Validation of a Quantification Method for Curcumin Derivatives and Their Hepatoprotective Effects on Nonalcoholic Fatty Liver Disease

Curcumin (CM), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are major curcumin derivatives found in the rhizome of turmeric (Curcuma longa L.), and have yielded impressive properties to halt various diseases. In the present study, we carried out a method validation for curcumin derivatives and analyzed the contents simultaneously using HPLC with UV detection. For validation, HPLC was used to estimate linearity, range, specificity, accuracy, precision, limit of detection (LOD), and limit of quantification (LOQ). Results showed a high linearity of the calibration curve, with a coefficient of correlation (R2) for CM, DMC, and BDMC of 0.9999, 0.9999, and 0.9997, respectively. The LOD values for CM, DMC, and BDMC were 1.16, 1.03, and 2.53 ng/μL and LOQ values were 3.50, 3.11, and 7.67 ng/μL, respectively. Moreover, to evaluate the ability of curcumin derivatives to reduce liver lipogenesis and compare curcumin derivatives’ therapeutic effects, a HepG2 cell model was established to analyze their hepatoprotective properties. Regarding the in vivo study, we investigated the effect of DMC, CM, and BDMC on nonalcoholic fatty liver disease (NAFLD) caused by a methionine choline deficient (MCD)-diet in the C57BL/6J mice model. From the in vitro and in vivo results, curcumin derivatives alleviated MCD-diet-induced lipid accumulation as well as high triglyceride (TG) and total cholesterol (TC) levels, and the protein and gene expression of the transcription factors related to liver adipogenesis were suppressed. Furthermore, in MCD-diet mice, curcumin derivatives suppressed the upregulation of toll-like receptors (TLRs) and the production of pro-inflammatory cytokines. In conclusion, our findings indicated that all of the three curcuminoids exerted a hepatoprotective effect in the HepG2 cell model and the MCD-diet-induced NAFLD model, suggesting a potential for curcuminoids derived from turmeric as novel therapeutic agents for NAFLD.

Curcumins and its derivatives as potential inhibitors of New Coronavirus (COVID-19) main protease: an in silico strategy

Coronavirus (COVID-19) disease outbreak caused a worldwide pandemic with a powerful lethal potential and still, there is no specific treatment to it. Natural bioactive molecules like curcumins were investigated in this work aiming to block the active site of COVID-19 Main protease (Mpro), since they present several biological activities, being more suitable in terms of fewer side effects, once this disease overloads the immune system of patients. Hereby, curcumin and several derivatives were screened for their ability to react with Mpro receptors (PDB: 6LU7). N3, Azithromycin (AZT), and Baracitinib (BRT) were evaluated as positive controls and in combined therapeutics possibilities with curcumins. N3, AZT, and BRT bound to different protein receptors, and also it was observed that N3 bound in the same site as hexahydrocurcumin and curcumin glucuronide bound at the AZT’s site and bisdemethoxycurcumin, curcumin, curcumin sulfate, cyclocurcumin, demethoxycurcumin, dihydrocurcumin and hexahydrocurcuminol bound at BRT’s site. All molecules analyzed have high force interaction fields. Once the viral activity is mainly intracellular, these compounds also were evaluated for their hydropathic abilities. All molecules were classified and considered capable of membrane cell invading. These results suggest that the therapeutic approach of the curcumin derivatives associated with AZT and the antiviral inhibitor N3 is promissory for future evaluation of their synergism in in vitro and in vivo tests to define their additional viability in the treatment of COVID-19.

Modeling the Properties of Curcumin Derivatives in Relation to the Architecture of the Siloxane Host Matrices

Research in the field of natural dyes has constantly focused on methods of conditioning curcumin and diversifying their fields of use. In this study, hybrid materials were obtained from modified silica structures, as host matrices, in which curcumin dyes were embedded. The influence of the silica network structure on the optical properties and the antimicrobial activity of the hybrid materials was monitored. By modifying the ratio between phenyltriethoxysilane:diphenyldimethoxysilane (PTES:DPDMES), it was possible to evaluate the influence the organosilane network modifiers had on the morphostructural characteristics of nanocomposites. The nanosols were obtained by the sol–gel method, in acid catalysis. The nanocomposites obtained were deposited as films on a glass support and showed a transmittance value (T measured at 550 nm) of around 90% and reflectance of about 11%, comparable to the properties of the uncovered support. For the coatings deposited on PET (polyethylene terephthalate) films, these properties remained at average values of T550 = 85% and R550 = 11% without significantly modifying the optical properties of the support. The sequestration of the dye in silica networks reduced the antimicrobial activity of the nanocomposites obtained, by comparison to native dyes. Tests performed on Candida albicans fungi showed good results for the two curcumin derivatives embedded in silica networks (11–18 mm) by using the spot inoculation method; in comparison, the alcoholic dye solution has a spot diameter of 20–23 mm. In addition, hybrids with the CA derivative were the most effective (halo diameter of 17–18 mm) in inhibiting the growth of Gram-positive bacteria, compared to the curcumin derivative in alcoholic solution (halo diameter of 21 mm). The results of the study showed that the presence of 20–40% by weight DPDMES in the composition of nanosols is the optimal range for obtaining hybrid films that host curcumin derivatives, with potential uses in the field of optical films or bioactive coatings.

