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Journal of Chemical Neuroanatomy Sep 2022Specialized cutaneous Schwann cells (SCs), termed nociceptive SCs, were recently discovered. Their function is not fully understood, but they are believed not only to...
Specialized cutaneous Schwann cells (SCs), termed nociceptive SCs, were recently discovered. Their function is not fully understood, but they are believed not only to support peripheral axons in mouse skin by forming a mesh-like neural-glio networking structure in subepidermal area, but also contributing to transduction of mechanical sensation and neuropathic pain. Diabetic neuropathy (DPN) is one of the most common complication of diabetes, however, the mechanisms behind painful and painless DPN remain unclear. Using a mouse model of DPN, we want to investigate if there are quantitative differences in nociceptive SC density between the condition of hyperglycemia-induced sensory abnormalities and control condition and at which stage in the disease the damage occurs. Here, we developed a set of counting rules for nociceptive SCs based on immunofluorescent staining, and applied the method to quantify the density of nociceptive SCs in control mice (n = 10), mice with nociceptive hypersensitivity at early diabetic stage (n = 5), and mice with sensory hyposensitivity at late diabetic stage (n = 5) in the Streptozotocin (STZ) model of type 1 diabetes. Nociceptive SCs were identified as S100/Sox10/DAPI cells abutting to peripheral nerves, with the somas located within 25 µm depth in the subepidermal area and outside glands and large fiber bundles. Hypersensitive diabetic mice had decreased nociceptive SC density, despite having normal epidermal nerve fiber density, compared with age-matched control mice (P = 0.023). In contrast, there was a reduction in intraepidermal nerve fiber density but no difference in nociceptive SC density between hyposensitive diabetic mice and the age-matched control mice. This study provides a detailed description of how to identify and quantify nociceptive SC and demonstrates that nociceptive SC density declines before nerve fiber deterioration, which supports previous observations that nociceptive SCs are critical for maintenance of cutaneous sensory nerves.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Nociception; Schwann Cells; Streptozocin
PubMed: 35680105
DOI: 10.1016/j.jchemneu.2022.102118 -
Biomolecules Sep 2022Diabetic nephropathy (DN) is a common complication of diabetes mellitus. While there has been a great advance in our understanding of the pathogenesis of DN, no... (Review)
Review
Diabetic nephropathy (DN) is a common complication of diabetes mellitus. While there has been a great advance in our understanding of the pathogenesis of DN, no effective managements of this chronic kidney disease are currently available. Therefore, continuing to elucidate the underlying biochemical and molecular mechanisms of DN remains a constant need. In this regard, animal models of diabetes are indispensable tools. This review article highlights a widely used rodent model of non-obese type 2 diabetes induced by nicotinamide (NA) and streptozotocin (STZ). The mechanism underlying diabetes induction by combining the two chemicals involves blunting the toxic effect of STZ by NA so that only a percentage of β cells are destroyed and the remaining viable β cells can still respond to glucose stimulation. This NA-STZ animal model, as a platform for the testing of numerous antidiabetic and renoprotective materials, is also discussed. In comparison with other type 2 diabetic animal models, such as high-fat-diet/STZ models and genetically engineered rodent models, the NA-STZ model is non-obese and is less time-consuming and less expensive to create. Given that this unique model mimics certain pathological features of human DN, this model should continue to find its applications in the field of diabetes research.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucose; Humans; Hypoglycemic Agents; Niacinamide; Oxidation-Reduction; Rodentia; Streptozocin
PubMed: 36139064
DOI: 10.3390/biom12091225 -
BioMed Research International 2022Type 1 diabetes mellitus (T1DM) is a chronic disease represented by insulin-causing pancreatic -cell disruption and hyperglycemia. Therefore, it is necessary to...
Type 1 diabetes mellitus (T1DM) is a chronic disease represented by insulin-causing pancreatic -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 -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.
