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Cardiac fibrosis (c-fibrosis) is a critical factor in cardiovascular diseases, leading to impaired cardiac function and heart failure. This study aims to optimize the isoproterenol (ISO)-induced c-fibrosis model and evaluate the therapeutic efficacy of dendrosomal nano-curcumin (DNC) in both in-vitro and in-vivo conditions. Also, we were looking for the differentially expressed genes following the c-fibrosis induction. At the in-vitro condition, primary cardiac fibroblasts were exclusively cultured on collagen-coated or polystyrene plates and, were treated with ISO for fibrosis induction and post-treated or co-treated with DNC. RT-qPCR and flow cytometry analysis indicated that DNC treatment attenuated the fibrotic effect of ISO treatment in these cells. At the in-vivo condition, our findings demonstrated that ISO treatment effectively induces cardiac (and pulmonary) fibrosis, characterized by pro-fibrotic and pro-inflammatory gene expression and IHC (α-SMA, COL1A1, and TGFβ). Interestingly, fibrosis symptoms were reduced following the pretreatment, co-treatment, or post-treatment of DNC with ISO. Additionally, the intensive RNAseq analysis suggested the COMP gene is differentially expressed following the c-fibrosis and our RT-qPCR analysis suggested it as a novel potential marker. Overall, our results promise the application of DNC as a potential preventive or therapy agent before and after heart challenges that lead to c-fibrosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Beikzadeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Nano-drug delivery systems have become a promising approach to overcoming problems such as low solubility and cellular uptake of drugs. Along with various delivery devices, dendrimers are widely used through their unique features. PEG-citrate dendrimers are biocompatible and nontoxic, with the ability to improve drug solubility. Curcumin, a naturally occurring polyphenol, has multiple beneficial properties, such as antiviral activities. However, its optimum potential has been significantly hampered due to its poor water solubility, which leads to reduced bioavailability. So, the present study attempted to address this issue and investigate its antiviral effects against HIV-1., Method: The G2 PEG-citrate dendrimer was synthesized. Then, curcumin was conjugated to it directly. FTIR, HNMR, DLS, and LCMS characterized the structure of products. The conjugate displayed an intense yellow color. In addition, increased aqueous solubility and cell permeability of curcumin were achieved based on flow cytometry results. So, it could be a suitable vehicle for improving the therapeutic applications of curcumin. Moreover, cell toxicity was assessed using XTT method. Ultimately, the SCR HIV system provided an opportunity to evaluate the level of HIV-1 inhibition by the curcumin-dendrimer conjugate using a p24 HIV ELISA kit., Results: The results demonstrated a 50% up to 90% inhibition of HIV proliferation at 12 μm and 60 μm, respectively. Inhibition of HIV-1 at concentrations much lower than CC50 (300 µM) indicates a high potential of curcumin-dendrimer conjugate against this virus., Conclusion: Thereby, curcumin-dendrimer conjugate proves to be a promising tool to use in HIV-1 therapy., (© 2024. The Author(s).)

Background: Drug combination therapy is preferred over monotherapy in clinical research to improve therapeutic effects. Developing a new nanodelivery system for cancer drugs can reduce side effects and provide several advantages, including matched pharmacokinetics and potential synergistic activity. This study aimed to examine and determine the efficiency of the gemini surfactants (GSs) as a pH-sensitive polymeric carrier and cell-penetrating agent in cancer cells to achieve dual drug delivery and synergistic effects of curcumin (Cur) combined with tamoxifen citrate (TMX) in the treatment of MCF-7 and MDA-MB-231 human BC cell lines., Methods: The synthesized NPs were self-assembled using a modified nanoprecipitation method. The functional groups and crystalline form of the nanoformulation were examined by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and dynamic light scattering (DLS) used to assess zeta potential and particle size, and the morphological analysis determined by transmission electron microscopy (TEM). The anticancer effect was evaluated through an in vitro cytotoxicity MTT assay, flow cytometry analysis, and apoptosis analysis performed for mechanism investigation., Results: The tailored NPs were developed with a size of 252.3 ± 24.6 nm and zeta potential of 18.2 ± 4.4 mV capable of crossing the membrane of cancer cells. The drug loading and release efficacy assessment showed that the loading of TMX and Cur were 93.84% ± 1.95% and 90.18% ± 0.56%, respectively. In addition, the drug release was more controlled and slower than the free state. Polymeric nanocarriers improved controlled drug release 72.19 ± 2.72% of Tmx and 55.50 ± 2.86% of Cur were released from the Tmx-Cur-Gs NPs after 72 h at pH = 5.5. This confirms the positive effect of polymeric nanocarriers on the controlled drug release mechanism. moreover, the toxicity test showed that combination-drug delivery was much more greater than single-drug delivery in MCF-7 and MDA-MB-231 cell lines. Cellular imaging showed excellent internalization of TMX-Cur-GS NPs in both MCF-7 and MDA-MB-231 cells and synergistic anticancer effects, with combination indices of 0.561 and 0.353, respectively., Conclusion: The combined drug delivery system had a greater toxic effect on cell lines than single-drug delivery. The synergistic effect of TMX and Cur with decreasing inhibitory concentrations could be a more promising system for BC-targeted therapy using GS NPs., (© 2024. The Author(s).)

Different immunomodulation strategies have been used to manage COVID-19 due to the complex immune-inflammatory processes involved in the pathogenesis of this infection. Curcumin with its powerful anti-inflammatory and antiviral properties could serve as a possible COVID-19 therapy. In this study, a randomized, double-blinded, placebo-controlled trial was performed to investigate the effectiveness and safety of nano-curcumin oral soft gels as a complementary therapy in moderate-severe COVID-19 patients. Hydroxychloroquine (HCQ) plus sofosbuvir was routinely administered to all 42 COVID-19 patients, who were randomly assigned to receive 140 mg of nano-curcumin or placebo for 14 days. CT scans of the chest were taken, and blood tests were run for all patients at time points of 0, 7, and 14 days. Our results indicated that C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels significantly decreased from baseline in the nano-curcumin-treated group on day 7. Furthermore, blood levels of D-dimer, CRP, serum ferritin, ESR, and inflammatory cytokines including IL-6, IL-8, and IL-10 decreased more significantly in the nano-curcumin-treated group after 14 days. Additionally, the nano-curcumin group showed significant improvements in chest CT scores, oxygen saturation levels, and hospitalization duration. Based on our data, oral administration of nano-curcumin may be regarded as a promising adjunct treatment for COVID-19 patients due to its ability to speed up chest clearance and recovery., (© 2023 John Wiley & Sons Ltd.)

