ABSTRACT
Alzheimer's disease severely perturbs transition metal homeostasis in the brain leading to the accumulation of excess metals in extracellular and intraneuronal locations. The amyloid beta protein binds these transition metals, ultimately causing severe oxidative stress in the brain. Metal chelation therapy is an approach to sequester metals from amyloid beta and relieve the oxidative stress. Here we have designed a mixed N/O donor Cu chelator inspired by the proposed ligand set of Cu in amyloid beta. We demonstrate that the chelator effectively removes Cu from amyloid beta and suppresses reactive oxygen species (ROS) production by redox silencing and radical scavenging both inâ vitro and in cellulo. The impact of ROS on the extent of oxidation of the different aggregated forms of the peptide is studied by mass spectrometry, which, along with other ROS assays, shows that the oligomers are pro-oxidants in nature. The aliphatic Leu34, which was previously unobserved, has been identified as a new oxidation site.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Chelating Agents/pharmacology , Copper/pharmacology , Reactive Oxygen Species/antagonists & inhibitors , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Chelating Agents/chemical synthesis , Chelating Agents/chemistry , Copper/chemistry , Humans , Ligands , Reactive Oxygen Species/metabolismABSTRACT
Osteoporosis is a disease, which causes huge economic and social burden. Using natural compound to treat such disease is beneficial for the fewer side effects and effectiveness. D-(-)-salicin (DSA) is a component extracted from the bark of Populus and Salix species. In our research, we discovered that DSA suppressed RANKL-induced differentiation of osteoclast in vitro in a dose-dependent manner. It was also found that the mineral resorbing activity by osteoclasts was depressed via DSA. For the mechanism, we confirmed the inhibitory effect, by which DSA suppressed osteoclast formation and function, was through the inhibition of ROS signaling, MAPK and NF-κB cascades. DSA also suppressed the expression and activity of NFATc1. Therefore, by inhibiting the ROS production, MAPK and NF-κB signal cascade, DSA inhibited the osteoclast differentiation and function in vitro.
Subject(s)
Benzyl Alcohols/pharmacology , Glucosides/pharmacology , Osteoclasts/drug effects , Populus/chemistry , Signal Transduction/drug effects , Actins , Animals , Blotting, Western , Cell Differentiation , Cyclooxygenase Inhibitors/pharmacology , Femur/cytology , Gene Expression/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Osteoclasts/cytology , Osteoclasts/physiology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Sincalide , Tibia/cytologyABSTRACT
Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders worldwide. It is caused by the degeneration of dopaminergic neurons from the substantia nigra pars compacta. This neuronal loss causes the dopamine deficiency that leads to a series of functional changes within the basal ganglia, producing motor control abnormalities. L-DOPA is considered the gold standard for PD treatment, and it may alleviate its clinical manifestations for some time. However, its prolonged administration produces tolerance and several severe side effects, including dyskinesias and gastrointestinal disorders. Thus, there is an urgent need to find effective medications, and current trends have proposed some natural products as emerging options for this purpose. Concerning this, curcumin represents a promising bioactive compound with high therapeutic potential. Diverse studies in cellular and animal models have suggested that curcumin could be employed for the treatment of PD. Therefore, the objective of this narrative mini-review is to present an overview of the possible therapeutic effects of curcumin and the subjacent molecular mechanisms. Moreover, we describe several possible nanocarrier-based approaches to improve the bioavailability of curcumin and enhance its biological activity.
Subject(s)
Brain/drug effects , Curcumin/administration & dosage , Nanoparticles/administration & dosage , Parkinson Disease/drug therapy , Animals , Biological Availability , Brain/metabolism , Curcumin/chemistry , Curcumin/pharmacokinetics , Drug Liberation , Glutathione Peroxidase/metabolism , Humans , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/metabolism , Nanoparticles/chemistry , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Parkinson Disease/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Treatment Outcome , Up-Regulation/drug effectsABSTRACT
Cancer, a fatal disease, is also one of the main causes of death worldwide. Despite various developments to prevent and treat cancer, the side effects of anticancer drugs remain a major concern. Ascorbic acid is an essential vitamin required by our bodies for normal physiological function and also has antioxidant and anticancer activity. Although the body cannot synthesize ascorbic acid, it is abundant in nature through foods and other natural sources and also exists as a nutritional food supplement. In anticancer drug development, ascorbic acid has played an important role by inhibiting the development of cancer through various mechanisms, including scavenging reactive oxygen species (ROS), selectively producing ROS and encouraging their cytotoxicity against tumour cells, preventing glucose metabolism, serving as an epigenetic regulator, and regulating the expression of HIF in tumour cells. Several ascorbic acid analogues have been produced to date for their anticancer and antioxidant activity. The current review summarizes the mechanisms behind ascorbic acid's antitumor activity, presents a compilation of its derivatives and their biological activity as anticancer agents, and discusses delivery systems such as liposomes, nanoparticles against cancer, and patents on ascorbic acid as anticancer agents.
