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The growing smooth talk in the field of natural compounds is due to the ancient and current interest in herbal medicine and their potentially positive effects on health. Dozens of antidiabetic natural compounds were reported and tested in vivo, in silico, and in vitro. The role of these natural compounds, their actions on the insulin signaling pathway, and the stimulation of the glucose transporter-4 (GLUT4) insulin-responsive translocation to the plasma membrane (PM) are all crucial in the treatment of diabetes and insulin resistance. In this review, we collected and summarized a group of available in vivo and in vitro studies which targeted isolated phytochemicals with possible antidiabetic activity. Moreover, the in silico docking of natural compounds with some of the insulin signaling cascade key proteins is also summarized based on the current literature. In this review, hundreds of recent studies on pure natural compounds that alleviate type II diabetes mellitus (type II DM) were revised. We focused on natural compounds that could potentially regulate blood glucose and stimulate GLUT4 translocation through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. On attempt to point out potential new natural antidiabetic compounds, this review also focuses on natural ingredients that were shown to interact with proteins in the insulin signaling pathway in silico, regardless of their in vitro/in vivo antidiabetic activity. We invite interested researchers to test these compounds as potential novel type II DM drugs and explore their therapeutic mechanisms.

Type 2 diabetes (T2D) is a chronic metabolic disease, which could affect the daily life of patients and increase their risk of developing other diseases. Synthetic anti-diabetic drugs usually show severe side effects. In the last few decades, plant-derived drugs have been intensively studied, particularly because of a rapid development of the instruments used in analytical chemistry. We tested the efficacy of Gundelia tournefortii L. (GT) in increasing the translocation of glucose transporter-4 (GLUT4) to the myocyte plasma membrane (PM), as a main strategy to manage T2D. In this study, GT methanol extract was sub-fractionated into 10 samples using flash chromatography. The toxicity of the fractions on L6 muscle cells, stably expressing GLUTmyc, was evaluated using the MTT assay. The efficacy with which GLUT4 was attached to the L6 PM was evaluated at non-toxic concentrations. Fraction 6 was the most effective, as it stimulated GLUT4 translocation in the absence and presence of insulin, 3.5 and 5.2 times (at 250 μg/mL), respectively. Fraction 1 and 3 showed no significant effects on GLUT4 translocation, while other fractions increased GLUT4 translocation up to 2.0 times. Gas chromatography–mass spectrometry of silylated fractions revealed 98 distinct compounds. Among those compounds, 25 were considered anti-diabetic and glucose disposal agents. These findings suggest that GT methanol sub-fractions exert an anti-diabetic effect by modulating GLUT4 translocation in L6 muscle cells, and indicate the potential of GT extracts as novel therapeutic agents for T2D.

Fetuin-A (Fet-A), a hepatokine associated with insulin resistance, obesity, and incident type 2 diabetes, is shown to exist in both phosphorylated and dephosphorylated forms in circulation. However, studies on fetuin-A phosphorylation status in insulin-resistant conditions and its functional significance are limited. We demonstrate that serum phosphofetuin-A (Ser312) levels were significantly elevated in high-fat diet-induced obese mice, insulin-resistant Zucker diabetic fatty rats, and in individuals with obesity who are insulin resistant. Unlike serum total fetuin-A, serum phosphofetuin-A was associated with body weight, insulin, and markers of insulin resistance. To characterize potential mechanisms, fetuin-A was purified from Hep3B human hepatoma cells. Hep3B Fet-A was phosphorylated (Ser312) and inhibited insulin-stimulated glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Furthermore, single (Ser312Ala) and double (Ser312Ala + Ser120Ala) phosphorylation-defective Fet-A mutants were without effect on glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Together, our studies demonstrate that phosphorylation status of Fet-A (Ser312) is associated with obesity and insulin resistance and raise the possibility that Fet-A phosphorylation may play a role in regulation of insulin action.

