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Cancer metabolism regulation by phytonutrients

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Abstract

In spite of the advanced researches, preventive measures, and treatment options, cancer remains a growing ailment all over the world and its prevalence is estimated to increase in future. Cellular metabolic alterations have been documented as a hallmark of cancer. Metabolic regulation is an intricately coupled process whose deregulation leads to tumor progression as well as metastasis. In order to thrive in the living system, cancer cells adapt different metabolic pathways (bioenergetics and biosynthesis). They replenish their metabolic demands by switching from normal metabolism to cancer metabolism by the process of metabolic rewiring. Recent researches suggest that starving cancer cells by the use of nontoxic chemical entities can give promising results regarding cancer proliferation. Natural products, especially those of plant origin, offer different chemical scaffolds to target cancer via modulation of multiple cell signaling cascades. Phytonutrients, the secondary metabolites from the plants, constitute edible phytochemicals which are abundantly found in vegetables, whole grains, and fruits. The growing numbers of evidences suggest that phytonutrients exhibit anticancer as well as chemopreventive activities of these bioactive molecules against several cancers by targeting the various significant enzymes of glycolysis, the PPP pathway, TCA cycle, and serine metabolism. This book chapter presents an update for the scientific community about targeting the cancer metabolism by phytonutrients. The alterations in the cancer metabolism in the context of bioenergetics, biosynthesis, and mitochondrial functions have been discussed while presenting the impact of phytonutrients as modulators of potential metabolic effectors in the cancer metabolism.

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Abstract Oxidative stress is one of the earliest defects involved in the development of diabetes-induced cognitive impairment. Nrf2 is the master regulator of the cellular antioxidant system can be regulated by some microRNAs. The study aimed to evaluate the effects of quercetin (QC) and quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on Nrf2-controlled antioxidant genes through the redox-sensitive miR-27a. Expression levels of miR-27a, Nrf2, SOD1, GPX1, and CAT were measured by quantitative real-time PCR. Moreover, the oxidative stress parameters including total antioxidant capacity (TAC) and histological alterations were investigated. The expression level of miR-27a was significantly up-regulated in diabetic rats. While expression levels of Nrf2, SOD1, GPX1, and CAT were significantly down-regulated under diabetic condition. Interestingly, QCSPIONs decreased expression level of miR-27a and subsequently enhanced the expression levels of Nrf2, SOD1, and CAT to the control level. No significant difference was observed in the expression level of GPX1. Besides, QC in pure and especially conjugated form was able to normalize TAC and regenerate pathological lesions in STZ-diabetic rats. Our result demonstrates that QCSPIONs as an effective combined therapy can decrease miR-27a expression, which in turn increases the Nrf2 expression and responsive antioxidant genes, resulting in improvement of memory dysfunction in diabetic rats.
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Background: Gracilaria algae is red macro algae which has demonstrated considerable anti-inflammatory effects. Our objective was to compare the efficacy of Gracilaria algae topical cream 3% versus Clobetasol cream 0.05% in treatment of plaque-type psoriasis. Material and methods: 30 adult patients with baseline modified PASI score ≤12 were randomized to receive either Clobetasol or Gracilaria algae cream on right or left-sided symmetric plaques once daily for 8 weeks and follow-up of 4 weeks. Modified PASI score, patient's satisfaction using VAS and Global Physician Assessment score (GPA) were assessed to evaluate clinical response. Results: 30 patients with 94 symmetrical psoriasis plaques were enrolled in this trial. The mean baseline modified PASI score of both sides was similar; however, at the end of trial, modified PASI score was reduced more on the sides treated with Gracilaria algae cream (0.80±0.19% vs. 0.63±0.25%, P<0.05). No significant difference was found regarding Mean Physician Global Assessment score (PGA) between the 2 groups (p>0.05). Patients' satisfaction was significantly higher in favor of algae cream only at week 8 of the intervention (P<0.05). Conclusion: Gracilaria algae cream can be an effective and safe alternative of Clobetasol in the treatment of plaque type psoriasis. This article is protected by copyright. All rights reserved.
