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Natural Compounds for Treatment and Prevention of Diabetes, Inflammation, Oxidative Stress and Reproductive Diseases

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 39570

Special Issue Editors

Department of Science, University of Basilicata, Potenza, Italy
Interests: secondary metabolite isolation; structural determination; oxidative stress; nutraceuticals; bioactive molecules; cholinesterase inhibitory activity; Alzheimer’s disease; cytotoxic effects
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Etiler-Ankara, Turkey
Interests: in vivo biological activities (esp. cell signaling; wound healing; anti-inflammatory; antinociceptive; anti-endometriotic; anti-urolithiatic; anti-colitis; anti-adhesion and antioxidant activities) of the natural sources used in traditional medicine through biological activity-guided fractionation and isolation assays
Department of Science, University of Basilicata, Potenza, Italy
Interests: plant extraction; natural extracts; oxidative stress; natural antioxidants; nutraceuticals; natural bioactive molecules; biological activity; antioxidant activity; enzyme inhibitory activity; diabetes; Alzheimer’s disease; cytotoxic effects
Department of Veterinary Medicine, University of Perugia, Perugia, Italy
Interests: veterinary endocrinology and animal reproductive physiology: corpus luteum; ovulation; reflex ovulation; ovulation-inducing factors; nerve growth factor; nitric oxide; prostaglandins; rabbit; sperm preservation methods (freeze drying); physiology of nutrition: fasting; obesity; cannabinoids; leptin; adipokines; apelin; resistin; polyunsaturated fatty acids; polyphenols

Special Issue Information

Dear Colleagues,

Recent advances in phytotherapy and nutraceutics have led to the concept that natural compounds play a serious role in multiple aspects of both human and animal physiology, leading to clear health-promoting effects. Diabetes, a state of chronic hyperglycemia, is a major cause of serious micro- and macrovascular diseases, therefore affecting nearly every system in the body. Diabetes represents clusters of serious diseases that result in the progressive deterioration of normal cell and organ function and physiology, including reproduction. Diabetes-related oxidative stress may also be the trigger for many alterations in sexual function and reproduction, and these are also connected with inflammation and oxidative stress. Growing evidence indicates that oxidative stress is increased in diabetes due to the overproduction of reactive oxygen species and decreased efficiency of antioxidant defenses—a process that starts very early and worsens over the course of the disease.

The main focus of this Special Issue is to extend the knowledge about the complexity of issues of diabetes, inflammation, oxidative stress, and reproduction in both humans and animals.

This Special Issue is mainly, though not exclusively, focused on the potential application and effectiveness of plant extracts and/or isolated pure compounds on diabetes and its related disorders, their prevention, and treatment or toxicology. Furthermore, studies describing effects such as diabetes correlation with oxidative stress and reproduction and the effects on enzymes, receptors, gene expression, and epigenetic modification are also welcome.

Research articles or reviews covering the effects of extracts and/or pure compounds (such as polyphenols, coumarins, alkaloids, terpenoids, tannins, saponins, glycosides, flavonoids, or semisynthetic derivatives), and their possible mechanisms of action evaluated in tube, in vitro, ex vivo, and in vivo, focusing on their aid in the control of the above-mentioned diseases, represent the prominent topic of this Special Issue and are welcome for inclusion.

Dr. Luigi Milella
Prof. Ipek Suntar
Dr. Daniela Russo
Dr. Margherita Maranesi
Guest Editors

Manuscript Submission Information

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Keywords

  • Natural Compounds
  • Diabetes
  • Inflammation
  • Oxidative Stress
  • Reproduction

Published Papers (10 papers)

