Silicon and Plants: Current Knowledge and Technological Perspectives.

Elemental silicon (Si), after oxygen, is the second most abundant element in the earth's crust, which is mainly composed of silicates. Si is not considered essential for plant growth and development, however, increasing evidence in the literature shows that this metalloid is beneficial to plants, especially under stress conditions. Indeed Si alleviates the toxic effects caused by abiotic stresses, e.g., salt stress, drought, heavy metals, to name a few. Biogenic silica is also a deterrent against herbivores. Additionally, Si ameliorates the vigor of plants and improves their resistance to exogenous stresses. The protective role of Si was initially attributed to a physical barrier fortifying the cell wall (e.g., against fungal hyphae penetration), however, several studies have shown that the action of this element on plants is far more complex, as it involves a cross-talk with the cell interior and an effect on plant metabolism. In this study the beneficial role of Si on plants will be discussed, by reviewing the available data in the literature. Emphasis will be given to the protective role of Si during (a)biotic stresses and in this context both priming and the effects of Si on endogenous phytohormones will be discussed. A whole section will be devoted to the use of silica (SiO2) nanoparticles, in the light of the interest that nanotechnology has for agriculture. The paper also discusses the potential technological aspects linked to the use of Si in agriculture and to modify/improve the physical parameters of plant fibers. The study indeed provides perspectives on the use of Si to increase the yield of fiber crops and to improve the thermal stability and tensile strength of natural fibers.

Front Plant Sci. 2017 8: 411.

Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality.

Prospective, controlled clinical trials in postmenopausal osteoporosis typically compare effects of an active drug with placebo in addition to vitamin D and calcium supplementation in both treatment arms. While clinical benefits are documented, the effect of this supplementation in the placebo arm and in clinical practice on bone material composition properties is unknown. The purpose of the present study was to evaluate these bone quality indices (specifically mineral/matrix, nanoporosity, glycosaminoglycan content, mineral maturity/crystallinity, and pyridinoline content) in patients that either received long-term vitamin D (400-1200IU) and calcium (1.0-1.5g) supplementation, or did not. We have analyzed by Raman microspectroscopy the bone forming trabecular surfaces of iliac crest in pre-treatment samples of a teriparatide study and the endpoint biopsies of the control arm obtained from the HORIZON trial. In general, the mineral/matrix ratio and the glycosaminoglycan (GAG) content was higher while nanoporosity, (a surrogate for tissue water content), the mineral maturity/crystallinity (MMC) and the pyridinoline (Pyd) content was lower in patients without long-term supplementation. Moreover, all indices were significantly dependent on tissue age. In conclusion, vitamin D and calcium supplementation is associated with altered mineral and organic matrix properties.

Bone. 2017 Feb; 95: 41-46.

Cancer risk in patients with osteoporosis: a population-based cohort study.

BACKGROUND: Osteoporosis has been associated with cancer development. We conducted a nationwide population-based cohort study in Taiwan to evaluate this possible association of osteoporosis with subsequent cancer development. METHODS: A total of 35,979 patients diagnosed with osteoporosis between 2000 and 2010 identified from the National Health Insurance Research Database comprised the osteoporosis cohort, and each patient was randomly frequency matched with one individual from the general population (without osteoporosis) based on age, sex, and year of osteoporosis diagnosis to form the non-osteoporosis (control) cohort. Cox proportional hazard regression analysis was used to calculate adjusted hazard ratios and 95% confidence intervals and determine the effect of osteoporosis on cancer risk. RESULTS: Patients with osteoporosis showed a significantly higher risk of developing liver and thyroid cancers and lower risk of colorectal cancer than did individuals without osteoporosis. Male patients with osteoporosis had a significantly increased risk for liver cancer, whereas female patients with osteoporosis had a significantly increased risk for thyroid cancer, but a significantly decreased risk for overall and colorectal cancers. In addition, more significant findings were observed when age </=64 years or the follow-up duration was </=5 years; however, a significantly lower risk for colorectal cancer was observed when follow-up duration was >5 years. Study limits including lack of data for some health-related behaviors, inclusion criteria of osteoporosis and potential selection bias have been discussed. CONCLUSION: Patients with osteoporosis showed a higher risk for liver and thyroid cancers and a lower risk for colorectal cancer than did control individuals. Stratified analyses by sex, age, and follow-up duration showed various patterns in different cancers.

Curr Med Res Opin. 2017 Apr; 33(4): 733-739.

Decreased Bone Mineral Density Is an Independent Predictor for the Development of Atherosclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: There is conflicting evidence regarding the association between decreased bone mineral density (BMD) and atherosclerosis. To this end, we performed a systematic review and meta-analysis to clarify the association. METHODS: To identify relevant studies, PubMed, Embase, and the Cochrane Library were systematically searched up to November 2015. All observational and comparative studies directly investigating the relationship between decreased BMD and clinical consequences of atherosclerotic vascular abnormalities, including carotid artery calcification (CAC), cardiovascular disease (CAD), and coronary artery disease (CAD) were obtained, without limitation of language or publication year. RESULTS: A total of 25 studies involving 10,299 patients were included. The incidence of atherosclerotic vascular abnormalities was significantly increased in low BMD patients, compared to patients with normal BMD (OR, 1.81, 95% CI [1.01, 2.19], p<0.00001)). Similar results were also observed for postmenopausal women (OR, 2.23, 95% CI [1.72, 2.89], p<0.00001). Subgroup analyses of osteopenia, osteoporosis, and normal BMD also revealed that the combined ORs for the incidence of atherosclerotic vascular abnormalities increased as BMD decreased. Of note, after adjusting for age, sex, body mass index (BMI) and other vascular risk factors, decreased BMD remained significantly associated with the incidence of atherosclerotic vascular abnormalities (OR, 2.96, 95% CI [2.25, 3.88], p < 0.00001). CONCLUSIONS: Based on the results of this study, decreased BMD is an independent predictor for the development of atherosclerosis in elderly individuals. Moreover, the risk of atherosclerotic vascular abnormalities increased as BMD decreased. Future studies focusing on individuals with different severities of atherosclerosis and comorbidities are of interest.

