Naringenin mitigates aluminum toxicity-induced learning memory impairments and neurodegeneration through amelioration of oxidative stress.

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.

Potential Effects of Traditional Chinese Medicine in Anti-Aging and Aging-Related Diseases: Current Evidence and Perspectives.

Aging and aging-related diseases present a global public health problem. Therefore, the development of efficient anti-aging drugs has become an important area of research. Traditional Chinese medicine is an important complementary and alternative branch of aging-related diseases therapy. Recently, a growing number of studies have revealed that traditional Chinese medicine has a certain delaying effect on the progression of aging and aging-related diseases. Here, we review the progress in research into using traditional Chinese medicine for aging and aging-related diseases (including neurodegenerative diseases, cardiovascular diseases, diabetes, and cancer). Furthermore, we summarize the potential mechanisms of action of traditional Chinese medicine and provide references for further studies on aging and aging-related diseases.

Therapeutic exploitation of ferroptosis.

Pathological breakdown of membrane lipids through excessive lipid peroxidation (LPO) was first described in the mid-20th century and is now recognized as a form of regulated cell death, dubbed ferroptosis. Accumulating evidence unveils how metabolic regulation restrains peroxidation of phospholipids within cellular membranes, thereby impeding ferroptosis execution. Unleashing these metabolic breaks is currently therapeutically explored to sensitize cancers to ferroptosis inducing anti-cancer therapies. Reversely, these natural ferroptotic defense mechanisms can fail resulting in pathological conditions or diseases such as ischemia-reperfusion injury, multi-organ dysfunction, stroke, infarction, or neurodegenerative diseases. This minireview outlines current ferroptosis-inducing anti-cancer strategies and highlights the detection as well as the therapeutic targeting of ferroptosis in preclinical experimental settings. Herein, we also briefly summarize observations related to LPO, iron and redox deregulation in patients that might hint towards ferroptosis as a contributing factor.

Opportunities and perspectives of small molecular phosphodiesterase inhibitors in neurodegenerative diseases.

Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aß oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment.

Overview of alkyl quercetin lipophenol synthesis and its protective effect against carbonyl stress involved in neurodegeneration.

Oxidative stress and carbonyl stress resulting from the toxicity of small aldehydes are part of the detrimental mechanisms leading to neuronal cell loss involved in the progression of neurodegenerative diseases such as Alzheimer's disease. Polyunsaturated alkylated lipophenols represent a new class of hybrid molecules that combine the health benefits of anti-inflammatory omega-3 fatty acids with the anti-carbonyl and oxidative stress (anti-COS) properties of (poly)phenols in a single pharmacological entity. To investigate the therapeutic potential of quercetin-3-docosahexaenoic acid-7-isopropyl lipophenol in neurodegenerative diseases, three synthetic pathways using chemical or chemo-enzymatic strategies were developed to access milligram or gram scale quantities of this alkyl lipophenol. The protective effect of quercetin-3-DHA-7-iPr against cytotoxic concentrations of acrolein (a carbonyl stressor) was assessed in human SHSY-5Y neuroblastoma cells to underscore its ability to alleviate harmful mechanisms associated with carbonyl stress in the context of neurodegenerative diseases.

Application of natural products in regulating ferroptosis in human diseases.

BACKGROUND: Ferroptosis is a type of cell death caused by excessive iron-induced peroxidation. It has been found to be involved in a variety of diseases, and natural products can be used to target ferroptosis in treatments. Natural products are biologically active compounds extracted or synthesized from nature. It is an important resource for the discovery of skeletons with a high degree of structural diversity and a wide range of bioactivities, which can be developed directly or used as a starting point for the optimization of new drugs. PURPOSE: In this review, we aim to discuss the interactions between natural products and ferroptosis in the treatment of human diseases. METHODS: Literature was searched in Pubmed, Science Direct, and Web of Science databases for the 11-year period from 2012 to 2023 using the search terms "natural products", "ferroptosis", "human disease", "neurodegenerative disease", "cardiovascular disease", and "cancer". RESULTS: In this research, the roles of natural products and ferroptosis were investigated. We suggest that natural products, such as terpenoids, flavonoids, polyphenols, alkaloids, and saponins, can be used in therapeutic applications for human diseases, as well as in ferroptosis. Additionally, the main mechanisms of ferroptosis were summarized and discussed. Furthermore, we propose that natural products can be utilized to enhance the sensitivity of cancer cells to ferroptosis, thus helping to overcome drug resistance and inhibit metastasis. Moreover, natural products have the potential to modulate the expression levels of ferroptosis-related factors. Finally, the future directions of this field were highlighted. CONCLUSION: The potential of natural products which focus on ferroptosis to treat human illnesses, particularly cancer, is very encouraging for human wellbeing.

Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1.

Integrin-linked kinase (ILK), a ß1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23µM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation.

Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers - Targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer.

The endoplasmic reticulum (ER) is a cellular organelle that is physiologically responsible for protein folding, calcium homeostasis, and lipid biosynthesis. Pathological stimuli such as oxidative stress, ischemia, disruptions in calcium homeostasis, and increased production of normal and/or folding-defective proteins all contribute to the accumulation of misfolded proteins in the ER, causing ER stress. The adaptive response to ER stress is the activation of unfolded protein response (UPR), which affect a wide variety of cellular functions to maintain ER homeostasis or lead to apoptosis. Three different ER transmembrane sensors, including PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1), are responsible for initiating UPR. The UPR involves a variety of signal transduction pathways that reduce unfolded protein accumulation by boosting ER-resident chaperones, limiting protein translation, and accelerating unfolded protein degradation. ER is now acknowledged as a critical organelle in sensing dangers and determining cell life and death. On the other hand, UPR plays a critical role in the development and progression of several diseases such as cardiovascular diseases (CVD), metabolic disorders, chronic kidney diseases, neurological disorders, and cancer. Here, we critically analyze the most current knowledge of the master regulatory roles of ER stress particularly the PERK pathway as a conditional danger receptor, an organelle crosstalk regulator, and a regulator of protein translation. We highlighted that PERK is not only ER stress regulator by sensing UPR and ER stress but also a frontier sensor and direct senses for gut microbiota-generated metabolites. Our work also further highlighted the function of PERK as a central hub that leads to metabolic reprogramming and epigenetic modification which further enhanced inflammatory response and promoted trained immunity. Moreover, we highlighted the contribution of ER stress and PERK in the pathogenesis of several diseases such as cancer, CVD, kidney diseases, and neurodegenerative disorders. Finally, we discuss the therapeutic target of ER stress and PERK for cancer treatment and the potential novel therapeutic targets for CVD, metabolic disorders, and neurodegenerative disorders. Inhibition of ER stress, by the development of small molecules that target the PERK and UPR, represents a promising therapeutic strategy.

Emerging role and mechanism of HACE1 in the pathogenesis of neurodegenerative diseases: A promising target.

HACE1 is a member of the HECT domain-containing E3 ligases with 909 amino acid residues, containing N-terminal ankyrin-repeats (ANK) and C-terminal HECT domain. Previously, it was shown that HACE1 is inactive in human tumors and plays a crucial role in the initiation, progression, and invasion of malignant tumors. Recent studies indicated that HACE1 might be closely involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. HACE1 interacts with its substrates, including Ras-related C3 botulinum toxin substrate 1 (Rac1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumor necrosis factor receptor (TNFR), and optineurin (OPTN), through which participates in several pathophysiological processes, such as oxidative stress, autophagy and inflammation. Therefore, in this review, we elaborately describe the essential substrates of HACE1 and illuminate the pathophysiological processes by which HACE1 is involved in neurodegenerative diseases. We provide a new molecular target for neurodegenerative diseases.

Iron Overload in Brain: Transport Mismatches, Microbleeding Events, and How Nanochelating Therapies May Counteract Their Effects.

Iron overload in many brain regions is a common feature of aging and most neurodegenerative diseases. In this review, the causes, mechanisms, mathematical models, and possible therapies are summarized. Indeed, physiological and pathological conditions can be investigated using compartmental models mimicking iron trafficking across the blood-brain barrier and the Cerebrospinal Fluid-Brain exchange membranes located in the choroid plexus. In silico models can investigate the alteration of iron homeostasis and simulate iron concentration in the brain environment, as well as the effects of intracerebral iron chelation, determining potential doses and timing to recover the physiological state. Novel formulations of non-toxic nanovectors with chelating capacity are already tested in organotypic brain models and could be available to move from in silico to in vivo experiments.

Therapeutic effects of resveratrol on epigenetic mechanisms in age-related diseases: A comprehensive review.

Recently, various studies have shown that epigenetic changes are associated with aging and age-related diseases. Both animal and human models have revealed that epigenetic processes are involved in aging mechanisms. These processes happen at multiple levels and include histone modification, DNA methylation, and changes in noncoding RNA expression. Consequently, changes in the organization of chromatin and DNA accessibility lead to the regulation of gene expression. With increasing awareness of the pivotal function of epigenetics in the aging process, researchers' attention has been drawn to how these epigenetic changes can be modified to prevent, stop, or reverse aging, senescence, and age-related diseases. Among various agents that can affect epigenetic, polyphenols are well-known phytochemicals found in fruits, vegetables, and plants. Polyphenols are found to modify epigenetic-related mechanisms in various diseases and conditions, such as metabolic disorders, obesity, neurodegenerative diseases, cancer, and cardiovascular diseases. Resveratrol (RSV) is a member of the stilbene subgroup of polyphenols which is derived from various plants, such as grapes, apples, and blueberries. Therefore, herein, we aim to summarize how RSV affects different epigenetic processes to change aging-related mechanisms. Furthermore, we discuss its roles in age-related diseases, such as Alzheimer's, Parkinson's, osteoporosis, and cardiovascular diseases.

