Low Concentrations Of Curcumin Research Articles

The Bright Side of Curcumin: A Narrative Review of Its Therapeutic Potential in Cancer Management.

Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits significant therapeutic potential in cancer management. This review explores curcumin's mechanisms of action, the challenges related to its bioavailability, and its enhancement through modern technology and approaches. Curcumin demonstrates strong antioxidant and anti-inflammatory properties, contributing to its ability to neutralize free radicals and inhibit inflammatory mediators. Its anticancer effects are mediated by inducing apoptosis, inhibiting cell proliferation, and interfering with tumor growth pathways in various colon, pancreatic, and breast cancers. However, its clinical application is limited by its poor bioavailability due to its rapid metabolism and low absorption. Novel delivery systems, such as curcumin-loaded hydrogels and nanoparticles, have shown promise in improving curcumin bioavailability and therapeutic efficacy. Additionally, photodynamic therapy has emerged as a complementary approach, where light exposure enhances curcumin's anticancer effects by modulating molecular pathways crucial for tumor cell growth and survival. Studies highlight that combining low concentrations of curcumin with visible light irradiation significantly boosts its antitumor efficacy compared to curcumin alone. The interaction of curcumin with cytochromes or drug transporters may play a crucial role in altering the pharmacokinetics of conventional medications, which necessitates careful consideration in clinical settings. Future research should focus on optimizing delivery mechanisms and understanding curcumin's pharmacokinetics to fully harness its therapeutic potential in cancer treatment.

Mitigation of Karenia brevis Cells and Brevetoxins Using Curcumin, a Natural Supplement

Curcumin, a natural plant product, was investigated as a mitigation tool against Karenia brevis, the toxic dinoflagellate responsible for Florida red tides. A series of laboratory bench-top studies were conducted with additions of 0.1, 1, 2, 3, 5, 10, 20, 30, and 40 mg/L curcumin to K. brevis at an average of 1.0 × 106 cells/L to determine the efficacy of curcumin against K. brevis cells and brevetoxins and to optimize treatment dosage. Treatment with 5 mg/L of curcumin reduced K. brevis cell abundance by 89% and total brevetoxins by 60% within 24 h. Lower concentrations of curcumin (0.1–3 mg/L) exhibited between a 2 and 45% reduction in K. brevis and a reduction in brevetoxins of between 2 and 44% within 24 h. At the highest curcumin doses, 30 and 40 mg/L, a 100% reduction in cell abundance was observed by 6 h, with reduction in total brevetoxins by at least 64% in 48 h. These results suggest that curcumin, used alone or potentially in combination with other technologies, is a promising K. brevis bloom mitigation option.

Low curcumin concentrations combined with blue light inhibits cutibacterium acnes biofilm-induced inflammatory response through suppressing MAPK and NF-κB in keratinocytes

BackgroundCurcumin has been employed as a photosensitizer agent during photodynamic therapy (PDT). Cutibacterium acnes (C. acnes) can cause an inflammatory response in human keratinocytes; however, no research has been conducted to determine whether curcumin and its photodynamic properties can prevent this inflammatory reaction. ObjectiveWe hypothesized that curcumin may control the C. acnes biofilm-induced inflammatory response in keratinocytes, either alone or in combination with blue light photodynamic therapy. MethodsFollowing C. acnes biofilm stimulation, human primary keratinocytes were treated with 20 μM curcumin solution alone or 5 μM curcumin with combined blue light irradiation. The amount of secreted protein was measured using an ELISA kit. The expression levels of Toll-like receptor 2 (TLR2) and its downstream proteins were determined using western blot. ResultsTreatment with 20 μM curcumin, but not 5 μM curcumin, reduced the inflammatory response to C. acnes biofilms in keratinocytes by blocking the TLR2/MAPK/NF-κB pathway. Interestingly, 5 μM curcumin combined with blue light also reduced the C. acnes biofilm-induced inflammation indicated above by blocking the TLR2/MAPK/NF-κB pathway. ConclusionCurcumin alone, in sufficient concentrations, or low-concentration curcumin with blue light had anti-inflammatory activity on keratinocytes stimulated by C. acnes biofilms through inhibition of MAPK and NF-κB signaling pathways by downregulating TLR2 expression.