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Changes in the environment and demography have been a defining factor throughout humans’ evolutionary history, reflected by noticeable changes in dietary habits. It can be seen in the shift from foraging-based eating and cooking to the domestication of animals and plants. Such environmental and dietary transitions led selective pressures are believed to have impacted human genome variation and associated traits. Genome variations caused by genetic adaptations to specific dietary components might have played a substantial role in diet-linked phenotypic differences among modern humans and their health conditions. Thus, a better-suited dietary behavior may help reduce the human health burden and shape the future of food. Advancing genome technologies have led to a tremendous expansion in the number of genome sequences from different modern and ancient human populations, that spread to broader geographical regions and adapted locally, leading to the era of population genomics. These developments have facilitated the path to detect and precisely map different locally adapted genetic variants, particular to the population of a region that was exposed to a specific environment and diet. These finely mapped genetic variants have varying impacts on food metabolism and can be used in the budding field of nutritional genomics to understand gene-diet-health interactions at the individual level, leading to the dietary choice based on individual health. This chapter briefly discusses how combination of population genetics and nutritional genomics can help in managing human health in the modern-day urban society.
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This study evaluated if the hepatic protective effect of Isoliquiritigenin (ISL) against doxorubicin (DOX)-treated rats involves upregulating sirtuin-1 (SIRT1) signaling. Adult male was divides into 5 groups (n = 6 rats/each) as control (vehicle), ISL (25 mg/kg), DOX (15 mg/kg), DOX + ISL, and DOX + ISL + EX-527 (a SIRT1 inhibitor, 5 mg/kg). ISL and EX-527 were administered 10 days before and after the single treatment of DOX. Also, cultured AML-12 hepatocytes (5 ×10⁴) were treated with 10 µM of ISL for 24 h with or without DOX-treatments (10 µM) and in the presence or absence of EX-527 (5 µM). ISL prevented hepatocyte damage and decreased serum levels of hepatic transaminases, hepatic levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and hepatic mRNA levels of Bax and caspases-3,8, and 9. In the liver of the control and DOX-treated rats, ISL reduced levels of malondialdehyde (MDA) but increased hepatic levels of glutathione (GSH), superoxide dismutase (SOD), and catalase, as well as mRNA levels of Bcl2. In vitro, ISL stimulated cell survival and lowered levels of ROS but increased GSH levels. In vivo and in vitro, in the livers of control and DOX-treated animals, ISL significantly increased the nuclear activity and mRNA levels of SIRT1, enhanced the nuclear levels of Nrf2, and reduced nuclear levels of NF-κB p65. In conclusion, ISL alleviates DOX-induced hepatocyte toxicity by stimulating the Nrf2/antioxidants axis and concomitant suppression of NF-κB, mainly by upregulating/activating SIRT1.
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Psoriasis is a long-lasting inflammatory skin disease lacking proper cure. Dysregulated activation of neutrophils is a major pathogenic factor in psoriasis. Formyl peptide receptor 1 (FPR1) triggers neutrophil activation in response to bacteria- or mitochondria-derived N-formyl peptides, but its significance in neutrophilic psoriasis remains unknown. In this study, we discovered two derivatives of ursolic acid, 3β-hydroxyurs-12,18-dien-28-oic acid (randialic acid B, RAB) and 3β-hydroxyurs-12,19-dien-28-oic acid (tomentosolic acid, TA), as FPR1 inhibitors in human neutrophils with ability to suppress psoriatic symptoms in mice. Both RAB and TA, triterpenoids of traditional medicinal plant Ilex kaushue, selectively inhibited reactive oxygen species production, elastase release, and CD11b expression in human neutrophils activated by FPR1, but not non-FPR1 agonists. Importantly, RAB and TA inhibited the binding of N-formyl peptide to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells, indicating FPR1 antagonism. Moreover, in assays induced by various concentrations of FPR1 agonist, both RAB and TA acted competitively for its binding to the FPR1 receptor. The FPR1-downstream signaling such as Ca²⁺ mobilisation and activation of Akt and MAPKs was also competitively inhibited. In addition, imiquimod-induced psoriasis-like symptoms, including epidermal hyperplasia, desquamation with scaling, neutrophil skin infiltration, and transepidermal water loss were significantly reduced by both RAB and TA. The results illustrate a possible role of human neutrophils FPR1 receptor in psoriasis-like inflammation. Accordingly, triterpenoids RAB and TA represent novel FPR1 antagonists and exhibit therapeutic potential for treating neutrophilic inflammatory skin diseases.
