Search Results (75)

Sourdough fermentation, driven by the biochemical activity of lactic acid bacteria (LAB), presents a scientifically promising approach to addressing nutritional limitations in cereal-based staples. This review critically examines both the underlying mechanisms by which LAB enhance the nutritional profile of sourdough and the translational challenges in realizing these benefits. Key improvements explored include enhanced mineral bioavailability (e.g., up to 90% phytate reduction), improved protein digestibility, an attenuated glycemic response (GI ≈ 54 vs. ≈75 for conventional bread), and the generation of bioactive compounds. While in vitro and animal studies extensively demonstrate LAB’s potential to reshape nutrient profiles (e.g., phytate hydrolysis improving iron absorption, proteolysis releasing bioactive peptides), translating these effects into consistent human health outcomes proves complex. Significant challenges hinder this transition from laboratory to diet, including the limited bioavailability of LAB-derived metabolites, high strain variability, and sensitivity to fermentation conditions. Furthermore, interactions with the food matrix and host-specific factors, such as gut microbiota composition, contribute to inconsistent findings. This review highlights methodological gaps, particularly reliance on in vitro or animal models, and the lack of long-term, effective human trials. Although LAB hold significant promise for nutritional improvements in sourdough, translating these findings to validated human benefits necessitates continued efforts in mechanism-driven strain optimization, the standardization of fermentation processes, and rigorous human studies. Full article

Transcription factors (TFs) are proteins that control gene expression by binding to specific DNA sequences and are essential for cell development, differentiation, and homeostasis. Dysregulation of TFs is implicated in numerous diseases, including cancer, autoimmune disorders, and neurodegeneration. While TFs were traditionally considered “undruggable” due to their lack of well-defined binding pockets, recent advances have made it possible to modulate their activity using diverse pharmacological strategies. Major TF families include NF-κB, p53, STATs, HIF-1α, AP-1, Nrf2, and nuclear hormone receptors, which take part in the regulation of inflammation, tumor suppression, cytokine signaling, hypoxia and stress response, oxidative stress, and hormonal response, respectively. TFs can perform multiple functions, participating in the regulation of opposing processes depending on the context. NF-κB, for instance, plays dual roles in immunity and cancer, and is targeted by proteasome and IKKβ inhibitors. p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat. STATs, especially STAT3 and STAT5, are oncogenic and targeted via JAK inhibitors or novel PROTAC degraders, for instance SD-36. AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK. Nrf2, a key antioxidant regulator, can be activated by agents like DMF or inhibited in chemoresistant tumors. Pharmacological strategies include direct inhibitors, activators, PROTACs, molecular glues, and epigenetic modulators. Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential. Full article

Type 2 diabetes mellitus (T2DM) represents a significant global health burden, especially in populations where rice constitutes a dietary staple. Parboiled rice (PBR), known for its lower glycemic index compared to conventional white rice (WR), may offer benefits in managing postprandial hyperglycemia. Nevertheless, the impact of PBR consumption on insulin sensitivity, β-cell function, and incretin hormone responses remains poorly understood. Methods: This randomized crossover pilot study aimed to assess and compare the acute effects of PBR and WR intake on postprandial glucose regulation, insulin sensitivity, β-cell functionality, and glucagon-like peptide-1 (GLP-1) responses in healthy subjects and individuals with T2DM. A total of 20 participants were recruited and evenly allocated into healthy (n = 10) and T2DM (n = 10) groups. Following the ingestion of either PBR or WR, blood samples were collected at fasting and various postprandial intervals to determine glucose, insulin, and GLP-1 levels. Insulin sensitivity and β-cell function were evaluated using HOMA-IR, Matsuda Index (MI), and Disposition Index (DI). Results: As expected, T2DM participants exhibited significantly elevated fasting glucose and insulin levels compared to healthy controls. Consumption of PBR led to significantly lower postprandial glucose responses in healthy subjects relative to WR. Although a similar trend of reduced glucose levels was observed in T2DM subjects after PBR intake, this reduction did not reach statistical significance. Parallel trends were observed in insulin secretion patterns. Moreover, GLP-1 responses were notably diminished in T2DM individuals compared to healthy participants. Importantly, MI and DI values significantly increased after PBR consumption in healthy individuals compared to those with T2DM, indicating improved insulin sensitivity and β-cell responsiveness. Conclusions: These preliminary findings suggest that PBR consumption may confer beneficial effects by lowering postprandial glucose and enhancing insulin sensitivity. Further studies with larger cohorts are warranted to confirm these outcomes and elucidate the physiological mechanisms behind PBR’s potential role in dietary management strategies for T2DM. Full article

