Unraveling diabetes complexity through natural products, miRNAs modulation, and future paradigms in precision medicine and global health.

BACKGROUND AND AIMS: The challenge posed by diabetes necessitates a paradigm shift from conventional diagnostic approaches focusing on glucose and lipid levels to the transformative realm of precision medicine. This approach, leveraging advancements in genomics and proteomics, acknowledges the individualistic genetic variations, dietary preferences, and environmental exposures in diabetes management. The study comprehensively analyzes the evolving diabetes landscape, emphasizing the pivotal role of genomics, proteomics, microRNAs (miRNAs), metabolomics, and bioinformatics. RESULTS: Precision medicine revolutionizes diabetes research and treatment by diverging from traditional diagnostic methods, recognizing the heterogeneous nature of the condition. MiRNAs, crucial post-transcriptional gene regulators, emerge as promising therapeutic targets, influencing key facets such as insulin signaling and glucose homeostasis. Metabolomics, an integral component of omics sciences, contributes significantly to diabetes research, elucidating metabolic disruptions, and offering potential biomarkers for early diagnosis and personalized therapies. Bioinformatics unveils dynamic connections between natural substances, miRNAs, and cellular pathways, aiding in the exploration of the intricate molecular terrain in diabetes. The study underscores the imperative for experimental validation in natural product-based diabetes therapy, emphasizing the need for in vitro and in vivo studies leading to clinical trials for assessing effectiveness, safety, and tolerability in real-world applications. Global cooperation and ethical considerations play a pivotal role in addressing diabetes challenges worldwide, necessitating a multifaceted approach that integrates traditional knowledge, cultural competence, and environmental awareness. CONCLUSIONS: The key components of diabetes treatment, including precision medicine, metabolomics, bioinformatics, and experimental validation, converge in future strategies, embodying a holistic paradigm for diabetes care anchored in cutting-edge research and global healthcare accessibility.

Novel Functional Food Properties of Forest Onion (Eleutherine bulbosa Merr.) Phytochemicals for Treating Metabolic Syndrome: New Insights from a Combined Computational and In Vitro Approach.

Metabolic syndrome is a global health problem. The use of functional foods as dietary components has been increasing. One food of interest is forest onion extract (FOE). This study aimed to investigate the effect of FOE on lipid and glucose metabolism in silico and in vitro using the 3T3-L1 mouse cell line. This was a comprehensive study that used a multi-modal computational network pharmacology analysis and molecular docking in silico and 3T3-L1 mouse cells in vitro. The phytochemical components of FOE were analyzed using untargeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Next, an in silico analysis was performed to determine FOE's bioactive compounds, and a toxicity analysis, protein target identification, network pharmacology, and molecular docking were carried out. FOE's effect on pancreatic lipase, α-glucosidase, and α-amylase inhibition was determined. Finally, we determined its effect on lipid accumulation and MAPK8, PPARG, HMGCR, CPT-1, and GLP1 expression in the preadipocyte 3T3-L1 mouse cell line. We showed that the potential metabolites targeted glucose and lipid metabolism in silico and that FOE inhibited pancreatic lipase levels, α-glucosidase, and α-amylase in vitro. Furthermore, FOE significantly (p < 0.05) inhibits targeted protein expressions of MAPK8, PPARG, HMGCR, CPT-1, and GLP-1 in vitro in 3T3-L1 mouse cells in a dose-dependent manner. FOE contains several metabolites that reduce pancreatic lipase levels, α-glucosidase, α-amylase, and targeted proteins associated with lipid and glucose metabolism in vitro.

Structural characterization of peroxyl radical oxidative products of antioxidant peptides from hydrolyzed proteins.

