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Colorectal cancer (CRC) is the third most common cancer and the leading cause of gastrointestinal cancer death. 90% of people diagnosed with colorectal cancer are over the age of 50; nevertheless, the illness is more aggressive among those detected at a younger age. Chemotherapy-based treatment has several adverse effects on both normal and malignant cells. The primary signaling pathways implicated in the advancement of CRC include hedgehog (Hh), janus kinase and signal transducer and activator of transcription (JAK/STAT), Wingless-related integration site (Wnt)/β-catenin, transforming growth factor-β (TNF-β), epidermal growth factor receptor (EGFR)/Mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), nuclear factor kappa B (NF-κB), and Notch. Loss of heterozygosity in tumor suppressor genes like adenomatous polyposis coli, as well as mutation or deletion of genes like p53 and Kirsten rat sarcoma viral oncogene (KRAS), are all responsible for the occurrence of CRC. Novel therapeutic targets linked to these signal-transduction cascades have been identified as a consequence of advances in small interfering RNA (siRNA) treatments. This study focuses on many innovative siRNA therapies and methodologies for delivering siRNA therapeutics to the malignant site safely and effectively for the treatment of CRC. Treatment of CRC using siRNA-associated nanoparticles (NPs) may inhibit the activity of oncogenes and MDR-related genes by targeting a range of signaling mechanisms. This study summarizes several siRNAs targeting signaling molecules, as well as the therapeutic approaches that might be employed to treat CRC in the future., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Most drugs or the natural substances reputed to display some biological activity are hydrophobic molecules that demonstrate low bioavailability regardless of their mode of absorption. Resveratrol and its derivatives belong to the chemical group of stilbenes; while stilbenes are known to possess very interesting properties, these are limited by their poor aqueous solubility as well as low bioavailability in animals and humans. Among the substances capable of forming nanomolecular inclusion complexes which can be used for drug delivery, cyclodextrins show spectacular physicochemical and biomedical implications in stilbene chemistry for their possible application in nanomedicine. By virtue of their properties, cyclodextrins have also demonstrated their possible use in green chemistry for the synthesis of stilbene glucosylated derivatives with potential applications in dermatology and cosmetics. Compared to chemical synthesis and genetically modified microorganisms, plant cell or tissue systems provide excellent models for obtaining stilbenes in few g/L quantities, making feasible the production of these compounds at a large scale. However, the biosynthesis of stilbenes is only possible in the presence of the so-called elicitor compounds, the most commonly used of which are cyclodextrins. We also report here on the induction of resveratrol production by cyclodextrins or combinatory elicitation with methyljasmonate in plant cell systems as well as the mechanisms by which they are able to trigger a stilbene response. The present article therefore discusses the role of cyclodextrins in stilbene chemistry both at the physico-chemical level as well as the biomedical and biotechnological levels, emphasizing the notion of "easy alliance" between these compounds and stilbenes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The discovery of new drugs for treating the new coronavirus (SARS-CoV-2) or repurposing those already in use for other viral infections is possible through understanding of the viral replication cycle and pathogenicity. This article highlights the advantage of targeting one of the non-structural proteins, helicase (nsp13), over other SARS-CoV-2 proteins. Highlighting the experience gained from targeting Nsp13 in similar coronaviruses (SARS-CoV and MERS) and known inhibitors, the article calls for research on helicase inhibitors as potential COVID-19 therapy., (Copyright © 2020 IMSS. All rights reserved.)