Recycling of electric and electronic waste products (e-waste) which amounted to more than 50 million metric tonnes per year worldwide is a massive and global operation. Unfortunately, an estimated 70 & ndash;80% of this waste has not been properly managed because the waste went from developed to low-income countries to be dumped into landfills or informally recycled. Such recycling has been carried out either directly on landfill sites or in small, often family-run recycling shops without much regulations or oversights. The process traditionally involved manual dismantling, cleaning with hazardous solvents, burning and melting on open fires, etc., which would generate a variety of toxic substances and exposure/hazards to applicators, family members, proximate residents and the environment. The situation clearly calls for global responsibility to reduce the impact on human health and the environment, especially in developing countries where poor residents have been shouldering the hazardous burden. on the other hand, formal e-waste recycling has been mainly conducted in small scales in industrialized countries. Whether the latter process would impose less risk to populations and environment has not been determined yet. Therefore, the main objectives of this review are: 1. to address current trends and emerging threats of not only informal but also formal e-waste management practices, and 2. to propose adequate measures and interventions. A major recommendation is to conduct independent surveillance of compliance with e-waste trading and processing according to the Basel Ban Amendment. The recycling industry needs to be carefully evaluated by joint effort from international agencies, producing industries and other stakeholders to develop better processes. Subsequent transition to more sustainable and equitable e-waste management solutions should result in more effective use of natural resources, and in prevention of adverse effects on health and the environment., Diagnosis, Monitoring and Prevention of Exposure-Related Noncommunicable Diseases (DiMoPEx) COST Action project [CA15129]; European UnionEuropean Commission, This work was supported by the Diagnosis, Monitoring and Prevention of Exposure-Related Noncommunicable Diseases (DiMoPEx) COST Action project (CA15129) and its Final Action Dissemination Grant from the European Union.

Diabetes mellitus is a metabolic disease that predominates, nowadays. It causes hyperglycemia and consequently major health complications. Type II diabetes is the most common form and is a result of insulin resistance in the target tissues. To treat this disease, several mechanisms have been proposed. The most direct route is via inhibiting the intestinal enzymes, e.g., α-glucosidase and α-amylase, responsible for intestinal polysaccharide digestion that therefore would reduce the absorption of monosugars through the intestinal walls. In this study, we shed the light on this route by testing the inhibitory effect of Ocimum basilicum extract on the enzymes α-glucosidase and α-amylase in vitro and in silico. Experimental procedures were performed to test the effect of the O. basilicum methanol extract from aerial parts followed by the in silico docking. 500 μg/mL of the extract led to 70.2% ± 8.6 and 25.4% ± 3.3 inhibition on α-glucosidase and α-amylase activity, respectively. Similarly, the effect of caffeic acid, a major extract ingredient, was also tested, and it caused 42.7% ± 3.0 and 47.1% ± 4.0 inhibition for α-amylase and α-glucosidase, respectively. Docking experiments were performed to predict the phytochemicals responsible for this robust inhibitory activity in the O. basilicum extracts. Several compounds have shown variable levels of inhibition, e.g., caffeic acid, pyroglutamic acid, and uvasol. The results indicated that O. basilicum can be a potent antidiabetic drug.

Naturally derived drugs and plant-based products are attractive commodities that are being explored for cancer treatment. This in vitro study aimed to investigate the role of Hypericum triquetrifolium (50% ethanol: 50% water) extract (HTE) treatment on apoptosis, cell cycle modulation, and cell cycle arrest in human colon cancer cell line (HCT-116). HTE induced cell death via an apoptotic process, as assayed by an Annexin V-Cy3 assay. Exposing HCT-116 cells to 0.064, 0.125, 0.25, and 0.5 mg/mL of HTE for 24 h led to 50 &plusmn, 9%, 71.6 &plusmn, 8%, 85 &plusmn, 5%, and 96 &plusmn, 1.5% apoptotic cells, respectively. HCT-116 cells treated with 0.25 and 0.5 mg/mL HTE for 3 h resulted in 38.9 &plusmn, 1.5% and 57.2 &plusmn, 3% cleavage of caspase-3-specific substrate, respectively. RT-PCR analysis revealed that the HTE extract had no effect on mRNA levels of Apaf-1 and NOXA. Moreover, the addition of 0.125 mg/mL and 0.25 mg/mL HTE for 24 h was clearly shown to attenuate the cell cycle progression machinery in HCT-116 cells. GC/MS analysis of the extract identified 21 phytochemicals that are known as apoptosis inducers and cell cycle arrest agents. All the compounds detected are novel in H. triquetrifolium. These results suggest that HTE-induced apoptosis of human colon cells is mediated primarily through the caspase-dependent pathway. Thus, HTE appears to be a potent therapeutic agent for colon cancer treatment.

