Alzheimer's disease (AD) represents a significant challenge among neurodegenerative disorders, as effective treatments and therapies remain largely undeveloped. Despite extensive research efforts employing various methodologies and diverse genetic models focused on amyloid-β (Aβ) pathology, the research for effective therapeutic strategies remains inconclusive. The key pathological features of AD include Aβ senile plaques, neurofibrillary tangles (NFTs), and the activation of neuroinflammatory pathways. Presently, investigations into AD and assessing potential treatments predominantly utilize Aβ transgenic models. Conversely, non-transgenic models may provide valuable insights into the multifaceted pathological states associated with AD. Thus, these models may serve as practical complementary tools for evaluating therapeutic and intervention strategies, since the primary AD risk factors are most frequently modeled. This review aims to critically assess the existing literature on AD non-transgenic models induced by streptozotocin, scopolamine, aging, mechanical stress, metals, and dietary patterns to enhance their application in AD research.

This study aimed to assess the herb-drug interactions between crude/silver nanoparticle (SNP)-loaded carob extract (Car, NCar, respectively) and donepezil-HCl (DPZ) and their impact on neurotherapeutic outcomes in a dementia model.

Carob pods were subjected to ethanol extraction, and their phytoconstituents were chromatographically analysed. SNP-loaded extract was synthesized and characterized, and dementia-like symptoms were induced in Wistar rats by repeated dosing with 175 mg/kg AlCl3 for 60 days, after which the animals were treated with Car, NCar, DPZ, and combinations of Car/NCar-DPZ for 30 days. The effect of carob formulations on DPZ bioavailability was in-silico profiled and the herb-drug interactions were mathematically assessed as combination indices.

Different formulations significantly improved cognitive/spatial memory functions, restored dysregulated brain redox and cholinergic functions, and markedly inhibited cholinesterase, as reflected by the reduction/absence of amyloid plaques and neurofibrillary tangles. In silico profiling of the major phytoconstituents revealed their non-P-glycoprotein substrate nature and CYP3A4, 2C19, and 2C9 inhibition, which might have improved the oral bioavailability of DPZ. The combination index calculations revealed strong synergy between DPZ and both carob formulations, with the strongest effect exhibited by the DPZ/NCar combination.

The co-administration of carob extract/SNPs represents a promising approach for enhancing the neurotherapeutic efficacy of DPZ.

Flavonoids are naturally occurring polyphenolic compounds known for their extensive range of biological activities. This review focuses on the inhibitory effects of flavonoids on acetylcholinesterase (AChE) and their potential as therapeutic agents for cognitive dysfunction. AChE, a serine hydrolase that plays a crucial role in cholinergic neurotransmission, is a key target in the treatment of cognitive impairments due to its function in acetylcholine hydrolysis. Natural polyphenolic compounds, particularly flavonoids, have demonstrated significant inhibition of AChE, positioning them as promising alternatives or adjuncts in neuropharmacology. This study specifically examines flavonoids such as quercetin, apigenin, kaempferol, and naringenin, investigating their inhibitory efficacy, binding mechanisms, and additional neuroprotective properties, including their antioxidant and anti-inflammatory effects. In vitro, in vivo, and in silico analyses reveal that these flavonoids effectively interact with both the active and peripheral anionic sites of AChE, resulting in increased acetylcholine levels and the stabilization of cholinergic signaling. Their mechanisms of action extend beyond mere enzymatic inhibition, as they also exhibit antioxidant and anti-amyloidogenic properties, thereby offering a multifaceted approach to neuroprotection. Given these findings, flavonoids hold considerable therapeutic potential as modulators of AChE, with implications for enhancing cognitive function and treating neurodegenerative diseases. Future studies should prioritize the enhancement of flavonoid bioavailability, evaluate their efficacy in clinical settings, and explore their potential synergistic effects when combined with established therapies to fully harness their potential as neurotherapeutic agents.

The neurological impairment induced by fluoride is associated with mitochondrial dysfunction. Normal mitochondrial permeability transition pore (mPTP) opening plays a pivotal role in mitochondrial function. However, it remains unclear whether p53-dependent mPTP-related mitochondrial apoptosis is associated with fluoride-induced neurological impairment, and the alleviation of naringin on those. In vivo, NaF-treated rats had impaired learning and memory abilities, damaged hippocampal structure, and higher respiratory exchange rates (RER). In vitro, the increased apoptosis rates, excessive opening of mPTP, and decreased mitochondrial membrane potential (MMP) were observed in PC12 cells treated with NaF. The protein expressions of p53, CytoC, and cleaved caspase 3 were significantly increased in hippocampi of rats treated with 50 mg/L and 100 mg/L NaF and in 40 mg/L and 80 mg/L NaF-treated PC12 cells, while the protein expression of CypD remains stable. And the changes of p53 and CypD were also confirmed by the immunofluorescence staining in vivo. After inhibiting the expression of p53 with pifithrin-α and p53-siRNA, the decreased apoptosis rates and mPTP opening, increased MMP, and decreased protein expressions of p53, CytoC, and cleaved caspase 3 were observed in NaF-treated PC12 cells. Rats, treated with NaF and naringin, had alleviated impaired neurological function, and had lower RER than rats treated with NaF alone. And compared with those in the NaF group, the decreased apoptosis rates and mPTP opening, and increased MMP were also found in PC12 cells treated with NaF and naringin. Furthermore, hippocampi of rats and PC12 cells treated with NaF and naringin had decreased protein expressions of p53, CytoC, and cleaved caspase 3. Our results indicate that fluoride activates the p53-dependent mPTP-related mitochondrial apoptosis, which then affects energy metabolism, resulting in neurological impairment. Additionally, naringin can alleviate this damage, and further studies on the potential health benefits of naringin are needed.

Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's Disease and other brain disorders as blood-brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, we developed a novel TGN decorated erythrocyte membrane-coated poly (lactic-co-glycolic acid) nanoparticle (TRNNs). The nanoparticle significantly boosted the penetration (7.3 times) in a U-118MG and HCMEC/D3 cell co-culture BBB model in vitro. Living image was performed to assess the TRNNs distribution in vivo. The fluorescence intensity in the isolated brain of TRDNs-treated mice was about 8 times that of the DNs-treated. In the novel object recognition test, the mice after administration of TRDNs showed higher recognition index (0.414 ± 0.016) than the model group (0.275 ± 0.019). A significant increase in the number of dendritic spines from TRNNs administrated mice hippocampi neurons was observed after Golgi stain. This improvement of neurons was also confirmed by the significant high expression of PSD95 protein level in hippocampi. We measured the OD values of Aβ25-35 induced PC12 cells that pre-treatment with different nanoparticles and concluded that TRNNs had a robust neuroprotection effect. Above all, functional biomimetic nanoparticles could increase the accumulation of naringenin into brain, thereby enable the drug to exert greater therapeutic effects.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative dementia. The etiology of AD is multifactorial, and its complex pathophysiology involves tau and amyloid-β deposition, increased oxidative stress, neuroinflammation, metabolic disorders, and massive neuronal loss. Due to its complex pathology, no effective cure for AD has been found to date. Therefore, there is an unmet clinical need for the development of new drugs against AD. Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents. Naringin, a naturally occurring flavanone glycoside, is predominantly found in citrus fruits and Chinese medicinal herbs. Mounting evidence shows that naringin and its aglycone, naringenin, have direct neuroprotective effects on AD, such as anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, and anti-neuroinflammatory effects, as well as metal chelation. Furthermore, they are known to improve disordered glucose/lipid metabolism, which is a high risk factor for AD. In this review, we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology. Additionally, we provide an overview of the current clinical applications of naringin and naringenin. The novel delivery systems for naringin and naringenin, which can address their widespread pharmacokinetic limitations, are also discussed. The literature indicates that naringin and naringenin could be multilevel, multitargeted, and multifaceted for preventing and treating AD.

Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace. Al degrades in to nanoparticulate form in the environment due to the routine process of bioremediation in human body. Al-NPs toxicity plays key role in the pathophysiology of neurodegeneration which is characterised by the development of neurofibrillary tangles and neuritic plaques which correlates to the Alzheimer's disease. This study evaluated the Al-NPs induced neurodegeneration and causative behavioral alterations due to oxidative stress, inflammation, DNA damage, β-amyloid aggregation, and histopathological changes in mice. Furthermore, the preventive effect of naringenin (NAR) as a potent neuroprotective flavonoid against Al-NPs induced neurodegeneration was assessed. Al-NPs were synthesized and examined using FTIR, XRD, TEM, and particle size analyzer. Mice were orally administered with Al-NPs (6 mg/kg b.w.) followed by NAR treatment (10 mg/kg b.w. per day) for 66 days. The spatial working memory was determined by novel object recognition, T-maze, Y-maze, and Morris Water Maze tests. We measured nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidised glutathione, and acetylcholine esterase, as well as cytokines analysis, immunohistochemistry, and DNA damage. Al-NPs significantly reduced the learning memory power, increased oxidative stress, reduced antioxidant enzymatic activity, increased DNA damage, altered the levels of cytokines, and increased β-amyloid aggregation in the cortex and hippocampus regions of the mice brain. These neurobehavioral impairments, neuronal oxidative stress, and histopathological alterations were significantly attenuated by NAR supplementation. In conclusion, Al-NPs may be potent neurotoxic upon exposure and that NAR could serve as a potential preventive measure in the treatment and management of neuronal degeneration.

The relationship between amyloid beta (Aβ) and oxidative stress (OS), both prominent factors in Alzheimer's disease-related neural degeneration, is deeply interconnected. The cleavage of the extracellular domain of Amyloid precursor protein (APP) and phosphorylating different substrates, respectively, the β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) and Glycogen synthase kinase-3-beta (GSK-3β) enzymes initiate the synthesis of Aβ, which causes cognitive deficits in AD. This study aimed to explore the protective potential of Coenzyme Q10 (CoQ10). It also sought to uncover any synergistic effects when combined with donepezil, an acetylcholinesterase inhibitor, in treating Alzheimer's disease in male albino rats, focusing on the modulation of the BACE-1/GSK-3β pathway. The experiment involved 70 rats categorized into different groups: control, donepezil alone, CoQ10 alone, AD-model, donepezil co-treatment, CoQ10 co-treatment, and CoQ10 + donepezil combination. Various assessments, such as cholinesterase activity, oxidative stress, serum iron profile, Brain Derived Neurotrophic Factor (BDNF), Tau protein, β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), phosphatase and tensin homolog (Pten), and Glycogen synthase kinase-3-beta (GSK-3β), were conducted on behavioral and biochemical aspects. CoQ10 treatment demonstrated memory improvement, enhanced locomotion, and increased neuronal differentiation, mainly through the inhibition of the dual BACE-1/GSK-3β. These findings were substantiated by histological and immunohistological examinations of the hippocampus.

Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive impairment and memory loss. In this study, AD was experimentally induced in rats using aluminum chloride (AlCl3) and D-galactose (D-gal). Fisetin (Fis), a natural compound with antioxidant and anti-inflammatory properties, has potential for neurodegeneration management, but its low bioavailability limits clinical applications. To address this, we synthesized and characterized Pluronic-2-Acrylamido-2-methylpropane sulfonic acid (PLUR-PAMPS) nanogels using gamma radiation and successfully loaded Fis onto them (Fis-PLUR-PAMPS). The optimal formulation exhibited minimal particle size, a highly acceptable polydispersity index, and the highest zeta-potential, enhancing stability and solubilization efficiency. Our goal was to improve Fis's bioavailability and assess its efficacy against AlCl3/D-gal-induced AD. Male albino Wistar rats were pre-treated orally with Fis (40 mg/kg) or Fis-PLUR-PAMPS for seven days, followed by a seven-day intraperitoneal injection of AlCl3 and D-gal. Behavioral assessments, histopathological analysis, and biochemical evaluation of markers related to AD pathology were conducted. Results demonstrated that Fis-PLUR-PAMPS effectively mitigated cognitive impairments and neurodegenerative signs induced by AlCl3/D-gal. These findings suggest that Fis-PLUR-PAMPS nanogels enhance Fis's bioavailability and therapeutic efficacy, offering a promising approach for AD management.

Aluminum is a potent neurotoxin, responsible for memory impairment and cognitive dysfunction. The neurotoxic effect of aluminum on cognitive impairment is well documented, however, exposure to aluminum in a time-dependent manner and post-exposure self-recovery still needs to be elaborated. This research aimed to (1) study the time-dependent effect of aluminum exposure by administering a total dose of 5850 mg/kg of Al over two different time periods: 30 and 45 days (130 and 195 mg/kg of AlCl3 respectively), and (2) study 20 days post-exposure self-recovery effect in both aluminum-exposed groups by giving distilled water. Cognitive abilities were investigated through Morris water maze test and hole board test and compared in both exposure and recovery groups. Oxidative stress markers and neurotransmitter levels were measured for both exposure and recovery groups. To understand the mechanism of aluminum exposure and recovery, immunohistochemical analysis of synaptophysin (Syp) and glial fibrillary acidic protein (GFAP) was performed. Results showed cognitive dysfunction, oxidative stress-induced damage, reduced neurotransmitter levels, decreased immunoreactivity of Syp, and increased GFAP. However, these parameters showed a larger improvement in the recovery group where rats were given aluminum for 30 days period in comparison to recovery group followed by 45 days of aluminum exposure. These results suggest that restoration of cognitive ability is affected by the duration of aluminum exposure. The study findings provide us with insight into the adverse effects of aluminum exposure and can be utilized to guide future preventive and therapeutic strategies against aluminum neurotoxicity.

The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl3)-induced rat model of Alzheimer's disease (AD). The Catechin-loaded Chitosan-Alginate nanocarriers were synthesized through ionotropic gelation (IG) method. Physio-chemical characterization was conducted with the Zetasizer Nano system, the scanning electron microscope, and the Fourier transform infrared spectroscopy. The experiments were performed over 21 days on six groups of male Wistar rats. The control group, AlCl3 treated group, Catechin group, nanocarrier group, treatment group 1 (AlCl3 + Catechin), and treatment group 2 (AlCl3 + nanocarrier). A behavioral study was done by the Morris water maze (MWM) test. In addition, the level of oxidative indices and acetylcholine esterase (AChE) activity was determined by standard procedures at the end of the study. AlCl3 induced a significant increase in AChE activity, along with a significant decrease in the level of Catalase (CAT) and total antioxidant capacity (TAC) in the hippocampus. Moreover, the significant effect of AlCl3 was observed on the behavioral parameters of the MWM test. Both forms of Catechin markedly improved AChE activity, oxidative biomarkers, spatial memory, and learning. The present study indicated that the administration of Catechin-loaded Chitosan-Alginate NPs is a beneficial therapeutic option against behavioral and chemical alteration of AD in male Wistar rats.

Naringenin (NAR) has various biological activities but low bioavailability. The current study examines the effect of Naringenin-loaded hybridized nanoparticles (NAR-HNPs) and NAR on depression induced by streptozotocin (STZ) in rats. NAR-HNPs formula with the highest in vitro NAR released profile, lowest polydispersity index value (0.21 ± 0.02), highest entrapment efficiency (98.7 ± 2.01%), as well as an acceptable particle size and zeta potential of 415.2 ± 9.54 nm and 52.8 ± 1.04 mV, respectively, was considered the optimum formulation. It was characterized by differential scanning calorimetry, examined using a transmission electron microscope, and a stability study was conducted at different temperatures to monitor its stability efficiency showing that NAR-HNP formulation maintains stability at 4 °C. The selected formulation was subjected to an acute toxicological test, a pharmacokinetic analysis, and a Diabetes mellitus (DM) experimental model. STZ (50 mg/kg) given as a single i.p. rendered rats diabetic. Diabetic rat groups were allocated into 4 groups: one group received no treatment, while the remaining three received oral doses of unloaded HNPs, NAR (50 mg/kg), NAR-HNPs (50 mg/kg) and NAR (50 mg/kg) + peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662 (1mg/kg, i.p.) for three weeks. Additional four non-diabetic rat groups received: distilled water (normal), free NAR, and NAR-HNPs, respectively for three weeks. NAR and NAR-HNPs reduced immobility time in forced swimming test and serum blood glucose while increasing serum insulin level. They also reduced cortical and hippocampal 5-hydroxyindoeacetic acid, 3,4-Dihydroxy-phenylacetic acid, malondialdehyde, NLR family pyrin domain containing-3 (NLRP3) and interleukin-1beta content while raised serotonin, nor-epinephrine, dopamine and glutathione level. PPAR-γ gene expression was elevated too. So, NAR and NAR-HNPs reduced DM-induced depression by influencing brain neurotransmitters and exhibiting anti-oxidant and anti-inflammatory effects through the activation PPAR-γ/ NLRP3 pathway. NAR-HNPs showed the best pharmacokinetic and therapeutic results.