Topics: Alloxan; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Dogs; Fructosamine; Insulin; Streptozocin
PubMed: 35978645
DOI: 10.1155/2022/5422287 -
Neuroendocrinology 2022In May 1982, the US Food and Drug Administration (FDA) approved the use of streptozotocin to treat pancreatic neuroendocrine tumors (panNETs). Thus, this year marks 40... (Review)
Review
In May 1982, the US Food and Drug Administration (FDA) approved the use of streptozotocin to treat pancreatic neuroendocrine tumors (panNETs). Thus, this year marks 40 years since that landmark date. This review of streptozotocin to treat panNETs is intended to commemorate this anniversary. A historical perspective of the chemical structure, pharmacokinetics, and mechanism of action of streptozotocin is followed by data from prospective and retrospective clinical studies. The last section of the review addresses the latest aspects and takes note of the prospects that lie ahead on the future horizon of the use of streptozotocin to treat panNETs, including ongoing clinical trials.
Topics: Humans; Neuroendocrine Tumors; Streptozocin; Retrospective Studies; Prospective Studies; Pancreatic Neoplasms
PubMed: 35537416
DOI: 10.1159/000524988 -
Biomedicine & Pharmacotherapy =... Jan 2020Amyloid-β (Aβ) activating the pyroptotic cell pathway has been reported to act as a component in the progression of Alzheimer's disease (AD). As another major...
Amyloid-β (Aβ) activating the pyroptotic cell pathway has been reported to act as a component in the progression of Alzheimer's disease (AD). As another major pathophysiological protein process in AD, the abnormal hyperphosphorylation of tau proteins exerts neurotoxic effects through a variety of mechanisms. However, data describing the relationship between hyperphosphorylated tau proteins and pyroptosis are very scarce. In this study, we used two hyperphosphorylated tau models, intracerebroventricular (ICV) forskolin (FSK, a PKA activator) rat model and ICV-streptozotocin (STZ) rat model; also, FSK and STZ treated PC12 cells as in vitro models to test the relationship between hyperphosphorylated tau proteins and pyroptosis. We found that FSK and STZ significantly increased the hyperphosphorylated tau level, pyroptosis-related protein in PC12 cell and rats' brain, and inhibited the activity of caspase-1 by caspase-1 inhibitor, caspase-1 siRNA, or incubated with Interleukin(IL)-1β/IL-18 neutralizing antibody could notably alleviate the FSK and STZ induced PC12 cells damage and improve the cognitive disorder in ICV-FSK and ICV-STZ rats. Suppressed the level of hyperphosphorylated tau by LiCl also significantly decreased caspase-1 activity and the content of inflammatory cytokines in FSK or STZ treated PC12 cells. In summary, our results demonstrated that inflammasomes mediated pyroptosis at least one underlying pathogenic mechanism for the neurotoxicity induced by hyperphosphorylated tau in PC12 cells and dementia rats. IL-1β and IL-18, the downstream of caspase-1, in turn increased hyperphosphorylated tau while spreading neuroinflammation.
Topics: Alzheimer Disease; Amino Acid Chloromethyl Ketones; Animals; Caspase 1; Colforsin; Inflammasomes; Interleukin-18; Interleukin-1beta; Male; PC12 Cells; Phosphorylation; Pyroptosis; Rats; Rats, Sprague-Dawley; Streptozocin; tau Proteins
PubMed: 31731189
DOI: 10.1016/j.biopha.2019.109618 -
Biomedicine & Pharmacotherapy =... Jun 2022Diabetic ulcer is a challenging complication of diabetes mellitus but current treatments cannot achieve satisfactory results. In this study, the effect of Huangbai...