Estrogenic molecules have been reported to regulate glucose homeostasis and may be beneficial for diabetes management. Here, we investigated the estrogenic effect of β-sitosterol-3-O-D-glucopyranoside (BSD), isolated from the fruits of Cupressus sempervirens and monitored its ability to regulate glucose utilization in skeletal muscle cells. BSD stimulated ERE-mediated luciferase activity in both ERα and ERβ-ERE luc expression system with greater response through ERβ in HEK-293T cells, and induced the expression of estrogen-regulated genes in estrogen responsive MCF-7 cells. In silico docking and molecular interaction studies revealed the affinity and interaction of BSD with ERβ through hydrophobic interaction and hydrogen bond pairing. Furthermore, prolonged exposure of L6-GLUT4myc myotubes to BSD raised the glucose uptake under basal conditions without affecting the insulin-stimulated glucose uptake, the effect associated with enhanced translocation of GLUT4 to the cell periphery. The BSD-mediated biological response to increase GLUT4 translocation was obliterated by PI-3-K inhibitor wortmannin, and BSD significantly increased the phosphorylation of AKT (Ser-473). Moreover, BSD-induced GLUT4 translocation was prevented in the presence of fulvestrant. Our findings reveal the estrogenic activity of BSD to stimulate glucose utilization in skeletal muscle cells via PI-3K/AKT-dependent mechanism.

The data presented in this article are related to the research article entitled "Regulation of GLUT4 activity in myotubes by 3-O-methyl-D-glucose" (Shamni et al., 2017) [1]. These data show that the experimental procedures used to analyze the effects of 3-O-methyl-D-glucose (MeGlc) on the rate of hexose transport into myotubes were valid and controlled. The stimulatory effect of MeGlc was limited to glucose transporter 4 (GLUT4) and was independent of ambient glucose and protein synthesis. Cornish-Bowden kinetic analysis of uptake data revealed that MeGlc attenuated indinavir-induced inhibition of hexose transport in a competitive manner.

Diabetes is a predominant metabolic disease nowadays due to the off-beam lifestyle of diet and reduced physical activity. Complications of the illness include the gene-environment interactions and the downstream genetic and epigenetic consequences, e.g., cardiovascular diseases, tumor progression, retinopathy, nephropathy, neuropathy, polydipsia, polyphagia, polyuria, and weight loss. This review sheds the light on the mechanistic insights of antidiabetic medicinal plants in targeting key organs and tissues involved in regulating blood glucose homeostasis including the pancreas, liver, muscles, adipose tissues, and glucose absorption in the intestine. Diabetes is also involved in modulating major epigenetic pathways such as DNA methylation and histone modification. In this respect, we will discuss the phytochemicals as current and future epigenetic drugs in the treatment of diabetes. In addition, several proteins are common targets for the treatment of diabetes. Some phytochemicals are expected to directly interact with these targets. We lastly uncover modeling studies that predict such plausible interactions. In conclusion, this review article presents the mechanistic insight of phytochemicals in the treatment of diabetes by combining both the cellular systems biology and molecular modeling.

Propolis is a resin that honeybees produce by mixing saliva and beeswax with exudate gathered from botanical sources. The presentin vitrostudy investigated the potential use of propolis as a multitarget therapeutic product and the physicochemical properties, chemical composition, and immunomodulatory, antioxidant, antibacterial, and anticancer properties of a propolis extract from the northern Morocco region (PNM). Pinocembrin, chrysin, and quercetin were the main phenolic compounds of PNM as measured in HPLC. The PNM showed significant inhibitory effects against all tested Gram-positive and Gram-negative strains and showed high antioxidant activities by scavenging free radicals with IC50 (DPPH = 0.02, ABTS = 0.04, and FRAP = 0.04 mg/ml). In addition, PNM induced a dose-dependent cytostatic effect in MCF-7, HCT, and THP-1 cell lines at noncytotoxic concentrations with IC50 values of 479.22, 108.88, and 50.54 μg/ml, respectively. The production of tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) was decreased in a dose-dependent manner in LPS-stimulated human peripheral blood mononuclear cells (PBMNCs), whereas the production of the anti-inflammatory interleukin-10 (IL-10) was increased in a dose-dependent manner reaching 15-fold compared to the levels measured in untreated PBMNCs. Overall, the results showed that the traditionally known multitarget therapeutic properties of the PNM seem to be mediated, at least in part, through cytostatic, antibacterial, and immunomodulatory effects.

