| BackgroundProteins remain essential to the physiological and biochemical processes of life.However,plant-based proteins are generally regarded to have reduced health risks compared to animal-based proteins.Moreover,the myriad of benefits derived from proteins are known to be carried out by various small peptides such as di-,tri-and oligopeptides encrypted within the primary structures of protein which are only released upon digestion or hydrolysis of the proteins.These food-derived bioactive peptides have been shown to exert significant effects on bodily systems and physiological states acting as immunomodulatory,antimicrobial,anti-hypertensive,anti-cancer,anti-aging and opiate-like biochemical substances.This way they are able to significantly modulate and impact the cardiovascular,endocrine,digestive,skeletal muscle and the nervous systems among others.Given the structural and molecular weight and size differences between proteins and peptides,it is conceivable that proteins and peptides from the same food source could show differential physiological and biochemical effects.Structure,molecular weight and size could potentially influence the ease of digestibility,absorbability and metabolic fate and the eventually physiological impact of bioactive molecules.Soybean is one of the richest sources of high quality plant proteins and nutrients noted for improving metabolism,obesity,cardiovascular diseases,aiding digestion,decreasing the risk of diabetes and promoting general bone health and physical wellbeing.Several peptides have been produced from soybean proteins and hydrolysates mainly through enzymatic hydrolysis and ultrafiltration and size exclusion chromatography extraction methods.These derived small molecular weight peptides have been shown to exhibit various physiological effects such as antioxidant,anti-aging and antimicrobial properties.Even though soybean protein combined with other nutrients has been shown to be effective in acute malnutrition,the potential differential effect of soybean protein and peptides on the attenuation of acute malnutrition remains to be studied.Significantly,the anabolic effect of soybean proteins and peptides in acute undernutrition has not been characterized.Acute malnutrition is a state of inadequate macronutrient especially protein and/or micronutrient availability.It is often characterized by significant unexplained weight loss and muscle protein breakdown which leads to the depletion of muscle mass.It remains a global challenge to a large portion of the population and it is highly prevalent in disease conditions such as cancer,diabetes,and other chronic diseases.Malnutrition significantly affects human health and wellbeing and it has been shown to be an effective predictor of disease prognosis,treatment outcomes and survival in many disease conditions.For example,the effect of various cancer treatments including fatigue,loss of appetite,nausea and vomiting and diarrhea coupled with increased nutrient requirements of the cancer condition conspire to induce substantial risk of malnutrition in patients.Body mass index(BMI)or BMI for age(BMI/A)is often used as a measure for evaluating weight loss and nutritional status in malnutrition states either alone or in combination with other parameters.Studies involving the use of cell models and rodents are often limited in their generalizability and application of the findings unto human populations due to the inability of these models to mimic human physiological status.Non-human primate(NHP)experiments offer the best possible in vivo closeness to human pathophysiology for robust studies which could easily be extrapolated unto humans.Using the same amount of soybean proteins and peptides,we sort to test the hypothesis that small molecular peptides could differentially induce weight gain and attenuate malnutrition status compared to whole proteins using malnourished cynomolgus monkey models and an application in at risk malnourished brain cancer patients undergoing chemotherapy.Objectives1.To explore the characteristic differences between soybean protein and peptides in improving weight gain and malnutrition.2.To investigate the effect of soybean peptide supplementation on nutritional status in high risk malnutrition conditions such as cancer.3.To explore whether soybean peptide-induced improvements in malnutrition translates into improvements in Qo L.4.To evaluate the potential molecular and biochemical mechanisms involved in soybean peptide-induced improvement in weight loss and malnutrition.MethodsSoybean peptides were prepared by enzymatic hydrolysis and structural elucidation was done with ultra-high pressure liquid chromatography-high-resolution mass spectrometer(UHPLC-MS/MS).Soybean peptides and proteins were subsequently produced and supplied by Guangzhou Taihao