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Diabetes mellitus (DM) is a chronic endocrine and metabolic disease indicated by the presence of hyperglycemia. It has been known that hyperglycemia and oxidative stress are the main culprit of all DM complications, including macrovascular complications. As a byproduct of lipid, protein, and carbohydrate metabolism, methylglyoxal (MGO) is a highly reactive substance which plays a positive signaling role in helping cells regain redox balance under oxidative stress circumstances. DM-related problems lead to an excess of mitochondrial superoxide in the heart and big and small vascular endothelial cells. Elevated intracellular reactive oxygen species induce impaired angiogenesis in reaction to ischemia, trigger several proinflammatory pathways, and result in enduring epigenetic modifications that propel the continuous expression of proinflammatory genes even after glucose levels return to normal. Over time, the significance of the extremely quick advanced glycation end-products (AGE) production caused by the extremely reactive MGO has been clarified. It is now evident that MGO causes vascular tissue to react maladaptively. Glyoxalase 1 (GLO1) is the primary enzyme in an organism's enzymatic glyoxalase defense mechanism, which converts MGO to D-lactate in order to counteract the harmful effects of MGO. Understanding the role of the MGO–GLO1 pathway in the etiology of vascular disease in diabetes has advanced significantly. Therefore, it can be summarized that vascular damage are linked to diabetes. The AGE precursor MGO are important in determining the connection between diabetes and vascular damage. MGO and AGEs play a role in several phases of the development of diabetes complications. MGO and AGEs may be useful therapeutic targets for diabetes's macrovascular problems. KEYWORDS: hyperglycemia, AGE, methylglyoxal, glyoxalase, D-lactate, gluthatione, oxidative stress.

BACKGROUND: Age contributes to body composition alteration, rises a common disorder in elderly known as sarcopenic obesity (SO), which is characterized by the combination of obesity (excess fat mass) and sarcopenia (reduced skeletal muscle mass) clinical form and function. CONTENT: The primary cause of SO is insulin resistance. Glucose transporter 4 (GLUT4) dysfunction results in impaired fatty acids oxidation. Decreased muscle mass results in lower mitochondria number and volume. Both will increase oxidative stress. Together with altered myokines in SO, oxidative stress was promoted and lead to higher M1 macrophages and failure in autophagy. The pro-inflammatory condition and dysbiosis links SO to a variety of cardiometabolic conditions, including non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. The mortality, comorbidities, cardiometabolic diseases, and disability or impairment of SO is higher compare to obesity or sarcopenia alone. Some treatments have been developed for SO including adequate dietary intake, vitamin D and antioxidant supplementation, and exercises. SUMMARY: SO is more prevalent among the elderly and has a significant negative impact on their quality of life. Therefore, maintaining muscle mass and strength as well as preventing obesity should be the key goals of initiatives to support healthy aging. KEYWORDS: aging, body composition, obesity, sarcopenia, skeletal muscle, metabolic syndrome

BACKGROUND: Essential oils (EO) are complex volatile, naturally synthesized compounds from aromatic plants. It considers as healthy, effective, and safe since they were coming from nature. Gardenia jasminoides, Boswellia serrata, Commiphora myrrha, Foeniculum vulgarae, and Daucus carota are known to have antimicrobials, antioxidants, antiinflammation properties against respiratory tract infection. However, despite its natural content, a safety profile needs to be observed. Therefore, in this study, EO blend (EOB) made from the combination of these 5 plants was assessed for its efficacy and safety for respiratory tract infection in human. METHODS: A multicentre, randomized, open-label, phase II controlled trial involving 80 hospitalized adults with COVID-19 was conducted. One group of subjects only received standard of care (SoC), while the other group receive SoC and EOB orally for 10 days. RESULTS: There were significant decrease in interleukin (IL)-6 level (p=0.016) and interferon (IFN)-γ level (p=0.012), as well as better respiratory rate (p=0.024) for the group receiving SoC and EOB compared to the group receiving SoC only. However, there was no significant differences in aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and the corrected QT interval (QTc) prolongation value in both groups. All subjects with adverse effects were improved and recovered, and there were no serious adverse events found. CONCLUSION: The combination of G. jasminoides, B. serrata, C. myrrha, F. vulgarae, and D. carota EOB could improve the inflammatory and clinical status and safe to be used as adjuvant therapy for treating COVID-19 in adults. KEYWORDS: essential oils, COVID-19, inflammation, safety

BACKGROUND: Fibronectin type III domain-containing protein 5 (FNDC5), or also known as irisin, has been identified for two decades but almost completely disregarded for 10 years. It is present in skeletal muscle, heart, and brain, and in reaction to exercise can transform white adipose tissue into brown. Since then, irisin has gained a lot of attention for its potencies in treating metabolic disorders. In this review article, the potential future of irisin especially on metabolism and aging process will be discussed. CONTENT: Sedentary lifestyle is acknowledged as risk factor for type 2 diabetes mellitus, obesity, immune system issues, asthma, and neurological or heart illness. Irisin is secreted by muscle cells when exercising, produced after the proteolytic cleavage of FNDC5 protein. Irisin has positive impacts on maintaining physiological balance including reducing inflammation, keeping the bone homeostasis, as well as influencing metabolic processes and the neurological system function. Due to these many and advantageous characteristics, irisin could be a possible choice for preventing and managing disorders associated with modern society, and finding the agents to increase irisin can be beneficial. SUMMARY: Irisin offers a fresh potential basis for kinesitherapy and shows promise as a therapeutic target due to its various biological activities. Irisin pathway can be activated through dietary changes, the use of natural substances and drugs and can interact with this signalling pathway which involved peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and uncoupling protein mRNA 1 (UCP1) to resolve obesity and its metabolic comorbidities. KEYWORDS: irisin, FNDC5, exercise, inflammation, obesity, nervous system

BACKGROUND: World Health Organization has reported four million people die every year due to obesity comorbidity, and the prevalence of obesity is keep increasing, especially after COVID-19. Obesity has been defined as a chronic disease involving adipose tissue dysfunction which leads to metabolic diseases and psychosocial consequences. The review article will highlight some recent researches regarding the new conceptual framework that integrates both metabolic drives, as well as to summarize the numerous discussions about the current understanding of hypothalamic control of food intake and energy homeostasis. CONTENT: Obesity apparently is not simply regulated only by food and exercise. Hypothalamus takes part in controlling energy intake and expenditure via appetite regulation. Hedonic control in cortical and subcortical brain areas process cognitive, reward, information, and executive function. Managing metabolic adaptation, browning the white adipose tissue, and preserving lean mass can be another strategy to safely manage obesity. SUMMARY: Obesity need to be managed in a multimodal strategy including neurophysiology and physiology approach, together with environment support. Thus, a weight regain can be prevented. Commitment from both scientific and regulation point of view can shed a light to eradicate obesity. KEYWORDS: adipocyte, appetite, nutrition, obesity, physical activity, reward, satiety