Influence of the Hydrophobicity of Pluronic Micelles Encapsulating Curcumin on the Membrane Permeability and Enhancement of Photoinduced Antibacterial Activity.

Apart from its well-known activity as an antimicrobial agent, Curcumin (CURC) has recently started to arouse interest as a photosensitizer in the photodynamic therapy of bacterial infections. The aim of the present study was to evidence the influence of the encapsulation of Curcumin into polymeric micelles on the efficiency of photoinduced microbial inhibition. The influence of the hydrophobicity of the selected Pluronics (P84, P123, and F127) on the encapsulation, stability, and antimicrobial efficiency of CURC-loaded micelles was investigated. In addition, the size, morphology, and drug-loading capacity of the micellar drug delivery systems have been characterized. The influence of the presence of micellar aggregates and unassociated molecules of various Pluronics on the membrane permeability was investigated on both normal and resistant microbial strains of E. coli, S. aureus, and C. albicans. The antimicrobial efficiency on the common pathogens was assessed for CURC-loaded polymeric micelles in dark conditions and activated by blue laser light (470 nm). Significant results in the reduction of the microorganism’s growth were found in cultures of C. albicans, even at very low concentrations of surfactants and Curcumin. Unlike the membrane permeabilization effect of the monomeric solution of Pluronics, reported in the case of tumoral cells, a limited permeabilization effect was found on the studied microorganisms. Encapsulation of the Curcumin in Pluronic P84 and P123 at very low, nontoxic concentrations for photosensitizer and drug-carrier, produced CURC-loaded micelles that prove to be effective in the light-activated inhibition of resistant species of Gram-positive bacteria and fungi.

Curcumin induces thermotolerance by reducing oxidative stress, apoptosis, and inflammation in buffalo mammary epithelial cells under heat shock conditions

The epithelial cell is the main basic unit of the udder in which milk synthesis takes place. Curcumin is well known for its antioxidant, anti-apoptotic, and anti- inflammatory properties. The present study was performed to test whether in vitro curcumin supplementation can alleviate the unfavorable impact of hyperthermia on buffalo mammary epithelial cells (BuMECs). The spontaneously immortalized BuMECs were divided into 7 groups (n = 9); 1) unstressed BuMECs (negative control, 37 °C); 2) BuMECs exposed to hyperthermia without curcumin treatment (positive control); 3–7) BuMECs cultured with different concentrations of curcumin (5, 10, 20, 40 and 60 μM), respectively, followed by hyperthermic exposure (42ºC) for 1 h and then returned to 37ºC. Changes in viability (MTT assay), proliferation (BrdU colorimetric immunoassay) and concentrations of antioxidant enzymes, CAT, and SOD (ELISA) of BuMECs were recorded. The gene expression study was performed using qRT-PCR. Lower concentrations of curcumin (5, 10 μM) maintained viability, enhanced proliferation, and content of antioxidant enzymes of heat stressed BuMECs. Curcumin induced thermotolerance and antioxidant status by upregulating the expression of antioxidants genes, anti-apoptotic genes and heat shock proteins in heat stressed BuMECs compared to the positive control group. Besides, curcumin reduced apoptosis and inflammation in BuMECs exposed to hyperthermia by downregulating the expression of genes and transcriptional factors associated with apoptosis and inflammatory immune response. The results reveal the potential roles of curcumin in eliminating the negative impact of hyperthermia on BuMECs by regulating the pathways of apoptosis, inflammation, and oxidative stress.

Bioadhesive Curcumin-Mediated Photodynamic Inactivation and Its Potential to Cause Undesirable Effects on Dental and Restorative Surfaces.