PLoS One. 2016 11(5): e0154740.

Use of silicon for skin and hair care: an approach of chemical forms available and efficacy.

Silicon is the second most abundant element on Earth, and the third most abundant trace element in human body. It is present in water, plant and animal sources. On the skin, it is suggested that silicon is important for optimal collagen synthesis and activation of hydroxylating enzymes, improving skin strength and elasticity. Regarding hair benefits, it was suggested that a higher silicon content in the hair results in a lower rate of hair loss and increased brightness. For these beneficial effects, there is growing interest in scientific studies evaluating the efficacy and safety of using dietary supplements containing silicon. Its use aims at increasing blood levels of this element and improving the skin and its annexes appearance. There are different forms of silicon supplements available and the most important consideration to be made in order to select the best option is related to safety and bioavailability. Silicon supplements are widely used, though there is wide variation in silicon bioavailability, ranging from values below 1% up to values close to 50%, depending on the chemical form. Therefore, the aim of this study was to evaluate the scientific literature related to the different chemical forms of silicon supplements available and the limitations and recent progress in this field. According to reported studies, among the different chemical forms available, the orthosilicic acid (OSA) presents the higher bioavailability, whereas the others forms have absorption inversely proportional to the degree of polymerization. However, clinical studies evaluating safety and efficacy are still lacking.

An Bras Dermatol. 2016 May-Jun; 91(3): 331-335.

An Insight into the Changes in Skin Texture and Properties following Dietary Intervention with a Nutricosmeceutical Containing a Blend of Collagen Bioactive Peptides and Antioxidants.

BACKGROUND: Skin aging is a multifactorial phenomenon which causes alterations in skin physiological functions and, most visibly, phenotypic changes. In particular, during the aging process, hyaluronic acid, collagen, and elastin fibers undergo structural and functional changes. AIMS: This study aimed to give an insight into the photo-protective benefits and efficacy of an oral liquid nutricosmeceutical containing collagen bioactive peptides and antioxidants to counteract the signs of aging. METHODS: A double-blind, randomized, placebo-controlled clinical trial was conducted by an independent esthetic clinic on 120 healthy volunteer subjects for 90 days. Subjects were divided into 2 groups: 60 subjects consumed 1 bottle (50 mL) of the nutricosmeceutical daily and the other 60 consumed 1 bottle (50 mL) of the placebo. Outcome measures were related to skin elasticity (expressed as Young's elasticity modulus) and skin architecture (histological analysis). In addition, the subjects recruited in this study underwent observational assessments through self-assessment questionnaires. RESULTS AND CONCLUSIONS: Overall, we demonstrated a significant increase in skin elasticity (+7.5%), p </= 0.001 and an improvement in skin texture after daily oral consumption of the nutricosmeceutical. We also obtained a positive patient feedback through the self-assessment questionnaires. Taken together these results show that this nutricosmeceutical supplement may have photo-protective effects and help improve skin health.

Skin Pharmacol Physiol. 2017 30(3): 146-158.

Oral supplementation with specific bioactive collagen peptides improves nail growth and reduces symptoms of brittle nails.

BACKGROUND: Brittle nail syndrome is a common problem among women and refers to nails that exhibit surface roughness, raggedness, and peeling. AIM: The goal of this study was to investigate whether daily oral supplementation with collagen peptides alleviates the symptoms of brittle nails and improves nail growth rate. METHODS: In this open-label, single-center trial, 25 participants took 2.5 g of specific bioactive collagen peptides (BCP, VERISOL(R) ) once daily for 24 weeks followed by a 4-week off-therapy period. Nail growth rate and the frequency of cracked and/or chipped nails as well as an evaluation of symptoms and global clinical improvement score of brittle nails were assessed by a physician during treatment and 4 weeks after discontinuation. RESULTS: Bioactive collagen peptides treatment promoted an increase of 12% nail growth rate and a decrease of 42% in the frequency of broken nails. Additionally, 64% of participants achieved a global clinical improvement in brittle nails, and 88% of participants experienced an improvement 4 weeks post-treatment. The majority of participants (80%) agreed that the use of BCP improved their nails' appearance, and were completely satisfied with the performance of the treatment. CONCLUSIONS: This study demonstrated that the daily ingestion of BCP increased nail growth and improved brittle nails in conjunction with a notable decrease in the frequency of broken nails.

J Cosmet Dermatol. 2017 Aug 08.

Photochemical crosslinking of soluble wool keratins produces a mechanically stable biomaterial that supports cell adhesion and proliferation.