Subject(s)
Antineoplastic Agents/therapeutic use , Antioxidants/therapeutic use , Ascorbic Acid/therapeutic use , Dietary Supplements , Gene Expression Regulation, Neoplastic , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , Ascorbic Acid/analogs & derivatives , Ascorbic Acid/metabolism , Biotransformation , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Epigenesis, Genetic , Glucose Transporter Type 1/genetics , Glucose Transporter Type 1/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liposomes/administration & dosage , Liposomes/chemistry , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Patents as Topic , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal Transduction , p300-CBP Transcription Factors/genetics , p300-CBP Transcription Factors/metabolismABSTRACT
Cisplatin (CisPT) is a chemotherapeutic drug that outcomes in adverse effects. In this study, we examined the effect of A. hydaspica ethyl acetate extract (AHE) in an animal model of cisplatin-induced acute kidney injury (AKI). 36 male Sprague Dawley rats were used in the AKI rat model, and CisPT (7.5 mg/kg BW, i.p) single dose was given. In the pretreatment module, AHE (400 mg/kgBW/day, p.o) was given for 7 days before and after CisPT injection. While in the post-treatment group AHE was administered for 7 days after a single CisPT shot. The standard group received silymarin (100 mg/kg BW, p.o) for 7 days before and after CisPT injection. In HCT 116 tumor xenografts (n = 32) two groups of mice were pretreated with 400 mg/kg AHE orally for 7 days and two groups were treated with distilled water. On day 7 of pretreatment one distilled water and one AHE pretreated group were injected i.p with 15 mg/kg bw dose followed by another dose of CisPT 2 wk later. AHE groups were additionally treated with 400 mg/kg AHE for 3 days/week for 2 weeks. CisPT significantly deteriorated renal function parameters, i.e., PH, specific gravity, total protein, albumin, urea, creatinine, uric acid, globulin and blood urea nitrogen. CisPT treatment increased oxidative stress markers, while lower renal antioxidant enzymes. AHE pretreatment ameliorates significantly (p < 0.0001) CisPT-induced alterations in serum and urine markers for kidney function. Furthermore, AHE pretreatment more efficiently (p < 0.001) decreases oxidative stress markers, attenuate NF-κB, and IL-6 protein and mRNA expression by augmenting antioxidant enzyme levels compared to post-treatment. The histological observations verified the protective effect of AHE. In tumor xenograft mice, AHE treatment significantly reduced CisPT induced oxidative stress while it did not interfere with the anticancer efficacy of cisplatin as shown by significance (p < 0.001) decrease in tumor size after treatment. A. hydaspica AHE might provide a prospective adjuvant that precludes CisPT-induced nephrotoxicity without compromising its antitumor potential.