Curcumin-mediated Photodynamic Inactivation (PDI) has shown great potential to disinfect specific sites on tooth enamel but may involve contact with restorative materials. Thus, before use in dentistry, it is necessary to investigate whether the PDI protocol causes undesirable changes in the surfaces of aesthetic restorative materials and dental enamel. This study investigated the effect of PDI mediated by curcumin (CUR) in a liquid crystal precursor system on color stability (ΔE), surface roughness (Ra), and microhardness (kgf) of three different composite resins and bovine dental enamel specimens. The microhardness and roughness readings were performed 60 days after the treatments while the color readings were performed immediately, 24, 48, and 72 h, 7, 14, 21, 30, and 60 days after the treatments. Results showed that CUR mediated-PDI does not seem to have the potential to promote any esthetic or mechanical changes to the surface of tooth enamel and can be applied safely in clinical practice. However, the results on color, roughness, and hardness obtained for composite resins show that some negative effects can be produced, depending on the type of restorative material; more experiments must be performed with different formulations and, perhaps, with lower concentrations of CUR.

Curcumin suppresses neuroinflammation to protect neurons by preventing NLRP3 inflammasome activation

Introduction Nucleotide-binding and oligomerization domain like receptors protein 3 (NLRP3) inflammasome-mediated interleukin (IL)-1β secretion plays an important role in the progression of Alzheimer’s disease (AD). Curcumin has been shown to improve cognitive impairment and learning ability of AD mice by reducing IL-1β secretion. However, its exact mechanism of action remains unclear. In the present study, we explored the relationship between the neuroprotective effect of curcumin and activation of the NLRP3 inflammasome pathway. Methods BV2 cells were primed with 500 ng/mL lipopolysaccharide (LPS) for 4 h and subsequently treated with 50 μM Aβ25-35 for 24 h or pretreated with 2.5–10 μM curcumin for 4 h and exposed to 50 μM Aβ25-35 for 24 h. The effects of curcumin and Aβ25-35 were assessed by the CCK8 assay. ELISA was used for the detection of IL-1β, IL-6, and tumor necrosis factor (TNF)-α levels in the supernatant of the cell culture medium. The viability of SH-SY5Y cells, which were incubated with conditioned medium (CM) was assessed using the CCK8 assay. The percentage of apoptotic SH-SY5Y cells incubated with CM was assessed using Annexin V-FITC/PI staining flow cytometry analysis. The expression levels of NLRP3, caspase-1 and IL-1β were observed by western blot and immunofluorescence staining analyses; the mRNA levels of nlrp3, caspase-1 and IL-1β were analyzed using qRT-PCR. Results Low (2.5 μM), medium (5 μM), and high (10 μM) concentrations of curcumin and 50 μM Aβ25-35 were used to perform the experiments in the present study. Curcumin attenuated the IL-1β, IL-6, and TNF-α release and increased SH-SY5Y cell activity, while decreasing the apoptotic percentage of SH-SY5Y cells using Aβ25-35 for cell stimulation ( p < 0.05). Furthermore, curcumin inhibited the expression of NLRP3, caspase-1 and IL-1β and nlrp3 in BV-2 cells ( p < 0.05), However, curcumin did not affect the expression levels of caspase-1 and IL-1β ( p > 0.05) Conclusion Overall, the data indicated that curcumin is a promising neuroprotective agent for suppressing neuroinflammation by inhibiting the NLRP3 inflammasome pathway.

Curcumin supplementation in the maturation medium improves the maturation, fertilisation and developmental competence of porcine oocytes.

This study was conducted to determine the effects of supplementing the maturation medium with the antioxidant curcumin on the in vitro maturation (IVM), fertilisation and development of porcine oocytes. Curcumin supplementation was performed at concentrations of 0, 5, 10, 20, and 40 µM. At concentrations of 5-20 µM, curcumin had significant positive effects (P < 0.05) on maturation and fertilisation rates compared to the non-treated group. Of the groups cultured with 5-20 µM curcumin, the number of oocytes with DNA-fragmented nuclei after IVM was significantly lower than in groups matured without curcumin. Moreover, curcumin supplementation at 10 µM also gave a significantly higher rate of blastocyst formation compared with oocytes matured without curcumin. Increasing the curcumin concentration to 40 µM yielded negative effects on fertilisation and embryonic development compared with the groups treated with lower concentrations of curcumin. Supplementation with 10 µM curcumin had beneficial effects on the oocyte maturation rate and DNA fragmentation index compared to the non-treated group both in the presence and absence of hydrogen peroxide. These results indicate that curcumin supplementation at a suitable concentration (10 µM) is potentially useful for porcine oocyte culture systems, in terms of protecting oocytes from various forms of oxidative stress.

