Deep metagenomic characterization of the gut virome in pregnant women with preeclampsia.

Preeclampsia (PE), a pregnancy-specific syndrome, has been associated with the gut bacteriome. Here, to investigate the impact of the gut virome on the development of PE, we identified over 8,000 nonredundant viruses from the fecal metagenomes of 40 early-onset PE and 37 healthy pregnant women and profiled their abundances. Comparison and correlation analysis showed that PE-enriched viruses frequently connected to Blautia species enriched in PE. By contrast, bacteria linked to PE-depleted viruses were often the Bacteroidaceae members such as Bacteroides spp., Phocaeicola spp., Parabacteroides spp., and Alistipes shahii. In terms of viral function, PE-depleted viruses had auxiliary metabolic genes that participated in the metabolism of simple and complex polysaccharides, sulfur metabolism, lipopolysaccharide biosynthesis, and peptidoglycan biosynthesis, while PE-enriched viruses had a gene encoding cyclic pyranopterin monophosphate synthase, which seemed to be special, that participates in the biosynthesis of the molybdenum cofactor. Furthermore, the classification model based on gut viral signatures was developed to discriminate PE patients from healthy controls and showed an area under the receiver operating characteristic curve of 0.922 that was better than that of the bacterium-based model. This study opens up new avenues for further research, providing valuable insights into the PE gut virome and offering potential directions for future mechanistic and therapeutic investigations, with the ultimate goal of improving the diagnosis and management of PE.IMPORTANCEThe importance of this study lies in its exploration of the previously overlooked but potentially critical role of the gut virome in preeclampsia (PE). While the association between PE and the gut bacteriome has been recognized, this research takes a pioneering step into understanding how the gut virome, represented by over 8,000 nonredundant viruses, contributes to this condition. The findings reveal intriguing connections between PE-enriched viruses and specific gut bacteria, such as the prevalence of Blautia species in individuals with PE, contrasting with bacteria linked to PE-depleted viruses, including members of the Bacteroidaceae family. These viral interactions and associations provide a deeper understanding of the complex dynamics at play in PE.

Anemoside B4, a new pyruvate carboxylase inhibitor, alleviates colitis by reprogramming macrophage function.

OBJECTIVES: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. METHODS: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. RESULTS: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. CONCLUSION: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.

Deep metagenomic characterization of gut microbial community and function in preeclampsia.

Preeclampsia (PE) is a pregnancy complication characterized by severe hypertension and multiple organ damage. Gut microbiota has been linked to PE by previous amplicon sequencing studies. To resolve the PE gut microbiota in a higher taxonomy resolution, we performed shotgun metagenomic sequencing on the fecal samples from 40 early-onset PE and 37 healthy pregnant women. We recovered 1,750 metagenome-assembled genomes (representing 406 species) from the metagenomic dataset and profiled their abundances. We found that PE gut microbiota had enriched in some species belonging to Blautia, Pauljensenia, Ruminococcus, and Collinsella and microbial functions such as the bacitracin/lantibiotics transport system, maltooligosaccharide transport system, multidrug efflux pump, and rhamnose transport system. Conversely, the gut microbiome of healthy pregnant women was enriched in species of Bacteroides and Phocaeicola and microbial functions including the porphyrin and chlorophyll metabolism, pyridoxal-P biosynthesis, riboflavin metabolism, and folate biosynthesis pathway. PE diagnostic potential of gut microbial biomarkers was developed using both species and function profile data. These results will help to explore the relationships between gut bacteria and PE and provide new insights into PE early warning.

Flavonoids in myocardial ischemia-reperfusion injury: Therapeutic effects and mechanisms.

Ischemic heart diseases are one of the major causes of death worldwide. Effective restoration of blood flow can significantly improve patients' quality of life and reduce mortality. However, reperfusion injury cannot be ignored. Flavonoids possess well-established antioxidant properties; They also have other benefits that may be relevant for ameliorating myocardial ischemia-reperfusion injury (MIRI). In this review, we focus on flavonoids with cardiovascular-protection function and emphasize their pharmacological effects. The main mechanisms of flavonoid pharmacological activities against MIRI involve the following aspects: a) antioxidant, b) anti-inflammatory, c) anti-platelet aggregation, d) anti-apoptosis, and e) myocardial-function regulation activities. We also summarized the effectiveness of flavonoids for MIRI.

