Glutathione in Brain Disorders and Aging

Glutathione is a remarkably functional molecule with diverse features, which include being an antioxidant, a regulator of DNA synthesis and repair, a protector of thiol groups in proteins, a stabilizer of cell membranes, and a detoxifier of xenobiotics. Glutathione exists in two states—oxidized and reduced. Under normal physiological conditions of cellular homeostasis, glutathione remains primarily in its reduced form. However, many metabolic pathways involve oxidization of glutathione, resulting in an imbalance in cellular homeostasis. Impairment of glutathione function in the brain is linked to loss of neurons during the aging process or as the result of neurological diseases such as Huntington’s disease, Parkinson’s disease, stroke, and Alzheimer’s disease. The exact mechanisms through which glutathione regulates brain metabolism are not well understood. In this review, we will highlight the common signaling cascades that regulate glutathione in neurons and glia, its functions as a neuronal regulator in homeostasis and metabolism, and finally a mechanistic recapitulation of glutathione signaling. Together, these will put glutathione’s role in normal aging and neurological disorders development into perspective.     

Neuroprotective Potential of Chrysin: Mechanistic Insights and Therapeutic Potential for Neurological Disorders

Chrysin, a herbal bioactive molecule, exerts a plethora of pharmacological effects, including anti-oxidant, anti-inflammatory, neuroprotective, and anti-cancer. A growing body of evidence has highlighted the emerging role of chrysin in a variety of neurological disorders, including Alzheimer’s and Parkinson’s disease, epilepsy, multiple sclerosis, ischemic stroke, traumatic brain injury, and brain tumors. Based on the results of recent pre-clinical studies and evidence from studies in humans, this review is focused on the molecular mechanisms underlying the neuroprotective effects of chrysin in different neurological diseases. In addition, the potential challenges, and opportunities of chrysin’s inclusion in the neurotherapeutics repertoire are critically discussed.     

Synthesis,Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs 1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC₅₀ = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC₅₀ = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs 1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.     

Effects of Grape Polyphenols on the Life Span and Neuroinflammatory Alterations Related to Neurodegenerative Parkinson Disease-Like Disturbances in Mice

Functional nutrition is a valuable supplementation to dietary therapy. Functional foods are enriched with biologically active substances. Plant polyphenols attract particular attention due to multiple beneficial properties attributed to their high antioxidant and other biological activities. We assessed the effect of grape polyphenols on the life span of C57BL/6 mice and on behavioral and neuroinflammatory alterations in a transgenic mouse model of Parkinson disease (PD) with overexpression of the A53T-mutant human α-synuclein. C57BL/6 mice were given a dietary supplement containing grape polyphenol concentrate (GPC—1.5 mL/kg/day) with drinking water from the age of 6–8 weeks for life. Transgenic PD mice received GPC beginning at the age of 10 weeks for four months. GPC significantly influenced the cumulative proportion of surviving and substantially augmented the average life span in mice. In the transgenic PD model, the grape polyphenol (GP) diet enhanced memory reconsolidation and diminished memory extinction in a passive avoidance test. Behavioral effects of GP treatment were accompanied by a decrease in α-synuclein accumulation in the frontal cortex and a reduction in the expression of neuroinflammatory markers (IBA1 and CD54) in the frontal cortex and hippocampus. Thus, a GP-rich diet is recommended as promising functional nutrition for aging people and patients with neurodegenerative disorders.     

Potential Therapeutic Benefits of Honey in Neurological Disorders: The Role of Polyphenols

Honey is the principal premier product of beekeeping familiar to Homo for centuries. In every geological era and culture, evidence can be traced to the potential usefulness of honey in several ailments. With the advent of recent scientific approaches, honey has been proclaimed as a potent complementary and alternative medicine for the management and treatment of several maladies including various neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, etc. In the literature archive, oxidative stress and the deprivation of antioxidants are believed to be the paramount cause of many of these neuropathies. Since different types of honey are abundant with certain antioxidants, primarily in the form of diverse polyphenols, honey is undoubtedly a strong pharmaceutic candidate against multiple neurological diseases. In this review, we have indexed and comprehended the involved mechanisms of various constituent polyphenols including different phenolic acids, flavonoids, and other phytochemicals that manifest multiple antioxidant effects in various neurological disorders. All these mechanistic interpretations of the nutritious components of honey explain and justify the potential recommendation of sweet nectar in ameliorating the burden of neurological disorders that have significantly increased across the world in the last few decades.     

