bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒03‒07
twenty papers selected by
Ayesh Seneviratne
University of Toronto
  1. CD74 is a regulator of hematopoietic stem cell maintenance.
  2. New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism.
  3. Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma.
  4. Oral administration of Akkermansia muciniphila elevates systemic antiaging and anticancer metabolites.
  5. Dietary Anti-Aging Polyphenols and Potential Mechanisms.
  6. Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications.
  7. Precision Nutrition to Activate Thermogenesis as a Complementary Approach to Target Obesity and Associated-Metabolic-Disorders.
  8. Physiology of Aging of Older Adults: Systemic and Oral Health Considerations-2021 Update.
  9. "Empowering" Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?
  10. MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
  11. Challenges in Studying Stem Cell Metabolism.
  12. Lysosomal Regulation of Metabolism in Quiescent Hematopoietic Stem Cells: More than Just Autophagy.
  13. The ketogenic diet preserves skeletal muscle with aging in mice.
  14. Crosstalk between Gut and Brain in Alzheimer's Disease: The Role of Gut Microbiota Modulation Strategies.
  15. Natural Bioactive Compounds Useful in Clinical Management of Metabolic Syndrome.
  16. Antioxidant and Anti-Inflammatory Potential of Polyphenols Contained in Mediterranean Diet in Obesity: Molecular Mechanisms.
  17. How does obesity promote breast cancer tumor growth?
  18. Vitamin D Regulation of Energy Metabolism in Cancer.
  19. Learning to mellow out GVHD.
  20. IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3.
  1. PLoS Biol. 2021 Mar 04. 19(3): e3001121
    CD74 is a regulator of hematopoietic stem cell maintenance.
    Shirly Becker-Herman, Milena Rozenberg, Carmit Hillel-Karniel, Naama Gil-Yarom, Mattias Kramer, Avital Barak, Lital Sever, Keren David, Lihi Radomir, Hadas Lewinsky, Michal Levi, Gilgi Friedlander, Richard Bucala, Amnon Peled, Idit Shachar.
      Hematopoietic stem and progenitor cells (HSPCs) are a small population of undifferentiated cells that have the capacity for self-renewal and differentiate into all blood cell lineages. These cells are the most useful cells for clinical transplantations and for regenerative medicine. So far, it has not been possible to expand adult hematopoietic stem cells (HSCs) without losing their self-renewal properties. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF), and its mRNA is known to be expressed in HSCs. Here, we demonstrate that mice lacking CD74 exhibit an accumulation of HSCs in the bone marrow (BM) due to their increased potential to repopulate and compete for BM niches. Our results suggest that CD74 regulates the maintenance of the HSCs and CD18 expression. Its absence leads to induced survival of these cells and accumulation of quiescent and proliferating cells. Furthermore, in in vitro experiments, blocking of CD74 elevated the numbers of HSPCs. Thus, we suggest that blocking CD74 could lead to improved clinical insight into BM transplant protocols, enabling improved engraftment.
    DOI:  https://doi.org/10.1371/journal.pbio.3001121
  2. Int J Hematol. 2021 Mar 05.
    New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism.
    Kazuhito Naka.
      Chronic myelogenous leukemia (CML) stem cells are the cellular source of the vast majority of mature CML cells and responsible for relapse of CML disease post-tyrosine kinase inhibitor (TKI) therapy. Although mature CML cells, whose active division is driven by BCR-ABL1 oncogene-dependent signaling, are reduced by TKI therapy, CML stem cells are resistant because they become quiescent via a heretofore elusive mechanism that is independent of oncogene signaling. Recent advances in highly sensitive metabolomics analyses, however, have unveiled new metabolic pathways that are essential for the survival of CML stem cells. With respect to glucose metabolism, CML stem cells elevate anaplerosis to sustain the TCA cycle. Blast crisis (BC)-CML stem cells increase their branched-chained amino acid (BCAA) metabolism. Recently, we showed that CML stem cell quiescence in vivo is regulated by lysophospholipid metabolism that is specific to these cells, namely cooperation between the stemness factors FOXO and β-catenin. These findings reveal biologically significant links between CML stemness and novel metabolic mechanisms. In this review, I describe these links in the contexts of glucose, amino acid, and lipid metabolism, and speculate on how innovative therapeutics might be designed to eradicate CML stem cells in vivo and overcome disease relapse post-TKI therapy.
