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CNS Neuroscience & Therapeutics Oct 2023Oxidative stress mediates the pathophysiology of diabetic neuropathy (DN) with activation of apoptotic pathway and reduction of autophagy. Arctigenin (ARC) is a natural...
BACKGROUND
Oxidative stress mediates the pathophysiology of diabetic neuropathy (DN) with activation of apoptotic pathway and reduction of autophagy. Arctigenin (ARC) is a natural lignan isolated from some plants of the Asteraceae family that shows antioxidant property. The present study aimed to explore the mechanistic neuroprotective effect of ARC on animal model for DN.
METHODS
DN was induced using streptozotocin (STZ) at a dose of 45 mg/kg, i.p, for five consecutive days and ARC was administered orally (25 or 50 mg) for 3 weeks. The mechanical sensitivity and thermal latency were determined using von Frey and hotplate, respectively. Beclin, p62, and LC3 were detected as markers for autophagy by western blot. Levels of reduced glutathione, lipid peroxides, and activities of catalase and superoxide dismutase were detected as readout for oxidative stress. Apoptotic parameters and histopathological changes were revealed in all experimental groups.
RESULTS
The present study showed deterioration of the function and structure of neurons as a result of hyperglycemia. Oxidative stress and impaired autophagy were observed in diabetic neurons as well as the activation of apoptotic pathway. ARC improved the behavioral and histopathological changes of diabetic mice. ARC combated oxidative stress through diminishing lipid peroxidation and improving the activity of antioxidant enzymes. This was concomitant by reducing the biomarkers of apoptosis. ARC augmented the expression of Beclin and LC3 while it lessened the expression of p62 indicating the activation of autophagy. These findings suggest that ARC can ameliorate DN by combating apoptosis and oxidative stress and improving autophagy.
Topics: Mice; Animals; Antioxidants; Streptozocin; Diabetes Mellitus, Experimental; Oxidative Stress; Lignans; Apoptosis; Diabetic Neuropathies; Autophagy
PubMed: 37170684
DOI: 10.1111/cns.14249 -
Journal of Pharmacological and... 2022The Göttingen Minipig is widely used in preclinical research and safety pharmacology, but standardisation of porcine electrocardiography (ECG) is lacking. The aim of...
BACKGROUND
The Göttingen Minipig is widely used in preclinical research and safety pharmacology, but standardisation of porcine electrocardiography (ECG) is lacking. The aim of this study was to investigate diurnal effects, change over time and choice of lead on ECG morphology and heart rate variability (HRV) in healthy and streptozotocin (STZ) induced diabetic Göttingen Minipigs.
METHODS
Diabetes was experimentally induced using STZ in 11 Göttingen Minipigs (DIA). Seven controls (CON) were included. 24-h ECG was recorded at baseline and four months. Morphological parameters (QRS and T wave duration, P- and T-wave amplitude, PR and QT (Bazett's (QTcb) or Fridericia (QTcf) correction) intervals and ST segment), presence of cardiac arrhythmias, heart rate (HR) and HRV (time and frequency domain) were analysed.
RESULTS
Four months after induction, DIA had decreased P-wave amplitude (P < 0.0001) and T-wave duration (P = 0.017), compared to CON. QTcb was lower in DIA, but not in CON. Both groups had decreased HR (P < 0.0001) and QRS duration (lead II, P = 0.04) and length of PR-segment increased (lead I and II, P < 0.01) while selected HRV parameters also increased (all P < 0.01). Time of day influenced HR, QRS duration, PR segment, ST segment, T- and P-wave amplitude and some parameters of HRV. Inter- and intra-observer variability of morphological measurements was low (<6%).
CONCLUSION
ECG parameters were influenced by time setting, diurnal variation and lead. Some ECG and HRV changes were found in diabetic minipigs four months after STZ induction. The findings underline the need for standardisation of ECG and HRV in Göttingen Minipigs.
Topics: Animals; Swine; Heart Rate; Swine, Miniature; Streptozocin; Electrocardiography; Arrhythmias, Cardiac; Diabetes Mellitus
PubMed: 36100059
DOI: 10.1016/j.vascn.2022.107221 -
Molecular Medicine (Cambridge, Mass.) Apr 2022Clinical data suggest that male reproductive dysfunction especially infertility is a critical issue for type 1 diabetic patient (T1D) because most of them are at the...
BACKGROUND
Clinical data suggest that male reproductive dysfunction especially infertility is a critical issue for type 1 diabetic patient (T1D) because most of them are at the reproductive age. Gut dysbiosis is involved in T1D related male infertility. However, the improved gut microbiota can be used to boost spermatogenesis and male fertility in T1D remains incompletely understood.
METHODS
T1D was established in ICR (CD1) mice with streptozotocin. Alginate oligosaccharide (AOS) improved gut microbiota (fecal microbiota transplantation (FMT) from AOS improved gut microbiota; A10-FMT) was transplanted into the T1D mice by oral administration. Semen quality, gut microbiota, blood metabolism, liver, and spleen tissues were determined to investigate the beneficial effects of A10-FMT on spermatogenesis and underlying mechanisms.