Toxoplasma gondii (T. gondii) remains as one of the controversial infections in the world. T. gondii is an important obligate intracellular protozoan parasite in the immune-deficient patients and pregnant women, sometimes leading to death and abortion, respectively. Herein, the adjuvant activity of nanocurcumin was assessed in the T. gondii killed vaccine model in BALB/c mice. In this study, 144 BALB/c mice were included in 8 groups and administered with different regimens of the vaccine; vac+30, 20 mg/kg of curcumin and nanocurcumin, vac + Freund's adjuvant, killed vac, vac + Alum adjuvant, and PBS via the subcutaneous route of immunization for three times with two-week intervals. Two weeks after the last immunization, the splenocytes' culture supernatant was evaluated for IL-4, IFN-γ, IL-2 and TNF-α cytokines and IFN-γ/IL-4, IFN-γ/TNF-α, and IL-2/IL-4 cytokine ratios using commercial ELISA kits. Specific total IgG antibodies, IgG1, and IgG2a were assessed with an optimized ELISA. Then the survival rate was determined 10 days after the experimental challenge. The results showed that the vaccine formulation in nanocurcumin at 20 mg/kg significantly increases IFN-γ cytokine and IFN-γ/IL4, IFN-γ/TNFα, and IL-2/IL4 ratios versus the vaccine formulated in curcumin, killed vaccine, and PBS group. In addition, specific total IgG antibody response showed that the vaccine formulated in nanocurcumin was more potent than that formulated in curcumin in the induction of humoral immune responses. Furthermore, results from the experimental challenge showed that nanocurcumin at a dose of 20 mg/kg could promote the life span of mice approximately by 12% versus the killed vaccine group. The present study showed that nanocurcumin in the vaccine formulation not only is more bioactive than curcumin in the modulation of cellular and humoral immune responses, but also provides more protectivity rate in the vaccinated mice on the killed T. gondii vaccine model. It seems that nanocurcumin can be used as an immunomodulator in vaccine formulation or as part of a complex adjuvant., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Curcumin was found to possess numerous pharmacological activities in clinical research, however, its biological effects together with radiation are yet to be addressed. The present study investigated whether the combined treatment of dendrosomal nanoformulation of curcumin (DNC) and gamma radiation can enhance the radiosensitivity of U87MG and MDA-MB-231 cell lines., Methods: U87MG and MDA-MB-231 cell lines were exposed to 2 Gray (Gy) and 10 μM DNC determined by MTT assay, then subjected to clonogenic assay, cell cycle assay, and flow cytometric apoptosis analysis. Acridine Orange/Ethidium Bromide (AO/EB) and 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) stained cells were used to study morphologic changes. The expression evaluation of putative cell cycle genes, i.e., P53, P21, CCND1, and CCNB1 was carried out by RT-qPCR., Results: Our findings indicated that the combined treatment with DNC and radiation might cooperatively augment the efficacy of ionizing radiation in the cancer cells and notably decrease the survival and viability of the cells in a time- and concentration-dependent manner. In addition to a synergistic effect deducted by sensitizer enhancement ratio (SER) assessment, co-treatment resulted in greater apoptotic cells than the individual treatments. Further experiments then indicated that DNC could effectively induce G2/M phase cell cycle arrest and apoptosis following irradiation. Conformably, there was a decrement of CCND1 and CCNB1 expression, and an increment of P53, P21 expression., Conclusions: The data implied that DNC as a radiosensitizer can enhance the lethal effect of ionizing radiation on cancer cells which could be a promising adjuvant therapy in clinical treatments., (© 2022. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Aims: Human papillomavirus (HPV) L1, L2 and E7 proteins were used as target antigens for development of preventive and therapeutic vaccines. Moreover, linkage of antigens to heat shock proteins (HSPs) could enhance the potency of vaccines. Curcumin and nanocurcumin compounds were suggested as the chemopreventive and chemotherapeutic agents against cancer. In this study, two multiepitope DNA and peptide-based vaccine constructs (L1-L2-E7 and HSP70-L1-L2-E7) were used along with curcumin and nanocurcumin to evaluate immune responses, and protective/therapeutic effects in tumor mouse model., Main Methods: At first, the multiepitope L1-L2-E7 and HSP70-L1-L2-E7 fusion genes were subcloned in eukaryotic and prokaryotic expression vectors. The recombinant multiepitope peptides were generated in E. coli strain. Then, the cytotoxic effects of curcumin and nanocurcumin were evaluated on HEK-293 T non-cancerous and C3 cancerous cells. Finally, mice vaccination was performed using different regimens. Curcumin and nanocurcumin compounds were administered alone or along with different vaccine constructs., Key Findings: Our data indicated that the use of nanocurcumin along with the multiepitope HSP70-L1-L2-E7 vaccine construct could completely protect mice against HPV-related C3 tumor cells, and eradicate tumors in a therapeutic test. Furthermore, nanocurcumin showed higher protection than curcumin alone. Generally, curcumin and nanocurcumin compounds could reduce tumor growth synergistically with the multiepitope vaccine constructs, but they did not influence the immune responses in different regimens., Significance: These data demonstrated that the designed multiepitope vaccine constructs along with curcumin and nanocurcumin can be used as a promising method for HPV vaccine development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Pressure ulcer (PU) is known as the third most costly disorder usually caused by prolonged pressure and stagnation in various parts of the body. Although several therapeutic approaches are employing, obstacles in appropriate healing for skin lesions still exist which necessitates new practical alternative or adjunctive treatments. Low level laser therapy (LLLT) as one of the mentioned new strategies have gained attention. Besides, curcumin is an herbal medicine extracted from turmeric with anti-inflammatory and antioxidative properties with promising beneficial therapeutic effects in wound healing. Employing dendrosomal nanoparticles, we overcome the hydrophobicity of curcumin in the present study. We hypothesized that combination treatment of DNC+LLLT (450 nm) simultaneously may promote the wound healing process., Material and Methods: MTT assay, PI staining followed by flowcytometry, scratch assay and intracellular ROS measurement were used to investigate the effects caused by DNC and LLLT (450 nm) alone and in combination, on proliferation, cell cycle, migration and oxidative stress mouse embryonic fibroblast cells, respectively. The levels of growth factors and pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA., Results: Our results indicated that combination exposure with DNC and LLLT leads to increased proliferation and migration of MEFs as well as being more efficient in significantly upregulating growth factors (TGF-β, VEGF) and decline in inflammatory cytokines (TNF-α, IL-6). Moreover, findings of this research provide persuasive support for the notion that DNC could reduce the LLLT-induced enhancement in intracellular ROS in mouse embryonic fibroblasts., Conclusion: Concurrent exposure to anti-oxidant concentrations of DNC and LLLT enriched S phase entry and therefor increased proliferation as well as migration on MEFs through regulating the expression levels growth factors and shortening the inflammatory phase by modulating of cytokines. It should be noted that DNC were able to reduce the laser-induced oxidative stress, during wound healing, representing an informative accompaniment with LLLT., Competing Interests: The authors have declared that no competing interests exist.

Side effects and chemotherapy resistance, demand new therapeutics with minimal side effects. Here, we investigated the combined effect of curcumin and metformin on the LNCaP prostate cancer cell line. LNCaP cells were treated with curcumin, metformin, and their combination at different concentrations. Cell viability was assessed by MTT assay and expression of Bax, Bcl-2, mTOR, hTERT, PUMA, p53 and p21 genes was analyzed by real-time PCR. Apoptosis and cell cycle were assessed by flow cytometry. Our results revealed that the viability of cells treated with curcumin, metformin, and their combination was significantly ( P  < 0.05) reduced with increasing the concentration and prolonging the treatment time. Meanwhile, the combination showed a synergistic effect within 48 h. In the curcumin treated group, the expression of Bcl-2 and hTERT genes diminished. In the metformin treated group, the expression of Bax and PUMA genes was enhanced while the expression of Bcl-2 , hTERT , mTOR , and p53 genes declined. Although all treatments induced apoptosis, the combination of curcumin and metformin showed the maximum level of apoptosis, cytotoxicity, and expression of Bax gene. The combination of curcumin and metformin showed synergistic effects within 48 h. This combination could be a potential therapeutic candidate for prostate cancer to be further investigated.

Mitochondrial malfunction plays a crucial role in cancer development and progression. Cancer cells show a substantially higher mitochondrial activity and greater mitochondrial transmembrane potential than normal cells. This concept can be exploited for targeting cytotoxic drugs to the mitochondria of cancer cells using mitochondrial-targeting compounds. In this study, a polyamidoamine dendrimer-based mitochondrial delivery system was prepared for curcumin using triphenylphosphonium ligands to improve the anticancer efficacy of the drug in vitro and in vivo. For the in vitro evaluations, various methods, such as viability assay, confocal microscopy, flow cytometry, reactive oxygen species (ROS), and real-time polymerase chain reaction analyses, were applied. Our findings showed that the targeted-dendrimeric curcumin (TDC) could successfully deliver and colocalize the drug to the mitochondria of the cancer cells, and selectively induce a potent apoptosis and cell cycle arrest at G2/M. Moreover, at a low curcumin dose of less than 25 μM, TDC significantly reduced adenosine triphosphate and glutathione, and increased the ROS level of the isolated rat hepatocyte mitochondria. The in vivo studies on the Hepa1-6 tumor-bearing mice also indicated a significant tumor suppression effect and the highest median survival days (Kaplan-Meier survival estimation and log-rank test) after treatment with the TDC construct compared to the free curcumin and untargeted construct. Besides its targeted nature and safety, the expected improved solubility and stability represent the prepared targeted-dendrimeric construct as an up-and-coming candidate for cancer treatment. The results of this study emphasize the promising route of mitochondrial targeting as a practical approach for cancer therapy, which can be achieved by optimizing the delivery method.

