Caffeine improves bladder function in diabetic rats via a neuroprotective effect.
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ABSTRACT:
SUBMITTER: Xue J
PROVIDER: S-EPMC8005692 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Diabetic bladder dysfunction (DBD) afflicts nearly half of diabetic patients, but effective treatment is lacking. In this study, IR-61, a novel heptamethine cyanine dye with potential antioxidant effects, was investigated to determine whether it can alleviate DBD. Rats were intraperitoneally injected with IR-61 or vehicle after diabetes was induced with streptozotocin. Before evaluating the effects of IR-61 in improving DBD by filling cystometry, we detected its distribution in tissues and subcellular organelles by confocal fluorescence imaging. Near infrared (NIR) imaging showed that IR-61 could accumulate at high levels in the bladders of diabetic rats, and confocal images demonstrated that it was mainly taken up by bladder smooth muscle cells (BSMCs) and localized in mitochondria. Then, filling cystometry illustrated that IR-61 significantly improved the bladder function of diabetic rats. The histomorphometry results showed that IR-61 effectively mitigated the pathological changes in bladder smooth muscle (BSM) in diabetic rats. Furthermore, IR-61 remarkably reduced the number of apoptotic BSMCs and the unfavorable expression of proteins related to the mitochondrial apoptotic pathway (Bcl-2, BAX, Cytochrome C, and cleaved Caspase-9) in diabetic rats. Moreover, the frozen section staining and transmission electron microscopy results proved that IR-61 significantly reduced the reactive oxygen species (ROS) levels and prevented the mitochondrial mass and morphology damage in the BSM of diabetic rats. In addition, IR-61 upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its associated antioxidant proteins in the BSM of diabetic rats. Together, these results indicate that IR-61 can improve the voiding function of rats with DBD by protecting the mitochondria of BSMCs from oxidative stress, which is possibly mediated through the activation of the Nrf2 pathway.
| S-EPMC8080033 | biostudies-literature
Project description:Thyrotropin-releasing hormone (TRH) and its analogs are able to stimulate the release of the endogenic dopamine (DA) in the central nervous system. However, this effect has not been tested in the Parkinson's disease (PD), which is characterized by the DA deficiency due to the dopaminergic neurons loss in the substantia nigra. Here, we investigated the therapeutic effect of Taltirelin, a long-acting TRH analog on 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. 1-10 mg/kg Taltirelin i.p. administration significantly improved the locomotor function and halted the electrophysiological abnormities of PD animals without inducing dyskinesia even with high-dose for 7 days treatment. Microdialysis showed that Taltirelin gently and persistently promoted DA release in the cortex and striatum, while L-DOPA induced a sharp rise of DA especially in the cortex. The DA-releasing effect of Taltirelin was alleviated by reserpine, vanoxerine (GBR12909) or AMPT, indicating a mechanism involving vesicular monoamine transporter-2 (VMAT-2), dopamine transporter (DAT) and tyrosine hydroxylase (TH). The in vivo and in vitro experiments further supported that Taltirelin affected the regulation of TH expression in striatal neurons, which was mediated by p-ERK1/2. Together, this study demonstrated that Taltirelin improved motor function of hemi-PD rats without inducing dyskinesia, thus supporting a further exploration of Taltirelin for PD treatment.
| S-EPMC6282053 | biostudies-literature
Project description:BackgroundWe recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). The primary objective of the present study was to examine the effects of GMP-grade RJX on wound and burn injury healing in diabetic rats.MethodsIn the present study, a rat model of T2DM was used that employs HFD in combination with a single injection of STZ intraperitoneally (i.p) at a moderate dose level (45 mg/kg). Anesthetized diabetic rats underwent full-thickness skin excision on the back or were subjected to burn injury via a heated brass probe and then started on treatments with normal saline (NS = vehicle) or RJX administered via intraperitoneal injections for three weeks.FindingsNotably, diabetic rats treated with the 1.25 mL/kg or 2.5 mL/kg RJX (DM+RJX groups) rapidly healed their wounds as fast as non-diabetic control rats. Inflammatory cell infiltration in the dermis along with fibrin and cell debris on the epithelial layer persisted for up to 14 days in the DM+NS group but not in RJX-treated groups. The histopathological score of wound healing on days 7 and 14 was better in diabetic rats treated with RJX than diabetic rats treated with NS and comparable to the scores for non-diabetic healthy rats consistent with an accelerated healing process. The residual wound area of RJX-treated rats was significantly smaller than that of NS-treated diabetic rats at each evaluation time point (P<0.001). The accelerating effect of RJX on diabetic wound healing was dose-dependent. We obtained similar results in the burn injury model. Our results demonstrate that RJX - at a dose level >10-fold lower than its clinical maximum tolerated dose (MTD) - accelerates the healing of excision wounds as well burn injury in diabetic rats.
