Bioavailability and Metabolism of Bioactive Peptide IRW with Angiotensin-Converting Enzyme 2 (ACE2) Upregulatory Activity in Spontaneously Hypertensive Rats.

Peptide IRW is the first food-derived angiotensin-converting enzyme 2 (ACE2) upregulator. This study aimed to investigate the pharmacokinetic characteristics of IRW and identify the metabolites contributing to its antihypertensive activity in spontaneously hypertensive rats (SHRs). Rats were administered 100 mg of IRW/kg of the body weight via an intragastric or intravenous route. The bioavailability (F %) was determined to be 11.7%, and the half-lives were 7.9 ± 0.5 and 28.5 ± 6.8 min for gavage and injection, respectively. Interestingly, significant blood pressure reduction was not observed until 1.5 h post oral administration, or 2 h post injection, indicating that the peptide's metabolites are likely responsible for the blood pressure-lowering activity. Time-course metabolomics revealed a significant increase in the level of kynurenine, a tryptophan metabolite, in blood after IRW administration. Kynurenine increased the level of ACE2 in cells. Oral administration of tryptophan (W), but not dipeptide IR, lowered the blood pressure and upregulated aortic ACE2 in SHRs. Our study supports the key role of tryptophan and its metabolite, kynurenine, in IRW's blood pressure-lowering effects.

Effects of Food Factors and Processing on Protein Digestibility and Gut Microbiota.

Protein is an essential macronutrient. The nutritional needs of dietary proteins are met by digestion and absorption in the small intestine. Indigestible proteins are further metabolized in the gut and produce metabolites via protein fermentation. Thus, protein indigestibility exerts a wide range of effects on gut microbiota composition and function. This review aims to discuss protein digestibility, the effects of food factors, such as protein sources, intake level, and amino acid composition, and making meat analogues. Besides, it provides an inventory of antinutritional factors and processing techniques that influence protein digestibility and, consequently, the diversity and composition of intestinal microbiota. Future studies are warranted to understand the implication of plant-based analogues on protein digestibility and gut microbiota and to elucidate the mechanisms concerning protein digestibility to host gut microbiota using various omics techniques.

Tripeptide IRW Improves AMPK/eNOS Signaling Pathway via Activating ACE2 in the Aorta of High-Fat-Diet-Fed C57BL/6 Mice.

This study aims to investigate the effect of tripeptide IRW on the local renin-angiotensin system (RAS), particularly angiotensin-converting enzyme 2 (ACE2), and their association with signaling pathways in the aorta of a high-fat-diet (HFD)-induced insulin-resistant mouse model. C57BL/6 mice were fed HFD (45% of the total calories) for six weeks, and then IRW was added to the diet (45 mg/kg body weight (BW)) for another eight weeks. ACE2 mRNA expression and protein level(s) were increased (p < 0.05), while angiotensin II receptor (AT1R) and angiotensin-converting enzyme (ACE) protein abundance was significantly reduced (p < 0.05) in the aorta of HFD mice treated by IRW. IRW supplementation also improved glucose transporter 4 (GLUT4) abundance (p < 0.05) alongside AMP-activated protein kinase (AMPK) (p < 0.05), Sirtuin 1 (SIRT1) (p < 0.05), and endothelial nitric oxide synthase (eNOS) (p < 0.05) expression. IRW downregulated the levels of endothelin 1 (ET-1) and p38 mitogen-activated protein kinases (p38 MAPK, p < 0.05). Furthermore, the levels of AMPK and eNOS in vascular smooth muscle cells (VSMCs) were significantly reduced in ACE2 knockdown cells treated with or without IRW (p < 0.01). In conclusion, this study provided new evidence of the regulatory role of IRW on the aortic ACE2 against metabolic syndrome (MetS) in an HFD-induced insulin-resistant model.

The Effect of Polyphenols on Kidney Disease: Targeting Mitochondria.