A targeted and controlled drug delivery system based on β-cyclodextrin (β-CD) for encapsulation and controlled release of hydrophobic drugs in the presence of maltogenic amylase (MAase), as a cyclodextrin-hydrolyzing enzyme, and trastuzumab antibody has been developed. In this study, the inclusion complex of curcumin (CUR), as a model anticancer compound, with β-CD was prepared and we constructed an antibody-enzyme bioconjugate (dextran mediated MAase-Trastuzumab bioconjugate) for controlled and targeted release of CUR at HER2 positive cancer cells (including SKBR3 and BT474). Immunocytochemistry analysis indicated that the MAase-Trastuzumab bioconjugate had significant binding affinities to HER2 positive cancer cells and demonstrated high enzyme activity to degrade β-CD in order to rapid release of CUR on targeted cell surface. Fluorescence microscopy images and cytotoxicity studies represent significantly greater cellular uptake and anti-proliferative effects of CUR by β-CD-CUR/MAase-Trastuzumab bioconjugate compared to free CUR and β-CD-CUR in presence and absence of MAase in HER2 positive cells. The results from flow cytometric assay suggest that the β-CD-CUR/MAase-Trastuzumab conjugate exhibited higher cytotoxic and apoptotic effects on cancer cells compared to other formulation. We demonstrate that this formulation has a potential application for targeted and controlled release of drugs in cancer therapy with increased therapeutic efficiency., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an autoimmune disease, associated with central nervous system (CNS) inflammation, demyelination, and axonal loss. Myelin, a multilayer membranous that covers nerve fibers, is essential for rapid impulse conduction. Oligodendrocytes that are generated either from CNS-resident oligodendrocyte progenitor cells (OPCs) or subventricular zone-derived neural stem cells (NSCs) are the myelinating cells of the CNS. The adult CNS maintains a certain endogenous potential to repair myelin damage. However, this process often fails as MS progresses. The origin of this failure is not fully understood, but it is likely to relate to progenitors/stem cells' arrestment in a quiescent state, incapable of generating new oligodendrocyte. Current treatments for MS are immunomodulatory or immunosuppressive medications, with little to no effect on myelin restoration. Recent studies have provided proof-of-principle that CNS remyelination can be promoted either via enhancing endogenous remyelination or by transplanting myelinating cells. Curcumin, a natural polyphenolic compound, has been shown to have therapeutic properties in several neurodegenerative diseases. Here, we investigated the effect of a curcumin nanoformulation, dendrosomal nanoparticles (DNC) on oligodendrogenesis and remyelination, both in vitro and in animal model of demyelination. We indicated that DNC enhanced oligodendrogenesis from NSCs and OPCs, in vitro in dose dependent manner. DNC also induced in vivo remyelination via promotion of oligodendrogenesis. Furthermore, DNC enhanced remyelination capacity of transplanted NSCs through promoting their survival and oligodendrogenesis capacity. Our findings suggest that DNC has significant beneficial effects in demyelinating conditions, either as mono-therapy or as being paired with transplantation approaches., (© 2020 John Wiley & Sons, Ltd.)

Aims: Platelet production improvement can resolve concerns about the limitations of external platelet supply and platelet transfusion in thrombocytopenia patients. To this end, scientists encourage to induce the generation of megakaryocyte and platelet. Curcumin is a safe ingredient of turmeric that affects various cellular pathways. The effect of this component on platelet production has not been yet reported., Main Methods: Our in vitro experiments include the investigation of the effects of nanocurcumin on megakaryocytes production from K562 cells and hematopoietic stem cells via megakaryocyte markers expression, DNA content, ROS, and morphologic analysis, and CFC assay. The regulatory functions of MAPKs pathways were also determined. In the in vivo study tissue distribution of nanocurcumin was determined and two treatment schedules were used to evaluate the capability of nanocurcumin to prevent the occurrence of Busulfan-induced thrombocytopenia in the mouse model., Key Finding: In vitro evidences demonstrated that nanocurcumin can induce MK production from K562 cells and hematopoietic stem cells. Inhibition of ERK1/2 and JNK pathways arrested this activity. In vivo experiments showed the uptake of nanocurcumin by tissues in mice. Administration of nanocurcumin could preserve bone marrow integrity and increase of the number of circulating platelets in the Busulfan-treated mice models., Significance: Our results have demonstrated that nanocurcumin administration can be useful for the improvement of megakaryocytes and platelet generation in vitro. This component may be exerting these beneficial effects on megakaryopoiesis by modulating ERK1/2 and JNK pathways. As well as nanocurcumin has the potential to prevent thrombocytopenia in chemotherapy threated mice., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In recent years, nanotechnology with modern advances in the macromolecular design of nano-carriers has proved to be helpful in the development of drugs delivery systems. This research represents a novel co-administration of nano-vehicles, known as liposomes. Liposomes efficiently encapsulate curcumin and bromocriptine (BR) in a polymer structure, which results in enhanced aqueous solubility of the mentioned hydrophobic agents and higher bioavailability of the drugs., Methods: Preparation of curcumin and BR liposomes were carried out by the thin film method, and the amounts of purified drug and its release were analyzed. After dose determination, the human lung cancer cells (QU-DB) were exposed to BR and curcumin liposomes for 12, 24, and 48 h. Then the viability and apoptosis assays were carried out by using tetrazolium dye and flow cytometry technique, respectively., Results: In this research, in vitro anti-cancer effects of former nano-formulations on lung cancer cells was confirmed, and no cytotoxicity effects of these nano-preparations were observed in the normal cells (HFLF-PI5)., Discussion: Our findings suggest the nano-liposomal drugs as effective anti-cancer agents; however, additional clinical examinations are required.

Aims: An important obstacle on the way of cell-based therapy is the risk of tumorigenicity in the patients benefit from these transplanted cells due to undifferentiated cells which participate in transplantation. Curcumin, the main compound of spice turmeric -as one of the natural products-was demonstrated to possess effective anti-cancer properties, with no significant effect on normal cells in dose and/or time-dependent manner. Furthermore many studies have been accomplished using curcumin for diabetes treatment. Therefore in this study we examined the efficacy of IPCs treated with curcumin in vivo., Main Methods: Differentiation efficiency investigated by flowcytometry. RNA extraction and real-time PCR performed for important genes in IPC differentiation and tumorigenesis including Insulin, Nestin, Ngn3, Pdx1, P21, and P53. Finally we investigated the efficiency of these differentiated and treated cells in diabetic rats., Key Findings: Our data indicates that nanocurcumin -in a specific dose-reduces the expression of Nestin with no significant effect on insulin expression in mRNA and protein level. Besides blood glucose level of diabetic rats which treated with DNC + cells, decreased from average 350 (mg/dI) to 100 (mg/dI). Checking out the pancreases of these rats, demonstrated that their endocrine segment was rebuilt. Moreover hematoxylin & eosin staining and IF results revealed that the Langerhans Islands were reformed., Significance: IPCs' which treated with DNC were able to efficiently control the blood glucose level in diabetic rats which these cells were transplanted to them. Hence Curcumin has the potential to be employed in this kind of cell therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Drug resistance remains a major challenge in the treatment of patients with ovarian cancer. Therefore, the development of new anticancer drugs is a clinical priority to develop more effective therapies. New approaches to improve clinical outcomes and limit the toxicity of anticancer drugs focus on chemoprevention. The aim of this study was to determine the effects of dendrosomal nanocurcumin (DNC) and oxaliplatin (Oxa) and their combination on cell death and apoptosis induction in human ovarian carcinoma cell lines analyzed by MTT assay and flow cytometry, respectively. The synergism effect of Oxa and DNC was analyzed using the equation derived from Chou and Talalay. In addition, real-time PCR was used to measure the effect of this combination on the expression levels of long non-coding RNAs with different expression in ovarian cancer and normal ovaries. Our data showed that the effect of DNC on cell death is more than curcumin alone in the same concentration. The greatest cell death effect was observed in combination of Oxa with DNC, while Oxa was added first, followed by DNC at 4 h interval (0/4 h). The findings indicated that DNC induced apoptosis significantly in both cell lines as compared to control groups; however, combination of both agents had no significant effect in apoptosis induction. In addition, combination of both agents significantly affects the relative expression of long non-coding RNAs investigated in the study as compared with mono therapy.

Curcumin as a flavonoid from the rhizome of Curcuma longa has antibacterial, antiviral and antifungal activity. Multidrug resistance in pathogenic bacteria is continuously increasing in hospitals. The aim of this study was to investigate the effect of curcumin encapsulated in micellar/polymersome nanoparticles as an efflux pump inhibitor (EPI) on the expression of mexX and oprM genes in curcumin-treated and -untreated isolates of Pseudomonas aeruginosa. Clinical isolates of Pseudomonas aeruginosa were treated with ciprofloxacin (sub-MICs) alone and/or in combination with curcumin-encapsulated in micellar/polymersome nanoparticles. The expression of mexX and oprM genes was quantitatively evaluated by qRT-PCR in curcumin-treated and -untreated bacteria after 24 h. Curcumin-encapsulated in nanoparticles (400 µg/mL) induced cell death up to 50% in ciprofloxacin-treated (1/2MIC) resistant isolates during 24 h, while the bacteria treated with ciprofloxacin (without curcumin) were not inhibited. Also, curcumin in different concentrations increased effect of ciprofloxacin (sub-MICs). Downregulation of mexX and oprM genes was observed in cells treated with curcumin and ciprofloxacin compared to cells treated with ciprofloxacin alone. It seems that curcumin can be used as complementary drug in ciprofloxacin-resistant isolates through downregulating genes involved in efflux pumps and trapping ciprofloxacin on bacterial cells and increasing the effects of drug.

