Mesenchymal Stem Cell-Derived Exosomes Loaded with Selenium or Nano Selenium as a Novel Therapeutic Paradigm for Streptozotocin-Induced Type 1 Diabetes in Rats.

Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterized by hyperglycemia due to insulin insufficiency as a consequence of the pancreatic ß-cells' auto-immune attack. Nowadays, the application of mesenchymal stem cell-derived exosomes (MSCs-Exs) as the main cell-free therapy for diabetes treatment is becoming more and more extensive. In non-autologous therapy, researchers are moving towards a new strategy based on loading MSC-Exs with certain drugs, aimed at maintaining and maximizing the function of exosomes at the function site and enhancing their efficiency and safety. This study aims to explore and compare the therapeutic potentialities of mesenchymal stem cell-derived exosomes (MSCs-Exs) loaded with either selenium (Se) or nano selenium (NSe), a natural antioxidant micronutrient, in the management of T1DM in rats. In our 4-week experiment, six rat groups were included, namely, control, Ex+Se, Ex+NSe, STZ-diabetic (D), D+ Ex+Se, and D+Ex+NSe groups. Both diabetic-treated groups showed marked pancreatic regenerative antioxidant, immunomodulatory, anti-inflammatory, and anti-apoptotic capacities, with the D+Ex+NSe injection showing superiority in managing diabetes hazards, as evidenced by various biochemical and histological assessments.

Tomatidine ameliorates high-fat-diet/streptozocin (HFD/STZ)-induced type 2 diabetes mellitus in mice.

OBJECTIVE: To investigate the effects of tomatidine (Td) on the progression of type 2 diabetes mellitus (T2DM) in mice and uncover the mechanism. METHODS: T2DM mice model was induced by high-fat diet (HFD) and intrabitoneal injection of streptozotocin (STZ). The mice were grouped as follows: 1, control; 2, T2D; 3, T2D + tomatidine (5 mg/kg); 4, T2D + tomatidine (10 mg/kg); 5, T2D + tomatidine (20 mg/kg). Fasting blood glucose was detected by glucose metre and fasting insulin was detected by the kit to determine the effect of Td on T2DM mice. ELISA, qPCR, and Immunoblot assays were performed to detect the effects of Td on the hepatic glucose homeostasis and inflammation of mice. Immunoblot assays further confirmed the mechanism. RESULTS: Td improved blood glucose and insulin resistance in T2DM mice. In addition, Td improved liver function and lipid metabolism disorder in T2DM mice. Td also affected the liver glucose homeostasis related genes in T2DM mice. Td alleviated serum inflammation in T2DM mice. We further found that Td activated AMPK pathway, therefore ameliorating T2DM. CONCLUSION: Td ameliorated HFD/STZ-induced T2DM in mice, suggesting that it could serve as a drug of T2DM.

Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet ß cells in various mouse models of diabetes with distinct age of initiation.

During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the ß cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of islet ß cells. Cre-LoxP systems were used to generate islet cell type-specific (α, ß, or δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing, thereinto ß-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing (scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled ß cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of ß cells and some of which transdifferentiated into a or δ cells in both youth- and adulthood-initiated mice while this phenomenon was barely observed in HFD models. ß cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into ß cells in STZ-treated mice (both youth- and adulthood-initiated). In addition to the re-dedifferentiation of ß cells, it is also highly likely that these "α or δ" cells transdifferentiated from pre-existing ß cells could also re-trans-differentiate into insulin-producing ß cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of ß cells. Our findings shed light on how islet ß cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.

Protective Effect of Total Lignans of Arctii Fructus on Retina in Rat Model of Type 2 Diabetes Mellitus / 中国实验方剂学杂志

