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Background Caffeic acid (CA) and related phenylpropanoic acids are ubiquitous natural products of the shikimic acid pathway origin. Due to the presence of diorthohydroxyl aromatic (catecholic) moiety, CA is not only one of the most potent antioxidant phenyl propanoids but also displays numerous other pharmacological effects ranging from antiinflammatory to anticancer effects. Objective Recent studies also demonstrated that CA both in its free form or conjugated with other groups such as quinic acid and sugars displays profound effects in the brain including protection from toxicity induced by a variety of agents and/or experimental models of Alzheimer's disease (AD). In this communication, the anti-AD therapeutic potential of CA and its two most common conjugated natural bioactive derivatives, chlorogenic acid (CGA) and caffeic acid phenethyl ester (CAPE), is scrutinised by reviewing literature in the past ten years. Besides the common global antioxidant effects, specific antiinflammatory mechanisms in the brain along with the various processes of β-amyloid formation, aggregation and neurotoxicity targets are discussed. Conclusion The mini-review also provides an insight into enhancing the therapeutic potential of existing anti-AD drugs by incorporating a CA structural moiety.

Objective To investigate the antioxidant, anti-α-glucosidase and pancreatic β-cell protective potential of Ensete superbum (E. superbum) seeds. Methods A variety of in vitro assays including radical scavenging, reducing power potential, phenolic content determination, α-glucosidase assay and pancreatic β-cell (1.4E7 cells) viability were employed for assessing the effect of methanolic extract of E. superbum seeds. Results The radical scavenging and reducing power effects comparable with the standard rutin were obtained while the enzyme inhibitory activity of the extract was 68-fold better than the standard antidiabetic drug, acarbose. The seed extract of E. superbum was packed-full of polyphenols with mean percentage gallic acid equivalent value of (38.2 ± 1.8) (n = 3). The protection of pancreatic cells from massive onslaught of hydrogen peroxide was far superior to that obtained for rutin. Conclusions The reputed antidiabetic therapeutic uses of the seeds extract of E. superbum may be justified on the basis of inhibition of carbohydrate enzymes, antioxidant effects and pancreatic β-cell protection.

Melatonin is an indoleamine with potent multifunctional biological and pharmacological effects, both receptor dependent and receptor-independent effects, including antioxidant, anticancer, antitumor, anti-inflammatory, anti-aging, anti-diabetic, antiviral, neuroprotective activities. Melatonin mitigates tissue injury via modification of abnormalities in redox status and other biochemical markers. At the molecular level, the biological and pharmacological activities of melatonin are attributed to the inhibition of nuclear factor-κappa beta (NF-κβ), c-Fos over expression and down-regulation of matrix metalloproteinases-3 (MMP-3), which are regulators of pro-inflammatory and pro-fibrotic cytokines. There are numerous scientific reports on the therapeutic potential of melatonin in treatment of asthma, respiratory diseases for infections, chronic obstructive pulmonary disease, lung cancer, pleural cavity diseases, as well as vascular pulmonary disease. In the present communication, we systematically review the therapeutic potential of melatonin in the treatment of respiratory diseases along with its molecular mechanism of actions.

Two known berberine derivatives and novel N-benzyl phenethylamines as open models of berberine were synthesized and evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents. While being less potent than the parent compound (IC50 = 0.70± 0.04 μM), both berberine derivatives performed as good AChE inhibitors (IC50 = 2.30 ± 0.29 μM and 7.8 ± 0.8 μM, respectively) and were at least 36 and four times more potent than berberine as radical scavengers. Among the synthesized compounds, demethyleneberberine bromide (2) was the most interesting because it showed both anticholinesterase and radical scavenging activities with the lowest IC50 values. As expected, catechol rings appeared as fundamental for antioxidant properties. Indeed, the most active scavenging compound in the simplified analog series was the one bearing two catechol moieties, which displayed higher potency than gallic acid.

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.

Ursolic acid (UA) is a pentacyclic triterpene which is found in common herbs and medicinal plants that are reputed for a variety of pharmacological effects. Both as an active principle of these plants and as a nutraceutical ingredient, the pharmacology of UA in the CNS and other organs and systems has been extensively reported in recent years. In this communication, the antioxidant and anti-inflammatory axis of UA’s pharmacology is appraised for its therapeutic potential in some common CNS disorders. Classic examples include the traumatic brain injury (TBI), cerebral ischemia, cognition deficit, anxiety, and depression. The pharmacological efficacy for UA is demonstrated through the therapeutic principle of one drug→multitargets→one/many disease(s). Both specific enzymes and receptor targets along with diverse pharmacological effects associated with oxidative stress and inflammatory signalling are scrutinised.

