Ursodeoxycholic acid ameliorates erectile dysfunction and corporal fibrosis in diabetic rats by inhibiting the TGF-ß1/Smad2 pathway.

Corporal tissue fibrosis is critical in diabetes-associated erectile dysfunction. Transforming growth factor-ß1/Small mothers against decapentaplegic-2 (TGF-ß1/Smad2) contributes to the induction of fibrosis in corporal tissue. Smad7 is accepted as a general negative regulator of Smad signaling, although its role in corporal fibrosis is unknown. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid used for biliary and liver related disorders and has antifibrotic effects in the liver. This study investigated the effects of UDCA on diabetic erectile dysfunction. Forty-eight male Spraque Dawley rats were divided into six groups: nondiabetic (n = 6), nondiabetic+20 mg/kg UDCA (n = 6), nondiabetic+80 mg/kg UDCA (n = 6), diabetic (n = 10), diabetic+20 mg/kg UDCA (n = 10), diabetic+80 mg/kg UDCA (n = 10). Diabetes was induced by intraperitoneal injection of 60 mg/kg Streptozocin. UDCA (20 and 80 mg/kg/day) or saline was subsequently administered via oral gavage for 56 days. Erectile function was evaluated as measurement of maximum intracavernosal pressure (m-ICP)/mean arterial pressure (MAP) and total ICP/MAP. Corporal tissues were evaluated by Western blotting and Masson's trichrome staining. Electrical stimulation-induced m-ICP/MAP responses were higher in UDCA-treated diabetic rats compared to untreated diabetic rats, respectively (20 mg/kg; 4 V: 0.77 ± 0.11 vs 0.45 ± 0.09, p = 0.0001 and 80 mg/kg; 4 V: 0.78 ± 0.11 vs 0.45 ± 0.09, p = 0.0001) UDCA prevented the increase in phospho-Smad2 and fibronectin protein expressions in diabetic corporal tissue both at 20 mg/kg (p = 0.0002, p = 0.002 respectively) and 80 mg/kg doses (p < 0.0001 for both). Smad7 protein expressions were significantly increased in the UDCA-treated diabetic groups compared to the untreated diabetic group (20 mg/kg: p = 0.0079; 80 mg/kg: p = 0.004). Furthermore, UDCA significantly prevented diabetes-induced increase in collagen (20 mg/kg: p = 0.0172; 80 mg/kg: p = 0.0003) and smooth muscle loss (20 mg/kg: p = 0.044; 80 mg/kg: p = 0.039). In conclusion, UDCA has a potential protective effect on erectile function in diabetic rats by altering fibrotic pathways via inhibition of TGF-ß1/Smad2 and activation of Smad7.

Uroprotective effect of pantoprazole against cyclophosphamide-induced cystitis in mice.

PURPOSE: The aim of the present study was to evaluate the potential uroprotective effect of pantoprazole (PPZ) in a mouse model of cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) due to its antioxidant and anti-inflammatory properties. METHODS: Balb/c mice received a single intraperitoneal (i.p.) injection of CP (300 mg/kg) to induce HC. PPZ (20, 50, and 100 mg/kg/day;i.p.) was administered for 3 consecutive days before the induction of HC. Mesna (30 mg/kg;i.p.) was administered 20 min before, 4 and 8 h after CP injection to compare the protective effects of PPZ. After 24 h of HC induction, the bladders were removed for functional studies, biochemical analyses, and histopathological examination. RESULTS: In vitro contractility studies demonstrated that CP-induced HC decreased the responsiveness of detrusor muscle strips to acetylcholine (ACh), which was reversed by PPZ pretreatment at all doses tested. However, mesna treatment was not able to improve responsiveness to ACh. Biochemical analyses showed that CP caused significant elevation of malondialdehyde (MDA), reduction of total glutathione (GSH), and increment of proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) level, which were measured in bladder homogenates. PPZ pretreatment at three doses found to be effective in reducing the CP-induced elevation of MDA and TNF-α levels. The highest dose of PPZ (100 mg/kg) caused a significant increase in GSH level. CP induced severe HC with marked bladder edema and histological disturbances which were partially abolished by PPZ pretreatment. CONCLUSIONS: Our results indicate that PPZ pretreatment could attenuate CP-induced HC by interfering with oxidative stress and modulating proinflammatory cytokines.

Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.

AIMS: TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. METHODS: Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS: In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS: TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

Does an alkaline environment prevent the development of bisphosphonate-related osteonecrosis of the jaw? An experimental study in rats.

OBJECTIVE: To investigate the preventive effect of locally applied sodium bicarbonate on bisphosphonate-related osteonecrosis of the jaw (BRONJ). STUDY DESIGN: Thirty-six Sprague-Dawley rats were divided into 4 groups. Animals in group I received 0.1 mg/kg sterile saline 3 times per week for 8 weeks. Groups II, III, and IV received intraperitoneal zoledronate injection in the same manner with the same frequency and duration. The right first molar tooth was extracted in groups III and IV. One mL 8.4% sodium bicarbonate (SB) was applied to the extraction socket at the time of extraction in group IV. The effect of locally applied SB as an alkalizing agent was evaluated by histomorphometric analysis. RESULTS: BRONJ was observed in none of the animals in the control groups, 67% of the animals in the tooth extraction group, and none of the animals in the local SB application group (P < .01). CONCLUSIONS: Administration of locally applied SB had positive effects on the prevention of BRONJ in animals, but further studies are required to verify the effectiveness of this form of treatment before its use in humans.

