Showing papers on "Curcumin published in 2018"
TL;DR: Turmeric and curcumin are nonmutagenic and are safe in pregnancy in animals but more studies in human are needed and there are still few trials and more studies are needed specially on nanoformulations.
Abstract: Curcumin is the major constituent of turmeric (Curcuma longa). Turmeric has been widely used as a spice in foods and for therapeutic applications such as anti-inflammatory, antihyperlipidemic, and antimicrobial activities. Turmeric and curcumin are nonmutagenic and nongenotoxic. Oral use of turmeric and curcumin did not have reproductive toxicity in animals at certain doses. Studies on human did not show toxic effects, and curcumin was safe at the dose of 6 g/day orally for 4-7 weeks. However, some adverse effects such as gastrointestinal upsets may occur. Moreover, oral bioavailable formulations of curcumin were safe for human at the dose of 500 mg two times in a day for 30 days, but there are still few trials and more studies are needed specially on nanoformulations and it should be discussed in a separate article. In addition, curcumin is known as a generally recognized as safe substance. This review discusses the safety and toxicity of turmeric and curcumin in medicine. Turmeric and curcumin are nontoxic for human especially in oral administration. Turmeric and curcumin are also safe in animals. They are nonmutagenic and are safe in pregnancy in animals but more studies in human are needed.
344 citations
TL;DR: The chemistry, metabolism, and absorption of curcumin, to which various reported health benefits have been ascribed, as well asCurcumin's degradation products and metabolites and their possible functions are discussed.
Abstract: Curcumin is a polyphenol found in turmeric (Curcuma longa), used as a spice, in food coloring, and as a traditional herbal medicine. It has been shown that curcumin has health benefits such as antioxidant, anti-inflammatory, and anticancer properties, improvement of brain function, and control of obesity and diabetes. However, native curcumin easily degrades and has low oral bioavailability, and a recent report has expressed doubt about curcumin's various effects. To overcome its low bioavailability, various curcumin formulations with enhanced bioavailability are currently being developed. This review discusses the chemistry, metabolism, and absorption of curcumin, to which various reported health benefits have been ascribed, as well as curcumin's degradation products and metabolites and their possible functions. Moreover, the research trend towards the obesity- and diabetes-preventing/suppressing aspects of curcumin and the latest case studies on highly water-dispersible and bioavailable curcumin formulations will be discussed. We summarize the challenges concerning research on curcumin's health benefits as follows: clarifying the relationship between curcumin's health benefits and the formation of curcumin-derived oxidation and degradation products and metabolites, determining whether curcumin itself or other components in turmeric are responsible for its effects, and conducting further human trials in which multiple research groups employ the same samples and conditions. High-bioavailability formulations would be useful in such future studies.
234 citations
TL;DR: Electronic databases were extensively searched and results showed that curcumin exerts remarkable protective and therapeutic effects of oxidative associated liver diseases through various cellular and molecular mechanisms.
Abstract: Oxidative stress has been considered a key causing factor of liver damage induced by a variety of agents, including alcohol, drugs, viral infections, environmental pollutants and dietary components, which in turn results in progression of liver injury, non-alcoholic steatohepatitis, non-alcoholic liver disease, liver fibrosis and cirrhosis. During the past 30 years and even after the major progress in the liver disease management, millions of people worldwide still suffer from an acute or chronic liver condition. Curcumin is one of the most commonly used indigenous molecules endowed by various shielding functionalities that protects the liver. The aim of the present study is to comprehensively review pharmacological effects and molecular mechanisms, as well as clinical evidence, of curcumin as a lead compound in the prevention and treatment of oxidative associated liver diseases. For this purpose, electronic databases including “Scopus,” “PubMed,” “Science Direct” and “Cochrane library” were extensively searched with the keywords “curcumin or curcuminoids” and “hepatoprotective or hepatotoxicity or liver” along with “oxidative or oxidant.” Results showed that curcumin exerts remarkable protective and therapeutic effects of oxidative associated liver diseases through various cellular and molecular mechanisms. Those mechanisms include suppressing the proinflammatory cytokines, lipid perodixation products, PI3K/Akt and hepatic stellate cells activation, as well as ameliorating cellular responses to oxidative stress such as the expression of Nrf2, SOD, CAT, GSH, GPx and GR. Taking together, curcumin itself acts as a free radical scavenger over the activity of different kinds of ROS via its phenolic, β-diketone and methoxy group. Further clinical studies are still needed in order to recognize the structure-activity relationships and molecular mechanisms of curcumin in oxidative associated liver diseases.
