treatment. All groups showed immunopositivity for 8-hydroxy-2'­deoxyguanosine (8-OHdG) and interleukin (IL-1ß) in the hepatocytes, inflammatory cells, and epithelial cells of bile ducts. Conclusion: BA can be used as an effective agent in the prevention and treatment of acute liver diseases due to its inhibitory properties in multiple pathways and its potent antioxidant effects.

Modified Glasgow Prognostic Score is a novel predictor of clinical outcome in heart failure with preserved ejection fraction.

Objectives. Although the modified Glasgow Prognostic Score (mGPS) has been reported to have prognostic value in patients with various cancers, the association between mGPS and prognosis in patients with heart diseases have not been well studied. The aim of this study was to evaluate the predictive value of mGPS in outcomes of patients with heart failure and preserved ejection fraction (HFpEF). Design. We prospectively followed consecutive adult patients with HFpEF admitted to the cardiology outpatient unit. Echocardiographic and laboratory data were recorded at enrolment. mGPS was scored as 0, 1, or 2 based on C-reactive protein (CRP) and albumin levels. Patients with both elevated CRP (>1 mg/dL) and hypoalbuminemia (<3.5 g/dL) are given mGPS of 2, patients with serum CRP ≤ 1 g/dL with or without hypoalbuminemia received scores of 0. Patients with only elevated CRP levels received mGPS of 1. The primary composite endpoint of the study was all-cause mortality or heart failure hospitalization through one year. Results. A total of 315 HFpEF outpatients were included, and 42 (13.3%) reached the primary endpoint at one year of follow-up. Compared to patients without mortality or heart failure-related hospitalization, patients who reached the primary endpoint during follow-up were older, were more likely be symptomatic, had higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and mGPS levels at study entry. Multivariate analysis showed that both NT-proBNP and mGPS were independent predictors of primary composite endpoint. Combining NT-proBNP with mGPS improved its prognostic value with an increase of area under the receiver operating characteristic curve from 0.759 to 0.822 (p = .001). Conclusion. This is the first study which demonstrates that mGPS is a predictor of outcomes in patients with HFpEF.

Decreased neurotensin levels as a biomarker in resistant hypertension.

Objective: Although neurotensin is found throughout the body including cardiovascular structures, the correlation of plasma neurotensin levels with resistant hypertension (RH) has never been examined. Therefore, we aimed to compare plasma neurotensin concentration, between patients with RH and those with controlled hypertension (CH).Methods: Forty-one patients with RH and 45 patients with CH who had undergone outpatient ambulatory blood pressure measurements were prospectively recruited. RH was defined as uncontrolled blood pressure despite using three antihypertensive agents including a diuretic or need of four or more drugs to control blood pressure. The demographic properties, medications, laboratory parameters including neurotensin levels, and echocardiographic parameters were recorded.Results: There was no significant difference among groups in terms of age, sex, smoking or body mass index. Office and ambulatory blood pressures and mean number of antihypertensive drugs used were significantly higher in patients with RH compared to patients with CH. Plasma neurotensin levels were significantly lower in patients with RH (median: 0.380 ng/ml; interquartile range: 0.292-0.471) than in the patients with controlled blood pressure (median: 0.638 ng/ml; interquartile range: 0.483-0.783). Multivariate and receiver-operating characteristics curve analyses showed that neurotensin is an independent predictor for RH and the optimal cut-off value of neurotensin for RH was lower than 0.509 ng/ml, with a sensitivity of 85.4% and a specificity of 73.3% (area under the curve = 0.793, 95% CI: 0.691-0.894, p < .001)Conclusion: This study is the first to show a correlation between lower neurotensin levels and RH.

Preoperative Right Ventricular Echocardiographic Parameters Predict Perioperative Cardiovascular Complications in Patients Undergoing Non-Cardiac Surgery.