ObjectiveTo investigate the protective effect of total lignans of Arctii Fructus on the retinal tissue in the rat model of type 2 diabetes mellitus. MethodWistar rats were randomized into normal， model， solvent， Shuangdan Mingmu Capsules （618 mg·kg-1）， and low-， medium-， and high-dose （100， 200， 400 mg·kg-1， respectively） total lignans of Arctii Fructus groups， with 16 rats in each group. The rat model was established by streptozotocin （STZ） combined with a high-fat diet and administrated with corresponding drugs by gavage once a day for 14 weeks. At the 14th week， blood was sampled for the collection of serum from the abdominal aorta after anesthesia， and bilateral eyeballs were collected and frozen. Hematoxylin-eosin （HE） staining was used to observe the histopathological changes of the retinal tissue in rats. The pathological changes of retinal vascular network in rats were observed by retinal vascular tissue digestion and mounting The levels of vascular endothelial growth factor （VEGF）， tumor necrosis factor-α （TNF-α）， and intercellular adhesion molecule-1 （ICAM-1） in the serum were determined by the ELISA kit. ResultCompared with the normal group， the solvent group showed pathological changes in the retinal tissue， reduced retinal ganglion cells （P<0.01）， and retinal thinning （P<0.01）， decreased E/P value in retinal blood vessels （P<0.01）， and elevated serum levels of VEGF， TNF-α， and ICAM-1 （P<0.01）. Compared with the model group， the total lignans of Arctii Fructus increased the retinal ganglion cells （P<0.01）， thickened the retina （P<0.01）， and lowered the serum levels of VEGF， TNF-α， and ICAM-1 （P<0.05， P<0.01）. ConclusionTotal lignans of Arctii Fructus may lower the VEGF， TNF-α， and ICAM-1 levels to protect the retina.

Systematic assessment of streptozotocin-induced diabetic metabolic alterations in rats using metabolomics.

Purpose: Type 1 diabetes is characterized by elevated blood glucose levels, which negatively impacts multiple organs and tissues throughout the body, and its prevalence is on the rise. Prior reports primarily investigated the serum and urine specimen from diabetic patients. However, only a few studies examined the overall metabolic profile of diabetic animals or patients. The current systemic investigation will benefit the knowledge of STZ-based type 1 diabetes pathogenesis. Methods: Male SD rats were arbitrarily separated into control and streptozotocin (STZ)-treated diabetic rats (n = 7). The experimental rats received 50mg/kg STZ intraperitoneal injection daily for 2 consecutive days. Following 6 weeks, metabolites were assessed via gas chromatography-mass spectrometry (GC-MS), and multivariate analysis was employed to screen for differentially expressed (DE) metabolites between the induced diabetic and normal rats. Results: We identified 18, 30, 6, 24, 34, 27, 27 and 12 DE metabolites in the serum, heart, liver, kidney, cortex, renal lipid, hippocampus, and brown fat tissues of STZ-treated diabetic rats, compared to control rats. Based on our analysis, the largest differences were observed in the amino acids (AAs), B-group vitamin, and purine profiles. Using the metabolic pathway analysis, we screened 13 metabolic pathways related to the STZ-exposed diabetes pathogenesis. These pathways were primarily AA metabolism, followed by organic acids, sugars, and lipid metabolism. Conclusion: Based on our GC-MS analysis, we identified potential metabolic alterations within the STZ-exposed diabetic rats, which may aid in the understanding of diabetes pathogenesis.

Therapeutic Efficacy of Natural Product 'C-Phycocyanin' in Alleviating Streptozotocin-Induced Diabetes via the Inhibition of Glycation Reaction in Rats.

Diabetes is a long-term metabolic disorder characterized by persistently elevated blood sugar levels. Chronic hyperglycemia enhances glucose-protein interactions, leading to the formation of advanced glycation end products (AGEs), which form irreversible cross-links with a wide variety of macromolecules, and accumulate rapidly in the body tissues. Thus, the objective of this study was to assess the therapeutic properties of C-phycocyanin (C-PC) obtained from Plectonema species against oxidative stress, glycation, and type 2 diabetes mellitus (T2DM) in a streptozotocin (STZ)-induced diabetic Wistar rat. Forty-five days of C-PC administration decreased levels of triglycerides (TGs), blood glucose, glycosylated hemoglobin, (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), liver and kidney function indices, and raised body weight in diabetic rats. C-PC suppressed biochemical glycation markers, as well as serum carboxymethyllysine (CML) and fluorescent AGEs. Additionally, C-PC maintained the redox state by lowering lipid peroxidation and protein-bound carbonyl content (CC), enhancing the activity of high-density lipoprotein cholesterol (HDL-C) and renal antioxidant enzymes, and preserving retinal and renal histopathological characteristics. Thus, we infer that C-PC possesses antidiabetic and antiglycation effects in diabetic rats. C-PC may also act as an antidiabetic and antiglycation agent in vivo that may reduce the risk of secondary diabetic complications.