Keratins extracted from various "hard tissues" such as wool, hair, and nails are increasingly being investigated as a source of abundant, biocompatible materials. In this study we explored a recent photochemical method to crosslink solubilized wool keratoses, with the aim of producing a mechanically favorable biomaterial. Wool proteins were isolated by oxidizing the disulfides and extracting the resulting soluble keratoses. The alpha- and gamma-keratose fractions were analyzed by liquid chromatography-mass spectrometry to identify their constituent proteins. Hydrogels were produced by covalent crosslinking of the alpha-keratoses via a photo-oxidative process catalyzed by blue light, a ruthenium complex, and persulfate. The presence of dityrosine crosslinks was demonstrated by high performance liquid chromatography and mass spectrometry analyses. The crosslinked alpha-keratose material had moderate tensile strength and elasticity, and high adhesive strength. The material displayed modest shrinking after crosslinking, however the shrinking could be prevented by crosslinking in the presence of 2.5% glycerol, resulting in gels that did not shrink or swell. Small solutes such as Tris and glycerol influenced the crosslink density and elastic modulus of the crosslinked material. The alpha-keratose was able to support adhesion and growth of NIH/3T3 fibroblasts in vitro. The fabrication of mechanically stable keratin biomaterials by this facile photo-crosslinking method may be useful for various tissue engineering applications.

J Biomed Mater Res A. 2010 Dec 1; 95(3): 901-911.

Dietary Supplementation with Specific Collagen Peptides Has a Body Mass Index-Dependent Beneficial Effect on Cellulite Morphology.

In this double-blind, placebo-controlled clinical study, we investigated the efficacy of specific bioactive collagen peptides (BCP) on the cellulite treatment of normal and overweight women. In total, 105 women aged 24-50 years with moderate cellulite were randomized to orally receive a daily dosage of 2.5 g BCP or a placebo over 6 months. The degree of cellulite was evaluated before starting the treatment and after 3 and 6 months of intake. In addition, skin waviness, dermal density, and the length of subcutaneous borderline were assessed. BCP treatment led to a statistically significant decrease in the degree of cellulite and a reduced skin waviness on thighs (P < 0.05) in normal weight women. Moreover, dermal density was significantly improved (P < 0.05) compared to placebo. The subcutaneous borderline showed a significant shortening after BCP intake compared to the beginning of the study, indicating cellulite improvement, but the data failed to reach statistical significance compared to placebo. The efficacy of BCP treatment was also confirmed in overweight women, although the impact was less pronounced in comparison with women of normal body weight. The results of the study demonstrated that a regular ingestion of BCP over a period of 6 months led to a clear improvement of the skin appearance in women suffering from moderate cellulite. Based on the current data, it can be concluded that a long-term therapy with orally administered BCP leads to an improvement of cellulite and has a positive impact on skin health.

J Med Food. 2015 Dec; 18(12): 1340-1348.

Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease.

Skeletal muscle is recognized as vital to physical movement, posture, and breathing. In a less known but critically important role, muscle influences energy and protein metabolism throughout the body. Muscle is a primary site for glucose uptake and storage, and it is also a reservoir of amino acids stored as protein. Amino acids are released when supplies are needed elsewhere in the body. These conditions occur with acute and chronic diseases, which decrease dietary intake while increasing metabolic needs. Such metabolic shifts lead to the muscle loss associated with sarcopenia and cachexia, resulting in a variety of adverse health and economic consequences. With loss of skeletal muscle, protein and energy availability is lowered throughout the body. Muscle loss is associated with delayed recovery from illness, slowed wound healing, reduced resting metabolic rate, physical disability, poorer quality of life, and higher health care costs. These adverse effects can be combatted with exercise and nutrition. Studies suggest dietary protein and leucine or its metabolite beta-hydroxy beta-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. Considerable evidence shows that use of high-protein oral nutritional supplements (ONS) can help maintain and rebuild muscle mass and strength. We review muscle structure, function, and role in energy and protein balance. We discuss how disease- and age-related malnutrition hamper muscle accretion, ultimately causing whole-body deterioration. Finally, we describe how specialized nutrition and exercise can restore muscle mass, strength, and function, and ultimately reverse the negative health and economic outcomes associated with muscle loss.

J Am Med Dir Assoc. 2016 Sep 01; 17(9): 789-796.

Protein Consumption and the Elderly: What Is the Optimal Level of Intake?

Maintaining independence, quality of life, and health is crucial for elderly adults. One of the major threats to living independently is the loss of muscle mass, strength, and function that progressively occurs with aging, known as sarcopenia. Several studies have identified protein (especially the essential amino acids) as a key nutrient for muscle health in elderly adults. Elderly adults are less responsive to the anabolic stimulus of low doses of amino acid intake compared to younger individuals. However, this lack of responsiveness in elderly adults can be overcome with higher levels of protein (or essential amino acid) consumption. The requirement for a larger dose of protein to generate responses in elderly adults similar to the responses in younger adults provides the support for a beneficial effect of increased protein in older populations. The purpose of this review is to present the current evidence related to dietary protein intake and muscle health in elderly adults.

Nutrients. 2016 Jun 08; 8(6).

Sarcopenia in daily practice: assessment and management.

