Objective To investigate diabetes‐associated changes in urinary bladder expression of cannabinoid receptors 1 and 2 ( CB1 and CB2 ) and the functional role of CB agonists and antagonists in mediating phasic contractions of isolated bladder strips using a streptozotocin‐induced diabetic rat model. Materials and Methods The bladder and dorsal root ganglion ( DRG ) were removed from diabetic rats and age‐matched controls 8–10 weeks after diabetes induction. Expression of CB1 and CB2 m RNA was studied using quantitative real‐time PCR and protein levels were determined by W estern blot analysis. The effect of increasing concentrations (0.1–100 μM) of the mixed CB1/CB2 agonist R (+)‐ WIN 55,212–2 ( WIN ), selective CB 1 antagonist ( AM 251) and selective CB 2 antagonist ( AM 630) on carbachol‐evoked contraction of bladder strips from control and diabetic rats was investigated. WIN ‐induced alterations of bladder strip contraction were then studied after pre‐incubation with AM 251 and AM 630. Results Diabetes induced decreased CB 1 protein and m RNA expression in both the bladder and DRG ( P < 0.05), while decreased CB 2 expression was observed in the bladder ( P < 0.05). WIN decreased the amplitude, but not frequency, of carbachol‐induced phasic contractions of bladder strips in a concentration‐dependent manner and this effect was diminished in the diabetic state. AM 630 and AM 251 had no effect on isolated detrusor muscle function. Moreover, pre‐incubation with AM 251 partially counteracted the effect of WIN on detrusor muscle contraction. Conclusion The results indicate that CB 1 and CB 2 are responsible for the pathogenesis of bladder dysfunction in diabetes mellitus and represent a viable target for pharmacological treatment of bladder cystopathy.
Purpose: [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol's antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT 3 receptor), in a cisplatin-induced pica model of rats. Methods: Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT 3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT 3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. Results: [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT 3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. Conclusion: This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT 3 receptor system. Keywords: [6]-gingerol, serotonin, cisplatin, pica, rats
We have previously found that modest chronic increases in maternal cortisol result in an enlarged fetal heart. To explore the mechanisms of this effect, we used intrapericardial infusions of a mineralocorticoid receptor (MR) antagonist (canrenoate) or of a glucocorticoid receptor (GR) antagonist (mifepristone) in the fetus during maternal infusion of cortisol (1 mg·kg⁻¹·day⁻¹). We have shown that the MR antagonist blocked the increase in fetal heart weight and in wall thickness resulting from maternal cortisol infusion. In the current study we extended those studies and found that cortisol increased Ki67 staining in both ventricles, indicating cell proliferation, but also increased active caspase-3 staining in cells of the conduction pathway in the septum and subendocardial layers of the left ventricle, suggesting increased apoptosis in Purkinje fibers. The MR antagonist blocked the increase in cell proliferation, whereas the GR antagonist blocked the increased apoptosis in Purkinje fibers. We also found evidence of activation of caspase-3 in c-kit-positive cells, suggesting apoptosis in stem cell populations in the ventricle. These studies suggest a potentially important role of corticosteroids in the terminal remodeling of the late gestation fetal heart and suggest a mechanism for the cardiac enlargement with excess corticosteroid exposure.
Cancer is still a global public health problem. Although remarkable success has been achieved in cancer diagnosis and treatment, the high recurrence and mortality rates remain severely threatening to human lives and health. In recent years, peptide nanomedicines with precise selectivity and high biocompatibility have attracted intense attention in biomedical applications. In particular, there has been a significant increase in the exploration of peptides and their derivatives for malignant tumor therapy and diagnosis. Herein, we review the applications of peptides and their derivatives in the diagnosis and treatment of bladder cancer, providing new insights for the design and development of novel peptide nanomedicines for the treatment of bladder cancer in the future.