Triple-negative breast cancer (TNBC) constitutes an important histological subtype of breast cancer with a highly metastatic phenotype. The aim of the current study was to investigate the possible synergism between dendrosomal nanocurcumin (DNC) and exogenously delivered p53 in producing anticancer effects on a TNBC cell line. MTT assay was exploited to determine the viability of MDA-MB-231 cells against DNC and measure the impact of p53 overexpresssion on DNC-related cytotoxicity. Annexin-V/PI staining followed by flow cytometry and wound healing assay were used to evaluate the effects of DNC and exogenous p53, alone and in combination, on apoptosis induction and migratory capacity of MDA-MB-231 cells, respectively. Also, quantitative real-time PCR was applied to analyze the transcript levels of EMT- and metastasis-associated genes. Cell viability measurements demonstrated that DNC suppresses the proliferation of MDA-MB-231 cells in a time- and dose-dependent mode and exogenous p53 elevates the sensitivity of cells to DNC-mediated cytotoxic effects. Apoptosis and wound healing assays indicated that combination treatment with DNC and exogenous p53 leads to significantly increased apoptosis and decreased migration of breast cancer cells, compared with single treatment. The results of gene expression analysis highlighted the high potency of combination strategy to significantly reduce the expression of ZEB1 and BMI1 transcript levels. Altogether, our findings reveal that DNC and exogenous p53 act in a synergistic manner to elicit anticancer effects on MDA-MB-231 breast cancer cells. Therefore, our combination approach might be considered as a promising strategy for the development of new therapeutic modalities against breast cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Despite positive results obtained from anticancer activities of curcumin, there are some obstacles that limit its use as an anticancer agent., Hypothesis/purpose: Different methods such as employing the dendrosomal curcumin (DNC) were examined to overcome such problems. There is increasing evidence representing long non-coding RNAs play important roles in biological processes. In this study, we focused on the roles of GAS5 in the anti-cancer effects of DNC on breast cancer., Methods: We used several methods including MTT assay, apoptosis assay, cell cycle analysis, transwell migration assay and RT-PCR., Results: We observed a significant increase in the expression of Tusc7, and GAS5 genes with DNC treatment of MCF7, MDA-MB231, and SKBR3 cells. Also, the combination of GAS5 down-regulation and DNC treatment showed lower percentages of apoptotic cells and a higher level of penetration through the membrane compared with DNC treatment alone. Furthermore, DNC induced a significant increase in the number of cells in sub G1/G1 phase and a decrease in the G2/M phase of the cell cycle. But, after GAS5 down-regulation alone opposite results was observed compared to DNC., Conclusion: We observed that GAS5 down-regulation can suppress many aspects of DNC anti-cancer effects in breast cancer cells, it seems that co-treatment with DNC and GAS5 over-expression may provide a clinically useful tool for drug-resistance breast cancer cells., (Copyright © 2018. Published by Elsevier GmbH.)

Despite advantageous antitumor properties of doxorubicin, the considerable cytotoxicity of this chemotherapeutic agent has made it necessary to develop combination treatment strategies. The aim of the current study was to investigate the possible synergism between dendrosomal nanocurcumin (DNC) and doxorubicin in eliciting anticancer effects on MDA-MB-231 metastatic breast cancer cells. The expression levels of CXCL12/CXCR4 axis and Hedgehog pathway genes were evaluated in patient-derived breast carcinoma tissues by qRT-PCR. MTT assay, Annexin V-FITC staining followed by flowcytomety and wound healing assay were used to measure the effects caused by DNC and doxorubicin, alone and in combination, on the viability, apoptosis induction, and migration of MDA-MB-231 cells, respectively. Also, qRT-PCR was exploited to analyze the expression of Smo, NF-κB and CXCR4 in cancer cells. Our results revealed that combination treatment with DNC and doxorubicin leads to significantly decreased viability, increased apoptosis, and reduced migration of breast cancer cells compared with using each drug alone. Also, combination treatment is more efficient that single treatment in reducing the expression levels of NF-κB and Smo transcripts. Our findings provide convincing support for the notion that DNC could synergistically enhance the anticancer effects of doxorubicin on metastatic breast cancer cells by improving its anti-proliferative, pro-apoptotic, and anti-migratory activities. This may be mediated, in part, by downregulating CXCR4, NF-κB, and Smo genes. Overall, the findings of the current study suggest that DNC might be used as a synergistic agent for enhancing therapeutic efficiency and reducing toxic effects of doxorubicin on breast cancer cells.

Purpose: We examined the potential of a dendrosomal nanoformulation of curcumin (DNC) for intervention of ionizing radiation (IR)-induced damage (particularly leading to atherosclerosis), employing an irradiated THP-1 macrophage model., Materials and Methods: Differentiated THP-1 macrophages were irradiated and treated with curcumin or DNC nanoformulation (and oxidized low density lipoprotein, ox-LDL, to promote foam cells). Chemical, biochemical, and genetics tools including viability and apoptosis, multiple ELISA, real-time PCR, Western blotting, enzyme activity, and fluorimetry assays were employed to illustrate IR damage as well as the DNC intervention potential., Results: DNC per se at 10 μM exerted no cytotoxic effects on macrophages. However, it caused apoptosis in 2 Gy-irradiated macrophages which were treated with ox-LDL, chiefly through a caspase-dependent pathway involving caspase-3. Concurrently, 10 μM DNC prevented the IR-induced rise in lipid accumulation (72% decrease compared to IR control, p < .0001), dil-oxLDL uptake (78% decrease, p < .005), protein and mRNA expression of cholesterol influx genes, CD36 and SR-A, NF-κB activation (81% less binding activity, p < .001; and lower nuclear presence of p65), cytokine (monocyte chemoattractant protein-1 and interleukin-1β) release, reactive oxygen species (ROS), and oxidative damage to DNA (37% decrease in 8-OHdG, p < .05) and lipids (62% decrease in 8-isoprostane, p < .005). DNC facilitated the uptake of curcumin in irradiated macrophages, increased glutathione peroxidase expression and activity, restored glutathione (GSH) level, and upregulated the expression of a cholesterol efflux gene, ABCA1. Two other antioxidants, resveratrol and N-acetyl cycteine (NAC), could simulate some of the beneficial effects of DNC against IR-induced CD36 expression and lipid accumulation, which were obviated by buthionine sulfoximine (BSO) pre-treatment of macrophages. However, some modulatory effects of DNC, particularly on lipid accumulation and the expression of SR-A and ABCA1 genes, seemed to be independent of its antioxidant effect, since they were still observed in BSO-pretreated macrophages, depleted of GSH., Conclusions: DNC treatment suppresses IR-induced oxidative damage, inflammation, and foam cell formation in macrophages through multiple mechanisms.

Objective: The aim of this paper is to investigate the effect of dendrosomal curcumin (DNC) on the expression of p53 in both p53 mutant cell lines SKBR3/SW480 and p53 wild-type MCF7/HCT116 in both RNA and protein levels., Background: Curcumin, derived from Curcumin longa, is recently considered in cancer related researches for its cell growth inhibition properties. p53 is a common tumor-suppressor gene involved in cancers and its mutation not only inhibits tumor suppressor activity but also promotes oncogenic activity., Method: Here, p53 mutant/Wild-type cells were employed to study the toxicity of DNC using MTT assay, Flow cytometry and Annexin-V, Real-time PCR and Western blot were used to analyze p53, BAX, Bcl-2, p21 and Noxa changes after treatment., Results: During the time, DNC increased the SubG1 cells and decreased G1, S and G2/M cells, early apoptosis also indicated the inhibition of cell growth in early phase. Real-Time PCR assay showed an increased mRNA of BAX, Noxa and p21 during the time with decreased Bcl-2. The expression of p53 mutant decreased in SKBR3/SW480, and the expression of p53 wild-type increased in MCF7/HCT116., Conclusion: Consequently, p53 plays an important role in mediating the survival by DNC, which can prevent tumor cell growth by modulating the expression of genes involved in apoptosis and proliferation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Protection against ionizing radiation (IR) and sensitization of cancer cells to IR are apparently contrasting phenomena. However, curcumin takes on these contrasting roles leading to either protection or enhanced apoptosis in different irradiated cells. Here we studied whether pretreatment with free curcumin or a novel dendrosomal nanoformulation of curcumin (DNC) could exert protective/sensitizing effects on irradiated THP-1 leukemia cells. We employed assays including MTT viability, clonogenic survival, DNA fragmentation, PI/Annexin V flow cytometry, antioxidant system (ROS, TBARS for lipid peroxidation, 8-OHdG and γH2AX for DNA damage, glutathione, CAT and GPx activity, enzymes gene expression), ELISA (NF-κB and Nrf2 binding, TNF-α release), caspase assay, siRNA silencing of caspase-3, and western blotting to illustrate the observed protective role of curcumin in comparison with the opposite sensitizing role of its nanoformulation at a similar 10 μM concentration. The in vivo relevance of this concentration was determined via intraperitoneal administration in mice. Curcumin significantly enhanced the antioxidant defense, while DNC induced apoptosis and reduced viability as well as survival of irradiated THP-1 cells. Nrf2 binding showed an early rise and fall in DNC-treated cells, despite a gradual increase in curcumin-treated cells. We also demonstrated that DNC induced apoptosis in THP-1 cells via caspase-3 activation; whereas in combination with radiation, DNC alternatively employed a caspase-independent apoptosis pathway involving cytochrome c release from mitochondria.

