Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation

Phenolics, which are secondary metabolites of plants, exhibit remarkable bioactivities. In this contribution, we have focused on their protective effect against chronic diseases rather than their antioxidant activities, which have been widely discussed in the literature. A large body of epidemiological studies has proven the bioactivities of phenolics in both standard compounds and natural extracts: namely, anticancer, anti-inflammatory, and antibacterial activities as well as reducing diabetes, cardiovascular disease, and neurodegenerative disease. Phenolics also display anti-analgesic, anti-allergic, and anti-Alzheimer's properties. Thus, this review provides crucial information for better understanding the bioactivities of phenolics in foods and fills a gap in the existing collective and overall knowledge in the field.

https://www.mdpi.com/1422-0067/19/6/1573/pdf

Bioactivities of Phenolics by Focusing on Suppression of Chronic Diseases: A Review

Natural polyphenols as versatile platforms for material engineering and surface functionalization

Phenolic acids from vegetables: A review on processing stability and health benefits

With recent insight into the development of dietary supplements and functional foods, search of effective phytochemical compounds and their mechanisms involved in prevention and management of diabetes and its complications are now being assessed. Cinnamic acid and its derivatives occur naturally in high levels of plant-based foods. Among various biological activities, cinnamic acid and its derivatives are associated with a beneficial influence on diabetes and its complications. The aim of the review is to summarize the potential mechanisms of these compounds for prevention and management of diabetes and its complications. Based on several in vitro studies and animal models, cinnamic acid and its derivatives act on different mechanism of actions, including stimulation of insulin secretion, improvement of pancreatic β-cell functionality, inhibition of hepatic gluconeogenesis, enhanced glucose uptake, increased insulin signaling pathway, delay of carbohydrate digestion and glucose absorption, and inhibition of protein glycation and insulin fibrillation. However, due to the limited intestinal absorption being a result of low bioavailability of cinnamic acid and its derivatives, current improvement efforts with entrapping into solid and liquid particles are highlighted. Further human clinical studies are needed to clarify the effects of cinnamic acid and its derivatives in diabetic patients.

https://www.mdpi.com/2072-6643/9/2/163/pdf

Cinnamic acid and its derivatives: Mechanisms for prevention and management of diabetes and its complications

Plant derived phenolic compounds have been shown to inhibit the initiation and progression of cancers by modulating genes regulating key processes such as: (a) oncogenic transformation of normal cells; (b) growth and development of tumors; and (c) angiogenesis and metastasis. Recent studies focusing on identifying the molecular basis of plant phenolics-induced cancer cell death have demonstrated down-regulation of: (a) oncogenic survival kinases such as PI3K and Akt; (b) cell proliferation regulators that include Erk1/2, D-type Cyclins, and Cyclin Dependent Kinases (CDKs); (c) transcription factors such as NF-kβ, NRF2 and STATs; (d) histone deacetylases HDAC1 and HDAC2; and (e) angiogenic factors VEGF, FGFR1 and MIC-1. Furthermore, while inhibiting oncogenic proteins, the phenolic compounds elevate the expression of tumor suppressor proteins p53, PTEN, p21, and p27. In addition, plant phenolic compounds and the herbal extracts rich in phenolic compounds modulate the levels of reactive oxygen species (ROS) in cells thereby regulate cell proliferation, survival and apoptosis. Furthermore, recent studies have demonstrated that phenolic compounds undergo transformation in gut microbiota thereby acquire additional properties that promote their biological activities. In vitro observations, preclinical and epidemiological studies have shown the involvement of plant phenolic acids in retarding the cancer growth. However, to date, there is no clinical trial as such testing the role of plant phenolic compounds for inhibiting tumor growth in humans. More over, several variations in response to phenolic acid rich diets-mediated treatment among individuals have also been reported, raising concerns about whether phenolic acids could be used for treating cancers. Therefore, we have made an attempt to (a) address the key structural features of phenolic acids required for exhibiting potent anti-cancer activity; (b) review the reported findings about the mechanisms of action of phenolic compounds and their transformation by gut microbiota; and (c) update the toxicological aspects and anti-tumor properties of phenolic compounds and extracts containing phenolic compounds in animals.

/pdf/an-overview-on-the-role-of-dietary-phenolics-for-the-18r23w5uo8.pdf

An overview on the role of dietary phenolics for the treatment of cancers

Recent studies from our group and many others have shown the ability of histone deacetylase (HDAC) inhibitors for retarding the growth of carcinomas of cervix, colon and rectum in vitro. A search for naturally occurring HDAC inhibitors continues due to the adverse effects associated with known HDAC inhibitors like SAHA and TSA. Therefore in the current study, naturally occurring cinnamic acids derivatives were screened for HDAC inhibitory effect using in silico docking method which identified cinnamic acids as potential candidates. Cinnamic acids (CA) are naturally occurring phenolic compounds known to exhibit anticancer properties. However, it is not clearly known whether the anticancer properties of CA derivatives are due to the inhibition of oncogenic HDACs, if so how the efficacy varies among various CA derivatives. Hence, the HDAC inhibitory potential of CA derivatives containing increasing number of hydroxylic groups or methoxy moieties was determined using Discovery Studio software and the most potent CA derivatives tested ex vivo (biochemical assay) as well as in vitro (using cell based assay). Among CA derivatives tested, dihydroxy cinnamic acid (DHCA, commonly known as caffeic acid) exhibited better interactions with HDAC2 (compared to other isoforms) in silico and inhibited its activity ex vivo as well as in vitro. Targeted reduction of HDAC activity using DHCA induced death of cancer cells by (a) generating reactive oxygen species, (b) arresting cells in S and G2/M phases; and (c) induction of caspase-3 mediated apoptosis. In conclusion, we demonstrated that DHCA inhibited cancer cell growth by binding to HDAC followed by the induction of apoptosis.

