Neuroprotective effects of punicalagin and/or micronized zeolite clinoptilolite on manganese-induced Parkinson's disease in a rat model: Involvement of multiple pathways.

BACKGROUND: Manganism, a central nervous system dysfunction correlated with neurological deficits such as Parkinsonism, is caused by the substantial collection of manganese chloride (MnCl2) in the brain. OBJECTIVES: To explore the neuroprotective effects of natural compounds, namely, micronized zeolite clinoptilolite (ZC) and punicalagin (PUN), either individually or in combination, against MnCl2-induced Parkinson's disease (PD). METHODS: Fifty male albino rats were divided into 5 groups (Gps). Gp I was used as the control group, and the remaining animals received MnCl2 (Gp II-Gp V). Rats in Gps III and IV were treated with ZC and PUN, respectively. Gp V received both ZC and PUN as previously reported for the solo-treated plants. RESULTS: ZC and/or PUN reversed the depletion of monoamines in the brain and decreased acetyl choline esterase activity, which primarily adjusted the animals' behavior and motor coordination. ZC and PUN restored the balance between glutamate/γ-amino butyric acid content and markedly improved the brain levels of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and decreased glycogen synthase kinase-3 beta activity. ZC and PUN also inhibited inflammatory and oxidative markers, including nuclear factor kappa-light-chain-enhancer of activated B cells, Toll-like receptor 4, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 and caspase-1. Bcl-2-associated X-protein and B-cell leukemia/lymphoma 2 protein (Bcl-2) can significantly modify caspase-3 expression. ZC and/or PUN ameliorated PD in rats by decreasing the levels of endoplasmic reticulum (ER) stress markers (p-protein kinase-like ER kinase (PERK), glucose-regulated protein 78, and C/EBP homologous protein (CHOP)) and enhancing the levels of an autophagy marker (Beclin-1). DISCUSSION AND CONCLUSION: ZC and/or PUN mitigated the progression of PD through their potential neurotrophic, neurogenic, anti-inflammatory, antioxidant, and anti-apoptotic activities and by controlling ER stress through modulation of the PERK/CHOP/Bcl-2 pathway.

Combined sulforaphane and ß-sitosterol mitigate olanzapine-induced metabolic disorders in rats: Insights on FOXO, PI3K/AKT, JAK/STAT3, and MAPK signaling pathways.

One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of sulforaphane (SFN) and ß-sitosterol (ßSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, ßSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or ßSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and ßSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-ß signaling pathways. The administration of SFN and/or ßSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways.

The consumption pattern and perception of using artificial sweeteners among the public in Tabuk region, Saudi Arabia.

Background: Obesity and weight gain have become major problems worldwide. Thus, several forms of alternative intense sweeteners are extensively used, offering a non-caloric sweet taste. To the best of our knowledge, no research has studied either the consumption pattern or the perception of using artificial sweeteners in Saudi Arabia. Objectives: Our research aimed to study the usage pattern of such artificial sweeteners in the Tabuk region and estimate the knowledge of and attitudes toward their usage among the population. Methods: A cross-sectional study promoted on multiple social media platforms and face-to-face interviews in different malls and hospitals in the Tabuk region. We grouped the participants into two major groups: the users and the non-users of artificial sweeteners. Each group has been subdivided into a healthy subgroup and those with a medical record subgroup. Participants' characteristics and their choice of sweeteners were analyzed using bivariate analysis. The age, gender, and education level of the participants were adjusted using binary logistic regression in order to adjust for potential confounders. Results: A total of 2,760 participants were included in our study. We found that more than 59% of the participants that were over 45 years old were non-hospitalized non-hospitalized diseased irrespective of their usage of artificial sweeteners. Furthermore, females, graduates, diabetics were significantly high irrespective of their subgroup. Moreover, Steviana® is the most commonly used artificial sweetener. In addition, healthy participants showed a greater perception of the usage and adverse effects of artificial sweeteners. Furthermore, bivariate analysis using logistic regression revealed significant associations (p < 0.05) with confounders such as gender, age, and education level. Conclusion: Educational programs and nutritional advice for the safe consumption and the daily permissible doses of artificial sweeteners are essential and should be directed specifically at females.

