Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of ...40-42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.
Age‐related cognitive failure is a main devastating incident affecting even healthy people. Alzheimer's disease (AD) is the utmost common form of dementia among the geriatric community. In the ...pathogenesis of AD, cerebrovascular dysfunction is revealed before the beginning of the cognitive decline. Mounting proof shows a precarious impact of cerebrovascular dysregulation in the development of AD pathology. Recent studies document that the mammalian target of rapamycin (mTOR) acts as a crucial effector of cerebrovascular dysregulation in AD. The mTOR contributes to brain vascular dysfunction and subsequence cerebral blood flow deficits as well as cognitive impairment. Furthermore, mTOR causes the blood–brain barrier (BBB) breakdown in AD models. Inhibition of mTOR hyperactivity protects the BBB integrity in AD. Furthermore, mTOR drives cognitive defect and cerebrovascular dysfunction, which are greatly prevalent in AD, but the central molecular mechanisms underlying these alterations are obscure. This review represents the crucial and current research findings regarding the role of mTOR signaling in cognitive aging and cerebrovascular dysfunction in the pathogenesis of AD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease involving aggregation of misfolded proteins inside the neuron causing prolonged cellular stress. The neuropathological hallmarks of ...AD include the formation of senile plaques and neurofibrillary tangles in specific brain regions that lead to synaptic loss and neuronal death. The exact mechanism of neuron dysfunction in AD remains obscure. In recent years, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal degeneration seen in AD. Apart from AD, many other diseases also involve misfolded proteins aggregations in the ER, a condition referred to as ER stress. The response of the cell to ER stress is to activate a group of signaling pathways called unfolded protein response (UPR) that stimulates a particular transcriptional program to restore ER function and ensure cell survival. ER stress also involves the generation of reactive oxygen species (ROS) that, together with mitochondrial ROS and decreased effectiveness of antioxidant mechanisms, producing a condition of chronic oxidative stress. The unfolded proteins may not always produce a response that leads to the restoration of cellular functions, but they may also lead to inflammation by a set of different pathways with deleterious consequences. In this review, we extensively discuss the role of ER stress and how to target it using different pharmacological approaches in AD development and onset.
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Even though the number of AD patients is rapidly growing, there is no effective treatment for this neurodegenerative disorder. At ...present, implementation of effective treatment approaches for AD is vital to meet clinical needs. In AD research, priorities concern the development of disease-modifying therapeutic agents to be used in the early phases of AD and the optimization of the symptomatic treatments predominantly dedicated to the more advanced AD stages. Until now, available therapeutic agents for AD treatment only provide symptomatic treatment. Since AD pathogenesis is multifactorial, use of a multimodal therapeutic intervention addressing several molecular targets of AD-related pathological processes seems to be the most practical approach to modify the course of AD progression. It has been demonstrated through numerous studies, that the clinical efficacy of combination therapy (CT) is higher than that of monotherapy. In case of AD, CT is more effective, mostly when started early, at slowing the rate of cognitive impairment. In this review, we have covered the major studies regarding CT to combat AD pathogenesis. Moreover, we have also highlighted the safety, tolerability, and efficacy of CT in the treatment of AD.
