Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis in the Pathology of Alzheimer's Disease.

Alzheimer's disease (AD) accounts for a major statistic among the class of neurodegenerative diseases. A number of mechanisms have been identified in its pathogenesis and progression which include the amyloid beta (Aß) aggregation, hyperphosphorylation of tau protein, oxidative stress, endoplasmic reticulum (ER) stress and apoptosis. These processes are interconnected and contribute significantly to the loss of neurons, brain mass and consequential memory loss and other cognitive difficulties. Oxidative stress in AD appears to be caused by excess of oxygen free radicals and extracellular Aß deposits that cause local inflammatory processes and activate microglia, another possible source of reactive oxygen species (ROS). ER Stress describes the accumulation of misfolded and unfolded proteins as a result of physiological and pathological stimuli including high protein demand, toxins, inflammatory cytokines, and mutant protein expression that disturbs ER homeostasis. When compared to age-matched controls, postmortem brain tissues from AD patients showed elevated levels of ER stress markers, such as PERK, eIF2α, IRE1α, the chaperone Grp78, and the downstream mediator of cell death CHOP. Apoptosis is in charge of eliminating unnecessary and undesired cells to maintain good health. However, it has been demonstrated that a malfunctioning apoptotic pathway is a major factor in the development of certain neurological and immunological problems and diseases in people, including neurodegenerative diseases. This article highlights and discussed some of the experimentally established mechanisms through which these processes lead to the development as well as the exacerbation of AD.

Isolation, characterization and modulatory potentials of ß-stigmasterol, ergosterol and xylopic acid from Anchomanes difformis on mitochondrial permeability transition pore in vitro.

Objective: Secondary metabolites and polyphenolic compounds from medicinal plants have been demonstrated to have multiple biological functions with promising research and development prospects. This study examined the effect of ß-stigmasterol (with ergosterol) and xylopic acid isolated from Anchomanes difformis on liver mitochondrial permeability transition pore (mPTP). Methods: The compounds were isolated by vacuum liquid chromatography. Mitochondrial swelling was assessed as changes in absorbance under succinate-energized conditions. Results: 1H and 13C NMR spectroscopic elucidation of the isolates affirmed the presence of ß-stigmasterol with ergosterol (1:0.3) and xylopic acid. The isolates reversed the increase in lipid peroxidation and inhibited the opening of mitochondrial permeability transition pores caused by calcium and glucose. Pharmacological inhibition of mPTP offers a promising therapeutic target for the treatment of mitochondrial-associated disorders. Conclusion: Reduction in the activity of calcium ATPase and the expression of Caspase-3 and -9 were observed, suggesting that they could play a role in protecting physicochemical properties of membrane bilayers from free radical-induced severe cellular damage and be useful in the management of diseases where much apoptosis occurs.

GC-MS analysis of aqueous extract of Nymphaea lotus and ameliorative potential of its biosynthesized gold nanoparticles against cadmium-induced kidney damage in rats.