Subject(s)
Acacia/chemistry , Acetates/chemistry , Acute Kidney Injury/prevention & control , Cytokines/antagonists & inhibitors , Inflammation Mediators/antagonists & inhibitors , Plant Extracts/pharmacology , Reactive Oxygen Species/antagonists & inhibitors , Acute Kidney Injury/chemically induced , Acute Kidney Injury/metabolism , Animals , Cisplatin , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cytokines/metabolism , Disease Models, Animal , HCT116 Cells , Humans , Inflammation Mediators/metabolism , Male , Mice, Nude , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays/methodsABSTRACT
Carbon tetrachloride (CCl4) is an abundant environmental pollutant that can generate free radicals and induce oxidative stress in different human and animal organs like the kidney, lung, brain, and spleen, causing toxicity. The present study evaluated the alleviative mechanism of the isolated polyphenolic fraction from seedless (pulp and skin) black Vitis vinifera (VVPF) on systemic oxidative and necroinflammatory stress in CCl4-intoxicated rats. Here, we found that the administration of VVPF to CCl4-intoxicated rats for ten days was obviously ameliorated the CCl4-induced systemic elevation in ROS, NO and TBARS levels, as well as MPO activity. Also, it upregulated the cellular activities of the enzymatic (SOD, and GPx) and non-enzymatic (TAC and GSH) antioxidants. Furthermore, the gene expression of the ROS-related necroinflammatory mediators (NF-κB, iNOS, COX-2, and TNF-α) in the kidney, brain, and spleen, as well as IL-1ß, and IL-8 in the lung were greatly restored. The histopathological studies confirmed these biochemical results and showed a noticeable enhancing effect in the architecture of the studied organs after VVPF intake. Thus, this study indicated that VVPF had an alleviative effect on CCl4-induced necroinflammation and oxidative stress in rat kidney, lung, brain, and spleen via controlling the ROS/NF-κB pathway.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Carbon Tetrachloride Poisoning/drug therapy , NF-kappa B/antagonists & inhibitors , Phytotherapy , Polyphenols/therapeutic use , Reactive Oxygen Species/antagonists & inhibitors , Vitis/chemistry , Animals , Anti-Inflammatory Agents/isolation & purification , Antioxidants/isolation & purification , Brain/drug effects , Brain/metabolism , Carbon Tetrachloride Poisoning/metabolism , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/genetics , Cytokines/biosynthesis , Cytokines/genetics , Drug Evaluation, Preclinical , Fruit/chemistry , Inhibitory Concentration 50 , Kidney/drug effects , Kidney/metabolism , Lung/drug effects , Lung/metabolism , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Oxidative Stress/drug effects , Plant Extracts/isolation & purification , Polyphenols/chemistry , Polyphenols/isolation & purification , Rats , Signal Transduction/drug effects , Spleen/drug effects , Spleen/metabolism , Thiobarbituric Acid Reactive Substances/analysisABSTRACT
Of all types of dementia, Alzheimer's disease is the type that has the highest proportion of cases and is the cause of substantial medical and economic burden. The mechanism of Alzheimer's disease is closely associated with the aggregation of amyloid-ß protein and causes neurotoxicity and extracellular accumulation in the brain and to intracellular neurofibrillary tangles caused by tau protein hyperphosphorylation in the brain tissue. Previous studies have demonstrated that sirtuin1 downregulation is involved in the pathological mechanism of Alzheimer's disease. The decrease of sirtuin1 level would cause Alzheimer's disease by means of promoting the amyloidogenic pathway to generate amyloid-ß species and thereby triggering amyloid-ß cascade reaction, such as tau protein hyperphosphorylation, neuron autophagy, neuroinflammation, oxidative stress, and neuron apoptosis. Currently, there is no effective treatment for Alzheimer's disease, it is necessary to develop new treatment strategies. According to the theory of traditional Chinese medicine and based on the mechanism of the disease, tonifying the kidneys is one of the principles for the treatment of Alzheimer's disease and Epimedium is a well-known Chinese medicine for tonifying kidney. Therefore, investigating the influence of the components of Epimedium on the pathological characteristics of Alzheimer's disease may provide a reference for the treatment of Alzheimer's disease in the future. In this article, we summarise the effects and mechanism of icariin, the main ingredient extracted from Epimedium, in ameliorating Alzheimer's disease by regulating sirtuin1 to inhibit amyloid-ß protein and improve other amyloid-ß cascade pathogenesis.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Drugs, Chinese Herbal/therapeutic use , Flavonoids/therapeutic use , Sirtuin 1 , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Drugs, Chinese Herbal/pharmacology , Flavonoids/pharmacology , Humans , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Sirtuin 1/biosynthesisABSTRACT