BACKGROUND: Sarcopenia is increasingly recognized as a correlate of ageing and is associated with increased likelihood of adverse outcomes including falls, fractures, frailty and mortality. Several tools have been recommended to assess muscle mass, muscle strength and physical performance in clinical trials. Whilst these tools have proven to be accurate and reliable in investigational settings, many are not easily applied to daily practice. METHODS: This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were afterwards organized for the whole group to make amendments and discuss further recommendations. RESULTS: This paper proposes some user-friendly and inexpensive methods that can be used to assess sarcopenia in real-life settings. Healthcare providers, particularly in primary care, should consider an assessment of sarcopenia in individuals at increased risk; suggested tools for assessing risk include the Red Flag Method, the SARC-F questionnaire, the SMI method or different prediction equations. Management of sarcopenia should primarily be patient centered and involve the combination of both resistance and endurance based activity programmes with or without dietary interventions. Development of a number of pharmacological interventions is also in progress. CONCLUSIONS: Assessment of sarcopenia in individuals with risk factors, symptoms and/or conditions exposing them to the risk of disability will become particularly important in the near future.

BMC Geriatr. 2016 Oct 05; 16(1): 170.

Protein Requirements during Aging.

Protein recommendations for elderly, both men and women, are based on nitrogen balance studies. They are set at 0.66 and 0.8 g/kg/day as the estimated average requirement (EAR) and recommended dietary allowance (RDA), respectively, similar to young adults. This recommendation is based on single linear regression of available nitrogen balance data obtained at test protein intakes close to or below zero balance. Using the indicator amino acid oxidation (IAAO) method, we estimated the protein requirement in young adults and in both elderly men and women to be 0.9 and 1.2 g/kg/day as the EAR and RDA, respectively. This suggests that there is no difference in requirement on a gender basis or on a per kg body weight basis between younger and older adults. The requirement estimates however are ~40% higher than the current protein recommendations on a body weight basis. They are also 40% higher than our estimates in young men when calculated on the basis of fat free mass. Thus, current recommendations may need to be re-assessed. Potential rationale for this difference includes a decreased sensitivity to dietary amino acids and increased insulin resistance in the elderly compared with younger individuals.

Nutrients. 2016 Aug 11; 8(8).

Implication of fructans in health: immunomodulatory and antioxidant mechanisms.

Previous studies have shown that fructans, a soluble dietary fiber, are beneficial to human health and offer a promising approach for the treatment of some diseases. Fructans are nonreducing carbohydrates composed of fructosyl units and terminated by a single glucose molecule. These carbohydrates may be straight or branched with varying degrees of polymerization. Additionally, fructans are resistant to hydrolysis by human digestive enzymes but can be fermented by the colonic microbiota to produce short chain fatty acids (SCFAs), metabolic by-products that possess immunomodulatory activity. The indirect role of fructans in stimulating probiotic growth is one of the mechanisms through which fructans exert their prebiotic activity and improve health or ameliorate disease. However, a more direct mechanism for fructan activity has recently been suggested; fructans may interact with immune cells in the intestinal lumen to modulate immune responses in the body. Fructans are currently being studied for their potential as "ROS scavengers" that benefit intestinal epithelial cells by improving their redox environment. In this review, we discuss recent advances in our understanding of fructans interaction with the intestinal immune system, the gut microbiota, and other components of the intestinal lumen to provide an overview of the mechanisms underlying the effects of fructans on health and disease.

ScientificWorldJournal. 2015 2015: 289267.

Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans.

The ingestion of intact protein or essential amino acids (EAA) stimulates mechanistic target of rapamycin complex-1 (mTORC1) signaling and muscle protein synthesis (MPS) following resistance exercise. The purpose of this study was to investigate the response of myofibrillar-MPS to ingestion of branched-chain amino acids (BCAAs) only (i.e., without concurrent ingestion of other EAA, intact protein, or other macronutrients) following resistance exercise in humans. Ten young (20.1 +/- 1.3 years), resistance-trained men completed two trials, ingesting either 5.6 g BCAA or a placebo (PLA) drink immediately after resistance exercise. Myofibrillar-MPS was measured during exercise recovery with a primed, constant infusion of L-[ring13C6] phenylalanine and collection of muscle biopsies pre and 4 h-post drink ingestion. Blood samples were collected at time-points before and after drink ingestion. Western blotting was used to measure the phosphorylation status of mTORC1 signaling proteins in biopsies collected pre, 1-, and 4 h-post drink. The percentage increase from baseline in plasma leucine (300 +/- 96%), isoleucine (300 +/- 88%), and valine (144 +/- 59%) concentrations peaked 0.5 h-post drink in BCAA. A greater phosphorylation status of S6K1Thr389 (P = 0.017) and PRAS40 (P = 0.037) was observed in BCAA than PLA at 1 h-post drink ingestion. Myofibrillar-MPS was 22% higher (P = 0.012) in BCAA (0.110 +/- 0.009%/h) than PLA (0.090 +/- 0.006%/h). Phenylalanine Ra was ~6% lower in BCAA (18.00 +/- 4.31 mumol.kgBM-1) than PLA (21.75 +/- 4.89 mumol.kgBM-1; P = 0.028) after drink ingestion. We conclude that ingesting BCAAs alone increases the post-exercise stimulation of myofibrillar-MPS and phosphorylation status mTORC1 signaling.

Front Physiol. 2017 8: 390.

Meals based on vegetable protein sources (beans and peas) are more satiating than meals based on animal protein sources (veal and pork) - a randomized cross-over meal test study.