BACKGROUND: Transthoracic echocardiography is frequently ordered before non-cardiac surgery (NCS), but the impact of preoperative echocardiography on perioperative outcomes in patients undergoing NCS is unknown. The present study aimed to evaluate the predictive value of preoperative right ventricular echocardiograhic parameters for the occurrence of perioperative cardiovascular complications (PCC) in patients undergoing NCS. METHOD: We reviewed the data of 660 patients aged ≥18 years and over (mean age 66.3±15 yr) who underwent preoperative comprehensive echocardiography before elective NCS between January 2015 and February 2019. Only patients who had undergone echocardiography before NCS were included. Echocardiographic measurements of right ventricular function, including tricuspid annular plane systolic excursion (TAPSE), Tei index, right ventricular fractional area change, and pulmonary artery systolic pressure, were retrospectively evaluated. The primary outcome of the study was major PCC defined as cardiac death, non-fatal cardiac arrest, severe arrhythmias requiring treatment, acute heart failure, acute coronary syndrome, pulmonary thrombo-embolism, and cardio-embolic stroke. RESULTS: Eighty (80) patients (12.1%) experienced PCC. Patients with PCC were older, and had a higher prevalence of coronary artery disease, heart failure, and diabetes mellitus. Patients with PCC had lower TAPSE (16.9±4.4 vs 20.8±4.2 mm; p<0.001) than patients without PCC. Multivariate logistic regression analysis showed that older age (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.25-4.65; p<0.01), presence of diabetes (OR, 1.78; 95% CI, 0.95-3.46; p=0.03), and TAPSE <17.6mm (OR, 3.12; 95% CI, 1.12-5.46; p=0.03) were significant variables associated with PCC. CONCLUSIONS: This is the first study to demonstrate that preoperative reduced right ventricular systolic function, as measured by TAPSE, is associated with increased rates of perioperative adverse cardiac events in patients undergoing NCS.

Neuroprotective effects of dietary borax in the brain tissue of rainbow trout (Oncorhynchus mykiss) exposed to copper-induced toxicity.

We aimed to investigate the modulating effects of dietary borax on the pathways in rainbow trout brain exposed to copper. For this aim, a comprehensive assessment was performed including biochemical (acetylcholinesterase (AChE), malondialdehyde (MDA), oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG), and caspase-3 levels) and transcriptional parameters (heat shock protein 70 (HSP70) and cytochromes P450 (CYP1A), glutathione peroxidase (gpx), superoxide dismutase (sod), and catalase (cat)) parameters and immunohistochemically staining of 8-OHdG. Special fish feed diets were prepared for the trial. These diets contained different concentrations of borax (1.25, 2.5, and 5 mg/kg) and/or copper (500 and 1000 mg/kg) at the period of pre- and co-treatment strategies for 21 days. At the end of the treatment periods, brain tissue was sampled for each experimental group. As a result, the biochemical parameters were increased and AChE activity decreased in the copper and copper-combined groups in comparison with the control group and also with only borax applications (p < 0.05). We observed an increase or decrease in particular biochemical parameters for the borax group in every application and we established that borax had protective effect against copper toxicity by decreasing and/or increasing the relevant biochemical parameters in brain tissue of fish. The biochemical results of borax and its combinations corresponded to the observations of gene expression data, which similarly concluded that HSP70 and CYP1A genes were strongly induced by copper (p < 0.05). In addition, the expression levels of the sod, cat, and gpx genes in the fish brains exposed to borax and the borax combination groups were significantly higher than the only copper-treated groups. In conclusion, borax supplementation provided significant protection against copper-induced neurotoxicity in trout.

Real-world stroke prevention strategies in nonvalvular atrial fibrillation in patients with renal impairment.

