Collagen supplementation in metabolic syndrome: a narrative review unraveling the biological mechanisms and effects.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome (MERS-CoV), which cause acute respiratory distress syndrome and case fatalities. COVID-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2 (ACE2), MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID-19 disease severity, which creates interest regarding the use of gliptins in management of COVID-19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2.

Angiotensin-converting Enzyme 2–containing Small Extracellular Vesicles and Exomeres Bind the Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

Background/Objectives: Collagen hydrolysates are widely used as nutritional ingredients for skin and joint health; however, growing evidence indicates that collagen may also exert beneficial effects on cardiometabolic pathways. Short peptides have been shown to modulate angiotensin-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV), key regulators of blood pressure and glucose homeostasis. This study aimed to assess the dual ACE- and DPP-IV inhibitory and GLP-1 stimulation activities, respectively of a tripeptide-enriched formulation (CH). The study was performed using a benchmark collagen hydrolysate (BCH) as reference. Methods: ACE and DPP-IV inhibitory activities were evaluated using in vitro enzymatic assays. Cellular compatibility and in situ DPP-IV inhibition were assessed in Caco-2 intestinal cells, while glucagon-like peptide-1 (GLP-1) secretion was measured in STC-1 enteroendocrine cells. The degree of hydrolysis was determined by OPA assay, and nanoLC–HRMS was used to characterize and compare the proteomic profiles of the samples. Results: Both hydrolysates exhibited dose-dependent ACE and DPP-IV inhibition; however, CH showed significantly higher inhibitory activity at comparable concentrations. CH also reduced cellular DPP-IV activity in Caco-2 cells and stimulated GLP-1 secretion in STC-1 cells, whereas BCH showed limited or non-significant cellular effects. Peptidomic analysis revealed an enrichment of short- and medium-length peptides in CH, while BCH contained a higher proportion of long peptides (>2000 Da). Consistently, CH exhibited a 1.7-fold higher degree of hydrolysis than BCH. Conclusions: The tripeptide-enriched collagen hydrolysate demonstrated superior enzymatic and cellular bioactivity compared with the benchmark formulation, supporting its potential as a multifunctional bioactive ingredient for health applications.