Application of the LMS method of constructing fetal reference charts: comparison with the original method.

Objectives: In view of the concern expressed about the current references, new references for fetal biparietal diameter and head circumference should be constructed for contemporary local populations.Methods: We conducted a retrospective cross-sectional study in two hospitals in Guangdong, Southern China. Fetal biparietal diameter and head circumference percentiles regression were fitted using Cole's LMS method. The BPD and HC data were then transformed into Z-scores that were calculated using two series of reference equations obtained from two methods: Cole's LMS method and the original "mean and SD method." Each Z-score distribution was presented as the mean and standard deviation. Finally, the sensitivity and specificity of each reference for identifying fetuses <2.5th or >97.5th percentile (based on the observed distribution of Z-scores) were calculated. The misclassified number and Youden's index were listed.Results: A total of 17,974 biparietal diameter and 18,269 head circumference measurements were chosen to establish a reference chart. The LMS method could fit the local population better than the "mean and SD method" as it had a lower number of misclassified fetuses and a higher Youden's index.Conclusion: The Cole's LMS method was able to construct a satisfied reference range of fetal head sizes in Southern China.

Synaptotagmin 1 regulates cortical granule exocytosis during mouse oocyte activation.

Synaptotagmin 1 (Syt1) is an abundant and important presynaptic vesicle protein that binds Ca2+ for the regulation of synaptic vesicle exocytosis. Our previous study reported its localization and function on spindle assembly in mouse oocyte meiotic maturation. The present study was designed to investigate the function of Syt1 during mouse oocyte activation and subsequent cortical granule exocytosis (CGE) using confocal microscopy, morpholinol-based knockdown and time-lapse live cell imaging. By employing live cell imaging, we first studied the dynamic process of CGE and calculated the time interval between [Ca2+]i rise and CGE after oocyte activation. We further showed that Syt1 was co-localized to cortical granules (CGs) at the oocyte cortex. After oocyte activation with SrCl2, the Syt1 distribution pattern was altered significantly, similar to the changes seen for the CGs. Knockdown of Syt1 inhibited [Ca2+]i oscillations, disrupted the F-actin distribution pattern and delayed the time of cortical reaction. In summary, as a synaptic vesicle protein and calcium sensor for exocytosis, Syt1 acts as an essential regulator in mouse oocyte activation events including the generation of Ca2+ signals and CGE.

Early-Onset Preeclampsia Is Associated With Gut Microbial Alterations in Antepartum and Postpartum Women.

Background: Imbalances in gut microbiota composition are linked to hypertension, host metabolic abnormalities, systemic inflammation, and other conditions. In the present study, we examined the changes of gut microbiota in women with early-onset preeclampsia (PE) and in normotensive, uncomplicated pregnant women during late pregnancy and at 1 and 6 weeks postpartum. Methods: Gut microbiota profiles of women with PE and healthy pregnant women in the third trimester and at 1 and 6 weeks postpartum were assessed by 16S rRNA gene amplicon sequencing. Plasma levels of interleukin-6 (IL-6), intestinal fatty acid-binding protein (I-FABP), zonulin, and lipopolysaccharide (LPS) were measured in the third trimesters. Results: At the genus level, 8 bacterial genera were significantly enriched in the antepartum samples of PE patients compared to healthy controls, of which Blautia, Ruminococcus2, Bilophila, and Fusobacterium represented the major variances in PE microbiomes. Conversely, 5 genera, including Faecalibacterium, Gemmiger, Akkermansia, Dialister, and Methanobrevibacter, were significantly depleted in antepartum PE samples. Maternal blood pressure and liver enzyme levels were positively correlated to the PE-enriched genera such as Anaerococcus, Ruminococcus2, Oribacterium, and Bilophila, while the fetal features (e.g., Apgar score and newborn birth weight) were positively correlated with PE-depleted genera and negatively correlated with PE-enriched genera. Moreover, maternal blood IL-6 level was positively associated with gut Bilophila and Oribacterium, whereas LPS level was negatively associated with Akkermansia. In terms of postpartum women, both the gut microbial composition and the PE-associated microbial alterations were highly consistent with those of the antepartum women. Conclusion: PE diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with uncomplicated pregnant women, which are associated with maternal clinical features (blood pressure level and liver dysfunction) and newborn birth weight. Moreover, these antepartum alterations in gut microbiota persisted 6 weeks postpartum.

