Curcumin induces stress response, neurite outgrowth and prevent NF-kappaB activation by inhibiting the proteasome function.
TL;DR: It is shown that curcumin disrupts UPS function by directly inhibiting the enzyme activity of the proteasome’s 20S core catalytic component, which causes an increase in half-life of IκB-α that ultimately leads to the down-regulation of NF-κB activation.
Abstract: Curcumin, a natural polyphenolic compound, has long been known as an anti-tumour and anti-inflammatory compound; although, the common mechanism through which it exhibits such properties are remains unclear. Recently, we reported that the curcumin-induced apoptosis is mediated through the impairment of ubiquitin proteasome system (UPS). Here, we show that curcumin disrupts UPS function by directly inhibiting the enzyme activity of the proteasome's 20S core catalytic component. Like other proteasome inhibitors, curcumin exposure induces neurite outgrowth and the stress response, as evident from the induction of various cytosolic and endoplasmic reticulum chaperones as well as induction of transcription factor CHOP/GADD153. The direct inhibition of proteasome activity also causes an increase in half-life of IkappaB-alpha that ultimately leads to the down-regulation of NF-kappaB activation. These results suggest that curcumin-induced proteasomal malfunction might be linked with both anti-proliferative and anti-inflammatory activities.
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TL;DR: In this article, a pH-responsive polyacetal-curcumin nanoconjugate (PA-C) was used to deliver into the intrathecal space in a rat model of contusive spinal cord injury with stem cell transplant.
Abstract: We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal-curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of β-III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments.
14 citations
TL;DR: Phenolic compounds are a large, heterogeneous group of secondary metabolites found in various plants and herbal substances and their utilization in cutaneous formulations sets challenges to drug development.
Abstract: Phenolic compounds are a large, heterogeneous group of secondary metabolites found in various plants and herbal substances. From the perspective of dermatology, the most important benefits for human health are their pharmacological effects on oxidation processes, inflammation, vascular pathology, immune response, precancerous and oncological lesions or formations, and microbial growth. Because the nature of phenolic compounds is designed to fit the phytochemical needs of plants and not the biopharmaceutical requirements for a specific route of delivery (dermal or other), their utilization in cutaneous formulations sets challenges to drug development. These are encountered often due to insufficient water solubility, high molecular weight and low permeation and/or high reactivity (inherent for the set of representatives) and subsequent chemical/photochemical instability and ionizability. The inclusion of phenolic phytochemicals in lipid-based nanocarriers (such as nanoemulsions, liposomes and solid lipid nanoparticles) is so far recognized as a strategic physico-chemical approach to improve their in situ stability and introduction to the skin barriers, with a view to enhance bioavailability and therapeutic potency. This current review is focused on recent advances and achievements in this area.
14 citations
TL;DR: Investigation of the cell uptake of Nigella sativa oil-PLGA microparticle by neuron-like PC-12 cells in comparison to surfactants revealed varying efficiencies, which may be partially attributed to the surface hydrophobicity of the microparticles.
Abstract: The aim of this study is to investigate the cell uptake of Nigella sativa oil (NSO)-PLGA microparticle by neuron-like PC-12 cells in comparison to surfactants; hydrophilic (Tween 80 & Triton X100) and hydrophobic (Span 80). Solvent evaporation was used to precisely control the size, zeta potential and morphology of the particle. The results revealed varying efficiencies of the cell uptake by PC-12 cells, which may be partially attributed to the surface hydrophobicity of the microparticles. Interestingly, the uptake efficiency of PC-12 cells was higher with the more hydrophilic microparticle. NSO microparticle showed evidence of being preferably internalised by mitotic cells. Tween 80 microparticle showed the highest cell uptake efficiency with a concentration-dependent pattern suggesting its use as uptake enhancer for non-scavenging cells. In conclusion, PC-12 cells can take up NSO-PLGA microparticle which may have potential in the treatment of neurodegenerative disease.
14 citations
Cites background from "Curcumin induces stress response, n..."
...Curcumin is one of the most extensively studied phytochemicals for its benefits in neuro-degenerative diseases (Dikshit et al., 2006; Yang et al., 2008; Zhao et al., 2011)....
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TL;DR: A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line.