    Keywords:  Anaplerosis; BCAA; CML stemness; Lysophospholipid
    DOI:  https://doi.org/10.1007/s12185-021-03112-y
  3. iScience. 2021 Feb 19. 24(2): 102128
    Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma.
    María Victoria Ruiz-Pérez, Lourdes Sainero-Alcolado, Ganna Oliynyk, Isabell Matuschek, Nicola Balboni, S J Kumari A Ubhayasekera, Marteinn Thor Snaebjornsson, Kamil Makowski, Kristina Aaltonen, Daniel Bexell, Dolors Serra, Roland Nilsson, Jonas Bergquist, Almut Schulze, Marie Arsenian-Henriksson.
      Many metabolic pathways, including lipid metabolism, are rewired in tumors to support energy and biomass production and to allow adaptation to stressful environments. Neuroblastoma is the second deadliest solid tumor in children. Genetic aberrations, as the amplification of the MYCN-oncogene, correlate strongly with disease progression. Yet, there are only a few molecular targets successfully exploited in the clinic. Here we show that inhibition of fatty acid synthesis led to increased neural differentiation and reduced tumor burden in neuroblastoma xenograft experiments independently of MYCN-status. This was accompanied by reduced levels of the MYCN or c-MYC oncoproteins and activation of ERK signaling. Importantly, the expression levels of genes involved in de novo fatty acid synthesis showed prognostic value for neuroblastoma patients. Our findings demonstrate that inhibition of de novo fatty acid synthesis is a promising pharmacological intervention strategy for the treatment of neuroblastoma independently of MYCN-status.
    Keywords:  biological sciences; cancer; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2021.102128
  4. Aging (Albany NY). 2021 Mar 02. 13
    Oral administration of Akkermansia muciniphila elevates systemic antiaging and anticancer metabolites.
    Claudia Grajeda-Iglesias, Sylvère Durand, Romain Daillère, Kristina Iribarren, Fabien Lemaitre, Lisa Derosa, Fanny Aprahamian, Noélie Bossut, Nitharsshini Nirmalathasan, Frank Madeo, Laurence Zitvogel, Guido Kroemer.
      The presence of Akkermansia muciniphila (Akk) in the human gut is associated with good health, leanness and fitness. Mouse experimentation has demonstrated positive effects for Akk, which counteracts aging, mediates antiobesity and antidiabetic effects, dampens inflammation and improves anticancer immunosurveillance. Clinical trials have confirmed antidiabetic effects for Akk. Here, we investigated the time-dependent effects of oral administration of Akk (which was live or pasteurized) and other bacteria to mice on the metabolome of the ileum, colon, liver and blood plasma. Metabolomics was performed by a combination of chromatographic and mass spectrometric methods, yielding a total of 1.637.227 measurements. Akk had major effects on metabolism, causing an increase in spermidine and other polyamines in the gut and in the liver. Pasteurized Akk (Akk-past) was more efficient than live Akk in elevating the intestinal concentrations of polyamines, short-chain fatty acids, 2-hydroxybutyrate, as well multiple bile acids, which also increased in the circulation. All these metabolites have previously been associated with human health, providing a biochemical basis for the beneficial effects of Akk.
    Keywords:  Akkermansia muciniphila; fecal microbial transplantation; metabolomics; microbiota; polyamines
    DOI:  https://doi.org/10.18632/aging.202739
  5. Antioxidants (Basel). 2021 Feb 13. pii: 283. [Epub ahead of print]10(2):
    Dietary Anti-Aging Polyphenols and Potential Mechanisms.
    Jing Luo, Hongwei Si, Zhenquan Jia, Dongmin Liu.
      For years, the consumption of a diet rich in fruits and vegetables has been considered healthy, increasing longevity, and decreasing morbidities. With the assistance of basic research investigating the potential mechanisms, it has become clear that the beneficial effects of plant-based foods are mainly due to the large amount of bioactive phenolic compounds contained. Indeed, substantial dietary intervention studies in humans have supported that the supplementation of polyphenols have various health-promoting effects, especially in the elderly population. In vitro examinations on the anti-aging mechanisms of polyphenols have been widely performed, using different types of natural and synthetic phenolic compounds. The aim of this review is to critically evaluate the experimental evidence demonstrating the beneficial effects of polyphenols on aging-related diseases. We highlight the potential anti-aging mechanisms of polyphenols, including antioxidant signaling, preventing cellular senescence, targeting microRNA, influencing NO bioavailability, and promoting mitochondrial function. While the trends on utilizing polyphenols in preventing aging-related disorders are getting growing attention, we suggest the exploration of the beneficial effects of the combination of multiple polyphenols or polyphenol-rich foods, as this would be more physiologically relevant to daily life.
