bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–05–02
28 papers selected by
Ayesh Seneviratne, University of Toronto



  1. Cells. 2021 Apr 13. pii: 880. [Epub ahead of print]10(4):
      During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.
    Keywords:  age-related diseases; aging; lipid metabolism
    DOI:  https://doi.org/10.3390/cells10040880
  2. Nutrients. 2021 Apr 19. pii: 1362. [Epub ahead of print]13(4):
      The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer's disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer's disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood-brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer's risk reduction.
    Keywords:  Alzheimer’s disease; ApoE4; astrocytes; blood–brain barrier; inflammation; insulin resistance; microglia; precision nutrition
    DOI:  https://doi.org/10.3390/nu13041362
  3. Mol Nutr Food Res. 2021 Apr 30. e2001076
       SCOPE: Mitochondria-associated membrane (MAM) connecting endoplasmic reticulum (ER) and mitochondria plays a significant role in lipid metabolism and Ca2+ homeostasis. Albeit sulforaphane (SFN) shows potential in ameliorating excessive fat accumulation and mitochondrial function, whether MAM is a target of SFN and its underling mechanisms are still unclear.
    METHODS AND RESULTS: High-fat-intake models are established both in vivo and in vitro. SFN widened the distance between ER and mitochondria and down-regulated MAM tether protein mitofusin-2. SFN reversed the increase of Ca2+ induced by fatty acid and inhibited the Ca2+ channel IP3R. Compared with high fat group, SFN alleviate Ca2+ overload in the mitochondria and suppressing mitochondrial calcium uniporter (MCU). Furthermore, SFN increased mitochondrial DNA quantities and mitochondria membrane potential, while decreased ROS production. Finally, SFN increased mitochondria complexes IV content and ATP synthesis.
    CONCLUSION: These results suggested that SFN balanced the Ca2+ homeostasis in the MAM through regulating Ca2+ flux by Ca2+ channel IP3R and MCU. This article is protected by copyright. All rights reserved.
    Keywords:  Ca2+ homeostasis; lipid metabolism; mitochondria function; mitochondria-associated membrane; sulforaphane
    DOI:  https://doi.org/10.1002/mnfr.202001076
  4. Cell Metab. 2021 Apr 22. pii: S1550-4131(21)00169-8. [Epub ahead of print]
      NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.
    Keywords:  NAD pathway metabolites; NAD(+); aging; disease; humans; mitochondria; transport; vitamin B3
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.003
  5. Cells. 2021 Apr 23. pii: 998. [Epub ahead of print]10(5):
      Aging and overweight increase the risk of developing type 2 diabetes mellitus. In this cross-sectional study, we aimed to investigate the potential mediating role of T-EMRA cells and inflammatory markers in the development of a decreased insulin sensitivity. A total of 134 healthy older volunteers were recruited (age 59.2 (SD 5.6) years). T cell subpopulations were analyzed by flow cytometry. Furthermore, body composition, HOMA-IR, plasma tryptophan (Trp) metabolites, as well as cytokines and adipokines were determined. Using subgroup and covariance analyses, the influence of BMI on the parameters was evaluated. Moreover, correlation, multiple regression, and mediation analyses were performed. In the subgroup of participants with obesity, an increased proportion of CD8+EMRA cells and elevated concentrations of plasma kynurenine (KYN) were found compared to the lower-weight subgroups. Linear regression analysis revealed that an elevated HOMA-IR could be predicted by a higher proportion of CD8+EMRA cells and KYN levels. A mediation analysis showed a robust indirect effect of the Waist-to-hip ratio on HOMA-IR mediated by CD8+EMRA cells. Thus, the deleterious effects of abdominal obesity on glucose metabolism might be mediated by CD8+EMRA cells in the elderly. Longitudinal studies should validate this assumption and analyze the suitability of CD8+EMRA cells as early predictors of incipient prediabetes.
