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Abstract

Virgin olive oil (VOO) is one of the key components of the Mediterranean diet owing to the presence of monounsaturated fatty acids and various bioactive compounds. These beneficial traits, which are usually associated with the cultivar genotype, are highlighting the demand of identifying characteristics of olive oil that will ensure its authenticity. In this work, the fatty acid (FA) composition of 199 VOO samples from Koroneiki, Megaritiki, Amfissis, and Manaki cultivars was determined and studied by chemometrics. Olive cultivar greatly influenced the FA composition, namely, oleic acid (from 75.36% for Amfissis to 65.81% for Megaritiki) and linoleic acid (from 13.35% for Manaki to 6.70% for Koroneiki). Spearman’s rho correlation coefficients revealed differences and similarities among the olive oil cultivars. The use of the forward stepwise algorithm identified the FAs arachidonic acid, gadoleic acid, linoleic acid, α-linolenic acid, palmitoleic acid, and palmitic acid as the most significant for the differentiation of samples. The application of linear and quadratic cross-validation discriminant analysis resulted in the correct classification of 100.00% and 99.37% of samples, respectively. The findings demonstrated the special characteristics of the VOO samples derived from the four cultivars and their successful botanical differentiation based on FA composition.

2.2. Fatty Acid Composition

The dominant FA was oleic acid (C18:1) with the highest concentrations observed in Amfissis (75.36 ± 1.14%) and Koroneiki (74.70 ± 1.58%) VOO samples. Lower levels were detected in Megaritiki (65.81 ± 2.75%) and Manaki (70.15 ± 1.72%) cultivars. Adversely, for the polyunsaturated FA, linoleic acid (C18:2), the highest levels were observed in the Manaki (13.35 ± 1.07%) and Megaritiki (12.51 ± 2.02%) cultivars. The major saturated FAs were palmitic acid (C16:0), determined in the highest concentration in Megaritiki (15.53 ± 1.01%), and stearic acid (C18:0) in Koroneiki (2.78 ± 0.28%) and Manaki (2.63 ± 0.15%) samples. Interestingly, the highest levels of oleic/linoleic acid (C18:1/C18:2) and MUFA/PUFA ratios were observed in the Koroneiki cultivar which indicates a high performance against oxidative deterioration [].

2.2. Fatty Acid Composition

ANOVA and subsequent post-hoc tests between FA in association with botanical origin were performed (). Statistically significant differences were observed among the VOOs based on the levels of palmitoleic acid (16:1) and gadoleic acid (20:1), indicating a strong contribution on the discrimination between the four cultivars. Other FA such as arachidonic acid (20:4) and linoleic acid (18:2) were also significant for the differentiation of VOOs from Koroneiki, Megaritiki, and Amfissis cultivars. From the obtained results it is evident that a further application of chemometric methods to FA composition could be successful for the classification of samples with regard to cultivar.

2.3. Correlation Coefficients

Correlations of FA concentrations from the combination of the four olive oil cultivars as well as in each cultivar separately () were studied using Spearman’s rho correlation coefficients to designate potent similarities and differences between the cultivars. From the combined FA results of the four cultivars, strong positive correlations (p ≤ 0.01) were observed (a) between palmitic acid (16:0)—palmitoleic acid (16:1), arachidic acid (20:0)—behenic acid (22:0), and arachidic acid (20:0)—stearic acid (18:0), while strong negative correlations were observed between gadoleic acid (20:1)—palmitoleic acid (16:1) and gadoleic acid (20:1)—palmitic acid (16:0). A medium to strong antagonistic relationships was detected among oleic acid (18:1)—linoleic acid (18:2), oleic acid (18:1)—palmitoleic acid (16:1), and oleic acid (18:1)—stearic acid (18:0) (). The correlations between palmitic acid (16:0)—palmitoleic acid (16:1) and arachidic acid (20:0)—stearic acid (18:0) have been previously reported from Stefanoudaki et al. [] and Kritioti et al. [] who studied olive oil samples from Mastoides, Koroneiki, and Cypriot (ladoelia) cultivars. The antagonistic relationship between oleic acid (18:1)—stearic acid (18:0) has also been reported by Kritioti et al. [].