BACKGROUND: Before WHO revoked the emergency use authorization for Chloroquine (CQ) and Hydroxychloroquine (HCQ) because of their side effects, it was suggested to use these two drugs for COVID-19 therapy. In addition, another derivate of quinine, namely Quinine Sulfate (QS), showed good in silico and in vitro antiviral activity against SARS-CoV-2. Prior the WHO revocation, this study was conducted to evaluate the efficacy of QS in mild-to-moderate COVID-19 patients. METHODS: This was an adaptive, controlled, multicenter, randomized, double-blind clinical trial involving mild-to-moderate COVID-19 patients in Indonesia. The participants were divided into 2 groups: the control group (standard COVID-19 treatment + placebo) and the treatment group (standard COVID-19 treatment + QS). The primary outcome was the efficacy of QS based on clinical status using a 7-point ordinal scale. The secondary outcomes were the efficacy of QS in terms of the incidence and duration of oxygen supplementation, incidence of mechanical ventilation, and length of stay. RESULTS: No significant difference in the efficacy parameters studied was found between the control group and the treatment group. The difference in the mean oxygen saturation was also measured and the results showed a significant difference where the treatment group had higher mean oxygen saturation than the control group (p=0.001). CONCLUSION: Although not significant, the treatment group showed better therapy outcomes compared to the control group. KEYWORDS: clinical trials, efficacy, quinine, chloroquine, hydroxychloroquine

IntroductionIn recent years, diverse initiatives have been carried out to control the COVID-19 pandemic, ranging from measures restricting social activities to analyzing drugs and vaccines. Studies on herbal medicines are also increasingly conducted in various countries as an adjuvant therapy or supplement. Therefore, this systematic review aimed to investigate the efficacy of herbal medicines analyzed from various countries through clinical trials with the randomized controlled trial method. The outcomes of Length of Stay (LOS), Negative Conversion Time (NCT), and Negative Conversion Rate (NCR) were the main focus.MethodsAn extensive review of literature spanning from 2019 to 2023 was carried out using well-known databases including PubMed, Scopus, and Cochrane. The search included relevant keywords such as “randomized controlled trial,” “COVID-19,” and “herbal medicine.”ResultsA total of 8 articles were part of the inclusion criteria with outcomes of LOS, NCT, and NCR. In terms of LOS outcomes, all types of herbal medicines showed significant results, such as Persian Medicine Herbal (PM Herbal), Persian Barley Water (PBW), Jingyin Granules (JY granules), Reduning Injection, and Phyllanthus emblica (Amla). However, only JY granules showed significant results in NCR outcome, while JY granules and Reduning Injection showed significant results in reducing NCT.ConclusionThese findings enrich our understanding of the potential benefits of herbal medicines in influencing LOS, NCR and NCT parameters in COVID-19 patients. Herbal medicines worked to treat COVID-19 through antiviral, anti-inflammatory, and immunomodulatory mechanisms.

Background. Obesity is expected to hinder efferocytosis due to ADAM17-mediated cleavage of the MER tyrosine kinase receptor, producing soluble MER (sMER) that disrupts MERTK binding to cell death markers. However, the intracellular efferocytosis pathway in central obesity remains elusive, particularly the role of low-grade chronic inflammation in its initiation and identification of binding signals that disrupt efferocytosis. Objective. We investigate the efferocytosis signaling pathway in men with central obesity and its relationship with inflammation, cell death, and related processes. Methods. A cross-sectional study was conducted, and clinical data and blood samples were collected from 56 men with central obesity (obese group) and 29 nonobese individuals (control group). Clinical evaluations and predefined biochemical screening tests were performed. The efferocytosis signaling pathway was investigated by measuring phosphatidylserine (PS), ADAM17, TNF-alpha (TNF-α), and sMER. Results. Metabolic syndrome was detected in more than half of the participants in the obese group according to the predefined tests. Mean levels of PS, TNF-α, and sMER were higher in the obese group but not significantly different from those of the control group. Further analysis based on waist circumference (WC) ranges in the obese group revealed a significant increase in PS and sMER levels between the control group and the obese group with WC greater than 120 cm. ADAM17 levels were significantly higher in the obese group than in the control group. PS was positively correlated with WC and ADAM17. ADAM17 was positively correlated with TNF-α and sMER, indicating impaired efferocytosis. Conclusions. Central obesity appeared to cause a disturbance in efferocytosis that began with cell damage and death, along with an enlargement of the WC and an ongoing inflammatory response. Efferocytosis was disrupted by proinflammatory cytokine regulators, which induced the production of sMER and interfered with the efferocytosis process.

BACKGROUND: Many chronic disorders, including vascular diseases, metabolic syndrome, and neurological diseases, are known to share a common factor of excessive inflammation. It takes a lot of energy to heal damaged tissue, which is a complicated process. The outcome is often suboptimal, with some degree of fibrosis, depending on the tissue's ability to regenerate and the strength of the inflammatory response. We may get new insights into disease causation and therapeutic strategies by better understanding endogenous regulatory points within the inflammatory response. CONTENT: Despite of the benefit in raising an inflammatory response, it also have unfavourable effects. Unresolved inflammation can over accumulate collagenous connective tissue and induce fibrosis, promote tissue dysfunction, and finally organ failure. Currently, the resolution of inflammation was described in terms of contemporary molecules as a different mechanisms from anti-inflammatory, since in resolution, the pathogen and apoptotic cells crumbs will be cleared and the macrophages will set back the tissue homeostasis. An active transition in the mediators that predominate in exudates occurs in conjunction with the remission of inflammation. These groups of inborn pro-resolution named resolvins, maresins, and protectins work to reduce inflammation by triggering certain pathways that support homeostasis rather than by suppressing the immune system. SUMMARY: The resolution of inflammation, once believed to be a passive process, is now understood to entail active biochemical programs that allow inflamed tissues to regain equilibrium. In this review, we spotlight the resolution to inflammation as a strategy to prevent tissue fibrosis and hinder the organ damage. KEYWORDS: inflammation; resolution; fibrosis; wound healing; specialized pro-resolving mediators.

Abstract Cell death is a basic physiological process that occurs in all living organisms. A few key players in these mechanisms, as well as various forms of cell death programming, have been identified. Apoptotic cell phagocytosis, also known as apoptotic cell clearance, is a well-established process regulated by a number of molecular components, including ‘find-me’, ‘eat-me’ and engulfment signals. Efferocytosis, or the rapid phagocytic clearance of cell death, is a critical mechanism for tissue homeostasis. Despite having similar mechanism to phagocytic clearance of infections, efferocytosis differs from phagocytosis in that it induces a tissue-healing response and is immunologically inert. However, as field of cell death has rapid expanded, much attention has recently been drawn to the efferocytosis of additional necrotic-like cell types, such as necroptosis and pyroptosis. Unlike apoptosis, this method of cell suicide allows the release of immunogenic cellular material and causes inflammation. Regardless of the cause of cell death, the clearance of dead cells is a necessary function to avoid uncontrolled synthesis of pro-inflammatory molecules and inflammatory disorder. We compare and contrast apoptosis, necroptosis and pyroptosis, as well as the various molecular mechanisms of efferocytosis in each type of cell death, and investigate how these may have functional effects on different intracellular organelles and signalling networks. Understanding how efferocytic cells react to necroptotic and pyroptotic cell uptake can help us understand how to modulate these cell death processes for therapeutic purposes.