    Keywords:  aging; antioxidant; cellular senescence; polyphenol
    DOI:  https://doi.org/10.3390/antiox10020283
  6. Mayo Clin Proc. 2021 Mar;pii: S0025-6196(20)30922-8. [Epub ahead of print]96(3): 788-814
    Hormonal and Metabolic Changes of Aging and the Influence of Lifestyle Modifications.
    Mark W Pataky, William F Young, K Sreekumaran Nair.
      Increased life expectancy combined with the aging baby boomer generation has resulted in an unprecedented global expansion of the elderly population. The growing population of older adults and increased rate of age-related chronic illness has caused a substantial socioeconomic burden. The gradual and progressive age-related decline in hormone production and action has a detrimental impact on human health by increasing risk for chronic disease and reducing life span. This article reviews the age-related decline in hormone production, as well as age-related biochemical and body composition changes that reduce the bioavailability and actions of some hormones. The impact of hormonal changes on various chronic conditions including frailty, diabetes, cardiovascular disease, and dementia are also discussed. Hormone replacement therapy has been attempted in many clinical trials to reverse and/or prevent the hormonal decline in aging to combat the progression of age-related diseases. Unfortunately, hormone replacement therapy is not a panacea, as it often results in various adverse events that outweigh its potential health benefits. Therefore, except in some specific individual cases, hormone replacement is not recommended. Rather, positive lifestyle modifications such as regular aerobic and resistance exercise programs and/or healthy calorically restricted diet can favorably affect endocrine and metabolic functions and act as countermeasures to various age-related diseases. We provide a critical review of the available data and offer recommendations that hopefully will form the groundwork for physicians/scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address age-related decline in heath.
    DOI:  https://doi.org/10.1016/j.mayocp.2020.07.033
  7. Cancers (Basel). 2021 Feb 18. pii: 866. [Epub ahead of print]13(4):
    Precision Nutrition to Activate Thermogenesis as a Complementary Approach to Target Obesity and Associated-Metabolic-Disorders.
    Marina Reguero, Marta Gómez de Cedrón, Sonia Wagner, Guillermo Reglero, José Carlos Quintela, Ana Ramírez de Molina.
      Obesity is associated to increased incidence and poorer prognosis in multiple cancers, contributing to up to 20% of cancer related deaths. These associations are mainly driven by metabolic and inflammatory changes in the adipose tissue during obesity, which disrupt the physiologic metabolic homeostasis. The association between obesity and hypercholesterolemia, hypertension, cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) is well known. Importantly, the retrospective analysis of more than 1000 epidemiological studies have also shown the positive correlation between the excess of fatness with the risk of cancer. In addition, more important than weight, it is the dysfunctional adipose tissue the main driver of insulin resistance, metabolic syndrome and all cause of mortality and cancer deaths, which also explains why normal weight individuals may behave as "metabolically unhealthy obese" individuals. Adipocytes also have direct effects on tumor cells through paracrine signaling. Downregulation of adiponectin and upregulation of leptin in serum correlate with markers of chronic inflammation, and crown like structures (CLS) associated to the adipose tissue disfunction. Nevertheless, obesity is a preventable risk factor in cancer. Lifestyle interventions might contribute to reduce the adverse effects of obesity. Thus, Mediterranean diet interventional studies have been shown to reduce to circulation inflammatory factors, insulin sensitivity and cardiovascular function, with durable responses of up to 2 years in obese patients. Mediterranean diet supplemented with extra-virgin olive oil reduced the incidence of breast cancer compared with a control diet. Physical activity is another important lifestyle factor which may also contribute to reduced systemic biomarkers of metabolic syndrome associated to obesity. In this scenario, precision nutrition may provide complementary approaches to target the metabolic inflammation associated to "unhealthy obesity". Herein, we first describe the different types of adipose tissue -thermogenic active brown adipose tissue (BAT) versus the energy storing white adipose tissue (WAT). We then move on precision nutrition based strategies, by mean of natural extracts derived from plants and/or diet derived ingredients, which may be useful to normalize the metabolic inflammation associated to "unhealthy obesity". More specifically, we focus on two axis: (1) the activation of thermogenesis in BAT and browning of WAT; (2) and the potential of augmenting the oxidative capacity of muscles to dissipate energy. These strategies may be particularly relevant as complementary approaches to alleviate obesity associated effects on chronic inflammation, immunosuppression, angiogenesis and chemotherapy resistance in cancer. Finally, we summarize main studies where plant derived extracts, mainly, polyphenols and flavonoids, have been applied to increase the energy expenditure.
