Secoisolariciresinol diglucoside (SDG) and tracheloside (TCL) are the main lignan components of flaxseed cake and safflower seed cake, which are by-products of oil extraction. Both SDG and TCL are metabolized into mammalian lignan enterolactone (EL) with the involvement of intestinal bacteria. In this research, we evaluated the anti-osteoporosis effects of SDG and the in vivo metabolites EL and enterodiol (ED) prepared in our previous work, as well as the newly isolated chemical constituents from safflower seed, including TCL, the lactone ring opening product of TCL (OTCL) and two alkaloids on the alloxan-induced zebrafish model. All the compounds showed significant anti-osteoporosis effects at 80 µM, with p < 0.05 for EL and p < 0.001 for other compounds compared with the model. SDG and TCL showed the most significant and concentration-dependent effects, with p < 0.001 compared with model at 20 µM. The alkaloids, N-coumaroylserotonin glucoside and N-feruloylserotonin glucoside, also showed anti-osteoporosis at 20 µM with p < 0.01, whereas EL, ED, and OTCL showed no significant effects. Quantitative real-time polymerase chain reaction revealed that SDG and TCL upregulated the expression of osteogenic genes Runx2, SP7, OPG, Col1a1a, Alp, ON, OPN, and OCN in alloxan-treated zebrafish. The in vivo metabolite of lignans, EL, showed significant anti-inflammatory effect (p < 0.01) at 20 µM, which might also help to combat osteoporosis and other complications caused by excessive immune response in the body. The results provided scientific data for using the oil extraction by-products as sources of anti-osteoporosis compounds. PRACTICAL APPLICATION: This study found that lignans in flaxseed cake and safflower seed cake exhibited anti-osteoporosis effects by upregulating the expression of osteogenic genes, making the oil extraction by-products sources of anti-osteoporosis compounds.

Mushrooms possess antihyperglycemic effect on diabetic individuals due to their nonfibrous and fibrous bioactive compounds. This study aimed to reveal the effect of different types of mushrooms on plasma glucose level and gut microbiota composition in diabetic individuals. The effects of five different mushroom species (Ganoderma lucidum, GLM; Pleurotus ostreatus, POM; Pleurotus citrinopileatus, PCM; Lentinus edodes, LEM; or Hypsizigus marmoreus, HMM) on alloxan-induced diabetic rats were investigated in this study. The results indicated that LEM and HMM treatments showed lower plasma glucose levels. For the microbiota composition, ACE, Chao1, Shannon, and Simpson were significantly affected by PCM and LEM treatments (p < .05), while ACE, Shannon, and Simpson indexes were affected by HMM treatment (p < .01). Simpson index was affected in positive control (C+) and POM groups. All these four indices were lower in GLM treatment (p < .05). Dietary supplementation of mushrooms reduced plasma glucose level directly through mushrooms\' bioactive compounds (agmatine, sphingosine, pyridoxine, linolenic, and alanine) and indirectly through stachyose (oligosaccharide) and gut microbiota modulation. In conclusion, LEM and HMM can be used as food additives to improve plasma glucose level and gut microbiome composition in diabetic individuals.

Oxidative stress and inflammation play important roles in the development of diabetes mellitus. p-Synephrine, the primary pharmacologically active protoalkaloid in Citrus species, has been popularly consumed as a dietary supplement for weight loss management. However, the effects of p-synephrine on diabetes mellitus and the action mechanisms have not been clearly elucidated. In this study, the in vitro antioxidant effects of p-synephrine were evaluated. The data showed that p-synephrine treatment exhibited significant scavenging effects against DPPH, ABTS and OH radicals and showed high reducing power. Diabetic mice were developed by alloxan injection, followed by p-synephrine administration to investigate its hypoglycemic effects in vivo. The results showed that p-synephrine intervention significantly prevented alloxan-induced alteration in body weight, organ indexes, serum uric acid content and serum creatinine content. Meanwhile, p-synephrine application significantly improved the lipid profiles, superoxide dismutase (SOD) and catalase (CAT) activities and glutathione (GSH) contents in the serum and kidneys of diabetic mice and reduced the malondialdehyde (MDA) content in the serum of diabetic mice. Further assays suggested that p-synephrine treatment improved alloxan-induced decreases of glucose tolerance and insulin sensitivity. Also, p-synephrine supplementation altered histopathological changes in the kidneys and interscapular brown adipose tissues in diabetic mice. In addition, p-synephrine administration inhibited renal inflammation through suppressing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) gene expression levels, as well as CD45 expression levels. The anti-inflammatory effects were probably involved in the regulation of nuclear factor-κB (NF-κB) activation and mitogen-activated protein kinase (MAPK) phosphorylation. In conclusion, p-synephrine application significantly ameliorated alloxan-induced diabetes mellitus by inhibiting oxidative stress via suppressing the NF-κB and MAPK pathways.

