Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Supplementation of guanidinoacetic acid and rumen-protected methionine increased growth performance and meat quality of Tan lambs.

OBJECTIVE: Tan lambs (n = 36, 3 mo old, 19.1±0.53 kg) were used to assess effects of dietary guanidinoacetic acid (GAA) and rumen-protected methionine (RPM) on growth performance, carcass traits, meat quality, and serum parameters. METHODS: Lambs were randomly assigned to three treatment groups, with 6 pens per group and 2 lambs per pen. Dietary treatments were: basal diet alone (I); basal diet supplemented with 0.08% GAA+0.06% RPM (II); and basal diet supplemented with 0.08% GAA+0.08% RPM (III). Diets were provided three times a day for 90 d. Intake per pen was recorded daily and individual lamb body weight (BW) was measured monthly. Carcass traits were measured after slaughter and meat quality at the end of the experiment, blood samples were taken on a subgroup of lambs for analysis of indicators mostly related to protein metabolism. RESULTS: Final BW and average daily gain for the first and second month, and for the entire experiment were greater in Treatment II compared to Treatment I (p<0.05), whereas feed to gain ratio was lower (p<0.05). Treatment II had the optimal dressing percentage and net meat weight proportion, as well as crude protein and intramuscular fat concentrations in muscles. Treatment II improved meat quality, as indicated by the greater water holding capacity, pH after 45 min and 48 h, and lower shear force and cooking loss. Dietary supplementation of GAA and RPM also increased the meat color a* and b* values at 24 h. Finally, Treatment II increased total protein, and serum concentrations of albumin and creatinine, but decreased serum urea nitrogen concentrations, indicating improved protein efficiency. CONCLUSION: In this study, 0.08% GAA+0.06% RPM supplementation improved growth performance and meat quality of Tan lambs.

Clinical Observation of Double Percutaneous Nephrostomy Combined with Ureter Occlusion Stent for Treating Cervical Cancer Complicated with Vesicovaginal Fistula.

Background: To evaluate the efficacy of double percutaneous nephrostomy (PCN) combined with ureter occlusion stent for treating cervical cancer complicated with vesicovaginal fistula (VVF). Materials and Methods: A retrospective analysis was performed for 12 patients with cervical cancer complicated with VVF. Regardless of surgical resection, radiotherapy alone or combined chemoradiotherapy were carried out in all patients. After VVF was diagnosed by gynecological examination, imaging, and cystoscopy, concurrent double PCN and ureter occlusion stent implantation were performed for all patients. Results: All patients successfully received ureter occlusion stent implantation after nephrostomy. The success rate of nephrostomy and stent placement was 100% (12/12). After intervention, urinary fistula immediately disappeared in all patients. One week post-surgery, bilateral hydronephrosis disappeared in 4 patients, and their renal insufficiency and renal function returned to normal. One month after operation, 6 patients with genital eczema or ulcer and 5 patients with urinary tract infection were cured. During follow-up, there were no recurrence in urinary fistula, renal dysfunction, and other complications. Conclusion: Double PCN combined with ureter occlusion stent could effectively treat cervical cancer complicated with VVF hydronephrosis, urinary tract infection, and renal insufficiency and contribute to alleviate all kinds of clinical discomfort.

Combined ultrasound with Fenton treatment for the degradation of carcinogenic polycyclic aromatic hydrocarbons in textile dying sludge.

To develop an effective method to remove the toxic and carcinogenic polycyclic aromatic hydrocarbons (CPAHs) from textile dyeing sludge, five CPAHs were selected to investigate the degradation efficiencies using ultrasound combined with Fenton process (US/Fenton). The results showed that the synergistic effect of the US/Fenton process on the degradation of CPAHs in textile dyeing sludge was significant with the synergy degree of 30.4. During the US/Fenton process, low ultrasonic density showed significant advantage in degrading the CPAHs in textile dyeing sludge. Key reaction parameters on CPAHs degradation were optimized by the central composite design as followed: H2O2 concentration of 152 mmol/L, ultrasonic density of 408 W/L, pH value of 3.7, the molar ratio of H2O2 to Fe2+ of 1.3 and reaction time of 43 min. Under the optimal conditions of the US/Fenton process, the degradation efficiencies of five CPAHs were obtained as 81.23% (benzo[a]pyrene) to 84.98% (benz[a]anthracene), and the benzo[a]pyrene equivalent (BaPeq) concentrations of five CPAHs declined by 81.22-85.19%, which indicated the high potency of US/Fenton process for removing toxic CPAHs from textile dyeing sludge.

Intraductal Radiofrequency Ablation Followed by Locoregional Tumor Treatments for Treating Occluded Biliary Stents in Non-Resectable Malignant Biliary Obstruction: A Single-Institution Experience.

OBJECTIVES: To determine the safety and feasibility of intraductal radiofrequency ablation (RFA) followed by locoregional tumor treatments in patients with non-resectable malignant biliary obstruction and stent re-occlusion. METHODS: Fourteen patients with malignant biliary obstruction and blocked metal stents were studied retrospectively. All had intraductal RFA followed by locoregional tumor treatments and were monitored clinically and radiologically. The practicality, safety, postoperative complications, jaundice remission, stent patency and survival time were analyzed. RESULTS: Combination treatment was successful for all patients. There were no severe complications during RFA or local treatments. All patients had stent patency restored, with a decline in serum bilirubin. Three patients had recurrent jaundice by 195, 237 and 357 days; two patients underwent repeat intraductal RFA; and one required an internal-external biliary drain. The average stent patency time was 234 days (range 187-544 days). With a median follow-up of 384 days (range 187-544 days), six patients were alive, while eight had died. There was no mortality at 30 days. The 3, 6, 12 and 18 month survival rates were 100%, 100%, 64.3% and 42.9%, respectively. CONCLUSION: Intraductal RFA followed by locoregional tumor treatments for occluded metal stents is safe and practically feasible and potential increase stent patency and survival times.