Alzheimer's disease is a progressive neurodegenerative disease and one of the most common causes of dementia. Despite recent advancements, there exists an unmet need for a suitable therapeutic option. This study aimed to evaluate the protective effects of the combination of resveratrol (20 mg/kg/day p.o.) and tannic acid (50 mg/kg/day p.o.) to reduce aluminium trichloride-induced Alzheimer's disease in rats.

Wistar rats weighing 150-200g were administered with aluminium chloride (100 mg/kg/day p.o.) for 90 days to induce neurodegeneration and Alzheimer's disease. Neurobehavioral changes were assessed using novel object recognition test, elevated plus maze test, and Morris water maze test. Histopathological studies were performed using H&E stain and Congo Red stains to check amyloid deposits. Further oxidative stress was measured in brain tissue.

Aluminium trichloride treated negative control group showed cognitive impairment in the Morris water maze test, novel object recognition test, and elevated plus maze test. Further, the negative control group showed significant oxidative stress, increase amyloid deposits, and severe histological changes. Treatment with the combination of resveratrol and tannic acid showed significant attenuation in cognitive impairment. The oxidative stress markers and amyloid plaque levels were significantly attenuated with the treatment.

The present study indicates the beneficial effects of resveratrol-tannic acid combination in AlCl3 induced neurotoxicity in rats.

Despite the effectiveness of ionizing radiation in treating cancer, it can damage healthy tissues in the vicinity. Due to the high radio-sensitivity of testicular tissues, radiation therapy may affect spermatogenesis, which may result in infertility. Hence, in this study testicular damage model is constructed to investigate the mitigation effect of Maca root powder and its potential radioprotective activity through both oxidative and endoplasmic reticulum (ER) stresses, besides the apoptotic pathway.

Male albino rats were exposed to 6Gy of whole-body gamma radiation single dose. Maca root powder (1 g/kg b.wt./day, by oral gavage) was administered for a week before irradiation, then d-galactose (300 mg/kg, by oral gavage) and Maca daily for another week.

Gamma radiation and d-galactose revealed a significant decrease in serum testosterone, sperm count, and motility and higher percentage of the sperm head abnormality, while Maca root treatment maintained all sperm morphology parameters. Maca root treatment demonstrated a notable defense against radiation-induced oxidative stress and ameliorated malonaldehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO), glutathione-S-transferase (GST) levels, reduced glutathione (GSH), oxidized glutathione (GSSG) and the ratio of GSH/GSSG in testis tissues. Exposure to gamma rays and d-galactose displayed a significant elevation in GRP78, CHOP, total caspase-3 as well as active (cleaved) caspase-3 levels, whereas treatment with Maca significantly reduced the ER and apoptotic markers levels. Also, Maca improved the histological changes of the disorganized seminiferous tubules induced by irradiation.

Our findings show for the first time that Maca has a protective effect on male reproductive damage induced by radiotherapy. Maca root reveals anti-apoptotic effect and protection against testicular damage via GRP78/CHOP/caspase-3 pathway.

Aluminum chloride (AlCl3) is a potent neurotoxic substance known to cause memory impairment and oxidative stress-dependent neurodegeneration. Naringenin (NAR) is a dietary flavonoid with potent antioxidant and anti-inflammatory properties which was implemented against AlCl3-induced neurotoxicity to ascertain its neuroprotective efficacy. Experimental neurotoxicity in mice was induced by exposure of AlCl3 (10 mg/kg, p.o.) followed by treatment with NAR (10 mg/kg, p.o.) for a total of 63 days. Assessed the morphometric, learning memory dysfunction (novel object recognition, T- and Y-maze tests), neuronal oxidative stress, and histopathological alteration in different regions of the brain, mainly cortex, hippocampus, thalamus, and cerebellum. AlCl3 significantly suppressed the spatial learning and memory power which were notably improved by administration of NAR. The levels of oxidative stress parameters nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione reductase, reduced glutathione, and the activity of acetylcholine esterase were altered 1.5-3 folds by AlCl3 significantly. Treatment of NAR remarkably restored the level of oxidative stress parameters and maintained the antioxidant defense system. AlCl3 suppressed the expression of neuronal proliferation marker NeuN that was restored by NAR treatment which may be a plausible mechanism. NAR showed therapeutic efficacy as a natural supplement against aluminum-intoxicated memory impairments and histopathological alteration through a mechanism involving an antioxidant defense system and neuronal proliferation.

Cognitive dysfunction can occur both in normal aging and age-related neurological disorders, such as mild cognitive impairment and Alzheimer's disease (AD). These disorders have few treatment options due to side effects and limited efficacy. New approaches to slow cognitive decline are urgently needed. Dietary interventions (nutraceuticals) have received considerable attention because they exhibit strong neuroprotective properties and may help prevent or minimize AD symptoms. Biological aging is driven by a series of interrelated mechanisms, including oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy, which function through various signaling pathways. Recent clinical and preclinical studies have shown that dietary small molecules derived from natural sources, including flavonoids, carotenoids, and polyphenolic acids, can modulate oxidative damage, cognitive impairments, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, autophagy dysregulation, and gut microbiota dysbiosis. This paper reviews research on different dietary small molecules and their bioactive constituents in the treatment of AD. Additionally, the chemical structure, effective dose, and specific molecular mechanisms of action are comprehensively explored. This paper also discusses the advantages of using nanotechnology-based drug delivery, which significantly enhances oral bioavailability, safety, and therapeutic effect, and lowers the risk of adverse effects. These agents have considerable potential as novel and safe therapeutic agents that can prevent and combat age-related AD.

Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and cognitive abilities, primarily in the elderly. The burden of AD extends beyond patients, impacting families and caregivers due to the patients' reliance on assistance for daily tasks. The main features of the pathogenesis of AD are beta-amyloid plaques and neurofibrillary tangles (NFTs), that strongly correlate with oxidative stress and inflammation. NFTs result from misfolded and hyperphosphorylated tau proteins. Various studies have focused on tau phosphorylation, indicating protein phosphatase 2A (PP2A) as the primary tau phosphatase and glycogen synthase kinase-3 beta (GSK-3β) as the leading tau kinase. Experimental evidence suggests that inhibition of PP2A and increased GSK-3β activity contribute to neuroinflammation, oxidative stress, and cognitive impairment. Hence, targeting PP2A and GSK-3β with pharmacological approaches shows promise in treating AD. The use of natural compounds in the drug development for AD have been extensively studied for their antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties, demonstrating therapeutic advantages in neurological diseases. Alongside the development of PP2A activator and GSK-3β inhibitor drugs, natural compounds are likely to have neuroprotective effects by increasing PP2A activity and decreasing GSK-3β levels. Therefore, based on the preclinical and clinical studies, the potential of PP2A and GSK-3β as therapeutic targets of natural compounds are highlighted in this review.

