Antihypertensive Peptides Research Articles

DeepForest-HTP: A Novel Deep Forest Approach for Predicting Antihypertensive Peptides

Hypertension is a major preventable risk factor for cardiovascular disease, affecting over 1.5 billion adults worldwide. Antihypertensive peptides (AHTPs) have gained attention as a natural therapeutic option with minimal side effects. This study proposes a Deep Forest-based machine learning framework for AHTP prediction, leveraging a multi-granularity cascade structure to enhance classification accuracy. We integrated data from BIOPEP-UWM and three previously used datasets, totaling 2000 peptide sequences, and introduced novel feature extraction methods to build a comprehensive dataset for model training.This study represents the first application of Deep Forest for AHTP identification, demonstrating substantial classification performance advantages over traditional methods (e.g., SVM, CNN, and XGBoost) as well as recent mainstream prediction models (Ensemble-AHTPpred, CNN-SVM Ensemble, and mAHTPred). Requiring no complex manual feature engineering, the model adapts flexibly to various data needs, offering a novel perspective for efficient AHTP prediction and promising utility in hypertension management.On the benchmark dataset, the model achieved high accuracy, sensitivity, and AUC, providing a robust tool for identifying safe and effective AHTPs. However, future efforts should incorporate larger and more diverse independent validation datasets to further improve the model and enhance its generalizability. Additionally, the model's predictive accuracy relies on known AHTP targets and sequence features, potentially limiting its ability to detect AHTPs with uncharacterized or atypical properties.

Insight into the interaction of serum albumin with antihypertensive peptide Val-Ala-Pro from bovine casein hydrolysate based on the biolayer interferometry, multi-spectroscopic analysis and computational evaluation

Insight into the interaction of serum albumin with antihypertensive peptide Val-Ala-Pro from bovine casein hydrolysate based on the biolayer interferometry, multi-spectroscopic analysis and computational evaluation

Discovery of a novel nanomolar angiotensin-I converting enzyme inhibitory peptide with unusual binding mechanisms derived from Chlorella pyrenoidosa

Chlorella pyrenoidosa (C. pyrenoidosa) has been cultivated in large quantities, and was proven to be antihypertensive when consumed orally. However, the antihypertensive peptides derived from C. pyrenoidosa remains scarce. In this study, trypsin was chosen to prepare the hydrolysate of C. pyrenoidosa, which was then fractionated by column chromatography. And ninety-nine peptides were identified by LC-MS/MS, after which 10 peptides were chosen by docking-based virtual screening and demonstrated the ability to inhibit ACE. Among them, LVAKA (LV-5) had the lowest IC50 (26.66 μM). LV-5, LKKAP, and PGLRP were identified as non-competitive ACE inhibitory peptides that exhibited significant stability in the face of extreme pH and high temperatures. Insilico and in-vitro simulated gastrointestinal digestion revealed that these three peptides could release ACE inhibitory peptide fragments after digestion. The sequence optimization of LV-5 led to the identification of LRAKA (LR-5), which was recognized as a novel nanomolar ACE peptide with an IC50 of 350 nM in-vitro and a potent antihypertensive effect in-vivo. Moreover, molecular dynamic simulation indicated that LR-5 interacted with an unconventional binding site in ACE. These findings underscore the potential of Chlorella as a source of antihypertensive peptides and suggest a promising future for the use of Chlorella-derived peptides in the management of hypertension.

Research on the Synergistic Inhibition of Angiotensin-Converting Enzyme (ACE) by the Gastrointestinal Digestion Products of the ACE Inhibitory Peptide FPPDVA.

To gain a deeper understanding of the ACE inhibition effect, the inhibitory effect of ACE-inhibiting peptide (ACEIP) FPPDVA's digestive products on ACE was further investigated. Two novel peptides, PD (IC50 = 161.1 ± 1.10 μM) and DV (IC50 = 66.51 ± 0.99 μM) were identified in the digestive products of FPPDVA using LC-MS/MS. The Peptide Mix (FPPDVA, PD, and DV) exhibited a remarkable synergistic effect on ACE inhibition by significantly enhancing it by up to 508% compared to the individual peptides alone. Furthermore, theoretical simulations suggest that the Peptide Mix synergistically inhibits ACE activity by forming more stable complexes with the active site of ACE, facilitated by an increased number of hydrogen bonds. Additionally, Lineweaver-Burk plot analysis and spectroscopic studies further verified the presence of these stable complexes. ITC results show that the combination of Peptides Mix and ACE is a spontaneous exothermic process driven by entropy. The study showed that FPPDVA has a stronger inhibitory effect on ACE after digestion, making it suitable as an antihypertensive peptide in functional foods.