| S-EPMC9201994 | biostudies-literature
Project description:BackgroundDiabetes mellitus (DM) is a serious and growing global health burden. It is estimated that 80% of diabetic patients have micturition problems such as poor emptying, urinary incontinence, urgency, and urgency incontinence. Patients with diabetic bladder dysfunction are often resistant to currently available therapies. It is necessary to develop new and effective treatment methods.AimTo examine the therapeutic effect of human amniotic fluid stem cells (hAFSCs) therapy on bladder dysfunction in a type 2 diabetic rat model.MethodsSixty female Sprague-Dawley rats were divided into five groups: Group 1, normal-diet control (control); group 2, high-fat diet (HFD); group 3, HFD plus streptozotocin-induced DM (DM); group 4, DM plus insulin treatment (DM + insulin); group 5, DM plus hAFSCs injection via tail vein (DM + hAFSCs). Conscious cystometric studies were done at 4 and 12 wk after insulin or hAFSCs treatment to measure peak voiding pressure, voided volume, intercontraction interval, bladder capacity, and residual volume. Immunoreactivities and/or mRNA expression of muscarinic receptors, nerve growth factor (NGF), and sensory nerve markers in the bladder and insulin, MafA, and pancreatic-duodenal homeobox-1 (PDX-1) in pancreatic beta cells were studied.ResultsCompared with DM rats, insulin but not hAFSCs treatment could reduce the bladder weight and improve the voided volume, intercontraction interval, bladder capacity, and residual volume (P < 0.05). However, both insulin and hAFSCs treatment could help to regain the blood glucose and bladder functions to the levels near controls (P > 0.05). The immunoreactivities and mRNA expression of M2- and M3-muscarinic receptors (M2 and M3) were increased mainly at 4 wk (P < 0.05), while the number of beta cells in islets and the immunoreactivities and/or mRNA of NGF, calcitonin gene-related peptide (CGRP), substance P, insulin, MafA, and PDX-1 were decreased in DM rats (P < 0.05). However, insulin and hAFSCs treatment could help to regain the expression of M2, M3, NGF, CGRP, substance P, MafA, and PDX-1 to near the levels of controls at 4 and/or 12 wk (P > 0.05).ConclusionInsulin but not hAFSCs therapy can recover the bladder dysfunction caused by DM; however, hAFSCs and insulin therapy can help to regain bladder function to near the levels of control.
| S-EPMC9157602 | biostudies-literature
Project description:In the present study, we aimed to evaluate the effect of Sirt1, Sirt3 and combined activation in high fructose diet-induced insulin resistance rat heart and assessed the cardiac function focusing on mitochondrial health and function. We administered the Sirt1 activator; SRT1720 (5 mg/kg, i.p.), Sirt3 activator; Oroxylin-A (10 mg/kg i.p.) and the combination; SRT1720 + Oroxylin-A (5 mg/kg and 10 mg/kg i.p.) daily from 12th week to 20th weeks of study. We observed significant perturbations of most of the cardiac structural and functional parameters in high fructose diet-fed animals. Administration of SRT1720 and Oroxylin-A improved perturbed cardiac structural and functional parameters by decreasing insulin resistance, oxidative stress, and improving mitochondrial function by enhancing mitochondrial biogenesis, OXPHOS expression and activity in high fructose diet-induced insulin-resistant rats. However, we could not observe the synergistic effect of SRT1720 and Oroxylin-A combination. Similar to in-vivo study, perturbed mitochondrial function and oxidative stress observed in insulin-resistant H9c2 cells were improved after activation of Sirt1 and Sirt3. We observed that Sirt1 activation enhances Sirt3 expression and mitochondrial biogenesis, and the opposite effects were observed after Sirt1 inhibition in cardiomyoblast cells. Taken together our results conclude that activation of Sirt1 alone could be a potential therapeutic target for diabetes-associated cardiovascular complications.
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Project description:Diabetes mellitus is an independent risk factor for ischemic stroke. Both diabetes mellitus and stroke are linked to systemic inflammation that aggravates patient outcomes. Stellate ganglion block can effectively regulate the inflammatory response. Therefore, it is hypothesized that stellate ganglion block could be a potential therapy for ischemic stroke in diabetic subjects. In this study, we induced diabetes mellitus in rats by feeding them a high-fat diet for 4 successive weeks. The left middle cerebral artery was occluded to establish models of ischemic stroke in diabetic rats. Subsequently, we performed left stellate ganglion block with 1% lidocaine using the percutaneous posterior approach 15 minutes before reperfusion and again 20 and 44 hours after reperfusion. Our results showed that stellate ganglion block did not decrease the blood glucose level in diabetic rats with diabetes mellitus but did reduce the cerebral infarct volume and the cerebral water content. It also improved the recovery of neurological function, increased 28-day survival rate, inhibited Toll like receptor 4/nuclear factor kappa B signaling pathway and reduced inflammatory response in the plasma of rats. However, injection of Toll like receptor 4 agonist lipopolysaccharide 5 minutes before stellate ganglion block inhibited the effect of stellate ganglion block, whereas injection of Toll like receptor 4 inhibitor TAK242 had no such effect. We also found that stellate ganglion block performed at night had no positive effect on diabetic ischemic stroke. These findings suggest that stellate ganglion block is a potential therapy for diabetic ischemic stroke and that it may be mediated through the Toll like receptor 4/nuclear factor kappa B signaling pathway. We also found that the therapeutic effect of stellate ganglion block is affected by circadian rhythm.
