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Ketogenic diet in the treatment of cancer - Where do we stand?
Weber, DD, Aminzadeh-Gohari, S, Tulipan, J, Catalano, L, Feichtinger, RG, Kofler, B
Molecular metabolism. 2020;33:102-121
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A literature review paper looking at complementary approaches to improve the efficacy of standard anticancer therapies – specifically the Ketogenic Diet (KD), characterised as a high-fat (90%), low-carbohydrate (2%) diet with adequate amounts of protein (8%). The KD is a low- cost adjuvant to cancer therapy and is considered promising due to its potential to target metabolic alterations in tumour cells. Research shows it potentially limits tumour growth, whilst protecting healthy cells from damage by chemotherapy or radiation and reducing inflammation. The ketones produced by the high ratio of fat in the diet are used to create ATP energy, which cancerous cells are unable to use. Preclinical studies show that in most cases the KD slowed tumour growth, prolonged survival rate, and delayed the initiation of tumours although this may be influenced by cancer type and genetic background. This implies it’s important to evaluate KD efficiency against each individual cancer rather than as a collective anticancer therapy. Gold standard therapy for some cancers is surgery, radiation, and chemotherapy. However aggressive cancer types with poor prognosis need new approaches where standard therapy is less successful. The authors recognise there is insufficient RCT evidence with large patient cohorts but smaller studies are emerging showing positive results for a KD with patients exceeding their expected lifespan, with reduced tumour growth and progression, reduced glucose up-take at the tumour site and overall improved quality of life. KD seemingly creates an environment in which cancer cells cannot thrive making it a promising adjuvant as a patient-specific multifactorial therapy.
Abstract
BACKGROUND Cancer is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of standard anticancer therapies. The ketogenic diet, a high-fat, low-carbohydrate diet with adequate amounts of protein, appears to sensitize most cancers to standard treatment by exploiting the reprogramed metabolism of cancer cells, making the diet a promising candidate as an adjuvant cancer therapy. SCOPE OF REVIEW To critically evaluate available preclinical and clinical evidence regarding the ketogenic diet in the context of cancer therapy. Furthermore, we highlight important mechanisms that could explain the potential antitumor effects of the ketogenic diet. MAJOR CONCLUSIONS The ketogenic diet probably creates an unfavorable metabolic environment for cancer cells and thus can be regarded as a promising adjuvant as a patient-specific multifactorial therapy. The majority of preclinical and several clinical studies argue for the use of the ketogenic diet in combination with standard therapies based on its potential to enhance the antitumor effects of classic chemo- and radiotherapy, its overall good safety and tolerability and increase in quality of life. However, to further elucidate the mechanisms of the ketogenic diet as a therapy and evaluate its application in clinical practice, more molecular studies as well as uniformly controlled clinical trials are needed.
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Recent Advances in Psoriasis Research; the Clue to Mysterious Relation to Gut Microbiome.
Komine, M
International journal of molecular sciences. 2020;21(7)
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Psoriasis is a chronic inflammatory disease where the skin forms bumpy red patches covered with white scales. There is no cure, but medications have focused on supressing the immune response. There is a link between the gut microbiome and psoriasis but it is poorly understood. This review includes the current understanding of how psoriasis develops and discusses the recent findings to support further research in this area. The composition of the gut microbiome affects inflammation in the whole body. This inflammation is associated with cardiovascular disease, diabetes mellitus and other inflammatory disorders. Recent studies have linked cardiovascular disease, insulin resistance, and metabolic syndrome to an imbalance in the gut microbiome. Psoriasis is often found alongside these conditions with similar abnormalities in gut bacteria. An imbalance in gut microbiome could cause certain people to develop psoriasis. The role of the gut microbiome needs to be further clarified but mounting evidence for this gut/skin link means that other therapeutic options may be available for treatment in the future.
Abstract
Psoriasis is a chronic inflammatory cutaneous disease, characterized by activated plasmacytoid dendritic cells, myeloid dendritic cells, Th17 cells, and hyperproliferating keratinocytes. Recent studies revealed skin-resident cells have pivotal roles in developing psoriatic skin lesions. The balance in effector T cells and regulatory T cells is disturbed, leading Foxp3-positive regulatory T cells to produce proinflammatory IL-17. Not only acquired but also innate immunity is important in psoriasis pathogenesis, especially in triggering the disease. Group 3 innate lymphoid cell are considered one of IL-17-producing cells in psoriasis. Short chain fatty acids produced by gut microbiota stabilize expression of Foxp3 in regulatory T cells, thereby stabilizing their function. The composition of gut microbiota influences the systemic inflammatory status, and associations been shown with diabetes mellitus, cardiovascular diseases, psychomotor diseases, and other systemic inflammatory disorders. Psoriasis has been shown to frequently comorbid with diabetes mellitus, cardiovascular diseases, psychomotor disease and obesity, and recent report suggested the similar abnormality in gut microbiota as the above comorbid diseases. However, the precise mechanism and relation between psoriasis pathogenesis and gut microbiota needs further investigation. This review introduces the recent advances in psoriasis research and tries to provide clues to solve the mysterious relation of psoriasis and gut microbiota.
