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The effect of oleanolic acid, metformin, and their combination on the FSI level, FPG level, and HOMA-IR in db/db mice. (a) The FPG level was measured after 8 h of fasting in db/db mice treated with vehicle, oleanolic acid, metformin, or the combination for 4 weeks. (b) The FSI level was measured after 8 h of fasting in db/db mice treated with vehicle, oleanolic acid, metformin, or the combination for 4 weeks. (c) The HOMA-IR index was calculated for each group. Data are shown as the mean ± SEM. P*<0.05, P**<0.01, and P***<0.001 indicate significant differences for comparisons with the vehicle group; P#<0.05 indicates significant differences for comparisons with the monotherapy group (n=6).
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Aims and background:
Type 2 diabetes is a chronic disease that cannot be treated adequately using the known monotherapies, especially when the disease progresses to an advanced stage. In this study, we explore the possibility of treating the disease with a novel combination approach of oleanolic acid (OA), a glycogen phosphorylase (GP) inhibitor,...
Citations
... In a fourweek treatment of male mice, the combination significantly lowered blood glucose and insulin levels, improved liver pathology, and enhanced glycogen-synthesis-related mRNA expression. The therapy also positively influenced signaling pathways, indicating synergistic effects in improving diabetes symptoms [84]. In the antibacterial study assessing the synergistic combination of OA and UA, the testing on four pathogens revealed synergistic effects when combined with β-lactam antibiotics (ampicillin and oxacillin) against Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, and Listeria monocytogenes. ...
The growing interest in oleanolic acid (OA) as a triterpenoid with remarkable health benefits prompts an emphasis on its efficient use in pharmaceutical research. OA exhibits a range of pharmacological effects, including antidiabetic, anti-inflammatory, immune-enhancing, gastroprotective, hepatoprotective, antitumor, and antiviral properties. While OA demonstrates diverse pharmacological effects, optimizing its therapeutic potential requires overcoming significant challenges. In the field of pharmaceutical research, the exploration of efficient drug delivery systems is essential to maximizing the therapeutic potential of bioactive compounds. Efficiently delivering OA faces challenges, such as poor aqueous solubility and restricted bioavailability, and to unlock its full therapeutic efficacy, novel formulation strategies are imperative. This discussion thoroughly investigates different approaches and advancements in OA drug delivery systems with the aim of enhancing the biopharmaceutical features and overall efficacy in diverse therapeutic contexts.
... It also exhibited that OA was able to accelerate glucose transport by increasing p-Akt levels and GS levels, as well as decreasing GP levels [94,95]. Furthermore, OA has positive effects on diabetes via increasing PI3K/Akt and AMPK phosphorylation, phosphoenolpyruvate carboxykinase (PEPCK), and G6Pase levels, as well as decreasing the level of the mammalian target of rapamycin (mTOR) [96]. It was discovered that OA could improve insulin resistance through the activation of the level of the insulin receptor substrate (IRS-1) and PI3K/Akt [97]. ...
... In addition, OA may improve insulin resistance via the reduction in the expression of mTOR via PI3K/Akt. OA can also inhibit gluconeogenesis by reducing the expression of G6Pase and PEPCK [96]. IRS signaling is a common pathological mechanism of insulin resistance [150]; OA alleviated insulin resistance by increasing the level of IRS-1, which was achieved by PI3K/Akt [97]. ...
Metabolic syndromes (MetS) and related cardiovascular diseases (CVDs) pose a serious threat to human health. MetS are metabolic disorders characterized by obesity, dyslipidemia, and hypertension, which increase the risk of CVDs’ initiation and development. Although there are many availabile drugs for treating MetS and related CVDs, some side effects also occur. Considering the low-level side effects, many natural products have been tried to treat MetS and CVDs. A five-cyclic triterpenoid natural product, oleanolic acid (OA), has been reported to have many pharmacologic actions such as anti-hypertension, anti-hyperlipidemia, and liver protection. OA has specific advantages in the treatment of MetS and CVDs. OA achieves therapeutic effects through a variety of pathways, attracting great interest and playing a vital role in the treatment of MetS and CVDs. Consequently, in this article, we aim to review the pharmacological actions and potential mechanisms of OA in treating MetS and related CVDs.