This work aimed to characterize oxidative products of five unique antioxidant peptides (P1: YFDEQNEQFR, P2: GQLLIVPQ, P3: SPFWNINAH, P4: NINAHSVVY, P5: RALPIDVL) from hydrolyzed oat proteins. Peptides were reacted with 2,2'-Azobis(2-amidinopropane) dihydrochloride, a common peroxyl radical generator. Chromatographic data showed that peptide P3 was the most oxidized (67 ± 4 %) while also displaying the most ability to scavenge radicals in the oxygen absorbance capacity assay (ORAC) with an activity of 2.16 ± 0.09 µM Trolox equivalents/µM peptide. Structural characterization using mass spectrometry showed the presence of four oxidative products of P3, three of which were mono-oxygenated and the fourth di-oxygenated. The identification of these oxidative products is new and provides an opportunity to investigate their biological function. A good correlation (r = 0.889) between the degree of oxidation and the ORAC data, demonstrates the usefulness of using oxidative peptide data to predict their radical scavenging activities.

Synthesis, characterization, and antibacterial activity studies of two Co(II) complexes with 2-[(E)-(3-acetyl-4-hydroxyphenyl)diazenyl]-4-(2-hydroxyphenyl)thiophene-3-carboxylic acid as a ligand.

Two new Cobalt(II) complexes 12 and 13 have been synthesized from 2-[(E)-(3-acetyl-4-hydroxyphenyl)diazenyl]-4-(2-hydroxyphenyl)thiophene-3-carboxylic acid (11) as a novel ligand. These three new compounds were characterized on the basis of their powder X-Ray Diffraction, UV-Vis, IR, NMR, elemental analysis and MS spectral data. DFT/B3LYP mode of calculations were carried out to determine some theorical parameters of the molecular structure of the ligand. The purity of the azoic ligand and the metal complexes were ascertained by TLC and melting points. The analysis of the IR spectra of the polyfunctionalized azo compound 11 and its metal complexes 12 and 13, reveals that the coordination patterns of the ligand are hexadentate and tetradentate respectively. Based on the UV-Vis electronic spectral data and relevant literature reports, the ligand and derived complexes were assigned the E (trans) isomer form. Likewise, octahedral and square-planar geometries were respectively assigned to the cobalt(II) complexes. The broth microdilution method was used for antibacterial assays through the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The ligand 11 displayed moderate antibacterial activity (MIC = 32-128 µg/mL) against Staphylococcus aureus ATCC25923, Escherichia coli ATCC25922, Pseudomonas aeruginosa and Klebsiella pneumoniae 22. The octahedral cobalt(II) complex 12 showed moderate activity against Pseudomonas aeruginosa (MIC = 128 µg/mL) and Klebsiella pneumoniae 22 (MIC = 64 µg/mL) and none against Staphylococcus aureus ATCC25923 and Escherichia coli ATCC25922, whereas the square-planar complex 13 displayed moderate activity only on Klebsiella pneumoniae 22 (MIC = 64 µg/mL).

Revealing Novel Source of Breast Cancer Inhibitors from Seagrass Enhalus acoroides: In Silico and In Vitro Studies.

Enhalus arcoides is a highly beneficial type of seagrass. Prior studies have presented proof of the bioactivity of E. acoroides, suggesting its potential to combat cancer. Therefore, this study aims to delve deeper into E. acoroides bioactive molecule profiles and their direct biological anticancer activities potentials through the combination of in-silico and in-vitro studies. This study conducted metabolite profile analysis on E. acoroides utilizing HPLC-ESI-HRMS/MS analysis. Two extraction techniques, ethanol and hexane, were employed for the extraction process. Furthermore, the in-silico study was conducted using molecular docking simulations on the HER2, EGFR tyrosine kinase and HIF-1α protein receptor. Afterward, the antioxidant activity of E. acoroides metabolites was examined to ABTS, and the antiproliferative activity was tested using an MTT assay. An in-silico study revealed its ability to combat breast cancer by inhibiting the HER2/EGFR/HIF-1α pathway through molecular docking. In addition, the MTT assay demonstrated that higher dosages of metabolites from E. acoroides increased the effectiveness of toxicity against cancer cell lines. Additionally, the study demonstrated that the metabolites possess the ability to function as potent antioxidants, effectively inhibiting a series of carcinogenic mechanisms. Ultimately, this study showed a new approach to unveiling the E. acoroides metabolites' anticancer activity through inhibiting HER2/EGFR/HIF-1α receptors, with great cytotoxicity and a potent antioxidant property to prevent a carcinogenic cascade.