RESULTS
We found that A10-FMT significantly decreased blood glucose and glycogen, and increased semen quality in streptozotocin-induced T1D subjects. A10-FMT improved T1D-disturbed gut microbiota, especially the increase in small intestinal lactobacillus, and blood and testicular metabolome to produce n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to ameliorate spermatogenesis and semen quality. Moreover, A10-FMT can improve spleen and liver functions to strengthen the systemic environment for sperm development. FMT from gut microbiota of control animals (Con-FMT) produced some beneficial effects; however, to a smaller extent.
CONCLUSIONS
AOS-improved gut microbiota (specific microbes) may serve as a novel, promising therapeutic approach for the improvement of semen quality and male fertility in T1D patients via gut microbiota-testis axis.
Topics: Animals; Diabetes Mellitus, Type 1; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Humans; Male; Mice; Mice, Inbred ICR; Semen Analysis; Streptozocin; Testis
PubMed: 35468731
DOI: 10.1186/s10020-022-00473-w -
Journal of Molecular Endocrinology Apr 2022Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The...
Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels are increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hyperglycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+channel-dependent Ca2+influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells.
Topics: Animals; Glucagon; Hyperglycemia; Kidney; Mice; Mice, Knockout; Receptors, G-Protein-Coupled; Streptozocin; Urotensins
PubMed: 35244607
DOI: 10.1530/JME-21-0199 -
Nutrition & Diabetes Feb 2022The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and...
The pro-apoptotic kinase Mammalian Sterile 20-like kinase 1 (MST1), an integral component of the Hippo pathway, is a key regulator of organ size, stress response, and tissue homeostasis; its aberrant hyperactivation is linked to multiple pathological disorders including diabetes. Here we show that MST1 deletion in mice resulted in improved glucose tolerance and insulin secretion, and restored pancreatic β-cell mass as a result of improved β-cell survival and proliferation in the combined high fat/high sucrose and streptozotocin (HFS/STZ) model of β-cell destruction and diabetes. Importantly, the glucose-lowering effects in the MST1-knockout (KO) mice could be accounted to the enhanced β-cell mass and improved insulin secretion without changes in insulin sensitivity. Metabolic and morphological data suggest that normalization of blood glucose and insulin secretion, islet architecture, and β-cell mass by MST1 deletion in response to diabetes-induced injury occurs as a result of improved β-cell survival and proliferation establishing MST1 as potent regulator of physiological β-cell turnover.
Topics: Animals; Diabetes Mellitus; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mammals; Mice; Mice, Knockout; Streptozocin
PubMed: 35136036
DOI: 10.1038/s41387-022-00186-3 -
Scientific Reports May 2023Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic β-cells or...
Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic β-cells or proximal tubular epithelial cells through the glucose transporter, GLUT2. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of STZ-treated tubular epithelial cells in vitro showed the activation of the p53 signaling pathway. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transporters. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, pretreatment with an SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.
Topics: Mice; Animals; Streptozocin; Tumor Suppressor Protein p53; Sodium-Glucose Transporter 2 Inhibitors; Kidney; Signal Transduction; Antineoplastic Agents; Kidney Tubules, Proximal
PubMed: 37248327
DOI: 10.1038/s41598-023-35850-w -
Biomedicine & Pharmacotherapy =... Sep 2022Oxidative stress, a key player in diabetic retinopathy (DR), is associated with retinal cell apoptosis. This study investigated the effect of tocotrienol-rich fraction...
Oxidative stress, a key player in diabetic retinopathy (DR), is associated with retinal cell apoptosis. This study investigated the effect of tocotrienol-rich fraction (TRF), a potent antioxidant, towards visual behaviour, retinal morphology, cells apoptosis and redox status in streptozotocin (STZ)-induced DR rats. Sprague-Dawley rats were divided into 3 groups: non-diabetic (N), was injected with citrate buffer intraperitoneally, diabetic treated with vehicle (DV), and diabetic treated with TRF (DT), were injected with STZ intraperitoneally (55 mg/kg) to induce diabetes. DT received 100 mg of TRF/kg orally for 12-weeks, whereas DV and N received vehicle. The general and visual-behaviour responses were assessed at week 12 in an open field arena. Rats were then sacrificed, and retinae were processed for haematoxylin and eosin (H&E) and terminal transferase-mediated dUTP nick end-labelling (TUNEL) staining. Retinal antioxidant, lipid peroxidation and anti-apoptotic markers were measured. The general and visual-behaviour responses in DT were comparable to N. Retinal thickness and cell counts were lower in DV and DT compared to N. Lower number of TUNEL-positive cells were observed in DT compared to DV (1.48-fold, p < 0.001) which correlated with retinal caspase-3 expression (2.31-fold, p < 0.001). The retinal oxidative stress in DT was lower than DV as indicated by higher reduced glutathione (2.10-fold, p < 0.05), superoxide dismutase (1.12-fold, p < 0.05) and catalase (1.40-fold, p < 0.001), and lower malondialdehyde (2.54-fold, p < 0.001). In conclusion, oral TRF (100 mg/kg) supplementation for 12-weeks reduces retinal oxidative stress in STZ-induced DR rats, which in turn reduces retinal cell apoptosis and protects retinal morphology. These findings were associated with preservation of the visual-behaviour responses.