    Keywords:  bioactive compounds; metabolic diseases; precision nutrition; thermogenesis
    DOI:  https://doi.org/10.3390/cancers13040866
  8. Dent Clin North Am. 2021 Apr;pii: S0011-8532(20)30094-X. [Epub ahead of print]65(2): 275-284
    Physiology of Aging of Older Adults: Systemic and Oral Health Considerations-2021 Update.
    Lisa A Thompson, Helen Chen.
      Most oral health care providers encounter older adults in their practices and can play a critical role in supporting independence and quality of life for this aging cohort. Physiologic and structural oral cavity changes associated with normal aging may affect the presentation and oral health care of older adults. This article reviews the normative aging of dentition and oral structures and physiologic changes associated with normal aging, including cardiovascular, metabolic, and musculoskeletal changes, and how they may affect oral health. Oral health providers should be aware of normal aging processes when they plan care or schedule procedures for older adults.
    Keywords:  Age-dependent changes; Aging adults; Clinical significance; Normal aging; Oral health; Physiology; Systemic
    DOI:  https://doi.org/10.1016/j.cden.2020.11.002
  9. Int J Mol Sci. 2021 Feb 12. pii: 1824. [Epub ahead of print]22(4):
    "Empowering" Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?
    Matthias Mietsch, Rabea Hinkel.
      With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the "stem- less" approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.
    Keywords:  aging; cardiovascular; heart; mitochondria; senescence; stem cell; transplantation
    DOI:  https://doi.org/10.3390/ijms22041824
  10. Cancer Cell. 2021 Mar 03. pii: S1535-6108(21)00108-2. [Epub ahead of print]
    MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism.
    Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C Wheat, Oliver Bohorquez, Swathi-Rao Narayanagari, Samuel J Taylor, Luis A Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong, Guillermina Lozano, Andrea Pellagatti, Jacqueline Boultwood, Amit Verma, Ulrich Steidl.
      MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number and competitive advantage. Utilizing five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic conditions to overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of β-Catenin in a p53-independent manner. Wnt/β-Catenin inhibitors reverse MDMX-induced pre-LSC properties, and synergize with MDMX-p53 inhibitors. Wnt/β-Catenin signaling correlates with MDMX expression in patients with preleukemic myelodysplastic syndromes and is associated with increased risk of progression to AML. Our work identifies MDMX overexpression as a pervasive preleukemic-to-AML transition mechanism in different genetically driven disease subtypes, and reveals Wnt/β-Catenin as a non-canonical MDMX-driven pathway with therapeutic potential for progression prevention and cancer interception.
    Keywords:  CK1α; MDMX; acute myeloid leukemia; cancer interception; myelodysplastic syndromes; precision prevention; preleukemia; preleukemic stem cells; targeted therapy; β-Catenin
    DOI:  https://doi.org/10.1016/j.ccell.2021.02.006
  11. Cell Stem Cell. 2021 Mar 04. pii: S1934-5909(21)00066-7. [Epub ahead of print]28(3): 409-423
    Challenges in Studying Stem Cell Metabolism.
    Cesar A Perez-Ramirez, Heather R Christofk.
      The expanding field of stem cell metabolism has been supported by technical advances in metabolite profiling and novel functional analyses. While use of these methodologies has been fruitful, many challenges are posed by the intricacies of culturing stem cells in vitro, along with the distinctive scarcity of adult tissue stem cells and the complexities of their niches in vivo. This review provides an examination of the methodologies used to characterize stem cell metabolism, highlighting their utility while placing a sharper focus on their limitations and hurdles the field needs to overcome for the optimal study of stem cell metabolic networks.
    DOI:  https://doi.org/10.1016/j.stem.2021.02.016
  12. Cell Stem Cell. 2021 Mar 04. pii: S1934-5909(21)00067-9. [Epub ahead of print]28(3): 374-377
    Lysosomal Regulation of Metabolism in Quiescent Hematopoietic Stem Cells: More than Just Autophagy.
    Saghi Ghaffari.