    Keywords:  T-EMRA cells; elderly; insulin resistance; kynurenine pathway; obesity
    DOI:  https://doi.org/10.3390/cells10050998
  6. Nat Metab. 2021 Apr 26.
      Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
    DOI:  https://doi.org/10.1038/s42255-021-00385-9
  7. Geriatrics (Basel). 2021 Apr 06. pii: 37. [Epub ahead of print]6(2):
      Aging is a primary risk factor for the progressive loss of function, disease onset, and increased vulnerability to negative health-related outcomes. These clinical manifestations arise in part from declines in mitochondrial, metabolic, and other processes considered to be hallmarks of aging. Collectively, these changes can be defined as age-associated cellular decline (AACD) and are often associated with fatigue, reduced strength, and low physical activity. This manuscript summarizes a recent Gerontological Society of America Annual Scientific Meeting symposium that explored mechanisms, clinical signs, and emerging cellular nutrition interventions for AACD. The session opened by highlighting results of an expert consensus that developed an initial framework to identify self-reported symptoms and observable signs of AACD in adults aged >50 years. Next, findings from the multi-ethnic molecular determinants of sarcopenia study were discussed, showing impaired mitochondrial bioenergetic capacity and NAD+ metabolism in skeletal muscle of older adults with sarcopenia. Lastly, recent clinical evidence was presented linking urolithin A, a natural mitophagy activator, to improved mitochondrial and cellular health. The virtual panel discussed how stimulation of mitochondrial function via biological pathways, such as mitophagy and NAD+ augmentation, could improve cellular function and muscle health, potentially impacting clinical signs of AACD and overall healthy aging.
    Keywords:  AACD; accelerated aging and cellular decline; age-associated cellular decline; cellular nutrition; mitochondria; muscle; nicotinamide riboside; sarcopenia; urolithin A
    DOI:  https://doi.org/10.3390/geriatrics6020037
  8. Front Med (Lausanne). 2021 ;8 517226
      This article overviews positive aging concepts and strategies to enhance well-being in the elderly and then presents a translation of theories on positive aging to practical approaches for Positive Aging. Drawing upon positive psychology and positive aging research and tools, this program is designed to help older adults improve their well-being by acquiring skills and strategies to cope with present and future challenges. The Mental Fitness Program for Positive Aging (MFPPA) can enhance seniors' quality of life by increasing their vital involvement and active engagement in life. This model is most appropriate for community dwelling individuals. It can easily be conducted in wide range of adult education programs in community centers, sheltered homes, and primary care clinics. It can also be conducted through online psychoeducational training.
    Keywords:  mental health; positive health; positive psychology; successful aging; well—being
    DOI:  https://doi.org/10.3389/fmed.2021.517226
  9. Molecules. 2021 Apr 22. pii: 2438. [Epub ahead of print]26(9):
      Polyphenols and omega-3 polyunsaturated fatty acids from fish oils, i.e., eicosapentaenoic and docosahexaenoic acids, are well-recognized nutraceuticals, and their single antioxidant and anti-inflammatory properties have been demonstrated in several studies found in the literature. It has been reported that the combination of these nutraceuticals can lead to three-fold increases in glutathione peroxidase activity, two-fold increases in plasma antioxidant capacity, decreases of 50-100% in lipid peroxidation, protein carbonylation, and urinary 8-isoprotanes, as well as 50-200% attenuation of common inflammation biomarkers, among other effects, as compared to their individual capacities. Therefore, the adequate combination of those bioactive food compounds and their single properties should offer a powerful tool for the design of successfully nutritional interventions for the prevention and palliation of a plethora of human metabolic diseases, frequently diet-induced, whose etiology and progression are characterized by redox homeostasis disturbances and a low-grade of chronic inflammation. However, the certain mechanisms behind their biological activities, in vivo interaction (both between them and other food compounds), and their optimal doses and consumption are not well-known yet. Therefore, we review here the recent evidence accumulated during the last decade about the cooperative action between polyphenols and fish oils against diet-related metabolic alterations, focusing on the mechanisms and pathways described and the effects reported. The final objective is to provide useful information for strategies for personalized nutrition based on these nutraceuticals.
    Keywords:  docosahexaenoic acid; eicosapentaenoic acid; inflammation; metabolic disorders; nutraceuticals; omega-3 polyunsaturated fatty acids; oxidative stress; plant bioactives
    DOI:  https://doi.org/10.3390/molecules26092438
  10. Molecules. 2021 Apr 25. pii: 2506. [Epub ahead of print]26(9):
      Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.