The papaya plant ( Carica papaya L . ) is a member of the small family of plants, Caricaceae. As one of the fastest growing trees in the tropics and sub-tropical regions, the fresh fruits of papaya and related products such as juices have significant dietary values to humans. This chapter assesses the therapeutic potential of papaya products for diabetes and associated diseases. Starting from the botanical/taxonomic perspectives, the chemistry and pharmacology of not only the fruits but also leaves, fermented papaya preparations (FFP) and latex/enzymes primarily extracted from unripe fruits are scrutinised. Chemical components identified as antihyperglycaemic and antihyperlipidaemic agents along with mechanisms of action in the various cellular, animals and human/clinical models are also outlined. Beyond direct antidiabetic effect, the growing trend of FFP in dietary supplement application and mechanism of papaya as wound healing and antihypertensive agent are further discussed.

The link between Type 2 diabetes (T2D) and obesity is well established. This chapter provides an overview of lipid metabolism from chemistry to physiological regulations. The topics discussed include the fundamental processes of lipid digestion in the gastro intestinal system, the challenge of transporting non-polar lipids through aqueous media of the body such as the blood, storage in vital organs (primarily the liver and adipose tissues) and utilization as energy source especially during a period of carbohydrate starvation. The regulatory mechanisms in cholesterol and fatty acids synthesis and key pharmacological targets for therapeutic agents are exhibited. The neuronal, hormonal, and metabolic regulation of lipid metabolism under normal and diabetes/obesity conditions are also presented.

Plant secondary metabolites are represented by thousands of compounds of diverse structural groups which are synthesized through a handful of biosynthetic pathways. While the general metabolic processes are common to all plants, the expression of genes and enzymes unique to certain family of plants are the basis for the diversity in the chemistry and pharmacology of the different taxonomic groups. This chapter provides an overview of plant secondary metabolites such as terpenoids (mono-, di-, tri-, and tetraterpenes), flavonoids, phenolic acids and derivatives, alkaloids, coumarins and polyketides, among others. Representative compounds of the various biosynthesis pathways and therapeutic principles as antidiabetic agents are presented.

Known by its local name as bitter melon, karela or bitter gourd, the edible fruits of Momordica charantia L. (Family, Cucurbitaceae) are becoming increasingly popular for treating diabetes and associated diseases. Displaying over 248 compounds belonging to the lipids, phenolics, terpenoids and alkaloids classes of compounds, this chapter exhibits the unique potential of bitter melon as a source of pharmacologically active natural products. The plethora of animal and cellular models showing the antihyperglycaemic, lipid lowering and antiobesity effects of the plant are exhibited. Active principles ranging from conjugated fatty acids to terpenoids, alkaloids, carbohydrates and proteins are identified. Mechanisms of actions ranging from specific targets in insulin signalling pathways to general anti-inflammatory, antioxidant, carbohydrate digestion inhibitions, and organoprotective effects are presented. The effects of bitter melon preparations in adipogenesis and insulin sensitivity or resistance in vital organs along with activity profile in human subjects are scrutinised.

Guava ( Psidium guajava L) is a member of the myrtle family of Myrtaceae. The plant is indigenous to the tropical Americas though it is now widely cultivated in many tropical and sub-tropical countries for a variety of uses, but primarily, for its edible fruits. This chapter examines the growing trend of guava applications both in traditional medicine and dietary supplements for type 2 diabetes (T2D) and associated diseases. As exhibited in this chapter with well over 230 chemical structures belonging to phenolic acids, flavonoids, tannins and terpenoids, among others, guava is a classic example of plants used as synthetic machineries to obtain diverse and complex natural products. Numerous animal models and in vitro studies showing the antihyperglycaemic, antihyperlipidaemic and antiobesity potential of the guava leaves and fruits are presented. Mechanistic studies displaying the effects of extracts and active principles, in insulin signaling, glycaemic and lipid controls and potential applications in diabetes associated diseases including hypertension and nephropathies are discussed.

Due to their ability to thrive in drier environments through morphological (thick, waxy cuticle, shallow roots, water storage, etc.) and biochemical (Crassulacean acid metabolism) adaptation as well as the ease of vegetative propagation, largescale exploitation of cactus pear (or prickly pear) has been advocated in recent years both for human food, medicine, dietary fibres and supplements, natural colourants, etc. Represented by Opuntia ficus-indica , the various cactus pear species of the family Cactaceae that are indicated to display antidiabetic and/or antiobesity effects are exhibited in this chapter. Their chemical composition that attributes to their pharmacological effects with mechanistic approach in vitro, animal models and human trials are discussed. Of the active components of interest are the betalains of the fruits, the phenolic compositions dominated by flavonoid glycosides and phenolic acids, and polysaccharides and/or dietary fibres.