BACKGROUND: The data regarding stroke prevention strategies in nonvalvular atrial fibrillation (NVAF) are limited especially in patients with renal impairment (RI). We sought to evaluate management dilemmas in patients with concurrent NVAF and RI in RAMSES (ReAl-life Multicenter Survey Evaluating Stroke Prevention Strategies inTurkey) study. METHODS: We conducted a prospective, multicenter, nation-wide registry in NVAF patients in outpatient cardiology clinics. All consecutive patients with NVAF were enrolled in RAMSES study (ClinicalTrials.gov identifier NCT02344901). The baseline data were collected. Glomerular filtration rate (GFR) was estimated by Cockcroft-Gault equation. RESULTS: A total number of 6273 patients from 29 provinces of Turkey with the contribution of 83 investigators were enrolled to the study. Of the study population, 1964(33%) patients had RI which was defined as GFR < 60 mL/min. Patients with RI had significantly higher CHA2 DS2 VASc and HAS-BLED scores compared to those without RI (3·9 ± 1·5 vs. 2·9 ± 1·5, and 2·0 ± 1 vs. 1·4 ± 1; P < 0·001). Prior history of major bleeding (6·9% vs. 4·1%, P < 0·001) and stroke (16·2% vs. 11·8%, P < 0·001) was significantly higher among individuals with concomitant RI and NVAF. Although RI patients had a higher risk for thromboembolism, number of the patients who did not receive any anticoagulant therapy was higher in patients with RI than without RI (30·1 vs. 26·4%, P = 0·003). CONCLUSION: RAMSES study showed that one-third of the patients with NVAF had RI in the real-world setting. Although it is mandatory in most of the patients with concomitant NVAF and RI, nearly one-third of these patients did not receive any anticoagulant therapy.

Impact of valvular heart disease on oral anticoagulant therapy in non-valvular atrial fibrillation: results from the RAMSES study.

The definition of non-valvular atrial fibrillation (NVAF) is controversial. We aimed to assess the impact of valvular heart disease on stroke prevention strategies in NVAF patients. The RAMSES study was a multicenter and cross-sectional study conducted on NVAF patients (ClinicalTrials.gov identifier NCT02344901). The study population was divided into patients with significant valvular disease (SVD) and non-significant valvular disease (NSVD), whether they had at least one moderate valvular disease or not. Patients with a mechanical prosthetic valve and mitral stenosis were excluded. Baseline characteristics and oral anticoagulant (OAC) therapies were compared. In 5987 patients with NVAF, there were 3929 (66%) NSVD and 2058 (34%) SVD patients. The predominant valvular disease was mitral regurgitation (58.1%), followed by aortic regurgitation (24.1%) and aortic stenosis (17.8%). Patients with SVD had higher CHA2DS2VASc [3.0 (2.0; 4.0) vs. 4.0 (2.0; 5.0), p < 0.001] and HAS-BLED [2.0 (1.0; 2.0) vs. 2.0 (1.0; 2.0), p = 0.004] scores compared to patients with NSVD. Overall, 2763 (71.2%) of NSVD and 1515 (73.8%) of SVD patients were on OAC therapy (p = 0.035). When the patients with SVD were analyzed separately, the mean CHA2DS2VASc and HAS-BLED scores were higher in patients with mitral regurgitation compared to patients with aortic regurgitation and aortic stenosis [4.0 (3.0; 5.0), 3.0 (2.0; 4.0), 3.0 (2.0; 4.0) p < 0.001 and 2.0 (1.0; 3.0), 1.0 (1.0; 2.0), 1.0 (0.0; 2.0) p < 0.001, respectively]. In patients with SVD, 65.7% of mitral regurgitation, 82.6% of aortic regurgitation and 88.0% of aortic stenosis patients were on OAC therapy. One out of three NVAF patients had at least one moderate valvular heart disease with the predominance of mitral regurgitation. Patients with SVD were at greater risk of stroke and bleeding compared to patients with NSVD. Although patients with mitral regurgitation should be given more aggressive anticoagulant therapy due to their higher risk of stroke, they are undertreated compared to patients with aortic valve diseases.

Quinacrine, a PLA2 inhibitor, alleviates LPS-induced acute kidney injury in rats: Involvement of TLR4/NF-κB/TNF α-mediated signaling.