A Spheroid-Forming Hybrid Gold Nanostructure Platform That Electrochemically Detects Anticancer Effects of Curcumin in a Multicellular Brain Cancer Model.

In this study, a multifunctional platform that enables the highly efficient formation of 3D multicellular cancer spheroids and precise real-time assessments of the anticancer effects of curcumin in a brain tumor coculture model is reported. A highly conductive gold nanostructure (HCGN) is fabricated to facilitate cancer spheroid formation without using anti-cell adhesion molecules. A neuroblastoma (SH-SY5Y) and glioblastoma (U-87MG) coculture model is generated on HCGN with a specific cell-to-cell ratio (SH-SY5Y: U-87MG = 1:1), and their redox behaviors are successfully measured without destroying the distinct 3D structure of the multicellular spheroids. Using electrochemical signals as an indicator of spheroid viability, the effects of potential anticancer compounds on cocultured spheroids are further assessed. Remarkably, decreased cell viability in 3D spheroids caused by a low concentration of curcumin (30µM) is detectable using the electrochemical method (29.4%) but not with a conventional colorimetric assay (CCK-8). The detection is repeated more than ten times for both short- (63 h) and long-term cultivation (144 h) without damaging the spheroids, enabling real-time, non-destructive pharmacokinetic analysis of various drug candidates. Therefore, it can be concluded that the hybrid platform is a highly promising, precise, and high-throughput drug screening tool based on 3D cell cultivation.

Negligible Protection of Pancreas by Topical Curcumin in Streptozotocin Induced Diabetic Wounded Rats

Damage or non-functioning of beta cells of Langerhans is lets of pancreas causes Type I diabetes. Curcumin, a bioflavonoid, have shown some tissue regenerative properties. It has shown a very good wound healing actions in diabetic animals after topical applications. In view of this, we planned to study the regenerative action of curcumin on damaged pancreas of diabetic rats after its topical applications on wounds. Damage of pancreas and induction of Type I diabetes in rats was achieved by single intraperitoneal injection of streptozotocin (60mg/kg b.wt.). Thereafter, open excisional wounds were created and wounded rats were divided into three groups viz. i) healthy control (non-diabetic), ii) Diabetic control and iii) Diabetic-treated. Pluronic F-127 gel (25%) was applied topically on wounds of group I and II once daily for 19 days. Curcumin (0.3%) in gel was topically applied similarly on group III. Average body weight gain was less and blood glucose levels were high in group II and III. There were also higher levels of MDA in group II and III. Histopathologically, atrophy and loss of intactness of beta cells of langerhans is lets in the pancreas were evident in group II and III, as compared to group I. In conclusion, topical applications of curcumin on wounds of diabetic rats did not able to prevent the damage of beta cells of the pancreas produced by single intraperitoneal injection of streptozotocin (60mg/kg b.wt.). In future, the other higher or lower concentrations of curcumin and their nano-formulations may be tried to evaluate the protective actions.

The Impact of Curcumin on Bone Osteogenic Promotion of MC3T3 Cells under High Glucose Conditions and Enhanced Bone Formation in Diabetic Mice

Diabetic osteoporosis (DOP) is characterized by impaired bone microstructure and reduced bone density resulting from high glucose levels. Curcumin (CURC) is extensively applied in the treatment of inflammation-associated diseases. However, the effect of curcumin on bone metabolism in diabetic osteoporosis is unclear. Therefore, this study investigated the optimal concentration of curcumin on enhancing osteogenesis in diabetic osteoporosis. Osteoblasts were treated with a high or low concentration of curcumin under a series of concentrations of high-glucose conditions. Type 2 diabetic mice were intervened with curcumin. Cell proliferation, apoptosis, and osteogenesis-related gene expressions were evaluated by CCK-8, flow cytometry, and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Bone formation was evaluated by histological staining. The findings revealed that curcumin suppressed apoptosis and enhanced proliferation and osteogenesis-related gene expressions of osteoblasts under high glucose concentrations (p &lt; 0.05). The histological sections displayed reduced bone destruction and increased the growth rate of trabecular bone and the bone density of diabetic mice treated with curcumin, compared to diabetic mice. These results showed that curcumin could reverse the harmful effects of diabetic osteoporosis in a dose-dependent manner, and 10 μmol/L was regarded as the optimal concentration, which supports the potential use of curcumin for bone regeneration under high glucose concentrations.