The lung vascular endothelium is a semi-permeable barrier that regulates the flow of nutrients, ions, cytokines, and immune cells between blood and lung tissues. Being a source of inflammatory mediators, it plays a crucial role in maintaining pulmonary homeostasis and in driving immune responses.1 The main target for rhinoviruses (HRV) is the airway epithelium. However, we have recently shown that HRV16 may also infect the lung vascular endothelium via ICAM-1.1 As the vascular endothelium may express coronaviral entry receptors, including aminopeptidase N (AP-N), dipeptidyl peptidase 4 (DPP4), and angiotensin-converting enzyme 2 (ACE2), it may possibly be infected by human coronavirus 229E (HCoV229E) and highly pathogenic MERS-CoV and SARS-CoV-2.2 The latter one is responsible for currently ongoing COVID-19 pandemics.3 Seasonal peaks for HRV infections occur in early fall (September–November) and spring (March–May), whereas low pathogenic HCoVs which evoke mostly mild upper airway infections appear in winter and early spring (December–April). Both viruses overlap in March and April. HRV and HCoV co-infections or subsequent infections may lead to severe viral pneumonias. In such patients, the diffuse alveolar lung damage and thrombotic angiopathy in alveolar capillaries have been observed, which suggests an active involvement of the lung vascular endothelium.4 The effect of HRV on the expression of HCoV entry receptors on the lung vascular endothelium and its modulation by IL-33 widely distributed in asthmatic airways has not been elucidated. Firstly, we confirmed the HRV16 infection (MOI3) of human lung microvascular endothelial cells (HMVEC-L) (Figure 1A) and we observed the increase of IFN-β, RANTES (Figure 1B,C) IL-6, and TNF-α protein release (Figure S1A,B,C). Then, we noticed that HRV16 may enhance the expression of AP-N, DPP4, and ACE2 in HMVEC-L (Figures 1 and 2). The pattern of HRV16-induced ACE2 mRNA expression varied from DPP4 and AP-N. AP-N and DPP4 mRNA expression began to grow at 24 h and further increased at 72 h upon incubation with HRV16 (Figure 1D,G). In contrast, the transient enhancement of ACE2 mRNA expression occurred already at 5 hours (Figure 2A). Regardless of these differences, HRV16 led to the significant increase of AP-N, DPP4, ACE2, and TMPRSS2 surface protein expression observed by flow cytometry (Figures 1E,H and 2B,D) and confocal microscope (Figures 1F,I and 2C,E) (isotype controls and gating strategy: Figures S7 and S8). We did not notice any significant effect of HRV16 in lower MOI (0,1 and 1) on the expression of any receptor (Figures S2A–C). Recently, we have shown that IL-33 may enhance HRV-induced release of cytokines, chemokines, and growth factors by the lung vascular endothelium.5 In order to analyze the effect of IL-33, HMVEC-L were pre-incubated with IL-33 (10 ng/ml) for 24 h and subsequently exposed to HRV16 (MOI 0,1; 1; 3). These results confirmed our previous findings showing that IL-33 increased the capture of HRV16 by cells (Figure 1A). Despite IL-33 prevented the induction of AP-N, DPP4, and ACE2 mRNA expression by HRV16 (Figures 1D,G and 2A). At the same time, AP-N, DPP4, ACE2, and TMPRSS2 surface expressions were significantly lower, when HMVEC-L were infected with HRV16 upon the pre-treatment with IL-33 (Figures 1E,F,H,I and 2B–E). This effect of IL-33 was partially diminished by the blockade of ST2 receptor with anti-ST2 antibodies (3 μg/ml) before the pre-treatment of cells with IL-33 (Figure S3A,B,C). To note, IL-33 alone affected neither AP-N nor ACE2 and TMPSSR2 expression, whereas it slightly decreased the surface density of DPP4 (Figure 1H). IL-33 did not significantly change the effect of HRV16 in lower MOI (0,1; 1) on the receptor expression (Figure S2A,B,C). Our results led us to pose the question about the possible mechanism of the induction of AP-N, DPP4, and ACE2 with HRV16. First, heat-inactivated HRV16 did not exert any effect (Figure S4A,B,C,D), which indicates that the change in AP-N, DPP4, and ACE2 expression requires an active virus. Second, the pattern of ACE2 mRNA expression was similar to the expression of both HRV16 copy number and IFN-β mRNA, which suggests an activation of common cytoplasmatic pathways by the virus. ACE2 expression signatures were shown to overlap with type 1 and 2 IFN patterns. The neutralization of autocrine secreted IFN-β with anti-IFN-β antibodies (3 μg/ml) only prevented the increase of DPP4 mRNA expression (Figure S5A,B,C). Nevertheless, the increase of DPP4 and AP-N expression might be associated with autocrine action of other cytokines released by infected endothelium (i.e., IL-4,13; Figure S1D,E).6 This matter needs further elucidation. Mechanism of the inhibition of HRV16-induced AP-N, DPP4, and ACE2 expression by IL-33 appears to be more unclear, as we confirmed that IL-33 must affect cells prior to their exposure to the virus. When IL-33 was administered together with HRV16 at the same time, the inhibitory effect of IL-33 did not occur (Figure S6). In order to assess if HRV16 and IL-33 specifically regulate the expression of AP-N, DPP4, and ACE2 in HMVEC-L, we analyzed their effect on the secretion of inflammatory cytokines, including IFN-β, IL-4,6,13, and TNF-α. We observed that HRV16 alone increased IFN-β, IL-4,6,13, and TNF-α production. However, the pre-stimulation with IL-33 enhanced HRV16-induced secretion of IL-4,6,13, whereas it did not affect any release of IFN-β and TNF-α (Figure S1A–E). Moreover, HRV16 increased ICAM-1 expression, while the pre-stimulation of cells with IL-33 enhanced it further (Figure 2F–H). Blockade of ST2 receptor by anti-ST2 antibodies prevented the effect of IL-33 (Figure S3D). Interestingly, we noticed that the neutralization of IFN-β by anti-IFN-β antibodies decreased HRV16-induced ICAM-1 expression (Figure S5D). These results suggest that IL-33 may variously modulate the effect of HRV on the lung vascular endothelium. However, precise mechanisms need to be elucidated in further research. To sum up, our data indicate that rhinovirus may upregulate ACE2, DPP4, and AP-N surface expression on the lung vascular endothelium, thus leading to the increased susceptibility to infections with human coronaviruses. Interestingly, IL-33 may prevent the induction of the expression of coronavirus entry receptors by HRV on the endothelium. Thus, the protective feature of IL-33 might underlie the lower occurrence of coronavirus associated as compared to rhinovirus-related asthma exacerbations.3 Finally, we intend to emphasize that these data refer to the lung vascular endothelium although the airway epithelium is a prime target for both HRV and HCoV. However, the closeness of airway epithelium to endothelium lining mucosal vessels and alveolar capillaries enables the viral transmission between these tissues. Therefore, the possible modulation of coronavirus entry receptors by rhinovirus on the lung vascular endothelium and its clinical significance needs further research. The authors declare no conflict of interest. Izabela Gulbas involved in planning of experiments, cell cultures, real-time PCR, flow cytometry assessments, data analysis, and manuscript writing. Adrian Gajewski involved in BioPlex and ELISA. Mateusz Gawrysiak involved in virus propagation and preparation for cultures, help in flow cytometry assessments. Robert Szewczyk involved in sample staining for confocal analysis. Aleksandra Likońska involved in mRNA isolation. Sylwia Michlewska involved in confocal microscope analysis. Marek L. Kowalski involved in co-supervision and advisory role. Maciej Chałubiński involved in conceptualization, co-planning of experiments, data analysis, manuscript co-writing, and supervision. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