Mitochondrial function, including oxidative phosphorylation (OXPHOS), mitochondrial biogenesis, and mitochondria dynamics, are essential for the maintenance of renal health. Through modulation of mitochondrial function, the kidneys are able to sustain or recover acute kidney injury (AKI), chronic kidney disease (CKD), nephrotoxicity, nephropathy, and ischemia perfusion. Therapeutic improvement in mitochondrial function in the kidneys is related to the regulation of adenosine triphosphate (ATP) production, free radicals scavenging, decline in apoptosis, and inflammation. Dietary antioxidants, notably polyphenols present in fruits, vegetables, and plants, have attracted attention as effective dietary and pharmacological interventions. Considerable evidence shows that polyphenols protect against mitochondrial damage in different experimental models of kidney disease. Mechanistically, polyphenols regulate the mitochondrial redox status, apoptosis, and multiple intercellular signaling pathways. Therefore, this review attempts to focus on the role of polyphenols in the prevention or treatment of kidney disease and explore the molecular mechanisms associated with their pharmacological activity.

Peptides GWN and GW protect kidney cells against Dasatinib induced mitochondrial injury in a SIRT1 dependent manner.

Dasatinib, a small-molecule drug used as a treatment for chronic myeloid leukemia induces mitochondrial damage in embryonic kidney (293 T) cells (p < 0.05). This dasatinib induced mitochondrial injury in kidney cells was mitigated by H3K36me3 activating ovotransferrin-derived peptides GWN and GW. Pre-treatment of kidney cells with GWN and GW lead to elevation of cytoprotective sirtuins, SIRT1 and SIRT3, in response to dasatinib injury (p < 0.01) in vitro. Both peptides, GWN and GW, also reversed dasatinib induced the loss of mitochondria in kidney cells and promoted the protein expression of COX4 (p < 0.01). Mechanistically, loss of SIRT1 in kidney cells abolished the ability of GWN and GW to protect embryonic kidney cells against dasatinib injury in vitro. Overall, we provide cell based evidence showing that GWN and GW exhibit the ability to protect mitochondria against dasatinib-induced mitochondrial damage in a SIRT1 dependent manner.

The effect of genistein on insulin resistance, inflammatory factors, lipid profile, and histopathologic indices in rats with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, irregular menstruation, ovulatory dysfunction, and insulin resistance. Recent studies have reported the possible role of phytoestrogens in PCOS. This animal study aimed to evaluate the effects of genistein on insulin resistance, inflammatory factors, lipid profile, and histopathologic indices on PCOS. METHODS: PCOS was induced by 1 mg/kg of letrozole in adult Sprague-Dawley rats. The rats then received normal saline (PCOS group), 150 mg/kg of metformin, or 20 mg/kg of genistein dissolved in 1% methylcellulose solution for 42 days. Body weight, the glycemic and lipid profile, and inflammatory, antioxidative, and histopathological parameters were assessed at the end of the intervention. RESULTS: Treatment with genistein significantly alleviated the increased level of fasting blood insulin (p=0.16) and the homeostatic model assessment of insulin resistance (p=0.012). In addition, the genistein group had significantly lower levels of serum malondialdehyde (p=0.039) and tumor necrosis factor-alpha (p=0.003), and higher superoxide dismutase enzyme activity (p<0.001). Furthermore, the histopathological analysis indicated that genistein administration led to an increase in luteinization and the development of fewer cysts (p<0.05). CONCLUSION: Biochemical and histopathological analyses indicated that genistein administration to rats with PCOS induced significant remission in oxidative, inflammatory, and glycemic and histopathologic parameters.

Effect of hydroalcoholic extract of Berberis integerrima and resveratrol on ovarian morphology and biochemical parameters in Letrozole-induced polycystic ovary syndrome rat model: An experimental study.

