Adequate protein intake is essential for muscle growth and maintenance, as it provides the necessary amino acids for muscle synthesis and repair.

Protein has a high satiety value, which can help reduce hunger and calorie intake, supporting weight loss and weight management.

Higher protein intake has been associated with better bone health and a reduced risk of osteoporosis, due to its role in bone structure.

Protein is essential for the production of antibodies and immune cells, helping to maintain a strong and healthy immune system.

Protein is necessary for the repair and maintenance of various tissues in the body, including skin, hair, and nails.

Iron is necessary for the production of hemoglobin, a protein in red blood cells that carries oxygen from the lungs to the body's tissues.

Iron plays a key role in energy metabolism and is essential for the synthesis of ATP, the body's primary source of cellular energy.

Iron is involved in the production of white blood cells and antibodies, which support the body's immune system.

Selenium's role as an antioxidant is one of the most well-known and often cited benefits. This mineral is a key part of several enzymes necessary for protecting the body against oxidative damage and infection.

Selenium's crucial role in thyroid hormone metabolism is widely recognized. It contributes to converting thyroid hormone T4 (thyroxine) into its active form T3 (triiodothyronine).

Selenium's role in enhancing the immune system's response to infections is another commonly cited benefit. It's believed to boost the body's defense against bacterial and viral infections.

Niacin has been shown to lower LDL cholesterol levels, which may help reduce the risk of heart disease and stroke.

Niacin can help increase HDL cholesterol levels, improving the overall cholesterol profile and supporting heart health.

Niacin plays a vital role in the production of various neurotransmitters, supporting cognitive function and mental health.

Some research suggests that niacin may help improve blood sugar control in people with type 2 diabetes by enhancing insulin sensitivity.

Niacin has anti-inflammatory properties and can help improve skin health by reducing redness, inflammation, and symptoms of certain skin conditions.

Vitamin B-12 is essential for the production of red blood cells in the body. Deficiency can lead to a specific type of anemia called megaloblastic anemia.

Vitamin B-12 is needed for proper brain function and the synthesis of neurotransmitters. It may also play a role in preventing brain atrophy and memory loss associated with aging.

Vitamin B-12 is often touted for its role in energy production. It helps convert the food you eat into glucose, which gives you energy.

Beta-carotene is a precursor to vitamin A, which is essential for maintaining good vision and reducing the risk of age-related macular degeneration.

Phytosterols in the diet could help lower cholesterol levels.

Some studies suggest that carrots may provide cardiovascular protection through compounds which reduce oxidative stress and inflammation.

Studies suggest that celery may help lower blood pressure

Olive oil contains a number of compounds that have been shown to have anti-inflammatory effects, potentially reducing the risk of chronic diseases such as heart disease, cancer, and Alzheimer's.

Olive oil is rich in monounsaturated and polyunsaturated fats, which have been shown to have cardiovascular benefits such as reducing LDL ("bad") cholesterol and reducing the risk of heart disease.

Some studies have suggested that olive oil consumption may be associated with improved cognitive function and reduced risk of cognitive decline and Alzheimer's disease. However, more research is needed to confirm these findings.

Olive oil has been shown to have a number of digestive health benefits, including reducing inflammation, improving gut microbiota, and reducing the risk of digestive disorders such as inflammatory bowel disease.

Some studies have suggested that olive oil consumption may be associated with a reduced risk of certain types of cancer, including breast and colorectal cancer. However, more research is needed to confirm these findings.

Studies have shown that quercetin can inhibit inflammation and reduce oxidative stress, which can contribute to chronic diseases such as heart disease, diabetes, and cancer.

Research has suggested that quercetin may have cardioprotective effects, such as reducing blood pressure, inhibiting platelet aggregation, and improving endothelial function. However, more research is needed to confirm these findings.

Some studies have found that quercetin supplementation may improve endurance exercise performance and reduce fatigue. However, results are mixed, and more research is needed to establish the effectiveness of quercetin for this purpose.

