Integration of network pharmacology and proteomics analysis to identify key target pathways of Ginsenoside Re for myocardial ischemia.

BACKGROUND: Clinically, various diseases cause myocardial ischemia (MI), which further induces severe cardiac injury and leads to high mortality in patients. Ginsenoside Re, one of the major ginsenosides in ginseng, can regulate the level of oxidative stress in the injured myocardium. Thus, it may attenuate MI injury, but the related mechanism has not been comprehensively studied. PURPOSE: This study aimed to investigate the anti-MI effect and comprehensively mechanisms of Ginsenoside Re. STUDY DESIGN/METHODS: Oxygen-glucose deprivation (OGD), oxidative-induced cardiomyocyte injury, and isoproterenol-induced MI mice were used to explore their protective effect of Ginsenoside Re. An integrated approach of network pharmacology, molecular docking, and tandem mass tag proteomics was applied to determine the corresponding common potential targets of Ginsenoside Re against MI, such as target proteins and related pathways. The major anti-MI target proteins and related pathways were validated by immunofluorescence (IF) assay and Western blotting (WB). RESULTS: Ginsenoside Re (1.32-168.93 µM) had low toxicity to normal cardiomyocytes, and increased the survival of oxidative stress-injured (OGD-induced injury or H2O2-induced injury) cardiomyocytes in this concentration range. It regulated the reactive oxygen species (ROS) level in OGD-injured cardiomyocytes; stabilized the nuclear morphology, mitochondrial membrane potential (MMP), and mitochondrial function; and reduced apoptosis. Meanwhile, Ginsenoside Re (5-20 mg/kg) alleviated cardiac injury in MI mice and maintained cardiac function. Through network pharmacology and proteomics, the relevant mechanisms revealed several key pathways of Ginsenoside Re anti-MI, including inhibition of MAPK pathway protein phosphorylation, downregulation of phosphorylated PDPK1, AKT, and STAT3, and upregulation of TGF-ß3, ferroptosis pathway (upregulation of GPX4 and downregulation of phosphorylation level of MDM2) and AMPK pathway (regulating the synthesis of cholesterol in the myocardium by downregulation of HMGCR). The key proteins of these target pathways were validated by IF and/or WB. CONCLUSION: Ginsenoside Re may target MAPK, AKT, ferroptosis pathways and AMPK pathway to prevent and/or treat MI injury and protect cardiomyocytes from oxidative damage.

A comprehensive study of pre-eclampsia in IVF and natural conceptions: clinical phenotypes, perinatal outcomes and neonatal echocardiography.

RESEARCH QUESTION: What differences exist in the phenotypes of pre-eclampsia, perinatal outcomes and neonatal echocardiography between pregnancies conceived naturally and through IVF? DESIGN: Six hundred and ten women diagnosed with pre-eclampsia between January 2002 and December 2022 were included in this study. This research was conducted within the IVF and Maternal-Fetal Medicine Department of Kaohsiung Chang Gung Memorial Hospital, Taiwan. Participants were divided into two groups: those who achieved pregnancy through IVF, and those who conceived naturally. The phenotypes of pre-eclampsia and perinatal outcomes were assessed using a propensity-matched sample (n = 218), along with neonatal echocardiography. RESULTS: After conducting propensity score matching, the natural conception group had a higher prevalence of early-onset pre-eclampsia (53.9% versus 37.7%, P = 0.04) and exhibited more severe features of pre-eclampsia (89.1% versus 69.8%, P = 0.01) compared with the IVF group. Regarding perinatal outcomes, neonates in the IVF group had higher placental weights compared with the natural conception group (580 versus 480 g, P = 0.031). The prevalence of abnormal findings on neonatal echocardiography was similar between the groups. Multivariate analysis showed that greater gestational age at delivery reduced the likelihood of abnormal findings on echocardiography [adjusted risk ratio (aRR) 0.950, P = 0.001], while pregestational diabetes mellitus increased the likelihood of abnormal findings (aRR 1.451, P = 0.044). Septal defects were the most common type of defect, occurring in 16.1% of infants. CONCLUSION: The impact of IVF conception on the severity of pre-eclampsia is not as expected. Neonatal echocardiography revealed a higher prevalence of abnormalities in offspring of women with pre-eclampsia compared with the general population. However, these issues were not linked to the method of conception, suggesting the existence of undisclosed factors that could influence the clinical features and perinatal outcomes of pre-eclampsia.