2.3. Correlation Coefficients

A high degree of positive correlation coefficients were observed between palmitic (16:0)—palmitoleic acid (16:1) for all cultivars, especially in Manaki VOO samples (d). Differences were observed in arachidic acid (20:0)—behenic acid (22:0), medium to strong correlations were observed in Megaritiki and Amfissis, while in Koroneiki and Manaki were low positive (). Positive correlations of arachidic acid (20:0)—stearic acid (18:0) were detected in all cultivars except from Manaki where the significance level was above 0.01. Strong negative correlations were observed between gadoleic acid (20:1)—palmitoleic acid (16:1) in Manaki and Megaritiki while in Koroneiki and Amfissis the correlations were insignificant. Strong negative correlations were also observed in gadoleic acid (20:1)—palmitic acid (16:0) in all cultivars except for Koroneiki samples. Medium to strong negative correlations of oleic acid (18:1)—palmitoleic acid (16:1) were detected in all cultivars. Strong antagonistic relationships were detected among oleic acid (18:1)—linoleic acid (18:2) in all cultivars except Amfissis, and medium antagonistic relationships were among oleic acid (18:1)—stearic acid (18:0) for Koroneiki and Megaritiki VOO samples. Summarizing the above results, common correlation patterns were detected in the four cultivars for the FA palmitic acid (16:0)—palmitoleic acid (16:1) and oleic acid (18:1)—palmitoleic acid (16:1), while several differences were observed among the remaining FA of this study depicting the differences in each cultivar.

2.4. Principal Component Analysis

The variables that contributed primarily in component 1 () were palmitic (16:0), palmitoleic (16:1), oleic (18:1), stearic (18:0), gadoleic (20:1), arachidic (20:0), behenic (22:0), and linoleic acid (18:2), with the highest contribution observed from palmitoleic (16:1) and oleic (18:1) acid. Arachidonic acid (20:4) mainly contributed to the formation of the second axis, followed by stearic (18:0), lignoceric (24:0), and gadoleic acid (20:1). α-linolenic acid (18:3) had a major contribution in the third component (), palmitic (16:0), linoleic acid (18:2), and lignoceric acid (24:0). Based on the first two principal components a good separation has been achieved for the Megaritiki and Amfissis cultivars. Thus, the FA that participate in the formation of the two axes are successfully contributing to the differentiation of the VOO samples from Megaritiki and Amfissis. Nevertheless, VOO samples from the Manaki cultivar were not clearly separated from the Koroneiki samples. Consequently, other chemometric methods should be applied for their differentiation.

Abstract

Sydnone methides are described from which only one single example has been mentioned in the literature so far. Their deprotonation gave anions which can be formulated as π‐electron rich anionic N‐heterocyclic carbenes. Sulfur and selenium adducts were stabilized as their methyl ethers, and mercury, gold as well as rhodium complexes of the sydnone methide carbenes were prepared. Sydnone methide anions also undergo C−C coupling reactions with 1‐fluoro‐4‐iodobenzene under Pd(PPh3)4 and CuBr catalysis. 77Se NMR resonance frequencies and 1 J C4‐Se as well as 1 J C4‐H coupling constants have been determined to gain knowledge about the electronic properties of the anionic N‐heterocyclic carbenes. The carbene carbon atom of the sydnone methide anion 3 j resonates at δ=155.2 ppm in 13C NMR spectroscopy at −40 °C which is extremely shifted upfield in comparison to classical N‐heterocyclic carbenes.

Abstract

The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.

2. Immunomodulatory Effects of Curcumin

In some initial studies, curcumin supplementation showed no effect on the activity of natural killer (NK) cells in rats when given at doses of up to 40 mg/kg for up to five weeks []. However, in another study, Yadav et al. explored the immunomodulatory effects of curcumin and showed that this compound can increase NK cell cytotoxicity in vitro and that this effect can be further enhanced when curcumin was given along with IFN-γ treatment []. Increasing evidence indicates that curcumin exhibits its anti-inflammatory effects through the downregulation of NLRP3 inflammasomes []. Inflammasomes are multiprotein complexes that are responsible for innate immunity. The NLRP3, as a component of inflammasomes, can trigger immune response after detecting the products of damaged cells []. Curcumin can suppress NLRP3 inflammasome activation through regulation of the NF-κB signaling, leading also to suppression of IL-1β secretion []. For example, in malignant mesothelioma, curcumin has been found to exhibit its anticancer properties through regulation of signaling pathways affecting inflammasomes, such as IL-1 and NF-κB [].