In vivo assessment of inflammatory cytokines induced oxidative stress signalling, and troponin I gene dysregulation in cardiac tissue associated with chronic administration of boldenone and tramadol, alone or in combination.

INTRODUCTION: The risk of cardiotoxicity is associated with the use of anabolic-androgenic steroids and analgesics, several deaths were attributed to such medications. OBJECTIVES: This study investigates the effects of boldenone (BOLD) and tramadol (TRAM) alone or in combination on the heart. MATERIAL AND METHODS: Forty adult male rats were divided into four groups. Normal control group, BOLD (5 mg/kg, i.m.) per week, tramadol Hcl (TRAM) (20 mg/kg, i.p.) daily and a combination of BOLD (5 mg/kg) and TRAM (20 mg/kg), respectively for two months. Serum and cardiac tissue were extracted for determination of serum, aspartate aminotransferase (AST), creatine phosphokinase (CPK) and lipid profiles, tissue malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and histopathological examination. Troponin I gene expression was quantified in cardiac tissue using real-time polymerase chain reaction technique. RESULTS: Groups received BOLD and TRAM alone and in combination showed elevated serum biochemical parameters (AST, CPK) and deviations in lipid profiles, elevation in oxidative and inflammatory parameters (MDA, NO, TNF-α and IL-6), and decrease in GSH and SOD, up-regulated cardiac troponin I as well as distorted cardiac histopathological pictures. CONCLUSION: The current study elucidated the risk of administration of these drugs for sustained periods as well as the marked detrimental effects of using these drugs in combination.

Neuroprotective Effects of Some Nutraceuticals against Manganese-Induced Parkinson's Disease in Rats: Possible Modulatory Effects on TLR4/NLRP3/NF-κB, GSK-3ß, Nrf2/HO-1, and Apoptotic Pathways.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting the substantia nigra where functions controlling body movement take place. Manganese (Mn) overexposure is linked to a neurologic syndrome resembling PD. Sesamol, thymol, wheat grass (WG), and coenzyme Q10 (CoQ10) are potent antioxidants, anti-inflammatory, and anti-apoptotic nutraceuticals. We investigated the potential protective effects of these nutraceuticals alone or in combinations against MnCl2-induced PD in rats. Seven groups of adult male Sprague Dawley rats were categorized as follows: group (I) was the control, while groups 2-7 received MnCl2 either alone (Group II) or in conjunction with oral doses of sesamol (Group III), thymol (Group IV), CoQ10 (Group V), WG (Group VI), or their combination (Group VII). All rats were subjected to four behavioral tests (open-field, swimming, Y-maze, and catalepsy tests). Biochemical changes in brain levels of monoamines, ACHE, BDNF, GSK-3ß, GABA/glutamate, as well as oxidative stress, and apoptotic and neuroinflammatory biomarkers were evaluated, together with histopathological examinations of different brain regions. Mn increased catalepsy scores, while decreasing neuromuscular co-ordination, and locomotor and exploratory activity. It also impaired vigilance, spatial memory, and decision making. Most behavioral impairments induced by Mn were improved by sesamol, thymol, WG, or CoQ10, with prominent effect by sesamol and thymol. Notably, the combination group showed more pronounced improvements, which were confirmed by biochemical, molecular, as well as histopathological findings. Sesamol or thymol showed better protection against neuronal degeneration and some behavioral impairments induced by Mn than WG or CoQ10, partly via interplay between Nrf2/HO-1, TLR4/NLRP3/NF-κB, GSK-3ß and Bax/Bcl2 pathways.

Taurine attenuated methotrexate-induced intestinal injury by regulating NF-κB/iNOS and Keap1/Nrf2/HO-1 signals.