    Keywords:  anticancer; cancer therapy; hormonal therapy; phytomelatonin; pineal gland
    DOI:  https://doi.org/10.3390/molecules26092506
  11. Inflamm Bowel Dis. 2021 Apr 27. pii: izab039. [Epub ahead of print]
      Evidence from recent epidemiological data suggests that the patient population with inflammatory bowel disease (IBD) is chronologically aging. As these individuals become older, cellular senescence leads to a state of chronic inflammation. This process, known as inflammaging, is thought to be closely linked with biological aging and may be upregulated within IBD. As a consequence, we see an increased risk of aging-related disorders within IBD. In addition, we see that frailty, which results from physiologic decline, is increasing in prevalence and is associated with adverse clinical outcomes in IBD. As such, in this review we explore the potential overlapping biology of IBD and aging, discuss the risk of aging-related disorders in IBD, and describe frailty and its relation to clinical outcomes within IBD. Finally, we discuss current considerations for clinical care and potential research avenues for further investigation.
    Keywords:  aging; frailty; inflammatory bowel disease; senescence
    DOI:  https://doi.org/10.1093/ibd/izab039
  12. Blood. 2021 Apr 28. pii: blood.2020007932. [Epub ahead of print]
      Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired anti-metabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is to reprogram gene expression in a metabolism-dependent manner. MondoA (also known as MLXIP), a member of the MYC interactome, has been described as an example of such a metabolic sensor. However, the role of MondoA in malignancy is not fully understood and the underlying mechanism in metabolic responses remains elusive. By assessing patient data sets we found that MondoA overexpression is associated with a worse survival in pediatric common acute lymphoblastic leukemia (B-ALL). Using CRISPR/Cas9 and RNA interference approaches, we observed that MondoA depletion reduces transformational capacity of B-ALL cells in vitro and dramatically inhibits malignant potential in an in vivo mouse model. Interestingly, reduced expression of MondoA in patient data sets correlated with enrichment in metabolic pathways. The loss of MondoA correlated with increased tricarboxylic acid (TCA) cycle activity. Mechanistically, MondoA senses metabolic stress in B-ALL cells by restricting oxidative phosphorylation through reduced PDH activity. Glutamine starvation conditions greatly enhance this effect and highlight the inability to mitigate metabolic stress upon loss of MondoA in B-ALL. Our findings give a novel insight into the function of MondoA in pediatric B-ALL and support the notion that MondoA inhibition in this entity offers a therapeutic opportunity and should be further explored.
    DOI:  https://doi.org/10.1182/blood.2020007932
  13. Nutrients. 2021 Apr 08. pii: 1228. [Epub ahead of print]13(4):
      The Mediterranean diet (MD) has been recommended for type 2 diabetes (T2D) treatment. The impact of diet in shaping the gut microbiota is well known, particularly for MD. However, the link between MD and diabetes outcome improvement is not completely clear. This study aims to evaluate the role of microbiota modulation by a nonpharmacological intervention in patients with T2D. In this 12-week single-arm pilot study, nine participants received individual nutritional counseling sessions promoting MD. Gut microbiota, biochemical parameters, body composition, and blood pressure were assessed at baseline, 4 weeks, and 12 weeks after the intervention. Adherence to MD [assessed by Mediterranean Diet Adherence Screener (MEDAS) score] increased after the intervention. Bacterial richness increased after 4 weeks of intervention and was negatively correlated with fasting glucose levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Prevotella to Bacteroides ratio also increased after 4 weeks. In contrast, glycated haemoglobin (HbA1c) and HOMA-IR were only decreased at the end of study. Alkaline phosphatase activity was assessed in fecal samples and was negatively correlated with HbA1c and positively correlated with bacterial diversity. The results of this study reinforce that MD adherence results in a better glycemic control in subjects with T2D. Changes in gut bacterial richness caused by MD adherence may be relevant in mediating the metabolic impact of this dietary intervention.
