Carnosic Acid Protects INS-1 β-Cells against Streptozotocin-Induced Damage by Inhibiting Apoptosis and Improving Insulin Secretion and Glucose Uptake

Carnosic acid (CA), a natural polyphenolic diterpene derived from Rosmarinus officinalis, has been proven to possess a broad spectrum of medicinal properties. Nevertheless, no studies on its impact on pancreatic β-cells have been conducted to date. Herein, clonal rat INS-1 (832/13) cells were pretreated with CA for 24 h and then incubated with streptozotocin (STZ) for 3 h. Several functional experiments were performed to determine the effect of CA on STZ-induced pancreatic β-cell damage, including cell viability assay, apoptosis analysis, and measurement of the level of insulin secretion, glucose uptake, malondialdehyde (MDA), reactive oxygen species (ROS), and proteins expression. STZ treatment decreased cell survival, insulin secretion, glucose uptake, and increased apoptosis, MDA, and ROS production in INS-1 cells. Furthermore, protein expression/phosphorylation analysis showed significant down-regulation in insulin, PDX-1, PI3K, AKT/p-AKT, and Bcl₂. On the other hand, expression of BAX and BAD and cleaved PARP were significantly increased. Interestingly, preincubation with CA reversed the adverse impact of STZ at the cellular and protein expression levels. In conclusion, the data indicate that CA protects β-cells against STZ-induced damage, presumably through its modulatory effect on the different pathways, including the Pi3K/AKT/PDX-1/insulin pathway and mitochondria-mediated apoptosis.     

Brassica Genus Seeds: A Review on Phytochemical Screening and Pharmacological Properties

Traditionally, Brassica species are widely used in traditional medicine, human food, and animal feed. Recently, special attention has been dedicated to Brassica seeds as source of health-promoting phytochemicals. This review provides a summary of recent research on the Brassica seed phytochemistry, bioactivity, dietary importance, and toxicity by screening the major online scientific database sources and papers published in recent decades by Elsevier, Springer, and John Wiley. The search was conducted covering the period from January 1964 to July 2022. Phytochemically, polyphenols, glucosinolates, and their degradation products were the predominant secondary metabolites in seeds. Different extracts and their purified constituents from seeds of Brassica species have been found to possess a wide range of biological properties including antioxidant, anticancer, antimicrobial, anti-inflammatory, antidiabetic, and neuroprotective activities. These valuable functional properties of Brassica seeds are related to their richness in active compounds responsible for the prevention and treatment of various chronic diseases such as obesity, diabetes, cancer, and COVID-19. Currently, the potential properties of Brassica seeds and their components are the main focus of research, but their toxicity and health risks must also be accounted for.     

Alkaloidal Phytoconstituents for Diabetes Management: Exploring the Unrevealed Potential

The main characteristic feature of diabetes mellitus is the disturbance of carbohydrate, lipid, and protein metabolism, which results in insulin insufficiency and can also lead to insulin resistance. Both the acute and chronic diabetic cases are increasing at an exponential rate, which is also flagged by the World Health Organization (WHO) and the International Diabetes Federation (IDF). Treatment of diabetes mellitus with synthetic drugs often fails to provide desired results and limits its use to symptomatic treatment only. This has resulted in the exploration of alternative medicine, of which herbal treatment is gaining popularity these days. Owing to their safety benefits, treatment compliance, and ability to exhibit effects without disturbing internal homeostasis, research in the field of herbal and ayurvedic treatments has gained importance. Medicinal phytoconstituents include micronutrients, amino acids, proteins, mucilage, critical oils, triterpenoids, saponins, carotenoids, alkaloids, flavonoids, phenolic acids, tannins, and coumarins, which play a dynamic function in the prevention and treatment of diabetes mellitus. Alkaloids found in medicinal plants represent an intriguing potential for the inception of novel approaches to diabetes mellitus therapies. Thus, this review article highlights detailed information on alkaloidal phytoconstituents, which includes sources and structures of alkaloids along with the associated mechanism involved in the management of diabetes mellitus. From the available literature and data presented, it can be concluded that these compounds hold tremendous potential for use as monotherapies or in combination with current treatments, which can result in the development of better efficacy and safety profiles.     