Acute Kidney Injury (AKI) is a major factor in sepsis-related mortality and may occur due to lipopolysaccharide (LPS), an endotoxin produced by gram-negative bacteria that triggers a systemic acute inflammatory response. Quinacrine's (QC) renoprotective properties in sepsis and the underlying mechanism, however, are still not fully understood. This study was done to investigate the anti-inflammatory, antioxidative, and anti-apoptotic effects of QC, a phospholipase A2 (PLA2) inhibitor, against LPS-induced AKI. Rats were randomly divided into five groups: control group, QC30 group, LPS group, LPS+QC 10 group, and LPS+QC 30 group. The rats were administered intraperitoneally QC (10 and 30 mg/kg) for 3 days (once a day) prior to injection of LPS (3 mg/kg). Six hours after the LPS injection, the histopathological changes, oxidative stress, inflammation, and apoptosis in the collected kidney tissues were detected by hematoxylin and eosin staining, enzyme-linked immunosorbent assay (ELISA), real-time PCR (RT-PCR), and immunohistochemistry staining, respectively. QC pretreatment could successfully attenuate LPS-induced AKI, as evidenced by a decrease in tissue histopathological injury. Meanwhile, QC alleviated LPS-induced kidney oxidative stress; it reduced MDA levels and increased levels of SOD, CAT, GPX, and GSH. LPS-induced elevations in kidney TLR4, NF-κB, TNF-α, IL-1ß, IL-6, PLA2, caspase 3, and Bax contents were significantly attenuated in QC-treated groups. Our findings revealed a significant effect of QC: protecting against LPS-induced AKI through inhibition of PLA2 and decreasing inflammation, oxidative stress, and apoptosis. To treat LPS-induced AKI, QC may be an effective substance with an excellent protection profile.

Molecular insights into the antioxidative and anti-inflammatory effects of P-coumaric acid against bisphenol A-induced testicular injury: In vivo and in silico studies.

This study investigated the protective effects of p-coumaric acid (PCA) against bisphenol A (BPA)-induced testicular toxicity in male rats. The rats were divided into control, BPA, BPA+PCA50, BPA+PCA100, and PCA100 groups. Following a 14-day treatment period, various analyses were conducted on epididymal sperm quality and testicular tissues. PCA exhibited dose-dependent cytoprotective, antioxidant, and anti-inflammatory effects, ameliorating the decline in sperm quality induced by BPA. The treatment elevated antioxidant enzyme activities (SOD, GPx, CAT) and restored redox homeostasis by increasing cellular glutathione (GSH) and reducing malondialdehyde (MDA) levels. PCA also mitigated BPA-induced proinflammatory responses while reinstating anti-inflammatory IL-10 levels. Apoptotic parameters (p53 and p38-MAPK) were normalized by PCA in BPA-treated testicular tissue. Immunohistochemical and immunofluorescent analyses confirmed the cytoprotective and anti-inflammatory effects of PCA, evidenced by the upregulation of HO-1, Bcl-2, and Nrf-2 and the downregulation of the proapoptotic gene Bax in BPA-induced testicular intoxication. PCA corrected the disturbance in male reproductive hormone levels and reinstated testosterone biosynthetic capacity after BPA-induced testicular insult. In silico analyses suggested PCA's potential modulation of the oxidative stress KEAP1/NRF2/ARE pathway, affirming BPA's inhibitory impact on P450scc. This study elucidates BPA's molecular disruption of testosterone biosynthesis and highlights PCA's therapeutic potential in mitigating BPA's adverse effects on testicular function, showcasing its cytoprotective, anti-inflammatory, and hormone-regulating properties. The integrated in vivo and in silico approach offers a comprehensive understanding of complex mechanisms, paving the way for future research in reproductive health and toxicology, and underscores the importance of employing BPA-free plastic wares in semen handling.

Morinda citrifolia protective effects on paclitaxel-induced testis parenchyma toxicity: An experimental study.

