Expression of programmed death-ligand 1 protein in pulmonary squamous cell carcinoma correlates with tumour necrosis but not with tumour differentiation.

AIMS: Pulmonary squamous cell carcinoma (SqCC) represents the second most common non-small cell lung carcinoma type. The mechanisms which regulate programmed death ligand 1 (PD-L1) expression in this form of lung cancer are not fully elucidated yet. METHODS: We immunohistochemically determined the level of PD-L1 expression using the Tumour Proportion Score system in surgical resections of 133 patients with pulmonary SqCC. The results from PD-L1 immunohistochemistry were analysed in relation to tumour differentiation and the presence of necrotic areas comprising at least 20% of the tumour mass. RESULTS: No significant differences in terms of PD-L1 expression were found between SqCC subtypes as defined by the current WHO classification: better differentiated, keratinising tumours (12/24, 50.0 %) compared with less differentiated, non-keratinising and basaloid forms (62/109, 56.9 %) were PD-L1 positive in a comparable proportion of cases (p=0.1903). Contrary to that, SqCCs with the presence of necrosis (51/61, 83.6 %) had significantly more PD-L1-positive cases (p<0.001) compared with SqCCs without necrotic areas (23/72, 32.0 %) CONCLUSIONS: We demonstrated that PD-L1 expression in pulmonary SqCCs does not correlate with the traditionally defined degree of differentiation of these tumours. On the other hand, we found a significant association between the positive result of PD-L1 immunohistochemistry and tumour necrosis. Further investigation regarding the role of hypoxic pathways as presumable inducers of PD-L1 expression in pulmonary SqCCs might contribute to the understanding of this phenomenon.

Targeting phytoprotection in the COVID-19-induced lung damage and associated systemic effects-the evidence-based 3PM proposition to mitigate individual risks.

The risks related to the COVID-19 are multi-faceted including but by far not restricted to the following: direct health risks by poorly understood effects of COVID-19 infection, overloaded capacities of healthcare units, restricted and slowed down care of patients with non-communicable disorders such as cancer, neurologic and cardiovascular pathologies, among others; social risks-restricted and broken social contacts, isolation, professional disruption, explosion of aggression in the society, violence in the familial environment; mental risks-loneliness, helplessness, defenceless, depressions; and economic risks-slowed down industrial productivity, broken delivery chains, unemployment, bankrupted SMEs, inflation, decreased capacity of the state to perform socially important programs and to support socio-economically weak subgroups in the population. Directly or indirectly, the above listed risks will get reflected in a healthcare occupation and workload which is a tremendous long-term challenge for the healthcare capacity and robustness. The article does not pretend to provide solutions for all kind of health risks. However, it aims to present the scientific evidence of great clinical utility for primary, secondary, and tertiary care to protect affected individuals in a cost-effective manner. To this end, due to pronounced antimicrobial, antioxidant, anti-inflammatory, and antiviral properties, naturally occurring plant substances are capable to protect affected individuals against COVID-19-associated life-threatening complications such as lung damage. Furthermore, they can be highly effective, if being applied to secondary and tertiary care of noncommunicable diseases under pandemic condition. Thus, the stratification of patients evaluating specific health conditions such as sleep quality, periodontitis, smoking, chronic inflammation and diseases, metabolic disorders and obesity, vascular dysfunction, and cancers would enable effective managemenet of COVID-19-associated complications in primary, secondary, and tertiary care in the context of predictive, preventive, and personalized medicine (3PM).

Caution, "normal" BMI: health risks associated with potentially masked individual underweight-EPMA Position Paper 2021.

An increasing interest in a healthy lifestyle raises questions about optimal body weight. Evidently, it should be clearly discriminated between the standardised "normal" body weight and individually optimal weight. To this end, the basic principle of personalised medicine "one size does not fit all" has to be applied. Contextually, "normal" but e.g. borderline body mass index might be optimal for one person but apparently suboptimal for another one strongly depending on the individual genetic predisposition, geographic origin, cultural and nutritional habits and relevant lifestyle parameters-all included into comprehensive individual patient profile. Even if only slightly deviant, both overweight and underweight are acknowledged risk factors for a shifted metabolism which, if being not optimised, may strongly contribute to the development and progression of severe pathologies. Development of innovative screening programmes is essential to promote population health by application of health risks assessment, individualised patient profiling and multi-parametric analysis, further used for cost-effective targeted prevention and treatments tailored to the person. The following healthcare areas are considered to be potentially strongly benefiting from the above proposed measures: suboptimal health conditions, sports medicine, stress overload and associated complications, planned pregnancies, periodontal health and dentistry, sleep medicine, eye health and disorders, inflammatory disorders, healing and pain management, metabolic disorders, cardiovascular disease, cancers, psychiatric and neurologic disorders, stroke of known and unknown aetiology, improved individual and population outcomes under pandemic conditions such as COVID-19. In a long-term way, a significantly improved healthcare economy is one of benefits of the proposed paradigm shift from reactive to Predictive, Preventive and Personalised Medicine (PPPM/3PM). A tight collaboration between all stakeholders including scientific community, healthcare givers, patient organisations, policy-makers and educators is essential for the smooth implementation of 3PM concepts in daily practice.