Studies have shown that quercetin can induce apoptosis (programmed cell death) in cancer cells and inhibit the growth and spread of tumors in animal studies. However, more research is needed to determine its effectiveness in humans.

Some studies have suggested that quercetin may have neuroprotective effects and improve cognitive function in animal models and human trials.

Quercetin could have the ability to counteract PCOS complications.

Onion consumption has been shown to have cardioprotective effects

In particular, lowering the risk of cancer.

Vitamin K plays a key role in maintaining bone health. It is involved in the modification of osteocalcin, a protein that strengthens the composition of bones.

Vitamin K is believed to help prevent the hardening of arteries, which can reduce the risk of heart disease.

Thymol could be especially beneficial for helping to prevent cancer and inflamation.

Pot Roast

Water

Energy

Energy (by joule)

Protein

Total lipid (fat)

Carbohydrate, by difference

Calcium, Ca

Iron, Fe

Magnesium, Mg

Phosphorus, P

Potassium, K

Sodium, Na

Zinc, Zn

Copper, Cu

Manganese, Mn

Selenium, Se

Thiamin

Riboflavin

Niacin

Pantothenic acid

Vitamin B-6

Folate, total

Folate, food

Folate, DFE

Choline, total

Betaine

Vitamin B-12

Vitamin A, RAE

Retinol

Vitamin A, IU

Vitamin E (alpha-tocopherol)

Vitamin D (D2 + D3), International Units

Vitamin D (D2 + D3)

Vitamin D3 (cholecalciferol)

Vitamin K (phylloquinone)

Fatty acids, total saturated

SFA 14:0

SFA 16:0

SFA 17:0

SFA 18:0

SFA 24:0

Fatty acids, total monounsaturated

MUFA 14:1

MUFA 16:1

MUFA 17:1

MUFA 18:1

MUFA 18:1 c

MUFA 18:1-11 t (18:1t n-7)

MUFA 20:1

Fatty acids, total polyunsaturated

PUFA 18:2

PUFA 18:2 n-6 c,c

PUFA 18:2 CLAs

PUFA 18:3

PUFA 18:3 n-3 c,c,c (ALA)

PUFA 20:4

PUFA 20:5 n-3 (EPA)

Fatty acids, total trans

Fatty acids, total trans-monoenoic

TFA 18:1 t

Cholesterol

Tryptophan

Threonine

Isoleucine

Leucine

Lysine

Methionine

Cystine

Phenylalanine

Tyrosine

Valine

Arginine

Histidine

Alanine

Aspartic acid

Glutamic acid

Glycine

Proline

Serine

Hydroxyproline

Fiber, total dietary

Sugars, total including NLEA

Sucrose

Glucose

Fructose

Starch

Fluoride, F

Vitamin C, total ascorbic acid

Carotene, beta

Carotene, alpha

Lycopene

Lutein + zeaxanthin

Tocopherol, beta

Tocotrienol, alpha

Phytosterols

Galactose

Tocopherol, gamma

SFA 20:0

SFA 22:0

Beef (Chuck for stew)

Carrot

Celery

Olive Oil

Onion

Parsley

Red Wine

Thyme

Weight loss is the cornerstone of therapy for people with obesity because it can ameliorate or completely resolve the metabolic risk factors for diabetes, coronary artery disease, and obesity-associated cancers. The potential health benefits of diet-induced weight loss are thought to be compromised by the weight-loss-associated loss of lean body mass, which could increase the risk of sarcopenia (low muscle mass and impaired muscle function). The objective of this review is to provide an overview of what is known about weight-loss-induced muscle loss and its implications for overall physical function (e.g., ability to lift items, walk, and climb stairs). The currently available data in the literature show the following: 1) compared with persons with normal weight, those with obesity have more muscle mass but poor muscle quality; 2) diet-induced weight loss reduces muscle mass without adversely affecting muscle strength; 3) weight loss improves global physical function, most likely because of reduced fat mass; 4) high protein intake helps preserve lean body and muscle mass during weight loss but does not improve muscle strength and could have adverse effects on metabolic function; 5) both endurance- and resistance-type exercise help preserve muscle mass during weight loss, and resistance-type exercise also improves muscle strength. We therefore conclude that weight-loss therapy, including a hypocaloric diet with adequate (but not excessive) protein intake and increased physical activity (particularly resistance-type exercise), should be promoted to maintain muscle mass and improve muscle strength and physical function in persons with obesity.