BACKGROUND: Immunotherapy, particularly the idea of immune checkpoint blockage is currently draw much attention in cancer treatment. It has been approved as an adjuvant, however, it cannot be a single cancer treatment. CONTENT: The discovery of the basic ligand-receptor interactions between immune and cancer cells inside the tumor microenvironment has led to the current interest in immunotherapy, specifically immune checkpoint inhibition. Different ligands produced by cancer cells interact with immune cells' surface receptors, activating inhibitory pathways, such programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), that cause immune cells to become immunologically tolerant. On the other side, epigenetic modulators also play a critical role in enhancing the tumor microenvironment and regaining immunological recognition and immunogenicity. Some findings showed that such immune suppression can be reversed through various mechanisms involving antigens pathways, immune genetic, and epigenetic pathways. These findings have created a very encouraging foundation for research on the combination of epigenetic and immunotherapeutic drugs as cancer treatments. SUMMARY: The effectiveness of this suggested paradigm can only be demonstrated by clinical studies. Epigenetic treatment might replace immune checkpoint therapy as a powerful new cancer care technique that is generally well tolerated and should be proven with adequate clinical trials. KEYWORDS: epigenetics, immunotherapy, PTM, DNMT, HDAC, immune check point

BACKGROUND: Metastases are simply known as cancers spread to another part of the body, and often be responsible for the severity of cancer prognosis. Somehow, the complex mechanisms of metastases are not fully understood yet. CONTENT: The characteristic of cancer is akin to a never-healing wound. Cancer cells are plastic and dynamic as they build their niches and developed into metastases, even when they seem dormant. Therefore, cancer cells can survive the immune system. Recent research has shown the distinct biology of metastasis-initiating cell, which leads to tumor development in distant organs, immune surveillance evasion, and co-option of metastatic micro-environments. Effective cancer therapies must consider the regenerative states of metastatic malignancies and have careful observation of patient phenotypes. SUMMARY: This review aimed to provide an insight on genesis and characteristics of metastases, starting from its seeding and dormancy, until the advance phase. Thus, developing therapy for cancer metastases should not start as it grows, but even as earlier strategies since the primary tumor was detected. KEYWORDS: cancer metastasis, DTC, CTC, CSC, dormancy, pre-metastatic niche, plasticity

BACKGROUND: Metabolism impairment in obese condition usually initially triggered by inflammation and insulin signaling impairment. The involvement of metabolites, including lipids, amino acids, and ketone bodies, in altering insulin sensitivity has been revealed after massive data sets were provided by the studies regarding metabolomics and lipidomics. CONTENT: Metabolites were now understood to serve more than just the metabolism products, but also as active signaling molecules including in insulin and immunological actions. Different lipid metabolites can serve as signaling molecules to induce insulin resistance of sensitivity through a similar pathway, and impact on the inflammation status. Branched Chain Amino Acids (BCAA) and many amino acids have been correlated with mitochondrial dysfunction and insulin impairment. Ketogenic diet, supplementation and microbiota transplantation become the current strategies to set a preferable metabolites composition to modulate insulin sensitivity. SUMMARY: Thousands of metabolites can now be measured using technical and bioinformatics developments. Different types of amino acids, fatty acids, and bile acids are being studied in relation to altered metabolic states, particularly obesity and type 2 diabetes mellitus. A thorough knowledge of the metabolic changes that contribute to insulin resistance might lead to the discovery of new targets for enhancing insulin sensitivity and preventing and treating many metabolic disorders. KEYWORDS: metabolites, insulin resistance, lipids, amino acids, ketone bodies

BACKGROUND: Statins have been used for around three decades as the primary way to lower cholesterol and reduce the risk of atherosclerosis, but in some groups, statin resistance is common, and the danger of atherosclerosis is still high. CONTENT: Atherosclerosis was once believed to be caused by cholesterol and thrombotic material passively accumulating in the walls of arteries. However, current knowledge shows that the immune cells and inflammatory processes are essential in the formation, progression, and consequences of atherosclerotic lesions, characterized by a persistent inflammatory response, including thrombotic complications. Study of genetic, creating risk score for atherosclerosis, add more information to create more new therapies targeting low density lipoprotein cholesterol (LDL-C) receptor, and shows prospect. SUMMARY: Over time, atherosclerosis theories and treatment strategies have changed. While statins were widely used, they have now been supplanted by alternative options like the proprotein convertase subtilisin/kexin type 9 (PSCK9) inhibitor that manage atherosclerosis more effectively and comprehensive. KEYWORDS: atherosclerosis, cholesterol, inflammation, immune system, metabolism

BACKGROUND: Obesity incidence has risen dramatically during the last 50 years, reaching epidemic proportions. Obesity's growing prevalence, as well as its numerous metabolic and cardiovascular problems, poses a danger to human health and lifespan across the world. CONTENT: Numerous studies have shown that obesity causes inflammation, and suggest that inflammation may have a causal role in the development of insulin resistance, defective insulin secretion, and energy homeostasis disturbance. Obesity-induced inflammation is different from other inflammatory models because it includes tonic activation of the innate immune system, which has a long-term influence on metabolic balance. Inflammation can cause tissue damage by causing maladaptive responses such as fibrosis and necrosis. Obesity-induced inflammation is unique since it affects a variety of organs, including the adipose tissue, pancreas, liver, skeletal muscle, heart, and brain. These characteristics of obesity-induced inflammation make it difficult to decipher the underlying processes and how they affect metabolic systems. SUMMARY: The disruption of energy homeostasis caused by a positive energy balance is most likely the first trigger of metabolic inflammation, and the initial adaptive response aim to relieve the anabolic pressure caused by obesity. However, over time, this adaptive reaction becomes maladaptive, and the persistence of inflammation shows that the initial response has failed. The inflammation affects so many organ systems during obesity, and to develop novel treatment methods, a greater knowledge of the process was needed. KEYWORDS: obesity, inflammation, diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular diseases, heart failure

BACKGROUND: Aging is an unavoidable part of life, defined by a gradual loss in tissue and organ function and an increasing chance of death. Current studies of aging connected the genetic and epigenetic changes to cause this process. CONTENT: When the aging-related epigenetic alterations is accumulated, it may result in irregulated gene expression, metabolic instability, stem cell senescence and exhaustion, and imbalance of tissue homeostasis, which all accelerate the aging process. Altered epigenetic gene regulatory mechanisms such as DNA methylation, histone modification and chromatin remodeling, and non-coding RNAs can induce aging process, thus manipulating these processes give a chance for the success of age-delaying interventions. SUMMARY: Given updated tools and technologies to investigate the epigenetic regulation affecting aging processes, new therapeutic strategies to delay this process can be developed to increase longevity and improve quality of life. KEYWORDS: aging, epigenetic, senescence, autophagy, mitochondria, metabolism, rejuvenation

BACKGROUND: Aging tissues lose their homeostatic and regenerative capacities, which has been linked to the degeneration of the stem cells such as the tissue-specific stem cells, the stem cell niches, and systemic cues that regulate stem cell activity. CONTENT: The maintenance of tissue homeostatic and regeneration dependent on its tissue-specific stem cells, that —long-lived cells with the ability to self-renew and differentiate into mature cells. Understanding the molecular mechanisms that governs stem cell survival, self-renewal, quiescence, proliferation, and commitment to specific differentiated cell lineages is critical for identifying the drivers and effectors of age-associated stem cell failure. Such understanding will be critical for the development of therapeutic approaches that can decrease, and possibly reverse and repair the age-related degenerative process in aging tissues. SUMMARY: The exact mechanisms and reasons of aging process were not fully elucidated until now. Stem cells is one of the keys for maintaining tissues heath and understanding how stem cell decline with age will give us opportunities to find strategy in increasing somatic stem cells regenerative capacity and delay the aging process. KEYWORDS: adult stem cell, aging, epigenetic, metabolism, quiescence, senescence