Diabetes has become a critical challenge to the global health concerns. Cytotoxicity and development of resistance against available drugs for management of diabetes have shifted the focus of global scientific researchers from synthetic to herbal medications. Therefore, the current study was conducted to investigate the possible anti-hyperglycemic potential of Dryopteris stewartii using Swiss albino mice. To evaluate any possible toxic effect of the plant, acute oral toxicity test was performed while the anti-diabetic effects of aqueous and ethanol extracts at 500 mg/kg, positive, negative and normal control were assessed simultaneously. The anti-diabetic study revealed that aqueous extract has higher anti-diabetic potential than ethanol extract while lowered blood glucose level at second week reaching 150 mg/dL, exerting stronger anti-diabetic effects, compared to ethanol extract (190 mg/dL). Oral glucose tolerance findings revealed that aqueous extract decreased blood glucose level by -0.41-fold, compared to ethanol extract showing a decrease by only -0.29-folds. The histopathological evaluation of liver and pancreas of all groups revealed normal cell architecture with no morphological abnormalities. These results suggested the possible use of D. stewartii as anti-diabetic herbal drug in near future. However, these recommendations are conditioned by deep mechanistic studies.

UNASSIGNED: To explore the changes of circRNAs in the retina of diabetic patients without diabetic retinopathy (DR) to screen latent protective factor.
UNASSIGNED: The sequencing data of the retina from three diabetic donors that possess no noticeable pathological feature of the retina at ultimate eye inspection and three healthy donative samples were involved in this study. Herein, we carried out bioinformatics analysis to disclose the expression pattern and characteristics of circRNAs on the basis of Gene Ontology as well as KEGG pathway analyses. Then, sequencing data were applied to infer the interaction between selected circRNAs and miR-204-5p. The potential miRNA response elements for the annotated circRNAs and their target gene were speculated using TargetScan as well as miRanda.
UNASSIGNED: RNA sequencing detected 28,978 alternative circRNAs. Thereinto, 1063 were expressed with significant difference. circKMT2E was upregulated more than two folds in alloxan-induced diabetic retinal tissues compared with normal retinal tissues, exhibiting an expression trend opposite to miR-204-5p. Bioinformatics analysis showed that circKMT2E have four seed sequences on hsa-miR-204-5p. Thus, circKMT2E was speculated to have function on the basis of sponging miR-204-5p in order to participate in the pathogenetic process of DR. Besides, miR-204-5p was speculated to be able to bind SIRT1, which can interact with its target proteins, and adjusts various cell functions including cellular inflammatory responses, proliferation, as well as apoptosis.
UNASSIGNED: The upregulation of circKMT2E in the early stage of DR may be involved in its pathogenesis and may activate the SIRT1 signaling pathway to protect the retina by the sponge function to miR-204-5p.

OBJECTIVE: Lacto-ghrestatin is abovine milk-derived peptide with the sequence of LIVTQTMKG, named LGP9 here. This study aimed to investigate protective effects of LGP9 on diabetic β cells in vivo and in vitro.
RESULTS: Type-1-diabetic (T1D) mice were generated by alloxan (ALX; 50 mg/kg, i.v.) and received a four-week treatment schedule of LGP9 at 0.3 mg/kg and 1 mg/kg. Related biochemical parameters were analyzed, and the protein expression was evaluated by Western blotting. The results showed that LGP9 decreased body weight, water consumption and blood glucose, improved oxygen stress and upregulated IRS2/PI3K/Akt signaling in the pancreas of T1D mice. To further investigate the mechanism of LGP9 on the preventive effect of the pancreas, Rin-m5f cells were treated with 15 mM alloxan and followed with LGP9 at 30 μM and 90 μM. The results indicated that LGP9 rebalanced oxygen stress levels, increased cell proliferation, decreased cell apoptosis and activated IRS2/PI3K/Akt signaling.
CONCLUSIONS: LGP9 ameliorated alloxan-injured pancreatic β cells through IRS2/PI3K/Akt signaling. The finding provides important help for the research and development of LGP9 in therapeutics of diabetes.

Type 1 diabetes mellitus (T1DM) is a chronic disease represented by insulin-causing pancreatic β-cell disruption and hyperglycemia. Therefore, it is necessary to establish a variety of animal models of diabetes to study the pathogenesis and pathophysiology of it. However, there are few reports on the use of beagle dogs to establish an animal model of type 1 diabetes. This study aimed to explore a simple and feasible modeling method to establish a long-term and stable type 1 diabetes model in beagle dogs. Forty adult beagle dogs were randomly divided into control group and model group. After 24 h of fasting, streptozotocin (20 mg/kg) and alloxan (20 mg/kg) were injected through the cephalic vein. The second intravenous injection was given on the 4th day after the first injection. Insulin release testing was performed on the 7th day after the last intravenous injection. Fasting blood glucose and body weight were recorded monthly. Four months after the last injection, the serum fructosamine content and the ratio of glycated hemoglobin were detected. Then, the pancreatic tissue was harvested for histopathological examination. The results showed that the level of fasting blood glucose of the 16 dogs in the model group was consistently higher than 11.1 mmol/L for 4 consecutive months. Moreover, compared with the control group, the insulin release curve of the model group was flat with no increase. The body weight of the model group was significantly reduced, and the ratios of blood glucose, fructosamine, and glycosylated hemoglobin were significantly higher than those in the control group. Meanwhile, histopathological examination of the pancreas showed that the islet beta cells appeared to have vacuoles or even necrosis. In the model group, pancreatic β-cells were damaged and insulin release was reduced. These results suggest that the above modeling methods can induce long-term and stable type 1 diabetes models in beagle dogs.