A singleton pregnancy with placental chorioangioma and hydrops fetalis complicated with mirror syndrome and ritodrine-induced side effects: a case report.

BACKGROUND: Ritodrine hydrochloride is a widely used beta-adrenergic agonist used to stop preterm labor in Taiwan. Many side effects causing maternal morbidity and mortality have been reported. We report a case complicated with ritodrine-induced side effects and mirror syndrome that was associated with placental chorioangioma. CASE PRESENTATION: A 36-year-old singleton pregnant woman at 25 6/7 weeks of gestation, with an undiagnosed placental chorioangioma, underwent tocolysis due to preterm uterine contractions. Her clinical condition deteriorated, attributed to mirror syndrome and adverse events induced by ritodrine. An emergency cesarean section was performed at 27 1/7 weeks of gestation, delivering an infant with generalized subcutaneous edema. A placental tumor measuring 8.5 cm was discovered during the operation, and pathology confirmed chorioangioma. Gradual improvement in her symptoms and laboratory data was observed during the postpartum period. Identifying mirror syndrome and ritodrine-induced side effects poses challenges. Therefore, this case is educational and warrants discussion. CONCLUSION: Our case demonstrates mirror syndrome induced by chorioangioma, which is rare, and ritodrine-induced side effects. The cessation of intravenous ritodrine and delivery are the best methods to treat maternal critical status due to fluid overload.

Umbilical Cord Wraps around a Newborn's Legs like Ankle Shackles.

A 36-year-old woman, gravida 3, para 1 (previous cesarean section), with one medical abortion, and no history of systemic diseases presented an unremarkable medical history during prenatal visits. The final prenatal ultrasound at 38 weeks of gestation showed a vertex presentation, a weight of 2600 g, a normal amniotic fluid level, and the placenta located on the posterior wall of the uterus. Fetal cardiotocography conducted before delivery reported a reactive heart rate without decelerations. The Doppler wave analysis of the fetal umbilical artery was normal (the ratio of peak-systolic flow velocity to the end-diastolic flow velocity was 2.5) without the absence or reversal of end-diastolic velocity. The total score of the fetal biophysical profile by ultrasound was 8. The night before the scheduled cesarean section, she experienced heightened anxiety and was unable to sleep, noting "crazy" fetal movements throughout the night. During the cesarean section, it was discovered that the umbilical cord was wrapped around the newborn's legs, resembling ankle shackles. The fetal weight was 2740 g, and Apgar scores were 9 at the first minute and 10 at the fifth minute. The motility of the neonatal legs was normal without cyanosis or neurological adverse outcomes.

Synthesis and Application of a Near-Infrared Light-Emitting Fluorescent Probe for Specific Imaging of Cancer Cells with High Sensitivity and Selectivity.

Background: The preclinical diagnosis of tumors is of great significance to cancer treatment. Near-infrared fluorescence imaging technology is promising for the in-situ detection of tumors with high sensitivity. Methods: Here, a fluorescent probe was synthesized on the basis of Au nanoclusters with near-infrared light emission and applied to fluorescent cancer cell labeling. Near-infrared methionine-N-Hydroxy succinimide Au nanoclusters (Met-NHs-AuNCs) were prepared successfully by one-pot synthesis using Au nanoclusters, methionine, and N-Hydroxy succinimide as frameworks, reductants, and stabilizers, respectively. The specific fluorescence imaging of tumor cells or tissues by fluorescent probe was studied on the basis of SYBYL Surflex-DOCK simulation model of LAT1 active site of overexpressed receptor on cancer cell surface. The results showed that Met-NHs-AuNCs interacted with the surface of LAT1, and C_Score scored the conformation of the probe and LAT1 as five. Results: Characterization and in vitro experiments were conducted to explore the Met-NHs-AuNCs targeted uptake of cancer cells. The prepared near-infrared fluorescent probe (Met-NHs-AuNCs) can specifically recognize the overexpression of L-type amino acid transporter 1 (LAT1) in cancer cells so that it can show red fluorescence in cancer cells. Meanwhile, normal cells (H9c2) have no fluorescence. Conclusion: The fluorescent probe demonstrates the power of targeting and imaging cancer cells.