The role of sleep deprivation in streptozotocin-induced Alzheimer's disease-like sporadic dementia in rats with respect to the serum level of oxidative and inflammatory markers.

Numerous studies have shown the deleterious effects of sleep deprivation (SD) on memory. However, SD in various durations may induce different effects. Studies have reported that short-term or acute SD can improve cognitive functions. In addition, streptozotocin (STZ) significantly impairs learning and memory, and induces inflammation and oxidative stress. In this study, we aimed to investigate the effect of two types of SD (short term: 6 h; long term: 24 h) on STZ-induced spatial memory impairment in rats, with respect to the serum level of catalase (CAT), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß). Morris water maze apparatus was used to assess spatial memory performance and STZ was injected i.c.v., twice, and at the dose of 3 mg/kg, at an interval of 48 h. The results showed that only 24 h SD impaired spatial learning and memory in rats. In addition, 24 h SD attenuated anti-oxidant activity and increased the level of pro-inflammatory markers in the serum. STZ impaired spatial learning and memory, and attenuated anti-oxidant activity and increased the level of pro-inflammatory markers in the serum of rats. Furthermore, 6 h SD slightly and partially improved spatial memory and significantly improved anti-oxidant activity in rats, with no effect on STZ-induced inflammation. We suggest that STZ has more important mechanisms that are involved in its memory impairment effect, and maybe, STZ-induced inflammation has a more important role. We also suggest more detailed studies to investigate the potential therapeutic effect of SD (in different durations) on memory function, oxidative stress, and inflammation.

The Ultrastructure of Skeletal Muscle Capillaries of Streptozotocin Diabetic Rats and the Therapeutic Effect of Benfluorex.

Diabetes mellitus is a serious disease worldwide and causes other associated diseases. In this study, we observed the effect of streptozotocin (STZ)-induced diabetes and benfluorex treatment on muscular capillary ultrastructure. Adult male rats were used as the test subjects and each individual was intraperitoneally injected with one dose of STZ (45 mg/kg) to induce diabetes. Doses (50 mg/kg) of benfluorex were given to the subjects with tap water by intragastric gavage application once daily for 21 days. At the end of day 21, muscle tissues were obtained from animals and examined under transmission electron microscopy. From the data obtained with the electron microscope, it was observed that the control group had typical continuous capillary vascular structures in their muscles, while STZ caused disruptive disorder of the muscle cells in the capillary wall of the STZ-diabetic group. Additionally, the thickening of the basement membrane around endothelial cells, loss of mitochondrial crista in the muscle cells, enlarged endothelial cells, and narrowed vessel lumen were observed in the muscle tissue. The findings of our study revealed that STZ-induced diabetes disrupted the vascular structure, while benfluorex partially improved it.

Differences in brain activity between normal and diabetic rats under isoflurane anesthesia: a resting-state functional MRI study.

BACKGROUND: Altered neural activity based on the fractional amplitude of low-frequency fluctuations (fALFF) has been reported in patients with diabetes. However, whether fALFF can differentiate healthy controls from diabetic animals under anesthesia remains unclear. The study aimed to elucidate the changes in fALFF in a rat model of diabetes under isoflurane anesthesia. METHODS: The first group of rats (n = 5) received a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to cause the development of diabetes. The second group of rats (n = 7) received a single intraperitoneal injection of the same volume of solvent. Resting-state functional magnetic resonance imaging was used to assess brain activity at 4 weeks after STZ or solvent administration. RESULTS: Compared to the healthy control animals, rats with diabetes showed significantly decreased fALFF in various brain regions, including the cingulate cortex, somatosensory cortex, insula, and striatum (all P < 0.05). The decreased fALFF suggests the aberrant neural activities in the diabetic rats. No regions were detected in which the control group had a lower fALFF than that in the diabetes group. CONCLUSIONS: The results of this study demonstrated that the fALFF could be used to differentiate healthy controls from diabetic animals, providing meaningful information regarding the neurological pathophysiology of diabetes in animal models.