In Vitro Studies on Therapeutic Effects of Cannabidiol in Neural Cells: Neurons,Glia, and Neural Stem Cells

(‒)-Cannabidiol (CBD) is one of the major phytocannabinoids extracted from the Cannabis genus. Its non-psychoactiveness and therapeutic potential, partly along with some anecdotal—if not scientific or clinical—evidence on the prevention and treatment of neurological diseases, have led researchers to investigate the biochemical actions of CBD on neural cells. This review summarizes the previously reported mechanistic studies of the CBD actions on primary neural cells at the in vitro cell-culture level. The neural cells are classified into neurons, microglia, astrocytes, oligodendrocytes, and neural stem cells, and the CBD effects on each cell type are described. After brief introduction on CBD and in vitro studies of CBD actions on neural cells, the neuroprotective capability of CBD on primary neurons with the suggested operating actions is discussed, followed by the reported CBD actions on glia and the CBD-induced regeneration from neural stem cells. A summary section gives a general overview of the biochemical actions of CBD on neural cells, with a future perspective. This review will provide a basic and fundamental, but crucial, insight on the mechanistic understanding of CBD actions on neural cells in the brain, at the molecular level, and the therapeutic potential of CBD in the prevention and treatment of neurological diseases, although to date, there seem to have been relatively limited research activities and reports on the cell culture-level, in vitro studies of CBD effects on primary neural cells.     

The Therapeutic Potential of Celastrol in Central Nervous System Disorders: Highlights from In Vitro and In Vivo Approaches

Celastrol, the most abundant compound derived from the root of Tripterygium wilfordii, largely used in traditional Chinese medicine, has shown preclinical and clinical efficacy for a broad range of disorders, acting via numerous mechanisms, including the induction of the expression of several neuroprotective factors, the inhibition of cellular apoptosis, and the decrease of reactive oxygen species (ROS). Given the crucial implication of these pathways in the pathogenesis of Central Nervous System disorders, both in vitro and in vivo studies have focused their attention on the possible use of this compound in these diseases. However, although most of the available studies have reported significant neuroprotective effects of celastrol in cellular and animal models of these pathological conditions, some of these data could not be replicated. This review aims to discuss current in vitro and in vivo lines of evidence on the therapeutic potential of celastrol in neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, and cadmium-induced neurodegeneration, as well as in psychiatric disorders, such as psychosis and depression. In vitro and in vivo studies focused on celastrol effects in cerebral ischemia, ischemic stroke, traumatic brain injury, and epilepsy are also described.     

Synthesis and Biological Evaluation of Halogenated E-Stilbenols as Promising Antiaging Agents

The increased risk of illness and disability is related to the age inevitable biological changes. Oxidative stress is a proposed mechanism for many age-related diseases. The crucial importance of polyphenol pharmacophore for aging process is largely described thanks to its effects on concentrations of reactive oxygen species. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RSV) plays a critical role in slowing the aging process but has a poor bioavailabity after oral intake. In this present work, a series of RSV derivatives was designed, synthesized, and evaluated as potential antioxidant agents. These derivatives contain substituents with different electronic and steric properties in different positions of aromatic rings. This kind of substituents affects the activity and the bioavailability of these compounds compared with RSV used as reference compound. Studies of Log P values demonstrated that the introduction of halogens gives the optimum lipophilicity to be considered promising active agents. Among them, compound 6 showed the higher antioxidant activity than RSV. The presence of trifluoromethyl group together with a chlorine atom increased the antioxidant activity compared to RSV.     

Evaluation of the Antioxidant Activity of Nigella sativa L. and Allium ursinum Extracts in a Cellular Model of Doxorubicin-Induced Cardiotoxicity