BACKGROUND: Mitochondria became a driving force in evolution due to their ability to manufacture adenosine triphosphate (ATP) through respiration. The functioning of mitochondria within eukaryotic cells has evolved dramatically as a result of evolution. Recent research has revealed mitochondria form plasticity to keep the cell's needs and function. CONTENT: Mitochondria have long been regarded as the cell's "powerhouse," providing energy for cell metabolism through oxidative phosphorylation (OXPHOS). A lot of physiological processes were known to be mediated by mitochondria including immunity and autophagy, cell death mechanism, and stem cell reprogramming. Mitochondria can change their shape to form a tubular network that is controlled by fission and fusion processes. Mitochondrial dynamics is the equilibrium between these two opposing processes that regulates mitochondrial number, size, and positioning within the cytoplasm. SUMMARY: All of these discoveries opened up new research avenues and revealed new targets for targeted medication development. Calorie restriction, and the mimetic agents were developed to increase mitochondria biogenesis to improve human lifespan. KEYWORDS: mitochondria, metabolism, homeostasis, stress response, aging, epigenetic

BACKGROUND: Millions of cells in multicellular organisms regenerate every day to replace aged and died cells. Effective cell clearance (efferocytosis) is critical for tissue homeostasis, as the human body recycles its cellular components. We summarize what is known about the mechanisms of efferocytosis and how it impacts the physiology of the organism, effects on inflammation and the adaptive immune response, as well as the consequences of defects in this critical homeostatic mechanism in this review. CONTENT: Cell death is the process by which the human body replaces aged or damaged cells with new ones. It can be triggered by genetically encoded machinery or regulated cell death, or by specific pharmacologic or genetic interventions, resulting in accidental cell death. Dying cells release signals that entice phagocytes to engulf them in a process known as efferocytosis. Efferocytosis is a multistep process involving the release of “find me” and “eat me” signals and destruction of death cells by phagocytes. Different types of cell death including apoptosis and necroptosis can express pro- or anti-inflammatory signals via macrophage activity modulation. SUMMARY: Failed or ineffective efferocytosis can result in disruption of tissue homeostasis, which can contribute to the development of chronic inflammatory diseases such as atherosclerosis, obesity, diabetes, and heart failure. Therefore, any therapeutic strategy that enhances efferocytosis will have a beneficial effect on the treatment of these metabolic disorders. KEYWORDS: apoptosis, necroptosis, phagocytosis, efferocytosis, macrophage.

Compared to the normal tissues, cancer cells tend to have higher proliferation rate and often lost their ability to undergo apoptosis. In addition, cancer cells can separate themselves from their original tissue thus causing metastasis in other part of body. While undergoing program cell death, disordered cellular programming can happen. The main causes of this cellular programming anomaly are epigenetic and genetic alterations, which have been known as two separate mechanisms in carcinogenetic. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disturb the DNA methylation patterns, histone modifications, and nucleosome positioning, hence, the causing gene expression alternation. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. Epigenetic mechanisms changes could cause genetic mutations, and genetic mutations in epigenetic regulators could cause epigenome changes. Knowing that epigenome play a major role in the hierarchy of gene control mechanisms suggests that mutations might have impact on multiple pathways related to cancer phenotype. This pinpoint the fact that recently, the way the genes are organized and controlled are suggested to be a relevant factor for human carcinogenesis. Keywords: cancer genetic, cancer epigenetic, oncogens, tumor suppressor genes, driver mutation, passenger mutation

BACKGROUND: A lot of contemporary cancer research has concentrated on genetic influence. However, cancer also involves biochemical changes, such as metabolic adaptation to support the aberrant cell proliferation. CONTENT: The fast cell proliferation in cancer cells enforce a metabolic re-arrangement to promote their long-term survival. The increased glucose uptake and fermentation of glucose to lactate are common features of this altered metabolism known as “the Warburg effect”. These metabolic pathways regulation enable cancer cells to produce adenosine triphosphate (ATP) in an efficient way. Epigenetic and metabolic changes also both affect molecular rewiring in cancer cells and promote cancer development and progression. SUMMARY: Metabolic rewiring and epigenetic remodeling establishing a direct link between metabolism and nuclear transcription to promote the survival of tumor cells. A further understanding of how metabolic remodeling can result in epigenetic changes in tumors, affecting cancer cell differentiation, proliferation, and/or apoptosis, will lead to a new strategy for cancer therapy. KEYWORDS: cancer metabolism, epigenetics, metabolic reprogramming, molecular rewiring

BACKGROUND: Metabolomics is a developed technology that comprehensively analyzes the metabolites in biological specimens. It appears to be a prospective method in the practice of precision medicine. CONTENT: Metabolomic technologies currently surpass beyond the traditional clinical chemistry techniques. Metabolomic is capable to perform a precise analysis for hundreds to thousands of metabolites, therefore provide a detailed characterization of metabolic phenotypes and metabolic derangements that underlie disease, to represent an individual’s overall health status, furthermore to discover new precise therapeutic targets, and discovery of biomarkers, either for diagnosis or therapy monitoring purpose. SUMMARY: Adequate data processing and quantification methods are still needed to be developed to boost integrated -omics as a powerful clinical practice platform. KEYWORDS: metabolomic, precision medicine, phenotyping, biomarker, nutritional pattern

BACKGROUND: Hormesis was initially defined as a phenomenon where a small dose of harmful agent exposure to living organisms gives beneficial effects. The dose and time of this ‘tress’ exposure has become the object of investigation across the broad range of biomedical studies. CONTENT: Hormesis characterized by the biphasic dose-effect or time-effect relationship for any substance. Some hormetic mechanisms performed biological plasticity, involve oxidative damage which instead induce antioxidant enzyme production in various cells. Early-life stress can increase resilience in later life and lack of stress can lead to vulnerability. Many stressors like dietary factors and natural environmental toxins can be occupied for healthy growth or homeostasis, which exemplifies how illness is the doorway to health. SUMMARY: Hormesis reconcile many paradoxical phenomena exert opposite effects of the same substance, either a xenobiotic or an endogenous substance, a hormone or a metabolite, a genetic manipulation or an epigenetic alteration, an experimental intervention or a natural event. Human bodies are highly adaptive. A resilient body would be resulted after the ‘training’. In this review, we will elucidate the hormesis’ definition, mechanisms and pathways, and also how hormesis impacts in human health and lifespan. KEYWORDS: biphasic, cell signaling, dose response, hormesis, preconditioning

BACKGROUND: Hypothalamus is the master regulator of body’s systemic homeostasis including energy balance, body temperature, sleep, blood pressure, and circadian rhythms. This review article will highlight the shifting of the old paradigm of obesityinflammation-metabolic syndrome, which was focused on visceral organs and systemic inflammation, into a new model involving microinflammation in the master regulator of endocrine system, i.e., hypothalamus. CONTENT: Since the early stage of over-nutritional conditions and aging process, microinflammation in hypothalamus has started to emerge, due to the activation of several proinflammatory signaling pathways, especially the nuclear factor kappa B (NF-kB) and c-Jun N-terminal kinase (JNK)-mediated nuclear transcriptional programs. Together with intracellular organelle stress signals, these pathways develop a chronic microinflammatory environment in the hypothalamus leading to obesity and metabolic disorders. SUMMARY: Hypothalamic inflammation has been noted not only as an important driver of impaired energy balance, but also contribute in altered neurocircuit functions and promote obesity-associated metabolic impairment. KEYWORDS: hypothalamus, inflammation, metabolism, obesity, metabolic syndrome