Plants possess compounds serving as reducing agents for green synthesis of gold nanoparticles (AuNPs), which is currently considered for biomedical application. Exposure to cadmium (Cd) can affect the functional integrity of the several organs such as kidney and liver. Nymphaea lotus (NL) is known for its several medicinal properties, including its protective role against tissue damages. This study investigated the bioactive compounds in NL using gas chromatography-mass spectroscopy (GC-MS) and ameliorative potential of its biosynthesized AuNPs (NL-AuNPs) against Cd-induced nephrotoxicity in rats. The presence of bioactive compounds in N. lotus was investigated by GC-MS in aqueous extract of NL. Gold nanoparticles were synthesized using aqueous extract of NL. Thirty rats were grouped into six (n = 5). Group 1 served as control, while group 2, 3, 4 and 5 received CdCl2 (10 mg/kg) orally for five days. Thereafter, groups 3, 4, and 5, respectively, received silymarin (75 mg/kg), 5 and 10 mg/kg NL-AuNPs, orally for 14 days, while group 6 received 10 mg/kg NL-AuNPs only. Rats were sacrificed after treatment, and biochemical parameters and kidney histopathology were evaluated. Bioactive compounds of pharmacological importance identified include pyrogallol, oxacyclohexadecan-2-one, 22-Desoxycarpesterol, 7,22-Ergostadienol, ß-sitosterol and Dihydro-ß-agarofuran. Cadmium caused nephrotoxicity in rats, as evidenced by significant (p < 0.05) increase in the levels of kidney function markers (serum urea and creatinine) and inflammatory markers (Interleukin-6 (IL-6) and Nuclear Factor-κB (NF-κB)) when compared with control. These changes were significantly (p < 0.05) ameliorated by the spherically-synthesized NL-AuNPs (25-30 nm) with the 5 mg/kg NL-AuNPs more potent against kidney damage induced by Cd in rats but high doses of NL-AuNPs (≥10 mg/kg) could be suggested toxic. NL possess phytochemicals capable of reducing gold salts to nanoparticle form, and doses up to 5 mg/kg could be considered safe for the treatment of renal damage occasioned by cadmium.

Bioactivities of Garcinia kola enzymatic hydrolysates at different enzyme-substrate ratios.

Natural products, such as enzymatic hydrolysates and bioactive peptides from dietary sources, are safe alternatives to synthetic compounds linked to various deleterious effects. The purpose of this study is to determine the in vitro bioactivities (antioxidant and anti-inflammatory activities) of Garcinia kola seeds enzymatic hydrolysates (GKPHs) at different enzyme (pepsin)-substrate ratios. G. kola protein, isolated by alkaline solubilization and acid precipitation, was hydrolyzed with pepsin at varying enzyme-substrate (E:S) ratios. The antioxidant parameters investigated include 1,1-diphenyl-2-picrylhydrazyl (DPPH)-radical scavenging, hydrogen peroxide scavenging and ferrous ion (Fe2+) chelating activities. For anti-inflammatory properties, membrane stabilization and protein denaturation activities tests were used. GKPH produced at 1:32 had the highest degree of hydrolysis (66.27 ± 4.21%). All GKPHs had excellent in vitro anti-inflammatory properties. However, only enzymatic hydrolysates produced at 1:16 (E:S) ratio chelated iron (II) and as well had the highest percentage hemolysis inhibition of 84.45 ± 0.007%, percentage protein denaturation inhibition of 53.36 ± 0.01% at maximum concentration and exhibited highest DPPH scavenging activity (87.24 ± 0.10%). The enzymatic hydrolysates had excellent solubility, emulsifying and foaming properties. It could be deduced from this study that pepsin at a ratio of 1:16 of G. kola protein produced the most effective enzymatic hydrolysates in terms of their antioxidant and anti-inflammatory activities. G. kola pepsin enzymatic hydrolysates, thus, have potential in development as functional foods and as therapeutics pharmaceutical industries in the management of diseases associated with oxidative stress and inflammation owing to their excellent functional, antioxidant and anti-inflammatory properties.

Synthesized gold nanoparticles mediated by Crassocephalum rubens extract down-regulate KIM-1/NGAL genes and inhibit oxidative stress in cadmium-induced kidney damage in rats.

Cadmium (Cd) exposure induces kidney damage by mediating oxidative stress and inflammation. In this study, the role of Crassocephalum rubens-gold nanoparticles (C. rubens-AuNPs) in down-regulating kidney injury molecules-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) genes and inhibiting oxidative stress in Cd-induced kidney damage in rats was investigated. Thirty male Wistar rats were distributed randomly into six groups (n = 5). Group I served as control, while groups II, III, IV, and V rats were administered with 20 mg/kg b.w. cadmium chloride (CdCl2) for five consecutive days. Groups III, IV, and V rats were treated, 24 h after the last dose of CdCl2, with silymarin, 5 mg/kg and 10 mg/kg C. rubens-AuNPs, respectively, for 14 days. Group VI rats received 10 mg/kg C. rubens-AuNPs only for 14 days. Animals were sacrificed 24 h after the last dose of the treatment. Biochemical parameters such as kidney function markers, biomarkers of nephrotoxicity, and oxidative stress markers were assayed. Results indicated that 20 mg/kg b.w. CdCl2 caused kidney damage, as evidenced by significant (p < 0.05) increase in the levels of serum urea and creatinine, malondialdehyde, reduced level of superoxide dismutase (SOD), and increased mRNA expression of the kidney injury biomarkers (KIM-1 and NGAL genes), when compared with the control. However, these changes were attenuated by both doses of C. rubens-AuNPs when compared with Cd-induced nephrotoxic rats. It can be suggested that C. rubens-AuNPs have the potential to ameliorate kidney damage induced by Cd via oxidative stress inhibition and down-regulation of KIM-1/NGAL genes.