New triterpenoid saponin from the aerial part of Abrus canescens Welw ex. Bak. (Fabaceae) and their antibacterial activities.

The chemical investigation of the aerial part of Abrus canescens led to isolation of a new triterpenoid glycoside named Canescensoside (1) and four known compounds including longispinogenin-3-O-ß-D-glucuronopyranoside (2), ß-sitosterol-3-O-ß-D-glucoside (3), apigenin-7-O-ß-D-glucopyranoside (4) and apigenin-7-O-[α-L-rhamnopyranosyl-(1→3)-ß-D-glucopyranoside] (5). Structures of compounds were assigned by interpretation of their spectral data, mainly 1D and 2D NMR, HRESIMS, and by comparison with the reported data. The MeOH extract, EtOAc and n-BuOH fractions as well as isolated compounds were tested for their antibacterial activities against four bacteria strains among which, two Gram-negative (Pseudomonas aeruginosa ATCC 76110 and Escherichia coli ATCC 8739) and two Gram-positive (Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 25923) bacteria using the broth microdilution method. The MeOH extract and EtOAc fraction exhibited significant activities (MIC values ranging from 128 to 512 µg/mL) against all the tested bacteria. Compounds 2 and 3 showed the lowest MIC values of 55.47 and 50.40 µM, respectively.

Antibacterial stigmastane-type steroids and other constituents from the leaves of Vernonia glabra (Steetz) Vatke (Asteraceae).

Two new stigmastane steroids (1 and 2) were isolated from the methanol extract of the leaves of Vernonia glabra, together with seventeen known compounds (3-19) including one fatty acid, four triterpenoids, four steroids, one trinitropropanoyl glucoside, and seven flavonoids. The structures of compounds 1 and 2 were assigned based on their IR, NMR and MS data, and by comparison with literature values. The MeOH extract, its fractions and isolated compounds were subjected to in vitro antibacterial assay against two Gram-positive (Staphylococcus aureus ATCC25923 and Streptococcus pneumoniae ATCC49619) and two Gram-negative (Escherichia coli ATCC8739 and Klebsiella pneumoniae ATCC10031) bacteria, using broth microdilution method. The extract and fractions exhibited (16 ≤ MIC ≤ 512 µg/mL) antibacterial activities. The isolated and tested compounds were also active (16 ≤ MIC ≤ 128 µg/mL) against the four pathogenic bacteria, with compound 2 being the most active and E. coli, the most sensitive microorganism.

Peptidomics Analysis of Soy Protein Hydrolysates-Antioxidant Properties and Mechanism of their Inhibition of the Oxidation of Palm Olein during Frying Cycles.

This study determined for the first time the structure of the peptides (i.e., peptidomics) in soy protein hydrolysates and elucidated their effects on an oil's oxidative stability during frying cycles. The oil investigated was palm olein during 0, 4, 8, and 12 frying cycles of plantain banana chips. Proteins were extracted and hydrolyzed with two proteases. Trypsin hydrolysate (HTRY) exhibited higher anti-radical activity (DPPH, 70.2%) than the control (unhydrolyzed proteins, 33.49%) and pepsin hydrolysate (HPEP, 46.1%) at 200 µg/mL. HPEP however showed a 4.6-fold greater reduction of ferric ions (FRAP) while also possessing a higher peroxyl radical scavenging ability (716 ± 30 µM Trolox Eq/g) than HTRY (38.5 ± 35 µM Trolox Eq/g). During oil oxidative stability tests, HPEP improved the oxidative stability of the palm olein oil after 8 and 12 frying cycles, characterized by lower concentrations of hydroperoxides, and carbonyl and volatile compounds. HTRY however exerteda pro-oxidant activity. Structural data from SDS-PAGE and tandem mass spectrometry showed that the mechanism for the greater activity of the pepsin hydrolysate occurred due to unique structural features and a higher percentage of short-chain peptides. This was justified by a 25, 31, and 48% higher contents of tryptophan, histidine, and methionine, respectively (important amino acids with hydrogen atom transfer and electron-donating capacities) in the peptides identified in the pepsin hydrolysate.