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Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections.
Calder, PC, Carr, AC, Gombart, AF, Eggersdorfer, M
Nutrients. 2020;12(4)
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Acute respiratory tract infections are a major cause of morbidity and mortality across the globe with seasonal influenza epidemics and outbreaks of viruses, such as Covid-19. The authors support public hygiene practices and the development of vaccinations however call for further strategies in order to reduce the impact that these infections have on societies. The role nutrition plays in supporting the immune system is well established. This review article and opinion piece presents the evidence for Vitamins A, B6, B12, C, D, E and folate; trace elements including zinc, selenium, magnesium and copper; and omega-3 fatty acids in supporting the immune system. The authors call for the consumption of a well-balanced diet, with additional supplementation of key immune supportive nutrients. Well referenced and with a helpful table of the rationale and recommended nutrient intake levels, Nutrition Practitioners will find this article useful when working to support client immune health.
Abstract
Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.
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Impact of dietary anthocyanins on systemic and vascular inflammation: Systematic review and meta-analysis on randomised clinical trials.
Fallah, AA, Sarmast, E, Fatehi, P, Jafari, T
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2020;135:110922
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Low-grade chronic inflammation contributes to the development of various chronic conditions like diabetes mellitus type2, chronic kidney disease, stroke, atherosclerosis, cardiovascular diseases, and cancer. Anthocyanins, a member of the flavonoid family, are water-soluble pigments that give plants their red-orange to blue-violet colours and have been shown to have antioxidant properties. The aim of this review and meta-analysis of 32 randomised controlled trials was to evaluate the impact of pure anthocyanins or anthocyanin-rich extracts/powders on inflammatory markers. The quality of studies for the meta-analysis was high for the inflammatory markers CRP (C-reactive protein), IL-6, TNF-alpha, adiponectin, and VCAM-1. There was a significant reduction in the pro-inflammatory CRP, IL-6, TNF-alpha and VCAM-1, and a significant increase in the anti-inflammatory adinopectin. Quality of studies was poor for other inflammatory markers evaluated. Higher doses tended to have a bigger positive effect. The authors conclude that anthocyanins may reduce inflammation.
Abstract
Anthocyanins are natural bioactive compounds that have several health benefits. This systematic review and meta-analysis assessed the impact of dietary anthocyanins on markers of systemic and vascular inflammation. Meta-analysis of 32 randomised controlled trials indicated that dietary anthocyanins significantly decreased levels of C-reactive protein (CRP; -0.33 mg/l, 95% CI: -0.55 to -0.11, P = 0.003), interleukin-6 (IL-6; -0.41 ρg/ml, 95% CI: -0.70 to -0.13, P = 0.004), tumor necrosis factor-alpha (TNF-α; -0.64 ρg/ml, 95% CI: -1.18 to -0.09, P = 0.023), intercellular adhesion molecule-1 (-52.4 ng/ml, 95% CI: -85.7 to -19.1, P = 0.002), and vascular adhesion molecule-1 (VCAM-1; -49.6 ng/ml, 95% CI: -72.7 to -26.5, P < 0.001) while adiponectin level was significantly increased (0.75 μg/ml, 95% CI: 0.23 to 1.26, P = 0.004). The levels of interleukin-1β (IL-1β; -0.45 ρg/ml, 95% CI: -3.77 to 2.88, P = 0.793) and P-selectin (-6.98 ng/ml, 95% CI: -18.1 to 4.15, P = 0.219) did not significantly change. Subgroup analyses showed that administration of higher doses of anthocyanins (>300 mg/day) significantly decreased levels of CRP, IL-6, TNF-α, and VCAM-1. The results indicate that dietary anthocyanins reduce the levels of systemic and vascular inflammation in the subjects.
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Anti-aging Effects of Calorie Restriction (CR) and CR Mimetics based on the Senoinflammation Concept.