BACKGROUND: Since our conception to death, we were permanently exposed to nutrition. Indeed, food intake is the key of the environmental factor that modulates our gene. Nutrigenomics focus on how common dietary chemicals altering an individual’s genetic makeup including genome, proteome, and metabolome. While nutrigenetics refer to how the genetic variation gives different responses to nutrients. CONTENT: Nutrigenomics applied the high-throughput genomic-related tools to find out the influence of nutrients on the genes’ expression. While nutrigenetics (nutritional genetics) focus on the heterogenous response of gene variants to nutrients and dietary factors. Application nutrigenomics and nutrigenetics, integrated with system biology result in a precision nutrition as a relevant precise personal dietary change recommendation, thus will increase the motivation and sustain to whom the intervention is being delivered. SUMMARY: Individual diet recommendation is not simple. Many factors and tools should be involved adequately. The application of integrated -omics approaches, together with nutrigenomic and nutrigenetics for novel biomarker discovering and precision nutrition tailoring were expected to develop a healthier lifestyle and behavior. KEYWORDS: nutrigenetics, nutrigenomics, precision nutrition, metabolomics, system biology

BACKGROUND: Obesity has been decades become a highly interest study, accompanied by the realization that adipose tissue (AT) plays a major role in the regulation of metabolic function. CONTENT: In past few years, adipocytes classification, development, and differentiation has been significant changes. The white adipose tissue (WAT) can transform to a phenotype like brown adipose (BAT) type and function. Exercise and cold induction were the most common factor for fat browning; however batokines such as fibroblast growth factor (FGF)-21, interleukin (IL)-6, Slit homolog 2 protein (SLIT2)-C, and Meteorin-like protein (METRNL) perform a beneficial browning action by increasing peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α protein levels, a key factor to stimulate mitochondrial biogenesis and uncoupling Protein 1 (UCP1) transcription, thus change the WAT phenotype into beige. SUMMARY: AT recently known as a complex organ, not only bearing a storage function but as well as the master regulator of energy balance and nutritional homeostasis; brown and beige fat express constitutively high levels of thermogenic genes and raise our expectation on new strategies for fighting obesity and metabolic disorders. KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, inflammation, IR, metabolic disease

BACKGROUND: Along with its increased prevalence, in the past decade, cancer had joined the list of chronic debilitating diseases. Nutrition become substantial aspects, due to its time-dependent effect to modulate inflammation thus trigger carcinogenic effects by altering the immune check point. Thus, nutrition contributes to the progression and therapeutic response of cancer, both in human or animal models. CONTENT: Meat is well favored food with appreciable appealing. Due to its high nutritional values it plays a central role in human development. Meat or meat derivate are important sources of proteins, minerals and vitamins. Their nutritional importance is worth compare to their economic impact but recent publication of WHO has set the social alarm about the relationship between red and/or processed meat consumption and cancer. On the other side, some natural or biologic agents may inhibit or reverse tumor growth. Some phytochemical agents including curcumin, resveratrol, lycopene, folates and tea polyphenols clinically proved to tune the signaling pathways regulating cell proliferation and apoptosis in transformed cells, enhance the host immune system and sensitize malignant cells to cytotoxic agents. SUMMARY: Recent studies on chemopreventive agents involves a wide range of molecules, natural (plants, fruits and vegetables) or synthetic will provide better insights for cancer early pathogenesis, important end-point biomarker, and finally potential for reducing the burden of cancer. KEYWORDS: blocking agents, suppressing agents, red meat, processed meat, chemoprevention, phytochemicals

BACKGROUND: Mesenchymal stem (stromal) cells (MSCs) have a multipotent character, able to differentiate into several cell types, thus MSC serve as a cell reservoir for regenerative medicine. MSC therapeutic potency more associated to their immunosuppressive and anti-inflammatory properties rather than the multipotency, by its mechanism to secrete soluble factors with paracrine actions. CONTENT: MSC paracrine function was known to mediated partly by extracellular vesicles (EVs), which were released predominantly from the endosomal compartment contained in MSC secretome. EV contain a cargo bring micro RNA (miRNA), messenger RNA (mRNA), and proteins from their cells of origin, propose EV as a novel alternative to whole cell therapies, regarding the benefit of EV in safety and easier storage compared to the parent cells. SUMMARY: The discovery of EVs including exosomes in MSC secretome as key of stem cells beneficial function lead to the future hope of using cell-free regenerative therapies. KEYWORDS: MSC, secretome, conditioned media, extracellular vesicle, exosome

BACKGROUND: Giant transformations are going on currently in health care, and the greatest force behind this phenomenon is data. CONTENT: Big data has arrived into medicine field, lead to potential enhancement in accountability, quality, efficiency, and innovation. Most updated, artificial intelligence (AI) and machine-learning (ML) techniques rapidly developed, bring forth the big data analysis into more useful applications, from resource allocation to complex disease diagnosis. To realize this, a very large set of health-care data is needed for algorithms training and evaluation, including patients’ treatment data, patients respond to treatment, and personal patient information, such as genetic data, family history, health behavior, and vital signs. SUMMARY: Precision Health involving preventive, predictive, personalized and precise. The arrival of AI and ML will enhance and facilitates the improvement of this relationship through better accuracy, productivity, and workflow, thus develop a health system that will go beyond just curing disease, but further into wellness that preventing disease before it strikes, thus the patient–doctor bond is expected to be reformed and not be eroded. KEYWORDS: artificial intelligence, machine learning, deep learning, electronic health records, big data

BACKGROUND: Altered epigenetics is regarded to play quite a role in many chronic diseases including cancer, diabetes, obesity, dyslipidemia, hypertension and neurodegeneration, hence nutrition suggested to contribute in epigenetics and disease. CONTENT: Histone modifications, as a part of epigenetics mechanisms, depend on metabolites which acts as cofactors or substrates. Fluctuating levels of specific metabolites become the direct and rapid mechanisms to influence gene activity. Therefore, these metabolites may have a role as gatekeepers of chromatin, in chromatin landscape modulation as a response to key nutritional cues. Chemical modifications of histones and DNA have a critical role in epigenetic gene regulation including histone acetylation, and DNA methylation. Some enzymes add or remove such chemical modifications, and suggested to be sensitive to changes in intracellular metabolism, such as mutations in the metabolic enzymes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) can result in cancer. SUMMARY: As a response to their nutrient environment, organisms tend to rapidly alter their gene expression. Many evidences showed an epigenetic regulation of chromatin is coupled to the changes on metabolites levels due to this kind of response. These metabolites will lead the recruitment of transcriptional regulatory complexes to DNA, thus clearly influencing the dynamic chromatin landscape. KEYWORDS: metabolites, enzymes, epigenetics, chromatin, nutrition

BACKGROUND: Mitochondrial dysfunction known to be associated with most of human inherited disorders and diseases, including neurodegenerative disorders, cardiomyopathies, metabolic syndrome, muscle weakness, cancer, also obesity. CONTENT: Mitochondria charges for multiple anabolic and catabolic circuitries, as the main provider for adenosine triphosphate (ATP). Mitochondria also responsible for cellwide stress responses and control non-apoptotic cell death routines, such as autophagy and regulated necrosis. In other words, mitochondria play an extended role in regulating cellular functions, both vital and lethal, from physiological metabolism to stress responses and death to maintain adult tissue homeostasis. Furthermore, mitochondria are crucial for both embryonic and postembryonic development. Therefore, any defect or alteration in mitochondria signaling pathways will lead to a large number of diseases in human, including premature aging, neurodegenerative disorders, muscle weakness, cardiovascular disorders, and cancer. SUMMARY: Mitochondria perform a dynamic, integrated interconnected network, to maintain tissue homeostasis, beyond the cell boundaries and regulating cells and tissues communication. Certainly any mitochondrial dysfunction could direct to neurodegenerative diseases and metabolic disorders. KEYWORDS: mitochondria, UPR, mitochondrial quality control, proteostasis, mitohormesis, mitochondrial diseases