Food processing drives the toxic lectin reduction and bioactive peptide enhancement in Pinellia ternata

Processing can change the properties and flavors of food. Many plants in the Araceae family can be used as food or medicine, but their raw materials are usually toxic, such as Pinellia ternata tuber (PTT). After processing (processed PTT, PPTT), its toxicity is reduced. However, the mechanism remains unclear. In this study, a novel approach integrating liquid chromatography-mass spectrometry, feature-based molecular networking (FBMN), de novo sequencing, and protein database searching was applied to rapidly discover and characterize peptides in PPTT. Potential antihypertensive peptides were screened using in silico methods, angiotensin I-converting enzyme (ACE) inhibitory assay, and molecular docking analysis. A significant decrease was observed in toxic lectins after processing. Meanwhile, a total of 1,954 mass spectral nodes were discovered in PPTT, of which 130 were annotated as peptides by FBMN. These peptides, ranging from 2 to 21 amino acids, were rapidly identified using PEAKS. Notably, 98 peptides were derived from lectins, most of which increased after processing. Approximately 30% of identified peptides were screened for potential high antihypertensive activity in silico. Five peptides exhibited inhibitory effects on ACE, with two showing IC50 values of 131 and 185 μM. Dynamic profiling indicated that 7 to 9 days of processing is optimal for reducing toxicity and enhancing efficacy. More importantly, these peptides were also found in commercial PPTT, confirming their bioactivity contributions. These findings provide insights into the mechanism by which food processing drives the toxic lectin reduction and bioactive peptide enhancement in PTT, providing a novel approach to rapidly discover bioactive peptides, which can be extended to other foods in Araceae family.

Novel Bioactive Peptides from Red Bigeye (Priacanthus macracanthus) Flesh Protein

Red bigeye (Priacanthus macracanthus) is a common fish species in Malaysia. This study reported an in silico assessment of the main proteins in red bigeye flesh as precursors for bioactive peptides. Six major proteins were chosen as precursors from the proteomic profiles of red bigeye proteins. Analyses using the BIOPEP-UWM database found that Protein number 4 gave the highest total number of bioactive peptides (5052 peptides), with dominant bioactivity in angiotensin-I-converting enzyme (ACE) inhibition (1571 peptides) and dipeptidyl peptidase-IV (DPP-IV) inhibition (2238 peptides). The ACE inhibitors had a frequency of bioactive fragment occurrences (A) of 0.4098, while the DPP-IV inhibitors gave a frequency of 0.5805. In silico proteolysis using BIOPEP-UWM found that pepsin (pH > 2) was the most promising proteinase in releasing a high number of DPP-IV and ACE inhibitory peptides. A novel peptide with significant potential was identified as QYKF. This study shows that red bigeye is a potential source of antihypertensive and antidiabetic peptides.

Amino Acid Composition, Antioxidant and Antihypertensive Activity in Extracts from Mexican Añejo Cheese.

Authentic Mexican cheeses have potential health benefits, although there are few studies on their bioactive components. In this study, we analysed soluble extracts from añejo cheese from Zacazonapan (Mexico), obtained from two dairies (A and B) that used milk from cows of different breeds and differed in processing. The soluble extracts of Zacazonapan añejo cheese during ripening (0, 30, 95 and 180 days) were used to determine proximate composition, amino acid composition, peptide profile, molecular mass profile, antioxidant and antihypertensive activities. The molecular mass of the released protein fragments ranged from 0.10 to 22.43 kDa. During ripening, amino acids such as Pro, His, Tyr, Trp, Met, Cys, Ala, Gly, Leu and Val were present, which are associated with antioxidant activity. The inhibition of β-carotene bleaching was below 50 % at all ripening times. A significant difference between the cheese samples was observed only after 180 days. Amino acids associated with angiotensin-I converting enzyme (ACE-I) inhibition were found in the extracts (Trp, Phe, Tyr, Pro, Lys and Arg). The highest activity was observed in cheese ripened for 180 days (IC50 of cheese A and B was 0.38 and 0.42 mg/mL, respectively). These results suggest that Zacazonapan añejo cheese is a potential source of antioxidant and antihypertensive peptides, which are influenced by the dairy factor (milk source and production technique) and ripening time. This is relevant as there are no reports of these bioactivities in this type of cheese.