Natural products black cumin—Nigella sativa (N. sativa) and wild garlic—Allium ursinum (AU) are known for their potential role in reducing cardiovascular risk factors, including antracycline chemotherapy. Therefore, this study investigates the effect of N. sativa and AU water and methanolic extracts in a cellular model of doxorubicin (doxo)-induced cardiotoxicity. The extracts were characterized using Ultraviolet-visible (UV-VIS) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, Liquid Chromatography coupled with Mass Spectrometry (LC-MS) and Gas Chromatography coupled with Mass Spectrometry (GC-MS) techniques. Antioxidant activity was evaluated on H9c2 cells. Cytosolic and mitochondrial reactive oxygen species (ROS) release was evaluated using 2′,7′-dichlorofluorescin-diacetate (DHCF-DA) and mitochondria-targeted superoxide indicator (MitoSOX red), respectively. Mitochondrial membrane depolarization was evaluated by flow cytometry. LC-MS analysis identified 12 and 10 phenolic compounds in NSS and AU extracts, respectively, with flavonols as predominant compounds. FT-IR analysis identified the presence of carbohydrates, amino acids and lipids in both plants. GC-MS identified the sulfur compounds in the AU water extract. N. sativa seeds (NSS) methanolic extract had the highest antioxidant activity reducing both intracellular and mitochondrial ROS release. All extracts (excepting AU methanolic extract) preserved H9c2 cells viability. None of the investigated plants affected the mitochondrial membrane depolarization. N. sativa and AU are important sources of bioactive compounds with increased antioxidant activities, requiring different extraction solvents to obtain the pharmacological effects.     

The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders

Somatostatin (SST) is a well-known neuropeptide that is expressed throughout the brain. In the cortex, SST is expressed in a subset of GABAergic neurons and is known as a protein marker of inhibitory interneurons. Recent studies have identified the key functions of SST in modulating cortical circuits in the brain and cognitive function. Furthermore, reduced expression of SST is a hallmark of various neurological disorders, including Alzheimer’s disease and depression. In this review, we summarize the current knowledge on SST expression and function in the brain. In particular, we describe the physiological roles of SST-positive interneurons in the cortex. We further describe the causal relationship between pathophysiological changes in SST function and various neurological disorders, such as Alzheimer’s disease. Finally, we discuss potential treatments and possibility of novel drug developments for neurological disorders based on the current knowledge on the function of SST and SST analogs in the brain derived from experimental and clinical studies.Subject terms: Molecular neuroscience, Drug development     

Phytochemical Investigation and Biological Activities of Lantana rhodesiensis

Lantana rhodesiensis Moldenke is a plant widely used to treat diseases, such as rheumatism, diabetes, and malaria in traditional medicine. To better understand the traditional uses of this plant, a phytochemical study was undertaken, revealing a higher proportion of polyphenols, including flavonoids in L. rhodesiensis leaf extract and moderate proportion in stem and root extracts. The antioxidant activity of the extracts was also determined using three different assays: the radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, the FRAP method (Ferric-reducing antioxidant power) and the β-carotene bleaching test. The anti-malarial activity of each extract was also evaluated using asexual erythrocyte stages of Plasmodium falciparum, chloroquine-sensitive strain 3D7. The results showed that the leaf extract exhibited higher antioxidant and anti-malarial activities in comparison with the stem and root extracts, probably due to the presence of higher quantities of polyphenols including flavonoids in the leaves. A positive linear correlation was established between the phenolic compound content (total polyphenols including flavonoids and tannins; and total flavonoids) and the antioxidant activity of all extracts. Furthermore, four flavones were isolated from leaf dichloromethane and ethyl acetate fractions: a new flavone named rhodescine (5,6,3′,5′-tetrahydroxy-7,4′-dimethoxyflavone) (1), 5-hydroxy-6,7,3′,4′,5′-pentamethoxyflavone (2), 5-hydroxy-6,7,3′,4′-tetramethoxyflavone (3), and 5,6,3′-trihydroxy-7,4′-dimethoxyflavone (4). Their structures were elucidated by ¹H, ¹³CNMR, COSY, HSQC, HMBC, and MS-EI spectral methods. Aside from compound 2, all other molecules were described for the first time in this plant species.     