Comparison of Biochemical Parameters and Pathomorphological Changes in Rats Receiving Standard and High-Fat Diets during Modeling of Streptozotocin Diabetes.

The use of a high-fat diet, along with streptozotocin administration, can provide more profound insight into the mechanism of development of complications in diabetes, as well as their treatment. High-fat diet given over 3 weeks before intraperitoneal injection of streptozotocin in a dose of 40 mg/kg promoted the appearance of hyperglycemia in Wistar rats. The biochemical analysis of blood serum revealed increased levels of urea, triglycerides, cholesterol, AST, ALT, and concentration of inorganic phosphates and K+ ions in the high-fat diet group in comparison with the control. Both the biochemical analysis of the blood and histological analysis showed more pronounced abnormalities in rats receiving high-fat diet in comparison with animals receiving standard ration. These changes are the early markers for the development of nephropathy, impaired liver function, and microvascular disorders typical of patients with diabetes mellitus.

Diosgenin reduces phosphodiesterase 3B (PDE3B) through AMP-activated protein kinase/ mechanistic target of rapamycin (AMPK/mTOR) signaling pathway to ameliorate streptozotocin-induced pancreatic ß-cell apoptosis and dysfunction.

Diabetes mellitus is a metabolic disease caused by defective insulin secretion and/or insulin action. And insulin is the main hormone released by the pancreatic ß-cells. Diosgenin (DG) is a phytochemical with pharmacological activity that increases insulin secretion in streptozotocin (STZ)-induced pancreatic ß-cells of diabetic rats. In this paper, we investigated the effect and mechanism of DG on cell apoptosis and dysfunction in STZ-induced pancreatic ß-cells. Cell viability was detected by CCK-8, apoptosis by flow cytometry, and apoptosis-related protein expression by Western blot. Western blot and RT-qPCR were performed to detect the expression of related genes. The results showed that in STZ-induced INS-1 cells, DG could improve cell viability, inhibit apoptosis, attenuate oxidative stress levels and increase insulin secretion. Notably, PDE3B was highly expressed in STZ-induced INS-1 cells, while DG could significantly inhibit PDE3B expression in a dose-dependent manner. More importantly, overexpression PDE3B remarkably reversed the effect of DG on STZ-induced INS-1 cells. It is thus clear that DG might inhibit STZ-treated pancreatic ß-cell apoptosis and reduce dysfunction via downregulating PDE3B, which provided a more reliable theoretical basis for the treatment of diabetes mellitus with DG.

Comparatively analyzing the liver-specific transcriptomic profiles in Kunming mice afflicted with streptozotocin- and natural food-induced type 2 diabetes mellitus.

BACKGROUND: Streptozotocin is a classic drug used to induce diabetes in animal models. OBJECTIVE: The aim of this study is to investigate the liver transcriptome of Kunming mice with diabetes induced by either streptozotocin (STZ) or Non-STZ. METHODS: Forty male mice were randomly assigned into four groups: Control (Ctr, standard diet), mHH (high fat and high carbohydrate diet), mHS (high fat and high carbohydrate diet for 4 weeks followed by 60 mg/kg STZ for 3 consecutive days) and mSH (60 mg/kg STZ for 3 consecutive days followed by a high fat and high carbohydrate diet for 12 weeks). All mice injected with STZ were identified as diabetic despite the sequential feeding of high fat and high carbohydrate diets. RESULTS: Only 7 of 13 mice in the mHH group met the diagnostic criteria for diabetes. The asting blood glucose (FBG) of the mHH, mHS, mSH and Ctrl groups was 13.27 ± 1.14, 15.01 ± 2.59, 15.95 ± 4.38 and 6.28 ± 0.33 mmol/L at the 12th week, respectively. Compared with the mHH group, transcription was elevated in 85 genes in the livers of mHS mice, while 21 genes were downregulated and 97 genes were upregulated in the mSH group while 35 genes were decreased. A total of 43 co-expressed genes were identified in the mHS vs mHH and mSH vs mHH groups. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses showed that two corporate GO terms and two KEGG pathways were significantly annotated in the STZ-treated groups. Both the GO term and pathway were related to the metabolism mediated by p53. CONCLUSION: A high fat and high carbohydrate diet combined with a low dose of STZ can effectively induce diabetes in Kunming mice despite the abnormal expressions of genes in the liver. The differentially expressed genes were related to metabolism mediated by p53.