BACKGROUND: Recent nutrition recommendations advocate a reduction in protein from animal sources (pork, beef) because of environmental concerns. Instead, protein from vegetable sources (beans, peas) should be increased. However, little is known about the effect of these vegetable protein sources on appetite regulation. OBJECTIVE: To examine whether meals based on vegetable protein sources (beans/peas) are comparable to meals based on animal protein sources (veal/pork) regarding meal-induced appetite sensations. DESIGN: In total, 43 healthy, normal-weight, young men completed this randomized, double-blind, placebo-controlled, three-way, cross-over meal test. The meals (all 3.5 MJ, 28 energy-% (E%) fat) were either high protein based on veal and pork meat, HP-Meat (19 E% protein, 53 E% carbohydrate, 6 g fiber/100 g); high protein based on legumes (beans and peas), HP-Legume (19 E% protein, 53 E% carbohydrate, 25 g fiber/100 g); or low-protein based on legumes, LP-Legume (9 E% protein, 62 E% carbohydrate, 10 g fiber/100 g). Subjective appetite sensations were recorded at baseline and every half hour using visual analog scales until the ad libitum meal 3 h after the test meal. Repeated measurements analyses and summary analyses were performed using ANCOVA (SAS). RESULTS: HP-Legume induced lower composite appetite score, hunger, prospective food consumption, and higher fullness compared to HP-Meat and LP-Legume (p<0.05). Furthermore, satiety was higher after HP-Legume than HP-Meat (p<0.05). When adjusting for palatability, HP-Legume still resulted in lower composite appetite scores, hunger, prospective consumption, and higher fullness compared to HP-Meat (p<0.05). Furthermore, HP-Legume induced higher fullness than LP-Legume (p<0.05). A 12% and 13% lower energy intake, respectively, was seen after HP-Legume compared to HP-Meat or LP-Legume (p<0.01). CONCLUSION: Vegetable-based meals (beans/peas) influenced appetite sensations favorably compared to animal-based meals (pork/veal) with similar energy and protein content, but lower fiber content. Interestingly, a vegetable-based meal with low protein content was as satiating and palatable as an animal-based meal with high protein content.

Food Nutr Res. 2016 60: 32634.

Dietary protein supplementation in the elderly for limiting muscle mass loss.

Supplementation with whey and other dietary protein, mainly associated with exercise training, has been proposed to be beneficial for the elderly to gain and maintain lean body mass and improve health parameters. The main objective of this review is to examine the evidence provided by the scientific literature indicating benefit from such supplementation and to define the likely best strategy of protein uptake for optimal objectified results in the elderly. Overall, it appears that an intake of approximately 0.4 g protein/kg BW per meal thus representing 1.2-1.6 g protein/kg BW/day may be recommended taking into account potential anabolic resistance. The losses of the skeletal muscle mass contribute to lower the capacity to perform activities in daily living, emphasizing that an optimal protein consumption may represent an important parameter to preserve independence and contribute to health status. However, it is worth noting that the maximal intake of protein with no adverse effect is not known, and that high levels of protein intake is associated with increased transfer of protein to the colon with potential deleterious effects. Thus, it is important to examine in each individual case the benefit that can be expected from supplementation with whey protein, taking into account the usual protein dietary intake.

Amino Acids. 2017 Jan; 49(1): 33-47.

NUTRALYS((R)) pea protein: characterization of in vitro gastric digestion and in vivo gastrointestinal peptide responses relevant to satiety.

BACKGROUND: Pea protein (from Pisum sativum) is under consideration as a sustainable, satiety-inducing food ingredient. OBJECTIVE: In the current study, pea-protein-induced physiological signals relevant to satiety were characterized in vitro via gastric digestion kinetics and in vivo by monitoring post-meal gastrointestinal hormonal responses in rats. DESIGN: Under in vitro simulated gastric conditions, the digestion of NUTRALYS((R)) pea protein was compared to that of two dairy proteins, slow-digestible casein and fast-digestible whey. In vivo, blood glucose and gastrointestinal hormonal (insulin, ghrelin, cholecystokinin [CCK], glucagon-like peptide 1 [GLP-1], and peptide YY [PYY]) responses were monitored in nine male Wistar rats following isocaloric (11 kcal) meals containing 35 energy% of either NUTRALYS((R)) pea protein, whey protein, or carbohydrate (non-protein). RESULTS: In vitro, pea protein transiently aggregated into particles, whereas casein formed a more enduring protein network and whey protein remained dissolved. Pea-protein particle size ranged from 50 to 500 microm, well below the 2 mm threshold for gastric retention in humans. In vivo, pea-protein and whey-protein meals induced comparable responses for CCK, GLP-1, and PYY, that is, the anorexigenic hormones. Pea protein induced weaker initial, but equal 3-h integrated ghrelin and insulin responses than whey protein, possibly due to the slower gastric breakdown of pea protein observed in vitro. Two hours after meals, CCK levels were more elevated in the case of protein meals compared to that of non-protein meals. CONCLUSIONS: These results indicate that 1) pea protein transiently aggregates in the stomach and has an intermediately fast intestinal bioavailability in between that of whey and casein; 2) pea-protein- and dairy-protein-containing meals were comparably efficacious in triggering gastrointestinal satiety signals.

Food Nutr Res. 2015 59: 25622.

Therapeutic effects and safety of Rhodiola rosea extract WS(R) 1375 in subjects with life-stress symptoms—results of an open-label study.