Antioxidant Peptides Derived from Millet Bran Promote Longevity and Stress Resistance in Caenorhabditis elegans.

Millet bran as a by-product of millet grain processing remains a reservoir of active substances. In this study, functional millet bran peptides (MBPE) were obtained from bran proteins after alcalase hydrolysis and ultrafiltration. The activity of MBPE was assessed in vitro and in the model organism Caenorhabditis elegans (C. elegans). In vitro, compared to unhydrolyzed proteins, MBPE significantly enhanced the 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate (ABTS) and hydroxyl radicals scavenging activity, and the scavenging rate of MBPE with 15,000 U/g alcalase reached 42.79 ± 0.31%, 61.38 ± 0.41 and 45.69 ± 0.84%, respectively. In C. elegans, MBPE at 12.5 µg/mL significantly prolonged the lifespan by reducing lipid oxidation, oxidative stress, and lipofuscin levels. Furthermore, MBPE increased the activities of the antioxidant enzymes. Genetic analyses showed that MBPE-mediated longevity was due to a significant increase in the expression of daf-16 and skn-1, which are also involved in xenobiotic and oxidative stress responses. In conclusion, this study found that MBPE had antioxidant and life-prolonging effects, which are important for the development and utilization of millet bran proteins as resources of active ingredients.

Anti-Inflammatory, Antioxidant, Metabolic and Gut Microbiota Modulation Activities of Probiotic in Cardiac Remodeling Condition: Evidence from Systematic Study and Meta-Analysis of Randomized Controlled Trials.

Heart failure (HF) is a global pandemic with increasing prevalence and mortality rates annually. Its main cause is myocardial infarction (MI), followed by rapid cardiac remodeling. Several clinical studies have shown that probiotics can improve the quality of life and reduce cardiovascular risk factors. This systematic review and meta-analysis aimed to investigate the effectiveness of probiotics in preventing HF caused by a MI according to a prospectively registered protocol (PROSPERO: CRD42023388870). Four independent evaluators independently extracted the data using predefined extraction forms and evaluated the eligibility and accuracy of the studies. A total of six studies consisting of 366 participants were included in the systematic review. Probiotics are not significant in intervening left ventricular ejection fraction (LVEF) and high-sensitivity C-reactive protein (hs-CRP) when compared between the intervention group and the control group due to inadequate studies supporting its efficacy. Among sarcopenia indexes, hand grip strength (HGS) showed robust correlations with the Wnt biomarkers (p < 0.05), improved short physical performance battery (SPPB) scores were also strongly correlated with Dickkopf-related protein (Dkk)-3, followed by Dkk-1, and sterol regulatory element-binding protein 1 (SREBP-1) (p < 0.05). The probiotic group showed improvement in total cholesterol (p = 0.01) and uric acid (p = 0.014) compared to the baseline. Finally, probiotic supplements may be an anti-inflammatory, antioxidant, metabolic, and intestinal microbiota modulator in cardiac remodeling conditions. Probiotics have great potential to attenuate cardiac remodeling in HF or post-MI patients while also enhancing the Wnt signaling pathway which can improve sarcopenia under such conditions.

Dietary Supplementation of Caulerpa racemosa Ameliorates Cardiometabolic Syndrome via Regulation of PRMT-1/DDAH/ADMA Pathway and Gut Microbiome in Mice.

This study evaluated the effects of an aqueous extract of Caulerpa racemosa (AEC) on cardiometabolic syndrome markers, and the modulation of the gut microbiome in mice administered a cholesterol- and fat-enriched diet (CFED). Four groups of mice received different treatments: normal diet, CFED, and CFED added with AEC extract at 65 and 130 mg/kg body weight (BW). The effective concentration (EC50) values of AEC for 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and lipase inhibition were lower than those of the controls in vitro. In the mice model, the administration of high-dose AEC showed improved lipid and blood glucose profiles and a reduction in endothelial dysfunction markers (PRMT-1 and ADMA). Furthermore, a correlation between specific gut microbiomes and biomarkers associated with cardiometabolic diseases was also observed. In vitro studies highlighted the antioxidant properties of AEC, while in vivo data demonstrated that AEC plays a role in the management of cardiometabolic syndrome via regulation of oxidative stress, inflammation, endothelial function (PRMT-1/DDAH/ADMA pathway), and gut microbiota.