The current study aimed to investigate the sensitivity of male testis parenchyma cells to chemotherapy agents and the protective effects and mechanisms of Morinda citrifolia (Noni) administration against structural and functional changes before and after chemotherapy (Paclitaxel (PTX)). For this purpose, rats were randomly assigned into four groups (Control = G1, PTX 5 mg/kg = G2; PTX + Noni 10 mg/kg = G3, PTX + Noni 20 mg/kg = G4). PTX was injected intraperitoneally for 4 consecutive weeks, at a dose of 5 mg/kg to all groups except the control group. Then noni was administrated in 10 (G3) and 20 (G4) mg/kg groups orally (gavage) for 14 days. Biochemical analyses, Real-Time Polymerase Chain Reaction (PCR), and immunohistochemical analyses were performed. According to our results, Total Oxidative Stress (TOS) and Malondialdehyde (MDA) were significantly increased in the PTX group (P < 0.01). Superoxide Dismutase (SOD) enzyme activity and Total Antioxidant Capacity (TAC) levels were decreased (P < 0.01). The changes in the rats treated with PTX + Noni 20 mg/kg were noteworthy. The increased levels of IL1-ß (Interleukin 1 beta) and TNFα (tumor necrosis factor-alpha) with PTX were down-regulated after treatment with PTX + Noni 20 mg/kg (P < 0.01) (9 % and 5 % respectively). In addition, Noni restored the testicular histopathological structure by reducing caspase-3 expression and significantly (61 %) suppressed oxidative DNA damage and apoptosis (by regulating the Bax (bcl-2-like protein 4)/Bcl-2 (B-cell lymphoma gene-2) ratio). In conclusion, Noni reduced cellular apoptosis and drastically changed Caspase 8 and Bax/Bcl-2 levels. Furthermore, it considerably decreases oxidative damage and can be used in testicular degeneration.

Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases.

BACKGROUND: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. METHODS: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. FINDINGS: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. INTERPRETATION: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.

Effect of Oleanolic acid administration on hepatic AMPK, SIRT-1, IL-6 and NF-κB levels in experimental diabetes.

Objectives: Diabetes mellitus (DM) is an important public health problem all over the world, considering its complications and increasing prevalence. Oleanolic acid (OA) has anti-diabetic property via modulating glucose metabolism and acting as 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) / Sirtuin-1 (SIRT-1) activator and Interleukin 6 (IL-6) / Nuclear factor kappa B (NF-κB) inhibitor. This research questioned if the OA treatment amliorates the hepatic inflammatory profile in the diabetic rats. Methods: Twenty-eight male Sprague Dawley rats were first subjected to either no diabetes induction (healthy) or diabetes induction by i.p. injection of 50 mg/kg streptozotocin. Then rats in both groups were treated with either tap water or OA (5 mg/kg) within 1 ml tap water by oral gavage for 21 days. Results: The diabetic rats had higher hepatic MDA (2.88x) and serum AST (2.01x), ALP (2.22x), and ALT (4.27x) levels and 50% lower hepatic SOD level than the healthy rats. The OA treatment significantly reversed these antioxidant parameters in the diabetic rats. The diabetic rats had lower AMPK (85%) and hepatic SIRT-1 (47%) levels and higher hepatic NF-κB (53%) and IL-6 (34%) levels than the healthy rats. Comparing with the health rats, the OA treatment increased hepatic SIRT-1 level, but tended to increase hepatic AMPK level and decrease hepatic NF-κB and IL-6 levels in the diabetic rats. It was also partially effective to ameliorate degenerative changes and necrosis in the diabetic rats. Conclusion: The OA treatment can be considered to alleviate oxidative stress and reduce severity of inflammation in hepatocytes in the diabetic subjects.

Effects of oleanolic acid administration on renal NF-kB, IL-18, IL-6, YKL-40, and KIM-1 in experimental diabetic rats.