231 citations
TL;DR: The present review provides a comprehensive overview of the effects of curcumin on different immune cells and immune system‐related diseases.
Abstract: Curcumin is a dietary polyphenol from turmeric with numerous pharmacological activities. Novel animal and human studies indicate that curcumin can affect different immune cells, such as various T lymphocyte subsets, macrophages, dendritic cells, B lymphocytes and natural killer cells, which results in decreasing severity of various diseases with immunological etiology. The present review provides a comprehensive overview of the effects of curcumin on different immune cells and immune system-related diseases.
208 citations
TL;DR: In this article, the authors highlighted various miRNAs which could be affected by curcumin in various types of cancer and highlighted exosomes containing curcurumin as suitable therapeutic tools in cancer therapy.
Abstract: Curcumin is known as a natural dietary polyphenol which is extracted from Curcuma longa L. It has been shown that curcumin has a variety of pharmacological effects such as antioxidant, anti-cancer, anti-inflammatory, and anti-microbial activities. Anti-cancer effects of curcumin are due to targeting of a wide range of cellular and molecular pathways involved in cancer pathogenesis including NF-kB, MAPK, PTEN, P53, and microRNAs (miRNA) network. Multiple lines of evidence have indicated that curcumin exerts its therapeutic effects via regulating miRNA expression (e.g., miR-1, miR-7, miR-9, miR-34a, miR-181, miR-21, and miR-19) which could lead to the regulation of underlying cellular and molecular pathways involved in cancer pathogenesis. Exosomes are one of the important classes of biological vehicles which could be released from various types of cells such as cancer cells and stem cells and could change the behavior of recipient cells. It has been shown that treatment of cancer cells with different dose of curcumin leads to the release of exosomes containing curcumin. These exosomes could induce anti-cancer properties in recipient cells and reduce tumor growth. Hence, exosomes containing curcumin could be applied as powerful tools for cancer treatment. Here, we highlighted various miRNAs which could be affected by curcumin in various types of cancer. Moreover, we highlight exosomes containing curcumin as suitable therapeutic tools in cancer therapy.
199 citations
TL;DR: The current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis is assessed to assess the current limitations of cur cumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
Abstract: The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
199 citations
TL;DR: Overall, curcumin is a promising ingredient of novel functional foods, with protective efficacy in preventing certain diseases, and this comprehensive and updated review will be helpful for promoting human-based studies to facilitate its use in human health and diseases in the future.
Abstract: Curcumin is a principal curcuminoid of turmeric (Curcuma longa), which is commonly used as a spice in cooking and a yellow pigment in the food processing industry. Recent studies have demonstrated that curcumin has a variety of biological activities and pharmacological performances, providing protection and promotion of human health. In addition to presenting an overview of the gut metabolism of curcumin, this paper reviews the current research progress on its versatile bioactivity, such as antioxidant, anti-inflammatory, and immune-regulatory activities, and also intensively discusses its health benefits, including the protective or preventive effects on cancers and diabetes, as well as the liver, nervous system, and cardiovascular systems, highlighting the potential molecular mechanisms. Besides, the beneficial effects of curcumin on human are further stated based on clinical trials. Considering that there is still a debate on the beneficial effects of curcumin, we also discuss related challenges and prospects. Overall, curcumin is a promising ingredient of novel functional foods, with protective efficacy in preventing certain diseases. We hope this comprehensive and updated review will be helpful for promoting human-based studies to facilitate its use in human health and diseases in the future.
184 citations
TL;DR: It is proposed in this review that curcumin's potential as a therapeutic agent may not solely rely on its bioavailability, but rather its medicinal benefits may also arise from its positive influence on gastrointestinal health and function.
181 citations
TL;DR: Taking together, curcumin could be used as a safe and well‐tolerated adjunct to statins to control hyperlipidaemia more effectively than statins alone.