Diabetic ulcer is a challenging complication of diabetes mellitus but current treatments cannot achieve satisfactory results. In this study, the effect of Huangbai liniment (HB) and berberine on the wound healing in high fat diet/streptozotocin injection induced diabetic rats was investigated by RNA-seq technology. HB topical treatment promoted wound healing in the diabetic patients and diabetic rats, and it affected multiple processes, of which IL-17 signalling pathway was of importance. Inhibiting IL-17a by its inhibitor or antibody remarkably facilitated wound healing and HB significantly repressed the high IL-17 expression and its downstream targets, including Cxcl1, Ccl2, Mmp3, Mmp9, G-CSF, IL1B and IL6, in diabetic wounds, promoted T-AOC, SOD activity and GSH levels; decreased the levels of nitrotyrosine and 8-OHdG; enhanced angiogenesis-related CD31, PDGF-BB and ANG1 expression; inhibited cleaved caspase-3 levels and promoted TIMP1 and TGFB1. Moreover, berberine (a major component in HB) repressed the IL-17 signalling pathway, and promoted wound healing in diabetes mellitus. This study highlights the strategy of targeting IL-17a in diabetic wounds, deepens the understanding of wound healing in diabetes mellitus in a dynamic way and reveals the characteristics of HB and berberine in promoting wound healing of type 2 diabetes mellitus.
Topics: Animals; Berberine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Drugs, Chinese Herbal; Humans; Interleukin-17; Liniments; Rats; Streptozocin; Wound Healing
PubMed: 35430394
DOI: 10.1016/j.biopha.2022.112948 -
Nature Communications Sep 2023Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes. Most people with both conditions have type 2 diabetes, but it is unknown if type 1 and...
Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes. Most people with both conditions have type 2 diabetes, but it is unknown if type 1 and type 2 diabetes have identical effects on tuberculosis susceptibility. Here we show that male mice receiving a high-fat diet and streptozotocin to model type 2 diabetes, have higher mortality, more lung pathology, and higher bacterial burden following Mycobacterium tuberculosis infection compared to mice treated with streptozotocin or high-fat diet alone. Type 2 diabetes model mice have elevated plasma glycerol, which is a preferred carbon source for M. tuberculosis. Infection studies with glycerol kinase mutant M. tuberculosis reveal that glycerol utilization contributes to the susceptibility of the type 2 diabetes mice. Hyperglycemia impairs protective immunity against M. tuberculosis in both forms of diabetes, but our data show that elevated glycerol contributes to an additional adverse effect uniquely relevant to type 2 diabetes.
Topics: Humans; Male; Animals; Mice; Diabetes Mellitus, Type 2; Glycerol; Streptozocin; Tuberculosis; Mycobacterium tuberculosis
PubMed: 37730757
DOI: 10.1038/s41467-023-41519-9 -
Proceedings of the National Academy of... Jun 2023Patients with type 1 diabetes (T1D) suffer from insufficient functional β-cell mass, which results from infiltration of inflammatory cells and cytokine-mediated β-cell...
Patients with type 1 diabetes (T1D) suffer from insufficient functional β-cell mass, which results from infiltration of inflammatory cells and cytokine-mediated β-cell death. Previous studies demonstrated the beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R), such as MR-409 on preconditioning of islets in a transplantation model. However, the therapeutic potential and protective mechanisms of GHRH-R agonists on models of T1D diabetes have not been explored. Using in vitro and in vivo models of T1D, we assessed the protective propertie of the GHRH agonist, MR409 on β-cells. The treatment of insulinoma cell lines and rodent and human islets with MR-409 induces Akt signaling by induction of insulin receptor substrate 2 (IRS2), a master regulator of survival and growth in β-cells, in a PKA-dependent manner. The increase in cAMP/PKA/CREB/IRS2 axis by MR409 was associated with decrease in β-cell death and improved insulin secretory function in mouse and human islets exposed to proinflammatory cytokines. The assessment of the effects of GHRH agonist MR-409 in a model of T1D induced by low-dose streptozotocin showed that mice treated with MR-409 exhibited better glucose homeostasis, higher insulin levels, and preservation of β-cell mass. Increased IRS2 expression in β-cells in the group treated with MR-409 corroborated the in vitro data and provided evidence for the underlying mechanism responsible for beneficial effects of MR-409 in vivo. Collectively, our data show that MR-409 is a novel therapeutic agent for the prevention and treatment of β-cells death in T1D.
Topics: Humans; Animals; Mice; Diabetes Mellitus, Type 1; Streptozocin; Cytokines; Diabetes Mellitus, Experimental; Insulin; Pancreatic Neoplasms
PubMed: 37307472
DOI: 10.1073/pnas.2209810120 -
PloS One 2023Infection with Covid-19 has been associated with some medical complications namely diabetes, thrombosis, and hepatic and renal dysfunction among others. This situation...