Pharmacological,Neurochemical, and Behavioral Mechanisms Underlying the Anxiolytic- and Antidepressant-like Effects of Flavonoid Chrysin

Chrysin (5,7-dihydroxyflavone) is a flavonoid isolated from plants, such as Passiflora coerulea, Passiflora incarnata, and Matricaria chamomilla. This natural molecule exerts diverse pharmacological effects, which includes antioxidant, anti-inflammatory, anti-cancer, neuroprotective, and anti-apoptotic effects. Additionally, in brain structures, such as the hippocampus, prefrontal cortex, raphe nucleus, and striatum, involved in the physiopathology of anxiety and depression disorders, several neuropharmacological activities, including the activation of neurotransmitter systems (GABAergic, serotonergic, dopaminergic, and noradrenergic), neurotrophic factors, such as brain-derived neurotrophic factor and the nerve growth factor, and some signaling pathways are affected. The results showed that the anxiolytic and antidepressant-like effects of chrysin occurs through its interaction with specific neurotransmitter systems, principally the GABAergic and the serotonergic, and activation of other neurotrophic factors. However, it is not possible to discard the antioxidant and anti-inflammatory activities of chrysin while producing its anxiolytic- and antidepressant-like effects. Although these results have been obtained principally from pre-clinical research, they consistently demonstrate the potential therapeutic use of flavonoid chrysin as an anxiolytic and antidepressant agent. Therefore, this flavonoid could be considered as a promising novel therapy for anxiety and depression disorders.     

Neuroprotective Effect of Gallocatechin Gallate on Glutamate-Induced Oxidative Stress in Hippocampal HT22 Cells

Oxidative stress leads to protein degeneration or mitochondrial dysfunction, causing neuronal cell death. Glutamate is a neurotransmitter that nerve cells use to send signals. However, the excess accumulation of glutamate can cause excitotoxicity in the central nervous system. In this study, we deciphered the molecular mechanism of catechin-mediated neuroprotective effect on glutamate-induced oxidative stress in mouse hippocampal neuronal HT22 cells. Cellular antioxidant activity was determined using the 1,1-diphenyl-picryl hydrazyl (DPPH) assay and 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) staining. Furthermore, the levels of intracellular calcium (Ca²⁺) as well as nuclear condensation and protein expression related to neuronal damage were assessed. All five catechins (epigallocatechin gallate, gallocatechin gallate (GCG), gallocatechin, epicatechin gallate, and epicatechin) showed strong antioxidant effects. Among them, GCG exhibited the highest neuroprotective effect against glutamate excitotoxicity and was used for further mechanistic studies. The glutamate-induced increase in intracellular Ca²⁺ was reduced after GCG treatment. Moreover, GCG reduced nuclear condensation and the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinases (JNK) involved in cell death. The neuroprotective effect of GCG against glutamate-induced oxidative stress in HT22 cells was attributed to the reduction in intracellular free radicals and Ca²⁺ influx and also the inhibition of phosphorylation of ERK and JNK. Furthermore, the antioxidant effect of GCG was found to be likely due to the inhibition of phosphorylation of ERK and JNK that led to the effective suppression of neurocytotoxicity caused by glutamate in HT22 cells.     

Melissa officinalis L. Aqueous Extract Exerts Antioxidant and Antiangiogenic Effects and Improves Physiological Skin Parameters

Melissa officinalis (MO) is a medicinal plant well-known for its multiple pharmacological effects, including anti-inflammatory, anticancer and beneficial effects on skin recovery. In this context, the present study was aimed to investigate the in vitro and in vivo safety profile of an MO aqueous extract by assessing cell viability on normal (HaCaT—human keratinocytes) and tumor (A375—human melanoma) cells and its impact on physiological skin parameters by a non-invasive method. In addition, the antioxidant activity and the antiangiogenic potential of the extract were verified. A selective cytotoxic effect was noted in A375 cells, while no toxicity was noticed in healthy cells. The MO aqueous extract safety profile after topical application was investigated on SKH-1 mice, and an enhanced skin hydration and decreased erythema and transepidermal water loss levels were observed. The in ovo CAM assay, performed to investigate the potential modulating effect on the angiogenesis process and the blood vessels impact, indicated that at concentrations of 100 and 500 µg/mL, MO aqueous extract induced a reduction of thin capillaries. No signs of vascular toxicity were recorded at concentrations as high as 1000 μg/mL. The aqueous extract of MO leaves can be considered a promising candidate for skin disorders with impaired physiological skin parameters.     