Spray-drying microencapsulation of curcumin nanocomplexes with soy protein isolate: Encapsulation, water dispersion, bioaccessibility and bioactivities of curcumin

The spray-drying microencapsulation of curcumin encapsulated in soy protein isolate (SPI) nanocomplexes, as well as the influence of spray-drying on encapsulation, water redispersion behavior, bioaccessibility, and bioactivities (antioxidant and anti-cancer) of encapsulated curcumin, was investigated. The addition of soy soluble polysaccharide (SSPS) and/or maltodextrin (MD), alone or in a combination, prior to the spray-drying, greatly improved the microencapsulation performance of the nanocomplex, and water dispersion behavior of the corresponding spray-dried powders. Regardless of the addition of SSPS or MD, the spray-drying remarkably decreased the bioaccessibility of encapsulated curcumin, which seemed to be associated with the aggregation of the nanocomplexes. The curcumin encapsulated in the spray-dried nanocomplex exhibited a much higher oxygen radical absorbance capacity than free curcumin (in DMSO). Both free and encapsulated curcumin showed a remarkable cytotoxicity or anti-proliferation against human hepatal carcinoma HepG2 cells, but the effects were highly dose-dependent. In the cytotoxicity evaluation, at high curcumin concentrations, e.g., 40–80 μM, encapsulated curcumin induced apoptosis of the cells, to a significantly less extent, than free curcumin. However, in the anti-proliferation case, at low concentrations (e.g., <30 μM) the encapsulated curcumin exhibited a more effective inhibition of cell proliferation than free curcumin. At high concentrations (>30 μM), both free and encapsulated curcumin inhibited the cell proliferation via the arrest of cells in G2/M phase, while at low curcumin concentrations, the antioxidant activity might largely account for the inhibition effects. The findings would be of importance for the use of soy protein nanocarriers for encapsulation and delivery of poorly soluble bioactives, in the functional food formulations.

Curcumin combined with exposure to visible light blocks bladder cancer cell adhesion and migration by an integrin dependent mechanism.

Although the natural compound curcumin exerts antitumor properties in vitro, its clinical application is hampered due to rapid metabolism. Light exposure following curcumin application has been demonstrated to improve curcumin's bioavailability. Therefore, this investigation was directed towards evaluating whether light exposure in addition to curcumin application enhances curcumin's efficacy against bladder cancer cell adhesion and migration. RT112, UMUC3, and TCCSUP cells were incubated with low curcumin concentrations (0.1-0.4 μg/ml) and then exposed to 1.65 J/cm2 visible light for 5 min. Controls remained untreated or were treated with curcumin or light alone. Cell adhesion to Human umbilical vein endothelial cells (HUVECs), to immobilized collagen or fibronectin and chemotactic behavior, integrin α and β receptor expression with functional relevance, as well as focal adhesion kinase (total and phosphorylated FAK) were evaluated. Curcumin plus light, but neither curcumin nor light alone, significantly altered tumor cell adhesion and suppressed chemotaxis. Integrin α and β subtypes were dissimilarly modified, depending on the cell line. Suppression of pFAK was noted in RT112 and UMUC3, but not in TCCSUP cells. The integrins α3, α5, and β1 were involved in curcumin's regulation of adhesion and migration. Blocking studies revealed α3, α5, and β1 to be associated with TCCSUP adhesion and migration, whereas α5 and β1, but not α3 contributed to UMUC3 adhesion and migration. Integrin α5 and β1 controlled RT112 chemotaxis as well, but only α5 was involved in the RT112 adhesion process. Combining curcumin with light exposure enhances curcumin's anti-tumor potential.