Objectives: To investigated the potential of a novel dendrosomal nanoformulation of curcumin (DNC) in blocking radiation-induced changes in irradiated human umbilical vein endothelial cells (HUVECs), and their adhesion to human THP-1 monocytoid cells., Results: Co 60 gamma rays reduced viability, raised the expression of adhesion molecules, ICAM-1, VCAM-1 and E-selectin (mRNA and protein), augmented the adhesion of THP-1 cells to HUVECs, activated NF-κB binding, increased the release of pro-inflammatory cytokines (IL-6, IL-8 and MCP-1) and induced oxidative damage (reduced glutathione declined, while 8-OHdG and TBARS increased). 5 µM DNC significantly inhibited these radiation-induced changes, activated the Nrf-2 pathway, and effectively suppressed THP-1 adhesion to HUVECs, implicating p38 MAPK signaling., Conclusion: DNC treatment is a potential preventive method against inflammation and vascular damage from ionizing radiation.

Exposure to ionizing radiation (IR) could be detrimental to health. Oxidative stress, DNA damage, and inflammation are implicated in radiation damage. Curcumin, a natural polyphenol, has remarkable antioxidant, anti-inflammation and anticarcinogenic properties and is reported to protect cells and organisms against gamma-rays. We have recently enhanced solubility of curcumin via a novel dendrosomal nanoformulation (DNC). The objective of this study was to assess the potential efficacy of this nanoformulation in protecting human peripheral blood mononuclear cells (PBMC) against gamma-radiation. IR-induced damage was evident in reactive oxygen species, antioxidant enzymes activities, glutathione, lipid peroxidation, and viability assays. Treatment by DNC, showing superiority to curcumin, effectively counteracted these effects and reduced DNA damage as determined via 8-OHdG levels and lipid peroxidation as measured by the level of TBARS (as well as lipid hydroperoxides and 8-isoprostane). PBMC pretreatment by DNC prior to irradiation proved effective as well. Uptake kinetics revealed enhanced uptake of DNC compared to curcumin, particularly after irradiation. DNC suppressed IR-induced NF-κB activation 18 h post-irradiation. It induced Nrf2 binding activity early after irradiation which was sustained to 18 h. Gene expression analysis of a chosen set of radiation response genes in irradiated PBMC revealed a similar profile for DNA damage response and repair genes including FDXR, XPC, DDB2, and GADD45 in DNC-treated cells compared to IR control. However, in response to radiation, an altered profile of expression was noticed for CDKN1A (p21), MDM2, IFNG, and BBC3 (PUMA) genes after DNC treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The side-effects observed in conventional therapies have made them unpromising in curing Hepatocellular carcinoma; therefore, developing novel treatments can be an overwhelming significance. One of such novel agents is curcumin which can induce apoptosis in various cancerous cells, however, its poor solubility is restricted its application. To overcome this issue, this paper employed dendrosomal curcumin (DNC) was employed to in prevent hepatocarcinoma in both RNA and protein levels. Hepatocarcinoma cells, p53 wild-type HepG2 and p53 mutant Huh7, were treated with DNC and investigated for toxicity study using MTT assay. Cell cycle distribution and apoptosis were analyzed using Flow-cytometry and Annexin-V-FLUOS/PI staining. Real-time PCR and Western blot were employed to analyze p53, BAX, Bcl-2, p21 and Noxa in DNC-treated cells. DNC inhibited the growth in the form of time-dependent manner, while the carrier alone was not toxic to the cell. Flow-cytometry data showed the constant concentration of 20μM DNC during the time significantly increases cell population in SubG1 phase. Annexin-V-PI test showed curcumin-induced apoptosis was enhanced in Huh7 as well as HepG2, compared to untreated cells. Followed by treatment, mRNA expression of p21, BAX, and Noxa increased, while the expression of Bcl-2 decreased, and unlike HepG2, Huh7 showed down-regulation of p53. In summary, DNC-treated hepatocellular carcinoma cells undergo apoptosis by changing the expression of genes involved in the apoptosis and proliferation processes. These findings suggest that DNC, as a plant-originated therapeutic agent, could be applied in cancer treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver making up more than 80 percent of cases. It is known to be the sixth most prevalent cancer and the third most frequent cause of cancer related death worldwide. Epigenetic regulation constitutes an important mechanism by which dietary components can selectively activate or inactivate target gene expression. The miR-34 family members including mir-34a, mir-34b and mir-34c are tumor suppressor micro RNAs, which are expressed in the majority of normal tissues. Several studies have indicated silencing of miR-34 expression via DNA methylation in multiple types of cancers. Bioactive nutrients like curcumin (Cur) have excellent anticarcinogenic activity and minimal toxic manifestations in biological systems. This compound has recently been determined to induce epigenetic changes. However, Cur is lipophilic and has a poor systemic bioavailability and poor absorption. Its bioavailability is increased through employing dendrosome nanoparticles. The aim of the current study was to investigate the effect of dendrosomal nanocurcumin (DNC) on expression of mir-34 family members in two HCC cell lines, HepG2 and Huh7. We performed the MTT assay to evaluate DNC and dendrosome effects on cell viability. The ability of DNC to alter expression of the mir-34 family and DNA methyltransferases (DNMT1, DNMT3A and 3B) was evaluated using semi-quantitative and quantitative PCR. We observed the entrance of DNC into HepG2 and Huh7 cells. Gene expression assays indicated that DNC treatment upregulated mir34a, mir34b and mir34c expression (P<0.05) as well as downregulated DNMT1, DNMT3A and DNMT3B expression (P<0.05) in both HepG2 and Huh7 cell lines. DNC also reduced viability of Huh7 and HepG2 cells through restoration of miR-34s expression. We showed that DNC could awaken the epigenetically silenced miR-34 family by downregulation of DNMTs. Our findings suggest that DNC has potential in epigenetic therapy of HCC.

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of central nervous system (CNS). Polyphenol curcumin has been used in traditional medicine as an effective drug for a variety of diseases. Different formulations of curcumin are introduced to increase its stability and effectiveness. Here we have examined the effect of polymerized form of nano-curcumin (PNC) on experimental autoimmune encephalomyelitis (EAE) as an animal model of MS. EAE was induced in female Lewis rats and PNC or curcumin was daily administrated intraperitonealy from day 12-29 post immunization. When the prophylactic effect of PNC was under investigation, rats received PNC from the first day of immunization. Treatment with PNC resulted in decreased scores of disease in therapeutic and prophylactic administration when compared with control group. Staining by luxol fast blue and H&E and immuno-staining of lumbar spinal cord cross sections, confirmed a significant decrease in the amounts of demyelination, inflammation and BBB breaking down. Gene expression studies in lumbar spinal cord showed a corrected balance of pro-inflammatory and anti-inflammatory genes expression, decreased oxidative stress, improved remyelination and increased progenitor cell markers after treatment with PNC. Our results demonstrated an efficient therapeutic effect of PNC as an anti-inflammatory and anti-oxidative stress agent, with significant effects on the EAE scores and myelin repair mechanisms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Hepatocellular carcinoma is the fifth most common cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Epigenetic therapy of cancer is useful in reversing some of the cancer defects because of reversibility of the epigenetic alterations. Non-protein coding transcripts are the major part of our transcriptome. MEG3 is a tumor suppressor long non-coding RNA being expressed in many normal tissues. Methylation of MEG3 promoter region elicits the decrease in its expression in hepatocellular cancer cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status which is catalyzed via DNMT1, DNMT3A and 3B., Purpose: Herein, we aimed to study RNA-based epigenetic effects of dendrosomal curcumin (DNC) on hepatocellular cancer (HCC)., Study Design: To this end miRNA-dependent regulation of MEG3 expression under treatment with DNC was studied by evaluating the modulatory involvement of miR-29a for DNMT3A and 3B and miR-185 for DNMT1., Methods: We evaluated DNC entrance to HCC cells with the use of fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on HCC cell viability. The coding and non-coding genes expression analyses were done using quantitative-PCR., Results: In result we found that the DNC dependent overexpression of miR-29a and miR-185 (P < 0.01) can down-regulate the expression of DNMT1, 3A and 3B (P < 0.05) and subsequently overexpresses MEG3 (P < 0.05)., Conclusion: DNC potentially can induce DNA hypomethylation and reexpression of silenced tumor suppressor genes in HCC. These data suggest that DNC could be an effective choice for epigenetic therapy of HCC., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Colon cancer is one of the leading causes of cancer-associated death worldwide. The prognosis for advanced colorectal cancers remains dismal, mainly due to the propensity for metastatic progression. Accordingly, there is a need for effective anti-metastasis therapeutic agents. Since a great body of research has indicated anticancer effects for curcumin, we investigated the effects of dendrosomal curcumin (DNC) on cellular migration and adhesion of human SW480 cells and possible molecular mechanisms involved. Different methods were applied in this study including MTT, Scratch and adhesion assays as well as real-time PCR and transwell chamber assays. Based on the results obtained, DNC inhibits metastasis by decreasing Hef 1, Zeb 1 and Claudin 1 mRNA levels and can reduce SW480 cell proliferation with IC50values of 15.9, 11.6 and 7.64 μM at 24, 48 and 72 h post-treatment. Thus it might be considered as a safe formulation for therapeutic purpose in colorectal cancer cases.