Company Limited.Malnourished cynomolgus monkeys(Macaca fascicularis)of Chinese origin provided by the Conghua Huazhen Animal Breeding Farm,and kept at the Animal Experimental Center of the same institution were randomly put into 3 groups of 8 animals.Monkeys were put on an only conventional diet(Control group),or a conventional diet in addition to either 9 g of pure soybean peptides(Peptide group)or 9 g of whole soybean protein(Protein group)daily for 26days.Body weight(kg)and length were measured and body mass index(BMI)was calculated as the ratio of the weight in kilogram(kg)and length(L)in meters square(m~2).Blood samples were obtained before the start of the experiment(Day 0)and on day 26 for biochemistry analysis which was done at the Conghua Hospital of Traditional Chinese Medicine.To investigate the applicability of soybean peptide supplementation for weight gain and improved nutritional status,malnourished brain cancer patients receiving chemotherapy were randomized into 2 groups to receive 9 g soybean peptide twice per day(Peptide group)or only conventional treatment(Control group)over 2 chemotherapy cycles of 42 days.Data including weight and height were collected before the start of chemotherapy(Baseline)and at the end of the first(Day 21)and(Day 42)second chemotherapy cycles and BMI.Serum biochemistry and immune markers were derived from the routine laboratory test of patients.In addition,Qo L was assessed using the European Organization for Research and Treatment of Cancer(EORTC QLQ-C30)questionnaire version 3 at baseline(Day 0)and days 14,21,35and 42.To explore further the molecular interactions for the mechanisms of the weight gain and malnutrition attenuation effect of the soybean peptides,we simulated in silico digestion of the peptides using the Peptide-cutter in silico tool with pepsin(p H>2),trypsin and chymotrypsin as cleavage enzymes.The possible protein-ligand interaction for the attenuation of weight loss and muscle depletion was explored through molecular docking using Py Rx and the discovery studio tools.ResultsThe results showed that 9 g of daily soybean peptide supplementation induced a higher weight and BMI gain effect than whole soybean proteins in the malnourished monkeys compared controls.Compared to the control group(-0.94±7.79%),the protein group increased in weight by 5.9±14.34%(p=0.314)whiles the peptide group gained 14.50±11.7%(p<0.016).In addition,AST increased by 59.24±73.24%in the protein group compared to a decrease of54.46±10.74%in the peptide group(p<0.019).ALT increased substantially in the protein group(188.96±217.40%)while decreasing in the peptide group(4.06±50.98%,p<0.043).Furthermore,there were no significant differences in serum albumin and total proteins in the protein group(13.51±63.97%and 1.56±26.42 respectively)compared to the control(-4.78±and-3.23±10.69%respectively)group(p>0.05).However,albumin(37.13±31.61%)and total protein(11.12±12.42%)levels significantly increased in the peptide group compared to the control group(p<0.0.5).In the application in malnourished cancer patients,it was found that those on peptide supplementation significantly increased in weight from 27.7±12.0 to 29.1±12.4(p<0.003)and BMI from 14.14±2.01 to 15.15±2.08(p<0.002).No significant changes were observed in the control group.Furthermore,Qo L tended to be stable or improving in those consuming peptides compared to the control group which was stable or decreasing.Specifically,physical and emotional functioning and summary of Qo L scores significantly increased in the peptide group compared to the control group(p<0.05).In the molecular interaction analysis,we found that two components of the in silico digested soybean peptide,the tripeptide LEE and the free amino acid W,could effectively bind to the angiotensin-converting enzyme(ACE)receptor with binding affinities of-7.1 and-7.0respectively comparable to the chemical drug ACE inhibitor perindopril(binding affinity of-7.5)and the tripeptide VPP(binding affinity of-7.1).The visualization showed that peptide formed 4 strong hydrophobic bonds and 6 hydrogen bond interactions with the ACE receptor.ConclusionThis study showed that soybean peptides could differentially induce weight gain and attenuate malnutrition status and that peptides may be better tolerated in severe malnutrition conditions compared to whole proteins,potentially due to lesser metabolic stress.Furthermore,the soybean induced-improvement in nutritional status can be applied in high risk malnutrition conditions such as in cancer patients to improve general Qo L.Soybean peptides could potentially inhibit ACE activities and support the therapeutic application of soybean peptide LEE to attenuate muscle protein breakdown and weight loss to enhance body function and Qo L. |
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