Cynaroside extends lifespan and improves the neurondegeneration diseases via insulin/IGF-1 signaling pathway in Caenorhabditis elegans.

The evolutionarily conserved insulin/IGF-1 signaling pathway plays a central role in aging and aging related diseases such as neurodegeneration diseases. Inhibition of insulin/IGF-1 signaling pathway has been proposed as an effective way to extend lifespan and delay neurodegeneration diseases in different organisms. Cynaroside (Cyn), a flavonoid contained in many medical plants and in vegetables, had been shown to exhibit pharmacological properties such as anti-inflammatory, anti-tumor, and anti-oxidant effects. The study demonstrated that lifespan extension and neurodegeneration diseases improving could be achieved by targeting evolutionarily conserved insulin/IGF-1 pathway through using pharmacological interventions. Via using this approach in tractable model Caenorhabditis elegans, we found that 10 µM Cynaroside significantly promoted the healthy lifespan in wild-type animals. Furthermore, via genetic screen, we showed that Cynaroside acted on IGF-1-R /DAF-2, which was followed by the activation of transcription factor DAF-16/FOXO to extend the healthy lifespan. Intriguingly, Cynaroside also improved neurodegeneration diseases such as Alzheimer's and polyglutamine disease by suppressing insulin/IGF-1 signaling pathway. Our work suggests that Cynaroside may be a promising candidate for the prevention and treatment of aging and neurodegeneration diseases.

Molecular interplay between phytoconstituents of Ficus Racemosa and neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a significant global health concern, primarily affecting middle and older populations. Recently, there has been growing interest in herbal therapeutics as a potential approach to address diverse neuropathological conditions. Despite the widespread prevalence of NDs, limited phytochemical has been reported for their promising therapeutic potential with distinct underlying mechanisms. Additionally, the intricate molecular pathways influenced by herbal phytoconstituents, particularly in neurodegenerative disorders, are also not well documented. This report explores the phytoconstituents of Ficus racemosa (F. racemosa), an unfamiliar plant of the Moraceae family, for their potential interactions with pathological pathways of NDs. The influential phytoconstituents of F. racemosa, including polyphenols, glycosides, terpenoids, and furocoumarin, have been reported for targeting diverse pathological states. We proposed the most convincing molecular interplay between leading phytoconstituents and detrimental signalling cascades. However, extensive research is required to thoroughly understand the phytochemical persuaded intricate molecular pathway. The comprehensive evidence strongly suggests that F. racemosa and its natural compounds could be valuable in treating NDs. This points towards an exciting path for future research and the development of potential treatments based on a molecular level.

Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence.

Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.

Nano Lipid Carriers as a Promising Drug Delivery Carrier for Neurodegenerative Disorders - An Overview of Recent Advances.

The last few decades have seen a rise in the number of deaths caused by neurological disorders. The blood-brain barrier (BBB), which is very complex and has multiple mechanisms, makes drug delivery to the brain challenging for many scientists. Lipid nanoparticles (LNPs) such as nanoemulsions, solid-lipid nanoparticles, liposomes, and nano lipid carriers (NLCs) exhibit enhanced bioavailability and flexibility among these nanocarriers. NLCs are found to be very effective. In the last few decades, they have been a center of attraction for controlled drug delivery. According to the current global status of specific neurological disorders, out of all LNPs, NLC significantly reduces the cross-permeability of drugs through the BBB due to their peculiar properties. They offer a host of advantages over other carriers because of their biocompatibility, safety, non-toxicity, non-irritating behavior, stability, high encapsulation efficiency, high drug loading, high drug targeting, control of drug release, and ease in manufacturing. The biocompatible lipid matrix is ideally suited as a drug carrier system due to the nano-size range. For certain neurological conditions such as Parkinsonism, Alzheimer's, Epilepsy, Multiple sclerosis, and Brain cancer, we examined recent advances in NLCs to improve brain targeting of bioactive with special attention to formulation aspects and pharmacokinetic characteristics. This article also provides a brief overview of a critical approach for brain targeting, i.e., direct nose-to-brain drug delivery and some recent patents published on NLC".

Characterizing fibril morphological changes by spirooxindoles for neurodegenerative disease application.