Corn distillers solubles by two-step proteolytic hydrolysis as a new source of plant-based protein hydrolysates with ACE and DPP4 inhibition activities.

Proteins of low-value and underexplored corn distillers solubles (CDS) have not been considerably valorized. Hence, the influence of one-step enzymatic hydrolysis of proteins with alcalase (A), trypsin (T) or flavourzyme (F) and two steps with AT, TA, AF, FA, TF, or FT was assessed to release peptides with angiotensin-I converting enzyme inhibition (ACEi) and dipeptidyl peptidase4 inhibition (DPP4i). The AF hydrolysate was the best sample in terms of yield, protein content, degree of hydrolysis, ACEi (97.68 ± 1.09 %), and DPP4i (51.51 ± 0.28 %). Mass spectrometry of the most active AF hydrolysate (<3 kDa) identified new major peptides like APLA, PLFP, LFLP, LPPYL, PLYPLP, NDWHTGPL, LPPYLPS, GSPFLGQ, SWQQPIVGG. Bioinformatic analysis showed these can inhibit both ACE and DPP4. This is because peptides contain functional groups and adopt conformations significantly binding with other functional groups at enzyme active sites (p < 0.05). This establishes dual bioactivity of peptides, which may have applications in food, feed, and pharmaceutical industries.

Food Peptides, Gut Microbiota Modulation, and Antihypertensive Effects.

The gut microbiota is increasingly important in the overall human health and as such, it is a target in the search of novel strategies for the management of metabolic disorders including blood pressure, and cardiovascular diseases. The link between microbiota and hypertension is complex and this review is intended to provide an overview of the mechanism including the production of postbiotics, mitigation of inflammation, and the integration of food biological molecules within this complex system. The focus is on hydrolyzed food proteins and peptides which are less commonly investigated for prebiotic properties. The analysis of available data showed that food peptides are multifunctional and can prevent gut dysbiosis by positively affecting the production of postbiotics or gut metabolites (short-chain fatty acids, polysaccharides, biogenic amines, bile acids). Peptides and the postbiotics then displayed antihypertensive effects via the renin-angiotensin system, the gut barrier, the endothelium, and reduction in inflammation and oxidative stress. Despite the promising antihypertensive effect of the food peptides via the modulation of the gut, there is a lack of human studies as most of the works have been conducted in animal models.

Echinograciolide, a new antibacterial nor-triterpenoid and other constituents from Echinops gracilis O. Hoffm. (Asteraceae).

Antibacterial resistance is a serious threat against humankind and the search for new therapeutics is needed. This study aims to investigate the antibacterial activity of extracts and compounds from Echinops gracilis O. Hoffm. Standard chromatographic and spectroscopic methods were used to isolate and characterize compounds (1-15) from the methanol extract. The extract, chromatographic fractions and compounds 1-3, 8, 11, 13 and 14 were subjected to in vitro antibacterial assays against Staphylococcus aureus ATCC25923, Salmonella Typhi ATCC6539, Klebsiella pneumoniae 22, and Salmonella Typhi 68, using broth micro-dilution method. As results, a new nor-triterpenoid (1) and fourteen known compounds (2-15) were characterized. The extract and fractions displayed moderate (128 ≤ MIC ≤ 512 µg/mL) and significant (MIC 64 µg/mL) antibacterial activities. Compounds 1 and 14 showed the best anti-staphylococcal and anti-salmonella activity (MIC 16 µg/mL), respectively. These results partially justified the antimicrobial uses of E. gracilis in traditional medicine.

Effects of bioactive molecules on the concentration of biogenic amines in foods and biological systems.