The wild species of tomatoSolanum pennellii(Lpa) is more tolerant to salt-induced oxidative stress than the cultivated speciesSolanum lycopersicum(Lem), due to the increase of several antioxidative metabolites and enzymes in this species under stress. The increase of reduced glutathione (GSH), one of these metabolites, in NaCl-treated Lpa, is due at least partly to the elevation ofγ-glutamylcysteine synthetase (γ-ECS). Introgression line IL 8–3, which was found to include the Lpa orthologue of theγ-ECSgene (Lpaγ-ECS) in Lem's genetic background, was used to assign this gene to chromosome 8 and to assess its relative contribution to the effective antioxidative response of Lpa to stress. The growth of IL 8–3 and Lem plants responded similarly to NaCl and cadmium (Cd) stresses. In both genotypes, GSH and H2O2levels responded also similarly to NaCl stress. NaCl and Cd stresses affected similarly the transcription of theγ-ECSgene in leaves of both IL 8–3 and Lpa plants. The effect of buthionine sulfoximine (BSO), a competitive inhibitor of theγ-ECS enzyme, onγ-ECStranscription was also similar in these two genotypes. Taken together, these results suggest thatγ-ECSorthologues differ mainly in the regulation of their transcription and not at the post-transcriptional or translational levels. The mutation(s) led to these differences in the response of the two orthologues to the salinity and heavy metal stresses are expected to occur in acis-regulatory element(s) located relatively close toγ-ECS.

Recent advances in genomics, proteomics, cell biology and biochemistry of tumors have revealed new pathways that are aberrantly activated in numerous cancer types. However, the enormous amount of data available in this field may mislead scientists in focused research. As cancer cell growth and progression is often dependent upon the phosphoinositide 3-kinase (PI3K)/AKT pathway, there has been extensive research into the proteins implicated in the PI3K pathway. Using data available in the Human Protein Atlas database, the current study investigated the expression of 25 key proteins that are known to be involved with PI3K pathway activation in a distinct group of 20 cancer types. These proteins are AKTIP, ARP1, BAD, GSK3A, GSK3B, MERTK-1, PIK3CA, PRR5, PSTPIP2, PTEN, FOX1, RHEB, RPS6KB1, TSC1, TP53, BCL2, CCND1, WFIKKN2, CREBBP, caspase-9, PTK2, EGFR, FAS, CDKN1A and XIAP. The analysis revealed pronounced expression of specific proteins in distinct cancer tissues, which may have the potential to serve as targets for treatments and provide insights into the molecular basis of cancer.

First cloned in 2000, the human Histamine H4 Receptor (hH4R) is the last member of the histamine receptors family discovered so far, it belongs to the GPCR super-family and is involved in a wide variety of immunological and inflammatory responses. Potential hH4R antagonists are proposed to have therapeutic potential for the treatment of allergies, inflammation, asthma and colitis. So far, no hH4R ligands have been successfully introduced to the pharmaceutical market, which creates a strong demand for new selective ligands to be developed. in silico techniques and structural based modeling are likely to facilitate the achievement of this goal. In this review paper we attempt to cover the fundamental concepts of hH4R structure modeling and its implementations in drug discovery and development, especially those that have been experimentally tested and to highlight some ideas that are currently being discussed on the dynamic nature of hH4R and GPCRs, in regards to computerized techniques for 3-D structure modeling.

In the presentin vitrostudy, we tested the chemical composition, cytotoxicity and antidiabetic activity of two distinct extracts of wild Artichoke-like vegetable,Gundelia tournefortii: methanol and hexane. GC/MS phytochemical analysis ofG. tournefortiimethanol and hexane extracts revealed 39 compounds reported here for the first time inG. tournefortiiout of the 45 detected compounds. Only Stigmasterol was present in both extracts. The efficacy ofG. tournefortiiextracts in enhancing glucose transporter 4 (GLUT4) translocation to the plasma membrane (PM) was tested in L6 muscle cells stably expressing myc-tagged GLUT4 (L6-GLUT4myc) using cell-ELISA test. Results obtained here indicate that methanol and hexane extracts were safe up to 250 μg/ml as measured with MTT and the LDH leakage assays. The methanol extract was the most efficient in GLUT4 translocation enhancement. It increased GLUT4 translocation at 63 μg/ml 1.5- and 2-fold relative to the control in the absence and presence of insulin, respectively. These findings indicate thatG. tournefortiipossesses antidiabetic activity in part by enhancing GLUT4 translocation to the PM in skeletal muscle.

Aim: Based on knowledge from traditional Greco-Arab herbal medicine, this in vitro study aims to evaluate the cytotoxicity and the anti-inflammatory mechanism of Peganum harmala (P. harmala ) seeds by measuring the expression and release of both anti-inflammatory (IL-10) and proinflammatory (IL-1, IL-2, IL-6 and TNF-α) cytokines in human THP-1-derived macrophages. Methodology: Cells were treated with 1 μg lipopolyssacharide/ml (LPS) in the absence and presence of increasing concentrations of extracts from the P. harmala seeds (PHS-extract). During the entire experimental period, we used extract concentrations (up to 250 μg/ml) that had no cytotoxic effects as measured with MTT and LDH assays. The anti-inflammatory effects were assessed by measuring the levels of secretory proteins and mRNA of IL-1, IL-2, IL-6, IL-10 and TNF-α in LPS-activated (1 μg/ml) human THP-1-derived macrophages.