Known by its scientific name as Punica grantum L. of the family Lythraceae, the iconic pomegranate plant is deeply associated with human civilisation as food and sacred healing power. Starting from taxonomic revision through its rich history of utilization, this chapter outlines the chemical and pharmacological basis of pomegranate as potential therapy for diabetes and metabolic syndrome. Exhibiting over 200 chemical compounds isolated from the various plant tissues, the chapter tends to be a comprehensive reference resource on the chemistry of pomegranate. The in vitro, in vivo and clinical data on the various extracts and purified compounds related to hypoglycaemic, lipid lowering, antiobesity and antihypertensive effects are scrutinized along with general and specific mechanism of actions. The pharmacological effects including pharmacokinetics and toxicological profiles backed up by over 237 citations present the immense power of pomegranate as a learning resource in science and applications in the various industries.

Cinnamon represents a spice from the barks of a number of species belonging to the genus Cinnamomum . Touching on the history of uses and taxonomic/botanical attributes of Cinnamomum species , this chapter laid down the chemical and pharmacological basis of cinnamon for its potential application in modifying the pathology of type 2 diabetes (T2D) and associated diseases. Incredible level of animal studies and in vitro data are exhibited to outline the mechanism for cinnamon powders, extracts and active components ranging from the oil (cinnamaldehyde) to highly polar procyanidins in inducing antihyperglycaemic and antihyperlipidaemic effects in experimental models. The diverse and often contradictory clinical trials along with specific mechanisms including insulin signalling, carbohydrate digestion, genes expression, antioxidant and anti-inflammatory signalling molecules and mitochondrial biogenesis are discussed.

For thousands of years, medicinal plants have been used by mankind to treat numerous disease conditions including metabolic syndrome. In addition to common usage as herbs, spices, fruits, and beverages, there is now also a growing trend to employ many medicinal plants as dietary supplements. This chapter outlines the chemical and pharmacological basis of antidiabetic medicinal plants now rebranded as dietary supplements. It critically assesses the scientific evidences for the therapeutic potentials of Aloe vera (L.) Burm. f., Andrographis paniculata (Burm. F.), Wall. Ex Nees, banaba ( Lagerstroemia speciose (L) Pers), Cassia and Senna species including Senna auriculata (L) Roxb, S. alata (L.) Roxb., Ginkgo biloba L., ginseng ( Panax. ginseng C.A. Mey, P . quinquefolius L., and P. notoginseng ), aymnema ( Gymnema sylvestre (Retz.) R.Br. ex Sm.), Jamun ( Syzygium cumini (L.) Skeels), olive leaf extract ( Olea europaea (L.)), Scutellaria ( Scutellaria baicalesis Georgi), and St John's wort ( Hypericum perforatum L.).

This chapter outlines the pathophysiological sequel of persistent hyperglycaemia under type 2 diabetes (T2D). The microvascular changes including endothelial cells and associated pericytes along with macrovascular changes leading to diabetes complications such as diabetic nephropathy, retinopathy, neuropathy, and diabetic foot ulcers are discussed. On the molecular mechanisms of T2D complications, the biochemistry of advanced glycated end products, the cascades of oxidative stress and inflammatory mechanisms, and the polyol pathway are among those outlined. The role of these cellular and biochemical changes as pathological hallmark to the common acute and chronic T2D emergencies as well as therapeutic target options are presented.

This chapter is designed to show the breadth of ginger science from botany and chemistry to pharmacology in a plethora of experimental models including, cellular, animal and human trial studies. The diversity of ginger products from fresh to dry powders and oils means differential chemistry with respect to the gingerols, shogaols, and paradols as active principles, among others. Herein, their power to modulate hyperglycaemia, hyperlipidaemia, obesity, hypertension, and many other diabetes-associated abnormalities are presented. Mechanistic basis of discussion in insulin and adipogenesis signalling pathways that contribute to improvement of insulin sensitivity and lipid and glucose metabolism dysregulation by ginger products are exhibited. The structural diversity of ginger compounds in key inflammatory and oxidative stress targets that attribute to the organoprotective effects are systematically outlined to disentangle the complex science behind the crude preparations of ginger as food and medicine.