Glioblastoma multiforme is one of the most deadly malignant tumors, with more than 10,000 cases recorded annually in the United States. Various clinical analyses and studies show that certain chronic diseases, including cancer, interact between cell-reactive radicals rise and pathogenesis. Reactive oxygen and nitrogenous sources include endogenous (physiological processes), and exogenous sources contain reactive oxygen and nitrogen (xenobiotic interaction). The cellular oxidation/reduction shifts to oxidative stress when the regulation mechanisms of antioxidants are surpassed, and this raises the ability to damage cellular lipids, proteins, and nucleic acids. OBJECTIVE: This review is focused on how phytochemicals play crucial role against glioblastoma multiforme and to combat these, bioactive molecules and their derivatives are either used alone, in combination with anticancer drugs or as nanomedicine formulations for better cancer theranostics over the conventional approach. CONCLUSION: Bioactive molecules found in seeds, vegetables, and fruits have antioxidant, anti-inflammatory, and anticancer properties that may help cancer survivors feel better throughout chemotherapy or treatment. However, incorporating them into the nanocarrier-based drug delivery for the treatment of GBMs, which could be a promising therapeutic strategy for this tumor entity, increasing targeting effectiveness, increasing bioavailability, and reducing side effects with this target-specificity, drug internalization into cells is significantly improved, and off-target organ aggregation is reduced.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Biological Products/therapeutic use , Brain Neoplasms/drug therapy , Complementary Therapies/methods , Glioblastoma/drug therapy , Phytochemicals/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Biological Products/isolation & purification , Biological Products/pharmacology , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Humans , Oxidative Stress/drug effects , Oxidative Stress/physiology , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolismABSTRACT
Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Antioxidants/metabolism , Brain Neoplasms/metabolism , Drug Resistance, Neoplasm/drug effects , Glioblastoma/metabolism , Temozolomide/therapeutic use , Animals , Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/drug therapy , Drug Resistance, Neoplasm/physiology , Glioblastoma/drug therapy , Humans , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Temozolomide/pharmacologyABSTRACT
Formononetin is an isoflavone, found in herbs like Trifolium pratense, which executes a variety of physiological activities including anti-neurodegenerative effect. However, the molecular mechanism of formononetin-mediated neuroprotection remains unclear. In this study, we investigated the protective effect of formononetin on hydrogen peroxide (H2O2)-induced death of human neuroblastoma SH-SY5Y cells and its underlying molecular mechanism. Formononetin suppressed H2O2-induced cytotoxicity. H2O2-induced increase in the intracellular reactive oxygen species (ROS) levels was decreased by formononetin, together with the enhanced expression of the antioxidant genes. H2O2-induced elevation of the Bax/Bcl-2 ratio and cleaved caspase-3 and caspase-7 levels were lowered by formononetin treatment. Moreover, formononetin repressed H2O2-induced phosphorylation of mitogen-activated protein kinases (MAPKs). Nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA decreased antioxidant gene expression and elevated the H2O2-induced ROS level in the formononetin-treated cells. Furthermore, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling is involved in the activation of the nuclear translocation of Nrf2. These results indicate that the neuroprotective effect of formononetin against H2O2-induced cell death is due to a decrease in the ROS level with the enhanced expression of the antioxidant genes through activation of the PI3K/Akt-Nrf2 signaling. In addition, formononetin suppressed apoptosis through inhibition of phosphorylation of MAPKs in SH-SY5Y cells. Thus, formononetin is a potential therapeutic agent for the treatment of neurodegenerative diseases.