Topics: Animals; Antioxidants; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Oxidative Stress; Rats; Rats, Sprague-Dawley; Streptozocin; Superoxide Dismutase; Tocotrienols
PubMed: 36076612
DOI: 10.1016/j.biopha.2022.113533 -
Pflugers Archiv : European Journal of... Oct 2023Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI)...
Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis.
Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (HO), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.
Topics: Rats; Animals; Male; Diabetic Nephropathies; Streptozocin; Creatinine; Hydrogen Peroxide; Diabetes Mellitus, Experimental; Rats, Wistar; Kidney
PubMed: 37561129
DOI: 10.1007/s00424-023-02844-6 -
Biomedicine & Pharmacotherapy =... Dec 2023Diabetes is associated with aldosterone excess and the overactivation of its mineralocorticoid receptor (MR) which leads to the development of many cardiovascular...
Diabetes is associated with aldosterone excess and the overactivation of its mineralocorticoid receptor (MR) which leads to the development of many cardiovascular dysfunctions. Therefore, MR antagonists have been found to exert favorable effects on the cardiovascular system. Finerenone is a new nonsteroidal MR antagonist approved for the treatment of chronic kidney disease associated with type 2 diabetes. Clinical studies have demonstrated that finerenone improves cardiovascular outcomes. However, its influence on hemostasis in the cardioprotective effect is unknown. Therefore, the main aim of our study was to evaluate the effects of finerenone (10 mg/kg, p.o.) on selected hemostasis parameters in streptozotocin (180 mg/kg, i.p.)-induced diabetes. Since regulation of the MR activity is sex-dependent, the study was conducted in both female and male mice. The most beneficial effects of finerenone were observed in diabetic female mice which included a decrease in thrombus formation, attenuation of platelet activity, inhibition of the coagulation system, and activation of fibrinolysis. In contrast, in male diabetic mice only an attenuation of the coagulation system was observed. Furthermore, finerenone also exerted unfavorable effects, but only in normoglycemic mice, manifested as a slight increase in platelet activity in males and an enhancement of the coagulation system activity in females. Our study is the first to show the sex-dependent and glycemia-dependent effects of finerenone on hemostasis in diabetes. The occurrence of beneficial effects only in female diabetic mice requires in-depth study.
Topics: Mice; Male; Animals; Female; Diabetes Mellitus, Type 2; Streptozocin; Diabetes Mellitus, Experimental; Renal Insufficiency, Chronic; Hemostasis; Diabetic Nephropathies
PubMed: 38006618
DOI: 10.1016/j.biopha.2023.115910 -
Chemico-biological Interactions Aug 2021Streptozotocin exhibits tropism to insulin-producing beta-cells in mammals and has been used to model diabetes-like phenotypes in insects. We have previously shown...
Streptozotocin exhibits tropism to insulin-producing beta-cells in mammals and has been used to model diabetes-like phenotypes in insects. We have previously shown increased brain glucose levels and oxidative stress in STZ-treated nymphs of Nauphoeta cinerea. Here, we validate Nauphoeta cinerea as an experimental organism for studying STZ-induced metabolic disruptions by investigating the potential changes in the expression of inflammation and antioxidant related genes. Cockroaches were injected with 0.8% NaCl, 74 and 740 nmol of STZ. mRNA extracted from the head of cockroaches was used to estimate the RT-qPCR expression of inflammation and antioxidant genes. STZ-treatment upregulated the target genes of the JNK pathway (early growth factor response factor and reaper) but had no effect on PDGF-and VEGF-related factor 1. TOLL 1, the target gene of TOLL/NF-kB pathway was up regulated, while both the activator and target gene of the UPD3/JAK/STAT pathway [unpaired 3 and Suppressor of cytokine signalling at 36E] were upregulated. mRNA levels of primary antioxidants (superoxide dismutase and catalase) were increased in STZ treated nymphs but there was no effect on thioredoxins and Peroxiredoxin 4. Likewise, STZ treatment did not affect the expression of the delta class of the glutathione S-transferase gene family, but the sigma and theta classes of the GST family were upregulated. The STZ-induced N. cinerea gene expression modification demonstrates the involvement of primary antioxidants and the GST detoxification system in the cockroach oxidative stress response and buttresses the proposed crosstalk between inflammatory and redox pathways.
Topics: Animals; Antioxidants; Cockroaches; Cytokines; Dose-Response Relationship, Drug; Inflammation; NF-kappa B; RNA, Messenger; Signal Transduction; Streptozocin; Up-Regulation
PubMed: 34166651
DOI: 10.1016/j.cbi.2021.109563