BACKGROUND: The mechanism of aging goes along with age, one of which is characterized by cellular senescent, which occurs mostly in adipose tissue. Adipose tissue is the site of accumulation of large cell senescent, in the regulation of obesity and aging. Proteins p53 is marker for cell senescent, which are also known to induce inflammation. This study was aimed to determine the relationship between circulating protein p53 and high sensitivity C-reactive protein (hsCRP) in central obese men with inflammaging. METHODS: The study design is an observational study with cross-sectional approach. The subjects were 75 central obese men (waist circumference/WC > 90 cm), aged ≥ 45 years old. Subjects were divided into 2 age groups, those are middle age group: 45-59 years old (50.7%) and elderly group: ≥ 60 years old (49.3%). Examination of circulating p53 was done using enzyme-linked immunosorbent assay (ELISA) method, and the hsCRP examination was done by chemiluminescent method. RESULTS: It was found that there was a correlation between circulating p53 and hsCRP in elderly (r=-0.414; p

BACKGROUND: Current understanding in molecular character of natural killer (NK) cell, its function and mechanisms, send people the ideas to develop a NK cell-based immunotherapeutic strategies against human cancer. CONTENT: Before being regards as a cell-based cellular therapy, NK cell have to be clinical proven. Early studies with NK cells infusions for acute myeloid leukemia and lung cancer showed a promising result. NK cells need simplified methods for enriching and expanding, in addition to its transfection with chimeric antigen receptors (CARs). NK-92 arise as an assuring effector cells to augment monoclonal and bispecific antibody therapy. Thus, NK cells show a potential opportunity for cell engineering, outstep the era of T cells. SUMMARY: It is believed that NK cells bring a bright hope for future cancer immunotherapies, either alone or in combination as a harmonious therapy. KEYWORDS: NK cells, NK-92 cells, immunotherapy, CAR

BACKGROUND: Current cancer drugs and treatments are aiming at eradicating tumor cells, but often are more toxic then effective, killing also the normal cells and not selectively the tumor cells. There is good personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity, which called adoptive cell therapy (ACT). A review of the unique biology of T cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities. CONTENT: Chimeric antigen receptors (CAR) are recombinant receptors which provide both antigen-binding and T cell-activating functions. Many kind of CARs has been reported for the past few years, targeting an array of cell surface tumor antigens. Their biologic functions have extremely changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. The combination of CARs with costimulatory ligands, chimeric costimulatory receptors, or cytokines can be done to further enhance T cell potency, specificity and safety. CARs reflects a new class of drugs with exciting potential for cancer immunotherapy. SUMMARY: CAR-T cells have been arising as a new modality for cancer immunotherapy because of their potent efficacy against terminal cancers. They are known to exert higher efficacy than monoclonal antibodies and antibodydrug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors. KEYWORDS: chimeric antigen receptor, CAR-T cells, adoptive cell therapy, ACT, T cell receptor, TCR, cancer, immunotherapy

BACKGROUND: Atherosclerosis is a leading cause of vascular disease worldwide. During the past several decades, landmark discoveries in the field of vascular biology have evolved our understanding of the biology of blood vessels and the pathobiology of local and systemic vascular disease states and have led to novel disease-modifying therapies for patients. This review is made to understand the molecular mechanism of atherosclerosis for these future therapies. CONTENT: Advances in molecular biology and -omics technologies have facilitated in vitro and in vivo studies which revealed that blood vessels regulate their own redox milieu, metabolism, mechanical environment, and phenotype, in part, through complex interactions between cellular components of the blood vessel wall and circulating factors. Dysregulation of these carefully orchestrated homeostatic interactions has also been implicated as the mechanism by which risk factors for cardiopulmonary vascular disease lead to vascular dysfunction, structural remodeling and, ultimately, adverse clinical events. SUMMARY: Atherosclerosis is a heterogeneous disease, despite a common initiating event of apoB-lipoproteins. Despite of acute thrombotic complications, an adequate resolution response is mounted, where efferocytosis prevents plaque necrosis and a reparative scarring response (the fibrous cap) prevents plaque disruption. However, a small percentage of developing atherosclerotic lesions cannot maintain an adequate resolution response, which leading to the formation of clinically dangerous plaques that can trigger acute lumenal thrombosis and tissue ischemia and infarction. KEYWORDS: atherosclerosis, oxidative stress, inflammation, efferocytosis, foam cells, thrombosis

BACKGROUND: The strong inverse association of plasma levels of high-density lipoprotein cholesterol (HDL-C) with coronary heart disease (CHD) found in human epidemiological studies led to the development of the ‘HDL-C hypothesis’, which posits that intervention to raise HDL-C will result in reduced risk of CHD. However, recent evidence has raised doubts about the hypotheses that elevating HDL-C is necessarily therapeutic. Genetic variations that associate with altered HDL-C do not strongly associate with altered cardiovascular disease risk. CONTENT: HDL-mediated cholesterol efflux from macrophage foam cells or measurements of the flux of cholesterol from macrophages to the liver and feces seem to correlate better with atherosclerotic burden than with HDL-C levels. Thus, it may be time to modify the HDL-C hypothesis to the ‘HDL flux hypothesis’, where intervention to promote cholesterol efflux and reverse cholesterol transport will reduce CHD risk, regardless of whether it affects plasma HDL-C levels. A deeper understanding of the complex biology of HDL metabolism and its relationship to reverse cholesterol transport and atherothromobotic events is urgently needed. This might lead to biomarkers of HDL flux and functionality that are more informative than simple measurements of HDL-C levels. SUMMARY: It is now clear from recent clinical trial and genetic studies that some approaches to raising HDL-C levels may have no effect on CHD. This suggests the need to evaluate HDL-C-raising therapies in different clinical populations, as well as therapies targeted toward HDL flux and function rather than simply HDL-C elevation. Perhaps moving from a focus on the HDL-C hypothesis to a focus on the HDL flux hypothesis will permit a biologically based reassessment of the optimal therapeutic approach to targeting HDL for reduction in cardiovascular risk. KEYWORDS: reverse cholesterol transport, cholesterol efflux capacity, HDL dysfunction, HDL particle size, HDL lipidomics, HDL proteomics

BACKGROUND: Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs). CONTENT: The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer’s disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optica lmicroscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival. SUMMARY: Senescent cells and their senescence-associated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs. KEYWORDS: brain, aging, neurodegeneration, DNA damage, senescence, neuro-inflammation, mitochondria, lysosome, proteostasis, prion, amyloidosis

BACKGROUND: Low back pain (LBP) mostly caused by disc degeneration, reflects to a tremendous of health care system and economy. More knowledge about these underlying pathologies will improve the opportunities that may represent critical therapeutic targets. CONTENT: Basic research is advancing the understanding of the pathogenesis and management of LBP at the molecular and genetic levels. Cytokines such as matrix metalloproteinases, phospholipase A2, nitric oxide, and tumor necrosis factor-α are thought to contribute to the development of LBP. Mesenchymal stem cells (MSCs) transplant to cartilage-like cells and secrete extracellular matrix and encourage nucleus pulposus (NP) cell activity inhibiting NP cell apoptosis, together with some chemical mediators such as cytokines and growth factors become a safe and effective new strategy for intervertebral disc degeneration (IDD) treatment and regeneration. SUMMARY: IDD occurs where there is a loss of homeostatic balance with a predominantly catabolic metabolic profile. A basic understanding of the molecular changes occurring in the degenerating disc is important for practicing clinicians to help them to inform patients to alter lifestyle choices, identify beneficial or harmful supplements, or offer new biologic, genetic, or stem cell therapies. KEYWORDS: low back pain, intervertebral disc, degeneration, nucleus pulposus, annulus fibrosus, extracellular matrix, genetic, stem cells

