Propofol ameliorates cognitive deficits following splenectomy in aged rats by inhibiting ferroptosis via the SIRT1/Nrf2/GPX4 pathway.

The aim of this study was to investigate the mechanism by which propofol reduces postoperative cognitive dysfunction after splenectomy in aged rats. The rats in the model group and propofol group were subjected to splenectomy, and anesthetized with isoflurane and propofol, respectively. Utilizing the western blotting to assess the expression of sirtuin-1 (SIRT1) in the hippocampus. Molecular docking technology was used to predict the binding ability of propofol and SIRT1. Behavioral tests were performed using the Morris water maze, and the hippocampus was isolated for mechanistic investigations. Molecular docking showed that propofol and SIRT1 had a strong binding affinity. The expression of SIRT1 and its related proteins Nrf2, HO-1, NQO1, and GPX4 in the model rats was decreased compared with the sham group. Moreover, the model group exhibited cognitive decline, such as extended escape latency and decreased number of platform crossings. Pathological analysis showed that the number of apoptotic neurons, the levels of oxidative stress and neuroinflammation, the iron deposition, and the expressions of ACSL4 and TFR1 were increased, while the expressions of SLC7A11 and FTH1 were decreased in the hippocampal CA1 region within the model group. These pathological changes in the propofol group were, however, less than those in the model group. Nevertheless, the SIRT1 inhibitor increased these pathological changes compared with the propofol group. Compared with isoflurane, propofol inhibits ferroptosis in the hippocampus of splenectomized rats by causing less downregulation of the SIRT1/Nrf2/GPX4 pathway, thereby reducing the negative impact on cognitive function.

Outcomes and the effect of PGT-M in women with hormone-related hereditary tumor syndrome.

Purpose: To review the outcome of PGT-M in hormone-related hereditary tumor syndrome and evaluate the effect of ovarian induction on tumor growth in those patients. Methods: Medical records of PGT-M were retrospectively analyzed in patients with hormone-related heritage tumors in our reproductive center. A total of eleven women with hereditary breast and ovarian cancer (HBOC) (including BRCA1/2 mutation carriers), and Lynch syndrome (including MMR gene mutation carriers) were included. Thirteen IVF/PGT-M cycles were performed. Eleven for PGT-M and two for fertility preservation. The ovulation protocol, numbers of oocytes retrieved and two pronuclei (2PN) zygotes, PGT-M results, and clinical outcomes were analyzed. Tumor progression was also estimated by comparing transvaginal ultrasound (TVS), MR, CT, or colonoscopy according to the follow-up requirements of different tumors. Results: Eleven IVF/PGT-M cycles were performed with an antagonist protocol; Two cycles were performed with a mild stimulation protocol. The total dose of gonadotropin (Gn) was 1827 IU per patient (range from 1200 to 2625 IU). The median number of oocytes retrieved was 13 (range from 4 to 30), and the median number of 2PN zygotes was 8 (range from 2 to 16). A total of 32 embryos underwent PGT-M, and 9 (28.1%) embryos were suitable for transfer. Six transfer cycles were performed, and 5 cycles got clinical pregnancy (83%) with five newborns (83%). The follow-up examinations conducted 10-18 months after PGT-M/delivery revealed no new lesions or tumor progression. Conclusion: PGT-M results can provide important information for improving the consultation of hormone-related heritage tumor patients regarding their fertility preservation and reproductive options. Ovarian induction for women with hormone-related hereditary tumor syndrome is not associated with tumor progression.

Efficacy and prognosis of adjuvant treatment of endometrial cancer with medroxyprogesterone acetate COX regression analysis.

BACKGROUND: Endometrial cancer is one of the most commonly diagnosed gynecological cancers worldwide, and early-stage high-risk endometrial cancer has a poor prognosis. Adjuvant treatments after surgery, such as chemotherapy and radiotherapy, have been widely used in clinical practice to improve patient survival. Medroxyprogesterone acetate is a synthetic progestogen that has been reported to have potential anticancer effects in endometrial cancer. However, its efficacy, safety, and long-term prognostic benefits as an adjuvant treatment for endometrial cancer remain controversial. Therefore, this study aimed to observe the efficacy and prognostic impact of adjuvant medroxyprogesterone acetate treatment in patients with early-stage high-risk endometrial cancer and evaluate its safety. AIM: To observe the efficacy and prognosis of adjuvant treatment of endometrial cancer with medroxyprogesterone acetate and to evaluate its safety. METHODS: We collected the clinical data of 200 patients with early-stage high-risk endometrial cancer who were admitted to the Department of Obstetrics and Gynecology of our hospital from January 2018 to December 2022. The control group (100 patients) underwent conventional surgical treatment, and the study group (100 patients) was administered adjuvant medroxyprogesterone acetate tablets on top of the control group. The Kaplan-Meier curve analysis and log-rank test were performed to determine the possible factors influencing the 5-year cumulative survival rate in the patients. The Cox regression analysis was performed to identify the factors influencing the survival prognosis of endometrial cancer. RESULTS: According to the Cox regression analysis, age [hazard ratio (HR) = 4.636, 95% confidence interval (95%CI): 1.411-15.237], pathological type (HR = 6.943, 95%CI: 2.299-20.977), molecular typing (HR = 5.789, 95%CI: 3.305-10.141), and myometrial infiltration (HR = 5.768, 95%CI: 1.898-17.520) were factors influencing the prognosis of patients with early-stage high-risk endometrial cancer. CONCLUSION: Age, pathological type, molecular typing, and myometrial infiltration were all relevant factors affecting the prognosis of early-stage high-risk endometrial cancer. The potential long-term prognostic benefit of adjuvant postoperative radiotherapy in patients with early-stage high-risk endometrial cancer is worthy of clinical consideration.