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability and interrupts cognitive function. Heavy metal exposure like aluminum chloride is associated with neurotoxicity linked to neuro-inflammation, oxidative stress, accumulation of amyloid plaques, phosphorylation of tau proteins associated with AD like symptoms. The objective of the present investigation was to assess the effect 3-acetyl coumarin (3AC) in a rat model of AD. Preliminary screening was performed with SWISS ADME to check for the bioavailability of 3-AC and likeness score which proved favorable. 3-AC docked against Caspase 3, NF-κβ and tau protein kinase I exhibited good binding energies. Male rats were divided into six groups (n = 5). AlCl3 (100 mg/kg BW) was administered for 28 days before starting treatment to induce AD. Normal control rats received vehicle. Treatment groups received 10, 20 and 30 mg/kg 3-AC for 28 days. Rivastigmine (2 mg/kg) was the standard. Behavioral tests (EPM, MWM) were performed at 7-day intervals throughout study period. Rats showed improved spatial memory and learning in treatment groups during behavioral tests. Rats were euthanized on day 28. Inflammatory markers (IL-1β, IL-16 and TNFα) exhibited significant improvement (p < 0.001) in treated rats. Oxidative stress enzymes (SOD, CAT, GSH, MDA) were restored. Caspase3 and NF-κβ quantified through qRT-PCR also decreased significantly (p < 0.001) when compared to disease control group. Levels of acetyl cholinesterase, dopamine and noradrenaline were also restored in treated rats significantly (p < 0.001). 3-AC treatment restored neuroprotection probably because of anti-inflammatory, anti-oxidant and anti-cholinesterase potential; hence, this can be considered a promising therapeutic potential alternative.

Mitochondrial dysfunction is an early event in Alzheimer's disease (AD) pathogenesis. To assess the impact of vitamin D3 (Vit.D) on neurogenesis, we investigated its role in mitigating cognitive impairment and mitochondrial dysfunction through calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-mediated phosphorylation of Sirtuin1 (SIRT1) in an aluminum-chloride-D-galactose (AlCl3-D-gal)-induced AD rat model. Rats were distributed into four groups: control, AlCl3 + D-gal (10 + 60 mg/kg, ip), Vit.D (500 IU/kg, po), and AlCl3 + D-gal+Vit.D. Novel object recognition (NOR), Morris Water Maze, and passive avoidance (PA) tests were used to measure memory abilities. The hippocampal tissue was used to assess vitamin D3 receptor (VDR) and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α) expression by quantitative real-time polymerase chain reaction (qRT-PCR), CAMKK2, p-SIRT1, phosphorylated-AMP-activated protein kinase (p-AMPK), dynamin-related-protein-1 (Drp1), and mitofusin-1 (Mnf1) proteins by western blot and Ca2+ levels, endothelial nitic oxide synthase (eNOS), superoxide dismutase (SOD), amyloid beta (Aβ), and phospho tau (p-Tau) via enzyme-linked immunosorbent assay(ELISA) in addition to histological and ultrastructural examination of rat's brain tissue. Vit.D-attenuated hippocampal injury reversed the cognitive decline and Aβ aggregation, and elevated p-Tau levels in the AlCl3 + D-gal-induced AD rat model. In AlCl3 + D-gal-exposed rats, Vit.D induced VDR expression, normalized Ca2+ levels, elevated CAMKK2, p-AMPK, p-SIRT1, and PGC-1α expression. Vit.D reduced Drp1, induced Mnf1, increased mitochondrial membrane potential, preserved mitochondrial structure, restored normal mitochondrial function, and retained normal eNOS level and SOD activity in AlCl3 + D-gal rats. In conclusion, our findings proved that Vit.D may ameliorate cognitive deficits in AlCl3 + D-gal-induced AD by restoring normal mitochondrial function and reducing inflammatory and oxidative stress via CAMKK2-AMPK/SIRT1 pathway upregulation.

The purpose of this study was to investigate how thymol affects cognitive functions and the levels of MDA, GSH, Aβ1-42, ApoE, reelin, and LRP8 in an AD model induced in male Wistar albino rats with the application of D-galactose (D-gal) and aluminum chloride (AlCl3).

In this work, 3-month-old male Wistar albino rats were used. Group 1 served as the Control, Group 2 received 0.5 mL/day saline + 0.5 mL/day sunflower oil, Group 3 was administered 200 mg/kg/day AlCl3 + 60 mg/kg/day D-gal, Group 4 received 30 mg/kg/day thymol, and Group 5 was administered 200 mg/kg/day AlCl3 + 60 mg/kg/day D-gal + 30 mg/kg/day thymol. At the end of the 10-week experimental period, behavioral and memory tests were performed. GSH and MDA levels were measured in the obtained serum and brain tissue samples, while Aβ1-42, ApoE, reelin, and LRP8 levels were measured in brain tissue samples. Statistical analyses were performed using ANOVA test in Graphpad Prism V8.3 program. A p-value <0.05 was considered significant in intergroup analyses.

When the novel object recognition test (NORT) results were evaluated, the Alzheimer + thymol (ALZ+TYM) group showed a significant increase in the recognition index (RI) and discrimination index (DI) compared to the Alzheimer (ALZ) group at the 24th hour. Thymol reduced working memory errors (WME), reference memory errors (RME), and maze completion time at 48, 72, and 96 hours when evaluated in terms of spatial memory in rats with Alzheimer's disease. Furthermore, Aβ1-42 and ApoE levels were increased in the ALZ group compared to the control (C), while reelin and LRP8 levels were decreased in the ALZ group compared to the C group.

The data we obtained suggest that thymol may play an effective role in cognitive processes against AD and have an anti-Alzheimer's disease effect.

Alzheimer's disease (AD) causes dementia among older adults, increasing the global burden of dementia. Therefore, this study investigates the potential neuroprotective, antioxidant, and anticancer effects of chamomile essential oil (CCO) in Alzheimer's disease. CCO's main volatile compounds (VOCs) were α-bisabolol, camazulene, and bisabolol oxide A, representing 81 % of all VOCs. CCO scavenged 93 % of DPPH free radicals and inhibited the pathogenic bacteria, i.e., Staphylococcus aureus and Salmonella typhi, besides reducing 89 % of brain cancer cell lines (U87). Eighty albino rats were randomized into four groups: standard control, Alzheimer's disease group caused by AlCl3, and treated groups. The results indicated that the mean value of tumor necrosis factor α (TNF-α), amyloid precursor protein (APP), amyloid beta (Aβ), caspase-3, & B-cell lymphoma 2 (Bcl-2) was significantly elevated due to the harmful effect of AlCl3; however, CCO downregulated these values, and this effect was attributed to the considerable volatile compounds and phenolic compounds content. Additionally, CCO rats showed a significant increment in noradrenergic (NE), dopaminergic (DO), and serotoninergic systems with relative increases of 50, 50, and 14 % compared to diseased rats. The brain histology of CCO-treated rats showed a significant reduction in neuronal degeneration and improved brain changes, and its histology was close to that of the control brain. The results indicated that CCO offers a new strategy that could be used as an antioxidant and neuroprotective agent for AD due to its considerable contents of antioxidants and anti-inflammatory compounds.

The pathological features of Alzheimer's disease (AD), a progressive neurodegenerative disorder, include the deposition of extracellular amyloid beta (Aβ) plaques and intracellular tau neurofibrillary tangles. A decline in cognitive ability is related to the accumulation of Aβ in patients with AD. Autophagy, which is a primary intracellular mechanism for degrading aggregated proteins and damaged organelles, plays a crucial role in AD. In this review, we summarize the most recent research progress regarding the process of autophagy and the effect of autophagy on Aβ. We further discuss some typical monomers of natural products that contribute to the clearance of Aβ by autophagy, which can alleviate AD. This provides a new perspective for the application of autophagy modulation in natural product therapy for AD.

