Cancer chemopreventive and antioxidant activities of seed, skin, and pulp of Maximo hybrid grapes (IAC 138-22) at five different ripening stages

ABSTRACT: This study evaluated the composition and the cancer chemopreventive and antioxidant activities of the seed, skin, and pulp of Maximo hybrid grapes (IAC 138-22) harvested at different ripening stages. The content of total phenolic compounds and tannins were determined by the Folin-Ciocaulteau method, and total anthocyanins were determined using the differential pH method. Different chemical methods assessed the antioxidant activity. Cell viability (macrophage and melanoma skin cancer) and cancer chemopreventive activity were tested in cell lines by quinone reductase induction assay, TNF-α-induced NF-κB inhibitory activity assay, and aromatase inhibitory activity assay. The hybrid grape had high phenolic contents in both seeds and skin, significantly reduced upon ripening. The results showed that fruit ripening significantly affected both the composition and the antioxidant and cancer chemopreventive activities. Except for the anthocyanin content, the most significant results were observed for green seeds, with the greenest stage showing the best results. The green seeds showed the highest antioxidant activity, even when compared to free resveratrol. In the assessment of cancer chemopreventive activity, the green seeds showed the ability to inhibit N-FκB and aromatase activity, important factors for the early stage of cancer development. Besides, no extracts showed cytotoxicity. Therefore, this grape’s green seeds showed strong antioxidant and cancer chemopreventive activities confirmed herein, suggesting beneficial health effects.

New insights into antimalarial chemopreventive activity of antifolates

Antifolates targeting dihydrofolate reductase (DHFR) are antimalarial compounds that have long been used for malaria treatment and chemoprevention (inhibition of infection from mosquitoes to humans). Despite their extensive applications, the thorough understanding of antifolate activity against hepatic malaria parasites, especially resistant parasites, have yet to be achieved. Using a transgenic P. berghei harboring quadruple mutant dhfr from P. falciparum (Pb::Pfdhfr -4M ) , we demonstrate that quadruple mutations on Pfdhfr confer complete chemoprevention resistance to pyrimethamine, the previous generation of antifolate, but not to a new class of antifolate designed to overcome the resistance such as P218. Detailed investigation to pin-point stage-specific chemoprevention further demonstrated that it is unnecessary for the drug to be present throughout hepatic development. The drug is most potent against the developmental stages from early hepatic trophozoite to late hepatic trophozoite, but is not effective at inhibiting sporozoite and early hepatic stage development from sporozoite to early trophozoite. Our data shows that P218 also inhibited the late hepatic stage development, from trophozoite to mature schizonts to a lesser extent. With a single dose of 15 mg/kg, P218 prevented infection from up to 25,000 pyrimethamine-resistant sporozoites, a number equal to thousands of infectious mosquito bites. Additionally, the hepatic stage of malaria parasite is much more susceptible to antifolates than the asexual blood stage. This study provides important insights into the activity of antifolates, as a chemopreventive therapeutic which could lead to a more efficient and cost effective treatment regime.

The Beneficial Effect of Coarse Cereals on Chronic Diseases through Regulating Gut Microbiota

In recent years, chronic diseases including obesity, diabetes, cancer, cardiovascular, and neurodegenerative disorders have been the leading causes of incapacity and death globally. Increasing evidence suggests that improvements of lifestyle habits and diet is the most commonly adopted strategy for the prevention of chronic disorders. Moreover, many dietary compounds have revealed health-promoting benefits beyond their nutritional effects. It is worth noting that diet plays an important role in shaping the intestinal microbiota. Coarse cereals constitute important sources of nutrients for the gut microbiota and contribute to a healthy gut microbiome. Furthermore, the gut microbiota converts coarse cereals into functional substances and mediates the interaction between the host and these components. In this study, we summarize the recent findings concerning functional components of cereal grains and their potential chemopreventive activity via modulating the gut microbiota.

Cancer Chemopreventive Role of Dietary Terpenoids by Modulating Keap1-Nrf2-ARE Signaling System—A Comprehensive Update

ROS, RNS, and carcinogenic metabolites generate excessive oxidative stress, which changes the basal cellular status and leads to epigenetic modification, genomic instability, and initiation of cancer. Epigenetic modification may inhibit tumor-suppressor genes and activate oncogenes, enabling cells to have cancer promoting properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that in humans is encoded by the NFE2L2 gene, and is activated in response to cellular stress. It can regulate redox homoeostasis by expressing several cytoprotective enzymes, including NADPH quinine oxidoreductase, heme oxygenase-1, UDP-glucuronosyltransferase, glutathione peroxidase, glutathione-S-transferase, etc. There is accumulating evidence supporting the idea that dietary nutraceuticals derived from commonly used fruits, vegetables, and spices have the ability to produce cancer chemopreventive activity by inducing Nrf2-mediated detoxifying enzymes. In this review, we discuss the importance of these nutraceuticals in cancer chemoprevention and summarize the role of dietary terpenoids in this respect. This approach was taken to accumulate the mechanistic function of these terpenoids to develop a comprehensive understanding of their direct and indirect roles in modulating the Keap1-Nrf2-ARE signaling system.

