Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9-39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9-39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9-39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.
Mice ; Animals ; Male ; Proto-Oncogene Proteins c-akt/metabolism* ; Antioxidants ; Phosphatidylinositol 3-Kinases/metabolism* ; Semen/metabolism* ; Diabetes Mellitus

Child ; Humans ; Malacoplakia/pathology* ; Intestines/pathology*

Objective: To establish a survival prediction model based on the independent prognostic factors of long-term prognosis after laparoscopic liver resection(LLR) for intrahepatic cholangiocarcinoma(ICC). Methods: The clinical and pathological data of 351 consecutive patients with ICC who received radical LLR in 13 Chinese medical centers from August 2010 to May 2021 were collected retrospectively. There were 190 males and 161 females,aged(M(IQR)) 61(14)years(range:23 to 93 years). The total cohort was randomly divided into a training dataset(264 cases) and a validation dataset(87 cases). The patients were followed up by outpatient service or telephone,and the deadline for follow-up was October 2021. Based on the training dataset,the multivariate Cox proportional hazards regression model was used to screen the independent influencing factors of long-term prognosis to construct a Nomogram model. The Nomogram model's discrimination,calibration,and clinical benefit were evaluated through internal and external validation,and an assessment of the overall value of two groups was made through the use of a receiver operating characteristic(ROC) curve. Results: There was no significant difference in clinical and pathological characteristics and long-term survival results between the training and validation datasets(all P>0.05). The multivariate Cox analysis showed that CA19-9,CA125,conversion to laparotomy during laparoscopic surgery,and lymph node metastasis were independent prognostic factors for ICC patients after LLR(all P<0.05). The survival Nomogram was established based on the independent prognostic factors obtained from the above screening. The ROC curve showed that the area under the curve of 1, 3 and 5-year overall survival rates of patients in the training dataset were 0.794(95%CI:0.721 to 0.867),0.728(95%CI:0.618 to 0.839) and 0.799(95%CI:0.670 to 0.928),and those in the validation dataset were 0.787(95%CI:0.660 to 0.915),0.831(95%CI:0.678 to 0.983) and 0.810(95%CI:0.639 to 0.982). Internal and external validation proved that the model exhibited a certain discrimination,calibration,and clinical applicability. Conclusion: The survival Nomogram model based on the independent influencing factors of long-term prognosis after LLR for ICC(including CA19-9,CA125,conversion to laparotomy during laparoscopic surgery,and lymph node metastasis) exhibites a certain differentiation,calibration,and clinical practicability.
Bile Duct Neoplasms/surgery* ; Bile Ducts, Intrahepatic/pathology* ; CA-19-9 Antigen ; Cholangiocarcinoma/diagnosis* ; Female ; Humans ; Laparoscopy ; Lymphatic Metastasis ; Male ; Nomograms ; Prognosis ; Retrospective Studies

China/epidemiology* ; Coronary Angiography ; Coronary Artery Disease/diagnosis* ; Humans ; Registries ; Risk Assessment ; Risk Factors

Objective:To observe the effect of Wuzi Yanzong Wan made of different processed products on the apoptosis of spermatogenic cells in rats with kidney essence deficiency， and explore its protective effect on spermatogenic cells. Method:SD rats were randomly divided into the blank group， model group， whole raw product group， pharmacopoeia group and salt-processed product group， with 8 rats in each group. The kidney essence deficiency model was replicated by giving tripterygium glycoside tablets （the dose of 20 mg·kg^-1）. The flow cytometry （FCM） was used to analysis the apoptosis of spermatogenic cells in testis， the immunohistochemistry （IHC） and Western blot were used to detect the expression levels of B-cell lymphoma-2 （Bcl-2） and Bcl-2 associated X protein （Bax） in the testis. High performance liquid chromatography （HPLC） was used to compare the contents of eight components （chlorogenic acid， ellagic acid， hyperoside， isoquercitrin， verbascoside， astragalin， kaempferol and schisandrin） in Wuzi Yanzong Wan made of different processed products， the mobile phase was composed of acetonitrile （A）-0.4% phosphoric acid aqueous solution （B） for gradient elution （0-5 min， 5%-15%A； 5-10 min， 15%-17%A； 10-25 min， 17%A； 25-35 min， 17%-26%A； 35-60 min， 26%-56%A）， the detection wavelength was set at 254 nm. Result:Compared with the model group， the total apoptosis rate of spermatogenic cells， protein expression of Bax and Bcl-2 in each administration group were improved. Among them， the pharmacopoeia group and salt-processed product group had significant effects （P<0.01）， and the improvement effect of the pharmacopoeia group and salt-processed product group was significantly better than that of the whole raw product group （P<0.05）. The contents of chlorogenic acid， hyperoside， isoquercitrin and verbascoside in Wuzi Yanzong Wan were increased after the herbal medicines being processed with salt-water. The content of ellagic acid in the salt-processed product group increased， while it decreased in the pharmacopoeia group. The contents of verbascoside， astragalin， kaempferol and schisandrin in samples from the salt-processed product group were greater than those in samples from the pharmacopoeia group. Conclusion:Wuzi Yanzong Wan may reduce the apoptosis of spermatogenic cells in rat testis by inhibiting the expression of Bax and promoting the expression of Bcl-2， and exert its effect of nourishing kidney and enriching essence. The enhanced anti-spermatogenic effect of Wuzi Yanzong Wan after processing may be related to the changes in chemical composition content after processing.