Gallic and Hesperidin Ameliorate Electrolyte Imbalances in AlCl3-Induced Nephrotoxicity in Wistar Rats.

Nephrotoxicity is usually characterized by inefficiency of the kidney, thereby causing disruptions to electrolyte balance and blood acidity. This study aimed to evaluate the effect of hesperidin and gallic acid on serum electrolytes and ion pumps in Wistar rats subjected to aluminum chloride (AlCl3)-induced nephrotoxicity. Thirty Wistar rats were randomly divided into six groups of five animals apiece. Group one served as the negative control and received distilled water while the study lasted. Animals in groups 2-4 received 100 mg/kg/day AlCl3 throughout the study. Animals in groups 3 and 4 were also administered 100 mg/kg/day gallic acid and 100 mg/kg/day hesperidin, respectively. Groups 5 and 6 were treated with 100 mg/kg/day gallic acid only and 100 mg/kg/day hesperidin only, respectively. Treatments were administered orally via gavage for 28 days with distilled water as the vehicle. Animals were sacrificed after which levels of potassium, calcium, magnesium, phosphate, chloride, and bicarbonate ions were evaluated in the serum, while activities of Na+/K+ and Ca2+/Mg2+ ATPases were determined in kidney homogenate. Results showed that AlCl3 significantly (p < 0.05) inhibited activities of Na+/K+ and Ca2+/Mg2+ ATPases in addition to increasing serum levels of potassium, calcium, phosphate, and chloride, with concomitant decrease in serum levels of magnesium and bicarbonate. However, coadministration of AlCl3 with either gallic acid or hesperidin ameliorated all the disruptions caused by AlCl3. It could be concluded that gallic acid and hesperidin could be relevant in managing electrolyte imbalances and acidosis occasioned by kidney dysfunction.

Annona muricata L. peel extract inhibits carbohydrate metabolizing enzymes and reduces pancreatic ß-cells, inflammation, and apoptosis via upregulation of PI3K/AKT genes.

BACKGROUND AND OBJECTIVE: Annona muricata L. peel has been recognized for many ethnobotanical uses, including diabetes management. However, limited detailed scientific information about its mechanism of antidiabetic activity exists. The objective of this study was to evaluate the anti-diabetic properties of an aqueous extract of A. muricata peel (AEAMP) and its mechanism of action on alloxan-induced diabetic rats. METHODS: In vitro antidiabetic assays, such as α-amylase and α-glucosidase were analyzed on AEAMP. Alloxan monohydrate (150 mg/kg b.w) was used to induce diabetes in the rats. 150 mg/kg b.w positive control group doses of 6.67, 13.53, and 27.06 mg/kg were administered to 3 groups for twenty-one days. The positive control group was administered 30 mg/kg of metformin. The negative and normal control groups were administered distilled water. The fasting blood glucose, serum insulin, lipid profile, inflammatory cytokines, antioxidant markers, carbohydrate metabolizing enzymes, and liver glycogen were analyzed as well as PI3K/AKT and apoptotic markers PCNA and Bcl2 by RT-PCR. RESULTS: AEAMP inhibited α-amylase and α-glucosidase enzymes more effectively than acarbose. AEAMP reduced FBG levels, HOMA-IR, G6P, F-1,6-BP, MDA, TG, TC, AI, CRI, IL-6, TNF-α, and NF-κB in diabetic rats. Furthermore, in diabetic rats, AEAMP improved serum insulin levels, HOMA-ß, hexokinase, CAT, GST, and HDL-c. Liver PI3K, liver PCNA and pancreas PCNA were not significantly different in untreated diabetic rats when compared to normal rats suggesting alloxan induction of diabetes did not downregulate the mRNA expression of these genes. AEAMP significantly up-regulated expression of AKT and Bcl2 in the liver and pancreatic tissue. It is interesting that luteolin and resorcinol were among the constituents of AEAMP. CONCLUSIONS: AEAMP can improve ß-cell dysfunction by upregulating liver AKT and pancreatic PI3K and AKT genes, inhibiting carbohydrate metabolizing enzymes and preventing apoptosis by upregulating liver and pancreatic Bcl2. However, the potential limitation of this study is the unavailability of equipment and techniques for collecting more data for the study.