Cloning, Expression, and Characterization of a Highly Stable Heparinase I from Bacteroides xylanisolvens.

Heparinase I (Hep I), which specifically degrades heparin to oligosaccharide or unsaturated disaccharide, has an important role in the production of low molecular weight heparin (LMWH). However, low productivity and stability of heparinase I hinders its applications. Here, a novel heparinase I (BxHep-I) was cloned from Bacteroides xylanisolvens and overexpressed in soluble form in Escherichia coli. The expression conditions of BxHep-I were optimized for an activity of 7144 U/L. BxHep-I had a specific activity of 57.6 U/mg at the optimal temperature and pH of 30 °C and pH 7.5, with the Km and Vmax of 0.79 mg/mL and 124.58 U/mg, respectively. BxHep-I catalytic activity could be enhanced by Ca2+ and Mg2+, while strongly inhibited by Zn2+ and Co2+. Purified BxHep-I displayed an outstanding thermostability with half-lives of 597 and 158 min at 30 and 37 °C, respectively, which are the highest half-lives ever reported for heparinases I. After storage at 4 °C for one week, BxHep-I retained 73% of its initial activity. Molecular docking revealed that the amino acids Asn25, Gln27, Arg88, Lys116, His156, Arg161, Gln228, Tyr356, Lys358, and Tyr362 form 13 hydrogen bonds with the substrate heparin disaccharides in the substrate binding domain and are mainly involved in the substrate binding of BxHep-I. These results suggest that the BxHep-I with high stability could be a candidate catalyst for the industrial production of LMWH.

Combination of engineering the substrate and Ca2+ binding domains of heparinase I to improve the catalytic activity.

Heparinase I (EC 4.2.2.7), is an enzyme that cleaves heparin, showing great potential for eco-friendly production of low molecular weight heparin (LMWH). However, owing to its poor catalytic activity and thermal stability, the industrial application of heparinase I has been severely hindered. To improve the catalytic activity, we proposed to engineer both the substrate and Ca2+ binding domains of heparinase I. Several heparinases I from different organisms were selected for multiple sequence alignment and molecular docking to screen the key residues in the binding domain. Nine single-point mutations were selected to enhance the catalytic activity of heparinase I. Among them, T250D was the most highly active one, whereas mutations around Ca2+ binding domain yielded two active mutants. Mutant D152S/R244K/T250D with significantly increased catalytic activity was obtained by combined mutation. The catalytic efficiency of the mutant was 118,875.8 min-1·µM-1, which was improved 5.26 times. Molecular modeling revealed that the improved activity and stability of the mutants were probably attributed to the formation of new hydrogen bonds. The highly active mutant had great potential applications in industry and the strategy could be used to improve the performance of other enzymes.

HighlightsImproved catalytic activity of heparinase I by engineering the binding domains of substrate and Ca²⁺.The mutant D152S/R244K/T250D showed the highest catalytic performance.The increased hydrogen bonds attribute to the increased activity.

PKM2 regulates cigarette smoke-induced airway inflammation and epithelial-to-mesenchymal transition via modulating PINK1/Parkin-mediated mitophagy.

Cigarette smoke (CS) mediates inflammation and epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, contributing to airway remodeling in chronic obstructive pulmonary disease (COPD). Cross-talk between metabolic pathways and cell signaling has emerged as an important focus of research in the field of inflammation. Here, we established in vitro and in vivo models of CS-induced COPD to elucidate the role of pyruvate kinase M2 (PKM2), a glycolytic enzyme, in CS-induced airway remodeling. Exposure to CS significantly increased PKM2 expression in lung tissues of C57BL/6 mice and BEAS-2B cells, which positively related to the levels of airway inflammation and EMT. Administering PKM2 inhibitor shikonin attenuated CS-induced airway inflammation and EMT process. Moreover, knockdown of PKM2 by small-interfering RNA (siRNA) decreased the release of TNF-α and IL-8, ROS and reversed the CS extract (CSE)-induced changes of N-cadherin and E-cadherin in BEAS-2B cells. In CSE-treated cells, we also observed enhancement of PINK1/Parkin-mediated mitophagy, which were decreased by PKM2 siRNA. Furthermore, pretreatment with mitophagy inducer CCCP before CSE stimulation led to increased expressions of both nuclear and cytosolic PKM2, accompanied by reduction of TGF-ß-induced factor homeobox 2 (TGIF2), a repressor of TGF-ß1/smad pathway and EMT, while PKM2 knockdown restored the expression of TGIF2. Our results imply that CS induces PKM2 upregulation in airway epithelial cells, acting in synergism with PINK/Parkin-mediated mitophagy, which may initiate and exaggerate airway inflammation and EMT process. Further studies will be required to elucidate more molecular details and other pathways by which PKM2-mitophagy signaling regulates the effector function of airway epithelial.