Thresholds for Ambulatory Blood Pressure Monitoring Based on Maternal and Neonatal Outcomes in Late Pregnancy in a Southern Chinese Population.

Background In contrast to the general population, outcome-derived thresholds for diagnosing ambulatory hypertension in pregnancy are not yet available. We aimed to identify and compare outcome-derived ambulatory blood pressure (BP) monitoring thresholds for adverse perinatal outcomes by using approaches related and not related to clinic BP in a southern Chinese population. Methods and Results Ambulatory BP monitoring was performed in a cohort of 1768 high-risk participants in late pregnancy who were not taking antihypertensive medications. Participants were followed for composite maternal (severe complications) and neonatal (pregnancy loss, advanced neonatal care, and small for gestational age) outcomes. Modeling of clinic BP-unrelated approaches revealed a nonlinear threshold effect of ambulatory diastolic BP on the composite outcome, with increased risk for daytime ≥79 mm Hg and 24-hour measurement ≥76 mm Hg. For other ambulatory BP components showing linear associations with outcome, the following thresholds were identified: 131 mm Hg for daytime systolic, 121 mm Hg for nighttime systolic, 130 mm Hg for 24-hour systolic, and 73 mm Hg for night-time diastolic BP. These thresholds unrelated to clinic BP were lower than the equivalents yielding a similar probability of outcome to clinic BP of 140/90 mm Hg and were comparable with equivalents to clinic BP of 130/80 mm Hg. Conclusions Using an outcome-derived approach unrelated to clinic BP, we identified rounded thresholds to define ambulatory hypertension in at-risk women in late pregnancy in a southern Chinese population as follows: 130/80 mm Hg for daytime, 120/75 mm Hg for nighttime, and 130/75 mm Hg for 24-hour measurement. For wider clinical applicability and to align both nonpregnancy and pregnancy ambulatory BP monitoring with an outcomes-based approach, prospective, multiethnic, international studies from early pregnancy onward will be required.

Effects of Four Compounds from Gentianella acuta (Michx.) Hulten on Hydrogen Peroxide-Induced Injury in H9c2 Cells.

In previous studies, Gentianella acuta (Michx.) Hulten was reported to contain xanthones, iridoids, terpenoids, and sterols and is mainly used to cure hepatitis, jaundice, fever, headache, and angina pectoris. In this study, we used bioassay guided fractionation to identify compounds from G. acuta and investigated their activity against hydrogen peroxide (H2O2)-induced apoptosis of H9c2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic (GCLC) expression were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was evaluated using western blot. The results showed that all four compounds had protective effects on H9c2 cells. The transcription levels of HO-1 and GCLC significantly increased in H9c2 cells pretreated with norswertianolin (1), swetrianolin (2), demethylbellidifolin (3), and bellidifolin (4). However, compared to the model group, the transcription levels of Nrf2 were not enhanced by pretreatment with compounds 1, 2, and 4. The protein expression levels of HO-1 and GCLC in H9c2 cells were greater than that in the H2O2-treated group, and the expression of Nrf2 was not significantly changed except by swetrianolin treatment; inhibitors can reverse the protective effect by ZnPP (15 µM), BSO (10 µM), and brusatol (10 µM). The results indicated that the four compounds isolated from G. acuta inhibited the oxidative injury induced by H2O2 by activating the Nrf2/ARE pathway in H9c2 cells and provide evidence that G. acuta may be a potential therapeutic agent for the treatment of cardiovascular diseases.

