MAPK signalling pathway in cancers: Olive products as cancer preventive and therapeutic agents.

The mitogen-activated protein kinases (MAPKs) are fundamental in inflammation and cancer control, through the crosstalk between the redox regulated nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kB (NFκB) gene expression. MAPKs regulate various cellular activities involved in cancer progression, including proliferation, apoptosis and immune escape and blockade of upstream kinases is a current therapeutic strategy. However, these therapies are associated with some adverse effects and with the paradoxical activation of the MAPKs pathway. In the context of cancer prevention and treatment, it has been suggested that dietary factors are able to modulate cancer initiation and progression by interacting with the MAPKs. Within these dietary factors, virgin olive oil (VOO) is of particular interest due to its content in squalene, already used as drug delivery system in cancer therapy. The aim of this review is to discuss the studies pointing to the effects of olive-derived foodstuff and nutraceuticals on MAPKs signalling cascades. The reviewed experimental studies suggest that the stress-activated JNK and p38 MAPKs could be targets of olive-derived nutraceuticals. The latter, including phytochemicals from olive cultivation and processing wastes, could be adjuvants in chemotherapies, whereas VOO could be considered a "natural delivery system" of bioactive phytochemicals due to its high content in squalene.

Current insights into functions of phospholipase A2 receptor in normal and cancer cells: More questions than answers.

Lipid signaling network was proposed as a potential target for cancer prevention and treatment. Several recent studies revealed that phospholipid metabolising enzyme, phospholipase A2 (PLA2), is a critical regulator of cancer accelerating pathologies and apoptosis in several types of cancers. In addition to functioning as an enzyme, PLA2 can activate a phospholipase A2 receptor (PLA2R1) in plasma membrane. While the list of PLA2 targets extends to glucose homeostasis, intracellular energy balance, adipocyte development, and hepatic lipogenesis, the PLA2R1 downstream effectors are few and scarcely investigated. Among the most addressed PLA2R1 effects are regulation of pro-inflammatory signaling, autoimmunity, apoptosis, and senescence. Localized in glomeruli podocytes, the receptor can be identified by circulating anti-PLA2R1 autoantibodies leading to development of membranous nephropathy, a strong autoimmune inflammatory cascade. PLA2R1 was shown to induce activation of Janus-kinase 2 (JAK2) and estrogen-related receptor α (ERRα)-controlled mitochondrial proteins, as well as increasing the accumulation of reactive oxygen species, thus leading to apoptosis and senescence. These findings indicate the potential role of PLA2R1 as tumor suppressor. Epigenetic investigations addressed the role of DNA methylation, histone modifications, and specific microRNAs in the regulation of PLA2R1 expression. However, involvement of PLA2R1 in suppression of malignant growth and metastasis remains controversial. In this review, we summarize the recent findings that highlight the role of PLA2R1 in the regulation of carcinogenesis-related intracellular signaling.

Implications of farnesyltransferase and its inhibitors as a promising strategy for cancer therapy.

Ras proteins have been reported to play key role in oncologic diseases. Ras proteins are associated with cellular membranes for its carcinogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase is responsible for a type of Ras membrane targeting, which leads to cancer origin and progression. Inhibitors of farnesyltransferase have been developed as novel anticancer agents. In this review, the role of farnesyltransferase in cancer progression and development has been discussed. Further, the current status of development of farnesyltransferase inhibitors for cancer prevention and treatment has also been reviewed.

Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles.

Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.

Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives.

Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, naproxen, sulindac, celecoxib, and licofelone), statins and other natural agents-both individually, and in combinations. Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.

Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.

Novel histone deacetylase 8-selective inhibitor 1,3,4-oxadiazole-alanine hybrid induces apoptosis in breast cancer cells.

Identification of isoform-specific histone deacetylase inhibitors (HDACi) is a significant advantage to overcome the adverse side effects of pan-HDACi for the treatment of various diseases, including cancer. We have designed, and synthesized novel 1,3,4 oxadiazole with glycine/alanine hybrids as HDAC8-specific inhibitors and preliminary evaluation has indicated that 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)propanamide (10b)] to be a potent HDAC8 inhibitor. In the present study, the in vitro efficacy of the molecule in inhibiting the cancer cell proliferation and the underlying molecular mechanism was studied. 10b inhibited the growth of MDA-MB-231 and MCF7 breast cancer cells, with a lower IC50 of 230 and 1000 nM, respectively, compared to K562, COLO-205 and HepG2 cells and was not cytotoxic to normal breast epithelial cells, MCF10A. 10b was specific to HDAC8 and did not affect the expression of other class I HDACs. Further, a dose-dependent increase in H3K9 acetylation levels demonstrated the HDAC-inhibitory activity of 10b in MDA-MB-231 cells. Flow cytometric analysis indicated a dose-dependent increase and decrease in the percent apoptotic cells and mitochondrial membrane potential, respectively, when treated with 10b. Immunoblot analysis showed a modulation of Bax/Bcl2 ratio with a decrease in Bcl2 expression and no change in Bax expression. 10b treatment resulted in induction of p21 and inhibition of CDK1 proteins along with cytochrome c release from mitochondria, activation of caspases-3 and -9 and cleavage of poly ADP-ribose polymerase leading to apoptotic death of MDA-MB-231 and MCF7 cells. In conclusion, our results clearly demonstrated the efficacy of 10b as an anticancer agent against breast cancer.

Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity.

Oxadiazole is a heterocyclic compound containing an oxygen atom and two nitrogen atoms in a five-membered ring. Of the four oxadiazoles known, 1,3,4-oxadiazole has become an important structural motif for the development of new drugs and the compounds containing 1,3,4-oxadiazole cores have a broad spectrum of biological activity. Herein, we describe the design, synthesis and biological evaluation of a series of novel 2,5-disubstituted 1,3,4-oxadiazoles (10a-10j) as class I histone deacetylase (HDAC) inhibitors. The compounds were designed and evaluated for HDAC8 selectivity using in silico docking software (Glide) and the top 10 compounds with high dock score and obeying Lipinski's rule were synthesized organically. Further the biological HDAC inhibitory and selectivity assays and anti-proliferative assays were carried out. In in silico and in vitro studies, all compounds (10a-10j) showed significant HDAC inhibition and exhibited HDAC8 selectivity. Among all tested compounds, 10b showed substantial HDAC8 inhibitory activity and better anticancer activity which is comparable to the positive control, a FDA approved drug, vorinostat (SAHA). Structural activity relation is discussed with various substitutions in the benzene ring connected on 1,3,4-oxadizole and glycine/alanine. The study warranted further investigations to develop HDAC8-selective inhibitory molecule as a drug for neoplastic diseases. Novel 1,3,4-oxadizole substituted with glycine/alanine showed HDAC8 inhibition.

Anti-inflammatory Activity of PLA2 Inhibitory Saccharumoside-B.

BACKGROUND: Saccharumoside-B and its analogs were found to have anticancer potential in vitro. The present study reports acute toxicity, molecular docking, ADMET profile analysis, and in vitro and in vivo anti-inflammatory activity of saccharumoside-B for the first time. METHODS: The in vitro enzyme inhibitory activity of saccharumoside-B on PLA2, COX-1, COX-2, and 5-LOX enzymes was evaluated by the cell-free method, and its effect on TNF-α, IL1ß, and IL- 6 secretion levels in LPS stimulated THP-1 human monocytes was determined by ELISA-based methods. The anti-inflammatory activity was evaluated in vivo by carrageenan-induced rat paw edema model. To test its binding affinity at the active site pockets of PLA2 enzymes and assess drug-like properties, docking experiments and ADMET studies were performed. RESULTS: Saccharumoside-B showed selective inhibition of the sPLA2 enzyme (IC50 = 7.53 ± 0.232 µM), and thioetheramide-PC was used as a positive control. It showed significant inhibition (P ≤ 0.05) of TNF-α, IL-1ß, and IL-6 cytokines compared to the positive control dexamethasone. Saccharumoside-B showed a dose-dependent inhibition of carrageenan-induced rat paw edema, with a maximum inhibition (76.09 ± 0.75) observed at 3 hours after the phlogistic agent injection. Saccharumoside-B potentially binds to the active site pocket of sPLA2 crystal protein (binding energy -7.6 Kcal/Mol). It complies with Lipinski's Rule of Five, showing a promising safety profile. The bioactivity scores suggested it to be a better enzyme inhibitor. CONCLUSION: Saccharumoside-B showed significant PLA2 inhibition. It can become a potential lead molecule in synthesizing a new class of selective PLA2 inhibitors with a high safety profile in the future.

Drug Sensitivity Testing for Cancer Therapy, Key Areas.