/pdf/induction-of-colon-and-cervical-cancer-cell-death-by-3rzna2rpnc.pdf

Induction of colon and cervical cancer cell death by cinnamic acid derivatives is mediated through the inhibition of Histone Deacetylases (HDAC).

Histone deacetylases (HDACs), which modulate the expression of genes, are potential therapeutic targets in several cancers Targeted inhibition of HDAC prevents the expression of oncogenes thereby help in the treatment of cancers Hence, several pharmaceutical companies developed inhibitors of HDAC and tested them in preclinical models and in clinical trials SAHA (suberanilohydroxamic acid) is one such HDAC inhibitor developed for treating breast and colorectal carcinomas However, due to poor efficacy in clinical trials the utility of SAHA for treating cancers was discouraged Similarly another HDAC inhibitor Trichostatin-A (TSA) also showed promising results in clinical trials but exhibited severe adverse effects, which dampened the interest of using this molecule for cancer treatment Therefore, search for developing a potent HDAC inhibitor with minimal side effects still continues Hence, in this study we have screened benzoic acid and benzoic acid derivatives with hydroxylic (-OH) groups and methoxy (-OCH3) groups for their efficacy to bind to the TSA binding site of HDAC using molecular docking studies Molecules that showed much stronger affinity (than TSA) to HDAC were tested for inhibiting HDAC expressing cultured cancer cells DHBA but not Dimethoxy Benzoic Acid (DMBA) inhibited HDAC activity, leading to cancer cell growth inhibition through the induction of ROS and cellular apoptosis mediated by Caspase-3 In addition, DHBA arrested cells in G2/M phase of the cell cycle and elevated the levels of sub-G0-G1 cell population In summary, results of this study report that DHBA could be a strong HDAC inhibitor and inhibit cancer cell growth more effectively

Naturally occurring benzoic acid derivatives retard cancer cell growth by inhibiting histone deacetylases (HDAC).

Background: Cancer is a major cause of death worldwide. Limitations of current cancer therapies necessitate the search for new anticancer drugs. Plants represent an immeasurable source of bioactive compounds for drug discovery. The objective of this study was to assess the anti-proliferative and antioxidant potential of four indigenous South African plants commonly used in traditional medicine. Materials and Methods: The anti-proliferative activity of the plant extracts were assessed by the 2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2 H -Tetrazolium-5-Carboxanilide (XTT) assay on A431; HaCat; HeLa; MCF-7 and UCT-Mel 1 cells and sulforhodamine-B (SRB) assay on HCT-116 and HCT-15 cell lines. Antioxidant activity was determined using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide scavenging assays. Results: Three of the plant extracts ( Combretum mollefruit , Euclea crispa subsp. crispa leaves and stems and Sideroxylon inerme leaves and stems showed anti-proliferative activity on the A431 cells with IC 50 values ranging between 26.9 - 46.7 μg/ml. The Euclea crispa subsp. crispa extract also showed anti-proliferative activity on the MCF-7 cell line (45.7 μg/ml). All of the plant extracts ( Combretum molle leaves and fruit, Euclea crispa subsp. crispa leaves and stems, Sideroxylon  inerme leaves and stems and Terminalia prunioides leaves and stems) showed DPPH scavenging activity with IC 50 values ranging from 1.8 μg/ml to 11.5 μg/ml. Conclusion: These results indicate that the active extracts of Combretum molle , Euclea crispa subsp. Crispa and Sideroxylon inerme warrant further investigation to determine the mechanism of anti-proliferative activity against cancerous cells. These plant extracts also show potential for further evaluation in the prevention and treatment of cancer. Keywords: South African plants, Traditional medicine, Anti-proliferative activity, Antioxidant activity

/pdf/the-anti-proliferative-and-antioxidant-activity-of-four-5723o0lmjc.pdf

The anti-proliferative and antioxidant activity of four indigenous South African plants

Diallyl disulfide (DADS) is sulfur containing anti-cancer agent derived from garlic. Several in vitro studies have demonstrated the ability of DADS to inhibit the growth of cancer cells. However, only few studies have tested the ability of DADS to retard the development of tumor cells in animal models. Therefore, in this study we have measured the anti-tumor efficacy of DADS using wellestablished EAC tumor model representing a liquid-tumor. Analysis of the data showed a significant decrease in tumor growth as evidenced by a significant reduction in animal body weight in liquid tumor model. Mechanistically, DADS induced apoptosis by promoting caspase-3 expression and preventing the oxidative degradation of anti-tumor proteins such as p53 by upregulating antioxidant enzymes NQO1 and SOD; and reducing agents such as GSH. In summary, DADS appears to be a potential anti-cancer agent for considering it as a monotherapy or for selecting it as a component drug in the combination trials.

Preethi G. Anantharaju

Papers

An overview on the role of dietary phenolics for the treatment of cancers

Induction of colon and cervical cancer cell death by cinnamic acid derivatives is mediated through the inhibition of Histone Deacetylases (HDAC).

Naturally occurring benzoic acid derivatives retard cancer cell growth by inhibiting histone deacetylases (HDAC).

The anti-proliferative and antioxidant activity of four indigenous South African plants

Diallyl Disulfide (DADS) Retards the Growth of Breast Cancer Cells in Vitro and in Vivo Through Apoptosis Induction