Subject(s)
Cell Death/drug effects , Hydrogen Peroxide/toxicity , Isoflavones/pharmacology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Neurons/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Antioxidants/metabolism , Apoptosis/drug effects , Apoptosis/physiology , Cell Death/physiology , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression , Humans , Mitogen-Activated Protein Kinase Kinases/metabolism , NF-E2-Related Factor 2/biosynthesis , NF-E2-Related Factor 2/genetics , Neurons/metabolism , Phosphatidylinositol 3-Kinases/biosynthesis , Phosphatidylinositol 3-Kinases/genetics , Phytoestrogens/pharmacology , Proto-Oncogene Proteins c-akt/biosynthesis , Proto-Oncogene Proteins c-akt/genetics , Reactive Oxygen Species/metabolismABSTRACT
Morroniside, a major iridoid glycoside isolated from Cornus officinalis, has a variety of beneficial pharmacological properties. Although morroniside has recently been reported to exhibit anti-inflammatory and antioxidant effects, the detailed mechanism has not yet been fully elucidated. In this study, we investigated the inhibitory effect of morroniside on inflammatory and oxidative stress activated by lipopolysaccharide (LPS) in RAW 264.7 macrophages. Our results indicated that morroniside pretreatment significantly inhibited the LPS-induced phagocytic activity and release of pro-inflammatory factors, which was associated with blocking the expression of their regulatory genes. Morroniside also markedly suppressed the expression of myeloid differentiation factor 88 as well as Toll-like receptor 4 (TLR4), and attenuated the translocation of nuclear factor-κB (NF-κB) to the nucleus in LPS-treated RAW 264.7 macrophages. Furthermore, morroniside prevented the binding of LPS to the TLR4 on the cell surface. In addition, morroniside abolished reactive oxygen species (ROS) generation, and enhanced the expression of heme oxygenase-1 (HO-1) following activation of nuclear factor-E2-related factor 2 (Nrf2) in LPS-stimulated RAW 264.7 macrophages. However, zinc protoporphyrin, a specific inhibitor of HO-1, reversed the morroniside-mediated inhibition of inflammatory response in LPS-treated RAW 264.7 macrophages. In conclusion, our findings suggest that morroniside exerts LPS-induced anti-inflammatory and antioxidant effects by targeting the TLR4/NF-κB and Nrf2/HO-1 signaling pathways in RAW 264.7 macrophages. Taken together, our findings suggest that morroniside interacted structurally and electrochemically with TLR4/MD2 complex, consequently can be a potential functional agent to prevent inflammatory and oxidative damage.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Glycosides/pharmacology , Heme Oxygenase-1/genetics , Membrane Proteins/genetics , NF-E2-Related Factor 2/genetics , NF-kappa B/genetics , Toll-Like Receptor 4/genetics , Animals , Anti-Inflammatory Agents/isolation & purification , Antioxidants/isolation & purification , Cornus/chemistry , Gene Expression Regulation , Glycosides/isolation & purification , Heme Oxygenase-1/metabolism , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Membrane Proteins/metabolism , Mice , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/drug effects , Plant Extracts/chemistry , Protoporphyrins/pharmacology , RAW 264.7 Cells , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal Transduction , Toll-Like Receptor 4/metabolismABSTRACT
Ferroptosis is a new mode of cell death different from cell necrosis, autophagy, apoptosis, and pyroptosis, which depends on the accumulation of reactive oxygen species (ROS) caused by iron-mediated lipid peroxidation, exhibits cellular, molecular, and gene-level characteristics distinct from other cell deaths. Since ferroptosis discovery, it has become a new target for antitumor therapy actively explored by researchers. In this review, we provide an overview of the known mechanisms that regulate the sensitivity of cancer cells to ferroptosis and the research progress of ferroptosis-related drugs (western medicine, traditional Chinese medicine, and nanomedicine), as well as the relationship between ferroptosis and cancer treatment, tumor drug resistance, and antitumor immunotherapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Drug Resistance, Neoplasm/drug effects , Ferroptosis/drug effects , Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Apoptosis/physiology , Drug Delivery Systems/trends , Drug Resistance, Neoplasm/physiology , Ferroptosis/physiology , Humans , Immunotherapy/methods , Immunotherapy/trends , Lipid Metabolism/drug effects , Lipid Metabolism/physiology , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Neoplasms/metabolism , Pyroptosis/drug effects , Pyroptosis/physiology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: The root of Rehmannia glutinosa (R. glutinosa) is commonly used in various traditional Chinese herbal formulae to ameliorate nephropathy; however, little is known about its active component(s) and mechanisms. AIM: In the present study, we examined the protective effect and potential mechanism of rehmapicrogenin, a monomeric compound extracted from R. glutinosa, against Adriamycin (ADR)-induced nephropathy (AN) in vivo and in vitro. METHODS: In this study, an ADR-induced kidney injury model was employed to investigate the nephroprotective effects of rehmapicrogenin in mice. In vivo, ELISA kits, flow cytometry, haematoxylin-eosin staining, immunofluorescence techniques, and western blotting were used to evaluate the effect of rehmapicrogenin on kidney injury in mice. In vitro, the effects of rehmapicrogenin on NRK-52E cellular damage induced by ADR were determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The mechanism was investigated using ELISA kits, flow cytometry and In-Cell Western™ blotting. RESULTS: In vivo, rehmapicrogenin treatment significantly attenuated the pathological changes in the kidney induced by ADR; rescued weight, serum creatinine (Scr), blood urea nitrogen (BUN) and urine albumin (U-ALB) levels; reduced reactive oxygen species (ROS) accumulation; and decreased oxidative stress, the apoptosis rate, and cell survival in ADR-treated mice. Importantly, both in vivo and in vitro experimental results demonstrated that rehmapicrogenin regulates the Nrf2/ARE signalling pathway, the most important pathway for oxidative stress. Rehmapicrogenin attenuated ADR-induced kidney damage by reducing oxidative stress through the oestrogen receptor pathway. Moreover, after treatment with ICI 182780 (the oestrogen receptor-nonspecific antagonist Faslodex), the improvement induced by rehmapicrogenin was significantly reversed. CONCLUSIONS: In conclusion, rehmapicrogenin attenuates kidney damage by reducing inflammatory factor release through the oestrogen signalling pathway.