Curcumin and Its New Derivatives: Correlation between Cytotoxicity against Breast Cancer Cell Lines, Degradation of PTP1B Phosphatase and ROS Generation

Breast cancer is the most common cancer of women—it affects more than 2 million women worldwide. PTP1B phosphatase can be one of the possible targets for new drugs in breast cancer therapy. In this paper, we present new curcumin derivatives featuring a 4-piperidone ring as PTP1B inhibitors and ROS inducers. We performed cytotoxicity analysis for twelve curcumin derivatives against breast cancer MCF-7 and MDA-MB-231 cell lines and the human keratinocyte HaCaT cell line. Furthermore, because curcumin is a known antioxidant, we assessed antioxidant effects in its derivatives. For the most potent cytotoxic compounds, we determined intracellular ROS and PTP1B phosphatase levels. Moreover, for curcumin and its derivatives, we performed real-time microscopy to observe the photosensitizing effect. Finally, computational analysis was performed for the curcumin derivatives with an inhibitory effect against PTP1B phosphatase to assess the potential binding mode of new inhibitors within the allosteric site of the enzyme. We observed that two tested compounds are better anticancer agents than curcumin. Moreover, we suggest that blocking the -OH group in phenolic compounds causes an increase in the cytotoxicity effect, even at a low concentration. Furthermore, due to this modification, a higher level of ROS is induced, which correlates with a lower level of PTP1B.

Tailored Functionalization of Natural Phenols to Improve Biological Activity

Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols’ anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.

Identification of Compound CB-2 as a Novel Late-Stage Autophagy Inhibitor Exhibits Inhibitory Potency against A549 Cells

Autophagy has been recognized as a stress tolerance mechanism that maintains cell viability, which contributes to tumor progression, dormancy, and treatment resistance. The inhibition of autophagy in cancer has the potential to improve the therapeutic efficacy. It is therefore of great significance to search for new autophagy inhibitors. In the present study, after screening a series of curcumin derivatives synthesized in our laboratory, (E)-3-((E)-4-chlorobenzylidene)-5-((5-methoxy-1H-indol-3-yl)methylene)-1-methylpiperidin-4-one (CB-2) was selected as a candidate for further study. We found that CB-2 increased the LC3B-II and SQSTM1 levels associated with the accumulation of autophagosomes in non-small cell lung cancer (NSCLC) A549 cells. The increased level of LC3B-II induced by CB-2 was neither eliminated when autophagy initiation was suppressed by wortmannin nor further increased when autophagosome degradation was inhibited by chloroquine (CQ). CB-2 enhanced the accumulation of LC3B-II under starvation conditions. Further studies revealed that CB-2 did not affect the levels of the key proteins involved in autophagy induction but significantly blocked the fusion of autophagosomes with lysosomes. High-dose CB-2 induced the apoptosis and necrosis of A549 cells, while a lower dose of CB-2 mainly impaired the migrative capacity of A549 cells, which only slightly induced cell apoptosis. CB-2 increased the levels of mitochondrial-derived reactive oxygen species (ROS) while decreasing the mitochondrial membrane potential (MMP). Scavenging ROS via N-acetylcysteine (NAC) reversed CB-2-induced autophagy inhibition and its inhibitory effect against A549 cells. In conclusion, CB-2 serves as a new late-stage autophagy inhibitor, which has a strong inhibitory potency against A549 cells.

Curcumin Derivatives as Potential Mosquito Larvicidal Agents against Two Mosquito Vectors, Culex pipiens and Aedes albopictus

Vector-borne diseases have appeared or re-emerged in many Southern Europe countries making the transmission of infectious diseases by mosquitoes (vectors) one of the greatest worldwide health threats. Larvicides have been used extensively for the control of Aedes (Stegomyia) albopictus (Skuse, 1895) (Diptera: Culicidae) and Culex pipiens Linnaeus, 1758 (Diptera: Culicidae) mosquitoes in urban and semi-urban environments, causing the increasing resistance of mosquitoes to commercial insecticides. In this study, 27 curcuminoids and monocarbonyl curcumin derivatives were synthesised and evaluated as potential larvicidal agents against Cx. pipiens and Ae. albopictus. Most of the compounds were more effective against larvae of both mosquito species. Four of the tested compounds, curcumin, demethoxycurcumin, curcumin-BF2 complex and a monocarbonyl tetramethoxy curcumin derivative exhibited high activity against both species. In Cx. pipiens the recorded LC50 values were 6.0, 9.4, 5.0 and 32.5 ppm, respectively, whereas in Ae. albopictus they exhibited LC50 values of 9.2, 36.0, 5.5 and 23.6 ppm, respectively. No conclusive structure activity relationship was evident from the results and the variety of descriptors values generated in silico provided some insight to this end.