Animal medicines have been called "medicine with affinity to flesh and blood" by doctors of all ages, which always act as an important branch of Chinese medicine. They have various types, extensive sources and long application history, with unique cli-nical effects in anti-coagulation, anti-thrombosis, anti-fatigue, immune regulation, anti-tumor, anti-convulsion and so on. Most animal medicines contain proteins, fatty acids, and trimethylamine oxides, which are prone to decomposition and produce substances such as biological amines, aldehydes, ketones, alcohols, trimethylamine and ammonia with unpleasant odors. The stench produced by the combination of various odors can easily cause side effects such as nausea and vomiting, which would probably affect the drug compliance and clinical efficacy in patients, and block the development of high-quality animal medicines. At present, we have insufficient understanding on sources and formation mechanism of the stench of animal medicines, lacking development of taste-masking technology. Therefore, the universality, formation, vomiting mechanism, evaluation methods, and masking technology of stench of animal medicines were summarized in this paper, so as to deepen the recognition of stench, provide references for the development of animal medicines deodorization technology, enhance patients' compliance with animal medicines, and promote animal drugs to better serve public health in the new era.
Animals ; Fatigue ; Humans ; Neoplasms ; Taste ; Technology

Objective:High performance liquid chromatography (HPLC) fingerprints of liposoluble and water-soluble fractions of Xiaojinwan were established and the similarity of fingerprints was evaluated, so as to explore the quality consistency of Xiaojinwan. Method:Chromatographic separation was carried out on Welch Ultimate AQ-C₁₈ column (4.6 mm×250 mm, 5 μm) with the mobile phase of 0.1% phosphoric acid solution (A)-acetonitrile (B) for gradient elution (liposoluble fraction of 0-5 min, 40%B; 5-10 min, 40%-50%B; 10-20 min, 50%-60%B; 20-30 min, 60%-65%B; 30-40 min, 65%-70%B; 40-50 min, 70%-80%B; 50-60 min, 80%-90%B; 60-65 min, 90%-95%B; 65-75 min, 95%-100%B; 75-80 min, 100%B; water-soluble fraction of 0-20 min, 2%-5%B; 20-30 min, 5%-10%B; 30-37 min, 10%-20%B; 37-45 min, 20%-30%B; 45-50 min, 30%-40%B; 50-58 min, 40%B), the flow rate was 1 mL·min^-1, the column temperature was 30 ℃. The detection wavelengths of the liposoluble and water-soluble fractions were 202, 250 nm, and their injection volumes were 10, 20 μL, respectively. A total of 30 batches of Xiaojinwan from five manufacturers were detected by HPLC, the chromatographic peaks of each part were analyzed by principal component analysis (PCA) and identified. Result:A total of 55 chromatographic peaks were detected in the fingerprints, and the similarity of fingerprint of 30 batches of Xiaojinwan was quite different. The relative standard deviations (RSDs) of fingerprint similarity of liposoluble and water-soluble fractions of Xiaojinwan were 21.5% and 32.8%, respectively. There were significant differences in the quality of samples from different manufacturers and the same manufacturer, and the chemical consistency evaluation results were dominated by liposoluble fraction, and the main reason for the chemical difference of this preparation was the composition of Liquidambaris Resina. Conclusion:The quality consistency of Xiaojinwan is poor. The establishment of two-fraction fingerprint provides a new idea for the overall quality evaluation and control of Xiaojinwan, and can provide a reference for the quality consistency evaluation of traditional pills.