Ras proteins are pivotal in the regulation of cell proliferation signals, and their dysregulation is intricately linked to the pathogenesis of various malignancies. Peptide inhibitors hold distinct advantages in targeting Ras proteins, attributable to their extensive binding domains, which result from the smooth surfaces of the proteins. The array of specific strategies includes the employment of full hydrocarbon chains, cyclic peptides, linear peptides, and N-terminal nucleation polypeptides. These methods effectively suppress the Ras signaling pathway through distinct mechanisms, highlighting their potential as anti-neoplastic agents. Moreover, cutting-edge methodologies, including the N-terminal aspartate nucleation strategy and the utilization of hydrocarbon-stapled peptides, are transforming the landscape of therapeutics aimed at Ras proteins. These innovations highlight the promise of peptide libraries and combinatorial chemistry in augmenting binding affinity, specificity, and cellular permeability, which are pivotal for the development of potent anti-cancer agents. The incorporation of dual therapeutic strategies, such as the synergy between peptide inhibitors and conventional chemotherapy or the use of radiotherapy enhancers, emerges as a compelling strategy to bolster the efficacy of cancer treatments targeting the Ras-MAPK pathway. Furthermore, recent studies have demonstrated that Ras-targeting stabilized peptides can amplify the radio-sensitivity of cancer cells, offering an innovative approach to enhance the efficacy of radiation therapy within cancer management. Full article

Glandirana is a genus of frogs that includes G. rugosa, G. emeljanovi, G. minima, G. tientaiensis, G. susurra, G. nakamurai and G. reliquia. These frogs produce antimicrobial peptides (AMPs), which are endogenous antibiotics that possess antibacterial, antifungal, antiviral and anti-endotoxin activity and help keep the hosts free from infections. In these activities, microbial death is promoted by membranolytic mechanisms that are mediated by the cationic charge and amphiphilic α-helical structures of these peptides. In general, these peptides are selective for microbes, showing low levels of hemolytic and cytotoxic activity, as well as possessing other biological activities, including anticancer, antioxidative and insulinotrophic action. In this review, a brief overview of AMPs with a focus on those from amphibians is provided, along with the phylogeny and nomenclature of frogs and AMPs from the Glandirana genus. This review then provides a comprehensive, in-depth description of the antimicrobial and other biological activities of all AMPs produced by known frogs of the Glandirana for the period 1994 to 2024. This description includes a detailed discussion of the structure/function relationships and mechanisms involved in the membrane interactions that drive these biological activities, with comparisons between AMPs from the same frog and between frogs across the genus. Based on their biological properties, AMPs from frogs of the Glandirana genus have been proposed for investigation as potential therapeutic agents, such as in the treatment of cancers and diabetes, as well as antimicrobial agents in areas, including crop protection, the food industry and oral hygiene. Full article

Conformational freedom-restricted peptides, such as stapled peptides, play a crucial role in the advancement of functional peptide development. We synthesized stapled octapeptides using α-carbocyclic α,α-disubstituted α-amino acids, particularly 3-allyloxy-1-aminocyclopentane-1-carboxylic acid, as the crosslink motifs. The organocatalytic capabilities of the synthesized stapled peptides were assessed in an asymmetric nucleophilic epoxidation reaction because the catalytic activities are known to be proportional to α-helicity. Despite incorporating side-chain crosslinks, the enantioselectivities of the epoxidation reaction catalyzed by stapled octapeptides were found to be comparable to those obtained using unstapled peptides. Interestingly, the stapled peptides using α-carbocyclic α,α-disubstituted α-amino acids demonstrated higher reactivities and stereoselectivities (up to 99% ee) compared to stapled peptides derived from (S)-α-(4-pentenyl)alanine, a commonly used motif for stapled peptides. These differences could be attributed to the increased α-helicity of the former stapled peptide in contrast to the latter, as evidenced by the X-ray crystallographic structures of their N-tert-butoxycarbonyl derivatives. Full article