The rate of glucose influx to skeletal muscles is determined primarily by the number of functional units of glucose transporter-4 (GLUT4) in the myotube plasma membrane. The abundance of GLUT4 in the plasma membrane is tightly regulated by insulin or contractile activity, which employ distinct pathways to translocate GLUT4-rich vesicles from intracellular compartments. Various studies have indicated that GLUT4 intrinsic activity is also regulated by conformational changes and/or interactions with membrane components and intracellular proteins in the vicinity of the plasma membrane. Here we show that the non-metabolizable glucose analog 3-O-methyl-d-glucose (MeGlc) augmented the rate of hexose transport into myotubes by increasing GLUT4 intrinsic activity without altering the content of the transporter in the plasma membrane. This effect was not a consequence of ATP depletion or hyperosmolar stress and did not involve Akt/PKB or AMPK signal transduction pathways. MeGlc reduced the inhibitory potency (increased Ki) of indinavir, a selective inhibitor of GLUT4, in a dose-dependent manner. Kinetic analyses indicate that MeGlc induced changes in GLUT4 or GLUT4 complexes within the plasma membrane, which enhanced the hexose transport activity and reduced the potency of indinavir inhibition. Finally, we present a simple kinetic analysis for screening and discovering low molecular weight compounds that augment GLUT4 activity.

Diabetes has been recognized by ancient physicians and its main symptoms were known by the increased thirst, frequent urination, and tiredness. Medicinal plants were commonly used for treating these combined symptoms. In addition to several instructions for specific food consumption, a mild exercise was recommended. Currently, traditional medicine continues to be practiced in most Middle East, Asia, as well as developed countries. The current form of herbal medicine has historical roots in medieval Greco-Arab, ancient Egyptians, Chinese, and other ancient medicines. More than 800 plant species are reported as antidiabetic. Over 400 plants as well as 700 recipes and compounds have been scientifically evaluated for type 2 diabetes treatment. For instance, metformin, the most popular antidiabetic drug nowadays, was developed based on a biguanide compound isolated from French lilac. Medicinal herbs contain various bioactive compounds and thus can display multiple actions on insulin production as well as distinct insulin action mechanisms: insulin sensitizing, insulin mimicking, and inhibition of intestinal carbohydrate digestion and absorption. Herbal-derived insulin sensitizers act in a synergetic mechanism to increase glucose disposal and uptake by muscle, hepatic cells, and fat as well as those that control hepatic glycogen metabolism. This chapter provides a comprehensive overview on traditional herbal medicine including the historical background, medical innovations introduced by physicians and researchers, methods of therapies, and a state-of-the-art description of traditional herbal medicine.

Obesity is a global health problem affecting all age groups, leading to many complications such as type 2 diabetes, systemic hypertension, cardiovascular diseases, dyslipidemia, atherosclerosis, and stroke. Physiologically, obesity which arises from metabolic changes at tissue and organ levels results in an imbalance between energy intake and energy expenditure, which in turn results in increased fat accumulation in adipose tissue. Adipose tissue is an important endocrine organ, which secretes several hormones, including leptin and adiponectin and chemokines. These factors can regulate tumor behavior, inflammation, and the tumor microenvironment. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of pro-inflammatory factors. Cells from adipose tissue, such as cancer-associated adipocytes and adipose-derived stem cells, enter the cancer microenvironment to enhance pro-tumor effects. Dysregulated metabolism that stems from obesity including insulin resistance, hyperglycemia, and dyslipidemia can further affect tumor growth and development. Two different obesity treatment drugs are currently on the market: orlistat, which reduces intestinal fat absorption via inhibiting pancreatic lipase, and sibutramine, an anorectic or appetite suppressant. Both drugs have side effects, including increased blood pressure, dry mouth, constipation, headache, and insomnia. For this reason, a wide variety of natural materials has been explored for their obesity treatment potential. The present chapter focuses on the safety and efficacy of commonly used herbal medicines in the management of obesity through covering their beneficial effects and mechanism of action.