The trial was conducted to investigate the therapeutic effects and safety of a 4 week treatment with Rhodiola rosea extract WS(R) 1375 in subjects with life-stress symptoms. This was a multicentre, non-randomized, open-label, single-arm trial. One hundred and one subjects were enrolled in this clinical study and received the study drug at a dose of 200 mg twice daily for 4 weeks. Assessments with seven questionnaires included Numerical Analogue Scales of Subjective Stress Symptoms, Perceived Stress Questionnaire, Multidimensional Fatigue Inventory 20, Numbers Connecting Test, Sheehan Disability Scale and Clinical Global Impressions to cover various aspects of stress symptoms and adverse events. Invariably, all tests showed clinically relevant improvements with regard to stress symptoms, disability, functional impairment and overall therapeutic effect. Improvements were observed even after 3 days of treatment, as were continuing improvements after 1 and 4 weeks. Rhodiola rosea extract WS(R) 1375 was safe and generally well tolerated. Adverse events were mostly of mild intensity and no serious adverse events were reported. Rhodiola extract at a dose of 200 mg twice daily for 4 weeks is safe and effective in improving life-stress symptoms to a clinically relevant degree.

Phytother Res. 2012 Aug; 26(8): 1220-1225.

Rhodiola rosea in Subjects withProlonged or Chronic Fatigue Symptoms: Results of an Open-Label Clinical Trial.

BACKGROUND: Rhodiola rosea roots and rhizomes are a herbal medicine for temporary relief of stress symptoms such as fatigue and sensed weakness. A daily dosage of 400 mg is recommended. METHODS: A dry ethanolic extract of R. rosea (WS(R) 1375) was studied in 100 subjects with prolonged or chronic fatigue symptoms. In an uncontrolled, open-label multicenter clinical trial, the subjects were administered 2 x 200 mg WS(R) 1375 over 8 weeks. Outcome measures were scales and tests related to fatigue. They were evaluated in an exploratory data analysis to generate hypotheses regarding efficacy. The pilot character of the trial is marked by its broad focus on subjects suffering from fatigue in general and by its comparatively long duration. RESULTS: The greatest change was observed after 1 week of treatment. The fatigue symptoms continued to decline further, with statistically significant improvement at week 8. The safety assessments of WS(R) 1375 during the trial proved to be favorable, with most adverse events being of mild intensity and not related to the study drug. CONCLUSIONS: The results indicate that 2 x 200 mg WS(R) 1375 may be an effective treatment in subjects suffering from prolonged or chronic fatigue. The safety and tolerability of WS(R) 1375 also presented a favorable profile.

Complement Med Res. 2017 24(1): 46-52.

A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue.

The aim of the study was to assess the efficacy of the standardised extract SHR-5 of roots of Rhodiola Rosea L. in the treatment of individuals suffering from stress-related fatigue. The phase III clinical trial took the form of a randomised, double-blind, placebo-controlled study with parallel groups. Participants, males and females aged between 20 and 55 years, were selected according to the Swedish National Board of Health and Welfare diagnostic criteria for fatigue syndrome. A total of 60 individuals were randomised into two groups, one ( N = 30) of which received four tablets daily of SHR-5 extract (576 mg extract/day), while a second ( N = 30) received four placebo tablets daily. The effects of the extract with respect to quality of life (SF-36 questionnaire), symptoms of fatigue (Pines' burnout scale), depression (Montgomery -Asberg depression rating scale - MADRS), attention (Conners' computerised continuous performance test II - CCPT II), and saliva cortisol response to awakening were assessed on day 1 and after 28 days of medication. Data were analysed by between-within analyses of variance. No serious side effects that could be attributed to the extract were reported. Significant post-treatment improvements were observed for both groups (placebo effect) in Pines' burnout scale, mental health (SF-36), and MADRS and in several CCPT II indices of attention, namely, omissions, commissions, and Hit RT SE. When the two groups were compared, however, significant effects of the SHR-5 extract in comparison with the placebo were observed in Pines' burnout scale and the CCPT II indices omissions, Hit RT SE, and variability. Pre- VERSUS post-treatment cortisol responses to awakening stress were significantly different in the treatment group compared with the control group. It is concluded that repeated administration of R. ROSEA extract SHR-5 exerts an anti-fatigue effect that increases mental performance, particularly the ability to concentrate, and decreases cortisol response to awakening stress in burnout patients with fatigue syndrome.

Planta Med. 2009 Feb; 75(2): 105-112.

Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants.

Chronic fatigue syndrome (CFS) is characterized by chronic, medically unexplained fatigue associated with effort- and stress-intolerance, widespread pain, and impairment in sleep and concentration. Although this constellation of symptoms is highly prevalent in clinical practice, the pathophysiological mechanisms underlying CFS are poorly understood. Current evidence indicates similarities in symptomatology, and possibly etiology and pathogenesis, between CFS and depression. Additionally, there is significant overlap between CFS and the syndrome of fibromyalgia for which antidepressants have shown consistent efficacy. Data regarding antidepressant treatment of CFS is less copious and less uniformly positive, such that antidepressant use in CFS remains controversial. The current review aims to summarize available data related to antidepressants and other psychotropic agents in CFS to provide a platform for clinicians to make decisions in their treatment of this challenging syndrome. We identified relevant studies through a PubMed literature search with a combination of the following search terms: 'fatigue,' 'depression,' 'antidepressant,' 'etiology' (e.g., 'neurobiology,' 'neurotransmitter,' 'genetic'), 'diagnosis,' and 'treatment' (e.g., 'antidepressant' plus the specific name). In addition, studies were also identified via the reference sections of retrieved articles. The authors thoroughly reviewed major findings from the scanned literatures and eventually synthesized them, providing summary, interpretation, and future directions.