Preserving Healthy Muscle during Weight Loss.

Skeletal muscle is an integral body tissue playing key roles in strength, performance, physical function, and metabolic regulation. It is essential for athletes to ensure that they have optimal amounts of muscle mass to ensure peak performance in their given sport. However, the role of maintaining muscle mass during weight loss and as we age is an emerging concept, having implications in chronic disease prevention, functional capacity, and quality of life. Higher-protein diets have been shown to: (1) promote gains in muscle mass, especially when paired with resistance training; (2) spare muscle mass loss during caloric restriction; and (3) attenuate the natural loss of muscle mass that accompanies aging. Protein quality is important to the gain and maintenance of muscle mass. Protein quality is a function of protein digestibility, amino acid content, and the resulting amino acid availability to support metabolic function. Whey protein is one of the highest-quality proteins given its amino acid content (high essential, branched-chain, and leucine amino acid content) and rapid digestibility. Consumption of whey protein has a robust ability to stimulate muscle protein synthesis. In fact, whey protein has been found to stimulate muscle protein synthesis to a greater degree than other proteins such as casein and soy. This review examines the existing data supporting the role for protein consumption, with an emphasis on whey protein, in the regulation of muscle mass and body composition in response to resistance training, caloric restriction, and aging.

Supplemental protein in support of muscle mass and health: advantage whey.

The purpose of this work was to determine the effects of varying levels of dietary protein on body composition and muscle protein synthesis during energy deficit (ED). A randomized controlled trial of 39 adults assigned the subjects diets providing protein at 0.8 (recommended dietary allowance; RDA), 1.6 (2×-RDA), and 2.4 (3×-RDA) g kg(-1) d(-1) for 31 d. A 10-d weight-maintenance (WM) period was followed by a 21 d, 40% ED. Body composition and postabsorptive and postprandial muscle protein synthesis were assessed during WM (d 9-10) and ED (d 30-31). Volunteers lost (P<0.05) 3.2 ± 0.2 kg body weight during ED regardless of dietary protein. The proportion of weight loss due to reductions in fat-free mass was lower (P<0.05) and the loss of fat mass was higher (P<0.05) in those receiving 2×-RDA and 3×-RDA compared to RDA. The anabolic muscle response to a protein-rich meal during ED was not different (P>0.05) from WM for 2×-RDA and 3×-RDA, but was lower during ED than WM for those consuming RDA levels of protein (energy × protein interaction, P<0.05). To assess muscle protein metabolic responses to varied protein intakes during ED, RDA served as the study control. In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat-free mass during short-term weight loss.

Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: a randomized controlled trial.

A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality. Arginine, glutamine and cysteine precursors are the best prototypes. Because of a negative impact of imbalance and antagonism among amino acids on nutrient intake and utilisation, care should be exercised in developing effective strategies of enteral or parenteral provision for maximum health benefits. Such measures should be based on knowledge about the biochemistry and physiology of amino acids, their roles in immune responses, nutritional and pathological states of individuals and expected treatment outcomes. New knowledge about the metabolism of amino acids in leucocytes is critical for the development of effective means to prevent and treat immunodeficient diseases. These nutrients hold great promise in improving health and preventing infectious diseases in animals and humans.

Amino acids and immune function.