Sex Differences in the Effect of Diabetes on Cerebral Glucose Metabolism.

The neuroimaging literature indicates that brain structure and function both deteriorate with diabetes, but information on sexual dimorphism in diabetes-related brain alterations is limited. This study aimed to ascertain whether brain metabolism is influenced by sex in an animal model of diabetes. Eleven rats (male, n = 5; female, n = 6) received a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to develop diabetes. Another 11 rats (male, n = 5; female, n = 6) received the same amount of solvent through a single intraperitoneal injection. Longitudinal positron emission tomography scans were used to assess cerebral glucose metabolism before and 4 weeks after STZ or solvent administration. Before STZ or solvent injections, there was no evidence of sexual dimorphism in cerebral metabolism (p > 0.05). Compared with healthy control animals, rats with diabetes had significantly decreased brain metabolism in all brain regions (all p < 0.05). In addition, female diabetic rats exhibited further reduction in cerebral metabolism, relative to male diabetic rats (p < 0.05). The results of this study may provide some biological evidence, supporting the existence of a sexual dimorphism in diabetes-related complications.

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer's Disease (sAD) Mouse Model.

Tau cleavage plays a crucial role in the onset and progression of Alzheimer's Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)-a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic ß cells and to induce insulin resistance-mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-ß (Aß) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it's in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-ß axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.

Zingiber officinale (Ginger) hydroalcoholic extract improved avoidance memory in rat model of streptozotocin-induced diabetes by regulating brain oxidative stress.

OBJECTIVES: Diabetes mellitus associated cognitive impairment is suggested to be due to oxidative stress. Considering the anti-diabetic, antioxidant, antihyperlipidemic, and anti-inflammatory effects of Zingiber officinale, the present study aimed to investigate its effect on memory and oxidative stress factors in streptozotocin (STZ)-induced diabetic rats. METHODS: The rats were allocated into five groups: Control, Diabetic, Diabetic + Ginger 100, Diabetic + Ginger 200, and Diabetic + Ginger 400. Following diabetes induction by STZ (60 mg/kg), 100, 200, or 400 mg/kg Ginger was given for eight weeks. Passive avoidance test (PA) was done and thiol, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) measurements were carried out in the brain. RESULTS: The latency into the dark compartment decreased (p<0.001) and the number of entries and time spent in the dark chamber increased in the Diabetic group compared to the Control (p<0.001 for all). All three doses of extract improved performance of the rats in the PA test (p<0.001 for all). The hippocampal and cortical MDA level was higher (p<0.001) while CAT, SOD, and total thiol were lower (p<0.01-p<0.001) in the Diabetic group than the Control. Treatment with 200 and 400 mg/kg Z. officinale extract reduced hippocampal and cortical MDA (p<0.001) and improved CAT (p<0.001) while, just the dose of 400 mg/kg of the extract increased SOD and total thiol in hippocampal and cortical tissues (p<0.001) compared with Diabetic group. CONCLUSIONS: Z. officinale extract could improve memory by reducing the oxidative stress in STZ-induced diabetes model.

Anti-cataract effects of coconut water in vivo and in vitro.