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Background: Psoriasis is one of the most common chronic cutaneous skin disorders, having genetic and immunological components. It is currently unknown what exactly triggers it, or how far reaching are the etiological factors, although great strides have been made in uncovering the pathophysiological cascade. Presently, there is a wide diversity of treatment methods for psoriasis, yet not all are applicable for each patient. Selection of both drug and dosage depends on both the knowledge and experience of the treating dermatologist and also on the specific characteristics of each patient. Therefore, the treating physicians should be made aware of the management possibilities, their advantages and their side effects. Methods: We have performed a non-systematic literature review on the current treatment methods for psoriasis. We have included the studies, articles, and prescription information that provided the most relevant information regarding each therapeutic agent. Afterward, we divided the treatment methods according to delivery and illustrated the management protocols for adult, paediatric, and pregnant patients. Discussion and conclusions: Current therapies are divided into topical drugs, phototherapy, systemic and biological agents. Topical therapies and phototherapy are generally the first and second line of management respectively, being typically effective in treating mild to moderate forms of psoriasis. On the other hand, the chronic moderate to severe forms usually benefit from systemic drugs, whereas biologic agents are reserved for severe or unremitting cases, especially those suffering from psoriatic arthritis. Also of importance is the understanding of the pathophysiological mechanisms in psoriasis and how the selected drugs interfere in the pathological cascade. Furthermore, physicians should be able to recommend the appropriate therapy not only for adults but also for paediatric and pregnant patients as well. In the following manuscript, we present an updated version of these management options, alongside their indications, posology and most common side effects, a guide that may be useful for every practitioner in this field.
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Objective: Studies have shown that the use of herbal medicines can be effective in prevention and treatment of obesity/overweight and its related disorders. The purpose of the present study was to investigate the effect of nanocurcumin supplementation on anthropometric characteristics, lipid profile and C-reactive Protein (CRP) in overweight girls. Methods: This is a quasi-experimental study with pretest/posttest design. The subjects were 24 overweight students with a mean age of 22.48±1.64 years and body mass index (BMI) of 27.53±3.29 kg/m2. After receiving written consent from the subjects, they were randomly divided into two groups of supplement (n=12) and placebo (n=12). Supplement group consumed 80 mg nanocurcumin capsule daily for 6 weeks. Anthropometric indicators (weight, BMI and waist-to-hip ratio) were measured before and after the intervention and blood samples were collected to measure lipid profile parameters (low-density lipoprotein, total cholesterol, triglyceride, and high-density lipoprotein) and CRP level. Data were analyzed by dependent and independent t-tests. The significance level of the tests was set at P≤0.05. Results: Nanocurcumin supplementation for 6 weeks did not significantly affect the anthropometric indicators, lipid profile parameters and CRP level (P>0.05). Conclusion: It seems that the short-term nancurcumin supplementation cannot significantly affect anthropometric characteristics, lipid profile, and CRP level in overweight girls. Therefore, long-term use and different doses of this supplement are recommended.