In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Resveratrol and the biosynthetically related stilbenes are plant secondary metabolites with diverse pharmacological effects. The versatile functions of these compounds in plant defense mechanisms as phytoalexins on one hand, and in human health as potential pharmaceutical agents on the other, have attracted lots of interest in recent years to understand their biosynthetic pathways and their biological properties. Because of difficulties in obtaining resveratrol and its glucosylated derivatives as well as oligomeric forms in sufficient amounts for evaluation of their activity by plant sourcing or total synthesis, biotechnology may provide a competitive approach for the large-scale and low cost production of biologically active stilbenes. Additionally, one major limitation in the use of resveratrol and related aglycone derivatives as therapeutic agents is associated with their inherent poor aqueous solubility and low bioavailability. This article examines approaches for the synthesis of potential pharmacologically resveratrol derivatives in vivo by exploiting whole microorganisms, enzymatic and biocatalytic approaches allowing their full utilization for medicine, food and cosmetic applications. These methods also have the advantage of enabling the one-step production of stilbene compounds, compared to the time-consuming and environmentally unfriendly procedures used for their total synthesis or their extraction from plants. Increasing the desired products yield and biological activity through glucosylation (β-D-glucosides versus α-D-glucosides) and oligomerization methodologies of resveratrol including green chemistry methods in organic solvent-free media are discussed as well., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Plants, fungi, and microorganisms are equipped with biosynthesis machinery for producing thousands of secondary metabolites. These compounds have important functions in nature as a defence against predators or competitors as well as other ecological significances. The full utilization of these compounds for food, medicine, and other purposes requires a thorough understanding of their structures and the distinct biochemical pathways of their production in cellular systems. In this review, flavonoids as classical examples of secondary metabolites are employed to highlight recent advances in understanding how valuable compounds can be regulated at various levels. With extensive diversity in their chemistry and pharmacology, understanding the metabolic engineering of flavonoids now allows us to fine-tune the eliciting of their production, accumulation, and extraction from living systems. More specifically, recent advances in the shikimic acid and acetate biosynthetic pathways of flavonoids production from metabolic engineering point of view, from genes expression to multiple principles of regulation, are addressed. Specific examples of plants and microorganisms as the sources of flavonoids-based compounds with particular emphasis on therapeutic applications are also discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Numerous in vitro and in vivo studies on biological activities of phytostilbenes have brought to the fore the remarkable properties of these compounds and their derivatives, making them a top storyline in natural product research fields. However, getting stilbenes in sufficient amounts for routine biological activity studies and make them available for pharmaceutical and/or nutraceutical industry applications, is hampered by the difficulty to source them through synthetic chemistry-based pathways or extraction from the native plants. Hence, microbial cell cultures have rapidly became potent workhorse factories for stilbene production. In this review, we present the combined efforts made during the past 15 years to engineer stilbene metabolic pathways in microbial cells, mainly the Saccharomyces cerevisiae baker yeast, the Escherichia coli and the Corynebacterium glutamicum bacteria. Rationalized approaches to the heterologous expression of the partial or the entire stilbene biosynthetic routes are presented to allow the identification and/or bypassing of the major bottlenecks in the endogenous microbial cell metabolism as well as potential regulations of the genes involved in these metabolic pathways. The contributions of bioinformatics to synthetic biology are developed to highlight their tremendous help in predicting which target genes are likely to be up-regulated or deleted for controlling the dynamics of precursor flows in the tailored microbial cells. Further insight is given to the metabolic engineering of microbial cells with "decorating" enzymes, such as methyl and glycosyltransferases or hydroxylases, which can act sequentially on the stilbene core structure. Altogether, the cellular optimization of stilbene biosynthetic pathways integrating more and more complex constructs up to twelve genetic modifications has led to stilbene titers ranging from hundreds of milligrams to the gram-scale yields from various carbon sources. Through this review, the microbial production of stilbenes is analyzed, stressing both the engineering dynamic regulation of biosynthetic pathways and the endogenous control