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Research

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15 pages, 2195 KiB  
Article
Muscari comosum L. Bulb Extracts Modulate Oxidative Stress and Redox Signaling in HepG2 Cells
by Fabiana Giglio, Maria Antonietta Castiglione Morelli, Ilenia Matera, Chiara Sinisgalli, Rocco Rossano and Angela Ostuni
Molecules 2021, 26(2), 416; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020416 - 14 Jan 2021
Cited by 6 | Viewed by 2116
Abstract
Muscari comosum L. bulbs are commonly used as food in South Italy and also in folk medicine. By evaluating in vitro antioxidant activity and biological activities of their aqueous and methanol extracts, we shed light on the potential role, including both the nutraceutical [...] Read more.
Muscari comosum L. bulbs are commonly used as food in South Italy and also in folk medicine. By evaluating in vitro antioxidant activity and biological activities of their aqueous and methanol extracts, we shed light on the potential role, including both the nutraceutical and health benefits, of this plant. Total polyphenol content (TPC) and total flavonoid content (TFC) were evaluated by the Folin–Ciocalteu method and by the aluminum chloride method, respectively. Antioxidant activity was investigated by three in vitro assays and relative antioxidant capacity index (RACI) was calculated to compare results obtained by different tests. The extracts were tested to evaluate their possible involvement in redox homeostasis, using the human hepatoma (HepG2) cell line used as model. The extracts exhibited concentration/solvent dependent radical scavenging activity, as well as dysregulation of some genes involved in redox pathways by promoting Nrf2, SOD-2, GPX1, ABCC6 and ABCG2 expression. NMR metabolomics analysis suggests that HepG2 cells treated with Muscari comosum extracts experience changes in some metabolites involved in various metabolic pathways. Full article
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15 pages, 2591 KiB  
Article
Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice
by Zakiyatul Faizah, Bella Amanda, Faisal Yusuf Ashari, Efta Triastuti, Rebecca Oxtoby, Anny Setijo Rahaju, M. Aminudin Aziz, Maria Inge Lusida and Delvac Oceandy
Molecules 2020, 25(19), 4381; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25194381 - 24 Sep 2020
Cited by 15 | Viewed by 3336
Abstract
Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM—type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated [...] Read more.
Diabetes mellitus (DM) is one of the major causes of death in the world. There are two types of DM—type 1 DM and type 2 DM. Type 1 DM can only be treated by insulin injection whereas type 2 DM is commonly treated using anti-hyperglycemic agents. Despite its effectiveness in controlling blood glucose level, this therapeutic approach is not able to reduce the decline in the number of functional pancreatic β cells. MST1 is a strong pro-apoptotic kinase that is expressed in pancreatic β cells. It induces β cell death and impairs insulin secretion. Recently, a potent and specific inhibitor for MST1, called XMU-MP-1, was identified and characterized. We hypothesized that treatment with XMU-MP-1 would produce beneficial effects by improving the survival and function of the pancreatic β cells. We used INS-1 cells and STZ-induced diabetic mice as in vitro and in vivo models to test the effect of XMU-MP-1 treatment. We found that XMU-MP-1 inhibited MST1/2 activity in INS-1 cells. Moreover, treatment with XMU-MP-1 produced a beneficial effect in improving glucose tolerance in the STZ-induced diabetic mouse model. Histological analysis indicated that XMU-MP-1 increased the number of pancreatic β cells and enhanced Langerhans islet area in the severe diabetic mice. Overall, this study showed that MST1 could become a promising therapeutic target for diabetes mellitus. Full article
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11 pages, 2471 KiB  
Communication
Enhancement of an In Vivo Anti-Inflammatory Activity of Oleanolic Acid through Glycosylation Occurring Naturally in Stauntonia hexaphylla
by Le Ba Vinh, Nguyen Thi Minh Nguyet, Liu Ye, Gao Dan, Nguyen Viet Phong, Hoang Le Tuan Anh, Young Ho Kim, Jong Seong Kang, Seo Young Yang and Inkyu Hwang
Molecules 2020, 25(16), 3699; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25163699 - 13 Aug 2020
Cited by 13 | Viewed by 2794
Abstract
Stauntonia hexaphylla (Lardizabalaceae) has been used as a traditional herbal medicine in Korea and China for its anti-inflammatory and analgesic properties. As part of a bioprospecting program aimed at the discovery of new bioactive compounds from Korean medicinal plants, a phytochemical study of [...] Read more.