In the study, papain was used to hydrolyze tilapia (Oreochromis mossambicus) skin to obtain a tilapia skin hydrolysate (TSH) with dual angiotensin-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) inhibitory activities. The resulting TSH was sequentially fractionated by ultrafiltration, size exclusion separation chromatography, and reverse-phase high-performance liquid chromatography. Its inhibitory effects on ACE and DPP-IV were determined by commercial reagent kits. Two peptides purified from TSH were identified as Gly-Pro-Leu-Gly-Ala-Leu (GPLGAL) and Lys-Pro-Ala-Gly-Asn (KPAGN) by the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Inhibitory concentration (IC50) of GPLGAL on ACE and DPP-IV were 117.20±1.69 and 187.10±2.75µM, respectively. IC50 of KPAGN on ACE and DPP-IV were 137.40±2.33 and 259.20±2.85µM, respectively. The molecular simulation demonstrated that the binding affinities of GPLGAL to ACE and DPP-IV proteins were -8.5 and -7.4kcal/mol, respectively, whereas those of KPAGN to ACE and DPP-IV proteins were -7.9 and -6.7kcal/mol, respectively. GPLGAL interacted with 21 amino acid residues of the ACE active site, whereas KPAGN engaged with 19 amino acid residues. Additionally, GPLGAL interacted with 10 amino acid residues of the DPP-IV active site, whereas KPAGN engaged with 13 amino acid residues. The two peptides predominantly occupied the active sites of ACE (His513, Tyr523, and Ala354) and DPP-IV (Tyr662 and Arg125) through hydrogen bonding. This leads to the deactivation of ACE and DPP-IV. PRACTICAL APPLICATION: Accelerate tilapia skin development and high-value utilization; provide foundation for preparing the peptides with dual ACE and DPP-IV inhibiting activity.

Inhibition of dipeptidyl peptidase IV (DPP-IV) and angiotensin converting enzyme (ACE) are considered useful in managing 2 often associated conditions: diabetes and hypertension. In this study, corolase PP was used to hydrolyze Antarctic krill protein. The hydrolysate (AKH) was isolated by ultrafiltration and purified by size-exclusion chromatography, ion exchange chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC) sequentially. The in vitro inhibitory activities of all AKHs and several fractions obtained against ACE and DPP-IV were assessed. Two peptides, purified with dual-strength inhibitory activity against ACE and DPP-IV, were identified by TOF-MS/MS. Results indicated that not all fractions exhibited dual inhibitory activities of ACE and DPP-IV. The purified peptide Lys-Val-Glu-Pro-Leu-Pro had half-maximal inhibitory concentrations (IC50 ) of 0.93±0.05 and 0.73±0.04 mg/mL against ACE and DPP-IV, respectively. The other peptide Pro-Ala-Leu had IC50 values of 0.64±0.05 and 0.88±0.03 mg/mL against ACE and DPP-IV, respectively. This study firstly reported the sequences of dual bioactive peptides from Antarctic krill proteins, further provided new insights into the bioactive peptides responsible for the ACE and DPP-IV inhibitory activities from the Antarctic krill protein hydrolysate to manage hypertension and diabetes.

Bioactivity of collagen peptides derived from commercial animals: In silico investigation

Collagen is a protein and one of the main building blocks of our skin. It is found in bones, tendons, ligaments, internal organs, blood vessels, and the lining of the intestines. In our body, collagen enables the cohesion of tissues and organs, affects hydration, resistance and elasticity of the skin, reduces the risk of developing degenerative joint diseases. Its production decreases with age. As a result, more and more people are taking collagen supplements. It has been proven that doing so can bring many benefits to the body. Taking collagen orally can be an effective way to improve the quality of the skin, increase hydration and delay the aging process. Collagen peptides are potential therapeutic agents for treating osteoarthritis and maintaining joint health. Collagen supplementation may be an element of preventive medicine in the field of cardiovascular diseases. as it significantly reduces fat mass and increases lean mass, it also leads to lower LDL concentrations. A beneficial effect was also noted on hair and nails, as well as on brain function.