... A combination of Nrf2 activators, exercise, and metformin reduced diabetic complications (e.g., gain weight, water, calorie intake, blood glucose, insulin, and GLUT4 content) more efficiently than each treatment. 123,124,125 The combinations exhibited a greater impact on enhancing oxidative stress homeostasis by effectively activating Nrf2 signaling pathway and reducing the KEAP1 protein to a greater extent, but without considering the timing of Nrf2 activation. 126 The safety of the long-term effects of the combination therapy that includes Nrf2 activators is complicated by the role of Nrf2 in cancer onset and treatment. ...
Exercise has well-characterized therapeutic benefits in the management of type 2 diabetes mellitus (T2DM). Most of the beneficial effects of exercise arise from the impact of nuclear factor erythroid 2 related factor-2 (Nrf2) activation of glucose metabolism. Nrf2 is an essential controller of cellular anti-oxidative capacity and circadian rhythms. The circadian rhythm of Nrf2 is influenced by circadian genes on its expression, where the timing of exercise effects the activation of Nrf2 and the rhythmicity of Nrf2 and signaling, such that the timing of exercise has differential physiological effects. Exercise in the evening has beneficial effects on diabetes management, such as lowering of blood glucose and weight. The mechanisms responsible for these effects have not yet been associated with the influence of exercise on the circadian rhythm of Nrf2 activity. A better understanding of exercise-induced Nrf2 activation on Nrf2 rhythm and signaling can improve our appreciation of the distinct effects of morning and evening exercise. This review hypothesizes that activation of Nrf2 by exercise in the morning, when Nrf2 level is already at high levels, leads to hyperactivation and decrease in Nrf2 signaling, while activation of Nrf2 in the evening, when Nrf2 levels are at nadir levels, improves Nrf2 signaling and lowers blood glucose levels and increases fatty acid oxidation. Exploring the effects of Nrf2 activators on rhythmic signaling could also provide valuable insights into the optimal timing of their application, while also holding promise for timed treatment of type 2 diabetes.
... Importantly, very satisfying HGA by MREXU may be due to the presence of oleanolic acid in the plant [14,42]. The previous reports have revealed that oleanolic acid has a significant role in reducing blood glucose levels and impacts glycogen synthesis to act as a preventive and therapeutic advantage in diabetes [43,44]. The oleanolic acid promotes phosphorylation of AKT and AMPK to suppress the genes and proteins expression responsible for gluconeogenesis and glycolysis resulting a reduced hepatic glucose production [44]. ...
... The previous reports have revealed that oleanolic acid has a significant role in reducing blood glucose levels and impacts glycogen synthesis to act as a preventive and therapeutic advantage in diabetes [43,44]. The oleanolic acid promotes phosphorylation of AKT and AMPK to suppress the genes and proteins expression responsible for gluconeogenesis and glycolysis resulting a reduced hepatic glucose production [44]. A recent study has reported that X. uliginosa contains phytol [18]. ...
Xeromphis. uliginosa (Retz.) is an extinctive Bangladeshi medicinal plant that is locally used for the treatments of pain, diabetes, diarrhea, depressant, and other diseases. The present study was conducted to evaluate the peripheral analgesic activity (PAA), central analgesic activity (CAA), central nervous system antidepressant activity (CNS-AD), antidiarrheal activity (ADA), and hypoglycaemic activity (HGA) of methanolic root extract of X. uliginosa (MREXU) in a mice model. The acetic acid-induced writhing inhibition and tail flick method were applied to determine the PAA and CAA of MREXU. The CNS-AD was measured using the phenobarbitone sodium-mediated sleeping method whereas, the castor oil-induced antidiar-rheal method was used to determine the ADA of the crude extracts. To determine the HGA of MREXU crude extract, the tail tipping technique was conducted in a mice model. The MREXU displayed potential PAA and CAA in mice models. The MREXU 200 and 400 mg/kg significantly inhibit the number of writings along with diclofenac sodium. On the other hand, MREXU both doses significantly inhibit thermal stimulus after 60 and 90 minutes respectively. In the CNS-AD study, crude extract of 200 and 400 mg/kg significantly increase the onset of sleep by decreasing the duration of sleep. Similarly, the dose of 200 mg/kg significantly reduced diarrheal faeces for the whole 4 hours of experiments. The heartiest outcome of MREXU was displayed in the HGA assay. Both doses of MREXU significantly reduced the blood sugar level for the entire 3 hours of the experiments. In this study, it is revealed that the root of MREXU has extremely significant blood sugar-reducing activity, potential CNS-AD and mild to moderate nociceptive activity in the mice model.