Methotrexate (MTX) is a well-known and widely used cytotoxic chemotherapeutic agent. However, intestinal mucosa damage is a serious adverse effect of MTX. Taurine (TUR) is a sulfur-containing free ß-amino acid with antioxidant and therapeutic value against several diseases. The current study aimed to determine the protective effect of TUR against MTX-induced intestinal injury. Rats were allocated into four groups. The first group received vehicles only. The second group received TUR at a dose of 250 mg/kg i.p. For induction of intestinal injury, the rats in the third group were given MTX once at a dose of 20 mg/kg, i.p. The fourth group received TUR 7 days before and 7 days after MTX, as previously described. TUR significantly attenuated the cytokine release by suppressing NF-κB and iNOS expressions. Moreover, cotreatment with TUR attenuated the increased MDA level while it enhanced the antioxidant GSH and SOD levels mediated by effective downregulation of Keap1 expression, while the expression of Nrf2, HO-1, and cytoglobin were up-regulated. Additionally, TUR mitigated the apoptosis and proliferation indices by decreasing the elevated levels of intestinal PCNA and caspase-3. Finally, TUR potently increased the cytotoxic activity of MTX toward Caco-2, MCF-7, and A549 cancer cells. In conclusion, TUR was a promising agent for relieving MTX-mediated intestinal injury via various antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Trans-ferulic acid ameliorates cisplatin-induced testicular damage via suppression of TLR4, P38-MAPK, and ERK1/2 signaling pathways.

Testicular damage has been described as a common side effect of cisplatin (CDDP), which limits its clinical uses. Since oxidative injury and inflammatory response are the most pathological impact, estimation of natural antioxidant and anti-inflammatory agents like trans-ferulic acid (TFA) could protect against CDDP-induced testicular damage. In the current investigation, rats were assigned into four groups: normal, TFA (50 mg/kg/day, P.O), CDDP (10 mg/kg) as single intraperitoneal (I.P) injection at the end of the 5th day, and TFA+CDDP where TFA was administered 5 days before CDDP injection and 5 days after. Interestingly, TFA significantly restored testosterone levels and abrogated oxidative stress injury. Additionally, TFA effectively suppressed inflammatory cytokines. It also counteracted the inflammation via downregulation of TLR4 and IRF3, P38-MAPK, NF-κB-p65, JAK1, STAT3, ERK1, and ERK2. Besides, TFA can modulate AKT and p-AKT protein expressions. In parallel, TFA mitigated the histopathological aberration of the testis and prevented spermatogenesis disruption. On the other hand, TFA augmented the in vitro CDDP cytotoxicity on Caco-2 and MCF-7 cells. Interestingly, TFA enhanced the cytotoxic effect of CDDP via apoptosis induction in both the early and late stages of apoptosis. Collectively, TFA exhibited a potential protective effect against CDDP-induced testicular injury by inhibiting oxidative stress as well as TLR4/IRF3/INF-γ, P38-MAPK/NF-κB-p65/TNF-α, and JAK1/STAT-3/ERK1/2 inflammatory signaling pathways with enhancing its in vitro cytotoxic activity.

Combination of Captopril with Gliclazide Decreases Vascular and Renal Complications and Improves Glycemic Control in Rats with Streptozotocin- Induced Diabetes Mellitus.

BACKGROUND: The common antihypertensive angiotensin-converting enzyme (ACE) inhibitor captopril was reported to possess anti-oxidant and anti-inflammatory effects in different experimental models. Diabetic vascular complications arise from increased vascular endothelial inflammation and oxidative stress as well as decreased nitric oxide bioavailability in the vessel walls due to poor glycemic control. OBJECTIVE: This study aimed to evaluate the role of captopril and gliclazide in decreasing diabetes mellitus (DM) vascular complications caused by decreased cellular glucose uptake and impaired endothelial nitric oxide metabolism, as well as examine the effects of the combination on diabetic renal complication and plasma lipid profile. METHODS: Adult male Wister rats received captopril (25 mg/kg/day) and/or gliclazide (10 mg/kg/- day) by oral gavage daily for one month after induction of DM using streptozotocin (50 mg/kg, i.p., once). Serum glucose and insulin levels, inflammatory mediators like TNF-α, oxidative stress biomarkers like glutathione and nitric oxide, and plasma lipid profile were measured. Besides, histopathological examination of the thoracic aorta and kidney tissues, Western blot assessed the expression of nitric oxide synthase (NOS) subtypes in the thoracic aorta. RESULTS: Captopril significantly improved vascular architecture and oxidative stress and modulated nitric oxide synthesis via regulation of nitric oxide synthases, as well as decreased inflammation via down-regulating TNF-α, decreased systolic and diastolic blood pressure, and improved serum lipid profile in diabetic rats. Gliclazide increased serum insulin and decreased serum glucose, as well as its anti-oxidant and anti-inflammatory effects. CONCLUSION: Captopril showed a promising protective effect against DM vascular complications, at least via nitric oxide modulating effect, anti-oxidant effect, and anti-inflammatory activity that appeared in biochemical and histopathological findings, lipid profile, renal function, and architecture improvements. Combining gliclazide with captopril gives an additive effect through enhanced glycemic control and increased anti-oxidant and anti-inflammatory properties above captopril alone.