Excessive umbilical cord coiling confers risk of elevated nocturnal blood pressure and severe/early-onset preeclampsia.

BACKGROUND: The associations between umbilical cord coiling, feto-placental vascular resistance and maternal blood pressure (BP) are not well understood. METHOD: We retrospectively analyzed 502 pregnant women suspected of hypertensive disorders in the third trimester from a hospital-based cohort, who underwent ambulatory BP monitoring and umbilical artery Doppler velocimetry examinations within 14 days before delivery. By applying quantile regression, a significant quantile-dependent positive association between umbilical cord coiling index and umbilical artery pulsatility index (UAPIMOM; converted to multiples of median) was observed from above 0.75th quantiles for each parameter. RESULTS: Using the cutoffs both at the 0.75th quantile to define high umbilical cord coiling (≥0.28 coils/cm) and high UAPIMOM (≥1.30), respectively, a graded increase in BP level was observed from patients with both low, either high and both high categories. Multivariate linear and quantile regression revealed that the high umbilical cord coiling/high UAPIMOM interaction was significantly correlated with night-time mean DBP level. Moreover, umbilical cord hypercoiling (≥0.3 coils/cm) was significantly correlated with night-time DBP with an average increase of ∼5 mmHg from the 0.05th to 0.70th quantiles and independently predicted the occurrence of severe (odds ratio 2.32, 95% confidence interval: 1.22-4.41) and early-onset (odds ratio 2.43, 95% confidence interval: 1.18-4.97) preeclampsia after adjusting for covariates. Further mediation analysis showed that elevated high UAPIMOM (≥1.30) could explain 11.4% of the umbilical cord hypercoiling → high night-time DBP association. CONCLUSION: Therefore, this retrospective study identifies excessive umbilical cord coiling, and its interaction with increased feto-placental vascular resistance, as novel risk factors for nocturnal BP elevation and preeclampsia.

A review of the ethnopharmacology, phytochemistry, and pharmacology of Changium smyrnioides Wolff.

Changium smyrnioides Wolff is a monotypic species of the genus Changium Wolff which is only found in eastern China. C. smyrnioides has been used as a traditional medicine for ages to treat cough, vomiting, nausea, megrim, and carbuncle. It is also widely used to brew medicated liquor and health tea with other herbs in order to moisten the lungs and nourish blood and yin. This review comprehensively summarizes the up-to-date information on the botanical characterization, distribution, traditional uses, ethnopharmacology, phytochemistry, pharmacology, and toxicity of C. smyrnioides based on studies published in recent years. Phytochemical investigations have revealed that phenylpropanoids, volatile oils, fatty acids, phytosterols, and other bioactive compounds are contained in C. smyrnioides. Crude extracts and monomeric compounds isolated from C. smyrnioides have significant effects on the respiratory, immune, and vascular systems and exhibit favourable activities such as antitussive, eliminating phlegm, anti-asthmatic, immunoregulatory, antioxidant, anti-tumor, anti-fatigue, anti-hypoxia, and anti-atherosclerotic effects. C. smyrnioides is a promising medicinal herb with immense therapeutic and health-promoting effects. Therefore, further studies on the bioactive compounds and mechanisms of C. smyrnioides are necessary. Additional clinical and toxicological studies are warranted to evaluate its safety.

Trimester-Specific Weight Gain and Midpregnancy Diastolic Blood Pressure Rebound During Normotensive Pregnancy.