... Five studies analyzed the actions of OA on livers of insulin-resistant rodents [41][42][43][44][45][46]. The experiments of Wang et al. [41] and Wang et al. [42] reported that OA decreased the protein expression of glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) and increased the AMP-activated protein kinase (AMPK) and Akt phosphorylation in livers of type 2 diabetic mice. ...
... Five studies analyzed the actions of OA on livers of insulin-resistant rodents [41][42][43][44][45][46]. The experiments of Wang et al. [41] and Wang et al. [42] reported that OA decreased the protein expression of glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) and increased the AMP-activated protein kinase (AMPK) and Akt phosphorylation in livers of type 2 diabetic mice. In the first one, the following was also reported: a downregulation of the liver gene expression of glycogen phosphorylase (GP), PEPCK1, G-6-Pase, and glucose transporter type 2 (GLUT2), and a non-significant downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). ...
... In the first one, the following was also reported: a downregulation of the liver gene expression of glycogen phosphorylase (GP), PEPCK1, G-6-Pase, and glucose transporter type 2 (GLUT2), and a non-significant downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, in this study, OA augmented the phosphorylation of acetyl-CoA carboxylase (ACC) and of PI3K, and diminished the phosphorylation of mammalian target of rapamycin (mTOR) and of cAMP-response element-binding protein (CREB) [41]. In the second one, OA also increased the gene expression on mice livers of PGC-1α [42]. ...
Oleanolic acid (OA) is a natural triterpene widely found in olive leaves that possesses antioxidant, anti-inflammatory, and insulin-sensitizing properties, among others. These OA characteristics could be of special interest in the treatment and prevention of insulin resistance (IR), but greater in-depth knowledge on the pathways involved in these properties is still needed. We aimed to systematically review the effects of OA on the molecular mechanisms and signaling pathways involved in the development of IR and underlying oxidative stress in insulin-resistant animal models or cell lines. The bibliographic search was carried out on PubMed, Web of Science, Scopus, Cochrane, and CINHAL databases between January 2001 and May 2022. The electronic search produced 5034 articles but, after applying the inclusion criteria, 13 animal studies and 3 cell experiments were identified, using SYRCLE’s Risk of Bias for assessing the risk of bias of the animal studies. OA was found to enhance insulin sensitivity and glucose uptake, and was found to suppress the hepatic glucose production, probably by modulating the IRS/PI3K/Akt/FoxO1 signaling pathway and by mitigating oxidative stress through regulating MAPK pathways. Future randomized controlled clinical trials to assess the potential benefit of OA as new therapeutic and preventive strategies for IR are warranted.
... Moreover, the triterpene restored the expression ratio of phospho-IRS-1 (pIRS-1/IRS1) and phospho-Akt (pAkt)/Akt, which was significantly altered in fructose-induced diabetic rats, to the expression levels of the control group [35]. The involvement of this pathway in the anti-diabetic effect of oleanolic acid was also reported by Wang et al. [36] when exploring the synergic action of oleanolic acid with metformin to treat diabetes in db/db diabetic mice. The anti-hyperglycemic action of metformin is based on a decrease of liver glucose production by adenosine monophosphate activated protein kinase (AMPK)-dependent and independent mechanisms [37]. ...
... The anti-hyperglycemic action of metformin is based on a decrease of liver glucose production by adenosine monophosphate activated protein kinase (AMPK)-dependent and independent mechanisms [37]. The combination therapy of both metformin and oleanolic induced a significant reduction of blood glucose levels and improved liver function in diabetic mice compared to the monotherapy, involving AMPK-dependent pathways [36]. In particular, oleanolic acid plus metformin increased phosphorylation of Akt, PI3K, AMPK and acetyl-coenzyme A carboxylase (ACC), and increased liver glycogen, whereas it decreased the expression of proteins involved in liver gluconeogenesis and glycolysis (i.e., glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)) compared to those levels under monotherapy, and attenuated the liver phosphorylation of mammalian target of rapamycin (mTOR) and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) [36]. ...
