Gelatine nanoparticles encapsulating three edible plant extracts as potential nanonutraceutical agents against type 2 diabetes mellitus.

AIM: To optimise, and characterise gelatine nanoparticles (GNPs) encapsulating plant extracts and evaluate the glucose-lowering potential. METHODS: GNPs encapsulating plant extracts were prepared by desolvation method followed by adsorption. The GNPs were characterised by loading efficiency, loading capacity, particle size, zeta potential, SEM and FTIR. The glucose-lowering activity of GNPs was determined using oral glucose tolerance test in high-fat diet fed streptozotocin-induced Wistar rats. RESULTS: Loading efficiency and capacity, particle mean diameter, and zeta potential of optimised GNPs 72.45 ± 13.03% w/w, 53.05 ± 26.16% w/w, 517 ± 48 nm and (-)23.43 ± 9.96 mV respectively. GNPs encapsulating aqueous extracts of C. grandis, S. auriculata, and ethanol 70% v/v extracts of M. koenigii showed glucose-lowering activity by 17.62%, 11.96% and 13.73% (p < 0.05) compared to the non-encapsulated extracts. FTIR analysis confirmed the encapsulation of phytoconstituents into GNPs. SEM imaging showed spherical GNPs (174 ± 46 nm). CONCLUSION: GNPs encapsulating plant extracts show promising potential to be developed as nanonutraceuticals against diabetes.

Herbal Extracts Encapsulated Nanoliposomes as Potential Glucose-lowering Agents: An in Vitro and in Vivo Approach Using Three Herbal Extracts.

Encapsulation of polyphenol-rich herbal extracts into nanoliposomes is a promising strategy for the development of novel therapeutic agents against type 2 diabetes mellitus. An attempt was made to encapsulate aqueous, ethanol, and aqueous ethanol (70% v/v) extracts of Senna auriculata (L.) Roxb., Murraya koenigii (L.) Spreng,. and Coccinia grandis (L.) Voigt into nanoliposomes and to screen acute bioactivities in vitro and in vivo. A wide spectrum of bioactivity was observed of which aqueous extracts encapsulated nanoliposomes of all three plants showed high bioactivity in terms of in vivo glucose-lowering activity in high-fat diet-fed streptozotocin induced Wistar rats, compared to respective free extracts. The particle size, polydispersity index, and zeta potential of the aforementioned nanoliposomes ranged from 179-494 nm, 0.362-0.483, and (-22) to (-17) mV, respectively. The atomic force microscopy (AFM) imaging reflected that the nanoparticles have desired morphological characteristics and Fourier-transform infrared (FTIR) spectroscopy analysis revealed successful encapsulation of plant extracts into nanoparticles. However, only the S. auriculata aqueous extract encapsulated nanoliposome, despite the slow release (9% by 30 hours), showed significant (p < 0.05) in vitro α-glucosidase inhibitory activity and in vivo glucose-lowering activity compared to free extract, proving worthy for future investigations.

Nanoformulation of Plant-Based Natural Products for Type 2 Diabetes Mellitus: From Formulation Design to Therapeutic Applications.

Background: Herbal remedies are used to manage type 2 diabetes mellitus (type 2 DM) as the sole treatment or as a complementary therapy. Limitations of herbal remedies, such as poor stability and limited absorption, impede their development as therapeutic agents, which could be overcome by nanoformulations. Objectives: This review attempts to summarize the studies reported between 2009 and 2020 in the development of medicinal plant-based nanoformulations for the management of type 2 DM, discuss formulation methods, mechanisms of action, and identify gaps in the literature to conduct future research on nanoparticle-based herbal treatment options targeting type 2 DM. Methods: To retrieve articles published between January 2009 and December 2020, the electronic databases PubMed, Science Direct, and Google Scholar were searched with the keywords nanoparticle, plant, and diabetes in the entire text. Peer-reviewed research articles on herbal nanoformulations published in English-language based on in vitro and/or in vivo models of type 2 DM and/or its complications were included. The literature search and selection of titles/abstracts were carried out independently by 2 authors. The list of full-text articles was selected considering inclusion and exclusion criteria, with the agreement of all the authors. Results: Among the reported studies, 68% of the studies were on inorganic herbal nanoformulations, whereas 17% and 8% were of polymer-based and lipid-based herbal nanoformulations, respectively. Some of the important biological properties of nanoformulations included improvement in glycemic control and insulin levels, inhibition of the formation of advanced glycation end products, and regeneration of pancreatic ß cells. The aforementioned properties were observed by screening nanoformulations using in vitro cellular and noncellular models, as well as in vivo animal models of type 2 DM studied for acute or subacute durations. Only 2 clinical trials with patients with diabetes were reported, indicating the need for further research on medicinal plant-based nanoformulations as a therapeutic option for the management of type 2 DM. Conclusions: Medicinal plant extracts and isolated compounds have been nanoformulated using various methods. The properties of the nanoformulations were found superior to those of the corresponding herbal extracts and isolated compounds. At both the preclinical and clinical levels, there are a number of poorly explored research areas in the development and bioactivity assessment of herbal nanoformulations. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX) © 2022 Elsevier HS Journals, Inc.