Kim, DH, Bang, E, Jung, HJ, Noh, SG, Yu, BP, Choi, YJ, Chung, HY
Nutrients. 2020;12(2)
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Low grade, systemic, chronic inflammation is a feature of ageing and underlies many age-related chronic diseases states. As cells age their capacity to proliferate declines, which is referred to as cell senescence. Such senescent cells release multiple inflammatory markers contributing to a pro-inflammatory state. This is further aggravated by elevated oxidative stress and a reduced capacity to manage it, eventually leading to improper gene regulation and DNA damage. To define this age-related, complex inflammatory phenomena the authors introduced the term senoinflammation. A well-established intervention to reverse or slow down the ageing process and many ageing-associated diseases is calorie restriction (CR), by means of reducing overall caloric intake without malnutrition. CR exhibits potent anti-inflammatory effects, reduces age-associated oxidative stress, improves age-related metabolic dysregulation and enhances favourable gene expression. This review summarises how CR and CR-mimicking substances exert their anti-inflammatory effect and some of the cellular mechanism involved and may be of interest to those who are looking to get a more detailed understanding on ageing, inflammation and the benefits of CR.
Abstract
Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.
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The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.
Ilie, PC, Stefanescu, S, Smith, L
Aging clinical and experimental research. 2020;32(7):1195-1198
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The World Health Organisation declared COVID-19 caused by the virus SARS-CoV-2 a global pandemic. ACE-2 is the host cell receptor responsible for mediating infection by SARS-CoV-2. The main aim of this study was to assess the association between the mean levels of vitamin D in various countries and the mortality caused by COVID-19. A secondary aim was to identify any association/s between the mean vitamin D levels in various countries and the number of cases of COVID-19. This study is a cross-sectional analysis of based on studies carried out on European countries. Results indicate a potential crude association between the mean vitamin D levels in various European countries with COVID-19 cases and COVID-19 mortality. Authors conclude that further studies about vitamin D levels in COVID-19 patients with different degrees of disease severity should be performed.
Abstract
WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired. Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.
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Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes.
Zhu, L, She, ZG, Cheng, X, Qin, JJ, Zhang, XJ, Cai, J, Lei, F, Wang, H, Xie, J, Wang, W, et al
Cell metabolism. 2020;31(6):1068-1077.e3
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The novel coronavirus disease 2019 (COVID-19) is caused by infection from the newly emerged, highly contagious coronavirus SARS-CoV-2. The aim of this study was to analyse the association between plasma glucose levels and clinic outcomes in COVID-19 patients with type 2 diabetes (T2D). The study is a retrospective longitudinal, multi-centre study from a cohort of 7,337 COVID-19 cases enrolled among 19 hospitals. Results show that patients with pre-existing T2D received significantly more intensive integrated treatments to manage their symptoms of COVID-19 than the non-diabetic subjects. Furthermore, findings indicate that well-controlled blood glucose was associated with a markedly improved outcome of patients with COVID-19 and pre-existing T2D. Authors conclude that T2D is an important risk factor for COVID-19 progression and adverse endpoints, and well-controlled blood glucose is associated with a significant reduction in the composite adverse outcomes and death.
Abstract
Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.
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The impact of nutrition on COVID-19 susceptibility and long-term consequences.
Butler, MJ, Barrientos, RM
Brain, behavior, and immunity. 2020;87:53-54
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The impacts of Covid-19 are being felt across the world, affecting health, healthcare and economies. Statistics from across the world are showing that the elderly, those with underlying medical conditions and under-represented minority groups are particularly vulnerable to severe complications and have a higher risk of dying of Covid-19. This opinion piece presents arguments for the importance of focusing on diet to support health resilience in general and the immune system in particular, to minimise the impact of this and future viruses. Research is presented on excessive intake of saturated fat leading to chronic activation of the innate immune system (first line, rapid defence against infection), resulting in inflammation, and associated heightened susceptibility to complications of viral infection. The standard western diet (high saturated fat, refined carbohydrates and sugars, low levels of fibre, unsaturated fat and antioxidants) has also been shown to affect the adaptive immune system (second line, delayed defence against infection), depressing its action against infection. The piece also discusses possible long-term, future impacts of those recovered from Covid-19 infection, particularly in relation to neurodegenerative diseases such as Alzheimer’s. The authors call for fresh, healthy wholefoods to be readily available and affordable to everyone in society.