Extracellular vesicles are membranous particles, ranging from 30 nm to 10 µm in diameter, which are released by nearly all cell types to aid in intercellular communication. These complex vesicles carry a multitude of signaling moieties from their cell of origin, such as proteins, lipids, cell surface receptors, enzymes, cytokines, metabolites, and nucleic acids. A growing body of evidence suggests that in addition to delivering cargos into target cells to facilitate intercellular communication, extracellular vesicles may also play roles in such processes as cell differentiation and proliferation, angiogenesis, stress response, and immune signaling. As these vesicles have natural biocompatibility, stability in circulation, low toxicity, and low immunogenicity, and serve as efficient carriers of molecular cargos, these nanoparticles are ideal therapeutic candidates for regenerative medicine. Exploring and identifying the homeostatic functions of extracellular vesicles may facilitate the development of new regenerative therapies. In this review, we summarize the wound healing process, difficulties in stem cell therapies for regenerative medicine, and the applications of mesenchymal stromal cell-derived extracellular vesicles in improving and accelerating the wound healing process.

Extracellular vesicles: Emerging frontiers in wound healing.

To provide evidence-based recommendations regarding the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists, primary care clinicians, health care professionals, and other stakeholders.

American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD).

Protein therapeutics have drastically changed the landscape of treatment for many diseases by providing a regimen that is highly specific and lacks many off-target toxicities. The clinical utility of many therapeutic proteins has been undermined by the potential development of unwanted immune responses against the protein, limiting their efficacy and negatively impacting its safety profile. This review attempts to provide an overview of immunogenicity of therapeutic proteins, including immune mechanisms and factors influencing immunogenicity, impact of immunogenicity, preclinical screening methods, and strategies to mitigate immunogenicity.

Immunogenicity of Protein Pharmaceuticals.

Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia.

During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.

Muscles, exercise and obesity: skeletal muscle as a secretory organ.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Sphingosine 1-phosphate: Lipid signaling in pathology and therapy.

There exists a large body of scientific evidence to support protein intakes in excess of the recommended dietary allowance (RDA) (0.8 g protein/kg/day) to promote the retention of skeletal muscle and loss of adipose tissue during dietary energy restriction. Diet-induced weight loss with as low as possible ratio of skeletal muscle to fat mass loss is a situation we refer to as high-quality weight loss. We propose that high-quality weight loss is often of importance to elite athletes in order to maintain their muscle (engine) and shed unwanted fat mass, potentially improving athletic performance. Current recommendations for protein intakes during weight loss in athletes are set at 1.6-2.4 g protein/kg/day. However, the severity of the caloric deficit and type and intensity of training performed by the athlete will influence at what end of this range athletes choose to be. Other considerations regarding protein intake that may help elite athletes achieve weight loss goals include the quality of protein consumed, and the timing and distribution of protein intake throughout the day. This review highlights the scientific evidence used to support protein recommendations for high-quality weight loss and preservation of performance in athletes. Additionally, the current knowledge surrounding the use of protein supplements, branched chain amino acids (BCAA), β-hydroxy β-methylbutyrate (HMB), and other dietary supplements with weight loss claims will be discussed.

Protein Recommendations for Weight Loss in Elite Athletes: A Focus on Body Composition and Performance.

Although daily protein intake (PI) has been reported to be essential for regulating muscle mass, the distribution of daily PI in individuals is typically the lowest at breakfast and skewed toward dinner. Skewed protein intake patterns and inadequate PI at breakfast were reported to be negative factors for muscle maintenance.

Evenly Distributed Protein Intake over 3 Meals Augments Resistance Exercise-Induced Muscle Hypertrophy in Healthy Young Men.