of stilbene precursors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the present paper, we will discuss on the importance of autophagy in the central nervous system, and outline the relation between autophagic pathways and the pathogenesis of neurodegenerative disorders. The potential therapeutic benefits of naturally occurring phytochemicals as pharmacological modulators of autophagy will also be addressed. Our findings provide renewed insight on the molecular modes of protection by polyphenols, which is likely to be at least in part mediated not only by their potent antioxidant and anti-inflammatory effects, but also through modulation of autophagic processes to remove the aberrant protein aggregates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Organisms are constantly exposed to a broad range of pathological and stress-inducing agents, allergens and environmental chemicals that can induce infections, toxicity or other undesirable reactions. Our immune system has evolved over time in order to efficiently respond to these exogenous insults and maintain homeostasis. In particular, the innate immune system acts as primary barrier to prevent the entrance of invasive agents or allergens. This system is comprised of a diversity of cell types that are rapidly activated by recognition of common structures present in many potential pathogens known as pathogen-associated molecular patterns (PAMPs). The nuclear factor erythroid 2 related factor 2 (Nrf2) is a relevant basic leucine zipper (bZIP) transcription factor that is essential in the regulation of cell cycle homeostasis, cytoprotection, and innate immunity when cells are under stressful conditions. Although the role of Nrf2 in activating the expression of protective genes - such as antioxidant or anti-inflammatory - is known, its role in innate immunity and immune-related gene expression remains not yet clear. The present review summarizes current knowledge on Nrf2 signaling pathway structure and activity under both physiological state and upon oxidative stress. In addition, the relation between Nrf2 signaling pathway and the innate immune system is discussed, highlighting the potential therapeutic effects of diverse natural and synthetic compounds as Nrf2 regulators., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Platelets are small anucleated fragments derived from a megakaryocyte precursor. Platelets play a key role in many physiological functions especially in hemostasis and wound healing processes in order to maintain the integrity of the circulatory system. In addition, activated platelets release cytokines and chemokines which modulate the immune response and, in some cases of hyperactivation, they could be associated to the pathogenesis of inflammatory diseases. Flavonoids are polyphenolic compounds ubiquosly found in plants known to be potent antioxidants with positive effects against diverse diseases such as cancer, neurodegenerative or cardiovascular disease. It has been reported that some flavonoids possess anti-platelet aggregation effects though different pathways, being the inhibition of the arachidonic acid-based pathway the most representative mechanism of action. In the present review, the main sources of flavonoids, as well as their bioavailability and metabolism are summarized. Moreover, the available data about the anti-aggregation effects of flavonoids and the different mechanisms of action that has been proposed until now are also discussed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to normal cellular survival. Moreover, the important role of NF-κB factors in the central nervous system (CNS) through toll-like receptor (TLR) activation has been well established. This review demonstrates recent findings regarding therapeutic aspects of polyphenolic compounds for the treatment of neuroinflammation, with the aim of regulating TLR4. Polyphenols including flavonoids, phenolic acids, phenolic alcohols, stilbenes and lignans, can target TLR4 signaling pathways in multiple ways. Toll interacting protein expression could be modulated by epigallocatechin-3-gallate. Resveratrol may also exert neuroprotective effects via the TLR4/NF-κB/STAT signaling cascade. Its role in activation of cascade via interfering with TLR4 oligomerization upon receptor stimulation has also been reported. Curcumin, another polyphenol, can suppress overexpression of inflammatory mediators via inhibiting the TLR4-MAPK/NF-κB pathway. It can also reduce neuronal apoptosis via a mechanism concerning the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages. Despite a symphony of in vivo and in vitro studies, many molecular and pharmacological aspects of neuroinflammation remain unclear. It is proposed that natural compounds targeting TLR4 may serve as important pharmacophores for the development of potent drugs for the treatment of neurological disorders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Current ageing research is aimed not only at the promotion of longevity, but also at improving ‎health span‎ through the‎ discovery and development‎ of new therapeutic strategies‎‏‎ by investigating ‎molecular and ‎cellular ‎pathways involved in cellular senescence.