Infection with Covid-19 has been associated with some medical complications namely diabetes, thrombosis, and hepatic and renal dysfunction among others. This situation has created some concern about the use of relevant vaccines which might cause similar complications. In that regard, we planned to evaluate the impact of two of the relevant vaccines namely ChAdOx1-S and BBIBP-CorV on some of the blood biochemical factors and also on liver and kidneys functions following the immunization of healthy and streptozotocin-induced diabetic rats. Evaluation of the level of neutralizing antibody among the rats indicated that immunization with ChAdOx1-S induced a higher level of neutralizing antibody among both the healthy and diabetic rats compared to the BBIBP-CorV vaccine. Furthermore, the neutralizing antibody levels against both types of vaccines were significantly lower in diabetic rats than in healthy ones. On the other hand, no alterations were observed in the rats' sera biochemical factors, coagulation values and histopathological images of the liver and kidneys. Altogether these data besides of confirming the effectiveness of both vaccines, indicate that both vaccines have no hazardous side effects on rats and probably humans though clinical investigations are required to validate our present data.
Topics: Humans; Rats; Animals; Rats, Wistar; Streptozocin; Diabetes Mellitus, Experimental; COVID-19; Vaccination; Antibodies, Neutralizing; ChAdOx1 nCoV-19
PubMed: 37141219
DOI: 10.1371/journal.pone.0284601 -
Investigative Ophthalmology & Visual... Jun 2023Patients with diabetes have a higher incidence of infections, which are often more severe. This study aimed to investigate the impact of hyperglycemia on bacterial...
PURPOSE
Patients with diabetes have a higher incidence of infections, which are often more severe. This study aimed to investigate the impact of hyperglycemia on bacterial keratitis caused by Pseudomonas aeruginosa (Pa) in two mouse models of diabetes, streptozotocin-induced type 1 diabetes mellitus (T1DM) and db/db type 2 diabetes mellitus.
METHODS
The susceptibility of corneas to Pa was assessed by determining the inocula required to cause infectious keratitis. Dead or dying cells were identified using TUNEL staining or immunohistochemistry. Specific inhibitors were used to evaluate the role of cell death modulators in Pa keratitis. Cytokines and Treml4 expressions were analyzed using quantitative PCR, and the role of Treml4 in keratitis was determined using small interfering RNA technology.
RESULTS
DM corneas required significantly fewer inocula to develop Pa keratitis, with T1DM corneas requiring 750 inocula and type 2 diabetes mellitus corneas requiring 2000 inocula, compared with 10,000 inocula required for normal (NL) mice. T1DM corneas had more TUNEL-positive and fewer F4/80-positive cells than NL corneas. Phospho-caspase 8 (apoptosis) and -RIPK3 (necroptosis) staining was more intense in the epithelial and stromal layers of NL and T1DM corneas, respectively. Pa keratitis was augmented by targeting caspase-8 and prevented by RIPK3 inhibition in both NL and T1DM mice. Hyperglycemia suppressed IL-17A/F and augmented IL-17C, IL-1β, IL-1Ra, and TREML4, the downregulation of which protected T1DM corneas from Pa infection by suppressing necroptosis. RIPK3 inhibition blocked Pa infection in db/+ mice and significantly decreased the severity of keratitis in db/db mice.
CONCLUSIONS
Hyperglycemia exacerbates bacterial keratitis in B6 mice by skewing apoptosis toward necroptosis. Preventing or reversing this transition may serve as an adjunct therapy for treating microbial keratitis in patients with diabetes.
Topics: Mice; Animals; Pseudomonas aeruginosa; Streptozocin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Keratitis; Cornea; Mice, Inbred Strains; Eye Infections, Bacterial; Apoptosis; Hyperglycemia; Pseudomonas Infections; Mice, Inbred C57BL
PubMed: 37279395
DOI: 10.1167/iovs.64.7.14