Expert Opin Pharmacother. 2009 Jul; 10(10): 1561-1570.

Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity.

The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adaptogens in fatigue, and to provide a rationale at the molecular level for verified effects. Strong scientific evidence is available for Rhodiola rosea SHR-5 extract, which improved attention, cognitive function and mental performance in fatigue and in chronic fatigue syndrome. Good scientific evidence has been documented in trails in which Schisandra chinensis and Eleutherococcus senticosus increased endurance and mental performance in patients with mild fatigue and weakness. Based on their efficacy in clinical studies, adaptogens can be defined as a pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance. The beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO). The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the "stress-sensor" protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly, increased longevity.

Curr Clin Pharmacol. 2009 Sep; 4(3): 198-219.

Astaxanthin down-regulates Rad51 expression via inactivation of AKT kinase to enhance mitomycin C-induced cytotoxicity in human non-small cell lung cancer cells.

Astaxanthin has been demonstrated to exhibit a wide range of beneficial effects, including anti-inflammatory and anti-cancer properties. However, the molecular mechanism of astaxanthin-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Rad51 plays a central role in homologous recombination, and studies show that chemo-resistant carcinomas exhibit high levels of Rad51 expression. In this study, astaxanthin treatment inhibited cell viability and proliferation of two NSCLC cells, A549 and H1703. Astaxanthin treatment (2.5-20 muM) decreased Rad51 expression and phospho-AKT(Ser473) protein level in a time and dose-dependent manner. Furthermore, expression of constitutively active AKT (AKT-CA) vector rescued the decreased Rad51 mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitors (LY294002 or wortmannin) further decreased the Rad51 expression in astaxanthin-exposed A549 and H1703 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA or cotreatment with LY294002 further enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Additionally, mitomycin C (MMC) as an anti-tumor antibiotic is widely used in clinical NSCLC chemotherapy. Combination of MMC and astaxanthin synergistically resulted in cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced phospho-AKT(Ser473) level and Rad51 expression. Overexpression of AKT-CA or Flag-tagged Rad51 reversed the astaxanthin and MMC-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in astaxanthin and MMC co-treated cells. In conclusion, astaxanthin enhances MMC-induced cytotoxicity by decreasing Rad51 expression and AKT activation. These findings may provide rationale to combine astaxanthin with MMC for the treatment of NSCLC.

Biochem Pharmacol. 2016 Apr 01; 105: 91-100.

Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer.

Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention.

PLoS One. 2014 9(10): e109114.

Astaxanthin Inhibits Proliferation and Induces Apoptosis of Human Hepatocellular Carcinoma Cells via Inhibition of Nf-Kappab P65 and Wnt/Beta-Catenin in Vitro.

Hepatocellular carcinoma (HCC) is a malignant tumor that can cause systemic invasion; however, the exact etiology and molecular mechanism are unknown. Astaxanthin (ASX), a powerful antioxidant, has efficient anti-oxidant, anti-inflammatory, and other activities, and has great research prospects in cancer therapy. We selected the human hepatoma cell lines, LM3 and SMMC-7721, to study the anti-tumor effect and related mechanisms of ASX. The cell lines were treated with different concentrations of ASX, and its solvent DMSO as a control, for different time periods and the results were determined using CCK8, qRT-PCR, WB, apoptotic staining, and flow cytometry. ASX induced significant apoptosis of HCC cells, and its effect may have been caused by NF-kappaB p65 and Wnt/beta-catenin down-regulation via negative activation of PI3K/Akt and ERK. Antitumor research on ASX has provided us with a potential therapy for patients with hepatomas.

Mar Drugs. 2015 Sep 24; 13(10): 6064-6081.

Astaxanthin enhances pemetrexed-induced cytotoxicity by downregulation of thymidylate synthase expression in human lung cancer cells.

Pemetrexed, a multitargeted antifolate agent, has demonstrated clinical activity in non-small cell lung cancer (NSCLC) cells. Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to pemetrexed. Astaxanthin exhibits a wide range of beneficial effects including anti-cancer and anti-inflammatory properties. In this study, we showed that down-regulating of TS expression in two NSCLC cell lines, human lung adenocarcinoma H1650 and squamous cell carcinoma H1703 cells, with astaxanthin were associated with decreased MKK1/2-ERK1/2 activity. Enforced expression of constitutively active MKK1 (MKK1-CA) vector significantly rescued the decreased TS mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with a MKK1/2 inhibitor (U0126 or PD98059) further decreased the TS expression in astaxanthin-exposed NSCLC cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting ERK1/2 activity enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Combination of pemetrexed and astaxanthin resulted in synergistic enhancing cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-MKK1/2, phopho-ERK1/2, and TS expression. Overexpression of MKK1/2-CA reversed the astaxanthin and pemetrexed-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of MKK1/2-ERK1/2-mediated TS expression by astaxanthin is an important regulator of enhancing the pemetrexed-induced cytotoxicity in NSCLC cells.