The goal of type 2 diabetes (T2D) therapy is to achieve outcomes that are associated with the diagnosis of the disease itself and centred at reversing the increased levels of blood glucose and glycated haemoglobin. The common approaches in T2D management are lifestyle changes such as dietary control and exercise regimens as well as pharmacotherapy interventions. This chapter outlines the chemical and pharmacological profiles of the current T2D drugs of choices. The various classes of compounds starting from the old drugs of biguanides represented by metformin to new additions in recent years are exhibited. Among the other classes of drugs detailed are the glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) analogues and receptor agonists; dipeptidyl peptidase-4 (DPP-4), sodium–glucose cotransporter-2 (SGL2) and α-glucosidase inhibitors; sulfonylureas and meglitinides; thiazolidinedione; insulin preparations, etc.

With its fascinating historical, botanical and economic significance, coffee is now one of the most consumed beverages by mankind. Numerous prospective studies have almost unequivocally established the inverse association between risk for type 2 diabetes (T2D) and intake of both caffeinated and decaffeinated coffee. By disentangling the effect of acute coffee or caffeine intake on raising blood pressure, increased blood glucose and insulin resistance, from the long-term effect of coffee intake on metabolic syndrome, this chapter outlines the chemical and pharmacological basis of both roasted and unroasted coffee beans. These include, the polyphenolic compounds dominated by chlorogenic acids, the alkaloids such as trigonelline and its derivatives, diterpenes compounds (e.g. cafestol and kahweol) that have some positive outcome along with hypercholesterolaemic/hyperlipidaemic effect, etc. Data from in vitro, in vivo and plethora of clinical studies relevant to the various components of metabolic syndrome are presented.

Flavanones are a group of flavonoids that derive from their immediate chalcone precursors through the action of chalcone isomerase enzymes. The Aromatic A and B rings, C4-keto group, and the 15-carbon flavonoid skeleton are all evident in flavanones, but a notable absence of C2-C3 double bond and a lack of oxygenation at C-3 position of the C-ring makes them distinctively different from other groups such as flavonols (e.g., quercetin). On the basis of oxygenation level in the B ring, flavanones can vary from each other as exemplified by pinocembrin (no oxygenation), naringenin (4′-hydroxyl), or eriodictyol (3′,4′-dihydroxyl substitution). These groups are generally weaker free radical scavengers as compared to quercetin and derivatives though eriodictyol has a better free radical scavenging profile within the group due to the presence of the catechol functional moiety. In this communication, their antioxidant potential through the induction of antioxidant defenses is scrutinized. These compounds as exemplified by pinocembrin could induce the nuclear factor erythroid 2-related factor 2- (Nrf2-) heme oxygenase-1 (HO-1) axis leading to amelioration of oxidative stress in cellular and animal models. Their neuroprotective effect through such mechanism is discussed.

In this chapter, the chemistry of turmeric (rhizomes of Curcuma longa L.) including the curcuminoids and oil components are presented with special emphasis on biochemical mechanisms of turmeric extracts and compounds as therapeutic agents. An impressive list of in vitro protein-based and cellular assay systems, and chemically- and diet-induced as well as genetically obese/diabetic animal models are used to assess their therapeutic potential against metabolic syndrome. Human clinical trials and pharmacokinetic parameters used to improve the bioavailability and efficacy of turmeric/curcuminoids formulations are also presented. Mechanistically, the effects of extracts and curcuminoids are scrutinized for their effect on insulin signalling, glucose and lipid metabolism and pathologies associated with insulin resistance, adipogenesis, retinopathy, neuropathy, nephropathy, and wound complication, among others. Modulation of inflammatory and antioxidant signalling under various pathological conditions are further addressed to show the remarkable multifunctional nature of these natural products as potential modulators of metabolic syndrome.

Recent studies have shown the therapeutic potential of many common and exotic foods for treating diabetes and associated disorders such as obesity and cardiovascular complications. This chapter provide extensive discussion on the pharmacological and phytochemical basis of foods with growing importance in these pathologies. More specifically, the effects of foods, crude extracts and compounds isolated from cocoa ( Theobroma cacao ), coconut ( Cocos nucifera ), figs ( Ficus carica ), Moringa ( Moringa oleifera and M. stenopetala ), Soybean ( Glycine max ), Sweet potato ( Ipomoea batatas ), and Walnuts ( Juglans regia ) are discussed.