Jaw bone changes in rats after treatment with zoledronate and pamidronate.

OBJECTIVE: The aim of this study was to histopathologically evaluate the effects of pamidronate and zoledronate on the mandible in an animal model. STUDY DESIGN: Sixty female Sprague-Dawley rats were used in this study. Animals were divided into 6 groups (10 per group): control-1 (C1), injected with saline solution for 6 weeks; zoledronate-1 (ZA1), injected with zoledronate for 6 weeks; pamidronate-1 (PA1), injected with pamidronate for 6 weeks; control-2 (C2), injected with saline solution for 8 weeks; zoledronate-2 (ZA2), injected with zoledronate for 8 weeks; and pamidronate-2 (PA2), injected with pamidronate for 8 weeks. No dental procedures were performed on the animals. Rats were killed 2 days after the end of drug therapy, and the posterior and anterior mandible and femur of each rat were evaluated histopathologically. RESULTS: Histological examination revealed inflammation limited to the posterior mandible of the ZA2 and PA2 groups; the anterior mandible and femur were not affected. Soft tissue necrosis was evident in one rat in the ZA2 group. CONCLUSION: Specific, bisphosphonate-associated inflammatory bony and soft tissue changes were observed in the mandible, suggesting that these drugs may set the stage for altered healing associated with the development of bisphosphonate-related osteonecrosis of the jaw.

The effects of carbon dioxide pneumoperitoneum on ovarian blood flow, oxidative stress markers, and morphology during laparoscopy: a rabbit model.

OBJECTIVE: To determine the effect of CO(2) pneumoperitoneum on the ovaries in an experimental pneumoperitoneum model. DESIGN: Experimental controlled study. SETTING: University hospital. PATIENT(S): Sixteen adult female conventional rabbits. INTERVENTION(S): Group I (8 rabbits) was not subjected to intra-abdominal pressure (IAP). In group II (8 rabbits), IAP insufflation was performed at 12 mm Hg. In total, 60 minutes of pneumoperitoneum and 10 minutes of reperfusion were maintained. Ovarian blood flow (OBF) was studied using laser Doppler flowmetry. The time points of OBF measurements were as follows: OBFbaseline, 10 minutes before insufflation; OBF30min, 30 minutes after pneumoperitoneum; OBF60min, 60 minutes after pneumoperitoneum; and OBFreperfusion, 10 minutes after pneumoperitoneum desufflation. Mean OBF changes during CO(2) pneumoperitoneum (OBFmean) were also assessed. MAIN OUTCOME MEASURE(S): Blood perfusion units, tissue malondialdehyde values, and histopathologic damage scores. RESULT(S): In group II, mean OBF values were significantly lower than in group I, especially for OBF30min, OBF60min, OBFreperfusion, and OBFmean. The mean tissue malondialdehyde value for group II was significantly higher than in the control group (104.48 +/- 20.07 nmol/g vs. 64.12 +/- 8.77 nmol/g, respectively). Compared with group I, in group II histologic specimens of the ovaries had higher scores for follicular cell degeneration, vascular congestion, hemorrhage, and inflammatory cell infiltration. CONCLUSION(S): Pneumoperitoneum, even at normal IAP levels, leads to significant oxidative stress-induced biochemical and histologic damage to the ovaries.

Effects of papaverine and carbon dioxide alone or in combination on the blood flow of internal thoracic artery.

OBJECTIVE: The internal thoracic artery is frequently used as an arterial graft for coronary bypass. Spasms of internal thoracic artery may contribute to early myocardial ischemia. To prevent vasospasm and increase the blood flow, some vasodilatory agents (such as carbon dioxide or papaverine) are used. The aim of the study was to evaluate the combined effects of carbon dioxide and papaverine versus either alone on the blood flow of the internal thoracic artery. METHODS: One hundred patients undergoing coronary artery bypass grafting (28 women and 72 men) with similar characteristics were randomly divided into four groups. We used the classic technique without any vasodilatory management before surgery in group 1, papaverine injection into the endothoracic fascia in group 2, and carbodissection technique in groups 3 and 4. Initial free flows of the internal thoracic arteries were measured after cutting of the vessel. After the first measurement, the ITA pedicles were washed with papaverine solution and wrapped with gauze in the first and fourth groups. Blood flow measurements were repeated 15 minutes later in all groups. RESULTS: When vasodilatory management was applied during excision, the blood flows were significantly increased relative to group 1. The mean blood flows reached a significantly higher level in groups 1, 2, 3, and 4 at the second measurements. In groups 2 and 3, the increase at the first measurements compared to the first group's level was continuously high, but no additional increase was observed between the first and second measurements. In groups 1 and 4, regardless of whether a previous vasodilatory management was present, the increases measured at repeated measurements were significant versus each group's first measurements (P < .05). CONCLUSIONS: Vasodilatory management, such as injection of papaverine into endothoracic fascia or carbon dioxide insufflation applied during excision, increased the free blood flows of internal thoracic artery pedicles. Exogenously applied papaverine produces an additional and continuous vasodilatation regardless of whether a vasodilatory intervention was previously applied.