Application of nanoparticles has recently promising results for water insoluble agents like curcumin. In this study, we synthesized polymeric nanoparticle-curcumin (PNPC) and then showed its efficiency, drug loading, stability, and safety. Therapeutic effects of PNPC were also assessed on two cell lines and in an animal model of breast cancer. PNPC remarkably suppressed mammary and hepatocellular carcinoma cells proliferation (P < 0.05). Under the dosing procedure, PNPC was safe at 31.25 mg/kg and lower doses. Higher doses demonstrated minimal hepatocellular and renal toxicity in paraclinical and histopathological examinations. Tumor take rate in PNPC-treated group was 37.5% compared with 87.5% in control (P < 0.05). Average tumor size and weight were significantly lower in PNPC group than control (P < 0.05). PNPC increased proapoptotic Bax protein expression (P < 0.05). Antiapoptotic Bcl-2 protein expression, however, was lower in PNPC-treated animals than the control ones (P < 0.05). In addition, proliferative and angiogenic parameters were statistically decreased in PNPC-treated animals (P < 0.05). These results highlight the suppressing role for PNPC in in vitro and in vivo tumor growth models. Our findings provide credible evidence for superior biocompatibility of the polymeric nanocarrier in pharmacological arena together with an excellent tumor-suppressing response.

Curcumin is a potent natural anticancer agent, but its effectiveness is limited by properties such as very low solubility, high rate of degradation, and low rate of absorption of its hydrophobic molecules in vivo. To date, various nanocarriers have been used to improve the bioavailability of this hydrophobic biomaterial. This study investigates the encapsulation of curcumin in a novel nanostructure of monomethoxy poly(ethylene glycol)-oleate (mPEG-OA) and its anticancer effect. Tests were done to determine the critical micelle concentration (CMC), encapsulation efficiency, drug-loading efficiency, and cytotoxicity (against U87MG brain carcinoma cells and HFSF-PI3 cells as normal human fibroblasts) of some nanodevice preparations. The results of fluorescence microscopy and cell-cycle analyses indicated that the in vitro bioavailability of the encapsulated curcumin was significantly greater than that of free curcumin. Cytotoxicity evaluations showed that half maximal inhibitory concentrations of free curcumin and curcumin-loaded mPEG-OA for the U87MG cancer cell line were 48 μM and 24 μM, respectively. The Annexin-V-FLUOS assay was used to quantify the apoptotic effect of the prepared nanostructures. Apoptosis induction was observed in a dose-dependent manner after curcumin-loaded mPEG-OA treatments. Two common self-assembling structures, micelles and polymersomes, were observed by atomic force microscopy and dynamic light scattering, and the abundance of each structure was dependent on the concentration of the diblock copolymer. The mPEG-OA micelles had a very low CMC (13.24 μM or 0.03 g/L). Moreover, atomic force microscopy and dynamic light scattering showed that the curcumin-loaded mPEG-OA polymersomes had very stable structures, and at concentrations 1,000 times less than the CMC, at which the micelles disappear, polymersomes were the dominant structures in the dispersion with a reduced size distribution below 150 nm. Overall, the results from these tests revealed that this nanocarrier can be considered as an appropriate drug delivery system for delivering curcumin to cancer cells.

Glioblastoma is an invasive tumor of the central nervous system. Tumor recurrence resulting from ineffective current treatments, mainly due to the blood-brain barrier, highlights the need for innovative therapeutic alternatives. The recent availability of nanotechnology represents a novel targeted strategy in cancer therapy. Natural products have received considerable attention for cancer therapy because of general lower side effects. Curcumin is a new candidate for anticancer treatment, but its low bioavailability and water solubility represent the main disadvantages of its use. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, termed dendrosome, to overcome these problems. Dendrosomal curcumin was prepared as 142 nm spherical structures with constant physical and chemical stability. The inhibitory role of dendrosomal curcumin on the proliferation of U87MG cells, a cellular model of glioblastoma, was evaluated by considering master genes of pluripotency and regulatory miRNA (microribonucleic acid). Methylthiazol tetrazolium assay and flow cytometry were used to detect the antiproliferative effects of dendrosomal curcumin. Annexin-V-FLUOS and caspase assay were used to quantify apoptosis. Real-time polymerase chain reaction was used to analyze the expression of OCT4 (octamer binding protein 4) gene variants (OCT4A, OCT4B, and OCT4B1), SOX-2 (SRY [sex determining region Y]-box 2), Nanog, and miR-145. Dendrosomal curcumin efficiently suppresses U87MG cells growth with no cytotoxicity related to dendrosome. Additionally, the accumulation of cells in the SubG1 phase was observed in a time- and dose-dependent manner as well as higher rates of apoptosis after dendrosomal curcumin treatment. Conversely, nonneoplastic cells were not affected by this formulation. Dendrosomal curcumin significantly decreased the relative expression of OCT4A, OCT4B1, SOX-2, and Nanog along with noticeable overexpression of miR-145 as the upstream regulator. This suggests that dendrosomal curcumin reduces the proliferation of U87MG cells through the downregulation of OCT4 (octamer binding protein 4) variants and SOX-2 (SRY [sex determining region Y]-box 2) in an miR-145-dependent manner.

Curcumin is a potential natural anticancer drug with limited bioavailability due to the lack of solubility in aqueous solvents. The present study is designed to investigate the preventive effects of polymeric nanocarrier-curcumin (PNCC) on colon carcinogenesis in an azoxymethane-induced rat tumor. Forty rats were divided into control, curcumin- and PNCC-treated groups. Animals received azoxymethane (AOM) as a carcinogenic agent (15 mg/kg, s.c.) weekly for two consecutive weeks. They were given curcumin 0.2% and PNCC two weeks before till 14 weeks after the last injection of AOM. In the end, post euthanasia, the entire gastrointestinal tract was scrutinized for tumors, and the rest of the body for metastatic deposits. Tumor number, size and location were characterized. The histopathological and immunohistochemistry examinations were also performed on colon tissue. In vivo, curcumin nanoparticles inhibited colon cancer growth in animal model. The tumors incidence and number decreased by nanocurcumin comparison with control. Furthermore, the nuclear/cytoplasmic ratio, epithelial stratification, nuclear dispolarity, goblet depletion, structural abnormality, and the expression of Beta-catenin and Bcl-2 proteins were reduced in PNCC compared to others groups (P<0.05). In addition, Bax protein expression was significantly increased in PNCC in comparison with control and curcumin-treated groups (P<0.001). The present study demonstrated the potential anticancer effects of PNCC in a typical animal model. The results provide evidence that nanopolymeric curcumin exerts a significant chemopreventive effect on AOM-initiated colon cancer through cell proliferation inhibition and apoptosis induction. More investigations are needed to confirm its safety for human use., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Curcumin, the main compound of spice turmeric, is one of the natural products that has been shown to possess effective anti-cancer properties. However, the absorption efficacy of curcumin is too low to make dramatic results in therapy. Therefore, we based the main aim of this study on improving the bioavailability of curcumin taking advantage of dendrosome nanoparticles; and subsequently evaluating in vitro and in vivo anti-tumor properties of dendrosomal curcumin. In vitro studies were carried out utilizing A431 and WEHI-164 cell lines and mouse embryonic normal fibroblasts. Our data revealed that dendrosomal curcumin not only exhibits a much higher bioavailability than void curcumin (P<0.05) but also inhibits the proliferation of cancer cells (P<0.01) in a time- and dose-dependent manner that could be ascribed to the induction of apoptosis. However, dendrosome did not indicate any toxic effect on different types of cell lines. For in vivo studies, BALB/c tumor-bearing mice were treated with dendrosomal curcumin, void curcumin, dendrosome and PBS. The results indicated that dendrosomal curcumin reduces significantly the tumor size in comparison with void curcumin and control samples (P<0.05). Furthermore, in animals treated with dendrosomal curcumin a longer survival was observed (P<0.01). We also found that the mice treated with dendrosomal curcumin, showed a significant increase in splenocyte proliferation and IFN-γ production as well as a significant decrease in IL-4 production. This can be a proof of anti-tumor immunity caused by dendrosomal curcumin. The findings demonstrate that dendrosomal curcumin offers a great potential to be a promising anti-cancer therapeutic agent., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective(s): Targeting the lytic cycle of the Epstein-Barr virus (EBV) has been considered a new treatment strategy for malignancies caused by this virus. This study aimed to investigate the effect of Dendrosomal NanoCurcumin (DNC) to prevent cell transformation and inhibit the expression of viral lytic gene expression in the generation of lymphoblastoid cell line (LCL). Materials and Methods: Cell viability of LCLs and PBMCs was performed by MTT assay, and flow cytometry (Annexin/PI) was used for evaluation of apoptosis. CD markers on the surface of generated LCL (CD19) cells were examined for cell validation. The effect of DNC on transformation was evaluated by examining cell morphology and determining the expression level of lytic genes BZLF1, Zta, BHRF1, and BRLF1 of EBV using Real-time PCR. Student's t-test was used for statistical analysis. Results: The MTT assay showed that DNC can inhibit the proliferation of LCL in a dose-dependent manner. The 50% cytotoxic concentration (CC50) of DNC and curcumin for LCL was determined 38.8 µg/ml and 75 µg/ml, respectively after 72 hr. Also, Real-time PCR data analysis showed that DNC in 30 µg/ml concentration significantly inhibited cell transformation in the LCL and significantly reduced viral lytic genes such as BZLF1, Zta, BHRF1, and BRLF1expression compared to control. Conclusion: Overall, these findings show that DNC reduces the expression of the viral lytic cycle genes and also the induction of cell apoptosis and finally prevents the generation of LCL. [ABSTRACT FROM AUTHOR]