BACKGROUND: Fagara zanthoxyloides Lam., an African traditional medicinal plant, is used for treatment of malaria and diabetes.
OBJECTIVE: To investigate the antidiabetic property of ethyl acetate fraction of F. zanthoxyloides root-bark (EAFFZRB) on alloxan-induced diabetic rats.
METHODS: Extraction, isolation, preliminary phytochemical analysis, and acute toxicity study of ethanol extract and fractions of F. zanthoxyloides root-bark were achieved using standard methods. Phyto-constituents in EAFFZRB were identified using HPLC technique. Forty-eight male Wistar rats (140-185 g) were randomized into 6 groups (n = 8). Groups 1 and 2 served as normal and negative controls, respectively. Diabetes was induced in test groups (2-6) using 150 mg/kg body weight (b.w) Alloxan monohydrate. Rats in groups 4-6 received of 200, 400 and 600 mg/kg b.w. EAFFZRB orally, respectively, for 21 days. Group 3 rats received 5 mg/kg b.w Glibenclamide. The effect of EAFFZRB on alterations in hematological, biochemical, and histological indices of study rats were assessed.
RESULTS: Extraction of 3500 g ethanol extract yielded 15.71 g EAFFZRB. HPLC fingerprint of EAFFZRB indicated presence of luteolin, rutin, quercetin, apigenin, cinnamic acid and catechin. Diabetes triggered significant (p < 0.05) alterations in b.w., hematological, biochemical and histological indices of test rats relative to normal control. Treatment with EAFFZRB (LD50 = 3807.9 mg/kg b.w.) resulted in remarkable improvements in altered b.w. changes, hematological, biochemical and histological parameters of diabetic rats.
CONCLUSIONS: The study demonstrated the antidiabetic potential of EAFFZRB, providing scientific basis for traditional use of the plant in treatment of diabetes and its complications.

Codonopsis pilosula (Franch.) Nannf. (CPN), mainly planted in the northwest region, is a traditional Chinese medicine/good health food for nourishing qi and promoting blood circulation. This study firstly evaluated the inhibitory effects of the CPN extraction (CPNE) on α-glucosidase in vitro and in vivo, and tentatively confirmed its chemical ingredients by employing UHPLC-Triple-TOF-MS/MS. The CPNE had strong inhibitory activities against mammalian α-glucosidase (sucrase and maltase) and yeast α-glycosidase with semi-inhibitory concentrations (IC50) of 0.241 mg mL-1, 0.326 mg mL-1 and 1.167 mg mL-1, respectively. In addition, the CPNE could significantly decrease the postprandial blood glucose (PBG) levels in the sucrose/maltose/starch tolerance assays of diabetic mice. Furthermore, a total of 29 compounds, including 3 alkaloids, 13 phenolic acids, 8 alcohol glycosides and 5 alkynosides, were assigned based on comparison with the standards and references, as well as the analysis of main fragments. These results demonstrated that CPN could be used as an adjuvant therapy or dietary supplements to effectively control the occurrence and development of diabetes.

Diabetes mellitus (DM), an endocrine syndrome characterized by high blood glucose levels due to abrogated insulin activity. The existing treatments for DM have side effects and varying degrees of efficacy. Therefore, it is paramount that novel approaches be developed to enhance the management of DM. Therapeutic plants have been accredited as having comparatively high efficacy with fewer adverse effects. The current study aims to elucidate the phytochemical profile, anti-hyperlipidemic, and anti-diabetic effects of methanolic extract D. salicifolia (leaves) in Alloxan-induced diabetic mice. Alloxan was injected intraperitoneally (150 mg kg-1, b.w), to induced diabetes in mice. The mice were divided into three groups (n=10). Group 1 (normal control) received normal food and purified water, Group II (diabetic control) received regular feed and clean water and group III (diabetic treated) received a methanolic extract of the plant (300 mg kg-1) for 28 days with a typical diet and clean water throughout the experiment. Blood samples were collected to checked serum glucose and concentration of LDL, TC, TG. The extract demonstrated significant antihyperglycemic activity (P<0.05), whereas improvements in mice\'s body weight and lipid profiles were observed after treatment with the extract. This study establishes that the extract has high efficacy with comparatively less toxicity that can be used for DM management.