Bilberries and blueberries are represented by various species of the genus Vaccinum in the plant family of Ericaceae. Powered by their polyphenol composition which is largely dominated by anthocyanins, the numerous health benefits of these fruits including for treating type 2 diabetes (T2D) and associated diseases have been advocated in recent years. This chapter examines, the botany, chemistry, pharmacokinetics profile and pharmacology of these plants. From the color of the fruits to the biologically active principles, the chemistry of bilberries and blueberries that attribute to hypoglycemic, antiobesity and lipid lowering effects are presented. In vitro, animal models and human clinical trials that relate to their health benefits in diabetes pathologies including hypertension and retinopathy are scrutinized. As with the mechanistic-based lines of evidences in favor of their health claims, controversies that arose from numerous experimental variables are discussed.

Manufactured from the leaves and buds of Camellia sinensis (L.) Kuntze, tea is the second most popular beverage consumed by mankind only after water. In this chapter, the chemical composition of the white, green, black, oolong and other teas along with the transformation of catechins by the fermentation process to higher degree of polymerization leading to the formation of theaflavins, and thearubigins among others are discussed. Catechins, especially epigallocatechin gallate (EGCG), as the predominant chemical components, their transformed products, and caffeine as active principals of the various tea preparations are further assessed for their potential health benefit related to metabolic syndrome. The various experimental models in vitro and in vivo are used to discuss therapeutic relevance on molecular mechanistic bases from glycaemic and lipid control to mechanisms of cardiovascular complications. Comprehensive analysis of clinical studies on crude extracts and purified active principles are also presented.

At least four species of pumpkin ( Cucurbita pepo , C. moschata, C. ficifolia and C. maxima ) are known to have antidiabetic, antiobesity and lipid lowering effects in the various animal and cellular models. This chapter exhibits the therapeutic potential of these common food and nutraceutical ingredients by looking into their distinct chemical composition and mechanism of action that attributes to their claimed health outcome in type 2 diabetes (T2D) and associated diseases.

Abelmoschus esculentus (L.) Moench is a member of the Malvaceae family. Known by its common name okra or lady finger, the fruits have been used by mankind as food for a millennia. The plant has also got a rich history of traditional medicinal values of which therapeutic applications for type 2 diabetes (T2D) and associated diseases have been implicated in recent years. This chapter scrutinizes all the available in vitro and in vivo data on antidiabetic, antiobesity and potential lipid lowering effects. The chemistry and pharmacology of okra, particularly the predominant quercetin glycosides and polysaccharides or fiber content that attributes to the implicated disease conditions are discussed.

Rooibos ( Aspalathus linearis (Burm. Fil.) R. Dalhgr. spp. linearis ; Fabaceae) is one of the commercial herbal tea products with a long history of local usage in South Africa. This chapter outlines the transformation of this plant from limited local use to international significance as beverage and food supplement. The chemical basis of the flavonoids and related phenolic compounds-dominated chemistry in the unfermented and fermented products that may account to the claimed health benefit of the plant are discussed. Special emphasis is given to pathologies of type-2 diabetes (T2D), obesity and/or hyperlipidaemia and hypertension as classical components of metabolic syndrome modulated by rooibos. Mechanistic studies from in vitro and animal studies that allowed therapeutic potential assessment for the plant along with the pharmacologically active principles are outlined.

Native to the subtropics of South America, yerba mate ( Ilex paraguariensis A.St.-Hil., Aquifoliaceae) has a long history of usage as a beverage plant far before the conquest of the region by the Spaniards. This chapter outlines the transformation of this local beverage as commercial product which is now extended for treatment of obesity, diabetes and associated diseases. The chemistry of the polyphenolic components dominated by quinic and shikimic acids esters of caffeoyl, feruloyl and other structural moieties; flavonoids such as rutin, saponins and the alkaloidal compounds such as caffeine are the basis for the claimed health benefits of yerba mate commercial products. Data from in vitro and animal studies dominated by obesity models are used to systematically present the mechanisms and potential applications of this plant in metabolic syndrome. Further scrutiny on toxicological and therapeutic implications are based on clinical trials where promising effects are recorded for yerba mate.