Metformin/Donepezil combination modulates brain antioxidant status and hippocampal endoplasmic reticulum stress in type 2 diabetic rats.

PURPOSE: Diabetes mellitus is associated with perturbations in brain biochemical parameters associated with dementia. This study aimed at comparing the effect of metformin and metformin/donepezil combination on oxidative stress, endoplasmic reticulum stress and inflammation in the brain of diabetic Wistar rats. METHODS: Diabetes was induced by single intraperitoneal injection of 40 mg/kg streptozotocin after administration of 10% fructose for 14 days. Animals were randomly assigned to four groups of five animals each. Group 1 was the normal control and received only distilled water. Groups 2 and 3 were diabetic rats treated with metformin/donepezil combination and metformin only respectively, while group 4 was diabetic control. Treatment lasted for 21 days after confirmation of diabetes. Activities of acetylcholinesterase (AchE), butyrylcholinesterase (BchE), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase were evaluated in the brain of diabetic rats. Enzyme-linked immunosorbent assay was used to estimate brain levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) malondialdehyde and glucose transporter-4 (GLUT4), while expression of endoplasmic reticulum stress markers - glucose regulated protein-78 (GRP78), activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) was determined using real-time PCR in the hippocampus of diabetic rats. RESULTS: Treatment with metformin/donepezil combination significantly reduced the activities of AchE, BchE as well as levels of malondialdehyde, TNF-α and IL-6, while the activities of SOD, GPx and catalase were significantly increased in the brain. Moreover, expression of ER stress markers was attenuated in the hippocampus. CONCLUSION: Metformin/donepezil combination appeared more efficacious than metformin only and could be considered for managing diabetes-associated dementia.

Effects of gender, age and treatment duration on lipid profile and renal function indices in diabetic patients attending a teaching hospital in South-Western Nigeria.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is associated with diabetic nephropathy and hyperlipidemia. Gender, age, medication adherence, lifestyle, culture and socioeconomic status could be sources of diversity in T2DM leading to differences in predisposition, development and clinical presentation. OBJECTIVES: Therefore, this study aimed to investigate the influence of gender, age and treatment duration on kidney and lipid-related biochemical indices of T2DM patients attending Ekiti State University Teaching Hospital, Ado-Ekiti, Nigeria (EKSUTH). METHODS: Blood from diabetic patients and healthy subjects was analysed for fasting blood glucose (FBG), renal function parameters and lipid profile. Influence of age, gender and treatment duration on indices was assessed using standard baseline values. RESULTS: Dyslipidemia was pronounced among female diabetics while the incidence of diabetes was found to be higher in middle-age. The percentage of diabetics with high levels of FPG, urea, creatinine, cholesterol, triglyceride and low density lipoprotein-cholesterol after 9-10 years of treatment were lower compared with the percentage after 5-6 years of treatment. CONCLUSION: Gender, age and treatment duration influenced clinical course of T2DM among patients presenting at EKSUTH but long term treatment appeared to improve T2DM among patients.