      The depth of quiescence in hematopoietic stem cells (HSCs) dictates their potency and is sensitive to metabolic perturbations. Recent evidence suggests that lysosomal functions distinct from autophagic processes are pivotal in regulating quiescence versus activation by potential control of the access to a nutrient reservoir required for HSC activation.
    DOI:  https://doi.org/10.1016/j.stem.2021.02.017
  13. Aging Cell. 2021 Mar 06. e13322
    The ketogenic diet preserves skeletal muscle with aging in mice.
    Marita A Wallace, Nicholas W Aguirre, George R Marcotte, Andrea G Marshall, Leslie M Baehr, David C Hughes, Karyn L Hamilton, Megan N Roberts, Jose Alberto Lopez-Dominguez, Benjamin F Miller, Jon J Ramsey, Keith Baar.
      The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
    Keywords:  aging; ketogenic diet; mice; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13322
  14. Nutrients. 2021 Feb 21. pii: 690. [Epub ahead of print]13(2):
    Crosstalk between Gut and Brain in Alzheimer's Disease: The Role of Gut Microbiota Modulation Strategies.
    Umair Shabbir, Muhammad Sajid Arshad, Aysha Sameen, Deog-Hwan Oh.
      The gut microbiota (GM) represents a diverse and dynamic population of microorganisms and about 100 trillion symbiotic microbial cells that dwell in the gastrointestinal tract. Studies suggest that the GM can influence the health of the host, and several factors can modify the GM composition, such as diet, drug intake, lifestyle, and geographical locations. Gut dysbiosis can affect brain immune homeostasis through the microbiota-gut-brain axis and can play a key role in the pathogenesis of neurodegenerative diseases, including dementia and Alzheimer's disease (AD). The relationship between gut dysbiosis and AD is still elusive, but emerging evidence suggests that it can enhance the secretion of lipopolysaccharides and amyloids that may disturb intestinal permeability and the blood-brain barrier. In addition, it can promote the hallmarks of AD, such as oxidative stress, neuroinflammation, amyloid-beta formation, insulin resistance, and ultimately the causation of neural death. Poor dietary habits and aging, along with inflammatory responses due to dysbiosis, may contribute to the pathogenesis of AD. Thus, GM modulation through diet, probiotics, or fecal microbiota transplantation could represent potential therapeutics in AD. In this review, we discuss the role of GM dysbiosis in AD and potential therapeutic strategies to modulate GM in AD.
    Keywords:  diet; gut dysbiosis; microbial metabolites; neurodegenerative diseases; probiotics
    DOI:  https://doi.org/10.3390/nu13020690
  15. Nutrients. 2021 Feb 16. pii: 630. [Epub ahead of print]13(2):
    Natural Bioactive Compounds Useful in Clinical Management of Metabolic Syndrome.
    Annalisa Noce, Manuela Di Lauro, Francesca Di Daniele, Anna Pietroboni Zaitseva, Giulia Marrone, Patrizia Borboni, Nicola Di Daniele.
      Metabolic syndrome (MetS) is a clinical manifestation characterized by a plethora of comorbidities, including hyperglycemia, abdominal obesity, arterial hypertension, and dyslipidemia. All MetS comorbidities participate to induce a low-grade inflammation state and oxidative stress, typical of this syndrome. MetS is related to an increased risk of cardiovascular diseases and early death, with an important impact on health-care costs. For its clinic management a poly-pharmaceutical therapy is often required, but this can cause side effects and reduce the patient's compliance. For this reason, finding a valid and alternative therapeutic strategy, natural and free of side effects, could represent a useful tool in the fight the MetS. In this context, the use of functional foods, and the assumption of natural bioactive compounds (NBCs), could exert beneficial effects on body weight, blood pressure and glucose metabolism control, on endothelial damage, on the improvement of lipid profile, on the inflammatory state, and on oxidative stress. This review focuses on the possible beneficial role of NBCs in the prevention and in the clinical management of MetS and its comorbidities.
    Keywords:  arterial hypertension; diabetes mellitus; dyslipidemia; functional foods; low-grade inflammatory state; metabolic syndrome; natural bioactive compounds
    DOI:  https://doi.org/10.3390/nu13020630
  16. Molecules. 2021 Feb 12. pii: 985. [Epub ahead of print]26(4):
    Antioxidant and Anti-Inflammatory Potential of Polyphenols Contained in Mediterranean Diet in Obesity: Molecular Mechanisms.