Abstract: A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure-activity-relationships as well as eventual correlations with the pathways described for Multiple Myeloma were discussed. Each of the major compound classes in this review (alkaloids, phenolics, terpenes) revealed interesting candidates, such as dioncophyllines, a group of naphtylisoquinoline alkaloids, which showed pronounced and selective induction of apoptosis when substituted in position 7 of the isoquinoline moiety. Interestingly, out of the phenolic compound class, two of the most noteworthy constituents belong to the relatively small subclass of xanthones, rendering this group a good starting point for possible further drug development. The class of terpenoids also provides noteworthy constituents, such as the highly oxygenated diterpenoid oridonin, which exhibited antiproliferative effects equal to those of bortezomib on RPMI8226 cells. Moreover, triterpenoids containing a lactone ring and/or quinone-like substructures, e.g., bruceantin, whitaferin A, withanolide F, celastrol, and pristimerin, displayed remarkable activity, with the latter two compounds acting as inhibitors of both NF-κB and proteasome chymotrypsin-like activity.
11 citations
TL;DR: Results suggest that cetuximab initiates pathways that result in the stabilization of Eme1, thereby resulting in enhanced DNA repair, reducing the effectiveness of DNA-damaging therapies.
11 citations
Cites background from "Curcumin induces stress response, n..."
...d1EGFP is a destabilized enhanced green fluorescence protein, which contains a proline, glutamate, serine, and threonine sequence at its C terminus and has a half-life of ~1 hour [28,29]....
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TL;DR: It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease.
Abstract: Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, conside...
3,990 citations
Journal Article•
TL;DR: Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis, and Pharmacologically,Curcumin has been found to be safe.
Abstract: Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF- κB, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. Curcumin, derived from turmeric (vernacular name: Haldi), is a rhizome of the plant Curcuma longa. The medicinal use of this plant has been documented in Ayurveda (the Indian
2,453 citations
TL;DR: It appears that when given orally, curcumin is far less active than after i.p. administration, and systemic effects seem to be questionable after oral application except that they occur at very low concentrations ofCurcumin, which does not exclude a local action in the gastrointestinal tract.
Abstract: The data reviewed indicate that extracts of Curcuma longa exhibit anti-inflammatory activity after parenteral application in standard animal models used for testing anti-inflammatory activity It turned out that curcumin and the volatile oil are at least in part responsible for this action It appears that when given orally, curcumin is far less active than after ip administration This may be due to poor absorption, as discussed Data on histamine-induced ulcers are controversial, and studies on the secretory activity (HCl, pepsinogen) are still lacking In vitro, curcumin exhibited antispasmodic activity Since there was a protective effect of extracts of Curcuma longa on the liver and a stimulation of bile secretion in animals, Curcuma longa has been advocated for use in liver disorders Evidence for an effect on liver disease in humans is not yet available From the facts that after oral application only traces of curcumin were found in the blood and that, on the other hand, most of the curcumin is excreted via the faeces it may be concluded that curcumin is absorbed poorly by the gastrointestinal tract and/or underlies presystemic transformation Systemic effects therefore seem to be questionable after oral application except that they occur at very low concentrations of curcumin This does not exclude a local action in the gastrointestinal tract
1,714 citations
TL;DR: It is demonstrated that curcumin (diferuloylmethane), a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-κB activation.
1,326 citations
TL;DR: The molecular sequelae of PS-341 treatment in MM cells are characterized and the rationale for future clinical trials of this promising agent, in combination with conventional and novel therapies, to improve patient outcome in MM is explained.
Abstract: The proteasome inhibitor PS-341 inhibits IκB degradation, prevents NF-κB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells. PS-341 has marked clinical activity even in the setting of relapsed refractory MM. However, PS-341-induced apoptotic cascade(s) are not yet fully defined. By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent. The transcriptional profile of PS-341-treated cells involved down-regulation of growth/survival signaling pathways, and up-regulation of molecules implicated in proapoptotic cascades (which are both consistent with the proapoptotic effect of proteasome inhibition), as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (which can correspond to stress responses against proteasome inhibition). Further studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic proteins and triggers a dual apoptotic pathway of mitochondrial cytochrome c release and caspase-9 activation, as well as activation of Jun kinase and a Fas/caspase-8-dependent apoptotic pathway [which is inhibited by a dominant negative (decoy) Fas construct]. Stimulation with IGF-1, as well as overexpression of Bcl-2 or constitutively active Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3 domain of Bcl-2 family members or the heat-shock protein 90 enhance tumor cell sensitivity to proteasome inhibition. These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM.
763 citations