    Keywords:  Mediterranean diet; gut microbiota; type 2 diabetes
    DOI:  https://doi.org/10.3390/nu13041228
  14. Geriatr Psychol Neuropsychiatr Vieil. 2021 Apr 26.
      The range of non-pharmacological interventions (NPIs) available for people over 60 years of age is continuously expanding, both in terms of prevention and therapy. They have been empirically selected for centuries and more recently developed through epigenetic studies, clinical trials and technological innovations, and their development has increased and diversified around the world. Residual questions concern: 1) the scope of such treatments which appears to overlap with alternative medicines, 2) their evaluation, which some researchers say is impossible, and 3) their implementation in the elderly, which appears to be overly complicated. This article addresses these three questions and presents digital tools developed by the CEPS University Platform facilitating the evaluation of NPIs in the field of healthy aging. The transformation of the health system, which has become necessary to meet the needs of baby boomers, will widen the arsenal of health-related solutions. The combination of approaches to medicine and health has become personalised, comprehensive and integrative. NPIs will play a major role in the coming century. These practices differ from alternative medicines, general public health messages and socio-cultural approaches through continuous research, a quality approach and traceability of use. NPIs today constitute a complementary ecosystem for biomedical treatments which are increasingly becoming economically and legally consolidated.
    Keywords:  intervention study; non-pharmacological intervention; positive health; successful ageing
    DOI:  https://doi.org/10.1684/pnv.2021.0929
  15. J Clin Med. 2021 Apr 14. pii: 1693. [Epub ahead of print]10(8):
      In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.
    Keywords:  chronic critical illness; lipids; lipoproteins; sepsis
    DOI:  https://doi.org/10.3390/jcm10081693
  16. Front Oncol. 2021 ;11 639387
      Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. In this review, the contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML will be highlighted.
    Keywords:  AML; IDH; acute myeloid leukemia; enasidenib; isocitrate dehydrogenase; ivosidenib; target therapy
    DOI:  https://doi.org/10.3389/fonc.2021.639387
  17. Anim Sci J. 2021 Jan;92(1): e13557
      The greatest improvement in carbohydrates studies on pig nutrition and health is that carbohydrates are classified more clearly, which is based not only on their chemical structure but also on their physiological characteristics. Besides its primary energy source, different types and structures of carbohydrates are a benefit for nutrition and health functions in pigs, which are involved in promoting growth performance and intestinal functions, regulating the community of gut microbiota, and modulating the lipids and glucose metabolism. The underlying mechanism of carbohydrates regulates the lipids and glucose metabolism through their metabolites (short-chain fatty acids [SCFAs]) and mainly via the SCFAs-GPR43/41-PYY/GLP1, SCFAs-AMP/ATP-AMPK, and SCFAs-AMPK-G6Pase/PEPCK pathways. Emerging research had evaluated an optimal combination in different types and structures of carbohydrates, which could enhance growth performance and nutrient digestibility, promote intestinal functions, and increase the abundances of butyrate-producing bacteria in pigs. Overall, compelling evidence supports the notion that carbohydrates play important roles in both nutrition and health functions in pigs. Moreover, identifying the carbohydrates combinations will be of both theoretical and practical values for developing the technology of carbohydrates balance in pigs.
    Keywords:  carbohydrates; growth performance; gut microbiota; intestinal functions; pigs
    DOI:  https://doi.org/10.1111/asj.13557
  18. Molecules. 2021 Apr 02. pii: 2029. [Epub ahead of print]26(7):
      Flavonoids represent an important group of bioactive compounds derived from plant-based foods and beverages with known biological activity in cells. From the modulation of inflammation to the inhibition of cell proliferation, flavonoids have been described as important therapeutic adjuvants against several diseases, including diabetes, arteriosclerosis, neurological disorders, and cancer. Cancer is a complex and multifactor disease that has been studied for years however, its prevention is still one of the best known and efficient factors impacting the epidemiology of the disease. In the molecular and cellular context, some of the mechanisms underlying the oncogenesis and the progression of the disease are understood, known as the hallmarks of cancer. In this text, we review important molecular signaling pathways, including inflammation, immunity, redox metabolism, cell growth, autophagy, apoptosis, and cell cycle, and analyze the known mechanisms of action of flavonoids in cancer. The current literature provides enough evidence supporting that flavonoids may be important adjuvants in cancer therapy, highlighting the importance of healthy and balanced diets to prevent the onset and progression of the disease.
    Keywords:  cancer; cell signaling; flavonoids
    DOI:  https://doi.org/10.3390/molecules26072029
  19. Cells. 2021 Apr 28. pii: 1037. [Epub ahead of print]10(5):
      Inflammation is part of the aging process, and the inflammatory innate immune response is more exacerbated in older individuals when compared to younger individuals. Similarly, there is a difference in the response to systemic infection that varies with age. In a recent article by Hoogland et al., the authors studied the microglial response to systemic infection in young (2 months) and middle-aged mice (13-14 months) that were challenged with live Escherichia coli to investigate whether the pro- and anti-inflammatory responses mounted by microglia after systemic infection varies with age. Here, we comment on this study and its implications on how inflammation in the brain varies with age.
