Supplementation with low molecular weight peptides from fish protein hydrolysate reduces acute mild stress-induced corticosterone secretion and modulates stress responsive gene expression in mice

First evidence started to demonstrate the anxiolytic effects of low molecular weight peptides extracted from natural products, such as fish hydrolysate, but their underlying mechanisms remain to be elucidated. The objective of this study was to evaluate the effect of a chronic administration of fish hydrolysate on stress reactivity and to understand the mechanisms involved. Stress response (corticosterone secretion, expression of stress-responsive genes) was measured in Balb/c mice supplemented with fish hydrolysate (300 mg/kg body weight) or vehicle daily for 7 days before being submitted to an acute mild stress protocol. Our results demonstrated that 30 min after stress induction, fish hydrolysate decreased corticosterone level compared to control mice. Moreover, fish hydrolysate supplementation modulated expression of stress responsive genes involved in hypothalamic pituitary adrenal axis regulation, circadian rhythm and aging process. These findings suggest that fish hydrolysate represents an innovative strategy to prevent stress-induced aversive effects and participate in stress management

Fish Hydrolysate Supplementation Containing n-3 Long Chain Polyunsaturated Fatty Acids and Peptides Prevents LPS-Induced Neuroinflammation

Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1β (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation

Oral supplementation with fish cartilage hydrolysate accelerates joint function recovery in rat model of traumatic knee osteoarthritis

Abstract The objective of this study was to evaluate the effects of oral fish cartilage hydrolysate (FCH) on symptoms and joint tissue structure in rat developing osteoarthritis induced surgically. Osteoarthritis was induced in the right knee of mature male Lewis rats (n = 12/group) by surgical transection of the anterior cruciate ligament (ACLT) combined with partial medial meniscectomy (pMMx). Two weeks after surgery, rats were treated orally with either control (sterile H2O) or FCH for four weeks. Pain and function were assessed by dynamic weight‐bearing test (incapacitance test), electronic Von Frey (EVF; hindpaw allodynia threshold), and pressure algometer (knee allodynia threshold). Time and groups differences at each time point were evaluated using a mixed model. The histological features were evaluated eight weeks after surgery using OARSI score. Mann–Whitney test nonparametric test was applied to compare OARSI score. ACTL/pMMx surgery significantly reduced weight‐bearing and increased allodynia and sensitivity thresholds of the operated paw/knee. Globally, FCH improved these parameters faster, but no significant difference between control and FCH groups was observed. Eight weeks after surgery, rats developed moderate OA lesions. Compared with control, FCH did not significantly modify OA lesion severity assessed using the OARSI score. In this mechanically induced OA model, 4 weeks of supplementation with FCH had no significant effect on cartilage lesion, but tends to accelerate pain relief and joint function recovery. This positive trend may have opened the way for further investigation of FCH as potential treatment of joint discomfort associated with OA

Benefits of Circulating Human Metabolites from Fish Cartilage Hydrolysate on Primary Human Dermal Fibroblasts, an Ex Vivo Clinical Investigation for Skin Health Applications

International audienceDue to its significant exposure to stressful environmental factors, the skin undergoes a high remodeling rate over time, which alters not only its appearance but also its functionality. This alteration of the skin, namely photoaging, is characterized by dryness and a loss of elasticity that mainly originates from the dysregulation of dermal fibroblast activities. In order to overcome such tissue outcome, cosmetic products have evolved toward nutricosmetics, thus promoting beauty from within. Among bio-actives of interest, bio-peptides deriving from plant or animal sources may exert various biological activities beyond their nutritional value. However, studies remain mostly descriptive and the mode of action at the cellular level in clinic remains a concern. In a recent clinical trial, it was showed that supplementation with a fish cartilage hydrolysate (FCH) improved signs of chronological and photoaging-induced skin changes in healthy women. Here, using an original ex vivo clinical approach adapted to nutricosmetic purpose, we further demonstrated that this fish cartilage hydrolysate was absorbed and that the circulating metabolites produced in humans following FCH intake stimulate human dermal fibroblast growth, promote specific hyaluronan production, up-regulate elastin synthesis and inhibit MMP-1 and 3 expression along with the enhancement of TGF-β release. Altogether, these data provide clues on the mechanisms likely contributing to the beneficial impact of FCH on human skin functionality by supporting hydration, elasticity and limiting the expression of catabolic factors involved in photoaging onset

Fish Hydrolysate Supplementation Prevents Stress-Induced Dysregulation of Hippocampal Proteins Relative to Mitochondrial Metabolism and the Neuronal Network in Mice