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Psoriasis is a refractory inflammatory skin disease affecting 2 %–3 % of the world population, characterized by the infiltration and hyper-proliferation of inflammatory cells and aberrant differentiation of keratinocytes. Targeting the IL-23/ Th17 axis has been well recognized as a promising therapeutic strategy, as the IL-23/ Th17 signal plays a vital role in the pathology of psoriasis. Three pentacyclic triterpene compounds isolated from loquat leaves have been reported with significant inhibitory effects on RORγt transcription activity and Th17 cell differentiation, and excellent performance in preventing lupus nephritis pathogenesis. However, the potential effects of these pentacyclic triterpene compounds on psoriasis remain unknown. In this study, we demonstrated the potent therapeutic effects of these pentacyclic triterpene compounds on psoriasis. These three pentacyclic triterpene compounds significantly alleviated skin inflammation as well as aberrant keratinocyte proliferation in an imiquimod-induced mouse psoriasis model. These compounds also inhibited the infiltration of immune cells and the level of pro-inflammatory cytokine in the dermis, as well as the cells number and changed the cytokine profiling expression of Th17 cells. These compounds could reduce the amount of CD4⁺ and CD8⁺ T cells in local lymph node, but not in spleen, which is different from hydrocortisone, the positive control treatment. These results suggest better performance of these compounds than steroids on treating psoriasis with less side effects on the integrated immune system. In summary, our findings uncover the potent therapeutic effects of pentacyclic triterpene compounds on psoriasis, providing potential candidate compounds for drug development.
Article
Background Curcumin demonstrated many pharmacological effects including antioxidants, anti-inflammation, eliminating free radicals, anti-tumor, lipid regulation, and anti-coagulation. Objective This study aimed to assess and compare curcumin and nano-curcumin effects on lipid profile, oxidative stress, and inflammatory factors related to patients ‘heart. Method This randomized, double-blind, placebo-controlled clinical trial was conducted on 90 patients undergoing coronary elective angioplasty which were randomly divided into 3 groups. The doses administered for 8 weeks were a 500 mg capsule of curcumin daily for the first group and an 80 mg capsule of nano-curcumin for the second group. However, the placebo group received capsules like curcumin. Lipid profile, oxidative stress factors, and inflammatory markers were measured at the baseline and end of the experiment. Results Statistically significant changes were observed in the total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C) in the intervention groups to the control group (p<0.05). Curcumin and nano-curcumin supplementation also improved significant changes in plasma levels of total antioxidant capacity (TAC), malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), high-sensitivity C-reactive protein (hs-CRP), Interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in comparison to the placebo (p<0.05). Furthermore, the nano-curcumin group compared to the curcumin group demonstrated significant changes (p<0.05) in TC, TG, SOD, MDA and TNF-α levels. Conclusion The effects of curcumin on nano formula may be better for cardiac patients due to its high bioavailability.
Article
It is known that the intake of alcoholic beverages may impair genetic and epigenetic regulatory events with consequent crucial effects on cell phenotypes and that its association with selected genotypes can lead to a different risk of cancer in the population. The aim of this review is to pick up selected studies on this topic and recapitulate some of the biochemical and nutrigenetic/nutrigenomic aspects involved in the impact of dietary low-dose alcohol consumption on the switching-on or -off of tumorigenic pathways. These include i) the existence of predisposing or protective human genotypes and the relationship between dietary compounds and alcohol in the promotion or inhibition of carcinogenesis; ii) the effects of other components of alcoholic drinks in the modulation of the expression of oncogenes and oncosuppressors, the autophagic flux and the onset of apoptosis, with examples of their cytospecificity; and iii) the role of alcoholic beverage consumption within particular dietary regimens, including the Mediterranean diet. Taking all the data into account, several alcohol-associated bioactive dietary compounds appear capable to modulate peculiar intracellular pathways predisposing to or protecting from cancer. Advances in the nutrigenetic, nutrigenomic and nutriepigenetic knowledge complementing the biochemical and molecular approaches will help in unveiling their impact on health outcome.