A precise understanding of the role of dietary protein in bone health has been evasive despite decades of research. It is known that a dietary acid load is harmful to bone, and sulfur-containing amino acids are metabolized to provide such an acid load. It is also known that protein elevates urine calcium loss. However, recent clinical studies and a meta-analysis have indicated either no effect or a modest benefit associated with higher protein intakes. These contradictory considerations may be explained by the existence of a two-faced relationship between protein and bone, with simultaneous positive and negative pathways. In opposition to the negative effects of dietary acid load, protein may exert positive effects related to improving calcium absorption, increasing insulin-like growth factor 1, or improving lean body mass, which, in turn, improves bone strength. Putative mechanisms behind these pathways are reviewed here, and some limitations in the historical literature as well as suggested measures to counter these in the future are identified. When positive and negative pathways are considered in tandem, protein may offer modest benefits to bone in the presence of adequate dietary calcium and acid-neutralizing fruits and vegetables.

Dietary protein and bone health: harmonizing conflicting theories.

Flow cytometry is a routinely available laboratory method to study cells in suspension from a variety of human sources. Application of this technology as a clinical laboratory method has evolved from the identification of cell-surface proteins to characterizing intracellular proteins and providing multiple different techniques to assess specific features of adaptive and innate immune function. This expanded menu of flow cytometric testing approaches has increased the utility of this platform in characterizing and diagnosing disorders of immune function.

Flow cytometry: Surface markers and beyond.

Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.

Role of advanced glycation end products in cellular signaling.

There is a current need for a therapy that can alleviate the social and economic burden that presents itself with debilitating and recurring musculoskeletal soft tissue injuries and disorders. Currently, several therapies are emerging and undergoing trials in animal models; these focus on the manipulation and administration of several growth factors implicated with healing. However, limitations include in vivo instability, reliance on biocompatible and robust carriers and restricted application procedures (local and direct). The aim of this paper is therefore to critically review the current literature surrounding the use of BPC 157, as a feasible therapy for healing and functional restoration of soft tissue damage, with a focus on tendon, ligament and skeletal muscle healing. Currently, all studies investigating BPC 157 have demonstrated consistently positive and prompt healing effects for various injury types, both traumatic and systemic and for a plethora of soft tissues. However, to date, the majority of studies have been performed on small rodent models and the efficacy of BPC 157 is yet to be confirmed in humans. Further, over the past two decades, only a handful of research groups have performed in-depth studies regarding this peptide. Despite this, it is apparent that BPC 157 has huge potential and following further development has promise as a therapy to conservatively treat or aid recovery in hypovascular and hypocellular soft tissues such as tendon and ligaments. Moreover, skeletal muscle injury models have suggested a beneficial effect not only for disturbances that occur as a result of direct trauma but also for systemic insults including hyperkalamia and hypermagnesia. Promisingly, there are few studies reporting any adverse reactions to the administration of BPC 157, although there is still a need to understand the precise healing mechanisms for this therapy to achieve clinical realisation.

Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing.

Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm2; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.

A Vitamin D, Calcium and Leucine-Enriched Whey Protein Nutritional Supplement Improves Measures of Bone Health in Sarcopenic Non-Malnourished Older Adults: The PROVIDE Study.

Adequate consumption of dietary protein is critical for the maintenance of optimal health during normal growth and aging. The current Recommended Dietary Allowance (RDA) for protein is defined as the minimum amount required to prevent lean body mass loss, but is often misrepresented and misinterpreted as a recommended optimal intake. Over the past two decades, the potential muscle-related benefits achieved by consuming higher-protein diets have become increasingly clear. Despite greater awareness of how higher-protein diets might be advantageous for muscle mass, actual dietary patterns, particularly as they pertain to protein, have remained relatively unchanged in American adults. This lack of change may, in part, result from confusion over the purported detrimental effects of higher-protein diets. This manuscript will highlight common perceptions and benefits of dietary protein on muscle mass, address misperceptions related to higher-protein diets, and comment on the translation of academic advances to real-life application and health benefit. Given the vast research evidence supporting the positive effects of dietary protein intake on optimal health, we encourage critical evaluation of current protein intake recommendations and responsible representation and application of the RDA as a minimum protein requirement rather than one determined to optimally meet the needs of the population.

Dietary Protein and Muscle Mass: Translating Science to Application and Health Benefit.