‎ Understanding the mechanism of action ‎of ‎polyphenolic compounds targeting mTOR (mechanistic target of rapamycin) and related pathways opens up new directions ‎‎to revolutionize ways to slow down the ‎onset and development of age-dependent degeneration. Herein, we will ‎discuss the mechanisms by which polyphenols can delay the‎ molecular ‎pathogenesis of ageing via manipulation or more specifically inhibition of mTOR-signaling pathways. We will also discuss the implications of polyphenols in targeting mTOR and its related ‎pathways‎‎ on ‎health life span extension and longevity.‎., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Quercetin is an important flavonoid that is ubiquitously present in the diet in a variety of fruits and vegetables. It has been traditionally viewed as a potent antioxidant and anti-inflammatory molecule. However, recent studies have suggested that quercetin may exert its beneficial effects independent of its free radical-scavenging properties. Attention has been placed on the effect of quercetin on an array of mitochondrial processes. Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria-induced apoptosis. The present review evaluates recent evidence on the ability of quercetin to interact with the abovementioned pathways, and critically analyses how, such interactions can exert protection against mitochondrial damage in response to toxicity induced by several exogenously and endogenously-produced cellular stressors, and oxidative stress in particular., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mitochondria are dynamic double-membrane bound organelles which have key roles in a variety of cellular functions such as energy producing, regulation of calcium flux, cellular stress responses including autophagy and apoptosis. A growing body of evidence indicates that mitochondrial dysfunction is the main culprit in a myriad of diseases such as neurodegenerative disease. This fact opens a new therapeutic window based on targeting mitochondrial dysfunction for treatment of these diseases. Recently an abundance of evidence shows the promising role of polyphenolic compounds on mitochondrial structure and function. Curcumin, a well-known polyphenolic compound, is an abundant component of turmeric. The promising roles of curcumin against different diseases are highly publicized. The aim of the present work is to critically review the scientific evidence to provide a clear view of how curcumin improves mitochondrial dynamics regarding mitochondrial biogenesis and mitophagy. We also present curcumin biosynthesis, source, bioavailability and metabolism in order to give an overview of this compound., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ginsenosides represent the major bioactive components of ginseng. These triterpenoid saponins have been shown to exert numerous beneficial effects on the human body. Recent evidences suggest that ginsenosides may be useful for the management and treatment of several diseases of the central nervous system (CNS). In particular, numerous in vitro and in vivo models have shown that ginsenosides can modulate numerous pharmacological effects on the brain, including attenuation of excitotoxicity, oxidative stress and neuroinflammation, maintenance of neurotransmitter balance, anti-apoptotic effects, and mitochondrial stabilization effects. Regulations of these pathophysiological mechanisms have been shown to improve cognitive function and protect the brain against several neurodegenerative diseases. This review will critically address the pharmacological effects and mechanisms of action of ginsenosides in the CNS, and particularly those associated with therapeutic efficacies in Parkinson's disease, Alzheimer's disease, Huntington's disease, and traumatic brain injury, and ischemia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

According to the World Health Organization, two billion people will be aged 60 years or older by 2050. Aging is a major risk factor for a number of neurodegenerative disorders. These age-related disorders currently represent one of the most important and challenging health problems worldwide. Therefore, much attention has been directed towards the design and development of neuroprotective agents derived from natural sources. These phytochemicals have demonstrated high efficacy and low adverse effects in multiple in vitro and in vivo studies. Among these phytochemicals, dietary flavonoids are an important and common chemical class of bioactive products, found in several fruits and vegetables. Luteolin is an important flavone, which is found in several plant products, including broccoli, pepper, thyme, and celery. Numerous studies have shown that luteolin possesses beneficial neuroprotective effects both in vitro and in vivo. Despite this, an overview of the neuroprotective effects of luteolin has not yet been accomplished. Therefore, the aim of this paper is to provide a review of the available literature regarding the neuroprotective effects of luteolin and its molecular mechanisms of action. Herein, we also review the available literature regarding the chemistry of luteolin, its herbal sources, and bioavailability as a pharmacological agent for the treatment and management of age-related neurodegenerative disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)