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.

Clinical management of cyclophosphamide (CYP) results in numerous side effects including hemorrhagic cystitis (HC), which is characterized by inflammation and oxidative stress damage. Intravesical hyaluronic acid (HA) supplementation, a therapeutic method to restore barrier function of bladder, avoid the stimulation of metabolic toxicants on bladder and reduce inflammatory response, has shown good results in acute or chronic bladder diseases. However, there are unmet medical needs for the treatment of HC to temporarily restore bladder barrier and reduce inflammation. Herein, sulfhydryl functionalized HA (HA-SH) and dimethyl sulfoxide (DMSO) were used to prepared a hydrogel system for optimizing the treatment of HC. We systematically evaluated the physicochemical of hydrogels and their roles in a rat model of CYP-induced HC. The prepared hydrogels exhibited outstanding gel forming properties, injectability, and biosafety. Swelling and retention studies showed that hydrogels were stable and could prolong the residence time of HA in the bladder. Histopathology and vascular permeability studies indicated that the hydrogels significantly attenuated bladder injury caused by CYP administration. Moreover, the hydrogels also showed excellent anti-inflammation and anti-oxidation properties. In conclusion, these data suggest that intravesical instillation of HA-SH/DMSO hydrogels reduces CYP-induced bladder toxicity and this work provides a new strategy for the prevention and early treatment of HC.

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Purpose: To explore an efficient preventive strategy for radiation cystitis. Methods: We instilled IR-780 into the bladders of rats 1 h before bladder irradiation, and its bio-distribution was observed at different times. Bladders were then examined for pathogenic alterations and inflammation levels by day 3 and week 12 postirradiation, and the functional characteristics of the bladder were tested via cystometry by week 12. Human uroepithelial sv-huc-1 cells were used to determine the effect of IR-780 on cell viability, regardless of irradiation. We measured the intracellular levels of oxidative stress, DNA damage, apoptosis proportion, and the expression of antioxidant proteases and apoptotic caspases in IR-780 pretreated cells after radiation.Results: IR-780 is localized in the urothelium after intravesical instillation in vivo. Ionizing radiation could induce acute impairment of the bladder urothelium and inflammation in the bladder on day 3. Fibrosis of the irradiated bladder progressed and eventually affected voiding function at 12 weeks. Treatment with IR-780 before irradiation ameliorated these changes. In vitro, IR-780 protected against cell viability and apoptosis of sv-huc-1 cells after irradiation. Additionally, IR-780 may assist in eliminating reactive oxygen species and repairing irradiation-induced DNA damage. Conclusion: Our data indicate that IR-780 can be used before irradiation to prevent acute urinary mucosal injury and late bladder dysfunction. Moreover, early urothelial impairment plays a significant role in radiation cystitis development.

This study aimed to evaluate the therapeutic effect of IR-61, a novel mitochondrial heptamethine cyanine dye with antioxidant effects, on diabetes mellitus-induced erectile dysfunction (DMED). Eight-week-old male Sprague–Dawley rats were intraperitoneally injected with streptozotocin (STZ) to induce type 1 diabetes. Eight weeks after STZ injection, all rats were divided into three groups: the control group, DM group, and DM + IR-61 group. In the DM + IR-61 group, the rats were administered IR-61 (1.6 mg kg −1 ) twice a week by intravenous injection. At week 13, erectile function was evaluated by determining the ratio of the maximal intracavernous pressure to mean arterial pressure, and the penises were then harvested for fluorescent imaging, transmission electron microscopy, histological examinations, and Western blot analysis. Whole-body imaging suggested that IR-61 was highly accumulated in the penis after intravenous injection. IR-61 treatment significantly improved the maximal ICP of diabetic rats. Additionally, IR-61 ameliorated diabetes-induced inflammation, apoptosis, and phenotypic transition of corpus cavernosum smooth muscle cells (CCSMCs) in penile tissue. IR-61 also attenuated mitochondrial damage, reduced reactive oxygen species production in the corpus cavernosum and upregulated sirtuin1 (SIRT1), sirtuin3 (SIRT3), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and heme oxygenase expression in penile tissue. In conclusion, IR-61 represents a potential therapeutic option for DMED by protecting the mitochondria of CCSMCs, which may be mediated by activation of the SIRT1, SIRT3, and Nrf2 pathways.