The effects of Xiao-Ban-Xia-Tang (XBXT) formula on cisplatin and 1-PBG induced emesis and gut microbiota were studied in this experiment. Cisplatin and 1-PBG induced pica rat models were established, the amount of kaolin intake was observed, and the effects of XBXT and ondansetron on the gut microbiota were studied by 16S rDNA gene analysis. The results showed that XBXT and ondansetron could ameliorate the acute and delayed pica induced by cisplatin and 1-PBG. XBXT decreased Firmicutes in the cisplatin treated rats. Ondansetron decreased the alpha diversity of the gut microbiota, and it decreased Firmicutes and increased Bacteroidetes in the cisplatin and 1-PBG treated rats. XBXT was as effective as ondansetron in the treatment of pica, while ondansetron was more likely to cause gut microbiota dysbiosis than XBXT. Our study provided new avenues for the roles and mechanisms of XBXT on the prevention and treatment of CINV.
Transition of the epithelium of the fetal lung from fluid secretion to fluid reabsorption requires changes in the expression of ion channels. Corticosteroids regulate expression of several of these channels, including the epithelium sodium channel (ENaC) subunits and aquaporins (AQP). We investigated the ontogenetic changes in these ion channels in the ovine fetal lung during the last half of gestation, a time of increasing adrenal maturation. Expression of the mRNAs for the chloride channels, cystic fibrosis transmembrane conductance regulator (CFTR), and chloride channel 2 (CLCN2) decreased with age. Expression of mRNAs for AQP1, AQP5, and for subunits of ENaC (α, β, γ) increased with age. In the fetal sheep the expression of ENaCβ mRNA was dramatically higher than the expression of ENaCα or ENaCγ, but expression of ENaCβ protein decreased with maturation, although the ratio of the mature (112 kDa) to immature (102 kDa) ENaCβ protein increased with age, particularly in the membrane fraction. In contrast, ENaCα mRNA and protein both increase with maturation, and the mature form of ENaCα (68 kDa) predominates at all ages. A modest increase in fetal cortisol, within the range expected to occur naturally in late gestation but prior to active labor, increased ENaCα mRNA but not ENaCβ, ENaCγ, or AQP mRNAs. We conclude that in the ovine fetal lung, appearance of functional sodium channels is associated with induction of ENACα and ENaCγ, and that ENaCα expression may be induced by even small, preterm increases in fetal cortisol.
Two rat models of cisplatin and 1-phenylbiguanide hydrochloride induced pica were established. The amount of kaolin intake was observed, and the effects of Xiao-Ban-Xia-Tang formula and ondansetron on the gut microbiota were studied by 16S rDNA gene analysis.
We sought to determine if connective tissue growth factor (CTGF) is necessary for the formation of corneal haze after corneal injury. Mice with post-natal, tamoxifen-induced, knockout of CTGF were subjected to excimer laser phototherapeutic keratectomy (PTK) and the corneas were allowed to heal. The extent of scaring was observed in non-induced mice, heterozygotes, and full homozygous knockout mice and quantified by macrophotography. The eyes from these mice were collected after euthanization for re-genotyping to control for possible Cre-mosaicism. Primary corneal fibroblasts from CTGF knockout corneas were established in a gel plug assay. The plug was removed, simulating an injury, and the rate of hole closure and the capacity for these cells to form light reflecting cells in response to CTGF and platelet-derived growth factor B (PDGF-B) were tested and compared to wild-type cells. We found that independent of genotype, each group of mice was still capable of forming light reflecting haze in the cornea after laser ablation (p = 0.40). Results from the gel plug closure rate in primary cell cultures of knockout cells were not statistically different from serum starved wild-type cells, independent of treatment. Compared to the serum starved wild-type cells, stimulation with PDGF-BB significantly increased the KO cell culture's light reflection (p = 0.03). Most interestingly, both reflective cultures were positive for α-SMA, but the cellular morphology and levels of α-SMA were distinct and not in proportion to the light reflection seen. This new work demonstrates that corneas without CTGF can still form sub-epithelial haze, and that the light reflecting phenotype can be reproduced in culture. These data support the possibilities of growth factor redundancy and that multiple pro-haze pathways exist.
For the requirement of the mining hydraulic pump/motor test,a new type advanced test-bed is developed by the technologies such as electro-hydraulic proportional valve,AC frequency conversion,PLC and so on.The systemic performance and technical characteristic of the test-bed is introduced.
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