Exploration of potential antihypertensive peptides derived from farmed Chinese giant salamander (Andrias davidianus)

Exploration of potential antihypertensive peptides derived from farmed Chinese giant salamander (Andrias davidianus)

Characterization and molecular docking of tetrapeptides with cellular antioxidant and ACE inhibitory properties from cricket (Acheta domesticus) protein hydrolysate

Wide-ranging bioactivities of enzymatically digested insect protein to produce peptides have been targeted for functional food development. In this study, fractionated peptides obtained from cricket (Acheta domesticus) protein hydrolysate by alcalase digestion were identified and evaluated for their bioactivities. Peptide fractions F44, F45, and F46, isolated through size exclusion chromatography, demonstrated strong cytoprotective effects on SH-SY5Y and HepG2 cells exposed to H2O2. This was evidenced by a 2-fold decrease in reactive oxygen species (ROS) accumulation in the cells and a 3-fold upregulation of genes encoding antioxidant enzymes. The F45 peptide fractions also showed chemical antioxidant activities ranging from approximately 290 to 393 mg trolox/g peptide, measured by DPPH, ABTS, and FRAP assays. Furthermore, F45 demonstrated the highest angiotensin-converting enzyme I (ACE) inhibitory activity, 57.93 %. F45 induced higher levels of Nrf2, SOD1, SOD2, CAT, GSR, and GPx4 gene expression in SH-SY5Y and HepG2 cells compared to cells treated with H2O2 and no peptides (p < 0.05). Cells treated with H2O2 and F45 exhibited significantly increased antioxidant enzyme activity, including SOD, CAT, GSR, and GPx (p < 0.05). The F45B fraction from F45 was sequenced to obtain FVEG and FYDQ tetrapeptides. Molecular docking analysis revealed their high binding affinity to cellular antioxidant enzymes (SOD, CAT, GSR, GPx1, and GPx4), an antioxidant-related protein (Keap1), and ACE. These results suggest that the novel tetrapeptides from Acheta domesticus demonstrate important biological activities, establishing them as significant cellular antioxidant activities and a potential source of antihypertensive peptides.

Potential Impact of Bioactive Peptides from Foods in the Treatment of Hypertension.

High blood pressure (BP) is the main preventable risk factor for cardiovascular diseases (CVDs). Much research is aimed at finding natural alternatives to control or prevent hypertension (HT), since some hypertensive patients do not respond to current pharmacological treatments or show undesirable side effects. Forty relevant articles have been selected from various scientific literature databases. The results reveal that angiotensin-converting enzyme (ACE) inhibition is the most reported mechanism of action of antihypertensive peptides. The active peptides have a great variety of origins. Biopeptides with a molecular weight of <3 kDa, short chain <20 amino acids, and a hydrophobic amino acid sequence at the C- and N-terminus exhibit higher antihypertensive activity. They also show good stability to enzymatic hydrolysis and gastrointestinal digestion, and no toxicity. To determine antihypertensive effectiveness, in vitro and in vivo animal studies are the most frequent developed, with few in silico studies and only one human clinical trial. There is interesting potential for antihypertensive peptides as promising natural candidates for the development of functional foods, nutraceuticals and drugs for preventive or therapeutic treatment of hypertension. The aim of this review is to study the role of food-derived bioactive peptides in HT.

Two Novel Angiotensin-Converting Enzyme (ACE) Inhibitory and ACE2 Upregulating Peptides from the Hydrolysate of Pumpkin (Cucurbita moschata) Seed Meal.