Umbelliferone attenuates gentamicin-induced renal toxicity by suppression of TLR-4/NF-κB-p65/NLRP-3 and JAK1/STAT-3 signaling pathways.

Nephrotoxicity is the most common adverse effect of gentamicin (GNT). This study aimed to investigate the possible nephroprotective effect of umbelliferone (UMB), against GNT-induced nephrotoxicity. Rats were allocated into the control group; UMB group (50 mg/kg/day, P.O. for 15 days); GNT group (100 mg/kg/day, i.p., for 8 days); and GNT + UMB group. By the end of the experimental period, serum creatinine, urea, and uric acid as well as urine KIM-1 and urine albumin/creatinine ratio were evaluated to estimate kidney function. Moreover, tissue samples were collected for assessment of ERK1/2, p-ERK1/2, TLR-4, p38 MAPK, NF-κB-p65, NLRP-3, IkBα, TNF-α, IL-1ß, JAK1, STAT-3, p-STAT, and cleaved caspase-3. In support, the histopathological examination of renal tissues was performed. UMB improves kidney function through regulation of renal serum biomarkers, with alleviations of histological abrasions induced by GNT. Besides, UMB downregulates renal protein expressions of ERK1/ERK2, TLR-4, and p38MAPK, with subsequent suppression of NF-κB-p65/NLRP-3 inflammasome and JAK1/STAT-3 pathways as well as cleaved caspase-3. In parallel, UMB induced IkBα upregulation. Collectively, UMB markedly amended all GNT-induced renal changes. These nephroprotective outcomes could be attributed to its ability to impede TLR-4/NF-κB-p65/NLRP-3 inflammasome and JAK1/STAT-3 pathways activation, as well as to its anti-inflammatory property.

The protective effect of inosine against rotenone-induced Parkinson's disease in mice; role of oxido-nitrosative stress, ERK phosphorylation, and A2AR expression.

Parkinson's disease (PD) is a severe disabling syndrome in which neuroinflammation and various signaling pathways are believed to mediate dopaminergic neurodegeneration. Here, the possible disease-modifying effects of the purine nucleoside inosine were examined against rotenone-induced PD. Mice were allocated into six groups, namely, a normal control group receiving dimethylsulfoxide, a PD control group receiving rotenone, a standard treatment group receiving L-dopa/carbidopa together with rotenone, and three treatment groups receiving inosine in low, medium, and high doses together with rotenone. At the end of the experimental protocol, three behavioral tests were performed to assess PD motor manifestations, namely, wire-hanging test, wood-walking test, and stair test. After performing the behavioral study, mice striata were isolated for the colorimetric assay of hypoxanthine, the enzyme-linked immunosorbent assay of dopamine, tumor necrosis factor-α, interleukin-6 and nitrite, the Western blot estimation of total and phosphorylated extracellular signal-regulated kinase (tERK and pERK), the polymerase chain reaction estimation of adenosine A2A receptor (A2AR) expression, as well as the histopathological examination of substantia nigra and striatal tissue. Inosine protected against PD progression in a dose-dependent manner, with the effect comparable to the standard treatment L-dopa/carbidopa, evidenced by behavioral, biochemical, and histologic findings. The beneficial antiparkinsonian effect of inosine could be attributed to the ability of the drug to ameliorate neuroinflammation and oxido-nitrosative stress, together with suppression of ERK phosphorylation and down-regulation of A2AR expression. Inosine could therefore be considered as a disease-modifying agent against PD, but further studies are claimed to confirm such effects clinically.