Regul Toxicol Pharmacol. 2016 Nov; 81: 353-361.

Stereoisomers of Astaxanthin Inhibit Human Colon Cancer Cell Growth by Inducing G2/M Cell Cycle Arrest and Apoptosis.

Astaxanthin (AST) is a xanthophyll carotenoid with potential protective effects against carcinogenesis. Different stereoisomers of AST (ASTs) exist in a variety of food sources. Due to limited information on the bioactivities of ASTs, the present study investigated the inhibitory effects of ASTs on HCT116 and HT29 human colon cancer cells. ASTs investigated herein included 3S,3'S (S) from Haematococcus pluvialis, 3R,3'R (R) from Phaffia rhodozyma, and a statistical mixture (S: meso: R = 1:2:1) (M) from synthetic AST. Cell viability assay showed that ASTs all inhibited colon cancer cell growth in a time-dependent (24-72 h) and dose-dependent (4-16 muM) manner, and there was no significant difference among the IC50 values of ASTs (p > 0.05). Flow cytometry analysis indicated that ASTs induced G2/M cell cycle arrest and cellular apoptosis in cancer cells. The cell cycle arrest caused by ASTs was associated with increases in the expression levels of p21Cip1/Waf1, p27, and p53, as well as decreases in the levels of CDK4 and CDK6. Meanwhile, the apoptosis induced by ASTs was confirmed by activation of caspase-3 and PARP in the cancer cells. The results indicated that hydroxyl (OH) at C3 and C3' of terminal ring structure might not be the major factor that affects the anticancer activity of AST. This study revealed important information on the inhibitory effects of ASTs on human colon cancer cells, which provided a basis for using ASTs as chemopreventive agents for colon cancer.

J Agric Food Chem. 2016 Oct 11.

Astaxanthin Inhibits PC-3 Xenograft Prostate Tumor Growth in Nude Mice.

Prostate cancer (PCa), the most common malignancy in men, is a major cause of cancer deaths. A better understanding of the mechanisms that drive tumor initiation and progression may identify actionable targets to improve treatment of this patient group. As a dietary carotenoid, astaxanthin has been demonstrated to exert beneficial effects against inflammation, cardiovascular disease, oxidative damage, or different cancer sites. This study used intragastric administration of astaxanthin to detect its role on tumor proliferation, apoptosis, microRNA (miRNA) overexpression, and microbacteria composition change by establishing androgen-independent PCa cell PC-3 xenograft nude mice. Nude mice were inoculated with androgen-independent prostate cancer PC-3 cells subcutaneously. The intervention was started when tumors reached 0.5-0.6 cm in diameter. Mice were intragastrically administered 100 mg/kg astaxanthin (HA), 25 mg/kg astaxanthin (LA), or olive oil (TC). The results showed that 100 mg/kg astaxanthin significantly inhibited tumor growth compared to the TC group, with an inhibitory rate of 41.7%. A decrease of Ki67 and proliferating cell nuclear antigen (PCNA) as well as an increase of cleaved caspase-3 were observed in HA-treated tumors, along with increasing apoptotic cells, obtained by TUNEL assay. The HA significantly elevated the levels of tumor suppressors miR-375 and miR-487b in tumor tissues and the amount of Lactobacillus sp. and Lachnospiraceae in mice stools, while there was no significant difference between LA and TC groups. These results provide a promising regimen to enhance the therapeutic effect in a dietary supplement manner.

Mar Drugs. 2017 Mar 08; 15(3).

International incidence and mortality trends of liver cancer: a global profile.

We examined the global incidence and mortality rates of liver cancer, and evaluated the association between incidence/mortality and socioeconomic development (Human Development Index [HDI] and Gross Domestic Product [GDP]) using linear regression analysis. The average annual percent change (AAPC) of the trends was evaluated from join-point regression analysis. The global incidence of liver cancer varied widely by nine-fold, and was negatively correlated with HDI (men: r = -0.232, p = 0.003; women: r = -0.369, p < 0.001) and GDP per capita (men: r = -0.164, p = 0.036; women: r = -0.212, p = 0.007). Its mortality showed a similarly negative correlation with both indices. The greatest incidence rise in men was observed in Poland (AAPC = 17.5, 95% C.I. = 5.6, 30.9) and Brazil (AAPC = 13.2, 95% C.I. = 5.9, 21.0), whereas Germany (AAPC = 6.6, 95% C.I = 2.0, 11.5) and Norway (AAPC = 6.5, 95% C.I. = 3.2, 10.0) had the greatest increase in women. The mortality rates paralleled the incidence rates in most countries. For mortality, Malta (AAPC = 11.5, 95% C.I. = 3.9, 19.8), Australia (AAPC = 6.8, 95% C.I. = 2.2, 11.5) and Norway (APCC = 5.6, 95% C.I. = 2.8, 8.5) reported the biggest increase among men; whilst Australia (AAPC = 13.4, 95% C.I. = 7.8, 19.4) and Singapore (AAPC = 7.7, 95% C.I. = 4.1, 11.5) showed the most prominent rise among women. These epidemiological data identified countries with potentially increasing trends of liver cancer for preventive actions.

Sci Rep. 2017 Mar 31; 7: 45846.

Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin.

Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and peroxisome proliferator-activated receptor gamma (PPARgamma). Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX.

Mar Drugs. 2015 Jul 14; 13(7): 4310-4330.