Pumpkin (Cucurbita moschata) seed meal (PSM), the major byproduct of pumpkin seed oil industry, was used to prepare angiotensin-converting enzyme (ACE) inhibitory and angiotensin-converting enzyme 2 (ACE2) upregulating peptides. These peptides were isolated and purified from the PSM hydrolysate prepared using Neutrase 5.0 BG by ultrafiltration, Sephadex G-15 column chromatography, and reversed-phase high-performance liquid chromatography. Two peptides with significant ACE inhibition activity were identified as SNHANQLDFHP and PVQVLASAYR with IC50 values of 172.07 and 90.69 μM, respectively. The C-terminal tripeptides of the two peptides contained Pro, Phe, and Tyr, respectively, and PVQVLASAYR also had Val in its N-terminal tripeptide, which was a favorable structure for ACE inhibition. Molecular docking results declared that the two peptides could interact with ACE through hydrogen bonds and hydrophobic interactions. Furthermore, the two peptides performed protective function on EA.hy926 cells by decreasing the secretion of endothelin-1, increasing the release of nitric oxide, and regulating the ACE2 activity. In vitro simulated gastrointestinal digestion showed the two peptides exhibited good stability against gastrointestinal enzyme digestion. In conclusion, PSM is a promising material for preparing antihypertensive peptides.

Peptidomics-based identification of antihypertensive and antidiabetic peptides from sheep milk fermented using Limosilactobacillus fermentum KGL4 MTCC 25515 with anti-inflammatory activity: in silico, in vitro, and molecular docking studies.

This study investigated the synthesis of bioactive peptides from sheep milk through fermentation with Limosilactobacillus fermentum KGL4 MTCC 25515 strain and assessed lipase inhibition, ACE inhibition, α-glucosidase inhibition, and α-amylase inhibition activities during the fermentation process. The study observed the highest activities, reaching 74.82%, 70.02%, 72.19%, and 67.08% (lipase inhibition, ACE inhibition, α-glucosidase inhibition, and α-amylase inhibition) after 48h at 37°C, respectively. Growth optimization experiments revealed that a 2.5% inoculation rate after 48h of fermentation time resulted in the highest proteolytic activity at 9.88mg/mL. Additionally, fractions with less than 3kDa of molecular weight exhibited superior ACE-inhibition and anti-diabetic activities compared to other fractions. Fermentation of sheep milk with KGL4 led to a significant reduction in the excessive production of NO, TNF-α, IL-6, and IL-1β produced in RAW 267.4 cells upon treatment with LPS. Peptides were purified utilizing SDS-PAGE and electrophoresis on 2D gels, identifying a maximum number of proteins bands ranging 10-70kDa. Peptide sequences were cross-referenced with AHTPDB and BIOPEP databases, confirming potential antihypertensive and antidiabetic properties. Notably, the peptide (GPFPILV) exhibited the highest HPEPDOCK score against both α-amylase and ACE.

Understanding the Transepithelial Transport and Transbilayer Diffusion of the Antihypertensive Peptide Asn-Cys-Trp: Insights from Caco-2 Cell Monolayers and the DPPC Model Membrane.

Understanding the transport mechanism of the peptide Asn-Cys-Trp (NCW) is crucial to improving its intestinal absorption and bioavailability. This study investigated the absorption of NCW through Caco-2 cell monolayers and its interaction with the DPPC bilayers. Results revealed that after a 3 h incubation, the Papp (AP-BL) and Papp (BL-AP) values of NCW at a concentration of 5 mmol/L were (22.24 ± 4.52) × 10-7 and (6.63 ± 2.31) × 10-7 cm/s, respectively, with the transport rates of 1.59 ± 0.32 and 0.62 ± 0.20%, indicating its moderate absorption. NCW was found to be transported via PepT1 and paracellular transport pathways, as evidenced by the significant impact of Gly-Pro and cytochalasin D on the Papp values. Moreover, NCW upregulated ZO-1 mRNA expression. Further investigation of the ZO-1-mediated interaction between NCW and tight junction proteins will contribute to a better understanding of the paracellular transport mechanism of NCW. The interaction between NCW and the DPPC bilayers was predominantly driven by entropy. NCW permeated the bilayers through electrostatic, hydrogen bonding, and hydrophobic interactions, resulting in increased fluidity, flexibility, and disorder as well as phase transition and phase separation of the bilayers.

Cultivable microbial diversity, peptide profiles, and bio-functional properties in Parmigiano Reggiano cheese.