Interactions of Ascorbic Acid, 5-Caffeoylquinic Acid,and Quercetin-3-Rutinoside in the Presence and Absence of Iron during Thermal Processing and the Influence on Antioxidant Activity

Bioactive compounds in fruit and vegetables influence each other’s antioxidant activity. Pure standards, and mixtures of the common plant compounds, namely ascorbic acid, 5-caffeoylquinic acid, and quercetin-3-rutinoside (sum 0.3 mM), in the presence and absence of iron, were analyzed pre- and post-thermal processing in an aqueous solution. Antioxidant activity was measured by total phenolic content (TPC), 1,1-diphenyl-2-picrylhydrazyl (DPPH), and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (TEAC) radical-scavenging assays. Ionic ferrous iron (Fe²⁺) and ferric iron (Fe³⁺) were measured photometrically. For qualification and quantification of reaction products, HPLC was used. Results showed that thermal processing does not necessarily lead to a decreased antioxidant activity, even if the compound concentrations decreased, as then degradation products themselves have an antioxidant activity. In all used antioxidant assays the 2:1 ratio of ascorbic acid and 5-caffeoylquinic acid in the presence of iron had strong synergistic effects, while the 1:2 ratio had strong antagonistic effects. The pro-oxidant iron positively influenced the antioxidant activity in combination with the used antioxidants, while ferrous iron itself interacted with common in vitro assays for total antioxidant activity. These results indicate that the antioxidant activity of compounds is influenced by factors such as interaction with other molecules, temperature, and the minerals present.     

The Potential Effects of Phytoestrogens: The Role in Neuroprotection

Phytoestrogens are naturally occurring non-steroidal phenolic plant compounds. Their structure is similar to 17-β-estradiol, the main female sex hormone. This review offers a concise summary of the current literature on several potential health benefits of phytoestrogens, mainly their neuroprotective effect. Phytoestrogens lower the risk of menopausal symptoms and osteoporosis, as well as cardiovascular disease. They also reduce the risk of brain disease. The effects of phytoestrogens and their derivatives on cancer are mainly due to the inhibition of estrogen synthesis and metabolism, leading to antiangiogenic, antimetastatic, and epigenetic effects. The brain controls the secretion of estrogen (hypothalamus-pituitary-gonads axis). However, it has not been unequivocally established whether estrogen therapy has a neuroprotective effect on brain function. The neuroprotective effects of phytoestrogens seem to be related to both their antioxidant properties and interaction with the estrogen receptor. The possible effects of phytoestrogens on the thyroid cause some concern; nevertheless, generally, no serious side effects have been reported, and these compounds can be recommended as health-promoting food components or supplements.     

Study of Neuroprotection by a Combination of the Biological Antioxidant (Eucalyptus Extract) and the Antihypertensive Drug Candesartan against Chronic Cerebral Ischemia in Rats

Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus. Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits (p < 0.001) than the treatment with Eucalyptus or Candesartan alone (p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.     

Bioactivity of Two Polyphenols Quercetin and Fisetin against Human Gastric Adenocarcinoma AGS Cells as Affected by Two Coexisting Proteins

It is recognized that minor dietary components polyphenols have anticancer effects on digestive tract, lung, leukemia, and other cancers, while polyphenols also can covalently or noncovalently interact with major dietary components proteins such as casein, soybean proteins, whey proteins, and bovine serum albumin. Thus, whether the noncovalent interaction between the molecules of two polyphenols (quercetin and fisetin) and two proteins (bovine serum albumin and casein) has positive or negative impact on anticancer activities of the polyphenols against human gastric adenocarcinoma AGS cells was assessed in this study. The two polyphenols had obvious anticancer activities to the cells, because dose levels as low as 20–160 μmol/L caused reduced cell viability of 30.0–69.4% (quercetin) and 24.6–63.1% (fisetin) (using a cell treatment time of 24 h), or 9.9–48.6% (quercetin) and 6.4–29.9% (fisetin) (using a cell treatment time of 48 h). However, the cell treatments by the polyphenols in the presence of the two proteins mostly caused lower polyphenol activity toward the cells, compared with those treatments by the polyphenols in the absence of the proteins. Specifically, the presence of the proteins led to reduced growth inhibition in the cells, because higher cell viability of 33.2–86.7% (quercetin) and 29.1–77.7% (fisetin) at 24 h, or 14.1–66.8% (quercetin) and 7.9–59.0% (fisetin) at 48 h, were measured in these treated cells. The two coexisting proteins also yielded the polyphenol-treated cells with less mitochondrial membrane potential loss, less formation of reactive oxygen species, and decreased cell apoptosis. Thus, it is highlighted that the noncovalent interaction between dietary polyphenols and proteins resulted in weakened anticancer ability for the polyphenols to the gastric cancer cells.