Phenolic compounds as Nrf2 inhibitors: potential applications in cancer therapy.

Cancer is a leading cause of death worldwide and involves an oxidative stress mechanism. The transcription factor Nrf2 has a crucial role in cytoprotective response against oxidative stress, including cancer growth and progression and therapy resistance. For this reason, inhibitors of Nrf2 are new targets to be studied. Traditional plant-based remedies rich in phytochemicals have been used against human cancers and phenolic compounds are known for their chemopreventive properties. This comprehensive review offers an updated review of the role of phenolic compounds as anticancer agents due to their action on Nrf2 inhibition. In addition, the role of naturally-occurring bioactive anticancer agents are covered in the clinical applications of polyphenols as Nrf2 inhibitors. Video Abstract.

Natural essential oils as a new therapeutic tool in colorectal cancer.

Colorectal cancer (CRC) is the third most revalent type of cancer in the world and the second most common cause of cancer death (about 1 million per year). Historically, natural compounds and their structural analogues have contributed to the development of new drugs useful in the treatment of various diseases, including cancer. Essential oils are natural odorous products made up of a complex mixture of low molecular weight compounds with recognized biological and pharmacological properties investigated also for the prevention and treatment of cancer. The aim of this paper is to highlight the possible role of essential oils in CRC, their composition and the preclinical studies involving them. It has been reviewed the preclinical pharmacological studies to determine the experimental models used and the anticancer potential mechanisms of action of natural essential oils in CRC. Searches were performed in the following databases PubMed/Medline, Web of science, TRIP database, Scopus, Google Scholar using appropriate MeSH terms. The results of analyzed studies showed that EOs exhibited a wide range of bioactive effects like cytotoxicity, antiproliferative, and antimetastatic effects on cancer cells through various mechanisms of action. This updated review provides a better quality of scientific evidence for the efficacy of EOs as chemotherapeutic/chemopreventive agents in CRC. Future translational clinical studies are needed to establish the effective dose in humans as well as the most suitable route of administration for maximum bioavailability and efficacy. Given the positive anticancer results obtained from preclinical pharmacological studies, EOs can be considered efficient complementary therapies in chemotherapy in CRC.

Clinical applications of artificial intelligence and machine learning in cancer diagnosis: looking into the future.

Artificial intelligence (AI) is the use of mathematical algorithms to mimic human cognitive abilities and to address difficult healthcare challenges including complex biological abnormalities like cancer. The exponential growth of AI in the last decade is evidenced to be the potential platform for optimal decision-making by super-intelligence, where the human mind is limited to process huge data in a narrow time range. Cancer is a complex and multifaced disorder with thousands of genetic and epigenetic variations. AI-based algorithms hold great promise to pave the way to identify these genetic mutations and aberrant protein interactions at a very early stage. Modern biomedical research is also focused to bring AI technology to the clinics safely and ethically. AI-based assistance to pathologists and physicians could be the great leap forward towards prediction for disease risk, diagnosis, prognosis, and treatments. Clinical applications of AI and Machine Learning (ML) in cancer diagnosis and treatment are the future of medical guidance towards faster mapping of a new treatment for every individual. By using AI base system approach, researchers can collaborate in real-time and share knowledge digitally to potentially heal millions. In this review, we focused to present game-changing technology of the future in clinics, by connecting biology with Artificial Intelligence and explain how AI-based assistance help oncologist for precise treatment.

In vitro evaluation of different organic matrices used to modulate silicon bioavailability.

Silicon (Si) has numerous health properties. It is an element of the extracellular matrix; it is involved in collagen synthesis, bone mineralization, and immune system modulation; and it reduces metal accumulation in Alzheimer's disease and the risk of atherosclerosis. Given its poor intestinal absorption, Si is ingested in the form of orthosilicic acid (OSA) to promote its bioavailability. The aim of this work was to compare different commercial dietary supplements containing stabilized OSA to ascertain their bioaccessibility, bioavailability, and safety in a model of human intestinal epithelium. Biocompatibility with the glycocalyx was also investigated. Supplements containing collagen, maltodextrins, and choline as OSA stabilizers were analyzed. Bioaccessibility was explored by means of an in vitro digestive process. Bioavailability was investigated using a Caco2 cell line alone, or co-culturing with a HT29-MTX cell line. The safety of the compounds tested (in terms of intestinal epithelium integrity) was judged on the grounds of MTS assay, transepithelial electrical resistance, and apparent permeability. The three formulations were also tested in a Caco2 cell model of intestinal glycocalyx Si retention. The choline-formulated OSA formulation outperformed the maltodextrin-stabilized supplement, with a Si bioavailability about 14 times higher (P < .05). The choline-formulated OSA formulation increased cell permeability, with consequent intestinal epithelium disruption. The supplements' absorption and bioavailability (and harmfulness) differed considerably, depending on the OSA stabilizer involved. Of the three formulations tested, the collagen-formulated OSA represents the best Si dietary supplement.