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This paper reports clinical and metabolic studies of two Italian siblings with a novel form of persistent isolated hypermethioninaemia, i.e. abnormally elevated plasma methionine that lasted beyond the first months of life and is not due to cystathionine β‐synthase deficiency, tyrosinaemia I or liver disease. Abnormal elevations of their plasma S‐adenosylmethionine (AdoMet) concentrations proved they do not have deficient activity of methionine adenosyltransferase I/III. A variety of studies provided evidence that the elevations of methionine and AdoMet are not caused by defects in the methionine transamination pathway, deficient activity of methionine adenosyltransferase II, a mutation in methylenetetrahydrofolate reductase rendering this activity resistant to inhibition by AdoMet, or deficient activity of guanidinoacetate methyltransferase. Plasma sarcosine (N‐methylglycine) is elevated, together with elevated plasma AdoMet in normal subjects following oral methionine loads and in association with increased plasma levels of both methionine and AdoMet in cystathionine β‐synthase‐deficient individuals. However, plasma sarcosine is not elevated in these siblings. The latter result provides evidence they are deficient in activity of glycine N‐methyltransferase (GNMT). The only clinical abnormalities in these siblings are mild hepatomegaly and chronic elevation of serum transaminases not attributable to conventional causes of liver disease. A possible causative connection between GNMT deficiency and these hepatitis‐like manifestations is discussed. Further studies are required to evaluate whether dietary methionine restriction will be useful in this situation.
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Luteolin (LU) is a flavonoid compound and metformin hydrochloride (MH) is a kind of drug. Studies have shown that both LU and MH have the function of hypoglycemic effect. However, there are few reports indicating that LU cooperated with MH (LU·MH) can relieve lipid metabolism disorders and optimize intestinal flora compositions of high-fat diet mice. In this research, we investigated the effects of LU, MH and LU·MH on lipid metabolism disorders and intestinal flora composition in high-fat diet mice. The study found that compared with high-fat diet (HFD) alone, LU, MH and LU·MH could significantly reduce the lipid metabolism disorder. Furthermore, compared with LU or MH alone, the biochemical indicators of LU·MH were significantly improved and the results of the histopathological section also showed that LU·MH has stronger liver repair ability. It revealed that the potential mechanisms of the LU·MH alleviating lipid metabolism disorders were involved in the simultaneous regulation of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1. In addition, LU·MH could regulate the intestinal flora compositions. This includes significantly reducing the ratio of Firmicutes and Bacteroidetes(F/B) and at the family level, increasing the relative abundance of Lachnospiraceae, Helicobacteraceae, Marinifilaceae and Peptococcaceae to relieve lipid metabolism disorders. In conclusion, the work found that LU·MH regulates the signal pathway of SREBP-1c/FAS and SREBP-1c/ACC/Cpt-1 simultaneously and decreases the ratio of F/B, as well as increases the relative abundance of certain microbiota to alleviate the lipid metabolism disorders of HFD-fed mice.
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Tyrosinaemia type III is a rare disorder caused by a deficiency of 4‐hydroxyphenylpyruvate dioxygenase, the second enzyme in the catabolic pathway of tyrosine. The majority of the nine previously reported patients have presented with neurological symptoms after the neonatal period, while others detected by neonatal screening have been asymptomatic. All have had normal liver and renal function and none has skin or eye abnormalities. A further four patients with tyrosinaemia type III are described. It is not clear whether a strict low tyrosine diet alters the natural history of tyrosinaemia type III, although there remains a suspicion that treatment may be important, at least in infancy.
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The hypothesis of the current study was that flavonol and polysaccharides obtained during catechins extraction from green tea may enhance the effect of catechins on preventing pancreatic lipase activity, free glycerol absorption and accumulation in adipocytes co-cultured with Caco-2 cell after in vitro digestion. Catechins rich extract from green tea (GCT: 10 mg), GCT formulated with polysaccharides (GTP: 1 mg) and flavonol extract (GFV: 0.1 mg) strongly inhibited lipase activity during digestion while increasing lipolysis in adipocytes. Lipid accumulation in adipocytes was significantly reduced in GCT (10 mg) + GTP (1 mg) + GFV (1 mg) (100–87.27%) compared to control (p < 0.05). When targeted single flavonols (myricetin, quercetin, and kaempferol) were added into catechins in GCT (EGCG), the lipid accumulation in adipocyte ranged from 82.07 to 89.11% of control. EGCG (3 mg) + Quercetin (0.3 mg) transported the lowest amount of glycerol (2.18 ± 0.18 mM) in aqueous fraction from the digesta to the Caco-2 cell. Results from the current study suggested that co-consumption of catechin rich green tea extracts with by-products including flavonols and polysaccharides obtained during green tea processing could be potential natural components on anti-obesity by preventing lipid intestinal absorption and accumulation in adipocytes.