The Two Mono-Carbonyl Curcumin Analogs, PGV-1 and CCA-1.1: The Chemopreventive Activity Against DMH-Induced Colorectal Cancer Rat and Proteins Target Candidate Involved

Pentagamavunone-1 and its newest derivatives, CCA-1.1, possess an outstanding cytotoxic activity against several cancer cell lines, especially colorectal cancer. We are continuing to explore the anti-colorectal cancer properties of PGV-1 and CCA-1.1 against DMH-induced colorectal cancer rats and expound the potential protein target in colorectal adenocarcinoma. We utilized DMH 60 mg/kg (subcutaneous injection once a week for 16 weeks) to induce colorectal cancer. PGV-1 and CCA-1.1 at 10 and 20 mg/kg (orally twice a week for 16 weeks) were co-administered with DMH. The WBC count increased in a single DMH group and was countered by co-administration of PGV-1 and CCA-1.1, but no significant differences in RBC. Single DMH treatment for 16 weeks resulted in 80% adenocarcinoma. In contrast, co-administration with PGV-1 and CCA-1.1 suppressed most of the carcinogenic characteristics and symptoms of the pre-malignancy condition. Furthermore, bioinformatics analysis showed that CCA-1.1 has more specific targets than PGV-1, including CDK1, CDK2, MMP3, MMP14, and CYP3A4, which regulate the cell cycle arrest, cancer cell migration, and xenobiotic metabolism, respectively. Interestingly, CCA-1.1 targets CYP3A4, which possibly interrupts DMH metabolism and prevents the initiation of DMH-colorectal carcinogenesis. In conclusion, CCA-1.1 performed better chemopreventive effects against DMH colorectal cancer and might replace PGV-1 to be promoted as a more effective anti-colorectal cancer agent.

Improvement of Nutraceutical Value of Parsley Leaves (Petroselinum crispum) upon Field Applications of Beneficial Microorganisms

Parsley (Petroselinum crispum) is an important aromatic herb that has gained importance in food and cosmetic industry, and it is used as medicinal plant due to the presence of compounds with biological activity. Several studies have demonstrated antioxidant, antimicrobial or cancer chemopreventive activity of different parts of parsley plants. We showed that the nutritional value of parsley leaves can be improved by treatments with beneficial microorganisms on the field crop. Streptomyces fulvissimus strain AtB-42 and Trichoderma harzianum strain T22 were applied, as singly or in combination (microbial consortium), at transplanting and two weeks later. After harvesting, plants were subjected to metabolomic analysis by LC and GC-MS. Spectrometric analysis resulted in the identification of seven polar metabolites. Results showed a significant difference in relative abundance of these metabolites among treatments. The AtB-42 application, alone or in combination with T22, induced the accumulation of petroselinic acid, while T22, alone or in combination, induced the accumulation of xanthotoxol/bergaptol and its derivative xanthotoxin/bergapten. The microbial consortium increased the accumulation of capsanthone compared to single treatments. No statistically relevant differences were found for the volatile fraction. It can be concluded that S. fulvissimus and T. harzianum significantly induced metabolic profile change of parsley and the accumulation of metabolites with nutraceutical value.

New insights into antimalarial chemopreventive activity of antifolates

Antifolates targeting dihydrofolate reductase (DHFR) are antimalarial compounds that have long been used for malaria treatment and chemoprevention (inhibition of infection from mosquitoes to humans). Despite their extensive applications, the thorough understanding of antifolate activity against hepatic malaria parasites, especially resistant parasites, have yet to be achieved. Using a transgenic P. berghei harboring quadruple mutant dhfr from P. falciparum (Pb::Pfdhfr-4M), we demonstrate that quadruple mutations on Pfdhfr confer complete chemoprevention resistance to pyrimethamine, the previous generation of antifolate, but not a new class of antifolate designed to overcome the resistance such as P218. Detailed investigation to pin-point stage-specific chemoprevention further demonstrated that it is unnecessary for the drug to be present throughout hepatic development. The drug is most potent against the developmental stages from early hepatic trophozoite to late hepatic trophozoite, but is not effective at inhibiting sporozoite and early hepatic stage development from sporozoite to early trophozoite. Our data shows that P218 also inhibited the late hepatic stage development, from trophozoite to mature schizonts to a lesser extent. With a single dose of 15 mg/kg, P218 prevented infection from up to 25,000 pyrimentamine-resistant sporozoites, a number equal to thousands of infectious mosquito bites. Additionally, the hepatic stage of malaria parasite is much more susceptible to antifolates than the asexual blood stage. This study provides important insights into the activity of antifolates, as a chemopreventive therapeutic which could lead to a more efficient and cost effective treatment regime.