    Keywords:  aging; infection; inflammation; microglia; sepsis
    DOI:  https://doi.org/10.3390/cells10051037
  20. Cancers (Basel). 2021 Apr 20. pii: 1973. [Epub ahead of print]13(8):
      Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.
    Keywords:  cancer stem cell; catecholamines; cell plasticity; epithelial-to-mesenchymal transition; metabolism reprogramming
    DOI:  https://doi.org/10.3390/cancers13081973
  21. Cells. 2021 Apr 20. pii: 951. [Epub ahead of print]10(4):
      Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number of actionable targets whose clinical exploration will help achieve the goal of optimizing beneficial effects while avoiding undue interference with host defenses or other unwanted actions. This review aims to furnish the foundation for this quest by critical evaluation of the current state of anti-inflammatory interventions within close reach of clinical application, with a primary focus on innate immunity. In particular, this paper highlights the pathway from the inflammasome, through interleukin (IL)-1 to IL-6 supported by a promising body of pre-clinical, clinical, and human genetic data. This paper also considers the use of biomarkers to guide allocation of anti-inflammatory therapies as a step toward realizing the promise of precision medicine. The validation of decades of experimental work and association studies in humans by recent clinical investigations provides a strong impetus for further efforts to target inflammation in atherosclerosis to address the considerable risk that remains despite current therapies.
    Keywords:  acute coronary syndromes; cytokines; innate immunity; ischemic heart disease; myocardial infarction; thrombosis; vascular biology
    DOI:  https://doi.org/10.3390/cells10040951
  22. Cell Stem Cell. 2021 Apr 21. pii: S1934-5909(21)00161-2. [Epub ahead of print]
      Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity.
    Keywords:  Alzheimer's disease; aging; de-differentiation; induced neurons (iNs); neuronal cell cycle re-entry; rejuvenation
    DOI:  https://doi.org/10.1016/j.stem.2021.04.004
  23. J Hematol Oncol. 2021 Apr 26. 14(1): 70
       BACKGROUND: BCL-2 inhibition through venetoclax (VEN) targets acute myeloid leukemia (AML) blast cells and leukemic stem cells (LSCs). Although VEN-containing regimens yield 60-70% clinical response rates, the vast majority of patients inevitably suffer disease relapse, likely because of the persistence of drug-resistant LSCs. We previously reported preclinical activity of the ribonucleoside analog 8-chloro-adenosine (8-Cl-Ado) against AML blast cells and LSCs. Moreover, our ongoing phase I clinical trial of 8-Cl-Ado in patients with refractory/relapsed AML demonstrates encouraging clinical benefit. Of note, LSCs uniquely depend on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. VEN inhibits OXPHOS in LSCs, which eventually may escape the antileukemic activity of this drug. FAO is activated in LSCs isolated from patients with relapsed AML.
    METHODS: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Western blotting was used to validate results from GSEA. HPLC was used to measure intracellular accumulation of 8-Cl-ATP, the cytotoxic metabolite of 8-Cl-Ado. To quantify drug synergy, we created combination index plots using CompuSyn software. The log-rank Kaplan-Meier survival test was used to compare the survival distributions of the different treatment groups in a xenograft mouse model of AML.
    RESULTS: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p ≤ 0.006). We show here that 8-Cl-Ado in the LSC-enriched population suppressed FAO by downregulating gene expression of proteins involved in this pathway and significantly inhibited the oxygen consumption rate (OCR), an indicator of OXPHOS. By combining 8-Cl-Ado with VEN, we observed complete inhibition of OCR, suggesting this drug combination cooperates in targeting OXPHOS and the metabolic homeostasis of AML cells.
    CONCLUSION: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.