The in vivo antiinflammatory and analgesic activities of the crude ethanol extract and chemical constituents of Clausena anisata roots were investigated. The crude extract, which was devoid of any visible acute toxicity, displayed significant antiinflammatory effect at the dose of 1000 mg/kg (p.o.) when assessed using the carrageenan-induced oedema model. In the acetic acid-induced writhing and hot plate tests, it produced a very significant (p0.001); dose- dependent analgesic effect, with maximum analgesic activity of 72.1% at 1000 mg/kg (p.o.). Phytochemical analysis of the crude extract resulted in the isolation of four coumarins (anisocoumarin B, osthol, imperatorin and xanthotoxol) and a carbazole alkaloid, heptaphylline. Among the isolated compounds, osthol and anisocournarin B produced the highest antiinflammatory activity at 9 mg/kg (p.o.): slightly better than the positive control, indomethacin. Except for xanthotoxol, all the isolated compounds administered at 6 mg/kg (p.o.) produced significant analgesic activity and higher than diclofenac; with- heptaphylline being the most potent (48.7%). The analgesic activity of anisocoumarin B (50.4%) was the highest among the isolates tested and the standard, tramadol, in the hot plate test. The nonselective opioid receptor antagonist, naloxone, abolished the analgesic effect of the crude extract and the tested isolates (anisocoumarin B and xanthotoxol) in the hot plate test suggesting an effect via the central opioidergic system. These findings provide the scientific basis for the use of C. anisata roots in traditional medicine as antiinflammatory and analgesic agents.

Diabetes mellitus (DM) is a chronic metabolic disease with high morbimortality rates. DM has two types: type 1, which is often associated with a total destruction of pancreatic beta cells, and non-insulin-dependent or type 2 diabetes mellitus (T2DM), more closely associated with obesity and old age. The main causes of T2DM are insulin resistance and/or inadequate insulin secretion. Protein-tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling pathways and plays an important role in T2DM, as its overexpression may induce insulin resistance. Thus, since PTP1B may be a therapeutic target for both T2DM and obesity, the search for novel and promising natural inhibitors has gained much attention. Hence, several marine organisms, including macro and microalgae, sponges, marine invertebrates, sea urchins, seaweeds, soft corals, lichens, and sea grasses, have been recently evaluated as potential drug sources. This review provides an overview of the role of PTP1B in T2DM insulin signaling and treatment, and highlights the recent findings of several compounds and extracts derived from marine organisms and their relevance as upcoming PTP1B inhibitors. In this systematic literature review, more than 60 marine-derived metabolites exhibiting PTP1B inhibitory activity are listed. Their chemical classes, structural features, relative PTP1B inhibitory potency (assessed by IC 50 values), and structure–activity relationships (SARs) that could be drawn from the available data are discussed. The upcoming challenge in the field of marine research—metabolomics—is also addressed. N. Martins would like to thank the Portuguese Foundation for Science and Technology (FCT–Portugal) for the Strategic project, reference numbers UID/BIM/04293/2013 and “NORTE2020-Programa Operacional Regional do Norte” (NORTE-01-0145-FEDER-000012).

International audience; 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.

Aim. The effects of the water extract of the leaves of Euphorbia Poissonii (Euphorbiacea) on frog heart contraction and its possible mechanism action were investigated. Method. By using the Langerdhorff model of the isolated frog heart preparation, the strength and frequency of heart contractions as well as cardiac output were measured under perfusion with test drugs. Results and conclusion. When assessed with digoxin and adrenaline as positive controls, the water extract (3 mg/mL) exhibited significant positive inotropic (70.00% improvement compared to baseline) and chronotropic (17.79% improvement) effects. Additionally, heart contractility was inhibited in the presence of propranolol and amlodipine, suggesting that the testing extract is having adrenergic properties. Reversible heart arrest was noticed at the dose of 6 mg/mL.

Myrianthus arboreus is use traditionally as an antidiabetic agent in Ghana. We reported the in vivo antidiabetic activity of its 70 % ethanol stem bark extract (MAB) which we found to be strongly concentrated in its EtOAc fraction using glucose uptake and enzyme inhibitory assays. The present study sought to investigate the in vivo hypoglycaemic and anti-hyperlipidaemic activity of this ethyl acetate fraction of MAB (MAB-EtOAc, 50 and 100 mg/kg) in streptozotocin (STZ)-induced diabetic rats for 21 days, isolate and evaluate the bioactive constituents responsible for the antidiabetic activity. In silico pharmacokinetic and toxicity properties of the most active compound was also determined. MAB-EtOAc significantly (p < 0.001) reduced the blood glucose levels while normalizing considerably the altered serum lipid parameters of the diabetic rats which was comparable to glibenclamide (5 mg/kg). Chemical investigation of MAB-EtOAc led to the isolation of seven known compounds including three flavanols which are reported for the first time in the plant: epicatechin (1), epigallocatechin (2), dulcisflavan (3), euscaphic acid (4), tormentic acid (5), sitosterol-3-O-β-d-glucopyranoside (6) and arjunolic acid (7). The compounds markedly inhibited the action of α-amylase and, except for 4 and 6, which stimulated considerably glucose uptake in C2C12 cells. Compounds 2, 3, 5, 6 and 7 which were further evaluated in STZ-induced diabetic rats demonstrated hypoglycaemic and anti-hyperlipidaemic activities which, however, were not comparable with MAB-EtOAc. Compound 3, the most active compound was predicted to be non-toxic, non-mutagenic, has reasonable oral bioavailability and a decent substrate for further drug development. The findings of this study show that the isolated compounds may contribute to the antidiabetic activity of M. arboreus and could serve as marker compounds for the quality control of herbal medicines that would be made from the plant.