Abstract: Curcumin is an herbal polyphenol extensively investigated for antioxidant, anti-inflammatory, and hypolipidaemic properties. In the present review, the efficacy of curcumin for improving a plasma lipid profile has been evaluated and compared with statins, a well-known class of medicines for treating hypercholesterolemia and hyperlipidaemia. Curcumin is presumably most effective in reducing triglyceride (TG), while statins are most efficient in lowering low-density lipoproteins-cholesterol (LDL-C). Additionally, various molecular and metabolic mediators of cholesterol and plasma lipid homeostasis are discussed in relation to how they are modulated by curcumin or statins. Overall, curcumin influences the same mediators of plasma lipid alteration as statins do. Almost all the pathways through which cholesterol trafficking takes place are affected by these agents. These include gastrointestinal absorption of dietary cholesterol, hepatocellular removal of plasma cholesterol, the mediators of reverse cholesterol transport, and removal of cholesterol from peripheral tissues. Moreover, the reactive oxygen species (ROS) scavenging potential of curcumin limits the risk of lipid peroxidation that triggers inflammatory responses causing cardiovascular diseases (CVD) and atherosclerosis. Taken together, curcumin could be used as a safe and well-tolerated adjunct to statins to control hyperlipidaemia more effectively than statins alone.
171 citations
TL;DR: This review summarizes the current state of knowledge with a focus on the anti-viral effect of curcumin, and their possible molecular mechanisms.
170 citations
TL;DR: The generation of supramolecular curcumin nanoagents through amino acid coordination driven self-assembly to simultaneously increase the biological stability and tumor accumulation ofCurcumin substantially enhanced the antitumor activity of Curcumin without discernible side effects.
Abstract: Clinical translation of curcumin has been highly obstructed by the rapid degradation and poor tissue absorption of this agent. Herein, we report on the generation of supramolecular curcumin nanoagents through amino acid coordination driven self-assembly to simultaneously increase the biological stability and tumor accumulation of curcumin. The biological stability of curcumin was significantly improved both through coordination and through molecular stacking. The sizes of these nanoagents can be readily manipulated to facilitate tumor accumulation. These favorable therapeutic features, together with high drug-loading capacities and responses to pH and redox stimuli, substantially enhanced the antitumor activity of curcumin without discernible side effects. Hence, supramolecular curcumin nanoagents may hold promise in moving forward the clinical application of curcumin as an effective anticancer drug.
TL;DR: Curcumin can directly inactivate IAV, inhibits IAV adsorption and replication; and its inhibition on IAV replication may be via activating Nrf2 signal and inhibiting IAV‐induced activation of TLR2/4, p38/JNK MAPK and NF‐&kgr;B pathways.
TL;DR: Both in vitro and in vivo studies showed that the curcumin nanoparticles had an appreciably higher bioavailability than that of freeCurcumin crystals (2.7-3.6-fold), which was mainly attributed to their higher bioaccessibility.
Abstract: There is great interest in developing colloidal delivery systems to enhance the water-solubility and oral bioavailability of curcumin, which is a hydrophobic nutraceutical claimed to have several health benefits In this study, a natural emulsifier was used to form sophorolipid-coated curcumin nanoparticles The curcumin was loaded into sophorolipid micelles using a pH-driven mechanism based on the decrease in curcumin solubility at lower pH values The sophorolipid-coated curcumin nanoparticles formed using this mechanism were relatively small (61 nm) and negatively charged (-41 mV) The nanoparticles also had a relatively high encapsulation efficiency (82%) and loading capacity (14%) for curcumin, which was present in an amorphous state Both in vitro and in vivo studies showed that the curcumin nanoparticles had an appreciably higher bioavailability than free curcumin crystals (27-36-fold), which was mainly attributed to their higher bioaccessibility These results may facilitate the development of n
TL;DR: Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway and indicates that curcumin could be an effective therapy for patients afflicted with ischemia.