Enzymatic Metabolism of Flavonoids by Gut Microbiota and Its Impact on Gastrointestinal Cancer.

Gastrointestinal (GI) cancer is a prevalent global health disease with a massive burden on health care providers. Internal and external factors such as obesity, smoking, diet (red meat), low socioeconomic status and infection with Helicobacter pylori are the critical risk factors of GI cancers. Flavonoids are natural phenolic compounds found abundantly in fruits and vegetables. Upon ingestion, 90% of flavonoids consumed require further enzymatic metabolism by the gut microbiome to enhance their bioavailability and absorption. Several epidemiological studies reported that consumption of flavonoids and their enzymatic conversion by gut microbes is strongly associated with the reduced risk of GI cancer development. This review summarizes the current knowledge on the enzymatic conversion of flavonoids by the human gut microbiome. It also addresses the underlying anti-GI cancer effects on metabolic pathways such as apoptosis and cellular proliferation. Overall, metabolites produced from flavonoid's enzymatic conversion illustrate anti-GI cancer effects, but the mechanisms of action need further clarification.

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention.

Multi-factorial mitochondrial damage exhibits a "vicious circle" that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.

Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects.

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

The interplay between the vaginal microbiome and innate immunity in the focus of predictive, preventive, and personalized medical approach to combat HPV-induced cervical cancer.

HPVs representing the most common sexually transmitted disease are a group of carcinogenic viruses with different oncogenic potential. The immune system and the vaginal microbiome represent the modifiable and important risk factors in HPV-induced carcinogenesis. HPV infection significantly increases vaginal microbiome diversity, leading to gradual increases in the abundance of anaerobic bacteria and consequently the severity of cervical dysplasia. Delineation of the exact composition of the vaginal microbiome and immune environment before HPV acquisition, during persistent/progressive infections and after clearance, provides insights into the complex mechanisms of cervical carcinogenesis. It gives hints regarding the prediction of malignant potential. Relative high HPV prevalence in the general population is a challenge for modern and personalized diagnostics and therapeutic guidelines. Identifying the dominant microbial biomarkers of high-grade and low-grade dysplasia could help us to triage the patients with marked chances of lesion regression or progression. Any unnecessary surgical treatment of cervical dysplasia could negatively affect obstetrical outcomes and sexual life. Therefore, understanding the effect and role of microbiome-based therapies is a breaking point in the conservative management of HPV-associated precanceroses. The detailed evaluation of HPV capabilities to evade immune mechanisms from various biofluids (vaginal swabs, cervicovaginal lavage/secretions, or blood) could promote the identification of new immunological targets for novel individualized diagnostics and therapy. Qualitative and quantitative assessment of local immune and microbial environment and associated risk factors constitutes the critical background for preventive, predictive, and personalized medicine that is essential for improving state-of-the-art medical care in patients with cervical precanceroses and cervical cancer. The review article focuses on the influence and potential diagnostic and therapeutic applications of the local innate immune system and the microbial markers in HPV-related cancers in the context of 3P medicine.

Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing.

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared a pandemic by WHO on March 11, 2020. Soon after its emergence in late December 2019, it was noticed that diabetic individuals were at an increased risk of COVID-19-associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects of COVID-19. Interestingly, in diabetic COVID-19 patients, while insulin administration was associated with adverse outcomes, Metformin treatment was correlated with a significant reduction in disease severity and mortality rates among affected individuals. Metformin was extensively studied for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral capabilities that would explain its ability to confer cardiopulmonary and vascular protection in COVID-19. Here, we describe the various possible molecular mechanisms that contribute to Metformin therapy's beneficial effects and lay out the scientific basis of repurposing Metformin for use in COVID-19 patients.

Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers.

Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.

Natural Compounds in Glioblastoma Therapy: Preclinical Insights, Mechanistic Pathways, and Outlook.

Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances-an integral component of the lifestyle medicine approach to chronic diseases-are examined as potential chemotherapeutic agents. These heterogenous substances exert anti-GBM effects by upregulating apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural substances' efficacy in GBM is constrained by their bioavailability and blood-brain barrier permeability; various chemical formulations are proposed to improve their pharmacological properties. Many of the reviewed substances are available as over-the-counter dietary supplements, underscoring their viability as lifestyle interventions. However, clinical trials remain necessary to substantiate the in vitro and in vivo properties of natural substances.

Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles.

Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities.

Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs.