Subject(s)
Acute Kidney Injury/prevention & control , Drugs, Chinese Herbal/therapeutic use , Estrogen Antagonists/therapeutic use , Estrogens , Reactive Oxygen Species/antagonists & inhibitors , Signal Transduction/drug effects , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Cell Line , Cytoprotection/drug effects , Cytoprotection/physiology , Drugs, Chinese Herbal/pharmacology , Estrogen Antagonists/pharmacology , Estrogens/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Rats , Reactive Oxygen Species/metabolism , Signal Transduction/physiologyABSTRACT
Berries are natural sources of anthocyanins, especially cyanidin-3-glucoside (C3G), and exhibit significant antioxidant, antidiabetic, anti-inflammatory, and cytoprotective effects against various oxidative stress-induced disorders. C3G and its metabolites possess higher absorption and bioavailability, and interaction with gut microbiota may enhance their health benefits. Various in vitro studies have shown the reactive oxygen species (ROS)-mitigating potential of C3G. However, in in vivo models, C3G exerts its cytoprotective properties by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-responsive element (ARE) pathway. Despite existing reports stating various health benefits of C3G, its antioxidant potential by modulating the Nrf2 pathway remains less identified. This review discusses the Nrf2-mediated antioxidant response of C3G in modulating oxidative stress against DNA damage, apoptosis, carcinogen toxicity, and inflammatory conditions. Furthermore, we have reviewed the recent clinical trial data to establish cross talk between a berry-rich diet and disease prevention.
Subject(s)
Anthocyanins/pharmacology , Anthocyanins/therapeutic use , Fruit/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Humans , NF-E2-Related Factor 2/antagonists & inhibitors , Neoplasms/metabolism , Neoplasms/prevention & control , Oxidative Stress/physiology , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolismABSTRACT
[Figure: see text].
Subject(s)
Acetylcysteine/pharmacology , Cerebral Hemorrhage/drug therapy , Free Radical Scavengers/therapeutic use , Selenium/pharmacology , Adult , Cerebral Hemorrhage/pathology , Female , Humans , Male , Middle Aged , Oxidative Stress/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Treatment OutcomeABSTRACT
Lead (Pb) is a known toxic heavy metal which accumulates in different tissues and causes oxidative stress (OS) and inflammation. The brain tissue is considered as one of the most vulnerable organs to the Pb-induced toxicity. The aim of this study was to investigate the therapeutic effects of vitamin D3 (VD) supplementation against the damages caused by chronic Pb toxicity in the cerebral cortex. Forty Wistar rats were divided into four equal groups and were treated as follows: control group received no treatment, VD group received 1000 IU/kg of VD by intramuscular injection every other day, Pb group received 1000 mg/L of Pb in drinking water, and Pb + VD group received VD and Pb simultaneously. The experiment lasted for 4 weeks and the analyses were conducted 24 h after the last administrations. The obtained results demonstrated that Pb significantly increased cortical lipid peroxidation and reactive oxygen species (ROS) levels. At the same time, there was a significant reduction in glutathione (GSH) content, catalase (CAT), and superoxide dismutase (SOD) activities, as well as a significant increase in the tissue level of inflammatory cytokines. Furthermore, Pb increased the messenger RNA (mRNA) expression level of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB). Anyhow, VD administration during the period of Pb exposure suppressed the OS and inflammation by increasing the antioxidant molecules and decreasing the inflammatory cytokines and consequently repaired Pb-induced cortical tissue damages. Remarkably, these responses were concomitant with the alterations in Nrf2 and NF-κB gene expressions. In conclusion, the present study discloses the potential protective effects for VD against Pb-induced neurotoxicity via anti-inflammatory and antioxidative mechanisms.