... The combination therapy of both metformin and oleanolic induced a significant reduction of blood glucose levels and improved liver function in diabetic mice compared to the monotherapy, involving AMPK-dependent pathways [36]. In particular, oleanolic acid plus metformin increased phosphorylation of Akt, PI3K, AMPK and acetyl-coenzyme A carboxylase (ACC), and increased liver glycogen, whereas it decreased the expression of proteins involved in liver gluconeogenesis and glycolysis (i.e., glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)) compared to those levels under monotherapy, and attenuated the liver phosphorylation of mammalian target of rapamycin (mTOR) and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) [36]. The complexity underlying the pathogenesis of diabetes, particularly in obesity suggests that combination therapy, including not only well-known anti-diabetic drugs, such as metformin but also new approaches, such as oleanolic acid, may be more effective in treating these metabolic disturbances. ...
Dietary components exert protective effects against obesity and related metabolic and cardiovascular disturbances by interfering with the molecular pathways leading to these pathologies. Dietary biomolecules are currently promising strategies to help in the management of obesity and metabolic syndrome, which are still unmet medical issues. Olive oil, a key component of the Mediterranean diet, provides an exceptional lipid matrix highly rich in bioactive molecules. Among them, the pentacyclic triterpenic acids (i.e., oleanolic acid) have gained clinical relevance in the last decade due to their wide range of biological actions, particularly in terms of vascular function, obesity and insulin resistance. Considering the promising effects of these triterpenic compounds as nutraceuticals and components of functional foods against obesity and associated complications, the aim of our review is to decipher and discuss the main molecular mechanisms underlying these effects driven by olive oil triterpenes, in particular by oleanolic acid. Special attention is paid to their signaling and targets related to glucose and insulin homeostasis, lipid metabolism, adiposity and cardiovascular dysfunction in obesity. Our study is aimed at providing a better understanding of the impact of dietary components of olive oil in the long-term management of obesity and metabolic syndrome in humans.
... Moreover, administration of OA slightly decreased glucose AUC during an IPGTT and an intravenous insulin tolerance test (IVITT). On the other hand, Male C57BL/KsJ-Lepdb (db/db) diabetic mice administered with OA (250 mg/kg) significantly reduced FBG, HOMA-IR and serum HDL levels and non-significantly reduced FSI [149]. More recently, Gamede et al. [150] conducted studies in high-fat high-carbohydrate (HFHC) diet-induced prediabetic male Sprague-Dawley rats, in which OA administration (80 mg/kg) for a period of 12 weeks originated a significant reduction in body weight, glycemia, HOMA2-IR and HbA1c indexes, as well as a reduction in the hepatic and muscle glycogen concentration in comparison to the non-OA-treated control rats. ...
Oleanolic acid, a pentacyclic triterpenoid ubiquitously present in the plant kingdom, is receiving outstanding attention from the scientific community due to its biological activity against multiple diseases. Oleanolic acid is endowed with a wide range of biological activities with therapeutic potential by means of complex and multifactorial mechanisms. There is evidence suggesting that oleanolic acid might be effective against dyslipidemia, diabetes and metabolic syndrome, through enhancing insulin response, preserving the functionality and survival of β-cells and protecting against diabetes complications. In addition, several other functions have been proposed, including antiviral, anti-HIV, antibacterial, antifungal, anticarcinogenic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic and anti-atherosclerotic activities, as well as interfering in several stages of the development of different types of cancer; however, due to its hydrophobic nature, oleanolic acid is almost insoluble in water, which has led to a number of approaches to enhance its biopharmaceutical properties. In this scenario, the present review aimed to summarize the current knowledge and the research progress made in the last years on the extraction and characterization of oleanolic acid and its biological activities and the underlying mechanisms of action.
... In addition to monotherapy, OA generated synergistic and complimentary actions in combined therapy with other antidiabetic drugs such as metformin and insulin. For instance, OA-metformin combination therapy significantly reduced blood glucose and insulin levels and improved liver pathology in diabetic mice [228]. Likewise, OA in synergy with 4IU insulin enhanced activation of the insulin signaling pathway and increased insulin-stimulated hypoglycemic activity [229]. ...