Biochemical characterization of high fat diet fed and low dose streptozotocin induced diabetic Wistar rat model.

The development of a stable disease model with an adequate biochemical profile is crucial for the preclinical investigation of new antidiabetic agents. This study aimed at optimization and characterization of high fat diet (HFD) fed streptozotocin (STZ) induced type 2 diabetes mellitus (type 2 DM) Wistar rat model. Wistar rats fed with HFD for four weeks received STZ (30, 40, and 50 mg/kg, intraperitoneal). Diabetic rats were observed for four more weeks and sacrificed. Non- injected healthy Wistar rats and HFD-fed rats were used as control groups. The glucose status and the lipid profile of the model were assessed. STZ-induced rats showed significant dose-dependent alterations in fasting serum insulin and glucose, homeostatic model assessment- insulin resistance (HOMA-IR), HOMA- ß cell function (HOMA- ß), quantitative insulin sensitivity check index (QUICKI), total cholesterol (TC), triglycerides (TG) and atherogenic index (AI). STZ 50 mg/kg group rats showed significant increase in glycated hemoglobin (HbA1c), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) levels compared to healthy rats. The atherogenic risk index (ARI), the Castelli risk index-I (CRII), and CRI-II were significantly (p < 0.05) high in the STZ 40 mg/kg and 50 mg/kg group rats. Results suggest that the Wistar rats fed with HFD rich in saturated fat for four weeks followed by a single intraperitoneal dose of 50 mg/kg of STZ would produce a stable diabetic model which closely mimic biochemical features of type 2 DM. Key messages: Wistar rats fed with HFD rich in saturated fat for four weeks followed by a single intraperitoneal dose of 50 mg/kg STZ would produce a stable diabetic model that closely mimics the biochemical characteristics of type 2 DM characterized by insulin resistance, relative insulin deficiency and impaired ß cell function.

Herbal Medicines Targeting the Improved ß-Cell Functions and ß-Cell Regeneration for the Management of Diabetes Mellitus.

There is an increasing trend of investigating natural bioactive compounds targeting pancreatic ß-cells for the prevention/treatment of diabetes mellitus (DM). With the exploration of multiple mechanisms by which ß-cells involve in the pathogenesis of DM, herbal medicines are gaining attention due to their multitasking ability as evidenced by traditional medicine practices. This review attempts to summarize herbal medicines with the potential for improvement of ß-cell functions and regeneration as scientifically proven by in vivo/in vitro investigations. Furthermore, attempts have been made to identify the mechanisms of improving the function and regeneration of ß-cells by herbal medicines. Relevant data published from January 2009 to March 2020 were collected by searching electronic databases "PubMed," "ScienceDirect," and "Google Scholar" and studied for this review. Single herbal extracts, polyherbal mixtures, and isolated compounds derived from approximately 110 medicinal plants belonging to 51 different plant families had been investigated in recent years and found to be targeting ß-cells. Many herbal medicines showed improvement of ß-cell function as observed through homeostatic model assessment-ß-cell function (HOMA-ß). Pancreatic ß-cell regeneration as observed in histopathological and immunohistochemical studies in terms of increase of size and number of functional ß-cells was also prominent. Increasing ß-cell mass via expression of genes/proteins related to antiapoptotic actions and ß-cell neogenesis/proliferation, increasing glucose-stimulated insulin secretion via activating glucose transporter-2 (GLUT-2) receptors, and/or increasing intracellular Ca2+ levels were observed upon treatment of some herbal medicines. Some herbal medicines acted on various insulin signaling pathways. Furthermore, many herbal medicines showed protective effects on ß-cells via reduction of oxidative stress and inflammation. However, there are many unexplored avenues. Thus, further investigations are warranted in elucidating mechanisms of improving ß-cell function and mass by herbal medicines, their structure-activity relationship (SAR), and toxicities of these herbal medicines.

Antioxidant activity and cellular uptake of the hydroxamate-based fungal iron chelators pyridoxatin, desferriastechrome and desferricoprogen.