Assessment of the clinical benefits of prenatal screening for toxoplasmosis in southern Taiwan.

OBJECTIVE: The present study aimed to investigate the seroprevalence and risk factors for toxoplasmosis among pregnant women in southern Taiwan and to determine the clinical benefits of screening for the same. MATERIALS AND METHODS: The current study included 458 pregnant women who received prenatal care from the first trimester at the Kaohsiung and Chiayi Chang Gung Memorial Hospitals during the time period from 2014 to 2015. Serological tests performed to detect the presence of Toxoplasma IgG and IgM antibodies. Amniocentesis was scheduled and real-time polymerase chain reaction (PCR) was employed to detect Toxoplasma DNA. Moreover, the maternal characteristics and risk factors, perinatal outcomes related to the seropositivity for Toxoplasma infection were analyzed. RESULTS: Among the pregnant patients included in the current study, 39/458 (8.5%) were IgG+ and 2/458 (0.6%) were IgM+. The present study analyzed the maternal characteristics and risk factors, perinatal outcome pertaining to the IgG seropositive group by means of the multiple logistic regression analysis revealed a female predominance (10.8%), compared to the males (6.4%), (adjusted OR = 0.48 (95%, 0.24-0.98), P = 0.043∗). The number cases with gestational age above 37 weeks at the time of delivery was significantly lower, compared to the cases below 37 weeks (adjusted OR = 0.32 (0.12-0.94), P = 0.038∗). Among one case with low avidity cannot exclude recent infection, the amniocentesis did not show any evidence of vertical transmission. CONCLUSION: The scenario may not warrant general screening and the results will not influence the clinical decisions. Although the present study failed to identify the maternal risk factors related to Toxoplasma infection, the results imply that health education is essential, owing to the slightly higher rate of preterm delivery in the IgG seropositive group.

HSPA4 Is a Biomarker of Placenta Accreta and Enhances the Angiogenesis Ability of Vessel Endothelial Cells.

Placenta accreta spectrum (PAS) accounts for 7% of maternal mortality and is associated with intraoperative and postoperative morbidity caused by massive blood loss, infection, and adjacent organ damage. The aims of this study were to identify the protein biomarkers of PAS and to further explore their pathogenetic roles in PAS. For this purpose, we collected five placentas from pregnant subjects with PAS complications and another five placentas from normal pregnancy (NP) cases. Then, we enriched protein samples by specifically isolating the trophoblast villous, deeply invading into the uterine muscle layer in the PAS patients. Next, fluorescence-based two-dimensional difference gel electrophoresis (2D-DIGE) and MALDI-TOF/MS were used to identify the proteins differentially abundant between PAS and NP placenta tissues. As a result, nineteen spots were determined as differentially abundant proteins, ten and nine of which were more abundant in PAS and NP placenta tissues, respectively. Then, specific validation with western blot assay and immunohisto/cytochemistry (IHC) assay confirmed that heat shock 70 kDa protein 4 (HSPA4) and chorionic somatomammotropin hormone (CSH) were PAS protein biomarkers. Further tube formation assays demonstrated that HSPA4 promoted the in vitro angiogenesis ability of vessel endothelial cells, which is consistent with the in vivo scenario of PAS complications. In this study, we not only identified PAS protein biomarkers but also connected the promoted angiogenesis with placenta invasion, investigating the pathogenetic mechanism of PAS.

A comprehensive system review of pharmacological effects and relative mechanisms of Ginsenoside Re: Recent advances and future perspectives.