It has become increasingly apparent that defective insulin signaling may increase the risk for developing Alzheimer’s disease (AD), influence neurodegeneration through promotion of amyloid formation or by increasing inflammatory responses to intraneuronal β-amyloid. Recent work has demonstrated that hyperglycemia is linked to cognitive decline, with elevated levels of glucose causing oxidative stress in vulnerable tissues such as the brain. The ability of β-amyloid peptide to form β-sheet-rich aggregates and induce apoptosis has made amyloid fibrils a leading target for the development of novel pharmacotherapies used in managing and treatment of neuropathological conditions such as AD-related cognitive decline. Additionally, deposits of β-sheets folded amylin, a glucose homeostasis regulator, are also present in diabetic patients. Thus, therapeutic compounds capable of reducing intracellular protein aggregation in models of neurodegenerative disorders may prove useful in ameliorating type 2 diabetes mellitus symptoms. Furthermore, both diabetes and neurodegenerative conditions, such as AD, are characterized by chronic inflammatory responses accompanied by the presence of dysregulated inflammatory biomarkers. This review presents current evidence describing the role of various small bioactive molecules known to ameliorate amyloidosis and subsequent effects in prevention and development of diabetes and AD. It also highlights the potential efficacy of peptide–drug conjugates capable of targeting intracellular targets.
... OA appears to be a promising therapeutic agent without the adipogenic activity observed with other antidiabetic therapeutic agents (Ayeleso et al. 2017). Wang et al. (2015) reported that OA improved glucose and insulin homeostasis in diabetic mice with positive effects against diabetic complications. This could also be linked to potentiating the insulin action effect of OA, which includes inhibition of gluconeogenesis in the liver and promotion of glucose utilization by extrahepatic tissues to normalize hyperglycemia. ...
Diabetes mellitus (DM) is a chronic metabolic disease that threatens the health of the world population. We investigated the effects of oleanolic acid (OA) administration on inflammation status and metabolic profile in streptozotocin (STZ) induced diabetic rats. Four experimental groups were established: healthy rats not administered OA, healthy rats administered OA, diabetic rats not administered OA, diabetic rats administered OA. OA, 5 mg/kg, was administered by oral gavage for 21 days. Serum samples collected at the end of the experiment and analyzed for toll–like receptor–9, interleukin-18, nuclear factor kappa B, malondialdehyde MDA, glucose, total cholesterol, triglycerides, high–density lipoprotein, low-density lipoprotein, calcium, phosphorus, magnesium and potassium. Pancreas tissue was examined for pathology. Induction of DM caused increased serum concentrations of inflammation and oxidative damage markers. DM also caused hyperglycemia-hyperlipidemia and decreased serum concentration of minerals. The islets of Langerhans were degenerated and necrotic. Administration of OA reversed the adverse effects of DM. OA treatment can ameliorate inflammation and oxidative damage due to DM by normalizing hyperglycemia and decreasing TLR-9, IL-18, NF-κB and MDA levels.
... In vivo [197] 80. Genipin Gardenia jasminoides Ellis fruit Stimulate insulin secretion in pan-27 creatic islet cells by regulating mitochondrial function. ...
Background:
Type 2 diabetes (adult onset diabetes) is the most common type of diabetes, accounting for around 90% of all diabetes cases with insulin resistance and insulin secretion defect. The key goal of anti-diabetic therapy is to increase the development of insulin, immunity and/or decrease the amount of blood glucose. While many synthetic compounds have been produced as antidiabetic agents, due to their side effects and limited effectiveness, their usefulness has been hindered.
Methods:
This systematic review investigated the bioactive compounds reported to possess activities against type 2 diabetes. Three (3) databases, PubMed, ScienceDirect and Google Scholar were searched for research articles published between January 2010 and October 2020. A total of 6464 articles were identified out of which 84 articles were identified to be elligible for the study.
Result and discussion:
From the data extracted, it was found that quercetin, Kaempferol, Rosmarinic acid, Cyanidin, Rutin, Catechin, Luteolin and Ellagic acid were the most cited bioactive compounds which all falls within the class of polyphenolic compounds. The major sources of these bioactive compounds includes citrus fruits, grapes, onions, berries, cherries, broccoli, honey, apples, green tea, Ginkgo biloba, St. John's wort, green beans, cucumber, spinach, tea, Rosmarinus officinalis, Aloe vera, Moringa oleifera, tomatoes, potatoes, oregano, lemon balm, thyme, peppermint, Ocimum basilicum, red cabbage, pears, olive oil and walnut.