Background: It is essential to find natural compounds with wound -healing properties that are accompanied by antibacterial effects. Therefore, in the present study, the wound -healing potential of curcumin dendrosomes on fibroblast cell line was evaluated. Methods: The HFF1 cell proliferation was evaluated by MTT test after 48 hours of curcumin (Cur) and curcumin dendrosomes (Cur.den) treatments. Scratching test was used to check cell migration and the expression levels of TNF - α and TGF - β genes in cells were studied by Real -Time PCR technique. To investigate the antibacterial activity of Cur and Cur.den against S. epidermidis, well diffusion and microdilution tests were used. Results: Cur.den improved significantly HFF1 cell proliferation and migration compared to both untreated control and Cur -treated cells. Moreover, this nanoformulation significantly overexpressed TGF - β and downregulated TNF - α genes compared to control cells. Both Cur and Cur.den reduced S. epidermidis growth in well diffusion assay and their MICs were measured at 200 and 100 µM, respectively. Conclusion: The Cur.den has a high potential to be used as a wound -healing drug. However, studies in animal models and clinical settings are recommended. [ABSTRACT FROM AUTHOR]

Innovative composites of biopolymers and nanomaterials have been exploited to fabricate wound dressings which show functional abilities to improve different stages of wound healing by a variety of mechanisms. In this study, a polymeric nanocomposite dressing is fabricated by electrospinning of a blend of sodium alginate (SA), poly vinyl alcohol (PVA) and graphene nanoplatelets (Gnp). The crosslinking of the nanofibers is done by thermal treatment followed by ionic bonding of the fibers. The crosslinked fibers are loaded by curcumin, a natural potent anti‐inflammatory compound, encapsulated in monomethoxy poly ethylene glycol‐oleate micelles/polymersomes (NCur). Results indicate that by incorporation of Gnp and NCur into the SA/PVA scaffold the tensile strength is not changed (~7 MPa) but the elongation to break and toughness of the scaffolds significantly increase from 11.25±2.6 and 50.56 to 35.5±5.1% and 125.9 Jm‐3, respectively. The scaffolds support the controlled release of curcumin for 24 h in vitro. Biocompatibility of the scaffolds has been confirmed by cell viability assay on mouse fibroblast cells. Overall, the findings demonstrate the potential applications of the spun fibers for wound dressing purposes. [ABSTRACT FROM AUTHOR]

The story of human dreams about curing all diseases, disorders and lesions is as old as human history. In the frontier of medical science, nanomedicine is trying to solve the problem. In this study, inspired by nanotechnology and using "grafting from" approach, a novel lignin-based nanogel was synthesized using atom transfer radical polymerization (ATRP) method. N-isopropylacrylamide (NIPAM) and N,N-dimethylaminoethylmethacrylate (DMAEMA) comonomers were graft copolymerized from fully brominated lignin as ATRP macroinitiator to synthesize lignin-g-P(NIPAM-co-DMAEMA) nanogel (LNDNG). By controlling the initial comonomer compositions and ATRP conditions, four LNDNG systems with different lower critical solution temperatures (LCSTs) of 32, 34, 37 and 42 °C were prepared. The LNDNGs were evaluated by GPC, FT-IR, 1H NMR, UV–Vis, DLS, SEM and TEM analyses. The prepared nanogels exhibited an average diameter of 150 nm with dual temperature and pH responsiveness. Curcumin (CUR) loading capacity and encapsulation efficiency of the LNDNGs were 49.69% and 92.62% on average, respectively. The cumulative release amount of loaded CUR was observed to be 65.36% after 72 h. The new lignin-based NGs proposed in the present work seems to be a promising, safe and comparable system in a near future. [ABSTRACT FROM AUTHOR]

Curcumin is an anti‐cancerous agent, but its low‐solubility limits its clinical use. The relationship between deregulation of miRNAs and their targets suggested that miRNAs can be interest targets of curcumin in treatment of different cancers. In this study, to overcome essential defects of the clinical usage of this golden drug, curcumin‐encapsulated polymersome nanoparticles (CPNs) have been developed, and the cytotoxicity effects were studied on MDA‐MB‐231 breast cancer cells. The expression level of miR‐182/125b and the expression pattern of some potential targets in apoptotic pathway, predicted by in silico approaches, were analyzed by RT‐qPCR in CPNs‐treated and untreated cells. Moreover, the amount of CASP9 and CASP8 proteins were determined by Western blotting. The effect of CPNs on cell migration were studied by scratch test and the level of EGFR, E‐cadherin, and beta‐catenin proteins were monitored in CPNs‐treated and untreated cells by western blotting. RT‐qPCR analysis identified the downregulation of miR‐125b and miR‐182 in CPNs‐treated cells and the upregulation of some predicted apoptotic target genes such as P53, CASP9 and BAX after 24 hours. Western blotting confirmed the effects of curcumin on the increase of cleaved CASP9 protein. Based on data from the current experiment, the migration of MDA‐MB‐231 cells was decreased after CPNs treatment. According to the results, CPNs, as suitable and compatible nanocarriers, can deliver curcumin into cancerous cells more effectively and can increase the therapeutic effects of curcumin on MDA‐MB‐231 cells partly by suppression of miR‐125b and miR‐182 as well as induction of apoptosis and inhibition of metastatic progression. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), characterized by neuroinflammation, oligodendrocytes (OLs) loss, and demyelination Curcumin, a natural phenolic substance, has been shown to have significant therapeutic properties in various neurodegenerative diseases, including MS. In our laboratory by loading curcumin in dendrosome nanoparticles we improved its solubility and bioavailability. Our previous study showed antiinflammatory and anti-oxidative effects of dendrosomal nano-curcumin (DNC) in experimental autoimmune encephalomyelitis (EAE) model of MS. Here, by using a toxic demyelination model, induced by cuprizone (CPZ), we investigated the protective effect of DNC on oligodendroglial lineage cells (OLLC) and myelin preservation in context of acute demyelination. CPZ is a copper chelator, thus its intake reduces the mitochondrial activity, activates oxidative stress response, leading to specific OLs death, due to their high-energy consumption. We also evaluated DNC effect on activation of astrocytes and microglia, which are enriched in both MS and CPZ demyelinated lesions. Our results demonstrated that DNC treatment protected Oligodendrocyte lineage cells (OLLCs) against CPZ toxin. Besides DNC treatment suppressed accumulation of astrocytes and microglia in CC of CPZ-fed mice, compared to PBS treated onse. Moreover, DNC treatment lead to higher index of luxol fast bluefast blue (LFB) and myelin-specific proteins, myelin basic protein (MBP) intensity in the corpus callosum (CC), as indicators of myelin content. These results suggest a potent pleiotropic therapeutic efficiency for DNC for protection of myelinating cells, possibly via suppression of astrocytes and microglia. [ABSTRACT FROM AUTHOR]

Background: This study was designed to investigate the effect of nano-curcumin supplementation on pentraxin 3 (PTX3) gene expression and serum level in migraine patients. Methods: The present study, performed as a clinical trial, included 38 episodic migraine patients in two groups that received either nano-curcumin or placebo over a two-month period. At the start and the end of the study, PTX3 gene expression and serum levels were measured. Results: After two months of treatment, PTX3 gene expression and serum levels were both significantly less in the nano-curcumin than in the placebo group (P= 0.01 and P< 0.001, respectively). No significant gene expression differences were found between the two groups. Conclusions: Curcumin may have a potential inhibitory effect on PTX3 gene expression and serum levels in migraine disease and can be considered as an efficient therapy in migraine management. [ABSTRACT FROM AUTHOR]