Targeting Ceramides and Adiponectin Receptors in the Islet of Langerhans for Treating Diabetes

Ceramides belong to the sphingolipid family and represent the central hub of the sphingolipid network. In obesity, oversupply of saturated fatty acids including palmitate raises ceramide levels which can be detrimental to cells. Elevated ceramides can cause insulin resistance, endoplasmic reticulum stress, and mitochondrial dysfunction. Studies over the last few decades have highlighted the role played by ceramides in pancreatic islet β-cell apoptosis, especially under glucolipotoxic and inflammatory conditions. This review focuses on ceramides and adiponectin receptor signaling, summarizing recent advancements in our understanding of their roles in islet β-cells and the discovery of zinc-dependent lipid hydrolase (ceramidase) activity of adiponectin receptors. The therapeutic potential of targeting these events to prevent islet β-cell loss for treating diabetes is discussed.     

Protective Effect of Portulaca oleracea on Streptozotocin-Induced Type I Diabetes-Associated Reproductive System Dysfunction and Inflammation

Background: Type-one diabetes (T1D), a chronic autoimmune disease with marked inflammatory responses, is associated with infertility complications and implications. Based on the anti-diabetic, antioxidant, and anti-hyperlipidemic potential of Portulaca oleracea (PO), this study aimed to evaluate the protective effect of this plant extract on streptozotocin-induced type-I-diabetes-associated reproductive system dysfunction and inflammation. Methods: Male rats were randomly divided into four experimental groups: control, diabetic, and treatment/s (PO extract at 100 or 300 mg/kg/daily). Then food and water consumption, body, testis and epididymis weights, histopathological evaluation, seminiferous tubules diameter, sperm count and motility, glucose levels, sex hormones, and inflammatory and oxidative stress markers were evaluated. Results: Our results showed that streptozotocin-induced diabetes significantly increased food and water consumption; increased glucose, MDA, TGF-β1, and TNF-α levels; and decreased the seminiferous tubules diameter, sperm count and motility, levels of LH, testosterone, total thiol, VEGF, and SOD activity. Interestingly, PO extract (phytochemically characterized by using liquid chromatography–mass spectrometry to detect bioactive molecules) significantly ameliorated these parameters and histopathological indexes’ damage in rats. Conclusion. Even if more preclinical assessments are needed to better characterize the mechanism/s of action, the results of this study will pave the way for the rational use of PO on diabetic-associated clinical complications and implications.     

Effects of Chemical Structures Interacting with Amine Oxidases on Glucose,Lipid and Hydrogen Peroxide Handling by Human Adipocytes

Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.     

Influence of Degree of Polymerization of Low-Molecular-Weight Chitosan Oligosaccharides on the α-Glucosidase Inhibition

Chitosan oligosaccharide (COS) is a bioactive compound derived from marine by-products. COS consumption has been demonstrated to lower the risk of diabetes. However, there are limited data on the inhibitory effect of low-molecular-weight COSs with different degrees of polymerization (DP) on α-glucosidase. This study investigates the α-glucosidase inhibitory activity of two low-molecular-weight COSs, i.e., S-TU-COS with DP2–4 and L-TU-COS with DP2–5, both of which have different molecular weight distributions. The inhibition constants of the inhibitors binding to free enzymes (K_i) and an enzyme–substrate complex (K_ii) were investigated to elucidate the inhibitory mechanism of COSs with different chain lengths. The kinetic inhibition model of S-TU-COS showed non-completive inhibition results which are close to the uncompetitive inhibition results with K_i and K_ii values of 3.34 mM and 2.94 mM, respectively. In contrast, L-TU-COS showed uncompetitive inhibition with a K_ii value of 5.84 mM. With this behavior, the IC₅₀ values of S-TU-COS and L-TU-COS decreased from 12.54 to 11.84 mM and 20.42 to 17.75 mM, respectively, with an increasing substrate concentration from 0.075 to 0.3 mM. This suggests that S-TU-COS is a more potent inhibitor, and the different DP of COS may cause significantly different inhibition (p < 0.05) on the α-glucosidase activity. This research may provide new insights into the production of a COS with a suitable profile for antidiabetic activity.     

The Study of Hypoglycemic Activity of 7-Terpenylcoumarins

Natural and synthetic coumarins are often considered privileged scaffolds for obtaining pharmacological agents with hypoglycemic activity. Chemical modification of coumarins often leads to antidiabetic agents with greater efficacy. In the present work, twenty monoterpene-substituted 7-hydroxycoumarins were synthesized. A new approach using the Mitsunobu reaction was shown to be effective for the synthesis of target compounds. All of the synthesized compounds were evaluated in an oral glucose tolerance test, and two of them containing geranyl and (-)-myrtenyl substituents showed in vivo hypoglycemic action. A possible mechanism of action of these compounds may include inhibition of DPP IV, which was proved in an in vitro test.