Stauntonia hexaphylla (Lardizabalaceae) has been used as a traditional herbal medicine in Korea and China for its anti-inflammatory and analgesic properties. As part of a bioprospecting program aimed at the discovery of new bioactive compounds from Korean medicinal plants, a phytochemical study of S. hexaphylla leaves was carried out leading to isolation of two oleanane-type triterpene saponins, 3-O-[β-d-glucopyranosyl (1→2)-α-l-arabinopyranosyl] oleanolic acid-28-O-[β-d-glucopyranosyl (1→6)-β-d-glucopyranosyl] ester (1) and 3-O-α-l-arabinopyranosyl oleanolic acid-28-O-[β-d-glucopyranosyl (1→6)-β-d-glucopyranosyl] ester (2). Their structures were established unambiguously by spectroscopic methods such as one- and two-dimensional nuclear magnetic resonance and infrared spectroscopies, high-resolution electrospray ionization mass spectrometry and chemical reactions. Their anti-inflammatory activities were examined for the first time with an animal model for the macrophage-mediated inflammatory response as well as a cell-based assay using an established macrophage cell line (RAW 264.7) in vitro. Together, it was concluded that the saponin constituents, when they were orally administered, exerted much more potent activities in vivo than their sapogenin core even though both the saponins and the sapogenin molecule inhibited the RAW 264.7 cell activation comparably well in vitro. These results imply that saponins from S. hexaphylla leaves have a definite advantage in the development of oral medications for the control of inflammatory responses. Full article
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10 pages, 1684 KiB  
Article
Isolation of Isocoumarins and Flavonoids as α-Glucosidase Inhibitors from Agrimonia pilosa L.
by Mi Jin Park and Young-Hwa Kang
Molecules 2020, 25(11), 2572; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25112572 - 31 May 2020
Cited by 11 | Viewed by 2470
Abstract
Agrimonia pilosa L. (AP) showed potent α-glucosidase inhibitory (AGI) activity, but it is uncertain what phytochemicals play a key factor. The phytochemical study of AP based on AGI activity led to the isolation of four isocoumarins; agrimonolide (1), agrimonolide-6-O-β- [...] Read more.
Agrimonia pilosa L. (AP) showed potent α-glucosidase inhibitory (AGI) activity, but it is uncertain what phytochemicals play a key factor. The phytochemical study of AP based on AGI activity led to the isolation of four isocoumarins; agrimonolide (1), agrimonolide-6-O-β-d-glucopyranoside (2), desmethylagrimonolide (3), desmethylagrimonolide-6-O-β-d-glucopyranoside (4), and four flavonoids; luteolin (5), quercetin (6), vitexin (7), and isovitexin (8). The four isocoumarins were isolated as α-glucosidase inhibitors for the first time. Isocoumarins, compound 1 (agrimonolide) and 3 (desmethylagrimonolide) showed strong α-glucosidase inhibitory activities with IC50 values of 24.2 and 37.4 µM, respectively. Meanwhile, isocoumarin and flavonoid glycosides showed weak AGI activity. In the kinetic analysis, isocoumarins, compounds 1 and 3 showed non-competitive inhibition, whereas flavonoid, compound 6 showed competitive inhibition. Full article
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15 pages, 2168 KiB  
Article
Sulfur Compounds Inhibit High Glucose-Induced Inflammation by Regulating NF-κB Signaling in Human Monocytes
by Eun Seong Jo, Nipin Sp, Dong Young Kang, Alexis Rugamba, Il Ho Kim, Se Won Bae, Qing Liu, Kyoung-Jin Jang and Young Mok Yang
Molecules 2020, 25(10), 2342; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25102342 - 17 May 2020
Cited by 12 | Viewed by 3646
Abstract
High glucose-induced inflammation leads to atherosclerosis, which is considered a major cause of death in type 1 and type 2 diabetic patients. Nuclear factor-kappa B (NF-κB) plays a central role in high glucose-induced inflammation and is activated through toll-like receptors (TLRs) as well [...] Read more.
High glucose-induced inflammation leads to atherosclerosis, which is considered a major cause of death in type 1 and type 2 diabetic patients. Nuclear factor-kappa B (NF-κB) plays a central role in high glucose-induced inflammation and is activated through toll-like receptors (TLRs) as well as canonical and protein kinase C-dependent (PKC) pathways. Non-toxic sulfur (NTS) and methylsulfonylmethane (MSM) are two sulfur-containing natural compounds that can induce anti-inflammation. Using Western blotting, real-time polymerase chain reaction, and flow cytometry, we found that high glucose-induced inflammation occurs through activation of TLRs. An effect of NTS and MSM on canonical and PKC-dependent NF-κB pathways was also demonstrated by western blotting. The effects of proinflammatory cytokines were investigated using a chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. Our results showed inhibition of the glucose-induced expression of TLR2 and TLR4 by NTS and MSM. These sulfur compounds also inhibited NF-κB activity through reactive oxygen species (ROS)-mediated canonical and PKC-dependent pathways. Finally, NTS and MSM inhibited the high glucose-induced expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and binding of NF-κB protein to the DNA of proinflammatory cytokines. Together, these results suggest that NTS and MSM may be potential drug candidates for anti-inflammation therapy. Full article
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Review