BACKGROUND: Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease. CONTENT: Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1b in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. SUMMARY: The aging myocardium with telomere shortening and accumulation of senescent cells restricts the tissue regenerative ability, which contributes to systolic or diastolic heart failure. Moreover, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments. KEYWORDS: aging, telomere, telomerase, aging heart, mitochondria, cardiac stem cell

BACKGROUND: The number of elderly population in the world keep increasing. In their advanced ages, many elderly face years of disability because of multiple chronic diseases, frailty, making them lost their independence. Consequently, this could have impacts on social and economic stability. A huge challenge has been sent for biomedical researchers to compress or at least eliminate this period of disability and increase the health span. CONTENT: Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human diseases. Accelerated telomere erosion was clearly correlated with a pack of metabolic and inflammatory diseases. Critically short telomeres or the unprotected end, are likely to form telomeric fusion, generating genomic instability, the cornerstone for carcinogenesis. Enlightening how telomeres involved in the mechanisms underlying the diseases’ pathogenesis was expected to uncover new molecular targets for any important diagnosis or therapeutic implications. SUMMARY: Telomere shortening was foreseen as an imporant mechanism to supress tumor by limiting cellular proliferative capacity by regulating senescence check point activation. Many human diseases and carcinogenesis are causally related to defective telomeres, asserting the importance of telomeres sustainment. Thus, telomere length assessment might serve as an important tool for clinical prognostic, diagnostic, monitoring and management. KEYWORDS: telomerase, cellular senescence, aging, cancer

BACKGROUND: The introduction of mechanism based targeted therapies to treat human cancers has been pledge as one of the results of three decades of remarkable progress of research into the mechanisms of cancer pathogenesis. We ponder how the description of hallmark principles is start to inform therapeutic development currently and may increasingly do so in the future. CONTENT: There are 10 biological capabilities involved as the hallmarks of cancer, during the multistep of human tumors development. These hallmarks simplify the complexities of neoplastic disease into a structured rational principles, includes sustaining proliferative signaling, eluding growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genome instability, inflammation, reprogramming energy metabolism and evading immune destruction. SUMMARY: The 10 hallmarks of cancer, in other words, the tumor’s distinctive and complementary capabilities that enable its growth and metastatic dissemination, continue to provide a solid foundation for understanding the biology of cancer. The acknowledgment of the widespread applicability of these concepts will increasingly influence the development of new manners to treat human cancer. KEYWORDS: hallmark of cancer, cancer genome, inflammation, cancer immunology, metastasis

BACKGROUND: Recently established genome editing technologies will open new avenues for biological research and development. Human genome editing is a powerful tool which offers great scientific and therapeutic potential. CONTENT: Genome editing using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPRassociated protein 9 (Cas9) technology is revolutionizing the gene function studies and possibly will give rise to an entirely new degree of therapeutics for a large range of diseases. Prompt advances in the CRISPR/Cas9 technology, as well as delivery modalities for gene therapy applications, are dismissing the barriers to the clinical translation of this technology. Many studies conducted showed promising results, but as current available technologies for evaluating off-target gene modification, several elements must be addressed to validate the safety of the CRISPR/Cas9 platform for clinical application, as the ethical implication as well. SUMMARY: The CRISPR/Cas9 system is a powerful genome editing technology with the potential to create a variety of novel therapeutics for a range of diseases, many of which are currently untreatable. KEYWORDS: genome editing, CRISPR-Cas, guideRNA, DSB, ZFNs, TALEN

BACKGROUND: Recent advances in our basic knowledge of the tissue damage and regeneration pathology have combined with a remarkable progress in stem cell biology so the prospect of clinical tissue repair strategies is a tangible reality. We tried to describe a better view about mesenchymal stem cell (MSC) mechanisms in wound healing and tissue regeneration, sending any ideas for next advanced therapies. CONTENT: Sustaining injury, whether minor or major, is part of every organism life. Therefore, efficient response mechanisms to damage have developed. Wound healing is a perplexing multi-step processes which can be divided into three major phases: inflammation, proliferation, and scar formation/remodeling. Though the compartementalization of this process into discrete stages give the illusion of simplicity, but in reality it is much more complicated. So that efficient healing can occur, complex interactions between multiple cell types, soluble factors and extracellular matrix components are required to rebuild the tissue. Even under optimal conditions, the healing process drives to fibrosis or scar. The latest technology that makes a huge difference in the wound healing process is stem cell therapy, which offers a novel approach to many diseases. SUMMARY: Wound healing therapies continue to rapidly evolve, with advances in basic science and engineering research heralding the development of new therapies, as well as ways to modify existing treatments. Stem cell-based therapy is one of the most promising therapeutic concepts for wound healing. Advances in stem cell biology have enabled researchers and clinicians alike with access to cells capable of actively modulating the healing response. KEYWORDS: wound healing, tissue regeneration, stem cells therapy

BACKGROUND: Current findings set a new understanding that every adult tissue has its own intrinsic progenitor or stem cell, give a potency for their innate turnover dynamics. This broke the old assumption that adult tissues cannot regenerate themselves. Localized tissue regeneration was regulatory oversight by a separate class of local cells originating as perivascular cells, suggested a profound influence on using specific cells for cell therapies as a health care delivery tool set. CONTENT: The mesenchymal stem cell (MSC) could be mobilized from the marrow or other depots or can be culture-expanded MSCs which are delivered to the damage site either by direct or systemic injection. MSCs act paracrine and autocrine by inducing a variety of cytokines and growth factors which suppress local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis, and stimulate mitosis and differentiation of tissue, intrinsic reparative or stem cells. These referred a trophic effects, different from the direct differentiation of MSCs into repair tissue. Thus, MSC suggested as a multidrug delivery vehicles in response of injury. In this regard, the trophic effects of MSCs may have profound clinical use. SUMMARY: Managing the body’s natural repair and regeneration capacities is the new frontier for modern medicine and the basis for the science of cell therapies. Study of MSCs become one avenue that being pursued to explore the endogenous tissue regeneration management, so that people have a great expectation to solve many severe diseases. KEYWORDS: mesenchymal stromal/stem cell, paracrine or autocrine activities, trophic mediator, inflammation, wound healing

BACKGROUND: Cancer is a disease of genomic instability, evasion of immune cells, and adaptation of the tumor cells to the changing environment. Genetic heterogeneity caused by tumors and tumor microenvironmental factors forms the basis of aggressive behavior of some cancer cell populations. CONTENT: Cancers arise in self-renewing cell populations and that the resulting cancers, like their normal organ counterparts, are composed of hierarchically organized cell populations. Self–renewing “cancer stem cells” (CSC) maintain tumor growth and generate the diverse populations constituting the tumor bulk. CSCs in multiple tumor types have been demonstrated to be relatively resistant to radiation and chemotherapy. The clinical relevance of these studies has been supported by neoadjuvant breast cancer trials that demonstrated increases in the proportions of CSCs after therapy. The CSC hypothesis has tremendously important clinical implications. SUMMARY: In summary, a large and accumulating body of evidence supports the CSC hypothesis, which has important implications for cancer prevention and therapy. The ultimate test of this hypothesis will require clinical trials demonstrating that targeting of these pathways reduces cancer incidence and improves outcomes for patients with cancer. KEYWORDS: Somatic mutation, tumor heterogeneity, metastasis, epithelial-mesenchymal transition, CSC niche

BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy. CONTENT: During immune surveillance, the host provides defense against foreign antigens, while ensuring it limits activation against self antigens. By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. The use of antibodies to block pathways inhibiting the endogenous immune response to cancer, known as checkpoint blockade therapy, has stirred up a great deal of excitement among scientists, physicians, and patients alike. Clinical trials evaluating the safety and efficacy of antibodies that block the T cell inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) have reported success in treating subsets of patients. Adoptive cell transfer (ACT) is a highly personalized cancer therapy that involve administration to the cancer-bearing host of immune cells with direct anticancer activity. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment. SUMMARY: For cancer treatment, 2011 marked the beginning of a new era. The underlying basis of cancer immunotherapy is to activate a patient’s own T cells so that they can kill their tumors. Reports of amazing recoveries abound, where patients remain cancer-free many years after receiving the therapy. The idea of harnessing immune cells to fight cancer is not new, but only recently have scientists amassed enough clinical data to demonstrate what a game-changer cancer immunotherapy can be. This field is no stranger to obstacles, so the future looks very promising indeed. KEYWORDS: immune checkpoint, adoptive cell transfer, neoantigen, monoclonal antibody

BACKGROUND: Obesity-induced inflammation contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disease. CONTENT:The last decade has seen a sharp increase in our appreciation for the macrophage as a critical regulator of metabolic status in obesity. Activation of adipose tissue (AT) macrophages within fat depots is coupled with the development of obesity-induced proinflammatory state and insulin resistance (IR). The activation of classically activated M1 macrophages at the expense of anti-inflammatory M2 macrophages has been causally linked to the development of AT inflammation and metabolic syndrome, a pathophysiological state aptly termed as ‘metainflammation’. It is recognized that several proinflammatory cytokines, including interleukin (IL)-1β, are implicated in disrupting insulin signaling. Our developing appreciation of links among obesity, inflammation and cardiovascular disease will require multiple complementary approaches to leverage new concepts into translatable outcomes. Careful characterization of human patients, particularly analysis of AT distribution, will be needed to stratify subjects that are most likely obese/metabolically healthy from those that are obese/metabolically unhealthy. SUMMARY: It has been suggested that individuals with the condition known as metabolically healthy obese (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non-metabolically healthy counterparts. A complications-centric model for the medical management of obesity emphasizes the identification and staging of complications, and treatment paradigm directed at patients who would gain the most benefit from weight loss. KEYWORDS: obesity, inflammation, insulin resistance, M1/M2 macrophage.

BACKGROUND: Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabolism. Moreover, disruption of circadian rhythms leads to obesity and metabolic disorders. CONTENT:Regularly alternating periods of light and darkness, such as normally occur with the rising and the setting of the sun, are essential for the maintenance of undisturbed circadian rhythms in all organisms including humans. The light-dark environment, as detected by specialized photoreceptors in the retinas, impacts the endogenous circadian clock in the anterior hypothalamus, the suprachiasmatic nuclei. These nuclei, via both neural and humoral signals, communicate with cells throughout the organism to establish regular circadian rhythms. The introduction of artificial sources of light roughly 150 years ago has significantly undermined the naturally occurring light-dark environment and, likewise, has disturbed circadian rhythms since light is now available at unusual times, i.e., at night. Light at night is known to cause circadian disruption and melatonin suppression. Many potentially pathophysiological consequences of these artificial light-mediated changes, include cancer, cardiovascular diseases, insomnia, metabolic syndrome, diabetes, and cognitive disorders may be aggravated by the increased exposure to light at night, which is inevitable in well-developed societies that have undergone extensive electrification. SUMMARY: Therefore, it is plausible that resetting of the circadian clock can be used as a new approach to attenuate obesity. Feeding regimens, such as restricted feeding, calorie restriction and intermittent fasting, provide a time cue and reset the circadian clock and lead to better health. In contrast, high-fat diet leads to disrupted circadian expression of metabolic factors and obesity. KEYWORDS: obesity, circadian clock, metabolism, chronodisruption.

BACKGROUND: Age-related muscle loss leads to lack of muscle strength, resulting in reduced posture and mobility and an increased risk of falls, all of which contribute to a decrease in quality of life. Skeletal muscle regeneration is a complex process, which is not yet completely understood. CONTENT: Skeletal muscle undergoes a progressive age-related loss in mass and function. Preservation of muscle mass depends in part on satellite cells, the resident stem cells of skeletal muscle. Reduced satellite cell function may contribute to the age-associated decrease in muscle mass. Recent studies have delineated that the aging process in organ stem cells is largely caused by age-specific changes in the differentiated niches, and that regenerative outcomes often depend on the age of the niche, rather than on stem cell age. It is likely that epigenetic states will be better define such key satellite cell features as prolonged quiescence and lineage fidelity. It is also likely that DNA and histone modifications will underlie many of the changes in aged satellite cells that account for age-related declines in functionality and rejuvenation through exposure to the systemic environment. SUMMARY: Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Decreased muscle stem cell function in aging has long been shown to depend on altered environmental cues, whereas the contribution of intrinsic mechanisms remained less clear. Signals in the aged niche were shown to cause permanent defects in the ability of satellite cells to return to quiescence, ultimately also impairing the maintenance of self-renewing satellite cells. Therefore, only anti-aging strategies taking both factors, the stem cell niche and the stem cells per se, into consideration may ultimately be successful. KEYWORDS: satellite cell, muscle, aging, niche, regenerations.

BACKGROUND: Recent evidence suggested that we grow old partly because of our stem cells grow old as a result of mechanisms that suppress the development of cancer over a lifetime. We believe that a further, more precise mechanistic understanding of this process will be required before this knowledge can be translated into human anti-aging therapies. CONTENT: A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of aging. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to aging. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. It is interesting that many of the rejuvenating interventions act on the stem cell compartments, perhaps reflecting shared genetic and biochemical pathways controlling stem cell function and longevity. Strategy to slow down the aging processes is based on caloric restriction refers to a dietary regimen low in calories but without undernutrition. Sirtuin (SIRT)1 and 3, increases longevity by mimicking the beneficial effects of caloric restriction. SIRT3 regulates stress-responsive mitochondrial homeostasis, and more importantly, SIRT3 upregulation rejuvenates aged stem cells in tissues. Resveratrol (3,5,4’-trihydroxystilbene), a natural polyphenol found in grapes and wine, was the most powerful natural activator of SIRT1. In fact, resveratrol treatment has been demonstrated to rescue adult stem cell decline, slow down bodyweight loss, improve trabecular bone structure and mineral density, and significantly extend lifespan. SUMMARY: Tissue-specific stem cells persist throughout the entire lifespan to repair and maintain tissues, but their self-renewal and differentiation potential become dysregulated with aging. Given that adult stem cells are thought to be central to tissue maintenance and organismal survival, SIRT3 may promote organismal longevity by maintaining the integrity of tissue-speciic stem cells. KEYWORDS: rejuvenation, aging, stem cell, DNA damage, sirtuin activator.