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Epidemiological data support the view that both obesity and cardiovascular diseases (CVD) account for a high proportion of total morbidity and mortality in adults throughout the world. Obesity and CVD have complex interplay mechanisms of genetic and environmental factors, including diet. Nutrition is an environmental factor and it has a predominant and recognizable role in health management and in the prevention of obesity and obesity-related diseases, including CVD. However, there is a marked variation in CVD in patients with obesity and the same dietary pattern. The different genetic polymorphisms could explain this variation, which leads to the emergence of the concept of nutrigenetics. Nutritional genomics or nutrigenetics is the science that studies and characterizes gene variants associated with differential response to specific nutrients and relating this variation to various diseases, such as CVD related to obesity. Thus, the personalized nutrition recommendations, based on the knowledge of an individual’s genetic background, might improve the outcomes of a specific dietary intervention and represent a new dietary approach to improve health, reducing obesity and CVD. Given these premises, it is intuitive to suppose that the elucidation of diet and gene interactions could support more specific and effective dietary interventions in both obesity and CVD prevention through personalized nutrition based on nutrigenetics. This review aims to briefly summarize the role of the most important genes associated with obesity and CVD and to clarify the knowledge about the relation between nutrition and gene expression and the role of the main nutrition-related genes in obesity and CVD.
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Spinal cord injury (SCI) is a neurological disorder associated with the loss of sensory and motor function. Understanding the precise dysregulated signaling pathways, especially apoptosis and autophagy following SCI, is of vital importance in developing innovative therapeutic targets and treatments. The present study lies in the fact that it reveals the precise dysregulated signaling mediators of apoptotic and autophagic pathways following SCI and also examines the effects of polyphenols and other candidate phytochemicals. It provides new insights to develop new treatments for post-SCI complications. Accordingly, a comprehensive review was conducted using electronic databases including, Scopus, Web of Science, PubMed, and Medline, along with the authors’ expertise in apoptosis and autophagy as well as their knowledge about the effects of polyphenols and other phytochemicals on SCI pathogenesis. The primary mechanical injury to spinal cord is followed by a secondary cascade of apoptosis and autophagy that play critical roles during SCI. In terms of pharmacological mechanisms, caspases, Bax/Bcl-2, TNF-α, and JAK/STAT in apoptosis along with LC3 and Beclin-1 in autophagy have shown a close interconnection with the inflammatory pathways mainly glutamatergic, PI3 K/Akt/mTOR, ERK/MAPK, and other cross-linked mediators. Besides, apoptotic pathways have been shown to regulate autophagy mediators and vice versa. Prevailing evidence has highlighted the importance of modulating these signaling mediators/pathways by polyphenols and other candidate phytochemicals post-SCI. The present review provides dysregulated signaling mediators and therapeutic targets of apoptotic and autophagic pathways following SCI, focusing on the modulatory effects of polyphenols and other potential phytochemical candidates.
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An increasing epidemic of obesity has become a serious public health concern primarily because it contributes to pathogenesis of many chronic diseases including type 2 diabetes, cardiovascular disease, hepatobiliary disease, obstructive sleep apnea, kidney disease, some types of cancer, among others. Consumption of a variety of phytochemicals has emerged as a promising potential for combating obesity and its comorbidities. However, the generally low aqueous solubility, stability, bioavailability, and target specificity of phytochemicals, along with their side-effects and toxicity seen when used at high doses, have restricted their clinical application. As a solution, phytochemicals can be encapsulated into nanoparticles to increase their stability and solubility, enhance their bioavailability, protect them from premature degradation in the body, prolong their circulation time, and thus enhancing their anti-obesity activity. In this review, we summarize problems and limitations of the prominent phytochemicals (epigallocatechin gallate, trans-resveratrol, curcumin, and quercetin), the major biocompatible and biodegradable nanoparticles, and efficacy of nano-encapsulated forms of these phytochemicals in combating obesity and its comorbidities. Keywords: Obesity, nanoparticles, epigallocatechin gallate, trans-resveratrol, curcumin, and quercetin