BACKGROUND: Ginsenoside Re (Re) belongs to protopanaxatriol saponins and exists in Panax ginseng, Panax quinquefolium, Panax notoginseng, and other plants in the Araliaceae family. Re has recently become a research focus owing to its pharmacological activities and benefits to human bodies. PURPOSE: To summarize recent findings regarding the pharmacological effects and mechanisms of Re and highlight and predict the potential therapeutic effects and systematic mechanism of Re. METHODS: Recent studies (2011-2021) on the pharmacological effects and mechanisms of Re were retrieved from Web of Science, PubMed, Google Scholar, Scopus, and Embase up to December 2021 using relevant keywords. Network pharmacology and bioinformatics analysis were used to predict the therapeutic effects and mechanisms of Re against potential diseases. RESULTS: Re presented a wide range of therapeutic and biological activities, including neuroprotective, cardiovascular, antidepressant, antitumorigenic, and others effects. The related pharmacological mechanisms of Re include the regulation of cholinergic and antioxidant systems in the brain; the induction of tumor cell apoptosis; the inhibition of tau protein hyperphosphorylation and oxidative stress; the activation of p38MAPK, ERK1/2, and JNK signals; the improvement of lipid metabolism; and the reduction of endothelial cell dysfunction. CONCLUSION: This paper summarizes comprehensively the current research progress of Re and provides new research insights into the therapeutic effects and mechanisms of Re against potential diseases.

Seroprevalence and risk factors for cytomegalovirus infection among pregnant women in southern Taiwan, 2014-2015.

OBJECTIVE: To investigate the seroprevalence of and risk factors for cytomegalovirus (CMV) infection among pregnant women in southern Taiwan. MATERIALS AND METHODS: From 2014 to 2015, pregnant women undergoing their first prenatal care visit participated in this study at Kaohsiung Chang Gung Memorial Hospital and Chiayi Chang Gung Memorial Hospital. A serologic test was performed for anti-CMV IgG/IgM. Transabdominal amniocentesis was scheduled for those with seropositive anti-CMV IgM. Extraction of CMV DNA was performed via real-time polymerase chain reaction (PCR). Maternal sociodemographic characteristics and risk factors for CMV seropositivity were analyzed. RESULTS: A total of 539 pregnant women undergoing their first prenatal visit were included. Eighty-three pregnant women were excluded for delivering at other hospitals. The overall seroprevalence rate of anti-CMV IgG in the remaining 456 cases was 87.28%. The seroprevalence rates of anti-CMV IgG(+)/IgM(+) and IgG(+)/IgM(-) were 1.32% and 85.96%, respectively. According to the anti-CMV IgG avidity test, only 3 pregnant women (0.65%) had primary CMV infection. Two of them underwent amniocentesis, and the results for both were negative for CMV DNA. According to the logistic regression analysis, the seropositivity of anti-CMV IgG was significantly associated with maternal age ≥30 (adjusted OR = 2.08, 95% CI: 1.10-3.94, p = 0.025) and the seropositivity of anti-CMV IgM was significantly associated with gestational weeks ≥37 when delivery (adjusted OR = 7.81, 95% CI: 1.23-49.58, p = 0.029). CONCLUSION: In southern Taiwan, among pregnant women, the CMV seroprevalence was high (87.28%), but the rate of primary CMV infection was very low (0.65%). Pregnant women aged more than 30 years had a significant risk of CMV seropositivity.

Synthesis, biological evaluation, pharmacokinetic studies and molecular docking of 4'''-acetyl-delicaflavone as antitumor agents.

Structural modification of natural products is the effective option to improve their pharmacological effects and drug properties. DLF is a lead compound of antitumor drug, which is a broad-spectrum, low toxic and high-efficient component isolated from Selaginella doederleinii Hieron by our research group. Here, we report the structural modification method of this component, and find that the acetylated product of C4'''- OH (C4'''-acetyl-delicaflavone, 4'''ADLF) has better inhibitory effect on the selected cancer cell lines, including, lung, liver, colon and cervical cancer cell lines. Since the increased water solubility of 4'''ADLF may lead to higher absorption rate and activity, we evaluate the pharmacodynamics in vitro and in vivo, and the pharmacokinetic of 4'''ADLF. It shows that 4'''ADLF inhibit the proliferation and induce cycle arrest in tumor cells, and had better anticancer activity and bioavailability than DLF.

Whether to transfer mosaic embryos: a cytogenetic view of true mosaicism by amniocentesis.