Objectives: Neuropathy, retinopathy, and nephropathy, known as the triopathy of diabetes, are the consequences of microvascular complications of diabetes. The present study aimed to investigate the potential protective effects of oleanolic acid (OA) administration against diabetic nephropathy considering biochemical and histopathological parameters. Materials and Methods: The rats with fasting blood glucose levels of 200 mg/dl and above were considered diabetic after induction of diabetes via injecting STZ. The other half of the rats were not injected with STZ (healthy rats). Both healthy and diabetic rats were then divided randomly into two subgroups to be administered with either OA (5 mg/kg) with 1 ml tap water by oral gavage or 1 ml tap water in the same route for 21 days. Serum urea-N, Ca, P, and Mg as well as renal tissue MDA, SOD, NF-κB, IL-6, IL-18, AMPK, YKL-40, and KIM-1 levels were measured. Results: OA administration partially decreased levels of serum urea-N and P, as well as levels of renal tissue MDA and inflammation markers (NF-κB, IL-6, IL-18, YKL-40, and KIM-1) in the diabetic rats. It also partially increased serum Ca and renal tissue AMPK levels in diabetic rats. These positive effects were also seen in renal tissue histopathology. Conclusion: OA treatment partially alleviated renal damage inflammatory and oxidative profiles in diabetic rats.

Global warming and glyphosate toxicity (I): Adult zebrafish modelling with behavioural, immunohistochemical and metabolomic approaches.

Global warming further increases the toxic threat of environmental pollutants on organisms. In order to reveal the dimensions of this threat more clearly, it is of great importance that the studies be carried out with temperature differences as close as possible to the temperature values that will represent the global climate projection. In our study, how the toxicity of glyphosate, which is widely used around the world, on zebrafish changes with temperature increases of 0.5° was investigated on behavioral and molecular basis. For this purpose, adult zebrafish were exposed to glyphosate at concentrations of 1 ppm and 5 ppm for 96 h in four environments with a temperature difference of 0.5° (28.5; 29.0; 29.5; 30.0 °C). At the end of the exposure, half of the zebrafish were sampled and remaining half were left for a 10-day recovery process. At the end of the trials, zebrafish were subjected to circadian rhythm and anxiety tests. In addition, histopathological, immunohistochemical and metabolome analyses were performed on brain tissues. As a result, it has been detected that anxiety and circadian rhythm were disrupted in parallel with the increased temperature and glyphosate concentration, and increased histopathological findings and 5-HT4R and GNAT2 immunopositivity in the brain. As a result of metabolome analysis, more than thirty annotated metabolites have been determined due to the synergistic effect of temperature increase and glyphosate exposure. As a conclusion, it was concluded that even a temperature increase of 0.5° caused an increasing effect of glyphosate toxicity in the zebrafish model.

Fluoride exposure causes behavioral, molecular and physiological changes in adult zebrafish (Danio rerio) and their offspring.

Fluoride exposure through drinking water, foods, cosmetics, and drugs causes genotoxic effects, oxidative damage, and impaired cognitive abilities. In our study, the effects of fluoride on anxiety caused by the circadian clock and circadian clock changes in a zebrafish model were investigated at the molecular level on parents and the next generations. For this purpose, adult zebrafish were exposed to 1.5 ppm, 5 ppm, and 100 ppm fluoride for 6 weeks. At the end of exposure, anxiety-like behaviors and sleep/wake behaviors of the parent fish were evaluated with the circadian rhythm test and the novel tank test. In addition, antioxidant enzyme activities and melatonin levels in brain tissues were measured. In addition, morphological, physiological, molecular and behavioral analyzes of offspring taken from zebrafish exposed to fluoride were performed. In addition, histopathological analyzes were made in the brain tissues of both adult zebrafish and offspring, and the damage caused by fluoride was determined. The levels of BMAL1, CLOCK, PER2, GNAT2, BDNF and CRH proteins were measured by immunohistochemical analysis and significant changes in their levels were determined in the F- treated groups. The data obtained as a result of behavioral and molecular analyzes showed that parental fluoride exposure disrupts the circadian rhythm, causes anxiety-like behaviors, and decreases the levels of brain antioxidant enzymes and melatonin in parents. In addition, delay in hatching, increase in death and body malformations, and decrease in blood flow velocity, and locomotor activity was observed in parallel with dose increase in offspring. On the other hand, an increase in offspring apoptosis rate, ROS level, and lipid accumulation was detected. As a result, negative effects of fluoride exposure on both parents and next generations have been identified.