The impact of a new standard labor protocol on maternal and neonatal outcomes.

PURPOSE: To analyze the clinical outcomes following the implementation of a new standard labor procedure. METHODS: This was a retrospective analysis that included a study group consisting of patients managed based on a new standard labor protocol and a control group comprising patients managed under an old standard labor protocol. The following maternal and perinatal outcomes were compared in the two groups: the indications for a cesarean section and the incidence of cesarean section, postpartum hemorrhage, fetal distress, neonatal asphyxia and pediatric intervention. We also compared the average number of days spent in the hospital, the incidence of medical disputes and hospitalization expenses. RESULTS: The cesarean section rates for the study and control groups were 19.29% (401/2079) and 33.53% (753/2246), respectively (P < 0.05). The main indications for a cesarean section in the study group were arrest of the active phase of labor, fetal distress and intrapartum fever; the percentages of each indication were significantly different from those of the control group (P < 0.001). The rates of postpartum hemorrhage in the study group and control group were 7.74% (130/1678) and 8.1% (121/1493), respectively (P = 0.710). The incidence rates of severe perineal lacerations were 0.48% (8/1678) for the study group and 0.2% (3/1493) for the control group (P = 0.187). The rates of forceps use were 4.29% (72/1678) in the study group and 2.41% (36/1493) in the control group (P = 0.004). The incidence rate of fetal distress in the study group was 6.24% (169/2709) and 4.67% (105/2246) (P = 0.006) in the control group. No significant difference was observed in the incidence of neonatal asphyxia and pediatric interventions between the two groups (0.74% (20/2709) vs. 8.12% (220/2709) and 17 (0.76%) vs. 161 (7.17%), respectively). The average length of hospital stay was 4.74 ± 1.15 and 2.13 ± 1.23 days (P < 0.01). The incidence of medical disputes was significantly different between the two groups: 1.44% (30/2079) in the study group and 0.53% (12/2246) in the control group (P < 0.01). The hospitalization expenses were 5401.29 ± 296.33 yuan in the study group and 5253.53 ± 3655.79 yuan in the control group (P = 0.06). CONCLUSIONS: The implementation of the new labor protocol reduced the cesarean section rate without negatively impacting maternal and neonatal outcomes. In practice, bed turnover and the hospital utilization rate should be better controlled, patient-doctor communication should be strengthened and the quality of obstetrical service should be improved.

[Serum relaxin in cervical incompetence patients].

OBJECTIVE: To analyze the serum relaxin and clinical character of cervical incompetence patients and normal pregnant women. METHODS: A total of 33 cervical incompetence patients (research group) and 33 normal pregnancy women with the same gestational age (control group) were recruited into the study. The serum relaxin level was detected with enzyme labeled immunosorbent assay (ELSIA) in the two groups, and the cervical length of early pregnancy period (cm), body mass index (BMI, kg/m2), frequency of polycystic ovary syndrome (%), gestational diabetes mellitus/diabetes mellitus (%) and outcomes in the two groups were analyzed with independent samples t test and chi-square test. RESULTS: All the cervical incompetence patients were recruited between Feb. 2008 and Sept. 2012, with the average termination gestational age of 30±6 weeks. Among them, 15 (45.45%) was abortion, 12 (36.36%) was preterm birth, 6 (16.18%) was term birth. The average BMI before pregnancy was 27±4 kg/m2, and the average serum relaxin was 2,748±82 mg/L; for the 33 patients in the control group, the average termination gestational age was 38±3 weeks, and 1 (3.03%) of them was abortion, 4 (12.12%) was preterm birth, 28 (84.85%) was term birth. The average BMI before pregnancy was 23±3 kg/m2, the average serum relaxin was 2,602±126 mg/L. Compared with the control group, the research group had more patients who complicated with polycystic ovary syndrome and gestational diabetes mellitus/diabetes mellitus (P<0.01, <0.05) and worse pregnancy outcomes (P<0.01); the average BMI before pregnancy and the average serum relaxin level of the research group were significantly higher than control group (P<0.01, P<0.01). Analysis through the unconditional logistic regression showed that BMI and serum relaxin were both independent risk factors of cervical incompetence. CONCLUSIONS: The high level of serum relaxin is an independent risk factor of cervical incompetence; women with polycystic ovary syndrome may more likely to have cervical incompetence and serum relaxin may have the predictive value for cervical incompetence.