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36 pages, 6913 KiB  
Review
The Promising Ability of Humulus lupulus L. Iso-α-acids vs. Diabetes, Inflammation, and Metabolic Syndrome: A Systematic Review
by Maria Ponticelli, Daniela Russo, Immacolata Faraone, Chiara Sinisgalli, Fabiana Labanca, Ludovica Lela and Luigi Milella
Molecules 2021, 26(4), 954; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26040954 - 11 Feb 2021
Cited by 15 | Viewed by 2848
Abstract
For centuries, natural medicines have represented the only option for treating human diseases and, nowadays, plant phytochemicals are considered as promising compounds to treat or prevent chronic conditions. Among them, hop flowers (Humulus lupulus L.), typically used in brewing industries to give [...] Read more.
For centuries, natural medicines have represented the only option for treating human diseases and, nowadays, plant phytochemicals are considered as promising compounds to treat or prevent chronic conditions. Among them, hop flowers (Humulus lupulus L.), typically used in brewing industries to give the typical aroma and flavor to beer, have attracted particular attention for their health promoting properties. Several in vivo/vitro studies and human interventional trials have demonstrated the beneficial effects of these molecules on weight gain, lipid metabolism, glucose homeostasis, insulin sensitivities, and inflammation by acting on different targets. All these activities suggest a possible role of bitter hop acid in preventing metabolic syndrome and its related diseases. A systematic quest on PubMed and Scopus databases was performed to identify pre-clinical and clinical studies focusing on this topic. This systematic review summarizes the results obtained by different cell lines, animal models, and human interventional trials to propose iso-α-acids as medical nutrition therapy to treat or prevent metabolic syndrome and its related disorders as diabetes, dislipidemia inflammation, etc. Full article
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16 pages, 961 KiB  
Review
The Role of Resveratrol in Mammalian Reproduction
by Rolando Pasquariello, Nicole Verdile, Tiziana A. L. Brevini, Fulvio Gandolfi, Cristiano Boiti, Massimo Zerani and Margherita Maranesi
Molecules 2020, 25(19), 4554; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25194554 - 05 Oct 2020
Cited by 68 | Viewed by 6774
Abstract
Resveratrol is one of the most investigated natural polyphenolic compounds and is contained in more than 70 types of plants and in red wine. The widespread interest in this polyphenol derives from its antioxidant, anti-inflammatory and anti-aging properties. Several studies have established that [...] Read more.
Resveratrol is one of the most investigated natural polyphenolic compounds and is contained in more than 70 types of plants and in red wine. The widespread interest in this polyphenol derives from its antioxidant, anti-inflammatory and anti-aging properties. Several studies have established that resveratrol regulates animal reproduction. However, the mechanisms of action and the potential therapeutic effects are still unclear. This review aims to clarify the role of resveratrol in male and female reproductive functions, with a focus on animals of veterinary interest. In females, resveratrol has been considered as a phytoestrogen due to its capacity to modulate ovarian function and steroidogenesis via sirtuins, SIRT1 in particular. Resveratrol has also been used to enhance aged oocyte quality and as a gametes cryo-protectant with mainly antioxidant and anti-apoptotic effects. In males, resveratrol enhances testes function and spermatogenesis through activation of the AMPK pathway. Furthermore, resveratrol has been supplemented to semen extenders, improving the preservation of sperm quality. In conclusion, resveratrol has potentially beneficial effects for ameliorating ovarian and testes function. Full article
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28 pages, 339 KiB  
Review
Brown Seaweeds for the Management of Metabolic Syndrome and Associated Diseases
by Daniela Gabbia and Sara De Martin
Molecules 2020, 25(18), 4182; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184182 - 12 Sep 2020
Cited by 34 | Viewed by 4920
Abstract
Metabolic syndrome is characterized by the coexistence of different metabolic disorders which increase the risk of developing type 2 diabetes mellitus and cardiovascular diseases. Therefore, metabolic syndrome leads to a reduction in patients’ quality of life as well as to an increase in [...] Read more.