Alzheimer's disease is a neurodegenerative disease that affects a large proportion of older adult people and is characterized by memory loss, progressive cognitive impairment, and various behavioral disturbances. Although the pathological mechanisms underlying Alzheimer's disease are complex and remain unclear, previous research has identified two widely accepted pathological characteristics: extracellular neuritic plaques containing amyloid beta peptide, and intracellular neurofibrillary tangles containing tau. Furthermore, research has revealed the significant role played by neuroinflammation over recent years. The inflammatory microenvironment mainly consists of microglia, astrocytes, the complement system, chemokines, cytokines, and reactive oxygen intermediates; collectively, these factors can promote the pathological process and aggravate the severity of Alzheimer's disease. Therefore, the development of new drugs that can target neuroinflammation will be a significant step forward for the treatment of Alzheimer's disease. Flavonoids are plant-derived secondary metabolites that possess various bioactivities. Previous research found that multiple natural flavonoids could exert satisfactory treatment effects on the neuroinflammation associated with Alzheimer's disease. In this review, we describe the pathogenesis and neuroinflammatory processes of Alzheimer's disease, and summarize the effects and mechanisms of 13 natural flavonoids (apigenin, luteolin, naringenin, quercetin, morin, kaempferol, fisetin, isoquercitrin, astragalin, rutin, icariin, mangiferin, and anthocyanin) derived from plants or medicinal herbs on neuroinflammation in Alzheimer's disease. As an important resource for the development of novel compounds for the treatment of critical diseases, it is essential that we focus on the exploitation of natural products. In particular, it is vital that we investigate the effects of flavonoids on the neuroinflammation associated with Alzheimer's disease in greater detail.

Environmental aluminum intoxication has shown increasingly alarming negative consequences on reproductive health. This needs mechanistic exploration and preventive management using medicines like herbal supplementation. The ameliorative effects of naringenin (NAR) against AlCl3-induced reproductive toxicity were thus evaluated in this study by assessing testicular dysfunction in albino male mice. A group of mice was treated with AlCl3 (10 mg/kg b.w./day) and then with NAR (10 mg/kg b.w./day) for a total of sixty-two days. Results show that treatment of AlCl3 significantly reduced the body weight and testis weight of mice. AlCl3 caused oxidative damage in mice as evidenced by an increase in the concentration of nitric oxide, advanced oxidation of protein product, protein carbonylation, and lipid peroxidation. Furthermore, diminished activity of antioxidant moieties included superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, and oxidized glutathione. Several histological changes, such as spermatogenic cell degeneration, germinal epithelium detachment, and structural abnormalities in seminiferous tubules, were observed in AlCl3-treated mice. Oral administration of NAR was found to restore body weight and testes weight and ameliorated reproductive dysfunctions. NAR decreased oxidative stress, replenished the antioxidant defense system, and improved histopathological alterations in the AlCl3-treated testes. Therefore, the present study suggests that the supplementation of NAR may be a beneficial strategy to mitigate AlCl3-induced reproductive toxicity and testicular dysfunction.

Dysregulation of protein homeostasis, proteostasis, is a distinctive hallmark of many neurodegenerative disorders and aging. Deleteriously, the accumulation of aberrant proteins in Alzheimer's disease (AD) is accompanied with a marked collapse in proteostasis network. The current study explored the potential therapeutic effect of vardenafil (VAR), a phosphodiesterase-5 inhibitor, in AlCl3/D-galactose (D-gal)-induced AD in rats and its possible underlying mechanisms. The impact of VAR treatment on neurobehavioral function, hippocampal tissue architecture, and the activity of the cholinergic system main enzymes were assessed utilizing VAR at doses of 0.3 mg/kg and 1 mg/kg. Additionally, the expression level of amyloid-beta and phosphorylated tau proteins in the hippocampus were figured out. Accordingly, VAR higher dose was selected to contemplate the possible underlying mechanisms. Intriguingly, VAR elevated the cyclic guanosine monophosphate level in the hippocampus and averted the repressed proteasome activity by AlCl3/D-gal; hence, VAR might alleviate the burden of toxic protein aggregates in AD. In addition, a substantial reduction in the activating transcription factor 6-mediated endoplasmic reticulum stress was demonstrated with VAR treatment. Notably, VAR counteracted the AlCl3/D-gal-induced depletion of nuclear factor erythroid 2-related factor 2 level. Moreover, the anti-senescence activity of VAR was demonstrated via its ability to restore the balance of the redox circuit. The modulation of phosphatidylinositol-3-kinase/protein kinase B/p53 pathway and the reduction of nuclear factor kappa B level, the key regulator of senescence-associated secretory phenotype mediators release, with VAR treatment were also elucidated. Altogether, these findings insinuate the possible therapeutic benefits of VAR in AD management.

Junk foods are typically low in essential nutrients, such as vitamins, minerals, and antioxidants. They are also loaded with trans fats and saturated fats, which can increase the level of triglycerides in the blood. High triglyceride levels can contribute to the development of non-alcoholic fatty liver disease (NAFLD), a condition where excess fat accumulates in the liver. A high intake of junk foods can lead to insulin resistance, a condition where the body's cells become less responsive to insulin. A diet lacking in nutrients and loaded with unwanted toxins can impair the liver's ability to detoxify harmful substances and damage its overall function. It is known that the regular consumption of junk food can be linked to memory impairment and cognitive decline. Several studies have shown that diets high in unhealthy fats, sugars, and processed foods can negatively impact brain health, including memory function. In this study, Wistar rats were used to model Late-Onset Alzheimer's Disease (LOAD), which was inspired by knowledge of the liver-brain axis's role in causing dementia. The model mimicked junk-food-induced liver-brain damage, and was developed by using the toxins d-galactosamine, ethanol and d-galactose. To begin with, the model rats demonstrated insulin resistance, a characteristic of LOAD patients. Glucose levels in both the brain and liver tissues were significantly elevated in the model, paralleling clinical findings in LOAD patients. High glucose levels in the brain lead to the increased production of advanced glycation end-products (AGEs), which, along with amyloid beta, harm neighbouring neurons. Histopathological analysis revealed deformed glial nodules, apoptotic neurons, and amyloid plaques in the brain section in the later stages of the disease. Simultaneously, the liver section displayed features of cirrhosis, including an effaced lobular architecture and the extravasation of red blood cells. Liver enzymes ALT, AST and ALP were consistently elevated with disease progression. Furthermore, immunohistochemistry confirmed the presence of amyloid precursor protein (APP) in the diseased brain. The positive expression of Hypoxia-Inducible Factor 3-Alpha (HIF3A) in the brain indicated hypoxic conditions, which is consistent with other LOAD studies. This model also exhibited damaged intestinal villi and excessive bowel and urinary incontinence, indicating malnutrition and a disturbed gut microbiome, which is also consistent with LOAD patients. Bioinformatics analysis on serum protein suggests a few affected molecular pathways, like the amyloid secretase pathway, androgen/oestrogen/progesterone biosynthesis, the apoptosis signalling pathway, the insulin/IGF pathway-protein kinase B signalling cascade, the Metabotropic glutamate receptor group I pathway, the Wnt signalling pathway, etc. Behavioural analysis confirmed memory decline and the loss of muscle strength with disease progression. Overall, this rat model of LOAD sheds valuable light on LOAD pathology and highlights the potential link between liver dysfunction, particularly induced by the excessive consumption of junk food, and LOAD. This study contributes to a deeper understanding of the complex molecular mechanisms involved in LOAD, paving the way for new possibilities in therapeutic interventions.

Dietary fruits and vegetables play a vital role as food and drugs and are the main sources of antioxidant defences against degenerative diseases, such as brain dysfunctions, cardiovascular diseases, immune system deteriorations, and cancers, brought on by oxidative damage. Phyllanthus emblica is a significant herbal remedy used in conventional medicine to recover lost strength and power. In this research, the potential value of Phyllanthus emblica as a food and drug is researched. The total phenolic, total flavonoid, and total tannin contents as well as the nutritional value, vitamin C, vitamin E, and mineral contents of different organs of P. emblica were evaluated. The antioxidant and antimicrobial activities of extracts and fractions of different organs of P. emblica were determined. A total of eleven flavonoids, simple phenolic, tannin-related phenolic, and tannin molecules were isolated from a hydroalcoholic extract of the leaves and fruits. The structures were identified by spectroscopic data and comparison with the literature values as gallic acid (1), naringenin 7-O-(6″-O-galloyl)-β-D-glucopyranoside (2), 3,3'-di-O-methyl ellagic acid-4'-O-β-d-glucopyranoside (3), 1-O-galloyl glycerol (4), 1,6-di-O-galloyl-β-d-glucopyranoside (5), flavogallonic acid bislactone (6), corilagin (7), ethyl gallate (8), urolithin M5 (9), (E)-p-coumaroyl-1-O-β-d-glucopyranoside (10), and 1,2,4,6-tetra-O-galloyl-β-d-glucopyranoside (11). Among them, compounds 3 and 10 are first isolated from the plant. Molecular docking was performed to investigate the comparative interactions between positive controls (galantamine and donepezil) and selected compounds utilizing acetylcholinesterase (4EY7) as a target receptor. Results exhibited the potency of these compounds against the target receptor. In summary, P. emblica has a wealth of minerals, vitamins C and E, and polyphenolic phytochemicals that may work together to treat infectious disease, prevent and/or treat oxidative-damage-related illnesses including Alzheimer's disease.