AIMS: Cancer is a high-mortality disease (9.6 million deaths in 2018 worldwide). Given various anticancer drugs, drug selection plays a key role in patient survival in clinical trials. METHODS: Drug Sensitivity Testing (DST), one of the leading drug selective systems, was widely practiced for therapeutic promotion in the clinic. Notably, DSTs assist in drug selection that benefits drug responses against cancer from 20-22% to 30-35% over the past two decades. The relationship between drug resistance in vitro and drug treatment benefits was associated with different tumor origins and subtypes. Medical theory and underlying DST mechanisms remain poorly understood until now. The study of the clinical scenario, sustainability and financial support for mechanism and technical promotions is indispensable. RESULTS: Despite the great technical advance, therapeutic prediction and drug selection by DST needs to be miniature, versatility and cost-effective in the clinic. Multi-parameters and automation of DST should be a future trend. Advanced biomedical knowledge and clinical approaches to translating oncologic profiles into drug selection were the main focuses of DST developments. With a great technical stride, the clinical architecture of the DST platform was entering higher levels (drug response testing at any stage of cancer patients and miniaturization of tumor samples). DISCUSSION: The cancer biology and pharmacology for drug selection mutually benefit the clinic. New proposals to reveal more therapeutic information and drug response prediction at genetic, molecular and omics levels should be estimated overall. CONCLUSION: By upholding this goal of non-invasive, versatility and automation, DST could save the life of several thousand annually worldwide. In this article, new insights into DST novelty and development are highlighted.

Features, Pharmacological Chemistry, Molecular Mechanism and Health Benefits of Lemon.

BACKGROUND: Citrus limon, a Mediterranean-grown citrus species of plants belonging to the Rutaceae family, occupies a place of an impressive range of food and medicinal uses with considerable value in the economy of the fruit of the country. Citrus fruits are economically important with large-scale production of both the fresh fruits and industrially processed products. The extracts and phytochemicals obtained from all parts of C. limon have shown immense therapeutic potential because of their anticancer, anti-tumor and anti-inflammatory nature, and also serve as an important ingredient in the formulation of several ethnic herbal medicines. These properties are mediated by the presence of different phytochemicals, vitamins and nutrients in the citrus fruits. MATERIAL AND METHODS: The methods involved in the preparation of the present article included the collection of information from various scientific databases, indexed periodicals, and search engines such as Medline Scopus google scholar PubMed, PubMed central web of science, and science direct. RESULTS: This communication presents an updated account of different pharmacological aspects of C. limon associated with its anti-oxidative, antiulcer, antihelmintic, insecticidal, anticancer, cytotoxic, and estrogenic activities. In addition, C. limon extracts possess hepatoprotective, anti-hyperglycemic, and antimicrobial properties. The present article includes the structure and function of different key chemical constituents from different parts of C. limon. Also, the possible molecular mechanisms of actions of bioactive compounds from C. limon are displayed. CONCLUSION: The traditional and ethno-medicinal literature revealed that C. limon is very effective in different pathologies. Most of these compounds possessing antioxidant properties would be implicated in offering health benefits by acting as potential nutraceuticals to humans with special reference to disease management of health and disease.

Salidroside - Can it be a Multifunctional Drug?

BACKGROUND: Salidroside is a glucoside of tyrosol found mostly in the roots of Rhodiola spp. It exhibits diverse biological and pharmacological properties. In the last decade, enormous research is conducted to explore the medicinal properties of salidroside; this research reported many activities like anti-cancer, anti-oxidant, anti-aging, anti-diabetic, anti-depressant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, etc. Objective: Despite its multiple pharmacological effects, a comprehensive review detailing its metabolism and therapeutic activities is still missing. This review aims to provide an overview of the metabolism of salidroside, its role in alleviating different metabolic disorders, diseases and its molecular interaction with the target molecules in different conditions. This review mostly concentrates on the metabolism, biological activities and molecular pathways related to various pharmacological activities of salidroside. CONCLUSION: Salidroside is produced by a three-step pathway in the plants with tyrosol as an intermediate molecule. The molecule is biotransformed into many metabolites through phase I and II pathways. These metabolites, together with a certain amount of salidroside may be responsible for various pharmacological functions. The salidroside based inhibition of PI3k/AKT, JAK/ STAT, and MEK/ERK pathways and activation of apoptosis and autophagy are the major reasons for its anti-cancer activity. AMPK pathway modulation plays a significant role in its anti-diabetic activity. The neuroprotective activity was linked with decreased oxidative stress and increased antioxidant enzymes, Nrf2/HO-1 pathways, decreased inflammation through suppression of NF-κB pathway and PI3K/AKT pathways. These scientific findings will pave the way to clinically translate the use of salidroside as a multi-functional drug for various diseases and disorders in the near future.

Publisher Correction: Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Role of GTPases in the Regulation of Mitochondrial Dynamics in Alzheimer's Disease and CNS-Related Disorders.

Data obtained from several studies have shown that mitochondria are involved and play a central role in the progression of several distinct pathological conditions. Morphological alterations and disruptions on the functionality of mitochondria may be related to metabolic and energy deficiency in neurons in a neurodegenerative disorder. Several recent studies demonstrate the linkage between neurodegeneration and mitochondrial dynamics in the spectrum of a promising era called precision mitochondrial medicine. In this review paper, an analysis of the correlation between mitochondria, Alzheimer's disease, and other central nervous system (CNS)-related disorders like the Parkinson's disease and the autism spectrum disorder is under discussion. The role of GTPases like the mfn1, mfn2, opa1, and dlp1 in mitochondrial fission and fusion is also under investigation, influencing mitochondrial population and leading to oxidative stress and neuronal damage.