RESEARCH QUESTION: Preimplantation genetic testing for aneuploidies has increasingly been employed for embryo selection, resulting in a recent surge in mosaic embryos. According to the cytogenetic results, which types of mosaic embryo survive early pregnancy, progress to the second trimester and finally result in a live birth? DESIGN: This study evaluated 30,587 pregnant women undergoing amniocentesis from January 2004 to March 2020 at the cytogenic centre of Kaohsiung Chang Gung Memorial Hospital. Samples from amniocentesis were cultured using the in-situ method. The types and distribution of level III chromosomal mosaicism (two or more cells with the same abnormality in two or more colonies and both culture dishes, clinically referred to as 'true mosaicism') were retrospectively reviewed. RESULTS: Among the 30,587 women, 78 cases (0.26%) of level III chromosomal mosaicism were identified. The types of chromosomal mosaicism were classified as sex chromosome mosaicism (SCM), autosomal chromosome mosaicism (ACM) and marker chromosome mosaicism (MCM), with SCM, ACM and MCM accounting for 58.97%, 32.05% and 8.97% of cases, respectively. The most common mosaic cell lines were monosomy X and trisomy 21. The most common mosaic cell line progressing to live birth was monosomy X. CONCLUSIONS: Mosaic monosomy X and trisomy 21 are the most common cell lines of true mosaicism determined by amniocentesis. Monosomy X mosaicism is the most common cell line in live births. For women considering the transfer of these types of mosaic embryo in a circumstance where euploid embryos are unavailable, clinicians should provide careful prenatal counselling, detailed ultrasonography and amniocentesis.

Recombinant production of two xylanase-somatostatin fusion proteins retaining somatostatin immunogenicity and xylanase activity in Pichia pastoris.

Somatostatin (SS) is one of the peptide hormones that regulate the endocrine system in animals. When SS is used to immunize animals, the correspondingly generated anti-SS antibody neutralizes the SS and, therefore, alleviates its growth inhibiting effects. This is of great value to the livestock industry; however, previously developed methods fail to obtain enough recombinant SS in an economical way. Herein, we describe the employment of a commonly used feed enzyme, i.e., xylanase, as a carrier protein for recombinant expression of SS in large quantity. The SS gene was fused to one of the two xylanase genes (XynCDBFV and BsXynC) and recombinantly expressed in Pichia pastoris. The purified xylanase-SS fusion proteins displayed excellent antigenicity and immunogenicity. In addition, they retained the enzymatic activities and thermostability of the xylanases, indicating that they can catalyze hydrolysis of xylan in plant cell wall of the animal feeds and stand the high temperature in feed pelleting. Thus, the xylanase-SS fusion proteins serve as an excellent candidate chimeric bifunctional vaccine-feed enzyme protein retaining both SS immunogenicity and xylanase activity. KEY POINTS: • Somatostatin is expressed in P. pastoris as fusion proteins with two xylanases. • The chimeric proteins retain both immunogenicity and xylanase activity. • The xylanase-SS proteins may serve as bifunctional proteins in livestock industry.

Right neck venous thrombosis following ovarian hyperstimulation syndrome in a patient with protein S deficiency: A case report and review of literature.

OBJECTIVE: The risk of venous thromboembolism in pregnancies increased in ovarian hyperstimulation syndrome (OHSS) after assisted reproductive technologies (ART). We present a rare case with protein S deficiency receiving ART treatment with OHSS, following right neck venous thromboembolism. CASE REPORT: A 34-year-old women with primary infertility underwent IVF treatment and presented with OHSS. However, thromboembolism in the right jugular and subclavian veins was diagnosed at eight weeks of gestation. She was continuously treated with low molecular weight heparin (LMWH) since eight weeks of gestation and the diagnosis of protein S deficiency was made. Due to placenta previa with massive bleeding, she gave live birth to two healthy babies via cesarean section at 34 weeks of gestation. CONCLUSION: Thromboembolism is one of life-threatening complications among women with OHSS. Although inherited thrombophilia is rare diseases, thrombophilia workup may be taken into consideration for women with thrombotic events.

Lethal acute aortic dissection complicated with ischemic bowels in the third trimester of pregnancy: A case report.