Non-small cell lung cancer (NSCLC) is one of the leading cancer killers. Apigenin (Api) and Naringenin (Nar) are natural bioactive substances obtained in various vegetables and fruits, possessing anti-tumor effects across multiple studies. This study investigated the latent synergistic antiproliferative functions of Api and Nar in A549 and H1299 NSCLC cells. Cell viability was determined after incubating with different concentrations of Api, Nar, or the combination of Api and Nar (CoAN) for 24 h. Analysis using the CompuSyn software revealed that the CI value of each combined dose was < 1, depicting that the two drugs had a synergistic inhibitory effect. The CoAN (A:N = 3:2) group with the lowest CI value was selected for subsequent experiments. The IC₅₀ of CoAN (A:N = 3:2) was used to determine the cell cycle, the expression ratio of Bax to Bcl2, Caspase 3 activity, and mitochondrial function to assess oxidative stress and apoptosis. The results established that CoAN treatment caused significant cytotoxicity with cell cycle arrest at G2/M phases. Furthermore, CoAN significantly enhanced mitochondria dysfunction, elevated oxidative stress, and activated the apoptotic pathway versus Api or Nar alone groups. Thus, the CoAN chemotherapy approach is promising and deserves further research.

The onset and progression of Alzheimer's disease (AD) are influenced by a variety of factors. These include oxidative stress, overexpression of acetylcholinesterase (AChE), depletion of acetylcholine levels, increased beta-secretase mediated conversion of Amyloid Precursor Protein (APP) to Amyloid Beta (Abeta), accumulation of Abeta oligomers, decrease in Brain Derived Neurotrophic factor (BDNF) and accelerated neuronal apoptosis due to elevated levels of caspase-3. The currently available therapeutic approaches are inadequate in affecting these pathological processes except maybe the overexpression of AChE (AChE inhibitors like donepezil, rivastigmine). There is an urgent need to develop disease modifying pharmacotherapeutic interventions which have appreciable safety and cost effectiveness. From previously reported in vitro studies and a preliminary assessment of neuroprotective effect in scopolamine induced dementia-like cognitive impairment in mice, vanillin has been used as the compound of interest in the present study. Vanillin, a phytoconstituent, has been used in humans, safely, in the form of a flavouring agent for various foods, beverages, and cosmetics. Owing to its chemical nature i.e. being a phenolic aldehyde, it has an additional antioxidant property that is congruent to the desirable characteristics that are sought in a suitable novel anti-AD agent. In our study, vanillin proved to have a nootropic effect in healthy Swiss albino mice as well as an ameliorative effect in aluminium chloride and D-galactose induced AD model in mice. Apart from tackling oxidative stress, vanillin was found to reduce the levels of AChE, beta secretase, caspase-3, enhance degradation of Abeta plaques and elevate the levels of BDNF, in cortical and hippocampal regions. Vanillin is a promising candidate for being incorporated into the search for safe and effective anti-AD molecules. However, further research might be needed to warrant its application clinically.

Aging is characterized by systemic chronic inflammation, which is accompanied by cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there is an urgent need for a systematic organization of inflammaging through dimensionality reduction. Factors secreted by senescent cells, known as the senescence-associated secretory phenotype (SASP), promote chronic inflammation and can induce senescence in normal cells. At the same time, chronic inflammation accelerates the senescence of immune cells, resulting in weakened immune function and an inability to clear senescent cells and inflammatory factors, which creates a vicious cycle of inflammation and senescence. Persistently elevated inflammation levels in organs such as the bone marrow, liver, and lungs cannot be eliminated in time, leading to organ damage and aging-related diseases. Therefore, inflammation has been recognized as an endogenous factor in aging, and the elimination of inflammation could be a potential strategy for anti-aging. Here we discuss inflammaging at the molecular, cellular, organ, and disease levels, and review current aging models, the implications of cutting-edge single cell technologies, as well as anti-aging strategies. Since preventing and alleviating aging-related diseases and improving the overall quality of life are the ultimate goals of aging research, our review highlights the critical features and potential mechanisms of inflammation and aging, along with the latest developments and future directions in aging research, providing a theoretical foundation for novel and practical anti-aging strategies.

Purpurin, an anthraquinone, has potent anti-oxidant and anti-inflammatory effects in various types of brain damage. In a previous study, we showed that purpurin exerts neuroprotective effects against oxidative and ischemic damage by reducing pro-inflammatory cytokines. In the present study, we investigated the effects of purpurin against D-galactose-induced aging phenotypes in mice. Exposure to 100 mM D-galactose significantly decreased cell viability in HT22 cells, and purpurin treatment significantly ameliorated the reduction of cell viability, formation of reactive oxygen species, and lipid peroxidation in a concentration-dependent manner. Treatment with 6 mg/kg purpurin significantly improved D-galactose-induced memory impairment in the Morris water maze test in C57BL/6 mice and alleviated the reduction of proliferating cells and neuroblasts in the subgranular zone of the dentate gyrus. In addition, purpurin treatment significantly mitigated D-galactose-induced changes of microglial morphology in the mouse hippocampus and the release of pro-inflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. In addition, purpurin treatment significantly ameliorated D-galactose-induced phosphorylation of c-Jun N-terminal kinase and cleavage of caspase-3 in HT22 cells. These results suggest that purpurin can delay aging by reducing the inflammatory cascade and phosphorylation of the c-Jun N-terminal in the hippocampus.

Background: Although aluminum (Al) is not biologically crucial to the human body, classical studies have demonstrated that excessive human exposure to Al can induce oxidative damage, neuroinflammatory conditions and neurotoxic manifestations implicated in Alzheimer's disease (AD). Exposure to Al was reported to be associated with oxidative damage, neuroinflammation, and to enhance progressive multiregional neurodegeneration in animal models. Several plant-derived natural biomolecules have been recently used to reduce the toxic effects of Al through decreasing the oxidative stress and the associated diseases. A good candidate still to be tested is an active natural furanocoumarin, the isoimperatorin (IMP) that can be extracted from Lemon and lime oils and other plants. Here, we examined the neuroprotective effects of IMP on aluminum chloride (AlCl3)-induced neurotoxicity in albino mice. Methods: Twenty-four male albino mice were used in this study. Mice were randomly devided into 5 groups. The first group was given distilled water as a control, the second group was given AlCl3 orally (10 mg/wt/day) starting from the 2nd week to the end of the 6th week, the third group received AlCl3 orally and IMP interperitoneally, i. p. (30 mg/wt/day) starting from week 2 till week 6 where IMP was supplement 1st and then 4 h later AlCl3 was given to mice. The fourth group received the control (IMP 30 mg/wt, i. p.) from the 2nd week till the end of the experiment. Rodent models of central nervous system (CNS) disorders were assessed using object location memory and Y-maze tests in 6th week began. Essential anti-inflammatory and oxidative stress indicators were evaluated, including interleukin-1 β (IL-1β), tumor necrosis factor α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity (CAT). In addition, serum levels of brain neurotransmitters such as corticosterone, acetylcholine (ACh), dopamine and serotonin in brain homogenates were measured calorimetrically. Results: The study results revealed that the daily treatment of AlCl3 upregulated the TNF-α and IL-1β levels, increased MDA accumulation, and decreased TAC and CAT activity. In addition, aluminum induced a reduction in concentrations of ACh, serotonin and dopamine in the brain. However, IMP significantly ameliorates the effect of AlCl3 through modulating the antioxidant and regulating the inflammatory response through targeting Nrf2 (NF-E2-related factor 2) and mitogen-activated protein kinase (MAPK). Conclusion: Thus, IMP might be a promising treatment option for neurotoxicity and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, which are associated with neuro-inflammation and oxidative stress.