OBJECTIVE: To determine the anti-cataract effects of coconut water (CW) in vivo and in vitro, and to explore the potential pathogenic mechanism. METHODS: In this study, 48 male Sprague-Dawley rats were randomly divided into 4 groups: control (CO), diabetic (DM), diabetic treated with CW (DM + CW), and diabetic treated with Glibenclamide (DM + Gli). Except for the CO group, in the other three groups, intraperitoneal injection of STZ (60 mg/kg) was conducted to establish diabetic models. The experiment was conducted for 20 weeks. The slit-lamp examination was undertaken during the period of experiment (20 weeks), and then, all rats were sacrificed. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the left lens were measured by using biochemical assays. The right lens was used for pathological analysis. The rat lens epithelial cells (LECs) were cultured in vitro and the subcultured cell were divided into four groups, namely the normal glucose group (5 mmol /L glucose, Group I), the high glucose group (40 mmol/L glucose, Group II), high glucose +5% CW group (Group III), and high glucose +10% CW group (Group IV). LECs were cultured under the conditions as described above for 48 h. Cell proliferation and the morphological changes were observed with interted phase contrast microscope.The level of cell apoptosis was determined by flow cytometry. the level of SOD, MDA and GSH-Px were also detected. RESULTS: The lens opacity index decreased in diabetic rats, and LECs apoptosis ratio also decreased in high glucose environments that received CW. Under treatment with CW, reduced MDA level and elevated activities of SOD and GSH-Px were detected, both in vivo and in vitro experiments. The increased severity of cataract and LECs apoptosis were noted in diabetic rats that received normal water, while CW markedly mitigated the enhanced cataract severity and the reduction of LECs induced by diabetes mellitus. CONCLUSION: CW is a functional food that can protect the lens from diabetic cataract. The possible underlying mechanism may be partly explained via the decreased oxidative stress in lens. However, further research needs to be conducted to indicate the pathogenic mechanism of anti-diabetic effects of CW.

LC-MS-Based Untargeted Metabolomics Reveals Early Biomarkers in STZ-Induced Diabetic Rats With Cognitive Impairment.

Diabetes in the elderly increases cognitive impairment, but the underlying mechanisms are still far from fully understood. A non-targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) was performed to screen out the serum biomarkers of diabetic mild cognitive impairment (DMMCI) in rats. Total 48 SD rats were divided into three groups, Normal control (NC) group, high-fat diet (HFD) fed group and type 2 diabetes mellitus (T2DM) group. The T2DM rat model was induced by intraperitoneal administration of streptozotocin (STZ, 35 mg/kg) after 6 weeks of high-fat diet (HFD) feeding. Then each group was further divided into 4-week and 8-week subgroups, which were calculated from the time point of T2DM rat model establishment. The novel object recognition test (NORT) and the Morris water maze (MWM) method were used to evaluate the cognitive deficits in all groups. Compared to the NC-8w and HFD-8w groups, both NOR and MWM tests indicated significant cognitive dysfunction in the T2DM-8w group, which could be used as an animal model of DMMCI. Serum was ultimately collected from the inferior vena cava after laparotomy. Metabolic profiling analysis was conducted using ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) technology. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to verify the stability of the model. According to variable importance in the project (VIP > 1) and the p-value of t-test (P < 0.05) obtained by the OPLS-DA model, the metabolites with significant differences were screened out as potential biomarkers. In total, we identified 94 differentially expressed (44 up-regulated and 50 down-regulated) endogenous metabolites. The 10 top up-regulated and 10 top down-regulated potential biomarkers were screened according to the FDR significance. These biomarkers by pathway topology analysis were primarily involved in the metabolism of sphingolipid (SP) metabolism, tryptophan (Trp) metabolism, Glycerophospholipid (GP) metabolism, etc. Besides, SP metabolism, Trp metabolism and GP metabolism mainly belonging to the lipid metabolism showed marked perturbations over DMMCI and may contribute to the development of disease. Taken collectively, our results revealed that T2DM could cause cognitive impairment by affecting a variety of metabolic pathways especially lipid metabolism. Besides, serum PE, PC, L-Trp, and S1P may be used as the most critical biomarkers for the early diagnosis of DMMCI.

Oral Administration of Lipopolysaccharide Prevents Cognitive Impairment in Streptozotocin-induced Diabetic Mice in a Blood Glucose-independent Manner.