Natural kaolinite was subjected to a successful exfoliation process into separated kaolinite nanosheets (KNs), followed by hybridization with β-cyclodextrin biopolymer (β-CD), forming an advanced ...bio-nanocomposite (β-CD/KNs). The synthetic products were evaluated as enhanced delivery structures for oxaliplatin chemotherapy (OXAPN). The hybridization of KNs with β-CD polymer notably enhanced the loading capacity to 355.3 mg/g (β-CD/KNs) as compared to 304.9 mg/g for KNs. The loading of OXAPN into both KNs and β-CD/KNs displayed traditional pseudo-first-order kinetics (R
> 0.85) and a conventional Langmuir isotherm (R
= 0.99). The synthetic β-CD/KNs validates a greater occupied effective site density (98.7 mg/g) than KNs (66.3 mg/g). Furthermore, the values of the n steric parameter (4.7 (KNs) and 3.6 (β-CD/KNs)) reveal the vertical orientation of the loaded molecules and the loading of them by multi-molecular mechanisms. These mechanisms are mainly physical processes based on the obtained Gaussian energy (<8 KJ/mol) and loading energy (<40 KJ/mol). The release profiles of both KNs and β-CD/KNs extend for about 120 h, with remarkably faster rates for β-CD/KNs. According to the release kinetic findings, the release of OXAPN displays non-Fickian transport behavior involving the cooperation of diffusion and erosion mechanisms. The KNs and β-CD/KNs as free particles showed considerable cytotoxicity and anticancer properties against HCT-116 cancer cell lines (71.4% cell viability (KNs) and 58.83% cell viability (β-CD/KNs)). Additionally, both KNs and β-CD/KNs significantly enhanced the OXAPN's cytotoxicity (2.04% cell viability (OXAPN/KNs) and 0.86% cell viability (OXAPN/β-CD/KNs).
Natural kaolinite underwent advanced morphological-modification processes that involved exfoliation of its layers into separated single nanosheets (KNs) and scrolled nanoparticles as nanotubes ...(KNTs). Synthetic nanostructures have been characterized as advanced and effective oxaliplatin-medication (OXAP) delivery systems. The morphological-transformation processes resulted in a remarkable enhancement in the loading capacity to 304.9 mg/g (KNs) and 473 mg/g (KNTs) instead of 29.6 mg/g for raw kaolinite. The loading reactions that occurred by KNs and KNTs displayed classic pseudo-first-order kinetics (R
> 0.90) and conventional Langmuir isotherms (R
= 0.99). KNTs exhibit a higher active site density (80.8 mg/g) in comparison to KNs (66.3 mg/g) and raw kaolinite (6.5 mg/g). Furthermore, compared to KNs and raw kaolinite, each site on the surface of KNTs may hold up to six molecules of OXAP (
= 5.8), in comparison with five molecules for KNs. This was accomplished by multi-molecular processes, including physical mechanisms considering both the Gaussian energy (<8 KJ/mol) and the loading energy (<40 KJ/mol). The release activity of OXAP from KNs and KNTs exhibits continuous and regulated profiles up to 100 h, either by KNs or KNTs, with substantially faster characteristics for KNTs. Based on the release kinetic investigations, the release processes have non-Fickian transport-release features, indicating cooperative-diffusion and erosion-release mechanisms. The synthesized structures have a significant cytotoxicity impact on HCT-116 cancer cell lines (KNs (71.4% cell viability and 143.6 g/mL IC-50); KNTs (11.3% cell viability and 114.3 g/mL IC-50). Additionally, these carriers dramatically increase OXAP's cytotoxicity (2.04% cell viability, 15.4 g/mL IC-50 (OXAP/KNs); 0.6% cell viability, 4.5 g/mL IC-50 (OXAP/KNTs)).
Monolluma quadrangula is a succulent bush traditionally used to treat diabetes and peptic ulcer. The present study aimed to investigate the effect of M. quadrangula hydroethanolic extract on glucose ...tolerance, insulin sensitivity, glucose metabolizing enzymes, lipid profile, and adiponectin expression in type 2 diabetic rats. In addition, the study evaluated the antioxidant and anti-inflammatory activities of the M. quadrangula extract. Type 2 diabetes was induced by feeding rats a high-fat diet (HFD) for 8 weeks followed by 30 mg/kg streptozotocin (STZ). Diabetic rats received 300 or 600 mg/kg M. quadrangula extract for 4 weeks. HFD/STZ diabetic rats showed impaired glucose tolerance, reduced insulin secretion, and insulin resistance. HFD and STZ induced a significant increase in serum cholesterol, triglycerides and proinflammatory cytokines, and liver lipid peroxidation. Treatment with M. quadrangula extract ameliorated these metabolic disturbances and increased liver glycogen, hexokinase activity, and antioxidants. M. quadrangula declined the activity of liver glucose-6-phosphatase and fructose-1,6-biphosphatase. In addition, M. quadrangula extract increased serum adiponectin levels and hepatic adiponectin expression in HFD/STZ diabetic rats. In conclusion, M. quadrangula exerts antidiabetic effect mediated via ameliorating glucose tolerance, insulin sensitivity, glucose metabolizing enzymes, and antioxidant defenses. Increased adiponectin levels and expression seems to mediate, at least in part, the antidiabetic effect of M. quadrangula.