This study aimed to prepare micro/nanocrystalline cellulose-loaded naringin (NAR) tablets and evaluate their neuro-protective/therapeutic potentials in Alzheimer's disease (AD) model. Micro/nanocellulose was prepared from different agro-wastes, and the different cellulose preparations were then used to formulate eight oral tablets of naringin micro/nanoparticles by direct compression. AD-like symptoms were induced in adult male Sprague Dawley rats by co-administration of 150 mg/kg AlCl₃ and 300 mg/kg D-galactose (oral administration/one week), and NAR tablets were assessed for neuroprotective/therapeutic potentials in terms of behavioral changes, levels of neurodegenerative and inflammatory markers, brain redox status, neurotransmitter tones, and cortex/hippocampus histopathological alterations. NAR treatments have significantly reversed the neurotoxic effect of AlCl₃ as demonstrated by improved spatial and cognitive memory functions and promoted antioxidant defense mechanisms in treated AD animals. Also, the neurodegeneration was markedly restrained as reflected by marked histopathological enhancement, and prevention/amelioration of neuropsychiatric disorders, besides the restorative effect on dysregulated neurotransmitters tone. Both NAR tablet forms showed an overall higher ameliorative effect compared to the DPZ reference drug. The formulated tablets represent promising neuroprotective/therapeutic agents for Alzheimer's disease.

It is strongly believed that aluminum is one of the insalubrious agents because of its neurotoxicity effects and influences on amyloid β (Aβ) production and tau protein hyperphosphorylation following oxidative stress, as one of the initial events in neurotoxicity. The autophagy process plays a considerable role in neurons in preserving intracellular homeostasis and recycling organelles and proteins, especially Aβ and soluble tau. Thus, autophagy is suggested to ameliorate aluminum neurotoxicity effects, and dysfunction of this process can lead to an increase in detrimental proteins. However, the relationship between aluminum neurotoxicity and autophagy dysregulation in some dimensions remains unclear. In the present review, we want to give an overview of the autophagy roles in aluminum neurotoxicity and how dysregulation of autophagy can affect aluminum neurotoxicity.

Astaxanthin (AST) is a second-generation antioxidant with anti-inflammatory and neuroprotective properties and could be a promising candidate for Alzheimer's disease (AD) therapy, but is shows poor oral bioavailability due to its high lipophilicity.

This study aimed to prepare and evaluate AST-loaded nanostructured lipid carriers (NLCs), for enhanced nose-to-brain drug delivery to improve its therapeutic efficacy in rat model of AD.

AST-NLCs were prepared using hot high-pressure homogenization technique, and processing parameters such as total lipid-to-drug ratio, solid lipid-to-liquid lipid ratio, and concentration of surfactant were optimized.

The optimized AST-NLCs had a mean particle size of 142.8 ± 5.02 nm, polydispersity index of 0.247 ± 0.016, zeta potential of -32.2 ± 7.88 mV, entrapment efficiency of 94.1 ± 2.46%, drug loading of 23.5 ± 1.48%, and spherical morphology as revealed by transmission electron microscopy. Differential scanning calorimetry showed that AST was molecularly dispersed in the NLC matrix in an amorphous state, whereas Fourier transform infrared spectroscopy indicated that there is no interaction between AST and lipids. AST displayed a biphasic release pattern from NLCs; an initial burst release followed by sustained release for 24 h. AST-NLCs were stable at 4-8 ±2°C for six months. Intranasal treatment of AD-like rats with the optimized AST-NLCs significantly decreased oxidative stress, amyloidogenic pathway, neuroinflammation and apoptosis, and significantly improved the cholinergic neurotransmission compared to AST-solution. This was observed by the significant decline in the levels of malondialdehyde, nuclear factor-kappa B, amyloid beta (Aβ_1‑42), caspase-3, acetylcholinesterase, and β-site amyloid precursor protein cleaving enzyme-1 expression, and significant increase in the contents of acetylcholine and glutathione after treatment with AST-NLCs.

NLCs enhanced the intranasal delivery of AST and significantly improved its therapeutic properties.

Citrus fruits occupy an important position in the context of the fruit trade, considering that both fresh fruits and processed products are produced on a large scale. Citrus fruits are recognized as an essential component of the human diet, thanks to their high content of beneficial nutrients such as vitamins, minerals, terpenes, flavonoids, coumarins and dietary fibers. Among these, a wide range of positive biological activities are attributed to terpenes and flavonoids derivatives. In this review, a list of bibliographic reports (from 2015 onwards) on the phytochemical composition, beneficial effects and potential applications of citrus fruits and their by-products is systematically summarized. In detail, information regarding the nutraceutical and medicinal value closely linked to the presence of numerous bioactive metabolites and their growing use in the food industry and food packaging, also considering any technological strategies such as encapsulation to guarantee their stability over time, were evaluated. In addition, since citrus fruit, as well as its by-products, are interesting alternatives for the reformulation of natural cosmetic products, the sector of the cosmetic industry is also explored. More in-depth knowledge of the latest information in this field will contribute to future conscious use of citrus fruits.

Alzheimer's disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to be attributed by extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles. Additionally, genetic factors such as abnormality in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2 play a role in the disease. As the current treatment aims to treat the symptoms and to slow the disease progression, there has been a continuous search for new nutraceutical agent or medicine to help prevent and cure AD pathology. In this quest, honey has emerged as a powerful nootropic agent. Numerous studies have demonstrated that the high flavonoids and phenolic acids content in honey exerts its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes the effect of main flavonoid compounds found in honey on the physiological functioning of the central nervous system, and the effect of honey intake on memory and cognition in various animal model. This review provides a new insight on the potential of honey to prevent AD pathology, as well as to ameliorate the damage in the developed AD.

Sarcococca saligna is a valuable source of bioactive secondary metabolites exhibiting antioxidant, anti-inflammatory and acetylcholinesterase inhibitory activities. The study was intended to explore the therapeutic pursuits of S. saligna in amelioration of cognitive and motor dysfunctions induced by D-galactose and linked mechanistic pathways. Alzheimer's disease model was prepared by administration of D-galactose subcutaneous injection100 mg/kg and it was treated with rivastigmine (100 mg/kg, orally) and plant extract for 42 days. Cognitive and motor functions were evaluated by behavioral tasks and oxidative stress biomarkers. Level of acetylcholinesterase, reduced level of glutathione, protein and nitrite level, and brain neurotransmitters were analyzed in brain homogenate. The level of apoptosis regulator Bcl-2, Caspases 3 and heat shock protein HSP-70 in brain homogenates were analyzed by ELISA and colorimetric method, respectively. AChE, IL-1β, TNF-α, IL-1α and β secretase expressions were analyzed by RT-PCR. S. saligna dose dependently suppressed the neurodegenerative effects of D-galactose induced behavioral and biochemical impairments through modulation of antioxidant enzymes and acetylcholinesterase inhibition. S. saligna markedly (P < 0.05) ameliorated the level of brain neurotransmitters, Bcl-2, HSP-70 and Caspases-3 level. S. saligna at 500-1000 mg/kg considerably recovered the mRNA expression of neurodegenerative and neuro-inflammatory biomarkers, also evident from histopathological analysis. These findings suggest that S. saligna could be applicable in cure of Alzheimer's disease.