2. Immunomodulatory Effects of Curcumin

Other studies have also determined the anti-inflammatory and anticancer properties of curcumin. In a clinical investigation where human chronic myelogenous leukemia cells (K562) were studied, curcumin treatment resulted in significant downregulation of IL-6, TLRs, IL-3 and STAT-1 []. In another randomized double-blind placebo-controlled trial, 80 patients with solid tumors were randomly assigned to 180 mg/day of curcuminoids supplementation or matched placebo for 8 weeks. All mediators of inflammation, including interleukins, TNF-α and monocyte chemotactic protein-1 were significantly lower in the curcuminoids versus placebo group []. When curcumin was given as part of a botanical drug containing multiple polyphenols, named APG-157 in a double-blind, randomized phase 1 clinical trial, where 12 patients with oral cancer were enrolled, reduced IL-1β, IL-6, and IL-8 concentrations were found in the saliva 24 h after treatment [].

2. Immunomodulatory Effects of Curcumin

Other studies have also determined the anti-inflammatory and anticancer properties of curcumin. In a clinical investigation where human chronic myelogenous leukemia cells (K562) were studied, curcumin treatment resulted in significant downregulation of IL-6, TLRs, IL-3 and STAT-1 []. In another randomized double-blind placebo-controlled trial, 80 patients with solid tumors were randomly assigned to 180 mg/day of curcuminoids supplementation or matched placebo for 8 weeks. All mediators of inflammation, including interleukins, TNF-α and monocyte chemotactic protein-1 were significantly lower in the curcuminoids versus placebo group []. When curcumin was given as part of a botanical drug containing multiple polyphenols, named APG-157 in a double-blind, randomized phase 1 clinical trial, where 12 patients with oral cancer were enrolled, reduced IL-1β, IL-6, and IL-8 concentrations were found in the saliva 24 h after treatment [].

2. Immunomodulatory Effects of Curcumin

Other studies have also determined the anti-inflammatory and anticancer properties of curcumin. In a clinical investigation where human chronic myelogenous leukemia cells (K562) were studied, curcumin treatment resulted in significant downregulation of IL-6, TLRs, IL-3 and STAT-1 []. In another randomized double-blind placebo-controlled trial, 80 patients with solid tumors were randomly assigned to 180 mg/day of curcuminoids supplementation or matched placebo for 8 weeks. All mediators of inflammation, including interleukins, TNF-α and monocyte chemotactic protein-1 were significantly lower in the curcuminoids versus placebo group []. When curcumin was given as part of a botanical drug containing multiple polyphenols, named APG-157 in a double-blind, randomized phase 1 clinical trial, where 12 patients with oral cancer were enrolled, reduced IL-1β, IL-6, and IL-8 concentrations were found in the saliva 24 h after treatment [].

3. Lung Cancer

Curcumin exhibits its therapeutic potential in lung cancer treatment by acting on the Wnt/β-catenin-dependent pathway in the human lung cancer cell line A549 []. Curcumin also suppresses the vascular endothelial growth factor (VEGF0 and NF-κB expression in the same cell line []. In addition, curcumin has been shown to inhibit the expression of enhancer of zeste homolog 2 (EZH2) in lung cancer cells, which was followed by a decrease in the expression of the Notch 1 gene []. Curcumin has exhibited cytotoxicity against non-small-cell lung cancer (NSCLC) through inhibition of cell proliferation, increased apoptosis, and G2/M arrest. Curcumin also induces ROS production, thus activating the DNA damage signaling pathway [].