Levels, composition profiles and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in sludge from ten textile dyeing plants.

As components of synthetic dyes, polycyclic aromatic hydrocarbons (PAHs) are present as contaminants in textile dyeing sludge due to the recalcitrance in wastewater treatment process, which may pose a threat to environment in the process of sludge disposal. In order to evaluate PAHs in textile dyeing sludge, comprehensive investigation comprising 10 textile dyeing plants was undertaken. Levels, composition profiles and risk assessment of 16 EPA-priority PAHs were analyzed in this study. The total concentrations of 16 PAHs (∑16 PAHs) varied from 1463 ± 177 ng g(-1) to 16,714 ± 1,507 ng g(-1) with a mean value of 6386 ng g(-1). The composition profiles of PAHs were characterized by 3- and 4-ring PAHs, among which phenanthrene, anthracene and fluoranthene were the most dominant components. The mean benzo[a]pyrene equivalent (BaPeq) concentration of ∑16 PAHs in textile dyeing sludge was 423 ng g(-1), which was 2-3 times higher than concentrations reported for urban soil. According to ecological risk assessment, the levels of PAHs in the textile dyeing sludge may cause a significant risk to soil ecosystem after landfill or dumping on soil.

[Expression and significance of Edg4 and Edg7 in the placentas of patients with hypertensive disorder complicating pregnancy].

OBJECTIVE: To study Edg4 and Edg7 expression in placenta of women with hypertensive disorder complicating pregnancy, and to investigate the relation between the expression of lysophosphatidic acid (LPA) and hypertensive disorder complicating pregnancy. METHODS: Immunohistochemical SP method was used to measure the expressions of Edg4 and Edg7 in placenta of women with normal pregnancy, 20 women with gestational hypertension, 20 with mild preeclampsia, and with severe preeclampsia. RESULTS: (1) LOCATION: immunohistochemical staining for Edg4 and Edg7 protein were located at the membrane and endochylema of cytotrophoblast as well as decidua cells. (2) The positive expression of Edg4 protein and Edg7 protein on membrane and endochylema of cytotrophoblast was 25% and 20% (normal women), 60% and 40% (gestational hypertension), 80% and 65% (mild preeclampsia), and 83.3% and 86.7% (severe preeclampsia). The expression of Edg4 and Edg7 protein in mild preeclampsia and severe preeclampsia was significantly correlated with the degree of differentiation (P < 0.05). The expression of Edg4 and Edg7 protein showed an insignificant difference in normal pregnant women and gestational hypertension (P > 0.05). (3) The positive expression of Edg4 protein and Edg7 protein on membrane and endochylema of decidua was 20% and 25% (normal pregnancy), 55% and 50% (gestational hypertension), 70% and 55% (mild preeclampsia), and 83.3% and 73.3% (severe preeclampsia) respectively. The expression of Edg4 and Edg7 protein in mild preeclampsia and severe preeclampsia showed a significant correlation with the degree of differentiation (P < 0.05). The expression of Edg4 and Edg7 protein showed an insignificant difference in normal pregnancy and gestational hypertension (P > 0.05). CONCLUSIONS: The high expression of Edg4 and Edg7 protein in the placentas of patients with hypertensive disorder complicating pregnancy indicates that LPA combines with Edg4 and Edg7, inducing the occurrence of hypertensive disorder complicating pregnancy.

[Vector construction and silencing effect of Edg4 gene targeted small interfering RNA in ovarian cancer cell line].

OBJECTIVE: To construct the recombinant eukaryotic expression vector pRNAT-U6.1-siEdg4 which carries small interfering RNA (siRNA) of Edg4 and observe the silencing effect of Edg4 gene targeted siRNA in ovarian cancer cell line SKOV3. METHODS: The Edg4 gene-targeted hairpin siRNA sequence was designed according to the Edg4 sequence in Genbank, and the two complementary oligo nucleotide strands were synthesized and annealed and inserted into the pRNAT-U6.1 plasmid to build a recombinant Edg4 siRNA eukaryotic expression vector, which was sequenced and identified to contain the correct Edg4 siRNA sequence. The human ovarian carcinoma cell lines SKOV3 were transfected with the vector using lipofectamine method. The efficiency of transfecting cells was observed with fluorescent microscope and the mRNA expression level of Edg4 gene was detected by real time quantitative PCR. The LPA levels in cell supernatants were detected using a biochemical method. And the apoptosis of SKOV3 cells induced by the vector was evaluated by flow cytometry. RESULTS: The recombinant eukaryotic expression vector was confirmed to contain correct Edg4 siRNA sequence by PCR and sequencing. After transfection large amounts of green fluorescence were seen in plasma and nuclei of SKOV3 cells and the positive cell rates were 64%. The expression level of Edg4 mRNA in transfected SKOV3 cell line was significantly decreased (0.05 +/- 0.01vs 0.29 +/- 0.04, P < 0.05). The decrease in LPA level in the cell supernatants was revealed [(3.0 +/- 1.0) vs (7.5 +/- 2.2)micromol/L, P < 0.05]. The apoptosis rate of transfected SKOV3 was increased obviously (53.38% vs 0.51%, P < 0.05). CONCLUSIONS: We have successfully constructed the recombinant eukaryotic expression vector containing Edg4 gene targeted siRNA (pRNAT-U6.1-siEdg4). The vector could effectively transfect SKOV3 cell line, and obviously suppress the Edg4 mRNA expression and induce cell apoptosis in ovarian cancer cell line SKOV3.