Alzheimer's disease (AD) is known as "type 3 diabetes". As thioredoxin binding protein (TXNIP) has been shown to be involved in brain insulin resistance, the present study evaluated the roles of TXNIP, phospho-insulin receptor substrate 1 (P-IRS-1), and phosphatidyl inositol-3 kinase (PI3K) in the pathogenesis of AD. The potential ameliorative effect of bromelain compared to donepezil was evaluated in an aluminum chloride (AlCl3)-induced AD in rats. Behavioral tests demonstrated similar improvements in exploratory activity, cognitive and spatial memory functions, anxiety, and depression levels between rats treated with bromelain and donepezil. Donepezil was superior to bromelain in improving locomotor activity. Histopathological examinations demonstrated neuronal degeneration in the AlCl3 group that was almost normalized by bromelain and donepezil. Moreover, there was deposition of amyloid plaques in the AlCl3 group that was improved by bromelain and donepezil. Acetylcholine esterase levels were significantly increased in rats treated with AlCl3 group and significantly decreased in rats treated with bromelain and donepezil. Furthermore, AlCl3 group showed a significantly increased TXNIP and P-IRS1 and a significantly reduced PI3K levels. These effects were ameliorated by bromelain and donepezil treatment. The present study demonstrates a previously unreported modulatory effect of bromelain on the TXNIP/P-IRS-1/PI3K axis in AD model.

Alzheimer's disease has emerged as one of the most challenging neurodegenerative diseases associated with dementia, loss of cognitive functioning and memory impairment. Despite enormous efforts to identify disease modifying technologies, the repertoire of currently approved drugs consists of a few symptomatic candidates that are not capable of halting disease progression. Moreover, these single mechanism drugs target only a small part of the pathological cascade and do not address most of the etiological basis of the disease. Development of therapies that are able to simultaneously tackle all the multiple interlinked causative factors such as amyloid protein aggregation, tau hyperphosphorylation, cholinergic deficit, oxidative stress, metal dyshomeostasis and neuro-inflammation has become the focus of intensive research in this domain. Flavonoids are natural phytochemicals that have demonstrated immense potential as medicinal agents due to their multiple beneficial therapeutic effects. The polypharmacological profile of flavonoids aligns well with the multifactorial pathological landscape of Alzheimer's disease, making them promising candidates to overcome the challenges of this neurodegenerative disorder. This review presents a detailed overview of the pleiotropic biology of flavonoids favourable for Alzheimer therapeutics and the structural basis for these effects. Structure activity trends for several flavonoid classes such as flavones, flavonols, flavanones, isoflavones, flavanols and anthocyanins are comprehensively analyzed in detail and presented.

Background: Phytochemicals have amazing biological effects in relation to age-related illnesses and are increasingly being studied in clinical trials. The goal of this study was to examine the effectiveness of the aqueous extracts of Rosmarinus officinalis L. (Rosemary) and Crocus sativus L. (Saffron) and their combinations as tau and β-amyloid antagonists in an Alzheimer's rat model. Methods: AlCl₃ and D-galactose (150 & 300 mg/kg) were used to create the Alzheimer's neuroinflammation rat model. The animals were subsequently given the two extracts and their combinations (500 mg/kg) along 15 days. The cognitive impairment, oxidative stress, tau & amyloid neuroproteins, acetylcholine, acetylcholinesterase neurotransmitters, proinflammatory cytokines, LC3 as an autophagy marker, computational analysis, and morphological alterations were all assessed. Results: When compared to the conventional donepezil and normal groups, the treated groups showed a significant improvement in all calculated parameters. The cortex and hippocampus have a better morphological appearance. In silico analysis found that these extracts may have an affinity for and impede the activity of some proteins thought to be essential regulators of disease progression. Conclusion: Rosemary and Saffron extracts by the power of their constituents were able to alleviate the neurotoxicity of AlCl₃ & D-galactose and regulate the natural autophagy process.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although substantial research has been conducted to elucidate the complex pathophysiology of AD, the therapeutic approach still has limited efficacy in clinical practice. Oxidative stress (OS) has been established as an early driver of several age-related diseases, including neurodegeneration. In AD, increased levels of reactive oxygen species mediate neuronal lipid, protein, and nucleic acid peroxidation, mitochondrial dysfunction, synaptic damage, and inflammation. Thus, the identification of novel antioxidant molecules capable of detecting, preventing, and counteracting AD onset and progression is of the utmost importance. However, although several studies have been published, comprehensive and up-to-date overviews of the principal anti-AD agents harboring antioxidant properties remain scarce. In this narrative review, we summarize the role of vitamins, minerals, flavonoids, non-flavonoids, mitochondria-targeting molecules, organosulfur compounds, and carotenoids as non-enzymatic antioxidants with AD diagnostic, preventative, and therapeutic potential, thereby offering insights into the relationship between OS and neurodegeneration.

Antioxidants are being explored as novel therapeutics for the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) through strategies such as chemically linking antioxidants to synthesize novel co-drugs. The main objective of this study was to assess the cytoprotective effects of the novel antioxidant compound VANL-100 in a cellular model of beta-amyloid (Aβ)-induced toxicity. The cytotoxic effects of Aβ in the presence and absence of all antioxidant compounds were measured using the 3-(4,5-dimethylthiazol-2-yl)2-5-diphenyl-2H-tetrazolium bromide (MTT) assay in SH-SY5Y cells in both pre-treatment and co-treatment experiments. In pre-treatment experiments, VANL-100, or one of its parent compounds, naringenin (NAR), alpha-lipoic acid (ALA), or naringenin + alpha-lipoic acid (NAR + ALA), was administrated 24 h prior to an additional 24-h incubation with 20 μM non-fibril or fibril Aβ_25-35. Co-treatment experiments consisted of simultaneous treatment with Aβ and antioxidants. Pre-treatment and co-treatment with VANL-100 significantly attenuated Aβ-induced cell death. There were no significant differences between the protective effects of VANL-100, NAR, ALA, and NAR + ALA with either form of Aβ, or in the effect of VANL-100 between 24-h pre-treatment and co-treatment. These results demonstrate that the novel co-drug VANL-100 is capable of eliciting cytoprotective effects against Aβ-induced toxicity.

Neurodegenerative disorders (NDs) are a cluster of progressive, severe, and disabling disorders that affect millions of people worldwide and are on the surge. These disorders are characterized by the gradual loss of a selectively vulnerable group of neurons. Due to the complex pathophysiological mechanisms behind neurodegeneration and despite enormous efforts and understanding of the occurrence and progression of NDs, there is still a lack of an effective treatment for such diseases. Therefore, the development of a new therapeutic strategy for NDs is an unmet clinical need. Various natural compounds extracted from medicinal plants or fruits have shown promising activities in treating different types of NDs by targeting multiple signaling pathways. Among natural entities, flavonoids have incited a rise in public and scientific interest in recent years because of their purported health-promoting effects. Dietary supplementation of flavonoids has been shown to mitigate the severity of NDs such as Parkinson's disease (PD), Alzheimer's disease (AD), and dementia by their antioxidant effects. Naringenin is a citrus flavonoid that is known to possess numerous biological activities like antioxidant, anti-proliferative, and anti-inflammatory activities. Therefore, naringenin has emerged as a potential therapeutic agent that exerts preventive and curative effects on several neurological disorders. Increasing evidence has attained special attention on the variety of therapeutic targets along with complex signaling pathways of naringenin, which suggest its possible therapeutic applications in several NDs. Derived from the results of several pre-clinical research and considering the therapeutic effects of this compound, this review focuses on the potential role of naringenin as a pharmacological agent for the treatment and management of Alzheimer's and Parkinson's disease. The overall neuroprotective effects and different possible underlying mechanisms related to naringenin are discussed. In the light of substantial evidence for naringenin's neuroprotective efficacy in several experimental paradigms, this review suggests that this molecule should be investigated further as a viable candidate for the management of Alzheimer's and Parkinson's disease, with an emphasis on mechanistic and clinical trials to determine its efficacy. PRACTICAL APPLICATIONS: Naringenin is a flavanone, aglycone of Naringin, predominantly found in citrus fruits with a variety of pharmacological actions. Naringenin has been shown to exhibit remarkable therapeutic efficacy and has emerged as a potential therapeutic agent for the management of a variety of diseases such as various heart, liver, and metabolic disorders. Similarly, it has shown efficacy in neurodegenerative illnesses. Therefore, this review enables us to better understand the neuroprotective effects and different possible underlying mechanisms of naringenin. Also, this review provides a new indication to manage the symptoms of NDs like AD and PD. Furthermore, naringenin will be useful in the field of medicine as a new active ingredient for the treatment of neurodegenerative disorders like AD and PD.