Alzheimer’s disease (AD) is the most common cause of dementia among older people, and the prevalence of this disease is estimated to rise quickly in the upcoming years. Unfortunately, almost all of ...the drug candidates tested for AD until now have failed to exhibit any efficacy. Henceforth, there is an increased necessity to avert and/or slow down the advancement of AD. It is known that one of the major pathological characteristics of AD is the presence of senile plaques (SPs) in the brain. These SPs are composed of aggregated amyloid beta (Aβ), derived from the amyloid precursor protein (APP). Pharmaceutical companies have conducted a number of studies in order to identify safe and effective anti-Aβ drugs to combat AD. It is known that α-, β-, and γ-secretases are the three proteases that are involved in APP processing. Furthermore, there is a growing interest in these proteases, as they have a contribution to the modulation and production of Aβ. It has been observed that small compounds can be used to target these important proteases. Indeed, these compounds must satisfy the common strict requirements of a drug candidate targeted for brain penetration and selectivity toward different proteases. In this article, we have focused on the auspicious molecules which are under development for targeting APP-processing enzymes. We have also presented several anti-AD molecules targeting Aβ accumulation and phosphorylation signaling in APP processing. This review highlights the structure-activity relationship and other physicochemical features of several pharmacological candidates in order to successfully develop new anti-AD drugs.
Human health is closely related to his environment. The influence of exposure to air pollutants on human health and well-being has been an interesting subject and gained much volume of research over ...the last 50 years. In general, polluted air is considered one of the major factors leading to many diseases such as cardiovascular and respiratory disease and lung cancer for the people. Besides, air pollution adversely affects the animals and deteriorates the plant environment. The overarching objective of this review is to explore the previous researches regarding the causes and sources of air pollution, how to control it and its detrimental effects on human health. The definition of air pollution and its sources were introduced extensively. Major air pollutants and their noxious effects were detailed. Detrimental impacts of air pollution on human health and well-being were also presented.
Neurodegeneration is the progressive loss of neuronal structures and functions that lead to copious disorders like Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis ...(ALS), and other less recurring diseases. Aging is the prime culprit for most neurodegenerative events. Moreover, the shared pathogenic factors of many neurodegenerative processes are inflammatory responses and oxidative stress (OS). Unfortunately, it is very complicated to treat neurodegeneration and there is no effective remedy. The rapid progression of the neurodegenerative diseases that exacerbate the burden and the concurrent absence of effective treatment strategies force the researchers to investigate more therapeutic approaches that ultimately target the causative factors of the neurodegeneration. Phytochemicals have great potential to exert their neuroprotective effects by targeting various mechanisms, such as OS, neuroinflammation, abnormal protein aggregation, neurotrophic factor deficiency, disruption in mitochondrial function, and apoptosis. Therefore, this review represents the molecular mechanisms of neuroprotection by multifunctional phytochemicals to combat age-linked neurodegenerative disorders.
Display omitted
•Phytochemicals activate PI3K/Akt, PKC, ERK1/2 signaling pathways to affect synaptic plasticity and memory formation.•Phytochemicals regulate the expression of antioxidant enzymes by activation of the Keep1/Nrf2/ARE pathway.•Phytochemicals control the secretases activity of the APP processing pathway and prevent the formation of neurotoxic Aβ.•Phytochemicals block mTOR activity and promote autophagic clearance of pathogenic proteins.•Phytochemicals enhance the activity of ETC and block the mitochondrial membrane permeability
PDF