Vicia plants-A comprehensive review on chemical composition and phytopharmacology.

The plants belonging to the genus Vicia are of great interest as a source of many bioactive compounds and micronutrients. A snapshot of their cultivation, habitat, main components, from which essential oils can be obtained, is given. The traditional medicinal uses of Vicia plants are also reported, as well as the wide spectrum of the main biological activities attributed to Vicia plants is discussed regarding potential health beneficial properties, in particular anti-Parkinson, anticholinesterase, antidepressant, anticonvulsant, antimicrobial, cytotoxic, antioxidant, antiinflammatory and antinociceptive, antidiabetic, antihemolytic, anticoagulant, estrogenic, diuretic, antihypoxic activities.

Curcumin nanoformulations for antimicrobial and wound healing purposes.

The development and spread of resistance to antimicrobial drugs is hampering the management of microbial infectious and wound healing processes. Curcumin is the most active and effective constituent of Curcuma longa L., also known as turmeric, and has a very long and strong history of medicinal value for human health and skincare. Curcumin has been proposed as strong antimicrobial potentialities and many attempts have been made to determine its ability to conjointly control bacterial growth and promote wound healing. However, low aqueous solubility, poor tissue absorption and short plasma half-life due its rapid metabolism needs to be solved for made curcumin formulations as suitable treatment for wound healing. New curcumin nanoformulations have been designed to solve the low bioavailability problem of curcumin. Thus, in the present review, the therapeutic applications of curcumin nanoformulations for antimicrobial and wound healing purposes is described.

The Wonderful Activities of the Genus Mentha: Not Only Antioxidant Properties.

Medicinal plants and their derived compounds have drawn the attention of researchers due to their considerable impact on human health. Among medicinal plants, mint (Mentha species) exhibits multiple health beneficial properties, such as prevention from cancer development and anti-obesity, antimicrobial, anti-inflammatory, anti-diabetic, and cardioprotective effects, as a result of its antioxidant potential, combined with low toxicity and high efficacy. Mentha species are widely used in savory dishes, food, beverages, and confectionary products. Phytochemicals derived from mint also showed anticancer activity against different types of human cancers such as cervix, lung, breast and many others. Mint essential oils show a great cytotoxicity potential, by modulating MAPK and PI3k/Akt pathways; they also induce apoptosis, suppress invasion and migration potential of cancer cells lines along with cell cycle arrest, upregulation of Bax and p53 genes, modulation of TNF, IL-6, IFN-γ, IL-8, and induction of senescence phenotype. Essential oils from mint have also been found to exert antibacterial activities against Bacillus subtilis, Streptococcus aureus, Pseudomonas aeruginosa, and many others. The current review highlights the antimicrobial role of mint-derived compounds and essential oils with a special emphasis on anticancer activities, clinical data and adverse effects displayed by such versatile plants.

Sisymbrium officinale, the Plant of Singers: A Review of Its Properties and Uses.

Sisymbrium officinale (hedge mustard and formerly called Erysimum officinale) is a common plant in wild lands of Europe and Africa. It is also cultivated for its seeds and leaves to be used in salad or mustard. Sisymbrium officinale is useful not only in culinary preparations, but it also seems to possess interesting therapeutic properties, especially for throat diseases such as aphonia and hoarseness. For this reason, it is commonly called "herb of singers" (in Italian, "Erba dei cantanti"). Indeed a cup of Sisymbrium officinale infusion is frequently consumed by singers before artistic performance, even if its beneficial ability still needs to be scientifically demonstrated. Some preliminary data can be analyzed, but new efforts and resources should be devoted to study and investigate a plant with valuable therapeutic potential. This review summarizes the data available for Sisymbrium officinale.

Editorial to the Special Issue "Biological and Pharmacological Activity of Plant Natural Compounds".

Plant natural products are a valuable source of compounds with a healthy potential effect on living organisms, including animals and humans [...].

Preclinical Pharmacological Activities of Epigallocatechin-3-gallate in Signaling Pathways: An Update on Cancer.

Epigallocatechin gallate (EGCG) is the main bioactive component of catechins predominantly present in svarious types of teas. EGCG is well known for a wide spectrum of biological activity as an anti-oxidative, anti-inflammatory, and anti-tumor agent. The effect of EGCG on cell death mechanisms via the induction of apoptosis, necrosis, and autophagy has been documented. Moreover, its anti-proliferative and chemopreventive action has been demonstrated in many cancer cell lines. It was also involved in the modulation of cyclooxygenase-2, in oxidative stress and inflammation of different cell processes. EGCG has been reported as a promising target for plasma membrane proteins, such as epidermal growth factor receptor (EGFR). In addition, it has been demonstrated a mechanism of action relying on the inhibition of ERK1/2, p38 MAPK, NF-κB, and vascular endothelial growth factor (VEGF). EGCG and its derivatives were used in proteasome inhibition and they were involved in epigenetic mechanisms. In summary, EGCG is the most predominant and bioactive constituent of teas and it has a pivotal role in cancer prevention. Its preclinical pharmacological activities are associated with complex molecular mechanisms that involve numerous signaling pathways.

Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice.

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-ß, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-ß and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.

Investigation of the molecular reactivity of bioactive oxiranylmethyloxy anthraquinones.

The design of a multitarget and multifunctional small molecule containing two functional groups reacting through different mechanisms represents an attractive goal for the medicinal chemist. The preparation of two bifunctional oxiranylmethyloxy anthraquinones, previously investigated as anticancer agents, is described here. These compounds combine a planar, DNA-intercalating and pro-oxidant anthraquinone scaffold and the alkylating epoxide functions which can covalently react with the nucleic acid. Their multilevel molecular reactivity was studied through a combination of analytical techniques: The DNA-binding properties were investigated using a mass spectrometry-based binding assay and by nuclear magnetic resonance, highlighting the formation of a covalent adduct with a nucleobase. Moreover, the contribution of the pro-oxidant redox cycling was evaluated.

Biological Effects of EF24, a Curcumin Derivative, Alone or Combined with Mitotane in Adrenocortical Tumor Cell Lines.

BACKGROUND: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. METHOD AND RESULTS: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 ± 2.4 µM and 4.9 ± 2.8 µM for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/ß-catenin, NF-κB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. CONCLUSION: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models.

Synergistic Effects of Plant Derivatives and Conventional Chemotherapeutic Agents: An Update on the Cancer Perspective.

Synergy is a process in which some substances cooperate to reach a combined effect that is greater than the sum of their separate effects. It can be considered a natural "straight" strategy which has evolved by nature to obtain more efficacy at low cost. In this regard, synergistic effects may be observed in the interaction between herbal products and conventional drugs or biochemical compounds. It is important to identify and exploit these interactions since any improvement brought by such kind of process can be advantageously used to treat human disorders. Even in a complex disease such as cancer, positive synergistic plant-drug interactions should be investigated to achieve the best outcomes, including providing a greater benefit to patients or avoiding adverse side effects. This review analyzes and summarizes the current knowledge on the synergistic effects of plant-drug interactions with a focus on anticancer strategies.

The natural history of autoimmune Addison's disease with a non-classical presentation: a case report and review of literature.

Autoimmune Addison's disease (AAD) is the most frequent cause of adrenocortical insufficiency. The natural history of AAD usually comprises five consecutive stages with the first stage characterized by the increase of plasma renin consistent with the impairment of pars glomerulosa, which is usually the first affected layer of the adrenal cortex. We describe a 19-year-old female with Hashimoto's thyroiditis (HT) who underwent an autoantibody screening due to having the personal and family history of other autoimmune diseases in the absence of relevant clinical manifestations. She was positive for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OH Ab) at high titers. She had increased basal levels of ACTH with normal basal cortisol not responding to ACTH stimulation, reduced levels of dehydroepiandrosterone-sulfate but normal levels of orthostatic renin and aldosterone. This scenario was consistent with a subclinical AAD presenting with first impairments in pars fasciculata and reticularis and conserved pars glomerulosa function. Only subsequently, progressive deficiency in pars glomerulosa function has become evident. Review of the literature showed that there was only one case, reported to date, with a similar atypical natural history of AAD. The strategies for screening for ACA/21-OH Ab in patients with HT are discussed.

Phytotherapeutics in cancer invasion and metastasis.

Cancer is a multifactorial disease, and therefore, a multitarget approach is needed to face the complex cancer biology, based on the combined use of different natural and synthetic anticancer agents able to target synergistically multiple signaling pathways involved in carcinogenesis, including angiogenesis and metastasis. In this view, the plant kingdom represents an unlimited source of phytotherapeutics with promising perspectives in the field of anticancer drug discovery. This narrative review aims to provide an updated overview on the bioactive phytochemicals exhibiting a promising potential as adjuvants in conventional anticancer therapies, with emphasis on antiangiogenic and antimetastatic activities.

The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line.

New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.

Investigation of N-cadherin/ß-catenin expression in adrenocortical tumors.

ß-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound ß-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). ß-catenin mutations were evaluated by sequencing, and ß-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in ß-catenin gene. qRT-PCR showed overexpression of ß-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear ß-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. ß-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and ß-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells.

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC.

Mitogen-Activated Protein Kinase Pathway: Genetic Analysis of 95 Adrenocortical Tumors.

Mitogen-activated protein kinase (MAPK) pathway is often deregulated in adrenocortical tumors (ACT) but with no concrete data confirming alteration rate. The objective of this study was to evaluate genetic alterations in key components of MAPK pathway. We found one BRAF mutation (p.V600E) and four HRAS silent mutations. No alteration was found in NRAS, KRAS, EGFR genes. The patient carrying BRAF mutation was further characterized by investigating his biomolecular and clinico-pathological findings. Therefore, even if MAPK signaling is activated in ACT, our results suggest that genetic alterations do not seem to represent a frequent mechanism of ACT tumorigenesis.