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Project description:Diabetic neuropathy is an important long-term complication of diabetes. This study explored the hypothesis that hydrogen sulfide (H2S) ameliorates neuropathic pain by controlling antiapoptotic and pro-apoptotic processes. The effects of a slow-releasing H2S donor, GYY4137, on the expression of antiapoptotic and pro-apoptotic genes and proteins, such as B-cell lymphoma 2 (Bcl2) and Bcl-2-like protein 4 (Bax), as well as caspases, cyclooxygenase (COX)-1 and COX-2, monocytes/macrophages, and endothelial cells, in the spinal cord of male Sprague-Dawley rats with streptozotocin-induced peripheral diabetic neuropathy, were investigated using reverse transcription-PCR, western blot and immunohistochemistry. The antihypoalgesic activities of GYY4137 on diabetic rats were evaluated using the tail flick test. Treatment of diabetic rats with GYY4137 attenuated thermal hypoalgesia and prevented both the diabetes-induced increase in Bax mRNA expression (p = 0.0032) and the diabetes-induced decrease in Bcl2 mRNA expression (p = 0.028). The GYY4137-treated diabetic group had increased COX-1 (p = 0.015), decreased COX-2 (p = 0.002), reduced caspase-7 and caspase-9 protein expression (p < 0.05), and lower numbers of endothelial and monocyte/macrophage cells (p < 0.05) compared to the non-treated diabetic group. In summary, the current study demonstrated the protective properties of H2S, which prevented the development of neuropathy related behavior, and suppressed apoptosis activation pathways and inflammation in the spinal cord. H2S-releasing drugs could be considered as possible treatment options of diabetic peripheral neuropathy.
| S-EPMC10706751 | biostudies-literature
Project description:Behavioral disorders affect most diabetic patients and Zinc (Zn) has been used among adjuvant therapies for involvement in the etiology of depression and anxiety, however, the results are still controversial. The objective of this study was to compare the antidepressant, anxiolytic and neuroprotective activity of the supplementation of two Zn compounds in an animal model of Diabetes Mellitus type 1 (DM1). Thirty-eight (38) adult rats were randomized into four groups: Control (C; n = 8); Diabetic (D; n = 10); Diabetic Zn Sulfate Supplement (DSZ; n = 10) and Diabetic Zn Gluconate Supplement (DGZ; n = 10). The DSZ group received Zn sulfate supplementation and the DGZ group received Zn gluconate supplementation at a dose of 15 mg/kg for 4 weeks. Data (mean ±SEM) were analyzed by the Mann-Whitney test with a significance level of p < 0.05. The results indicate that Zn gluconate supplementation in diabetic animals presented an antidepressant effect demonstrated through the results obtained in the Forced Swim Test, and neuroprotective effect by attenuating alterations in the cerebral cortex; while Zn sulfate supplementation in diabetic animals showed an anxiolytic effect demonstrated by the results obtained in the open field test and the elevated plus maze test. Considering the set of results, supplementation with both zinc compounds showed neurobehavioral benefits in diabetic animals with different effects depending on the type of anion associated with Zn.
| S-EPMC6985554 | biostudies-literature
Project description:Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.
| S-EPMC2973867 | biostudies-other
Project description:To examine the effects of human amniotic fluid stem cells (hAFSCs) transplantation on bladder function and molecular changes in diabetic rats, 60 female Sprague-Dawley rats were used for study. Three groups were assigned including sham control rats, streptozotocin (STZ, 60?mg/kg)-induced diabetic rats and STZ-induced diabetic rats plus bladder hAFSCs transplantation. Compared to controls, diabetic rats had decreased body weight but increased bladder weight. Cystometries showed non-voiding contraction, residual volume, voided volume and intercontraction interval increased significantly in diabetic rats at week 4 and 12 after DM induction, but improved after hAFSCs transplantation. The immunoreactivities and mRNAs of nerve growth factor (NGF) decreased significantly in diabetic bladder at week 4 and 12 after DM induction, but recovered after hAFSCs transplantation. The immunoreactivities and mRNAs of M2 and M3 muscarinic receptor increased significantly in diabetic bladder at week 4 after DM induction but recovered after hAFSCs transplantation. The immunoreactivity of 8-hydroxy-20-deoxyguanosine increased significantly in diabetic bladder at week 4 and 12 after DM induction but reduced after hAFSCs transplantation. The present study showed bladder dysfunction in STZ-induced diabetic rats could be improved by hAFSCs transplantation into bladder, which may be related to the recovery of bladder NGF and muscarinic receptors.
| S-EPMC5794746 | biostudies-literature