OBJECTIVE: Aortic dissection is a rare but lethal disease. We demonstrate a rare case of acute complicated Stanford type A aortic dissection in the third trimester. CASE REPORT: A 41-year-old primiparous patient with chronic hypertension was brought to our emergency department at 34 weeks of gestation. She presented with acute tearing chest pain radiating to her back. Computed tomography revealed a Stanford type A aortic dissection. Primary cesarean section followed by open cardiovascular surgery was performed. However, ischemic bowels and bowel perforation occurred on the 9th and 11th postoperative days, respectively, and the patient died of septic shock on the 12th postoperative day. CONCLUSION: Aortic dissection must be taken into consideration for pregnant women with chronic hypertension who present with acute tearing chest pain and pulseless unilateral extremities. Bowel ischemia may occur in patients with complicated Stanford type A aortic dissection.

Planned conservative management of placenta increta and percreta with prophylactic transcatheter arterial embolization and leaving placenta in situ for women who desire fertility preservation.

INTRODUCTION: The objective of our study was to demonstrate planned conservative management of placenta increta and percreta in a single tertiary center. METHODS: From April 2005 to July 2019, patients with placenta increta and percreta were managed conservatively at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. The severity of placenta invasion was diagnosed by magnetic resonance imaging (MRI). After delivery of the neonate, prophylactic transcatheter arterial embolization (TAE) was performed immediately. The placenta was left in situ and prophylactic antibiotics were administered during hospitalization. The patient profiles, outcomes, and complications were retrospectively reviewed. RESULTS: Based on the MRI findings, twenty-one patients with placenta increta or percreta were included. With prophylactic TAE, the mean surgical blood loss was 854.7 ± 478.2 mL. The mean natural resorption time of residual placenta was 4.69 ± 1.65 months. Regarding maternal complications, 4 patients (19%) had delayed postpartum hemorrhage (PPH), 12 patients (57.1%) developed postpartum infections, 3 patients (14.3%) progressed to sepsis, 4 patients (19%) underwent surgical evacuation, and 4 patients (19%) underwent hysterectomy. No maternal mortality was reported. Main neonatal complications were prematurity and respiratory distress. Regarding fertility, 16 (76.1%) patients had return of menstruation, and one (4.7%) had a subsequent pregnancy resulting in a live birth. DISCUSSION: Planned conservative management with prophylactic TAE and leaving placenta in situ is feasible and safe for women with placenta increta or percreta who desire fertility preservation. Delayed PPH and postpartum infection are common complications after conservative treatment.

Prophylactic Transcatheter Arterial Embolization Helps Intraoperative Hemorrhagic Control for REMOVING Invasive Placenta.

OBJECTIVES: The purpose of this article is to investigate the estimated blood loss in pregnant women undergoing cesarean section and placental extirpation to treat abnormal placentation and compare the outcomes of those who underwent prophylactic transcatheter arterial embolization (TAE) with those who did not. METHODS: A retrospective study was conducted on 17 pregnant women diagnosed with abnormal placentation in 2001⁻2018 in a single tertiary center. The patients were diagnosed by surgical finding, ultrasound, or magnetic resonance imaging (MRI). These patients were divided into two groups: a prophylactic TAE group (11 patients) and a control group (6 patients). In the former group, prophylactic TAE of the bilateral uterine artery (UA) and/or internal iliac artery (IIA) was performed immediately after delivery of the infant. The placenta was removed in both groups. The primary outcomes were estimated blood loss (EBL), units of packed red blood cell (pRBC) transfusion, operative time, whether hysterectomy was performed, whether the patient was transferred to the intensive care unit (ICU), and hospitalization days. The secondary outcome was maternal complications. RESULTS: Patients who received prophylactic TAE had significantly reduced intraoperative blood loss (990.9 ± 701.7 mL vs. 3448.3 ± 1767.4 mL, p = 0.018). Units of pRBC transfusion, operative time, hysterectomy, transfer to the ICU, and postoperative hospitalization days were not significantly different between the two groups. Thirteen patients (9 in the TAE group and 4 in the control group) received a blood transfusion during the operation. Three patients underwent a hysterectomy (1 in the TAE group and 2 in the control group). Five patients were transferred to the ICU (3 in the TAE group and 2 in the control group) for maternal complications or monitoring. In the prophylactic TAE group, 3 patients (27%) had a subsequent pregnancy within the next 5 years. CONCLUSIONS: Prophylactic TAE was safe and effective for reducing intraoperative hemorrhage from removing an invasive placenta in patients with abnormal placentation.