The hydroxamate class of compounds is well known for its pharmacological applications, especially in the context of chelation therapy. In this work we investigate the performance of the fungal hydroxamates pyridoxatin (PYR), desferriastechrome (DAC) and desferricoprogen (DCO) as mitigators of stress caused by iron overload (IO) both in buffered medium and in cells. Desferrioxamine (DFO), the gold standard for IO treatment, was used as comparison. It was observed that all the fungal chelators (in aqueous medium) or PYR and DAC (in cells) are powerful iron scavengers. However only PYR and DCO (in aqueous medium) or PYR (in cells) were also antioxidant against two forms of iron-dependent oxidative stress (ascorbate or peroxide oxidation). These findings reveal that PYR is an interesting alternative to DFO for iron chelation therapy, since it has the advantage of being cell permeable and thus potentially orally active.

Waspergillamide A, a Nitro depsi-Tetrapeptide Diketopiperazine from an Australian Mud Dauber Wasp-Associated Aspergillus sp. (CMB-W031).

Chemical profiling of extracts from a mud dauber wasp-associated fungus, Aspergillus sp. (CMB-W031), revealed a remarkably diverse array of secondary metabolites, with many biosynthetic gene clusters being transcriptionally responsive to specific culture conditions. Chemical fractionation of a jasmine rice cultivation yielded many known fungal metabolites, including the highly cytotoxic (-)-stephacidin B and an unprecedented nonribosomal peptide synthase derived nitro depsi-tetrapeptide diketopiperazine, waspergillamide A (1). All structures were assigned by detailed spectroscopic analysis and, where appropriate, chemical degradation and Marfey's analysis.

Talarazines A-E: Noncytotoxic Iron(III) Chelators from an Australian Mud Dauber Wasp-Associated Fungus, Talaromyces sp. (CMB-W045).

Chemical analysis of an Australian mud dauber wasp-associated fungus, Talaromyces sp. (CMB-W045), yielded five new coprogen siderophores, talarazines A-E (1-5), together with dimerumic acid (6), desferricoprogen (7), and elutherazine B (8). Structures inclusive of absolute configuration were assigned on the basis of detailed spectroscopic analysis and application of the C3 Marfey's method. We report on the noncytotoxic Fe(III) chelation properties of 1-8 and demonstrate that biosynthesis is regulated by available Fe(III) in culture media. We demonstrate a magnetic nanoparticule approach to extracting high-affinity Fe(III) binding metabolites (i.e., 8) from complex extracts.

Roseopurpurins: Chemical Diversity Enhanced by Convergent Biosynthesis and Forward and Reverse Michael Additions.

Cultures of the estuarine fungus Penicillium roseopurpureum (CMB-MF038) yielded a diverse array of polyketides, many of which were related via a highly convergent biosynthetic pathway. In addition to revising and assigning structures, and documenting chemical and biological properties, pro-drug cytotoxic properties were attributed to roseopurpurins H (10) and I (11) on the basis of in situ reverse Michael addition to a cytotoxic Michael acceptor (12).

Lipopolysaccharide (LPS) stimulation of fungal secondary metabolism.

We report on a preliminary investigation of the use the Gram-negative bacterial cell wall constituent lipopolysaccharide (LPS) as a natural chemical cue to stimulate and alter the expression of fungal secondary metabolism. Integrated high-throughput micro-cultivation and micro-analysis methods determined that 6 of 40 (15%) of fungi tested responded to an optimal exposure to LPS (0.6 ng/mL) by activating, enhancing or accelerating secondary metabolite production. To explore the possible mechanisms behind this effect, we employed light and fluorescent microscopy in conjunction with a nitric oxide (NO)-sensitive fluorescent dye and an NO scavenger to provide evidence that LPS stimulation of fungal secondary metabolism coincided with LPS activation of NO. Several case studies demonstrated that LPS stimulation can be scaled from single microplate well (1.5 mL) to preparative (>400 mL) scale cultures. For example, LPS treatment of Penicillium sp. (ACM-4616) enhanced pseurotin A and activated pseurotin A1 and pseurotin A2 biosynthesis, whereas LPS treatment of Aspergillus sp. (CMB-M81F) substantially accelerated and enhanced the biosynthesis of shornephine A and a series of biosynthetically related ardeemins and activated production of neoasterriquinone. As an indication of broader potential, we provide evidence that cultures of Penicillium sp. (CMB-TF0411), Aspergillus niger (ACM-4993F), Rhizopus oryzae (ACM-165F) and Thanatephorus cucumeris (ACM-194F) were responsive to LPS stimulation, the latter two examples being particular noteworthy as neither are known to produce secondary metabolites. Our results encourage the view that LPS stimulation can be used as a valuable tool to expand the molecular discovery potential of fungal strains that either have been exhaustively studied by or are unresponsive to traditional culture methodology.