Diabetes and obesity have reached epidemic proportions globally, and they are a major contributor to the development of many pathological processes including hypertension, hyperlipidemia, cardiovascular diseases, and certain types of cancer. Increased consumption of more energy-dense, nutrient-poor diets with high levels of carbohydrates and saturated fats, combined with reduced physical activity, has led to currently observed high rates of diabetes and obesity. A strong relationship exists between diabetes and obesity, with fat tissue playing an important role in diabetes, a disease characterized by hyperglycemia, insulin hyposecretion, and insulin resistance. The resistance manifests primarily as impaired ability of the muscle tissue to take up glucose and of the liver to curb glucose output in response to insulin. Eventually, pancreatic beta cell insufficiency leads to overt diabetes.

The utilization of herb-based products to prevent/treat diseases is a therapeutic modality that has stood the test of long history of use and has played important roles in the development of conventional medicine. Indeed, many of the currently utilized pharmacological classes of drugs include a phytochemical prototype. Aspirin, atropine, codeine, ephedrine, digoxin, L-dopa, morphine, quinine, reserpine, taxol, and tubocurarine are a few examples of drugs, which were originally discovered through the study of medicinal plants and traditional knowledge of indigenous people. Black seeds, garlic, ginseng, ginger, ginkgo, olive oil, pomegranate, milk thistle, and St. John’s wort are a few examples of medicinal plants, which are gaining popularity among modern physicians and researcher, and this trend is likely to continue partly due to high cost involved in the development of patentable synthetic drugs. There is growing evidence to show that pharmacological effects of medicinal plants are potentiated through synergistic mechanisms and/or side effect-neutralizing combinations.

Diabetes is one of the prominent metabolic disorders nowadays. It is associated with many complications, including polyuria, weight loss, polydipsia, polyphagia, blurred vision, retinopathy, neuropathy, and nephropathy. Ongoing research has advanced on the mechanisms accompanying the prevention and treatment of diabetes, and the vast majority of research papers in the field of drug design and pharmacokinetics concentrate on the mechanisms through which the homeostasis of serum glucose is achieved. Several organs are fundamental in the process of regulating blood glucose levels, namely, the pancreas, liver, muscles, and adipose tissues. On the one hand, pancreatic β-islets are responsible for insulin production. As such, some drugs are focused to augment the islet size, cell size and number, or insulin secretion levels. On the other hand, the liver is the most crucial organ to sense fluctuations in blood glucose concentration and respond via buffering mechanisms accordingly. Furthermore, muscle and adipose tissues play concomitant roles to withdraw extra glucose from the bloodstream. Several key enzymes (e.g., phosphofructokinase, phosphorylase, glucose-6-phosphatase, etc.), transporters (GLUT2, GLUT4, etc.), as well as cell surface receptors (IRS, TM7, and others) in the hepatic, muscular, and adipose tissues are major targets for antidiabetic drugs. Global control of blood glucose levels can be via insulin-dependent protein kinase B (PKB) or insulin-independent AMP-activated protein kinase (AMPK) signaling cascades. Additionally, several drugs target to soothe the cell damage associated with hyperglycemia. In this respect, antioxidants have invaluable effects that should not be ignored. Moreover, the simple routes for glycemic control are via the inhibition of glucose digestion and absorption. In this chapter, strategies to treat diabetes are discussed, with an emphasis on the phytochemical drugs used in the Middle East and their mechanisms of action.

Recent researches demonstrated the potential of phytochemicals to prevent and to counteract obesity. Multiple combinations of phytochemicals can result in a synergistic activity that increases their bioavailability and action on multiple molecular targets, offering advantages over chemical treatments. Herbal-derived compounds have potential for controlling appetite, inhibiting pancreatic lipase activity, stimulating thermogenesis and lipid metabolism, promoting lipolysis and adipogenesis, and inducing apoptosis in adipocytes. Appetite reduction and inhibiting pancreatic lipase activity represent the first line in the regulation of body weight. Stimulating lipolysis and thermogenesis represents an essential target for the development of anti-obesity drugs. Furthermore, targeting adipocyte life cycle using various dietary bioactives that affects different stages of adipocyte life cycle represents also an important target for the development of new anti-obesity drugs. In this regard, different stages of adipocyte development that are targeted by anti-obesity drugs can include preadipocytes, maturing preadipocytes, and mature adipocytes. Various herbal-derived active compounds, such as genistein, daidzein, cyanidin, proanthocyanidin, xanthohumol, apigenin and luteolin, kaempferol, myricetin, quercetin, epigallocatechin gallate, conjugated linoleic acid, docosahexaenoic acid, quercetin, resveratrol, and ajoene, affect adipocytes during specific stages of development, resulting in either the induction of apoptosis or inhibition of adipogenesis. Although numerous molecular targets that can be used for both treatment and prevention of obesity have been identified, targeted single cellular receptor or pathway has resulted in limited success. Therefore, targeting several cellular pathways simultaneously with multiple phytochemicals to achieve synergistic effects might be an appropriate approach in the management of obesity.