Biogenic amines (BAs) are a group of molecules naturally present in foods that contain amino acids, peptides, and proteins as well as in biological systems. In foods, their concentrations typically increase during processing and storage because of exposure to microorganisms that catalyze their formation by releasing amino acid decarboxylases. The concentrations of BAs above certain values are indicative of unsafe foods due to associate neuronal toxicity, allergenic reactions, and increase risks of cardiovascular diseases. There are therefore various strategies that focus on the control of BAs in foods mostly through elimination, inactivation, or inhibition of the growth of microorganisms. Increasingly, there are works on bioactive compounds that can decrease the concentration of BAs through their antimicrobial activity as well as the inhibition of decarboxylating enzymes that control their formation in foods or amine oxidases and N-acetyltransferase that control the degradation in vivo. This review focusses on the role of food-derived bioactive compounds and the mechanism by which they regulate the concentration of BAs. The findings are that most active molecules belong to polyphenols, one of the largest groups of plant secondary metabolites, additionally other useful +compounds are present in extracts of different herbs and spices. Different mechanisms have been proposed for the effects of polyphenols depending on the model system. Studies on the effects in vivo are limited and there is a lack of bioavailability and transport data which are important to assess the importance of the bioactive molecules.

Modulation of gut microbiota and markers of metabolic syndrome in mice on cholesterol and fat enriched diet by butterfly pea flower kombucha.

Clitoria ternatea, with an alternative name, Butterfly pea, is increasingly being explored for medical purposes and the development of a wide range of processed products. This study aimed to incorporate Butterfly pea into an innovative probiotic drink through a symbiotic culture of bacteria and yeast (SCOBY) fermentation and to evaluate the biological activity. The benefits of the drink, referred to as butterfly pea flower kombucha (KBPF) was determined in vitro and in metabolically disorder mice that receive a diet rich in cholesterol and fat (CFED). Forty white male were categorized into four groups, i.e., A = Control/Normal Diet; B = CFED alone; C = CFED + KBPF 65 mg/kg BW (Body Weight); D = CFED + KBPF 130 mg/kg BW, and then sacrificed after 6 weeks of intervention. Seventy-nine secondary metabolite compounds were successfully identified in KBPF using LC-HRMS. In vitro studies showed the potential activity of KBPF in inhibiting not only ABTS, but also lipid (lipase) and carbohydrate (α-amylase, α-glucosidase) hydrolyzing enzymes to levels similar to acarbose control at 50-250 µg/mL. In the in vivo study, the administration of KBPF (130 mg/kg BW) significantly alleviated metabolic disorders caused by high-fat diet. Specifically, lipid profile (HDL, LDL, TC, TG), blood glucose, markers of oxidative stress (SOD liver), metabolic enzymes (lipase, amylase), and markers of inflammation (PGC-1α, TNF-α, and IL-10) were in most cases restored to normal values. Additionally, the gut microbiota community analysis showed that KBPF has a positive effect (p = 0.01) on both the Bacteroidetes phylum and the Firmicutes phylum. The new KBPF drink is a promising therapeutic functional food for preventing metabolic diseases.

Synthesis, characterization and antimicrobial properties of two derivatives of pyrrolidine-2,5-dione fused at positions-3,4 to a dibenzobarrelene backbone.

A new diazo derivative of a pyrrolidine-2,5-dione (8) fused at position-3,4 to a dibenzobarrelene backbone has been prepared by coupling the previously reported N-arylsuccinimid (5) precursor with aryldiazonium ion of aniline. The initial step of the reaction involved the preparation of the intermediate 9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic anhydride (3) through [4 + 2]-cycloaddition between anthracene and maleic anhydride in refluxing xylene which was then condensed with para-aminophenol to give compound 5. Compounds 5 and 8 were characterized by their physical, elemental, and spectroscopic data. 2D-NMR (COSY, HSQC, and HMBC) techniques were used to confirm the structure of compound 5. Compounds 5 (MIC = 32-128 µg/mL) and 8 (MIC = 16-256 µg/mL) along with the precursor 3 (MIC = 64-128 µg/mL) displayed moderate to low antimicrobial activities against selected bacterial and fungal species when compared with those of nystatin (MIC = 0.50-2 µg/mL) and ciprofloxacin (MIC = 0.50-16 µg/mL) used as reference drugs.