BACKGROUND/AIM: Diabetes is a risk factor for dementia. However, no radical preventive method for diabetes-associated dementia has yet been developed. Our previous study revealed that oral administration of lipopolysaccharide (LPS) prevents high-fat diet-induced cognitive impairment. Therefore, we investigated here whether oral administration of LPS (OAL) could also prevent diabetes-associated dementia. MATERIALS AND METHODS: Diabetic mice were produced by intraperitoneal administration of streptozotocin (STZ), and then mice were orally administered LPS. Cognitive ability was evaluated using the Morris water maze, and gene expression was analyzed in isolated microglia. RESULTS: OAL prevented STZ-induced diabetic cognitive impairment, but did not affect blood glucose levels. Moreover, OAL promoted the expression of neuroprotective genes in microglia, such as heat shock protein family 40 (HSP40) and chemokine CCL7. CONCLUSION: OAL prevents diabetes-associated dementia, potentially via promotion of HSP40 and CCL7 expression in microglia.

Lactobacillus fermentum MCC2759 and MCC2760 Alleviate Inflammation and Intestinal Function in High-Fat Diet-Fed and Streptozotocin-Induced Diabetic Rats.

The growing incidence of type 2 diabetes and obesity has become a worldwide crisis with increased socio-economic burden. Changes in lifestyle and food habits resulting in dysbiosis of the gut microbiota and low-grade inflammation are linked to the rising incidence. The aim of this study was to investigate the effects of potential probiotic Lactobacillus fermentum MCC2759 and MCC2760 on intestinal markers of inflammation using a high-fat diet (HFD)-fed model and a streptozotocin (STZ)-induced diabetic model. Lact. fermentum administration showed improved oral glucose tolerance compared with the model controls of HFD (AUC 1518) and STZ (628.8). Plasma insulin levels improved in the Lact. fermentum treated groups of HFD + MCC2759 (129 ± 4.24 pmol/L) and HFD + MCC2760 (151.5 ± 9.19 pmol/L) in HFD study, while in STZ diabetic study, the insulin levels were normalized with Lact. fermentum administration, for D + MCC2759 (120.5 ± 7.77) and D + MCC2760 (138 ± 5.65 pmol/L) groups. The results showed reduction in inflammatory tone in liver, muscle, and adipose tissues of rats in both models with stimulation of anti-inflammatory IL-10 by real-time quantitative polymerase chain reaction. Additionally, the potential probiotic cultures also displayed normalization of markers related to intestinal barrier integrity (ZO-1), TLR-4 receptor, and insulin sensitivity (GLUT-4, GLP-1, adiponectin). Thus, the results suggest that Lact. fermentum could act as potential probiotic for lifestyle-related disorders such as obesity, diabetes, and metabolic syndrome as both prophylactic and adjunct therapies.

Analgesic and Antiallodynic Effects of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide in a Murine Model of Pain.

INTRODUCTION: Physical, chemical, thermal injuries along with infectious diseases lead to acute pain with associated inflammation, being the primary cause of hospital visits. Moreover, neuropathic pain associated with diabetes is a serious chronic disease leading to high morbidity and poor quality of life. OBJECTIVE: Earlier multiple sulphonamides have been reported to have an antinociceptive and antiallodynic profile. 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS), a synthetic sulfonamide with reported carbonic anhydrase inhibitory activity, was investigated for its potential effects in mice model of acute and diabetic neuropathic pain. METHODS AND RESULTS: 4-FBS was given orally (p.o.) one hour before the test and then mice were screened for antinociceptive activity by using the tail immersion test, which showed significant antinociceptive effect at both 20 and 40 mg/kg doses. To explore the possible mechanisms, thermal analgesia of 4-FBS was reversed by the 5HT3 antagonist ondansetron 1mg/kg intraperitoneally (i.p.) and by the µ receptor antagonist naloxone (1 mg/kg i.p.), implying possible involvement of serotonergic and opioidergic pathways in the analgesic effect of 4-FBS. Diabetes was induced in mice by a single dose of streptozotocin (STZ) 200 mg/kg i.p. After two weeks, animals first became hyperalgesic and progressively allodynic in the fourth week, which was evaluated through behavioral parameters like thermal and mechanical tests. 4-FBS at 20 and 40 mg/kg p.o. significantly reversed diabetes-induced hyperalgesia and allodynia at 30, 60, 90, and 120 minutes. CONCLUSION: These findings are significant and promising while further studies are warranted to explore the exact molecular mechanism and the potential of 4-FBS in diabetic neuropathic pain.