Subject(s)
Cholecalciferol/pharmacology , Lead/toxicity , NF-E2-Related Factor 2/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Signal Transduction/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Male , NF-E2-Related Factor 2/biosynthesis , NF-kappa B/biosynthesis , Oxidative Stress/drug effects , Oxidative Stress/physiology , Rats , Rats, Wistar , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal Transduction/physiologyABSTRACT
CONTEXT: Bufadienolide compounds occur in many plants and animal species and have strong cardiac and anti-inflammatory properties. The compounds have been recently investigated for cytotoxic and antitumor activity. OBJECTIVE: The cytotoxic effect of bersaldegenin-1,3,5-orthoacetate - a bufadienolide steroid occuring in plants from Kalanchoe genus (Crassulaceae), was evaluated with cervical cancer HeLa cells in vitro. MATERIALS AND METHODS: The cytotoxic activity of the compound (at 0.1-20.0 µg/mL) on the cells was determined by Real-Time Cell Analysis (RTCA) system for 24 h. The estimation of cell cycle arrest, reactive oxygen species (ROS) production, reduction of mitochondrial membrane potential (MMP), and caspases-3/7/9 activity in the HeLa cells treated with the compound was done by flow cytometry and luminometric technique. DNA damage in the cells was estimated by immunofluorescence staining and the comet assay with etoposide as a positive control. RESULTS: The compound had strong effect on the cells (IC50 = 0.55 µg/mL) by the suppression of HeLa cells proliferation in G2/M phase of cell cycle and induction of cell death through double-stranded DNA damage and reactive oxygen species overproduction. Furthermore, we did not observe an increase in the activity of caspase-3/7/9 in the treated cells as well as a decrease in cellular mitochondrial membrane potential. Gene expression analysis revealed the overexpression of NF-Kappa-B inhibitors genes (>2-fold higher than control) in the treated cells. CONCLUSIONS: Bersaldegenin-1,3,5-orthoacetate induces cell cycle arrest and caspase-independent cell death through double-stranded DNA damage. These results are an important step in further studies on cell death signalling pathways induced by bufadienolides.
Subject(s)
Bufanolides/pharmacology , Caspases/metabolism , Cell Cycle Checkpoints/drug effects , DNA Damage/drug effects , Plant Extracts/pharmacology , Uterine Cervical Neoplasms/metabolism , Animals , Bufanolides/isolation & purification , Bufanolides/therapeutic use , Bufonidae , Cell Cycle Checkpoints/physiology , Cell Death/drug effects , Cell Death/physiology , DNA Damage/physiology , Female , HeLa Cells , Humans , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/physiology , Plant Extracts/isolation & purification , Plant Extracts/therapeutic use , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Uterine Cervical Neoplasms/drug therapyABSTRACT
In spite of much awareness, diabetes mellitus continues to remain one of major reasons for mortality and morbidity rate all over the globe. Free radicals cause oxidative stress which is responsible for causing diabetes. The recent advancements in elucidation of ARE/keap1/Nrf2 pathway can help in better understanding of diabetes mellitus. Various clinical trials and animal studies have shown the promising effect of Nrf2 pathway in reversing diabetes by counteracting with the oxidative stress produced. The gene is known to dissociate from Keap1 on coming in contact with such stresses to show preventive and prognosis effect. The Nrf2 gene has been marked as a molecular player in dealing with wide intracellular as well as extracellular cellular interactions in different diseases. The regulation of this gene gives some transcription factor that contain antioxidant response elements (ARE) in their promoter region and thus are responsible for encoding certain proteins involved in regulation of metabolic and detoxifying enzymes.