Tomatoes’ skins as a rich source of natural pigments

Rhizome of Curcuma longa L. is rich in curcumin which is also an important natural pigment and has important biological activity. In order to obtain curcumin concentrated extracts, one-step and two-step processes were employed. The one step process involves supercritical carbon dioxide (scCO2) at 60 °C and 400 bar, ethanol at 25 °C and water at 60 °C, both at atmospheric pressure. Ethanol and/or water were used as solvents. In the two-step process, sequential extraction, using scCO2, was performed followed by ethanol or water extraction. All the extracts obtained were analyzed and results were reported for global extraction yield, the total phenolic content, total flavonoids, curcumin, antimalarial activity and antioxidant activity. The two-step process showed the highest global yield (23.4%) when water is used as solvent in the second step. However, high concentrations of curcumin and high antioxidant activity were obtained when ethanol is used as solvent. The supercritical extract presents low concentration of curcumin and high antimalarial activity; which shows that extracts of different compositions and functionality can be obtained from a sequential extraction.

Growth and Proliferation of Renal Cell Carcinoma Cells Is Blocked by Low Curcumin Concentrations Combined with Visible Light Irradiation.

The anti-cancer properties of curcumin in vitro have been documented. However, its clinical use is limited due to rapid metabolization. Since irradiation of curcumin has been found to increase its anti-cancer effect on several tumor types, this investigation was designed to determine whether irradiation with visible light may enhance the anti-tumor effects of low-dosed curcumin on renal cell carcinoma (RCC) cell growth and proliferation. A498, Caki1, and KTCTL-26 cells were incubated with curcumin (0.1–0.4 µg/mL) and irradiated with 1.65 J/cm2 visible light for 5 min. Controls were exposed to curcumin or light alone or remained untreated. Curcumin plus light, but not curcumin or light exposure alone altered growth, proliferation, and apoptosis of all three RCC tumor cell lines. Cells were arrested in the G0/G1 phase of the cell cycle. Phosphorylated (p) CDK1 and pCDK2, along with their counter-receptors Cyclin B and A decreased, whereas p27 increased. Akt-mTOR-signaling was suppressed, the pro-apoptotic protein Bcl-2 became elevated, and the anti-apoptotic protein Bax diminished. H3 acetylation was elevated when cells were treated with curcumin plus light, pointing to an epigenetic mechanism. The present findings substantiate the potential of combining low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in RCC.

The Antitumor Effect of Curcumin in Urothelial Cancer Cells Is Enhanced by Light Exposure In Vitro.

The natural compound curcumin exerts antitumor properties in vitro, but its clinical application is limited due to low bioavailability. Light exposure in skin and skin cancer cells has been shown to improve curcumin bioavailability; thus, the object of this investigation was to determine whether light exposure might also enhance curcumin efficacy in bladder cancer cell lines. RT112, UMUC3, and TCCSUP cells were preincubated with low curcumin concentrations (0.1-0.4 μg/ml) and then exposed to 1.65 J/cm2 visible light for 5 min. Cell growth, cell proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins along with acetylation of histone H3 and H4 were investigated. Though curcumin alone did not alter cell proliferation or apoptosis, tumor cell growth and proliferation were strongly blocked when curcumin was combined with visible light. Curcumin-light caused the bladder cancer cells to become arrested in different cell phases: G0/G1 for RT112, G2/M for TCCSUP, and G2/M- and S-phase for UMUC3. Proteins of the Cdk-cyclin axis were diminished in RT112 after application of 0.1 and 0.4 μg/ml curcumin. Cell cycling proteins were upregulated in TCCSUP and UMUC3 in the presence of 0.1 μg/ml curcumin-light but were partially downregulated with 0.4 μg/ml curcumin. 0.4 μg/ml (but not 0.1 μg/ml) curcumin-light also evoked late apoptosis in TCCSUP and UMUC3 cells. H3 and H4 acetylation was found in UMUC3 cells treated with 0.4 μg/ml curcumin alone or with 0.1 μg/ml curcumin-light, pointing to an epigenetic mechanism. Light exposure enhanced the antitumor potential of curcumin on bladder cancer cells but by different molecular action modes in the different cell lines. Further studies are necessary to evaluate whether intravesical curcumin application, combined with visible light, might become an innovative tool in combating bladder cancer.

Extrinsic or Intrinsic Apoptosis by Curcumin and Light: Still a Mystery.