International audienceOver the past several decades, stress has dramatically increased in occidental societies. The use of natural resources, such as fish hydrolysates, may be an attractive strategy to improve stress management. Our previous study demonstrated the anxiolytic effects of fish hydrolysate supplementation in mice exposed to acute mild stress by limiting stress-induced corticosterone release and modulating the expression of a number of stress-responsive genes. Here, we explore hippocampal protein modulation induced by fish hydrolysate supplementation in mice submitted to acute mild stress, with the aim of better elucidating the underlying mechanisms. Hippocampi from the same cohort of Balb/c mice supplemented with fish hydrolysate (300 mg.kg(-1) body weight) or vehicle daily for seven days before being submitted or not to an acute mild stress protocol (four groups, n = 8/group) were subjected to label-free quantitative proteomics analysis combined with gene ontology data mining. Our results show that fish hydrolysate supplementation prevented the observed stress-induced dysregulation of proteins relative to mitochondrial pathways and the neuronal network. These findings suggest that fish hydrolysate represents an innovative strategy to prevent the adverse effects of stress and participate in stress management

Oral supplementation with fish cartilage hydrolysate in an adult population suffering from knee pain and function discomfort: results from an innovative approach combining an exploratory clinical study and an ex vivo clinical investigation

Abstract Background Aging is frequently associated with impairments of the musculoskeletal system and many elderly people experience joint discomfort or pain which might reduce their ability to move and consequently alter their quality of life. A beneficial effect of fish cartilage hydrolysate (FCH) on pain and joint function has recently been shown in an ACLT/pMMx osteoarthritis rat model. Methods We therefore performed an exploratory, non-comparative, multi-centric clinical trial including 33 subjects with moderate knee joint discomfort and loss of functionality to investigate the efficacy of FCH on their algo-functional status. We further determined the potential health benefit of FCH in an original clinical ex vivo study investigating the role of FCH human metabolites on primary human chondrocytes. Results FCH significantly improved knee pain and function, as assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS). Moreover, FCH significantly reduced pain at rest and while walking, and patient global assessment (PGA), as assessed by the Visual Analogue Scale (VAS), and improved patients’ quality of life (SF-36). FCH metabolites decreased the synthesis of catabolic factors (MMP-13) and pro-inflammatory mediators (NO, PGE2) and limited the inhibitory effect of IL-1β on the synthesis of cartilage matrix components (GAG and collagen). Conclusions Thus, these data provide insights on the mode of action of FCH in humans and contribute to explain how FCH may relieve pain and improve joint function in subjects with knee discomfort. Although these preliminary data need to be confirmed in a randomized controlled trial, they strongly support the potential health benefit of such an active ingredient. Trial registration: The study was registered on clinicaltrials.gov with the identifier NCT04420091 (09/06/2020)

Additional file 1 of Oral supplementation with fish cartilage hydrolysate in an adult population suffering from knee pain and function discomfort: results from an innovative approach combining an exploratory clinical study and an ex vivo clinical investigation

Figure S1. Mean evolution (± SE) of the KOOS sub-scores over time: (a) KOOS Pain score over time; (b) KOOS Symptoms score over time; (c) KOOS Daily living activities score over time; (d) KOOS Sport and recreation function score over time; (e) Quality of life score over time ? FAS population. ***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05; ns, not significant. Figure S2. Mean evolution (± SE) of the SF-36 sub-scores over time: (a) SF-36 Physical functioning over time; (b) SF-36 Role limitations due to physical health over time; (c) SF-36 Energy/Fatigue over time; (d) SF-36 Pain over time; (e) SF-36 General health over time ? FAS population. ***p ≤ 0.001; **p ≤ 0.01; *p ≤ 0.05; ns, not significant. Table S1. Subjects? knee discomfort history description at the inclusion in the study ? FAS population. Table S2. Results of the repeated measures ANOVA models for KOOS global score and each subscale, and mean difference and effect size between baseline and 3 months of follow-up ? PP population ? N=24. Table S3. Results of the repeated measures ANOVA models for SF-36 global score and each subscale ? PP population ? N=24. Table S4. Results of the repeated measures ANOVA models for knee pain at rest and while walking and PGA using VAS scale, and mean difference and effect size between baseline and 3 months of follow-up ? PP population ? N=24. Table S5. Comparison of patients? treatment response between the first and the second follow-up ? PP population ? N=24. Table S6. Results of the comparison between the first and the second follow-up for compliance? FAS population. Table S7. Comparisons of subjects satisfaction between the two follow-up visits ? FAS population. Table S8. Results of the analysis of the time evolution for pain killer use and frequency of intake ? FAS population. Table S9: Listing of AE and SAE by decreasing order of frequency ? Safety population ? N=28 adverse events. Table S10. Distribution of link with FCH and action taken in response to AE ? Safety population ? N=28 adverse events. Table S11. Distribution of subjects at each visit ? Safety population ? N=32 patients. Table S12. Complete list of exclusion criteria. Figure S3. Primary human chondrocytes subjected to ex vivo procedures for validation of cell viability in human serum. Cell viability was measured with an XTT-based assay upon either FCS or human serum incubation (H-NAIVE for human naive serum and H-FCH for human serum enriched with circulating FCH metabolites) for 24 h and 48 h (A and B). Measures were performed in quadruplicates per condition/volunteer (n=10 volunteers). Values are presented as mean ± SD. The differences were considered statistically significant at p < 0.05 with ** for p < 0.01 and **** for p < 0.0001