Metabolic syndrome is characterized by the coexistence of different metabolic disorders which increase the risk of developing type 2 diabetes mellitus and cardiovascular diseases. Therefore, metabolic syndrome leads to a reduction in patients’ quality of life as well as to an increase in morbidity and mortality. In the last few decades, it has been demonstrated that seaweeds exert multiple beneficial effects by virtue of their micro- and macronutrient content, which could help in the management of cardiovascular and metabolic diseases. This review aims to provide an updated overview on the potential of brown seaweeds for the prevention and management of metabolic syndrome and its associated diseases, based on the most recent evidence obtained from in vitro and in vivo preclinical and clinical studies. Owing to their great potential for health benefits, brown seaweeds are successfully used in some nutraceuticals and functional foods for treating metabolic syndrome comorbidities. However, some issues still need to be tackled and deepened to improve the knowledge of their ADME/Tox profile in humans, in particular by finding validated indexes of their absorption and obtaining reliable information on their efficacy and long-term safety. Full article
33 pages, 2210 KiB  
Review
Molecules Isolated from Mexican Hypoglycemic Plants: A Review
by Sonia Marlen Escandón-Rivera, Rachel Mata and Adolfo Andrade-Cetto
Molecules 2020, 25(18), 4145; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184145 - 10 Sep 2020
Cited by 17 | Viewed by 5454
Abstract
Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work [...] Read more.
Like in many developing countries, in Mexico, the use of medicinal plants is a common practice. Based on our own field experience, there are at least 800 plants used for treating diabetes nowadays. Thus, their investigation is essential. In this context, this work aims to provide a comprehensive and critical review of the molecules isolated from Mexican hypoglycemic plants, including their source and target tested. In the last few years, some researchers have focused on the study of Mexican hypoglycemic plants. Most works describe the hypoglycemic effect or the mechanism of action of the whole extract, as well as the phytochemical profile of the tested extract. Herein, we analyzed 85 studies encompassing 40 hypoglycemic plants and 86 active compounds belonging to different classes of natural products: 28 flavonoids, 25 aromatic compounds, other than flavonoids, four steroids, 23 terpenoids, 4 oligosaccharides, and 1 polyalcohol. These compounds have shown to inhibit α-glucosidases, increase insulin secretion levels, increase insulin sensitivity, and block hepatic glucose output. Almost half of these molecules are not common metabolites, with a narrow taxonomic distribution, which makes them more interesting as lead molecules. Altogether, this analysis provides a necessary inventory useful for future testing of these active molecules against different hypoglycemic targets, to get a better insight into the already described mechanisms, and overall, to contribute to the knowledge of Mexican medicinal plants. Full article
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18 pages, 1156 KiB  
Review
Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus
by Dimitri Papukashvili, Nino Rcheulishvili and Yulin Deng
Molecules 2020, 25(9), 2029; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25092029 - 27 Apr 2020
Cited by 8 | Viewed by 4391
Abstract
Creatine supplementation of the population with type 2 diabetes mellitus (T2DM) combined with an exercise program is known to be a possible therapy adjuvant with hypoglycemic effects. However, excessive administration of creatine leads to the production of methylamine which is deaminated by the [...] Read more.
Creatine supplementation of the population with type 2 diabetes mellitus (T2DM) combined with an exercise program is known to be a possible therapy adjuvant with hypoglycemic effects. However, excessive administration of creatine leads to the production of methylamine which is deaminated by the enzyme semicarbazide-sensitive amine oxidase (SSAO) and as a result, cytotoxic compounds are produced. SSAO activity and reaction products are increased in the serum of T2DM patients. Creatine supplementation by diabetics will further augment the activity of SSAO. The current review aims to find a feasible way to ameliorate T2DM for patients who exercise and desire to consume creatine. Several natural agents present in food which are involved in the regulation of SSAO activity directly or indirectly are reviewed. Particularly, zinc-α2-glycoprotein (ZAG), zinc (Zn), copper (Cu), histamine/histidine, caffeine, iron (Fe), and vitamin D are discussed. Inhibiting SSAO activity by natural agents might reduce the potential adverse effects of creatine metabolism in population of T2DM. Full article
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