Curcumin—a rhizomal phytochemical from the plant Curcuma longa—is well known to inhibit cell proliferation and to induce apoptosis in a broad range of cell lines. In previous studies we showed that combining low curcumin concentrations and subsequent ultraviolet A radiation (UVA) or VIS irradiation induced anti-proliferative and pro-apoptotic effects. There is still debate whether curcumin induces apoptosis via the extrinsic or the intrinsic pathway. To address this question, we investigated in three epithelial cell lines (HaCaT, A431, A549) whether the death receptors CD95, tumor necrosis factor (TNF)-receptor I and II are involved in apoptosis induced by light and curcumin. Cells were incubated with 0.25–0.5 µg/mL curcumin followed by irradiation with 1 J/cm2 UVA. This treatment was combined with inhibitors specific for distinct membrane-bound death receptors. After 24 h apoptosis induction was monitored by quantitative determination of cytoplasmic histone-associated-DNA-fragments. Validation of our test system showed that apoptosis induced by CH11 and TNF-α could be completely inhibited by their respective antagonists. Interestingly, apoptosis induced by curcumin/light treatment was reversed by none of the herein examined death receptor antagonists. These results indicate a mechanism of action independent from classical death receptors speaking for intrinsic activation of apoptosis. It could be speculated that a shift in cellular redox balance might prompt the pro-apoptotic processes.

Curcumin induces concentration-dependent alterations in mitochondrial function through ROS in C2C12 mouse myoblasts.

Curcumin exhibits antioxidant properties in normal cells where the uptake is low, unlike in tumor cells where uptake is high and curcumin increases reactive oxygen species (ROS) production and cell death. Mitochondria are the main source and primary target of cellular ROS. We hypothesized that curcumin would regulate cellular redox status and mitochondrial function, depending on cell sensitivity and/or curcumin concentration in normal cells. We examined the differences between low and high concentrations of curcumin, with specific attention focused on ROS levels, mitochondrial function, and cell viability in mouse C2C12 myoblast under normal and simulated conditions of diabetes. Cells incubated with high concentrations of curcumin (10-50 μM) resulted in decreased cell viability and sustained robust increases in ROS levels. Mechanistic studies showed that increased ROS levels in cells incubated with 20 μM curcumin induced opening of mitochondrial permeability transition pores and subsequent release of cytochrome c, activation of caspases 9 and 3/7, and apoptotic cell death. Low concentrations of curcumin (1-5 μM) did not affect cell viability, but induced a mild increase in ROS levels, which peaked at 2 hr after the treatment. Incubation with 5 μM curcumin also induced ROS-dependent increases in mitochondrial mass and membrane potential. Finally, pretreatment with 5 μM curcumin prevented high glucose-induced oxidative cell injury. Our study suggests that mitochondria respond differentially depending on curcumin concentration-dependent induction of ROS. The end result is either cell protection or death. Curcumin may be an effective therapeutic target for diabetes and other mitochondrial diseases when used in low concentrations.

Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

Autophagy is a major mechanism for the dual effects of curcumin on renal cell carcinoma cells

The aim of this study was to explore the effects of curcumin on renal cell carcinoma（RCC） through regulating autophagy. Cell viabilities were determined by MTT assay in RCC cells after treatment with curcumin at different concentrations for various durations. ATG7 silencing RCC cells were established to test the role of autophagy. The levels of key proteins on autophagy pathway were analyzed by Western blot. We found out that following 24 h curcumin treatment, the viability of RCC cells had an increase at 5 μM and no significant change at 20 μM but a decrease at 80 μM. These effects were affected by the inhibition of autophagy. When pre-incubated with inhibitors of the AMPK and ER stress pathways, the LC3II levels of RCC cells at 5 μM and 20 μM of curcumin were significantly decreased; however, when treated with the inhibitor of the oxidative stress pathway, the LC3II levels of RCC cells at 80 μM were significantly decreased. In conclusion, the present study indicated Curcumin protected cells from death at low concentration but promotes cell death at high concentration. Autophagy played a dual role in curcumin's effects on RCC. The AMPK and ER stress pathways might be involved at low concentrations of curcumin to protect cells, while the oxidative stress pathway might take part in toxicity at high curcumin concentration.