Because of their natural origin and reduced side effects, we are watching worldwide an extensive growth and increased popularity in the field of herbal mixtures. In contrast to synthetic pharmaceuticals based upon single compounds, many medicinal plants exert their beneficial pharmacological effects through synergistic or additive mechanisms of multiple active compounds acting at single or multiple cellular/tissue target sites associated with a physiological/pathological process. These additive or synergistic pharmacological effects are known to reduce or to eliminate side effects associated with the use of synthetic drugs. Synergistic effect of phytochemicals likely has its origin in their functional role in promoting plant survival. For instance, a mixture of active principles having additive or synergistic effects at multiple target sites would not only ensure effectiveness against a wide range of herbivores or phytopathogens but also decrease the chances of these organisms developing resistance or adaptive responses.

The human Ether-a-go-go-Related-Gene (hERG) potassium (K+) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K+ channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K+ channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, −1.98, −2.49 and −3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products.

Diabetes mellitus is a common chronic global disease affecting children and adolescents in developed as well as developing countries. Diabetes type I and type II are the major types of diabetes mellitus. The former is an autoimmune disorder, leading to pancreatic β-cell dysfunction and thus inadequate production of insulin. The latter arises from reduced sensitivity to insulin in the target tissues (i.e., skeletal muscle, liver, and adipose tissue) and later on insufficient insulin secretion. In both cases, the common result is sustained hyperglycemia. Uncontrolled hyperglycemia over time leads to deteriorating blood vessels supplying the body organs, leading to heart, eyes, kidneys, and nerves system damage. For instance, macrovascular (atherosclerotic) and microvascular (retinopathy and nephropathy) disorders are the leading causes of morbidity and mortality in diabetic patients [1]. We can appreciate then that diabetes is not a single disease but rather a combination of metabolic disorders [2].

The incidence of cancer is increasing in the developed countries and even more so in developing countries parallel to the increase in life expectancy. In recent years, clinicians and researchers advocate the need to include supportive and palliative care since the establishment of the diagnosis and throughout the duration of treatment, with the goal of improving patients' quality of life. This patient-centered approach in supportive care is also shared by various traditional and complementary medicine approaches. Traditional Arab-Islamic medicine offers a variety of therapeutic modalities that include herbal, nutritional, and spiritual approaches. Physicians and scholars, such as Avicenna (980–1037), Rhazes (965–915), Al Zahrawi (936–1013), and Ibn al Nafis (1218–1288) referred to cancer etiology in various medicinal texts and suggested both preventive and therapeutic remedies to alleviate suffering. This review presents research data related to the anticancer activities of herbs used in Arab-Islamic medicine and allude to their potential role in improving the quality of life of cancer patients.

Islamic medicine, Arabic medicine, Arab-Islamic medicine, or Greco-Arab and Islamic medicine refers to medicine developed in the Golden Age of the Arab-Islamic civilization, which extended from Spain in the west to Central Asia and India in the east. In temporal terms it covered a period of roughly nine centuries, from the middle of the seventh to the end of the fifteenth century. Medicine was a central part of this medieval civilization. Famous Arab and Muslim physicians, e.g., Rhazes, Avicenna, Al Zahrawi, Ibn al Nafis studied and developed treatments regimes for cancer as well as most known diseases at that time. They described most types of cancers which were known at that time and suggested several therapies. This review is an eye-bird view on the ancient Arab-Greco and Islamic cancer diagnosis, herbal treatment and nowadays herbal treatment research.

The majority of the currently used cosmetics and drugs are natural products-based compounds or their deriva- tives. This could add weight to the argument that natural based products are inherently better tolerated in the body than synthetic chemicals and have higher chance to be approved as new drugs. The present study was undertaken to analyze a natural product database compared to synthetic chemicals and to search for discriminative physicochemical properties that may probably help in differentiating between natural and synthetic compounds. We have formulated rules to assess the natural likeness of chemicals and thereby discriminate between natural-based and synthetic chemicals. A Mathews Corre- lation Coefficient of 0.5 was obtained; nearly 81% of natural-based products and 68% of synthetic chemicals were pre- cisely classified using this filter. The property criteria for drug-likeness and lead-likeness are more pronounced in natural products rather than synthetic ones. The fraction of synthetic chemicals which are natural-like could have higher chance to be successful drug.