Berberine is the principal component of many popular medicinal plants (e.g. the genus Berberis, Coptis and Hydrastis among others) with a history of thousands of years of usage in traditional medicine. The numerous pharmacological activities of berberine reported in the last two decades have been attracting high level interests both within the scientific community, clinicians and the public at large. Despite enormous amount of efforts have been placed to show its therapeutic value for inflammatory bowel diseases (IBD), however, comprehensive up-to-date review article in this field is not yet available. In this communication, literature data from in vitro and in vivo experiments were scrutinised and concisely presented to demonstrate its anti-IBD potential. Beyond the known general antioxidant and anti-inflammatory effects of berberine, IBD-specific effects including gut epithelial barrier pathology, T cells as emerging targets, antinociceptive and other effects are discussed.

Medicinal plants have been known as one of the most important therapeutic agents since ancient times. During the last two decades, much attention has been paid to the health-promoting effects of edible medicinal plants, because of multiple beneficial effects and negligible adverse effects. Capparis spinosa L. is one of the most common medicinal plants, used widely in different parts of the world to treat numerous human diseases. This paper aims to critically review the available scientific literature regarding the health-promoting effects of C. spinosa, its traditional uses, cultivation protocols and phytochemical constituents. Recently, a wide range of evidence has shown that this plant possesses different biological effects, including antioxidant, anticancer and antibacterial effects. Phytochemical analysis shows that C. spinosa has high quantities of bioactive constituents, including polyphenolic compounds, which are responsible for its health-promoting effects, although many of these substances are present in low concentrations and significant changes in their content occur during processing. In addition, there is negligible scientific evidence regarding any adverse effects. Different health promotion activities, as well as tremendous diversity of active constituents, make C. spinosa a good candidate for discovering new drugs. However these findings are still in its infancy and future experimental and clinical studies are needed. Copyright © 2016 John Wiley & Sons, Ltd.

Rutin (quercetin-3-O-rutinoside) is a multifunctional natural flavonoid glycoside with profound effects on the various cellular functions under pathological conditions. Due to the ability of rutin and/or its metabolites to cross the blood brain barrier, it has also been shown to modify the cognitive and various behavioral symptoms of neurodegenerative diseases. In this review, its therapeutic potential for Alzheimer's disease (AD) is evaluated through appraisal of current literatures relevant to the various cellular and molecular targets of the disease. Among the most relevant mechanisms involved are effect on amyloid beta (Aβ) processing, aggregation and action; alteration of the oxidant-antioxidant balance associated with neuronal cell loss; removing the inflammatory component of neurodegeneration, etc. The effect of rutin resulting from its physicochemical features related to effects like metal chelation and bioavailability are also discussed.

The global impact of the new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infection that caused COVID-19 has been evident in the last few months from the unprecedented socioeconomic disruption to more than 600,000 deaths. The lack of vaccine and effective therapeutic agents for the disease prompted world-wide effort to test those antiviral therapeutics already in use for other diseases. Another interesting approach has been based on the pathological sequel of the disease that involve severe inflammatory reaction (or the cytokine storm) associated with pneumonia in critically ill patients. This article outlines the prophylaxis therapeutic potential of supplements vitamins and micronutrients in COVID-19. By ameliorating the inflammatory and oxidative stress associated with the disease and some direct antiviral effects, the application of these agents as adjuvants and other alternative approaches are discussed. Available clinical trials including those currently registered on these supplements are scrutinized.