Abstract
While all groups are affected by the COVID-19 pandemic, the elderly, underrepresented minorities, and those with underlying medical conditions are at the greatest risk. The high rate of consumption of diets high in saturated fats, sugars, and refined carbohydrates (collectively called Western diet, WD) worldwide, contribute to the prevalence of obesity and type 2 diabetes, and could place these populations at an increased risk for severe COVID-19 pathology and mortality. WD consumption activates the innate immune system and impairs adaptive immunity, leading to chronic inflammation and impaired host defense against viruses. Furthermore, peripheral inflammation caused by COVID-19 may have long-term consequences in those that recover, leading to chronic medical conditions such as dementia and neurodegenerative disease, likely through neuroinflammatory mechanisms that can be compounded by an unhealthy diet. Thus, now more than ever, wider access to healthy foods should be a top priority and individuals should be mindful of healthy eating habits to reduce susceptibility to and long-term complications from COVID-19.
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Clinical significance of nutritional risk screening for older adult patients with COVID-19.
Liu, G, Zhang, S, Mao, Z, Wang, W, Hu, H
European journal of clinical nutrition. 2020;74(6):876-883
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Literature shows that nutritional deficiency is common and serious in the elderly, with studies reporting malnourishment in 35–65% of elderly hospitalized patients and 25–60% of institutionalized older adults. The aim of this study to explore the relationship between nutritional risk and clinical outcome in patients older than 65 years with COVID-19. A secondary outcome was to investigate the ability of the (nutritional risk screening) NRS tools to predict worse-than-average clinical outcomes. The study is a retrospective cohort analysis which enrolled 141 patients (females n = 73). Patients were classified into either a normal group or a nutritional risk group according to the criterion of each NRS tool. Results indicate that patients with COVID-19 who classified as having a nutritional risk had significantly poorer clinical outcomes than those classified as normal following assessments by Nutrition Risk Screening 2002 (NRS 2002), Mini Nutrition Assessment Shortcut (MNA-sf), and Nutrition Risk Index (NRI). Authors conclude that the NRS 2002, MNAsf, and NRI are useful and practical tools for identifying older adult patients with COVID-19 who are at nutritional risk.
Abstract
OBJECTIVES The aim of this study was to assess the nutritional risks among older patients with COVID-19 and their associated clinical outcomes using four nutritional risk screening (NRS) tools: Nutrition Risk Screening 2002 (NRS 2002), Malnutrition Universal Screening Tool (MUST), Mini Nutrition Assessment Shortcut (MNA-sf), and Nutrition Risk Index (NRI). METHODS We retrospectively analyzed the data of patients with COVID-19 older than 65 years who were treated in our hospital from January 28, 2020 to March 5, 2020, and explored the relationship between nutritional risk and clinical outcomes. RESULTS A total of 141 patients with COVID-19 (46 common COVID-19, 73 severe COVID-19, and 22 extremely severe COVID-19) were enrolled in the study. NRS 2002 identified 85.8% of patients as having risk, with being identified 41.1% by MUST, 77.3% by MNA-sf, and 71.6% by NRI. The agreement strength was moderate between NRS 2002 and MNA-sf, NRI, fair between MUST and MNA-sf, NRI, fair between MNA-sf and NRI, poor between NRS 2002 and MUST (P < 0.01). After adjustment for confounding factors in multivariate regression analysis, patients in the risk group had significantly longer LOS, higher hospital expenses (except MNA-sf), poor appetite, heavier disease severity, and more weight change(kg) than normal patients by using NRS 2002, MNA-sf, and NRI(P < 0.05). CONCLUSIONS The NRS 2002, MNA-sf, and NRI are useful and practical tools with respect to screening for patients with COVID-19 who are at nutritional risk, as well as in need of additional nutritional intervention.
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Brown Adipose Crosstalk in Tissue Plasticity and Human Metabolism.
Scheele, C, Wolfrum, C
Endocrine reviews. 2020;41(1)
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Brown adipose tissue (BAT) is an important contributor to the regulation of metabolism via cellular communication with organs such as liver, muscle, gut and central nervous system. BAT is important for heat generation and is at high levels in human infants. Levels of activation of BAT decline as we age and it has been shown that the amount of BAT is smaller and its activity reduced in those with obesity and type 2 diabetes. To date, there is no answer to efficiently restore functional BAT in aging and obese subjects. This review looks at experiments done on the factors secreted from active BAT (batokines). The review aims to provide a structure for the processes and cell types involved in BAT and the recent findings of BAT whole-body communication are discussed. Altogether, these findings demonstrate that BAT has an adaptive capacity. Studying batokines, offers an alternative approach to identify novel drug targets for metabolic regulation.
Abstract
Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).