As a key component of the hair, skin, and nails, there is strong consumer interest in the dermatologic efficacy of oral collagen supplementation. Oral supplementation with collagen peptides has increased in popularity in recent years. There are relatively few studies investigating the dermatologic effects of ingested collagen peptides, many of which are limited by sample size and variability of results. The question remains whether there is sufficient evidence to support companies' promises and consumers' goals. In this review, we investigate and compare the claims surrounding collagen supplementation on Instagram and YouTube, made by collagen companies, and established in the literature. Although some studies have demonstrated that collagen supplementation can enhance skin qualities such as elasticity and hydration, dermatologic claims in the media surpass any evidence currently supported by the literature. More research is needed to establish knowledge of the effects and physiologic mechanism of collagen supplementation. Dermatologists should be aware of the unsubstantiated proclamations of collagen made by companies and in social media, as well as what evidence is established thus far, to be equipped to discuss collagen supplementation with patients.

BackgroundCoronavirus disease 2019 (COVID-19) is a recent pandemic infectious disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). COVID-19 may lead to acute kidney injury (AKI).Main textSARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4(DPP4) as entry point receptors in the alveolar type II cell of the lung. However, the expression of ACE2 is 100-fold higher in kidney tissue than the lung, though the potential entry point of SARS-CoV-2 for renal tissue and induction of AKI remains undefined. Therefore, reduction of ACE2 and high circulating angiotensin II in COVID-19 may together participate in the induction of AKI. Thereby, direct ACE2 activator is under investigation to be used as an effective therapy in the management COVID-19-induced AKI. Besides, the direct effect via invasion of SARS-CoV-2 may lead to glomerulopathy and renal proximal tubular necrosis.ConclusionCOVID-19 may associate with AKI due to direct effect of SARS-CoV-2 through ACE2 and DPP4 receptors or indirectly through the development of cytokine storm. Both ACE2 and DPP4 are interacted mutually in the pathogenesis of AKI. Thus, DPP4 inhibitors or ACE2 activators could reverse early AKI in COVID-19. Therefore, emerging of clinical trials is warranted to confirm the role of ACE2 and DPP4 modulators in COVID-19-induced AKI.

This systematic review evaluates the effects of oral collagen supplementation on skin hydration, elasticity, and wrinkle reduction. Collagen, a key protein in the skin, decreases with age, causing visible signs of aging. The review synthesizes findings from 31 articles, including randomized controlled trials, systematic reviews, and meta-analyses, focusing on the efficacy of hydrolyzed collagen (HC), collagen tripeptides (CP), and low molecular weight collagen peptides (LMWCP). The review also highlights collagen peptides' role in stimulating collagen synthesis, improving skin barrier function, and promoting hydration. Despite some limitations, the evidence supports collagen supplements, as a non-invasive option for improving skin health. Aim of the Study The study aims to evaluate the impact of oral collagen supplementation, particularly hydrolyzed collagen (HC), collagen tripeptides (CP), and low molecular weight collagen peptides (LMWCP), on improving skin hydration, elasticity, and wrinkle reduction. Materials and methods A review of the literature collected in the PubMed database was performed to gather information found under the key words “collagen supplementation," "skin aging," "hydrolyzed collagen," "collagen peptides," "skin hydration," "skin elasticity," and "wrinkle reduction."

A role for PYY3-36 in GLP1-induced insulin secretion

Novel membrane peptidase inhibitory peptides with activity against angiotensin converting enzyme and dipeptidyl peptidase IV identified from hen eggs

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.

IntroductionCollagen is a protein that has found widespread use both as an ingredient in cosmetics applied externally and as an oral supplement. This substance is obtained from a number of animal sources, including bovine tissues, as well as marine fish. The characteristic properties of collagen peptides, such as scientifically proven anti-inflammatory effects, activation of fibroblast skin cells, stimulation of synovial cells to produce hyaluronic acid, and much more make this type of supplement promising in improving the body's general condition and in alleviating the symptoms of many ailments. Numerous scientific studies have shown that supplementation with hydrolyzed collagen has a beneficial effect on both the overall condition of the skin by improving its elasticity, hydration level, and positive action on its protective barrier and on the musculoskeletal system, where, when combined with appropriately selected physical activity, it can help to reduce pain associated with conditions such as osteoarthritis and even increase the range of movement in the joints. Easy availability, user-friendly forms of administration, such as powders or ready-to-drink liquid formulations, and a low incidence of side effects make this supplementation highly beneficial for users. Aim of the studyThis study aims to discuss the known processes and review the evidence supporting the beneficial effects of hydrolyzed collagen supplementation on the human skin and musculoskeletal system.Material and methodThis article presents the current state of knowledge about the benefits of oral collagen peptide supplementation in various scientific articles. Publications describing the mechanisms of action and the effects of collagen supplementation on skin conditions and the musculoskeletal system, including recent reports in this field, were reviewed using the PubMed platform. The search included the keywords ‘collagen’, ‘collagen supplementation’, ‘nutritional supplement’, ‘recovery’