Abstract: Curcumin, a polyphenolic compound extracted from Curcuma longa, has drawn attention for its effective bioactivities against ischemia-induced injury. This study aimed to evaluate the neuroprotective effect of curcumin and investigate the underlying mechanism that mediates autophagy and inflammation in an animal model of middle cerebral artery occlusion (MCAO) in rats. Curcumin was delivered to Sprague Dawley male rats at a dose of 200 mg/kg curcumin by intraperitoneal injection 30 min after ischemia-reperfusion (I/R). LY294002, a specific inhibitor of the PI3K/Akt/mTOR pathway, as well as anisomycin, an activator of TLR4/p38/MAPK, was administered by ventricle injection 30 min before MCAO. The same volume of saline was given as a control. Brain infarction and neurological function were determined 24 h post-MCAO. Immunoblotting and immunofluorescence were used to detect alterations in autophagy-relevant proteins Akt, p-Akt, mTOR, p-mTOR, LC3-II, and LC3-I, and inflammation-related proteins TLR4, p-38, p-p38, and IL-1 in the ipsilateral hemisphere. Cerebral I/R injury resulted in significant alterations of LC3-II/LC3-I, IL-1, TLR4, and p-p38. Curcumin in MCAO rats significantly improved brain damage and neurological function by upregulating p-Akt and p-mTOR and downregulating LC3-II/LC3-I, IL-1, TLR4, p-38, and p-p38. However, these protective effects against ischemia could be suppressed when LY294002 or anisomycin was included. Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway. Furthermore, this study indicates that curcumin could be an effective therapy for patients afflicted with ischemia.
TL;DR: In vivo data show that curcumin attenuated IL-1β secretion and prevented high-fat diet–induced insulin resistance in wide-type C57BL/6 mice but not in Nlrp3-deficient mice, and suggest the potential clinical use ofCurcumin in NLRP3-driven diseases.
Abstract: Turmeric is traditionally used as a spice and coloring in foods. Curcumin is the primary active ingredient in the turmeric, and compelling evidence has shown that it has the ability to inhibit inflammation. However, the mechanism mediating its anti-inflammatory effects are not fully understood. We report that curcumin inhibited caspase-1 activation and IL-1β secretion through suppressing LPS priming and the inflammasome activation pathway in mouse bone marrow-derived macrophages. The inhibitory effect of curcumin on inflammasome activation was specific to the NLRP3, not to the NLRC4 or the AIM2 inflammasomes. Curcumin inhibited the NLRP3 inflammasome by preventing K+ efflux and disturbing the downstream events, including the efficient spatial arrangement of mitochondria, ASC oligomerization, and speckle formation. Reactive oxygen species, autophagy, sirtuin-2, or acetylated α-tubulin was ruled out as the mechanism by which curcumin inhibits the inflammasome. Importantly, in vivo data show that curcumin attenuated IL-1β secretion and prevented high-fat diet-induced insulin resistance in wide-type C57BL/6 mice but not in Nlrp3-deficient mice. Curcumin also repressed monosodium urate crystal-induced peritoneal inflammation in vivo. Taken together, we identified curcumin as a common NLRP3 inflammasome activation inhibitor. Our findings reveal a mechanism through which curcumin represses inflammation and suggest the potential clinical use of curcumin in NLRP3-driven diseases.
TL;DR: It is evident that better bioavailability of formulated curcumin products is mostly attributed to improved solubility, stability, and possibly low first-pass metabolism.
TL;DR: The effect of curcumin on Alzheimer's disease involves multiple signaling pathways: anti-amyloid and metal iron chelating properties, antioxidation and anti-inflammatory activities.
TL;DR: The data presented suggest that γ-cyclodextrinCurcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.
Abstract: The optimal health benefits of curcumin are limited by its low solubility in water and corresponding poor intestinal absorption. Cyclodextrins (CD) can form inclusion complexes on a molecular basis with lipophilic compounds, thereby improving aqueous solubility, dispersibility, and absorption. In this study, we investigated the bioavailability of a new γ-cyclodextrin curcumin formulation (CW8). This formulation was compared to a standardized unformulated curcumin extract (StdC) and two commercially available formulations with purported increased bioavailability: a curcumin phytosome formulation (CSL) and a formulation of curcumin with essential oils of turmeric extracted from the rhizome (CEO). Twelve healthy human volunteers participated in a double-blinded, cross-over study. The plasma concentrations of the individual curcuminoids that are present in turmeric (namely curcumin, demethoxycurcumin, and bisdemethoxycurcumin) were determined at baseline and at various intervals after oral administration over a 12-h period. CW8 showed the highest plasma concentrations of curcumin, demethoxycurcumin, and total curcuminoids, whereas CSL administration resulted in the highest levels of bisdemethoxycurcumin. CW8 (39-fold) showed significantly increased relative bioavailability of total curcuminoids (AUC0−12) in comparison with the unformulated StdC. The data presented suggest that γ-cyclodextrin curcumin formulation (CW8) significantly improves the absorption of curcuminoids in healthy humans.