Peptide-based therapeutics have traditionally faced challenges, including instability in the bloodstream and limited cell membrane permeability. However, recent advancements in α-helix stapled peptide modification techniques have rekindled interest in their efficacy. Notably, these developments ensure a highly effective method for improving peptide stability and enhancing cell membrane penetration. Particularly in the realm of antimicrobial peptides (AMPs), the application of stapled peptide techniques has significantly increased peptide stability and has been successfully applied to many peptides. Furthermore, constraining the secondary structure of peptides has also been proven to enhance their biological activity. In this review, the entire process through which hydrocarbon-stapled antimicrobial peptides attain improved drug-like properties is examined. First, the essential secondary structural elements required for their activity as drugs are validated, specific residues are identified using alanine scanning, and stapling techniques are strategically incorporated at precise locations. Additionally, the mechanisms by which these structure-based stapled peptides function as AMPs are explored, providing a comprehensive and engaging discussion. Full article

This review describes the discovery, structure, activity, engineered constructs, and applications of KR-12, the smallest antibacterial peptide of human cathelicidin LL-37, the production of which can be induced under sunlight or by vitamin D. It is a moonlighting peptide that shows both antimicrobial and immune-regulatory effects. Compared to LL-37, KR-12 is extremely appealing due to its small size, lack of toxicity, and narrow-spectrum antimicrobial activity. Consequently, various KR-12 peptides have been engineered to tune peptide activity and stability via amino acid substitution, end capping, hybridization, conjugation, sidechain stapling, and backbone macrocyclization. We also mention recently discovered peptides KR-8 and RIK-10 that are shorter than KR-12. Nano-formulation provides an avenue to targeted delivery, controlled release, and increased bioavailability. In addition, KR-12 has been covalently immobilized on biomaterials/medical implants to prevent biofilm formation. These constructs with enhanced potency and stability are demonstrated to eradicate drug-resistant pathogens, disrupt preformed biofilms, neutralize endotoxins, and regulate host immune responses. Also highlighted are the safety and efficacy of these peptides in various topical and systemic animal models. Finaly, we summarize the achievements and discuss future developments of KR-12 peptides as cosmetic preservatives, novel antibiotics, anti-inflammatory peptides, and microbiota-restoring agents. Full article

α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained. To further apply this method in targeted delivery, the alkynylbenzyl bromide linker was synthesized and conjugated with Coumarin 120 (AMC) and Camptothecin (CPT) by copper-catalyzed click chemistry, and then stapled between cysteine[2,4] of the LsIA to construct a fluorescent probe and two peptide-drug conjugates. The maximum emission wavelength of the LsIA fluorescent probe was 402.2 nm, which was essentially unchanged compared with AMC. The cytotoxic activity of the LsIA peptide-drug conjugates on human A549 was maintained in vitro. The results demonstrate that the stapling of cysteine[2,4] with alkynylbenzyl bromide is a simple and feasible strategy for the exploitation and utilization of the α-conotoxin LsIA. Full article

Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308. Full article

Medicinal chemistry is constantly searching for new approaches to develop more effective and targeted therapeutic molecules. The design of peptidomimetics is a promising emerging strategy that is aimed at developing peptides that mimic or modulate the biological activity of proteins. Among these, stapled peptides stand out for their unique ability to stabilize highly frequent helical motifs, but they have failed to be systematically reported. Here, we exploit chemically diverse helix-inducing i, i + 4 constraints—lactam, hydrocarbon, triazole, double triazole and thioether—on two distinct short sequences derived from the N-terminal peptidase domain of hACE2 upon structural characterization and in silico alanine scan. Our overall objective was to provide a sequence-independent comparison of α-helix-inducing staples using circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. We identified a 9-mer lactam stapled peptide derived from the hACE2 sequence (His34-Gln42) capable of reaching its maximal helicity of 55% with antiviral activity in bioreporter- and pseudovirus-based inhibition assays. To the best of our knowledge, this study is the first comprehensive investigation comparing several cyclization methods with the goal of generating stapled peptides and correlating their secondary structures with PPI inhibitions using a highly topical model system (i.e., the interaction of SARS-CoV-2 Spike RBD with hACE2). Full article