The longitudinal exposure-response relationship between trimester-specific gestational weight gain (GWG) and blood pressure (BP) during pregnancy is not well understood. We retrospectively assessed 1112 uncomplicated, normotensive pregnant women whose body weight and BP were measured from 12+0 to 40+0 weeks of gestation from a hospital-based cohort. By using growth curve modeling, a J-shaped pattern dominated diastolic BP (DBP) changing dynamics, with a midpregnancy drop at 20+0 to 22+0 weeks followed by a rebound. Using group-based trajectory modeling, 3 distinctive trajectories of DBP were identified: high-J shaped (18.5%), moderate-J shaped (48.3%), and low-J shaped (33.1%), as well as 3 distinctive GWG trajectories: high increasing (14.7%), moderate increasing (48.6%) and low increasing (36.8%). A temporal coincidence between the maximal rate of GWG and DBP transition from its nadir to rebound was observed during 20+0 to 22+0 weeks. Moreover, women in the high-increasing GWG group had the highest probability of being in the high-J DBP group. The GWG rate during the late midsecond trimester (22+0 to 26+0 weeks) was consistently associated with an elevated DBP level: for every 200 g/wk increase, the multivariable-adjusted odds ratio was 1.27 (95% confidence interval, 1.13-1.43) for the trajectory shift to the high-J group and 1.20 (95% confidence interval, 1.07-1.35) for the occurrence of diastolic prehypertension after 37+0 weeks. Furthermore, adding a trimester-specific GWG rate (22+0 to 26+0 weeks) contributed to the incremental yield for the prediction of diastolic prehypertension after 37+0 weeks. Our results thus provide the timing and extent of gestational weight control relevant to the optimized BP level during pregnancy.

Prehypertension During Normotensive Pregnancy and Postpartum Clustering of Cardiometabolic Risk Factors: A Prospective Cohort Study.

The nonstratification of blood pressure (BP) levels may underestimate future cardiovascular risk in pregnant women who present with BP levels in the range of prehypertension (120-139/80-89 mm Hg). We prospectively evaluated the relationship between multiple antepartum BP measurements (from 11(+0) to 13(+6) weeks' gestation to term) and the occurrence of postpartum metabolic syndrome in 507 normotensive pregnant women after a live birth. By using latent class growth modeling, we identified the following 3 distinctive diastolic BP (DBP) trajectory groups: the low-J-shaped group (34.2%; DBP from 62.5±5.8 to 65.0±6.8 mm Hg), the moderate-U-shaped group (52.6%; DBP from 71.0±5.9 to 69.8±6.2 mm Hg), and the elevated-J-shaped group (13.2%; DBP from 76.2±6.7 to 81.8±4.8 mm Hg). Notably, the elevated-J-shaped trajectory group had mean DBP and systolic BP levels within the range of prehypertension from 37(+0) and 26(+0) weeks of pregnancy, respectively. Among the 309 women who completed the ≈1.6 years of postpartum follow-up, the women in the elevated-J-shaped group had greater odds of developing postpartum metabolic syndrome (adjusted odds ratio, 6.55; 95% confidence interval, 1.79-23.92; P=0.004) than the low-J-shaped group. Moreover, a parsimonious model incorporating DBP (membership in the elevated-J-shaped group but not in the DBP prehypertension group as identified by a single measurement) and elevated levels of fasting glucose (>4.99 mmol/L) and triglycerides (>3.14 mmol/L) at term was developed, with good discrimination and calibration for postpartum metabolic syndrome (c-statistic, 0.764; 95% confidence interval, 0.674-0.855; P<0.001). Therefore, prehypertension identified by DBP trajectories throughout pregnancy is an independent risk factor for predicting postpartum metabolic syndrome in normotensive pregnant women.

[Study on identification of four kinds of Gentianaceae Mongolian medicine Digeda with spectroscopy techniques].

To study the identification of Gentianaceae Mongolian medicine Digeda with spectroscopy techniques, near infrared spectroscopy and differential scanning calorimetry techniques were applied to study on the identification of 4 kinds of Gentianaceae Mongolian medicine Digeda, and characteristic spectrums obtained were systematically analyzed. In NIR study, the four species of Digeda exist some differences in 4 250-4 400 cm(-1) and 5 650-5 800 cm(-1) of one-dimensional spectra, and show significant differences in 4 100- 4 400 cm(-1), 4 401-4 900 cm(-1) and 5 400-5 800 cm(-1) of the second derivative spectra. DSC curves of them present distinct topological pattern, characteristic peak and peak temperature. Using near infrared spectroscopy and differential scanning calorimetry analysis can realize efficient and accurate identification of four kinds of Mongolian medicine Digeda, and provide scientific basis for the efficient and accurate identification of other Gentianaceae Mongolian medicine Digeda.