TL;DR: All-natural colloidal delivery systems were developed to overcome challenges of low water-solubility, chemical instability, and poor oral bioavailability of curcumin, which consisted of saponin-coatedCurcumin nanoparticles formed using a pH-driven loading method.
Abstract: Curcumin is a bioactive phytochemical that can be utilized as a nutraceutical or pharmaceutical in functional foods, supplements, and medicines. However, the application of curcumin as a nutraceutical in commercial food and beverage products is currently limited by its low water-solubility, chemical instability, and poor oral bioavailability. In this study, all-natural colloidal delivery systems were developed to overcome these challenges, which consisted of saponin-coated curcumin nanoparticles formed using a pH-driven loading method. The physicochemical and structural properties of the curcumin nanoparticles formed using this process were characterized, including particle size distribution, surface potential, morphology, encapsulation efficiency, and loading capacity. Fourier transform infrared spectroscopy and X-ray diffraction indicated that curcumin was present in the nanoparticles in an amorphous form. The curcumin nanoparticles were unstable to aggregation at low pH values ( 200 mM), which was attributed to a reduction in electrostatic repulsion between them. However, they were stable at higher pH values (3 to 8) and lower NaCl levels (0 to 200 mM), due to a stronger electrostatic repulsion between them. They also exhibited good stability during refrigerated storage (4 °C) or after conversion into a powdered form (lyophilized). A simulated gastrointestinal tract study demonstrated that the in vitro bioaccessibility was around 3.3-fold higher for curcumin nanoparticles than for free curcumin. Furthermore, oral administration to Sprague Dawley rats indicated that the in vivo bioavailability was around 8.9-fold higher for curcumin nanoparticles than for free curcumin. These results have important implications for the development of curcumin-enriched functional foods, supplements, and drugs.
TL;DR: Curcumin may be a promising candidate drug in clinical application for IBD therapy through inhibiting NLRP3 inflammasome activation and IL‐1&bgr; production through inhibitory effect of curcumin on dextran sulfate sodium‐induced colitis in mice.
TL;DR: Results show that curcumin specifically inhibits tumor growth by increasing ROS levels over the threshold through the miscellaneous inhibition of ROS metabolic enzymes.
Abstract: Curcumin has been reported to exhibit anti-tumorigenic activity; however, since its precise actions remain unclear, its effects are considered to be deceptive. In the present study, we confirmed the anti-tumorigenic effects of curcumin on CML-derived leukemic cells in a xenograft model and in vitro culture system. In vitro pull-down and mass analyses revealed a series of enzymes (carbonyl reductase, glutathione-S-transferase, glyoxalase, etc.) that function in a reactive oxygen species (ROS) metabolic pathway as curcumin-binding targets, the expression of which was up-regulated in human leukemia. Curcumin increased ROS levels over the threshold in leukemic cells, and the antioxidant, glutathione (GSH) and overexpression of curcumin-binding enzymes partially mitigated the up-regulation of ROS and growth inhibition caused by curcumin. These results show that curcumin specifically inhibits tumor growth by increasing ROS levels over the threshold through the miscellaneous inhibition of ROS metabolic enzymes. Curcumin has potential in therapy to regulate ROS levels in tumor cells, thereby controlling tumor growth.
TL;DR: Mesoporous silica nanocarriers as accommodate drug molecule capsules were synthesized and capped by chitosan natural polymer acts as a pH-responsive shield to increase the solubility and improvement of anticancer properties of curcumin against U87MG glioblastoma cancer cell line.
Abstract: Mesoporous silica nanocarriers as accommodate drug molecule capsules were synthesized and capped by chitosan natural polymer. This nanocarrier acts as a pH-responsive shield to increase the solubility and improvement of anticancer properties of curcumin against U87MG glioblastoma cancer cell line. The encapsulation efficiency and drug-loading content were measured 88.1 ± 4.76% and 8.81 ± 0.47%, respectively. The curcumin release from the CS-MCM-41 was slow and sustained at low pH (42.72 ± 2.29%) compared to the environment pH (19.54 ± 1.36%) in 96 h. The MTT evaluations showed that IC50 after 72 h treatment with free curcumin and curcumin-loaded CS-MCM-41 were 15.20 and 5.21 μg/mL (p <0.05). respectively.