In December 2019, an unprecedented outbreak of pneumonia associated with a novel coronavirus disease 2019 (COVID-19) emerged in Wuhan City, Hubei province, China. The virus that caused the disease was officially named by the World Health Organization (WHO) as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to the high transmission rate of SARS-CoV-2, it became a global pandemic and public health emergency within few months. Since SARS-CoV-2 is genetically 80% homologous with the SARS-CoVs family, it is hypothesized that medications developed for the treatment of SARS-CoVs may be useful in the control and management of SARS-CoV-2. In this regard, some medication being tested in clinical trials and in vitro studies include anti-viral RNA polymerase inhibitors, HIV-protease inhibitors, anti-inflammatory agents, angiotensin converting enzyme type 2 (ACE 2) blockers, and some other novel medications. In this communication, we reviewed the general characteristics of medications, medical usage, mechanism of action, as well as SARS-CoV-2 related trials., Graphical abstract Image 1, Highlights • There are several medications suggested for SARS-CoV-2 treatment and/or controlling the symptoms. • Each medications used up to now has beneficial and some adverse effects and the results remain inconclusive. • Rapid onset of medication will be useful in high-risk patients to control the acute symptoms. • There is a concern about the unclear long-term adverse effects of medications.

Berberine is a natural pentacyclic isoquinoline alkaloid that has been isolated as the principal component of many popular medicinal plants such as the genus Berberis, Coptis and Hydrastis. The multifunctional nature of berberine as a therapeutic agent is an attribute of its diverse effects on enzymes, receptors and cell signalling pathways. Through specific and general antioxidant and anti-inflammatory mechanisms, its polypharmacology has been established. Intriguingly, this is despite the poor bioavailability of berberine in animal models and hence begging the question how it induces its reputed effects in vivo. A growing evidence now suggest the role of the gut microbiota, the so-called the hidden organ, as targets for the multifunctional role of berberine. Evidences are herein scrutinised to show that the structural and numerical changes in the gut microbiota under pathological conditions are reversed by berberine. Examples in the pharmacokinetics field, obesity, hyperlipidaemia, diabetes, cancer, inflammatory disease conditions, etc. are used to show the link between the gut microbiota and the polypharmacology of berberine.

Datura metel leaves are used by athletes to enhance their performances. The water extract of the leaves and seeds was tested for their cardiotonic effect. Langherdoff’s model for the measurement of the mechanical activity of isolated amphibian heart in ventricular perfusion was used to evaluate some parameters of cardiac contractility. The effect of the extracts was also compared to sympathetic agonist and antagonist. The leaves and seed extracts induced significant (p

Citrus pomace is a huge agro-food industrial waste mostly composed of peels and traditionally used as compost or animal feed. Owing to its high content of compounds beneficial to humans (e.g., flavonoids, phenol-like acids, and terpenoids), citrus waste is increasingly used to produce valuable supplements, fragrance, or antimicrobials. However, such processes require sustainable and efficient extraction strategies by solvent-free techniques for environmentally-friendly good practices. In this work, we evaluated the antimicrobial and antibiofilm activity of water extracts of three citrus peels (orange, lemon, and citron) against ten different sanitary relevant bacteria. Both conventional extraction methods using hot water (HWE) and microwave-assisted extraction (MAE) were used. Even though no extract fully inhibited the growth of the target bacteria, these latter (mostly pseudomonads) showed a significant reduction in biofilm biomass. The most active extracts were obtained from orange and lemon peel by using MAE at 100 &deg, C for 8 min. These results showed that citrus peel water infusions by MAE may reduce biofilm formation possibly enhancing the susceptibility of sanitary-related bacteria to disinfection procedures.

For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed.

Inflammatory bowel disease (IBD), commonly represented by ulcerative colitis and Crohn's disease, is a form of chronic inflammatory disorders of the gastrointestinal system. Its current drug treatment includes the use of antibiotics, 5-aminosalicylates, corticosteroids, immune-modifying agents and biologics such as anti-TNF agents and adhesion molecules blockers. These drugs have inherent problems of efficacy as many IBD sufferers need surgical intervention at some stage, high cost especially for the protein-based drugs, loss of efficacy and unwanted side effects. The discovery of novel drugs including those from natural sources that overcome the above mentioned drawbacks of the current therapy is therefore of great interest. While the flavonoid quercetin with proven antiinflammatory effect failed to show activity in vivo, its glycoside rutin has recently proven to possess a significant IBD therapeutic potential in experimental animals. In this communication, the pharmacological and pharmacokinetic profiles of rutin along with its ability to serve as a prodrug that deliver the bioactive quercetin close to the IBD site are discussed. Potential mechanisms of action far beyond antioxidant effects such as suppression of proinflammatory mediators' release and expression of inflammatory proteins (e.g. adhesion molecules, cyclooxygenase, nitric oxide synthase, etc.) are also scrutinized.