Proteins Commonly Linked to Autism Spectrum Disorder and Alzheimer's Disease.

Several years after the first publication of Barker's Hypothesis the identification of common patterns and pathways between genetic and epigenetic risk factors in neurodegenerative disorders is still an open problem. For the cases of Alzheimer's disease and Autism and by taking into consideration the increasing number of diagnosed cases globally, scientists focused on commonly expressed and related proteins like Amyloid beta and the mechanisms of their underlying dysfunctionalities. In this review paper, an attempt to specify significant correlations between proteins linked to Autism Spectrum Disorders and Alzheimer's Disease is presented. Both diseases are highlighted with an emphasis on the macromolecules that play a fundamental role in their development. These proteins are described and analyzed concerning the underlying pathology of these diseases.

HAART in HIV/AIDS Treatments: Future Trends.

AIDS (acquired immune deficient syndrome) is a deadly human viral infectious disease caused by HIV (human immune-deficient virus) infection. Almost every AIDS patient losses his/her life before mid 1990s. AIDS was once the 1st disease killer in US (1993). After one decade hard work, antiviral drug cocktails-high active anti-retroviral therapy (HAART) have been invented for almost all HIV infection treatments. Due to the invention of HAART, 80-90% HIV/AIDS patients still effectively response to HAART for deadly AIDS episode controls and life saving. Yet, this type of HIV therapeutics is incurable. HIV/AIDS patients need to take HAART medications regularly and even life-long. To counteract this therapeutic drawback, more revolutionary efforts (different angles of therapeutic modes/attempts) are urgently needed. In this article, the major progresses and drawbacks of HIV/AIDS chemotherapy (HAART) to HIV/AIDS patients have been discussed. Future trends (updating pathogenesis study, next generations of drug developments, new drug target discovery, different scientific disciplinary and so on) are highlighted.

Human Suicide Risk and Treatment Study.

INTRODUCTION: Suicide is still a major event of human mortality worldwide. Yet human suicide prediction, prevention and therapeutic systems at this moment are generally ineffective in the clinic. No diagnostic system is reliable for significantly suicidal prevention and mortality reduction. As a result, human suicide etiopathologic investigation (especially at genetic/molecular levels in the clinical settings) is quite necessary. In order to boost human suicide researches, emerging human suicide diagnostic/treatment study will be transformed from clinical symptom observations into new generations of candidate drug targets and therapeutics. To achieve this goal, associations between suicidal etiopathologic identification, genetic/bioinformatics-based diagnostics and putative drug targets must be exploited than ever before. After all, the interaction and relationships between environmental/ genetic/molecular clues and overall patient's risk prediction (environmental influences and different therapeutic targets/types) should be found out. CONCLUSION: In the future, effective clinical suicide prediction, prevention and therapeutic systems can be established via scientific expeditions and causality discovery.

Late-life Depression and Alzheimer Disease: A Potential Synergy of the Underlying Mechanisms.

A number of biological and clinical characteristics typical of late life depression (LLD) have been suggested by recent research findings. The close association of LLD with cognitive impairment is now well documented and evidenced. However, it is still not clear whether it is depression that leads to cognitive decline, and in more severe cases, to dementia. The work presented in this review article suggests that depression and dementia frequently and strongly copresent, even if the causality remains largely opaque.

Current Updates on Role of Lipids in Hematopoiesis.

Hematopoiesis is the process which generates all the mature blood cells from the rare pool of Hematopoietic stem cells (HSCs). Asymmetric cell division of HSCs provide it dual capacity for self-renewal and multi-potent differentiation. Hematopoiesis is a steady state process in which mature blood cells are produced at the same rate at which they are lost, establishing a homeostasis. HSCs are regulated through their environmental niche, cytokine signalling, and the orchestrated activities of various transcription factors. However, there is very little information available about the signal transduction events that regulate HSC function; in particular, the effects of bioactive lipids and lipid mediators are not well understood. Recent studies have added an important aspect of this process, introducing the role of lipids in cell fate decisions during hematopoiesis. The mechanisms of bioactive lipids and their derivatives have been studied extensively in signal transduction and various other cellular processes. This review focuses on various categories of lipids and their regulatory mechanisms in HSCs and their comment into different blood cells. Moreover, we also discuss the role of lipid signalling specifically in megakaryocyte and platelets.