    Abdelhafid Nani, Babar Murtaza, Amira Sayed Khan, Naim Akhtar Khan, Aziz Hichami.
      Nutrition transition can be defined as shifts in food habits, and it is characterized by high-fat (chiefly saturated animal fat), hypercaloric and salty food consumption at the expense of dietary fibers, minerals and vitamins. Western dietary patterns serve as a model for studying the impact of nutrition transition on civilization diseases, such as obesity, which is commonly associated with oxidative stress and inflammation. In fact, reactive oxygen species (ROS) overproduction can be associated with nuclear factor-κB (NF-κB)-mediated inflammation in obesity. NF-κB regulates gene expression of several oxidant-responsive adipokines including tumor necrosis factor-α (TNF-α). Moreover, AMP-activated protein kinase (AMPK), which plays a pivotal role in energy homeostasis and in modulation of metabolic inflammation, can be downregulated by IκB kinase (IKK)-dependent TNF-α activation. On the other hand, adherence to a Mediterranean-style diet is highly encouraged because of its healthy dietary pattern, which includes antioxidant nutraceuticals such as polyphenols. Indeed, hydroxycinnamic derivatives, quercetin, resveratrol, oleuropein and hydroxytyrosol, which are well known for their antioxidant and anti-inflammatory activities, exert anti-obesity proprieties. In this review, we highlight the impact of the most common polyphenols from Mediterranean foods on molecular mechanisms that mediate obesity-related oxidative stress and inflammation. Hence, we discuss the effects of these polyphenols on a number of signaling pathways. We note that Mediterranean diet (MedDiet) dietary polyphenols can de-regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and NF-κB-mediated oxidative stress, and metabolic inflammation. MedDiet polyphenols are also effective in upregulating downstream effectors of several proteins, chiefly AMPK.
    Keywords:  AMPK; MedDiet; NF-κB; inflammation; obesity; oxidative stress; polyphenols
    DOI:  https://doi.org/10.3390/molecules26040985
  17. Cell Metab. 2021 Mar 02. pii: S1550-4131(21)00067-X. [Epub ahead of print]33(3): 462-463
    How does obesity promote breast cancer tumor growth?
    Marc L Reitman.
      Obesity is a risk factor for many cancers. Maguire et al. (2021) found increased creatine synthesis by the adipocytes adjacent to breast cancers in obese mice. The creatine is transported into the cancer cells, producing larger tumors, possibly due to greater energy availability.
    DOI:  https://doi.org/10.1016/j.cmet.2021.02.011
  18. Br J Pharmacol. 2021 Mar 02.
    Vitamin D Regulation of Energy Metabolism in Cancer.
    Madeline P Sheeley, Chaylen Andolino, Violet A Kiesel, Dorothy Teegarden.
      Vitamin D exerts anti-cancer effects in recent clinical trials and preclinical models. The actions of vitamin D are primarily mediated through the hormonal form, 1,25-dihydroxyvitamin D (1,25(OH)2 D). Previous literature describing in vitro studies has predominantly focused on antitumorigenic effects of the hormone, such as proliferation and apoptosis. However, recent evidence has identified 1,25(OH)2 D as a regulator of energy metabolism in cancer cells, where requirements for specific energy sources at different stages of progression are dramatically altered. The literature suggests that 1,25(OH)2 D regulates energy metabolism, including glucose, glutamine, and lipid metabolism during cancer progression, as well as oxidative stress protection, as it is closely associated with energy metabolism. Mechanisms involved in energy metabolism regulation are an emerging area in which vitamin D may inhibit multiple stages of cancer progression.
    DOI:  https://doi.org/10.1111/bph.15424
  19. Blood. 2021 Mar 04. 137(9): 1142-1143
    Learning to mellow out GVHD.
    Takanori Teshima.
      
    DOI:  https://doi.org/10.1182/blood.2020009315
  20. PLoS One. 2021 ;16(3): e0247394
    IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3.
    Oleksi Petrenko, Jinyu Li, Velasco Cimica, Patricio Mena-Taboada, Ha Youn Shin, Stephen D'Amico, Nancy C Reich.
      The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The Eμ-myc transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated Eμ-myc mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6/JAK/STAT3 pathway in tumor development. Using the Eμ-myc lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, and this may contribute to advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for Eμ-myc driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in Eμ-myc driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required.
    DOI:  https://doi.org/10.1371/journal.pone.0247394
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