In brain and tumor cells, the hexokinase isoforms HK-I and HK-II bind to the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane. We have previously shown that HK-I decreases murine VDAC1 (mVDAC1) channel conductance, inhibits cytochrome c release, and protects against apoptotic cell death. Now, we define mVDAC1 residues, found in two cytoplasmic domains, involved in the interaction with HK-I. Protection against cell death by HK-I, as induced by overexpression of native or mutated mVDAC1, served to identify the mVDAC1 amino acids required for interaction with HK-I. HK-I binding to mVDAC1 either in isolated mitochondria or reconstituted in a bilayer was inhibited upon mutation of specific VDAC1 residues. HK-I anti-apoptotic activity was also diminished upon mutation of these amino acids. HK-I-mediated inhibition of cytochrome c release induced by staurosporine was also diminished in cells expressing VDAC1 mutants. Our results thus offer new insights into the mechanism by which HK-I promotes tumor cell survival via inhibition of cytochrome c release through HK-I binding to VDAC1. These results, moreover, point to VDAC1 as a key player in mitochondrially mediated apoptosis and implicate an HK-I-VDAC1 interaction in the regulation of apoptosis. Finally, these findings suggest that interference with the binding of HK-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents.

Diabetes has been recognized since ancient times, and its main symptoms were known by the increased thirst, frequent urination, and tiredness. Obesity is one of the major risk factors for a number of chronic diseases, especially type 2 diabetes (T2D), leading to increase in healthcare costs and decrease in life expectancy. Free fatty acids (FFA) represent a crucial link between obesity, inflammation, and insulin resistance and, as such, reduction in elevated plasma FFA should be an important therapeutic target in obesity and T2D. According to the World Health Organization (WHO), 35% of adults aged 20 and over were overweight in 2008, and 11% were obese. Moreover, T2D prevalence has increased from less than 10% in 1980 to more than 30% nowadays [1]. There are several types of glucose-lowering drugs [2], including insulin sensitizers (biguanides, metformin, and thiazolidinediones), insulin secretagogues (sulfonylureas, meglitinides), and α-glucosidase inhibitors (miglitol, acarbose). Most glucose-lowering drugs, however, may have side effects, such as severe hypoglycemia, idiosyncratic liver cell injury, lactic acidosis, permanent neurological deficit, digestive discomfort, headache, and dizziness [3, 4]. As a result, researchers are interested in finding more efficient medicines, with less side effects. Medicinal plant drug discovery provides important leads against various pharmacological targets including T2D and obesity. With the dramatically increasing prevalence of obesity and T2D worldwide, there is an urgent need for new strategies to combat the growing epidemic of these metabolic diseases. Diet is an essential factor affecting the development of obesity and T2D and it can either prevent or accelerate metabolic diseases. In searching for preventative and therapeutic strategies, it is therefore advantageous to consider the potential of certain medicinal plants as well as herbal-based foods and their bioactive compounds to prevent/treat the pathogenic processes associated with these diseases. To date, the concept of antidiabetic and antiobesity medicinal plants is highlighted in textbooks and pharmaceutical pamphlets and has been reported in thousands of scientific publications. Yet, most of these publications report the activity of a crude extract without testing its chemical composition or identifying the active compound(s) or even its mechanism of action. We believe that natural novel drugs are now more achievable due to modern techniques for separation, structure elucidation, screening, and bio- and chemoinformatics. But whatever approach is used, the medicinal plant efficacy will be based on in vitro or in vivo bioassays. This special issue on medicinal plants for the treatment of diabetes and obesity is a bird's eye view on up-to-date knowledge of promising traditional medicines and their active ingredients efficacy and mechanisms of action in treating obesity and T2D. Nine selected papers for publication in the present issue summarize the most recent knowledge and techniques to evaluate the medicinal plants and active compounds for their antidiabetic, antiobesity, and antioxidant activity in vitro and in vivo. Manuscripts in this special issue cover several aspects of recent developments in the fields of (a) medicinal plants, buckwheat honey, and natural compounds preventing metabolic disorders (including T2D) in vivo and in vitro; (b) antioxidant and anti-inflammatory natural products; (c) phenolic compounds that show adipogenesis activity in vitro; (d) herbal pharmacotherapy and phytochemical studies in vitro and in situ; (e) examining the reliability of potential antioxidant substance based on the selected assays; (f) studies involving toxicology and pharmacological mechanisms of action of medicinal plants used in vivo and in vitro.