Bone fragility is a major health concern, as the increased risk of bone fractures has devastating outcomes in terms of mortality, decreased autonomy, and healthcare costs. Efforts made to address this problem have considerably increased our knowledge about the mechanisms that regulate bone formation and resorption. In particular, we now have a much better understanding of the cellular events that are triggered when bones are mechanically stimulated and how these events can lead to improvements in bone mass. Despite these findings at the molecular level, most exercise intervention studies reveal either no effects or only minor benefits of exercise programs in improving bone mineral density (BMD) in osteoporotic patients. Nevertheless, and despite that BMD is the gold standard for diagnosing osteoporosis, this measure is only able to provide insights regarding the quantity of bone tissue. In this article, we review the complex structure of bone tissue and highlight the concept that its mechanical strength stems from the interaction of several different features. We revisited the available data showing that bone mineralization degree, hydroxyapatite crystal size and heterogeneity, collagen properties, osteocyte density, trabecular and cortical microarchitecture, as well as whole bone geometry, are determinants of bone strength and that each one of these properties may independently contribute to the increased or decreased risk of fracture, even without meaningful changes in aBMD. Based on these findings, we emphasize that while osteoporosis (almost) always causes bone fragility, bone fragility is not always caused just by osteoporosis, as other important variables also play a major role in this etiology. Furthermore, the results of several studies showing compelling data that physical exercise has the potential to improve bone quality and to decrease fracture risk by influencing each one of these determinants are also reviewed. These findings have meaningful clinical repercussions as they emphasize the fact that, even without leading to improvements in BMD, exercise interventions in patients with osteoporosis may be beneficial by improving other determinants of bone strength.

Bone quality: the determinants of bone strength and fragility.

The auxin-inducible degron (AID) system has emerged as a powerful tool to conditionally deplete proteins in a range of organisms and cell types. Here, we describe a toolkit to augment the use of the AID system in Caenorhabditis elegans. We have generated a set of single-copy, tissue-specific (germline, intestine, neuron, muscle, pharynx, hypodermis, seam cell, anchor cell) and pan-somatic TIR1-expressing strains carrying a co-expressed blue fluorescent reporter to enable use of both red and green channels in experiments. These transgenes are inserted into commonly used, well-characterized genetic loci. We confirmed that our TIR1-expressing strains produce the expected depletion phenotype for several nuclear and cytoplasmic AID-tagged endogenous substrates. We have also constructed a set of plasmids for constructing repair templates to generate fluorescent protein::AID fusions through CRISPR/Cas9-mediated genome editing. These plasmids are compatible with commonly used genome editing approaches in the C. elegans community (Gibson or SapTrap assembly of plasmid repair templates or PCR-derived linear repair templates). Together these reagents will complement existing TIR1 strains and facilitate rapid and high-throughput fluorescent protein::AID tagging of genes. This battery of new TIR1-expressing strains and modular, efficient cloning vectors serves as a platform for straightforward assembly of CRISPR/Cas9 repair templates for conditional protein depletion.

An expanded auxin-inducible degron toolkit for Caenorhabditis elegans.

Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for >40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.

Plasminogen: an enigmatic zymogen.

Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.

Fibroblast growth factor 21 controls mitophagy and muscle mass.

Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP's immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators-interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP's cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses.

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion.