Selenium as a Bioactive Micronutrient in the Human Diet and Its Cancer Chemopreventive Activity

This review answers the question of why selenium is such an important trace element in the human diet. Daily dietary intake of selenium and its content in various food products is discussed in this paper, as well as the effects of its deficiency and excess in the body. Moreover, the biological activity of selenium, which it performs mainly through selenoproteins, is discussed. These specific proteins are responsible for thyroid hormone management, fertility, the aging process, and immunity, but their key role is to maintain a redox balance in cells. Furthermore, taking into account world news and the current SARS-CoV-2 virus pandemic, the impact of selenium on the course of COVID-19 is also discussed. Another worldwide problem is the number of new cancer cases and cancer-related mortality. Thus, the last part of the article discusses the impact of selenium on cancer risk based on clinical trials (including NPC and SELECT), systematic reviews, and meta-analyses. Additionally, this review discusses the possible mechanisms of selenium action that prevent cancer development.

Lasius fuliginosus Nest Carton as a Source of New Promising Bioactive Extracts with Chemopreventive Potential

Six new water extracts (E1–E6) were obtained from nest carton produced by jet black ants Lasius fuliginosus and tested for their biochemical and bioactive properties, including antioxidative and anticancer effects. The present study demonstrated significant qualitative and quantitative differences in the content of individual biochemical constituents, as well as bioactive properties between the investigated samples. All tested extracts demonstrated antioxidant properties (determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) methods), and the highest antioxidative potential was recorded in extracts E1 and E2 (188.96 and 313.67 μg/mL of ascorbic acid equivalent for ABTS and 176.42 and 202.66 μg/mL for DPPH reagent). Furthermore the six extracts exhibited strong inhibitory activity towards human melanoma cells of the A-375 CRL-1619 line in a dose-dependent manner. The most interesting chemopreventive activity was exhibited by extract E2, which inhibited the proliferation of A-375 cells to the greatest extent, while having a minimal effect on Vero cells. The effect on cancer cells has been confirmed using the Electric Cell-substrate Impedance Sensing (ECIS) technique. Significant impedance changes have been detected in A-375 and Vero cells following the administration of extract E2. The obtained results are really promising and constitute the basis for further research on the nest carton of jet black ant.

Manool, a diterpene from Salvia officinalis, exerts preventive effects on chromosomal damage and pre-neoplastic lesions

The present study aimed to evaluate the effect of the manool diterpene on genomic integrity. For this purpose, we evaluated the influence of manool on genotoxicity induced by mutagens with different mechanisms of action, as well as on colon carcinogenesis. The results showed that manool (0.5 and 1.0 µg/mL) significantly reduced the frequency of micronuclei induced by doxorubicin (DXR) and hydrogen peroxide in V79 cells but did not influence genotoxicity induced by etoposide. Mice receiving manool (1.25 mg/kg) exhibited a significant reduction (79.5%) in DXR-induced chromosomal damage. The higher doses of manool (5.0 and 20 mg/kg) did not influence the genotoxicity induced by DXR. The anticarcinogenic effect of manool (0.3125, 1.25 and 5.0 mg/kg) was also observed against pre-neoplastic lesions chemically induced in rat colon. A gradual increase in manool doses did not cause a proportional reduction of pre-neoplastic lesions, thus demonstrating the absence of a dose-response relationship. The analysis of serum biochemical indicators revealed the absence of hepatotoxicity and nephrotoxicity of treatments. To explore the chemopreventive mechanisms of manool via anti-inflammatory pathways, we evaluated its effect on nitric oxide (NO) production and on the expression of the NF-kB gene. At the highest concentration tested (4 μg/mL), manool significantly increased NO production when compared to the negative control. On the other hand, in the prophylactic treatment model, manool (0.5 and 1.0 μg/mL) was able to significantly reduce NO levels produced by macrophages stimulated with lipopolysaccharide. Analysis of NF-kB in hepatic and renal tissues of mice treated with manool and DXR revealed that the mutagen was unable to stimulate expression of the gene. In conclusion, manool possesses antigenotoxic and anticarcinogenic effects and its anti-inflammatory potential might be related, at least in part, to its chemopreventive activity.