TL;DR: PE coumarin and curcumin loaded PEs were demonstrated as promising candidates to inhibit microbial growth and to prevent preferential killing of cancer cells compared to normal cells through improved bioavailability by nanoencapsulated emulsions.
TL;DR: Curcumin may inhibit proliferation and induce the autophagy and apoptosis in GC cells, and activated the P53 signaling pathway by up‐regulating P53 and P21, which also inhibited PI3K pathway through down-regulating PI3k, p‐Akt, and p‐mTOR.
Abstract: In this study, we aimed to investigate the effects of curcumin on cell activities of gastric cancer (GC), and the connection between curcumin and P53 as well as PI3K signaling. This study was conducted with two cell lines SGC-7901 and BGC-823, both were exposed to curcumin at the concentrations of 0 µM, 10 µM, 20 µM and 40 µM. MTT assay, flow cytometry (FCM) assay, transmission electron microscopy (TEM) were used to study the underlying mechanisms of curcumin in respective of proliferation, apoptosis and autophagy. Western blot assay was also employed to detect impacts of curcumin on tophosphatidylinositol-3 kinase (PI3K) and P53 signaling pathways-related proteins. MTT assay displayed that curcumin inhibited GC cell proliferation. FCM results indicated that curcumin induced the apoptosis of GC cells. TEM revealed that curcumin induced autophagy in GC cells. Western blot results showed that curcumin activated P53 signaling pathway and inhibited PI3K signaling pathway. Curcumin may inhibit proliferation and induce the autophagy and apoptosis in GC cells. Additionally, curcumin activated the P53 signaling pathway by up-regulating P53 and P21, which also inhibited PI3K pathway through down-regulating PI3K, p-Akt and p-mTOR. This article is protected by copyright. All rights reserved
TL;DR: Curcumin perturbs 26S proteasome activity via DYRK2 inhibition in various cancer cells and in the mouse cancer model leading to impairment of cell proliferation and reduction of cancer burden in mice, revealing an unexpected role of curcumin in DyrK2-proteasome inhibition.
Abstract: Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment.
TL;DR: The results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.
Abstract: Parkinson's disease (PD) pathology is characterized by the abnormal accumulation and aggregation of the pre-synaptic protein α-synuclein in the dopaminergic neurons as Lewy bodies (LBs). Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains obscure. Therefore, the present study was designed to understand such concealed mechanisms behind neuroprotective effects of curcumin. An animal model of PD was established by injecting lipopolysaccharide (LPS, 5 µg/5 µl PBS) into the substantia nigra (SN) of rats which was followed by curcumin administration (40 mg/kg b.wt (i.p.)) daily for a period of 21 days. Modulatory functions of curcumin were evident from the inhibition of astrocytic activation (GFAP) by immunofluorescence and NADPH oxidase complex activation by RT-PCR. Curcumin supplementation prevented the LPS-induced upregulation in the protein activity of transcription factor NFκB, proinflammatory cytokines (TNF-α, IL-1β, and IL-1α), inducible nitric oxide synthase (iNOS) as well as the regulating molecules of the intrinsic apoptotic pathway (Bax, Bcl-2, Caspase 3 and Caspase 9) by ELISA. Curcumin also resulted in significant improvement in the glutathione system (GSH, GSSG and redox ratio) and prevented iron deposition in the dopaminergic neurons as depicted from atomic absorption spectroscopy (AAS) and Prussian blue staining, respectively. Curcumin also prevented α-synuclein aggregates in the dopaminergic neurons as observed from gene as well as protein activity of α-synuclein using RT-PCR and IHC. Collectively, our results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.
TL;DR: The present work evaluated the feasibility of different pluronics utilized as modifiers to improve the stability and bioaccessibility of curcumin liposomes (cur-pluronic-Lps) and suggested that pluronics modification could significantly improve the absorption ofCurcumin.
TL;DR: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future.
Abstract: Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for α-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form. Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD). Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to α-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD. Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future.
TL;DR: Curcumin exhibits salutary effects against adenine‐induced CKD in rats by reducing inflammation and oxidative stress via up‐regulation of the transcription factor Nrf2.
Abstract: Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD. Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-β-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1β, IL-6 and TNF-α, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2.
TL;DR: The results were attributed to the protective effect of k-carrageenan to protein during in vitro digestion so that the access of digestive enzymes into the hydrogels was limited resulting in a reduction of gel matrix erosion and curcumin release.