    Keywords:  Acute myeloid leukemia; Fatty acid oxidation; Metabolism; Nucleoside analog; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s13045-021-01076-4
  24. Aging (Albany NY). 2021 Apr 26. 13
      We previously reported the neuroprotective effects of (+)-balasubramide derived compound 3C, but its action on atherosclerosis in vivo remains unknown. The study was designed to investigate the potential effects of 3C on atherogenesis and explore the possible underlying mechanisms. 3C ameliorated high-fat diet-induced body weight gain, hyperlipidemia, and atherosclerotic plaque burden in apolipoprotein E-deficient (ApoE-/-) mice after 10 weeks of treatment. 3C suppressed the expression of genes involved in triglyceride synthesis in liver. 3C prevented aortic inflammation as evidenced by reduction of adhesive molecule levels and macrophage infiltration. Mechanistic studies revealed that activation of AMP-activated protein kinase (AMPK) is central to the athero-protective effects of 3C. Increased AMPK activity by 3C resulted in suppressing interferon-γ (IFN-γ) induced activation of signal transducer and activator of transcription-1 (STAT1) and stimulator of interferon genes (STING) signaling pathways and downstream pro-inflammatory markers. Moreover, 3C inhibited ox-LDL triggered lipid accumulation and IFN-γ induced phenotypic switch toward M1 macrophage in RAW 264.7 cells. Our present data suggest that 3C prevents atherosclerosis via pleiotropic effects, including amelioration of lipid profiles, vascular inflammation and macrophage pro-inflammatory phenotype. 3C has the potential to be developed as a promising drug for atherosclerosis and related cardiovascular disease.
    Keywords:  (+)-balasubramide derivative 3C; AMPK; STAT1; STING; atherosclerosis
    DOI:  https://doi.org/10.18632/aging.202929
  25. Immunohorizons. 2021 Apr 28. 5(4): 219-233
      Lysophosphatidylcholine (LPC), a dominant lipid component of oxidized low-density lipoprotein, plays a major role in inflammation associated with atherosclerosis and neurodegenerative disorders. It activates inflammatory responses from macrophages, neuronal cells, and endothelial cells. However, the exact mechanism by which LPC promotes inflammation remains incompletely understood. In this study, we show that the production of inflammatory cytokines and cytotoxicity with LPC are both critically dependent on its ability to bring about release of ATP from cells. The induction of caspase-1-mediated IL-1β release with LPC from TLR-primed mouse and human macrophages and mouse neuronal cells is reduced in the presence of ATP-hydrolyzing enzyme, apyrase, and the inhibitors of purinergic signaling. ATP released from LPC-treated cells also promotes an IL-12p70hi, low phagocytic, and poorly costimulatory phenotype in macrophages in a caspase-1-independent manner. Treatment with apyrase reduces production of inflammatory cytokines with LPC in vivo. These findings reveal a previously unappreciated pathway for the generation of inflammatory responses with LPC, and these have significant implications for therapeutic intervention in chronic inflammatory disorders promoted by this lipid.
    DOI:  https://doi.org/10.4049/immunohorizons.2100023
  26. Nat Immunol. 2021 Apr 26.
      Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.
    DOI:  https://doi.org/10.1038/s41590-021-00921-5
  27. Nat Med. 2021 Apr 29.
      
    Keywords:  Cancer; Clinical trials; Machine Learning
    DOI:  https://doi.org/10.1038/d41591-021-00026-4
  28. Onco Targets Ther. 2021 ;14 2761-2772
      The properties of cancer stem cells (CSCs) have recently gained attention as an avenue of intervention for cancer therapy. In this review, we highlight some of the key roles of CSCs in altering the cellular microenvironment in favor of cancer progression. We also report on various studies in this field which focus on transformative properties of CSCs and their influence on surrounding cells or targets through the release of cellular cargo in the form of extracellular vesicles. The findings from these studies encourage the development of novel interventional therapies that can target and prevent cancer through efficient, more effective methods. These methods include targeting immunosuppressive proteins and biomarkers, promoting immunization against tumors, exosome-mediated CSC conversion, and a focus on the quiescent properties of CSCs and their role in cancer progression. The resulting therapeutic benefit and transformative potential of these novel approaches to stem cell-based cancer therapy provide a new direction in cancer treatment, which can focus on nanoscale, molecular properties of the cellular microenvironment and establish a more precision medicine-oriented paradigm of treatment.
    Keywords:  biomarkers; cancer; exosomes; molecular imaging; stem cell therapy
    DOI:  https://doi.org/10.2147/OTT.S260391