BACKGROUND: Resveratrol and Berberis integerrima (B. integerrima) are known to be natural antioxidants and regulators of human metabolism. However, the effects of resveratrol and B. integerrima on the ovarian morphology in polycystic ovary syndrome (PCOS) are not obvious. OBJECTIVE: This study aimed to determine the effect of the hydroalcoholic extract of B. integerrima in combination with resveratrol on some biochemical parameters and ovarian morphology in the letrozole-induced PCOS rat. MATERIALS AND METHODS: Seventy adult female Sprague-Dawley rats aged 10-12 weeks weighing 200 ± 20 gr were randomly divided into seven groups (n = 10/each). Group I): normal; Group II): vehicle; Group III): letrozole-induced PCOS 1 mg/kg letrozole orally, rats receiving 1 cc normal saline orally; Group IV): PCOS + receiving 150 mg/kg metformin orally; Group V): PCOS + receiving 20 mg/kg resveratrol orally; Group VI): PCOS + 3 gr/kg barberry orally; and Group VII): PCOS + receiving 3 gr/kg barberry and 20 mg/kg resveratrol orally. All animals were followed-up for 63 days. The biochemical parameters and histological assessments of ovaries were performed. RESULTS: Resveratrol alone and/or in combination with B. integerrima treatment in rats led to a significant decrease in low-density lipoprotein, triglyceride, malondialdehyde, and tumor necrosis factor-alpha concentrations (p = 0.02). The groups IV, V, VI, and VII showed a decrease in insulin resistance and an increase in the superoxide dismutase, total antioxidant capacity, and high-density lipoprotein (p = 0.01). No significant difference was observed between the level of serum glucose in the treatment groups. Number of cystic follicles had a significant decrease in barberry, resveratrol, and their combination groups (p < 0.001). CONCLUSION: Resveratrol, B. integerrima, and their combination as natural products with fewer side effects might be effective as an alternative medicine in treatment of PCOS.

Hydroalcoholic extract of Achillea millefolium improved blood glucose, liver enzymes and lipid profile compared to metformin in streptozotocin-induced diabetic rats.

BACKGROUND: Recent studies have reported that herbal extracts may have some protective effect against the complications of diabetes mellitus. This study aimed to investigate the effects of Achillea millefolium hydroalcoholic extract in comparison to metformin on liver damage, lipid abnormality, and glycemic control in diabetic rats. METHODS: Rats were randomly assigned to 7 groups of 10 animals. Diabetes was induced by injection of streptozotocin (STZ) to 4 groups of rats. Three groups of diabetic rats were given 250 mg/kg/day metformin, 25 mg/kg/day Achillea millefolium hydroalcoholic extract, or 100 mg/kg/day of this extract. Two non-diabetic groups were also given either 25 mg/kg/day or 100 mg/kg/day Achillea millefolium extract. Normal control and diabetic control rats received 1 mL/day of normal saline. Treatments were administered through oral gavage for 28 days. At the end, rats were anesthetized with ether and their serum samples were separated in order to measure blood glucose, serum total protein, lipids, and liver enzymes. RESULTS: There was a significant reduction in blood glucose, serum liver enzymes, triglycerides, and total- and LDL-cholesterol levels of the Achillea millefolium extract-treated groups compared to the other groups. In addition, there was a significant increment in body weight and HDL-cholesterol serum level in the Achillea millefolium-treated groups. CONCLUSION: Achillea millefolium extract compared to metformin reduces lipid abnormality, blood glucose and liver enzymes in STZ-induced diabetic rats. Future clinical studies are warranted to confirm our experimental findings in humans.

The Role of medicinal herbs in treatment of insulin resistance in patients with Polycystic Ovary Syndrome: A literature review.

Background Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine abnormalities in women. Due to the side effects of drugs, the tendency to use natural antioxidants and anti-inflammatory agents to regulate metabolism, hyperinsulinemia, and hyperlipidemia in PCOS patients has been increased. This review aimed to investigate the role of herbal substances on the treatment of PCOS. Methods The present review was carried out using keywords such as polycystic ovary syndrome and/or PCOS and/or herb. Databases including Web of Science, PubMed, and Science Direct were used to collect all related articles published from 1990 to 2019. We excluded studies unrelated to the PCOS and medical herbs. Results Overall, 361 records were identified through database searching. After primary screening and the full-texts assessment, 323 records were excluded, and 38 articles were finally included. The results indicate that some medicinal herbs may have a key role in treating PCOS. The compounds in these medical herbs can affect lipid profiles (Aloe vera, chamomile, and cinnamon), insulin resistance (cinnamon, chamomile, Aloe vera, and Camellia sinensis), blood glucose (Aloe vera, cinnamon, and Camellia sinensis), hormones (Aloe vera, silymarin, chamomile, fenugreek, Camellia sinensis, Heracleum persicum, Potentilla, Mentha spicata, Foeniculum vulgar, licorice, and Marrubium), and ovarian tissue (Aloe vera, chamomile, Camellia sinensis, Mentha spicata, and silymarin). Conclusion Natural substances such as Aloe vera, cinnamon, green tea, fenugreek, and silymarin can be used as a new supportive care for PCOS. Further clinical trials are warranted to confirm their benefits and safety.