Lactic acid bacteria (LAB) communities shape the sensorial and functional properties of artisanal hard-cooked and long-ripened cheeses made with raw bovine milk like Parmigiano Reggiano (PR) cheese. While patterns of microbial evolution have been well studied in PR cheese, there is a lack of information about how this microbial diversity affects the metabolic and functional properties of PR cheese. To fill this information gap, we characterized the cultivable fraction of natural whey starter (NWS) and PR cheeses at different ripening times, both at the species and strain level, and investigated the possible correlation between microbial composition and the evolution of peptide profiles over cheese ripening. The results showed that NWS was a complex community of several biotypes belonging to a few species, namely, Streptococcus thermophilus, Lactobacillus helveticus, and Lactobacillus delbrueckii subsp. lactis. A new species-specific PCR assay was successful in discriminating the cheese-associated species Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Lacticaseibacillus zeae. Based on the resolved patterns of species and biotype distribution, Lcb. paracasei and Lcb. zeae were most frequently isolated after 24 and 30 months of ripening, while the number of biotypes was inversely related to the ripening time. Peptidomics analysis revealed more than 520 peptides in cheese samples. To the best of our knowledge, this is the most comprehensive survey of peptides in PR cheese. Most of them were from β-caseins, which represent the best substrate for LAB cell-envelope proteases. The abundance of peptides from β-casein 38-88 region continuously increased during ripening. Remarkably, this region contains precursors for the anti-hypertensive lactotripeptides VPP and IPP, as well as for β-casomorphins. We found that the ripening time strongly affects bioactive peptide profiles and that the occurrence of Lcb. zeae species is positively linked to the incidence of eight anti-hypertensive peptides. This result highlighted how the presence of specific LAB species is likely a pivotal factor in determining PR functional properties.

Exploration of hypoglycemic peptides from porcine collagen based on network pharmacology and molecular docking.

In recent years, the extraction of hypoglycemic peptides from food proteins has gained increasing attention. Neuropeptides, hormone peptides, antimicrobial peptides, immune peptides, antioxidant peptides, hypoglycemic peptides and antihypertensive peptides have become research hotspots. In this study, bioinformatic methods were used to screen and predict the properties of pig collagen-derived hypoglycemic peptides, and their inhibitory effects on α-glucosidase were determined in vitro. Two peptides (RL and NWYR) were found to exhibit good water solubility, adequate ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties, potentially high biological activity, and non-toxic. After synthesizing these peptides, NWYR showed the best inhibitory effect on α-glucosidase with IC50 = 0.200±0.040 mg/mL, and it can regulate a variety of biological processes, play a variety of molecular functions in different cellular components, and play a hypoglycemic role by participating in diabetic cardiomyopathy and IL-17 signaling pathway. Molecular docking results showed that NWYR had the best binding effect with the core target DPP4 (4n8d), with binding energy of -8.8 kcal/mol. NWYR mainly bonded with the target protein through hydrogen bonding, and bound with various amino acid residues such as Asp-729, Gln-731, Leu-765, etc., thus affecting the role of the target in each pathway. It is the best core target for adjuvant treatment of T2DM. In short, NWYR has the potential to reduce type 2 diabetes, providing a basis for further research or food applications as well as improved utilization of pig by-products. However, in subsequent studies, it is necessary to further verify the hypoglycemic ability of porcine collagen active peptide (NWYR), and explore the hypoglycemic mechanism of NWYR from multiple perspectives such as key target genes, protein expression levels and differences in metabolites in animal models of hyperglycemia, which will provide further theoretical support for its improvement in the treatment of T2DM.

From in silico to in vitro: Hydrolysis of cheese whey to obtain peptides with anti-aging and anti-hypertensive activities

Our goal was to identify potential anti-aging and anti-hypertensive peptides from the most abundant protein in cheese whey (CW), β-lactoglobulin (BLG), using a multidisciplinary approach. These peptides were generated by three different proteases: trypsin, chymotrypsin and subtilisin. Our bioinformatics approach indicated that trypsin or subtilisin are good candidates for generating anti-hypertensive peptides, whereas chymotrypsin has the highest potential to generate anti-aging fragments, especially anti-elastase. This is mainly due to the presence of chymotryptic peptides with highly similar structures to elastase inhibitors. In addition, we aimed to perform the enzymatic hydrolysis of BLG and evaluate in vitro anti-aging and anti-hypertensive potential by assessing the inhibition to collagenase, elastase and angiotensin-converting enzyme (ACE). We found that chymotrypsin was able to generate a <10 kDa fraction of BLG-hydrolysate that reduces elastase activity (∼15%), which corroborates our interpretation of the in silico data. This fraction also showed reduced ACE activity (∼18%), though statistically similar to the intact protein (∼16%). Peptidomic analysis revealed that peptide sequences with predicted anti-elastase activity were present both in BLG and CW chymotrypsin-hydrolyzed samples, though at higher concentrations in the isolated protein, which may support our experimental results. Lastly, CW was hydrolyzed by chymotrypsin and spray-dried to be used as ingredient in a potentially functional milk-based drink. Hydrolysis significantly impacted the characteristics of the dried powder and the drink containing CW hydrolysate attained better evaluation in sensory analysis. Thus, enzymatic hydrolysis with chymotrypsin generated a potentially functional product that improves bioactivity and functionality of CW.