PURPOSE: This study aimed to assess the potential of flavonoids in combating CIPN. METHODS: PubMed and Google Scholar were used, and studies that investigated flavonoids in models of CIPN and models of neuropathic pain similar to CIPN were included. Only studies investigating peripheral mechanisms of CIPN were used. RESULTS: Flavonoids inhibit several essential mechanisms of CIPN, such as proinflammatory cytokine release, astrocyte and microglial activation, oxidative stress, neuronal damage and apoptosis, mitochondrial damage, ectopic discharge, and ion channel activation. They decreased the severity of certain CIPN symptoms, such as thermal hyperalgesia and mechanical, tactile, and cold allodynia. CONCLUSIONS: Flavonoids hold immense promise in treating CIPN; thus, future research should investigate their effects in humans. Specifically, precise pharmacological mechanisms and side effects need to be elucidated in human models before clinical benefits can be achieved.

Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis?

The nuclear factor-kappaB (NF-κB) signaling pathway is considered as a potential therapeutic target in cancer therapy. It has been well established that transcription factor NF-κB is involved in regulating physiological and pathological events including inflammation, immune response and differentiation. Increasing evidences suggest that deregulated NF-κB signaling can enhance cancer cell proliferation, metastasis and also mediate radio-as well as chemo-resistance. On the contrary, non-coding RNAs (ncRNAs) have been found to modulate NF-κB signaling pathway under different settings. MicroRNAs (miRNAs) can dually inhibit/induce NF-κB signaling thereby affecting the growth and migration of cancer cells. Furthermore, the response of cancer cells to radiotherapy and chemotherapy may also be regulated by miRNAs. Regulation of NF-κB by miRNAs may be mediated via binding to 3/-UTR region. Interestingly, anti-tumor compounds can increase the expression of tumor-suppressor miRNAs in inhibiting NF-κB activation and the progression of cancers. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can also effectively modulate NF-κB signaling thus affecting tumorigenesis. It is noteworthy that several studies have demonstrated that lncRNAs and circRNAs can affect miRNAs in targeting NF-κB activation. They can act as competing endogenous RNA (ceRNA) thereby reducing miRNA expression to induce NF-κB activation that can in turn promote cancer progression and malignancy.

Flavonoids against the SARS-CoV-2 induced inflammatory storm.

The disease severity of COVID-19, especially in the elderly and patients with co-morbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of proinflammatory cytokine mediators (cytokine storm). Flavonoids, important secondary metabolites of plants, have long been studied as therapeutic interventions in inflammatory diseases due to their cytokine-modulatory effects. In this review, we discuss the potential role of flavonoids in the modulation of signaling pathways that are crucial for COVID-19 disease, particularly those related to inflammation and immunity. The immunomodulatory ability of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, NLRP3 inflammasome, toll-like receptors (TLRs) or bromodomain containing protein 4 (BRD4), and the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2), might be beneficial in regulating the cytokine storm during SARS-CoV-2 infection. Moreover, the ability of flavonoids to inhibit dipeptidyl peptidase 4 (DPP4), neutralize 3-chymotrypsin-like protease (3CLpro) or to affect gut microbiota to maintain immune response, and the dual action of angiotensin-converting enzyme 2 (ACE-2) may potentially also be applied to the exaggerated inflammatory responses induced by SARS-CoV-2. Based on the previously proven effects of flavonoids in other diseases or on the basis of newly published studies associated with COVID-19 (bioinformatics, molecular docking), it is reasonable to assume positive effects of flavonoids on inflammatory changes associated with COVID-19. This review highlights the current state of knowledge of the utility of flavonoids in the management of COVID-19 and also points to the multiple biological effects of flavonoids on signaling pathways associated with the inflammation processes that are deregulated in the pathology induced by SARS-CoV-2. The identification of agents, including naturally occurring substances such as flavonoids, represents great approach potentially utilizable in the management of COVID-19. Although not clinically investigated yet, the applicability of flavonoids against COVID-19 could be a promising strategy due to a broad spectrum of their biological activities.

Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients.

Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine.

Mitochondrial injury plays a key role in the aetiopathology of multifactorial diseases exhibiting a "vicious circle" characteristic for pathomechanisms of the mitochondrial and multi-organ damage frequently developed in a reciprocal manner. Although the origin of the damage is common (uncontrolled ROS release, diminished energy production and extensive oxidative stress to life-important biomolecules such as mtDNA and chrDNA), individual outcomes differ significantly representing a spectrum of associated pathologies including but not restricted to neurodegeneration, cardiovascular diseases and cancers. Contextually, the role of predictive, preventive and personalised (PPPM/3P) medicine is to introduce predictive analytical approaches which allow for distinguishing between individual outcomes under circumstance of mitochondrial impairments followed by cost-effective targeted prevention and personalisation of medical services. Current article considers innovative concepts and analytical instruments to advance management of mitochondriopathies and associated pathologies.

Mitochondriopathies as a Clue to Systemic Disorders-Analytical Tools and Mitigating Measures in Context of Predictive, Preventive, and Personalized (3P) Medicine.

The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a "vicious circle" in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies.

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism.

Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism.

Resveratrol's Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism.

Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.