The escalating global incidence of obesity and chronic diet-related disorders, such as type 2 diabetes, hypertension, cardiovascular disease, malignancies, and celiac disease, has intensified the focus on dietary factors and disease risks. Rice, a dietary staple for billions, is under scrutiny, particularly polished or white rice, which is high in starch and in the glycemic index and low in nutrition due to the removal of the outer bran layer during milling. This study critically analyzes the comparison between whole brown rice (BR) and milled white rice in terms of health benefits. A significant finding is the enhancement of food nutrition through fermentation, which improves protein digestibility and mineral availability and releases peptides and amino acids. The study also highlights the increased antibacterial and antioxidant activity of foods, including health benefits, through fermentation. A comprehensive review of existing data on the nutritional content and health advantages of whole fermented BR grains is presented, alongside experiments in developing fermented BR-based foods. The safety, preservation, and the economic and environmental advantages of consuming regularly fermented BR instead of white or unfermented BR are discussed. Finally, the paper addresses the commercialization challenges and future opportunities for promoting fermented BR as a healthier food alternative. Full article

The species Chenopodium quinoa Willd. and Amaranthus hybridus L. are Andean staples, part of the traditional diet and gastronomy of the people of the highlands of Colombia, Ecuador, Peru, Bolivia, northern Argentina and Chile, with several ethnopharmacological uses, among them anticancer applications. This review aims to present updated information on the nutritional composition, phytochemistry, and antimicrobial and anticancer activity of Quinoa and Amaranth. Both species contribute to food security due to their essential amino acid contents, which are higher than those of most staples. It is highlighted that the biological activity, especially the antimicrobial activity in C. quinoa, and the anticancer activity in both species is related to the presence of phytochemicals present mostly in leaves and seeds. The biological activity of both species is consistent with their phytochemical composition, with phenolic acids, flavonoids, carotenoids, alkaloids, terpenoids, saponins and peptides being the main compound families of interest. Extracts of different plant organs of both species and peptide fractions have shown in vitro and, to a lesser degree, in vivo activity against a variety of bacteria and cancer cell lines. These findings confirm the antimicrobial and anticancer activity of both species, C. quinoa having more reported activity than A. hybridus through different compounds and mechanisms. Full article

The prevalence of inflammatory bowel disease (IBD) is progressively rising each year, emphasizing the significance of implementing rational dietary interventions for disease prevention. Oats, being a staple agricultural product, are abundant in protein content. This study aimed to investigate the protective effects and underlying mechanisms of oat peptides (OPs) in a mouse model of acute colitis induced by dextran sulfate sodium salt (DSS) and a Caco-2 cell model. The findings demonstrated that intervention with OPs effectively mitigated the symptoms associated with DSS-induced colitis. The physicochemical characterization analysis demonstrated that the molecular weight of the OPs was predominantly below 5 kDa, with a predominant composition of 266 peptides. This study provides further evidence of the regulatory impact of OPs on the Keap1-Nrf2 signaling axis and elucidates the potential role of WGVGVRAERDA as the primary bioactive peptide responsible for the functional effects of OPs. Ultimately, the results of this investigation demonstrate that OPs effectively mitigate DSS-induced colitis by preserving the integrity of the intestinal barrier and modulating the Keap1-Nrf2 axis. Consequently, these findings establish a theoretical foundation for the utilization of OPs as dietary supplements to prevent the onset of IBD. Full article

Immunogenic peptides from wheat gluten can be produced during digestion, which are difficult to digest by gastrointestinal proteases and negatively affect immune responses in humans. Gluten intolerance is a problem in countries where wheat is a staple food, and a gluten-free diet is commonly recommended for its treatment and prevention. Enzyme approaches for degradation of the peptides can be considered as a strategy for its prevention. Here, we isolated a gluten-degrading bacterium, Bacillus amyloliquefaciens subsp. plantarum, from wheat grains. The culture conditions for enzyme production or microbial use were considered based on gluten decomposition patterns. Additionally, the pH range for the activity of the crude enzyme was investigated. The bacterium production of gluten-degrading enzymes was temperature-dependent within 25 °C to 45 °C, and the production time decreased with increasing culture temperature. However, it was markedly decreased with increasing biofilm formation. The bacterium decomposed high-molecular-weight glutenin proteins first, followed by gliadin proteins, regardless of the culture temperature. Western blotting with an anti-gliadin antibody revealed that the bacterium decomposed immunogenic proteins related to α/β-gliadins. The crude enzyme was active in the pH ranges of 5 to 8, and enzyme production was increased by adding gliadin into the culture medium. In this study, the potential of the B. amyloliquefaciens subsp. plantarum for gluten-degrading enzyme production was demonstrated. If further studies for purification of the enzyme specific to the immunogenic peptides and its characteristics are conducted, it may contribute as a strategy for prevention of gluten intolerance. Full article