Mining anti-hypertensive peptides in animal food through deep learning: a case study of gastrointestinal digestive products of royal jelly

Mining anti-hypertensive peptides in animal food through deep learning: a case study of gastrointestinal digestive products of royal jelly

Novel Targets and Potential Mechanisms of Mizuhopecten yessoensis-Derived Tripeptide NCW as Antihypertensive Peptides.

Mizuhopecten yessoensis-derived tripeptide Asn-Cys-Trp (NCW) exhibits a potent antihypertensive effect in vivo. However, a lack of knowledge of the antihypertensive mechanism of tripeptide NCW limits its application for functional foods industrialization. The purpose of this study is to elucidate the corresponding targets and mechanisms of tripeptide NCW in hypertension regulation. Administration of tripeptide NCW for 3 weeks, the blood pressure of spontaneously hypertensive rats (SHRs) is significantly decreased. After sacrifice, the serum sample is analyzed using tandem mass tag (TMT)-based liquid chromatography with tandem mass spectrometry to identify differentially expressed proteins. The proteomic analysis indicates that tripeptide NCW administration alters serum protein profiles in SHR rats, significantly upregulating 106 proteins and downregulating 30 proteins. These proteins enhance the glycolysis, glucose, and TCA cycle, improve amino metabolism, trigger the cAMP/PKA, cGMP/PKG, PI3K/AKT, and AMPK signal pathways, and inhibit Ras-regulated JNK activation, TGF-β/MAPK, and TGF-β/ RhoA/ROCK pathways. Tripeptide NCW supplementation is demonstrated to regulate signal pathways involved in the control of blood pressure and regulate the energy and amino acids metabolic processes in serum, providing important insights into the protective effects of tripeptide NCW on hypertension.

Identification of antihypertensive peptides from lupine using a machine learning approach

Bioactive products with antihypertensive biological activity, isolated from natural sources, have been the subject of growing interest in recent years. This is due to their widespread use in medicine for the treatment and prevention of various diseases, as well as dietary supplements for athletes or their inclusion in diets for overweight people. One such source is Lupine. Lupine beans are delicious and useful. They can be used in food as a nutritional source of vegetable proteins. They are also rich in polyphenols, carotenoids, and phytosterols. The approaches to screen antihypertensive peptides, based on information technologies and more concretely on machine learning, doubtlessly have higher throughput and rapid speed than the in vivo and in vitro procedures. Therefore, the scientific literature abounds with articles offering various artificial intelligence algorithms for predicting food-derived antihypertensive peptides. In this study, an Adaptive Boosting (AdaBoost) algorithm was developed for these purposes. The results showed that the AdaBoost model as a novel auxiliary tool is feasible to screen for antihypertensive peptides derived from food, with high throughput and high efficiency.

The Potential of Sheep or Camel Milk Constituents to Contribute to Novel Dressings for Diabetic Wounds.

Impaired wound healing is a complication of diabetes, which constitutes a serious problem in clinical practice. Currently, there is a high demand on the market for local treatment options for difficult-to-heal wounds caused by diabetes. The development of dressings that accelerate wound healing has recently been the subject of much research. Sheep and camel milk is gaining importance due to the content of many bioactive substances with health-promoting effects, such as insulin, LF, proline, or CLA. Sheep and camel milk proteins are a promising source of insulin, antidiabetic, and antihypertensive peptides. Numerous studies show that local administration of insulin has a significant impact on the healing of diabetic wounds. Sheep and camel milk, due to the highest LF content among ruminants, reduces autoimmune inflammatory processes and protects against bacterial and viral infections in the wound environment. Sheep's milk has the highest content of proline and CLA, and their addition to a hydrogel dressing can help in the development of an effective dressing material. The production of hydrogel dressings containing sheep and camel milk, which are naturally rich in the bioactive substances presented in this review, may be a promising step in the market of specialized dressings for difficult-to-heal diabetic wounds.