Ferroptosis is an iron-dependent cell death pathway and participates in various diseases. Current evidence suggests that ferroptosis can obviously affect the function of blood cells. This paper aims to elaborate the role of ferroptosis in blood cells and related diseases. First, abnormal ferroptosis damages the developing red blood cells by breaking systemic iron homeostasis, leading to erythropoiesis suppression and anaemia. Ferroptosis mediates neutrophils recruitment and neutrophil extracellular trap formation (NETosis). In T-cells, ferroptosis induces a novel point of synergy between immunotherapy and radiotherapy. Additionally, ferroptosis may mediate B cells differentiation, antibody responses and lymphoma. Nevertheless, increased ferroptosis can ameliorate acute myeloid leukaemia and T-cell leukaemia/lymphoma by inducing iron-dependent cancer cells death. Besides, ferroptosis activates platelets by increasing P-selectin, thus causing thromboembolism. Ferroptosis mediates virus infection and parasite infection by driving T-cell death and preventing T-cell immunity. Interestingly, ferroptosis is also considered as a critical player in COVID-19 infections, while targetting ferroptosis may also improve thromboembolism and prognosis in patients with COVID-19 infection. Overall, the crucial role of ferroptosis in blood cells will show a new therapeutic potential in blood cell-related diseases.HighlightsFerroptosis shows a new therapeutic potential for blood cell-related diseases.Ferroptosis damages erythropoiesis and thus induces anaemia.Ferroptosis induces platelet activation and leads to thromboembolism.Ferroptosis regulates T-cell and B-cell immunity, which participant in infectious diseases.Inversely, ferroptosis ameliorates acute myeloid leukaemia and T-cell leukaemia.

Targetting ferroptosis for blood cell-related diseases.

Iron is an essential micronutrient for virtually all living cells. In infectious diseases, both invading pathogens and mammalian cells including those of the immune system require iron to sustain their function, metabolism and proliferation. On the one hand, microbial iron uptake is linked to the virulence of most human pathogens. On the other hand, the sequestration of iron from bacteria and other microorganisms is an efficient strategy of host defense in line with the principles of 'nutritional immunity'. In an acute infection, host-driven iron withdrawal inhibits the growth of pathogens. Chronic immune activation due to persistent infection, autoimmune disease or malignancy however, sequesters iron not only from infectious agents, autoreactive lymphocytes and neoplastic cells but also from erythroid progenitors. This is one of the key mechanisms which collectively result in the anemia of chronic inflammation. In this review, we highlight the most important interconnections between iron metabolism and immunity, focusing on host defense against relevant infections and on the clinical consequences of anemia of inflammation.

Iron in infection and immunity.

Anemia is common in elective surgery and is an independent risk factor for morbidity and mortality. Historical management of anemia has focused on the use of allogeneic blood transfusion but this in itself is not without risk. It too has been independently associated with morbidity and mortality, let alone the costs and relative shortage of this resource. In recognition of this, patient blood management (PBM) shifts the focus from the product to the patient and views the patient's own blood as a resource that should be conserved and managed appropriately as a standard of care. It consists of 3 pillars: the optimization of red blood cell mass; reduction of blood loss and bleeding; and optimization of the patient's physiological tolerance toward anemia. Integration of these 3 pillars in the form of multimodal care bundles and strategies into perioperative pathways should improve care processes and patient outcome. Preoperative anemia is most commonly caused by functional iron deficiency and should be treated with oral iron, intravenous iron, and/or recombinant erythropoietin. An individualized assessment of the thrombotic risk of discontinuing anticoagulant and antiplatelet medication should be balanced against the risk of perioperative bleeding. Neuraxial anesthetic techniques should be considered and minimally invasive surgery undertaken where appropriate. Cell salvage should be used if significant blood loss is anticipated and pharmacological treatments such as tranexamic acid and fibrin sealants have been shown to reduce blood loss. Point of care tests can guide the perioperative management of dynamic coagulopathy. Blood testing sampling should be performed only when indicated and when taken, sample volume and waste should be minimized. Restrictive blood transfusion thresholds and reassessment after single unit transfusion should be incorporated into clinical practice where appropriate. For PBM to become standard practice in routine surgical care, national health care quality change initiatives must set the agenda for change but the patient-centered approach to PBM should be delivered in a way that is also hospital centered. Characterization of the current practice of PBM at each hospital is crucial to facilitate the benchmarking of performance. Barriers to effective implementation such as lack of knowledge should be identified and acted on. Continuous audit of practice with a focus on transfusion rates and patient outcomes can identify areas in need of improvement and provide iterative feedback to motivate and inspire the main stakeholders.

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