Subject(s)
Antioxidant Response Elements , Diabetes Mellitus, Type 2/genetics , Diabetic Nephropathies/genetics , Hypoglycemic Agents/therapeutic use , Kelch-Like ECH-Associated Protein 1/genetics , NF-E2-Related Factor 2/genetics , Animals , Antioxidants/therapeutic use , Clinical Trials as Topic , Curcumin/analogs & derivatives , Curcumin/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Gene Expression Regulation , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Protein Binding , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Signal TransductionABSTRACT
Fibrotic diseases account for more than 8 million deaths worldwide annually. Reactive oxygen species (ROS) has been shown to activate pyroptosis and promote the production of interleukin (IL)-1ß and IL-18, leading to fibrosis development. However, the role of dual oxidase 1 (DUOX1)-induced ROS production and pyroptosis in cardiac fibrosis remains largely unknown. Activin A was used to induce ROS and pyroptosis in cardiomyocytes. ROS level, pyroptosis, and cytokine production were detected using Active Oxygen Detection Kit, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Western blotting analysis was used to measure expression changes of proteins. DUOX1 was silenced or overexpressed to investigate its role in fibrosis. We found that activin A induced ROS production and pyroptosis in cardiomyocytes, which was blocked by the ROS scavenger, N-acetyl-L-cysteine (NAC). Knockdown of DUOX1 reversed activin A-induced ROS production, pyroptosis, cytokine release, and the upregulation of proinflammatory proteins. Overexpression of DUOX1 resulted in opposite effects of knockdown DUOX1. Administration of an ROS scavenger blocked the effect of DUOX1 overexpression. Supplementation of IL-1ß and IL-18 caused significant fibrosis in human cardiac fibroblasts (hCFs). The knockdown of DUOX1 protected cardiomyocytes against activin A-induced fibrosis via the inhibition of ROS, cytokine release, and pyroptosis.
Subject(s)
Activins/pharmacology , Dual Oxidases/genetics , Myocytes, Cardiac/drug effects , Pyroptosis/drug effects , Reactive Oxygen Species/metabolism , Acetylcysteine/pharmacology , Activins/antagonists & inhibitors , Caspase 1/genetics , Caspase 1/metabolism , Coenzyme A Ligases/genetics , Coenzyme A Ligases/metabolism , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type III/genetics , Collagen Type III/metabolism , Dual Oxidases/antagonists & inhibitors , Dual Oxidases/metabolism , Free Radical Scavengers/pharmacology , Gene Expression Regulation , Humans , Interleukin-18/genetics , Interleukin-18/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress/drug effects , Primary Cell Culture , Pyroptosis/genetics , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Reactive Oxygen Species/agonists , Reactive Oxygen Species/antagonists & inhibitors , Signal Transduction , Smad2 Protein/genetics , Smad2 Protein/metabolism , Smad3 Protein/genetics , Smad3 Protein/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia camphorata (AC) is a rare functional fungus in Taiwan and is known as traditional Chinese medicine. It has been reported to inhibit proliferation and promote apoptosis in human cancer cells. AIM OF THE STUDY: To investigate the potential mechanism of apoptosis induced in colon cancer cells by Antrodia camphorata extract (ACE). MATERIALS AND METHODS: The MTT assay and crystal violet staining were used to determine relative cell viability in vitro at 24 and 48 h. The effects of ACE on apoptosis were determined by Hoechst 33342 staining and flow cytometric analysis following Annexin V-FITC/PI staining. The gene expression profile of HCT116 cells was assessed by the RNA sequencing system. In combination with RNA-seq data and qRT-PCR, Western blot analysis was used to evaluate expression of proteins. The intracellular ROS of HCT116 cells were determined using a DCFH-DA fluorescence probe. RESULTS: ACE significantly reduces cell viability in a dose-dependent manner and triggers apoptosis. To explore the underlying mechanism, we performed transcriptome analysis of ACE-treated colon cancer HCT116 cells. Bioinformatics analyses showed that ACE treatment is associated with pathways in cancer. We further used Cytoscape to analyze hub genes in this network. Among them, BMP4, which is associated with cancer cell death through regulation of the tumor suppressor p53, was significantly decreased at both mRNA and protein levels in ACE treatment groups. We found that cell death is reversible via inactivation or knockdown of p53 gene and reduction of reactive oxygen species (ROS) generation in response to ACE exposure, indicating that p53 plays an important role in ROS generation induced by ACE. Meanwhile, ROS scavenger NAC was used to verify that cell death is reversible via reduction of ROS. CONCLUSION: Our findings demonstrate that ACE has potential as an anticancer agent that induces apoptosis through BMP4 and p53-dependent response to ROS in human colon cancer.