Curcumin as a safe traditional compound has various benefits such as anticancer activities. However, low solubility in water is a problem. Herein, curcumin encapsulated in polymersome nanoparticles (CPNs) have been developed, the physicochemical properties have been evaluated, and cytotoxicity effects on HT29 cells were evaluated by MTT assay and annexin V/PI staining. The expression of stemness markers including CD44, CD133, and CD24, as well as miRNAs (miR‐126, miR‐34a, miR‐21, miR‐155, miR‐221, and miR‐222) and some potential targets, was evaluated in CPNs‐treated and untreated cells. Physicochemical analysis confirmed the encapsulation of curcumin in polymersomes and showed a spherical shape, an appropriate mean size of 259.5±1.5 nm, the acceptable polydispersity index of ~ 0.465, and the zeta potential of (‐8.74±0.2), as well as long‐term storage of CPNs at 4°C. According to the result, CPNs with the IC50 of 14 μg/ml increased apoptosis and induced S arrest in treated cells. Flow cytometry analysis showed the decrease in cancer stemness markers. RT‐qPCR analysis identified the downregulation of miR‐21, miR‐155, and miR‐221/222, as well as upregulation of miR‐34a, miR‐126, and deregulation of some apoptotic targets such as P53, CASP9, CASP8, CASP3, BAX, and BCl‐2 in CPNs‐treated cells. As a result, CPNs can be a safe and effective complementary agent to diminish cancer stem cells and tumor recurrence in colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

Tamoxifen is routinely used for treatment of Estrogen-positive breast carcinoma. Approximately, 50% of patients with metastatic cancer will develop resistance to Tamoxifen. In this research, Tamoxifen was combined with the anti-cancer compound Curcumin. Diblocknanopolymer was used to package the new formulation of Curcumin and Tamoxifen. Anti-cancer efficacy of the obtained compound was evaluated in Tamoxifen-sensitive (TS). MCF-7, Tamoxifen-resistant (TR) MCF-7 cancer cells and Fibroblast cells. MTT assay was used to evaluate anti-proliferation and toxicity. Flow cytometry and Annexin-V-FLUOS were used to assay anti-proliferation and induction of apoptosis respectively. Our results indicate that the obtained nano-compound is less toxic to normal cells compared to Tamoxifen alone, and has higher anti-proliferation and pro-apoptotic activity on TS-MCF-7 and TR-MCF-7. The nanopolymer reduces the Tamoxifen toxicity in normal cells and counters the developed resistance to the drug in cancer cells. [ABSTRACT FROM AUTHOR]

Objective(s): Despite the good results of anticancer activities by curcumin, there are some hurdles that limit the use of curcumin as an anticancer agent. Many methods were examined to overcome this defect like the use of the dendrosomal curcumin (DNC). There is increasing evidence that miRNAs play important roles in biological processes. In this study, we focus on the roles of microRNA-21 in the anti-cancer effects of DNC in breast cancer. Materials and Methods: Also, we have used different methods such as MTT, apoptosis, cell cycle analysis, transwell migration assay and RT-PCR to find out more. Results: We observed that miR-21 decreased apoptotic cells in both cells (from 6.35 % to 0.34 % and from 7.72 % to 1.32 % orderly) and DNC increased it. As well as, our findings indicated that cell migration capacity was increased by miR-21 over expression and was decreased by DNC. The combination of miR-21 vector transfection and DNC treatment showed lower percentage of apoptotic cells or a higher level of penetration through the membrane compared with DNC treatment alone. Furthermore, DNC induced a marked increase in the number of cells in sub G1/G1 phase and a decrease in G2/M phase of the cell cycle in both; but, we observed reverse results compared it, after transfection with miR-21 vector. Conclusion: We observed that miR-21 suppress many aspects of anti-cancer effects of DNC in breast cancer cells, it seems that co-treatment with DNC and mir-21 down-regulation may provide a clinically useful tool for drug-resistance breast cancer cells. [ABSTRACT FROM AUTHOR]

Objectives: To investigated the potential of a novel dendrosomal nanoformulation of curcumin (DNC) in blocking radiation-induced changes in irradiated human umbilical vein endothelial cells (HUVECs), and their adhesion to human THP-1 monocytoid cells. Results: Co gamma rays reduced viability, raised the expression of adhesion molecules, ICAM-1, VCAM-1 and E-selectin (mRNA and protein), augmented the adhesion of THP-1 cells to HUVECs, activated NF-κB binding, increased the release of pro-inflammatory cytokines (IL-6, IL-8 and MCP-1) and induced oxidative damage (reduced glutathione declined, while 8-OHdG and TBARS increased). 5 µM DNC significantly inhibited these radiation-induced changes, activated the Nrf-2 pathway, and effectively suppressed THP-1 adhesion to HUVECs, implicating p38 MAPK signaling. Conclusion: DNC treatment is a potential preventive method against inflammation and vascular damage from ionizing radiation. [ABSTRACT FROM AUTHOR]

Objective(s): Glioblastoma is the most lethal tumor of the central nervous system. Here, we aimed to evaluate the effects of exogenous delivery of p53 and a nanoformulation of curcumin called dendrosomal curcumin (DNC), alone and in combination, on glioblastoma tumor cells. Materials and Methods: MTT assay was exploited to measure the viability of U87-MG cells against DNC treatment. Cells were separately subjected to DNC treatment and transfected with p53-containing vector and then were co-exposed to DNC and p53 overexpression. Annexin-V-FLUOS staining followed by flow cytometry and real-time PCR were applied to examine apoptosis and analyze the expression levels of the genes involved in cell cycle and oncogenesis, respectively. Results: The results of cell viability assay through MTT indicated that DNC inhibits the proliferation of U87-MG cells in a time- and dose-dependent manner. Apoptosis evaluation revealed that p53 overexpression accompanied by DNC treatment can act in a synergistic manner to significantly enhance the number of apoptotic cells (90%) compared with their application alone (15% and 38% for p53 overexpression and DNC, respectively). Also, real-time PCR data showed that the concomitant exposure of cells to both DNC and p53 overexpression leads to an enhanced expression of GADD45 and a reduced expression of NF-κB and c-Myc. Conclusion: The findings of the current study suggest that our combination strategy, which merges two detached gene (p53) and drug (curcumin) delivery systems into an integrated platform, may represent huge potential as a novel and efficient modality for glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Background: NF-E2-related factor2 (Nrf2)-antioxidant response element (ARE) signaling pathway is the major defensive mechanism against oxidative stress and is up regulated by specific antioxidants and oxidants to comprise the chemoptotective response. Detection of ARE-activating compounds helps to develop new drugs and identify/quantify the tension range of the oxidants. Important reasons promoting this work are high throughput, rapid and inexpensive experiments relative to the in vitro studies for ARE-Nrf2 pathway monitoring of chemicals and environmental samples. Methods: In this study hepatoma Huh7 reporter cell line was generated which contains a luciferase gene under the control of an ARE. This is the first example of ARE construct containing one copy of extended consensus response element. The cells were treated with hydroquinone (HQ) and p-benzoquinone (BQ) (oxidative stress inducers) and the antioxidant, curcumin. Results: The luciferase activity was induced in a concentration-dependent manner in a concentration range of 1-2 μM for BQ and HQ. Curcumin was also validated as an ARE inducer in concentration above 10 μM. In addition, this reporter cell line provides a rapid detection as early as 4 h to respond to the ARE inducers. Conclusion: It is a powerful tool for the sensitive and selective screening of chemicals, drugs and environmental samples for their antioxidant and oxidant activities. [ABSTRACT FROM AUTHOR]

Objective: In recent decades, the anticancer effect of curcumin has been proven by several studies. Curcumin affects multiple cell signaling pathways and prevents cell proliferation, invasion, metastasis and angiogenesis. However, the aqueous solubility of curcumin and its bioavailability are very low which restricts its anticancer properties. In this research, we have synthesized a monomethoxy poly (ethylene glycol)-Oleate (mPEGOA) di-block copolymer and used a surface PEGylated poly (amidoamine) (PAMAM) dendrimer to improve bioavailability of curcumin in cancer cells. Methods: The critical micelle concentration (CMC) of mPEG-OA, drug loading efficiencies, and cytotoxicity in the human glioblastoma cell line (U87MG) of all the prepared nanodevices were thoroughly investigated. Results: Atomic force microscopy (AFM) and dynamic light scattering (DLS) studies have shown that mPEG-OA have two common nanostructures, micelles and polymerosomes. mPEG-OA micelles had a very low CMC (0.03 g/l). The IC50 of free curcumin (0.01 methanol solution) was 48 μM, curcumin-loaded mPEG-OA was 24 μM , and curcumin-loaded PAMAM dendrimer was 13 μM. Moreover, the PEGylated PAMAM was non-cytotoxic. Conclusion: The results indicated that by using these nanocarriers, the bioavailability of curcumin significantly increased compared to free curcumin. Overall, this research revealed that these curcumin nanocarriers could be considered as appropriate drug delivery systems for curcumin delivery in cancer cells. [ABSTRACT FROM AUTHOR]