Fibrillation of proteins and polypeptides, which leads to the deposition of plaques in cells and tissues has been widely associated with many neuropathological diseases. Inhibition of protein misfolding and aggregation is crucial for the prevention and treatment of these conditions. The growing interest in identifying inhibitor molecules to prevent the formation of fibrils in vivo has led to the results highlighted in this study. Due to their hydrophobic structure and potential to readily cross the blood brain barrier, a library of spirooxindole compounds were synthesized with those labelled Hd-63, Hd-66 and Hd-74 proving to be the most potent against fibril formation. Our spectroscopic analysis provides detailed insight, that the introduction of these spirooxindole compounds leads to morphological changes in the mechanism of fibril formation which prevent the formation of highly ordered fibrils, instead results in the formation of disordered aggregates which are not fibrillar in nature.

Effect of Hydroxytyrosol Derivatives of Donepezil on the Activity of Enzymes Involved in Neurodegenerative Diseases and Oxidative Damage.

Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer's disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress.

Yet another in vitro evidence that natural compounds introduced by diet have anti-amyloidogenic activities and can counteract neurodegenerative disease depending on aging.

A major issue in Alzheimer's disease (AD) research is to find some new therapeutic drug which decrease Amyloid-beta (Aß) aggregation. From a therapeutic point of view the major question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease. Natural compounds are capable of binding to different targets implicated in AD and exert neuroprotective effects. Aim of this study was to evaluate the in vitro inhibition of Aß1-42 fibrillogenesis in presence of Gallic acid, Rutin, Melatonin and ProvinolsTM . We performed the analysis with Transmission and Scanning Electron Microscopy, and with X-ray microanalysis. Samples treated with Rutin, that arises from phenylalanine via the phenylpropanoid pathway, show the best effective result obtained because a significantly fibril inhibition activity is detectable compared to the other compounds. Melatonin shows a better inhibitory activity than ProvinolsTM and Gallic acid at the considered concentrations.

Structure-Activity Relationships and Therapeutic Potential of Purinergic P2X7 Receptor Antagonists.

The purinergic P2X7 receptor (P2X7R), an ATP-gated non-selective cation channel, has emerged as a gatekeeper of inflammation that controls the release of proinflammatory cytokines. As a key player in initiating the inflammatory signaling cascade, the P2X7 receptor is currently under intense scrutiny as a target for the treatment of different pathologies, including chronic inflammatory disorders (rheumatoid arthritis and osteoarthritis), chronic neuropathic pain, mood disorders (depression and anxiety), neurodegenerative diseases, ischemia, cancer (leukemia), and many others. For these reasons, pharmaceutical companies have invested in discovering compounds able to modulate the P2X7R and filed many patent applications. This review article presents an account of P2X7R structure, function, and tissue distribution, emphasizing its role in inflammation. Next, we illustrate the different chemical classes of non-competitive P2X7R antagonists reported by highlighting their properties and qualities as clinical candidates for treating inflammatory disorders and neurodegenerative diseases. We also discuss the efforts to develop effective Positron Emission Tomography (PET) radioligands to progress the understanding of the pathomechanisms of neurodegenerative disorders, to provide evidence of drug-target engagement, and to assist clinical dose selection for novel drug therapies.

Identifying potential neuroprotective polyphenols targeting endoplasmic reticulum stress through an in silico approach.

The endoplasmic reticulum (ER) is essential in many cellular processes, including protein processing, lipid metabolism, and calcium storage. Dysregulation of ER function has been linked with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, etc. The primary pathological alteration explicated in the diseases is the accumulation of misfolded proteins in the neuronal cells. ER stress-associated activation of PERK-mediated pro-apoptotic cell death leads to neurodegeneration. In this study, we have primarily screened the potential polyphenols evidenced for neuroprotective activity. The 24 polyphenols were selected to explore their binding affinity towards various proteins of ER cascade such as pPERK (phospho-PERK), EIF2 (Eukaryotic Initiation Factor 2), and ATF4 (Activating Transcription Factor 4). On the basis of binding affinity, four phytopolyphenols were further selected for in-silico ADMET and molecular dynamic simulation. Among them curcumin found to be the most promising and serve as a potential hit against all three targets of ER cascade. The selected proteins' active site has demonstrated high stability of curcumin binding according to molecular dynamics findings. Though curcumin exhibited a significant hit in interaction with targets but needs to be further improved in drug-ability criteria. Thus, seventy derivatives of curcumin scaffold (from the published literature) were also screened with improve in druggability criteria, which showed good interaction with unfolded protein response related targets. The new scaffolds serve considerable potential to be developed as novel polyphenolic lead for neurodegenerative disorders.Communicated by Ramaswamy H. Sarma.