Abstract

The Lacinutrix genus was discovered in 2005 and includes 12 Gram-negative bacterial species. To the best of our knowledge, the secondary metabolite production potential of this genus has not been explored before, and examination of Lacinutrix species may reveal novel chemistry. As part of a screening project of Arctic marine bacteria, the Lacinutrix sp. strain M09B143 was cultivated, extracted, fractionated and tested for antibacterial and cytotoxic activities. One fraction had antibacterial activity and was subjected to mass spectrometry analysis, which revealed two compounds with elemental composition that did not match any known compounds in databases. This resulted in the identification and isolation of two novel isobranched lyso-ornithine lipids, whose structures were elucidated by mass spectrometry and NMR spectroscopy. Lyso-ornithine lipids consist of a 3-hydroxy fatty acid linked to the alpha amino group of an ornithine amino acid through an amide bond. The fatty acid chains were determined to be iso-C15:0 (1) and iso-C16:0 (2). Compound 1 was active against the Gram-positive S. agalactiae, while 2 showed cytotoxic activity against A2058 human melanoma cells.

2.5. Structure Elucidation

The structures of 1 and 2 () were elucidated using 1D (1H and 13C, ) and 2D (HSQC, HMBC, HSQC-TOCSY and COSY, COSY only recorded for 2). NMR experiments in methanol-d3 and UHPLC-HR-MS analysis. The compounds were determined to consist of a polar ornithine head group linked to a mono-hydroxylated 15:0 (1)/16:0 (2) iso-fatty acid through an amide bond. The structures of the individual variants of 1 and 2 could not be determined individually, but the presence of two stereoisomers in the 5-position could be observed as two near isochronous C-5 resonances and an unresolvable H-5 multiplet pattern.

Experimental design

Thirty male rats (8 weeks old, 172 ± 16 g) were randomly divided into 3 groups: A) sham (SHO) group; B) unilateral ureteral obstruction (UUO) group; C) ATRA treat (ATRA) group, 10 rats per group. Before surgery the rats were performed under general anesthesia (40 mg/kg ip sodium pentobarbital). The left ureter was either completely ligated with two separate silk ties without cutting off the ureter (group B/C) or manipulated similarly but not ligated (group A). ATRA dissolved in corn oil at a dose of 15 mg/kg (group C) or vehicle corn oil (group A/B) was orally administered from 3 days before surgery and on each day until rats were sacrificed after 14 and 28 days (n = 5 for each time point for all groups). Kidneys were removed for histological analysis or Western blot assay.

ARTA improves histopathologic changes in UUO rats

After ureteral ligation, the major signs of renal damage were hydronephrosis and thin renal cortex. From d 14 to d 28, the renal tubular dilation, loss of integrality for tubular brush border, and severity for inflammatory infiltration was significantly enhanced in UUO group when compared with SHO group (). In parallel, the renal interstitial area gradually widened and fibrosis gradually developed in UUO group, and the ATRA group was weaker than UUO group, as showed by the staining of Masson trichrome (). Meanwhile, RIF score was notably up-regulated in UUO rats when compared with that of sham rats. Compared with UUO rats, the RIF score was markedly down-regulated in rats of ATRA group at d 14 and d 28. The values were shown in .

ATRA affects the expressions of angpt-1, TGF-β1, Col-IV and FN in UUO rats

An imbalance of ECM synthesis and degradation was an important event in RIF, including expression of cytokines (e.g., TGF-β1) [,] and mesenchymal markers (e.g., Col-IV and FN) [,]. To assess the effect of ATRA on ECM in the renal interstitial, Angpt-1, TGF-β1, Col-IV and FN protein expression levels were determined by immunohistochemistry in UUO rats treated with or without ATRA, respectively. As shown in , in the group of UUO, TGF-β1, Col-IV and FN expressions were significantly up-regulated, whereas Angpt-1 expression was notably down-regulated than the group of SHO from d 14 to d 28 (p < 0.05). ATRA treatment can reduce TGF-β1, Col-IV and FN expressions and improved Angpt-1 expression at d 14 and d 28 than the UUO group (p < 0.05; ).

ATRA restores angpt-1 expression in UUO rats

To investigate the effect of ATRA on ECM accumulation in the RIF rats, Angpt-1 protein expression was determined using Western-blot method. As shown in , when compared with the group of sham, the expression of Angpt-1 in UUO group was markedly down-regulated from day of d 14 to d 28 (p < 0.05; ). Interestingly, ATRA treatment in group of UUO resulted in increased the expression of Angpt-1 on days 14 and 28 compared to the group of UUO (p < 0.05; ).