An anticoagulant/procoagulant self-converting and bleeding site-targeting systemic nanotherapy for rapidly controlling noncompressible bleeding without risk of thrombosis.

BACKGROUND: Hemorrhage, in particular noncompressible hemorrhage, is the leading cause of casualties in combat trauma and civilian trauma. Although systemic agents can stop bleeding at both inaccessible and accessible injury sites, the application of systemic hemostats in clinics is strictly limited by the nontargeting ability of hemostats and their subsequent potential for thromboembolic complications. OBJECTIVES: To engineer an anticoagulant/procoagulant self-converting and bleeding site-targeting systemic nanohemostat to rapidly control noncompressible bleeding without thrombosis risk. METHODS: A multiscale computer simulation was taken to guide the self-assembly of sulindac (SUL, a prodrug of the antiplatelets agent) and poly-L-lysine (a cation polymer with platelets activation ability) for forming poly-L-lysine/SUL nanoparticles (PSNs). In vitro platelet-adhering ability, platelet activation effect, and hemostasis activity of PSNs were evaluated. Then, the biosafety, level of thrombosis, targeting ability, and hemostasis effect of systemic applied PSNs were carefully evaluated in various hemorrhage models. RESULTS: PSNs were successfully prepared and showed good platelet adhesion and activation in vitro. The bleeding site-targeting ability and hemostatic efficiency in different bleeding models were leveled up by PSNs markedly compared with vitamin K and etamsylate in vivo. SUL in PSNs could be metabolized into sulindac sulfide at clot sites in 4 hours for antiplatelet aggregation, thus reducing thrombotic risk compared with other hemostatic agents, via the ingenious utilization of prodrug metabolism in terms of time intervals and the adhesion on platelets. CONCLUSION: PSNs are expected to be a low-cost, safe, efficient, clinically translatable first-aid hemostat for first-aid scenarios.

Advances in Oral Drug Delivery Systems: Challenges and Opportunities.

The oral route is the most preferred route for systemic and local drug delivery. However, the oral drug delivery system faces the harsh physiological and physicochemical environment of the gastrointestinal tract, which limits the bioavailability and targeted design of oral drug delivery system. Innovative pharmaceutical approaches including nanoparticulate formulations, biomimetic drug formulations, and microfabricated devices have been explored to optimize drug targeting and bioavailability. In this review, the anatomical factors, biochemical factors, and physiology factors that influence delivering drug via oral route are discussed and recent advance in conventional and novel oral drug delivery approaches for improving drug bioavailability and targeting ability are highlighted. We also address the challenges and opportunities of oral drug delivery systems in future.

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.

Biomaterial-Based Therapeutic Strategies for Obesity and Its Comorbidities.

Obesity is a global public health issue that results in many health complications or comorbidities, including type 2 diabetes mellitus, cardiovascular disease, and fatty liver. Pharmacotherapy alone or combined with either lifestyle alteration or surgery represents the main modality to combat obesity and its complications. However, most anti-obesity drugs are limited by their bioavailability, target specificity, and potential toxic effects. Only a handful of drugs, including orlistat, liraglutide, and semaglutide, are currently approved for clinical obesity treatment. Thus, there is an urgent need for alternative treatment strategies. Based on the new revelation of the pathogenesis of obesity and the efforts toward the multi-disciplinary integration of materials, chemistry, biotechnology, and pharmacy, some emerging obesity treatment strategies are gradually entering the field of preclinical and clinical research. Herein, by analyzing the current situation and challenges of various new obesity treatment strategies such as small-molecule drugs, natural drugs, and biotechnology drugs, the advanced functions and prospects of biomaterials in obesity-targeted delivery, as well as their biological activities and applications in obesity treatment, are systematically summarized. Finally, based on the systematic analysis of biomaterial-based obesity therapeutic strategies, the future prospects and challenges in this field are proposed.

A sulfur-limestone bioretention system for stormwater treatment: Nitrogen removal performance and microbial community.

A lab-scale sulfur-limestone based bioretention system with a submerged zone was used to remove nitrate-nitrogen (NO3--N) from stormwater. The results indicated that denitrification mainly occurred during the first 5 d of drying period. With the NO3--N concentration in the influent increasing from 20 to 50 mg/L, after 5 d of drying period 93.99-97.26% NO3--N was removed, and the effluent sulfate (SO42-) concentration ranged from 170.28 to 359.87 mg/L. When the NO3--N content in the influent was lower than 30 mg/L, the effluent SO42- concentration met the Chinese Quality Standard for Ground Water (GB/T 14848-2017). Compared with the woodchips bioretention, there was no organic matter leakage problem. Sulfur autotrophic denitrification process followed first-order kinetic model, and the reaction kinetic parameters (k) were 0.7392-1.1472 d-1. The dominant genera in the submerged zone were Thiobacillus and Halothiobacillus (>63.69%) which participated in the sulfur autotrophic denitrification process.

Characterizing omental PET/CT findings for differentiating tuberculous peritonitis from peritoneal carcinomatosis.

PURPOSE: To characterize and investigate PET/CT findings in the omentum in the differentiation of tuberculous peritonitis (TBP) and peritoneal carcinoma (PC). METHODS: Thirty-nine patients with TBP and 113 patients with PC who underwent PET/CT were retrospectively enrolled. The omental uptake intensity, distribution characteristics, contracture, size and boundary of soft-tissue lesions, and CT patterns were reviewed. RESULTS: Absent and focal FDG uptake in the lesser omentum was more common in the PC patients (P = 0.034 and P = 0.017, respectively), and diffuse FDG uptake in the lesser omentum was more common in the TBP patients (P < 0.001). An apron-like pattern in the greater omentum commonly occurred in the TBP patients (P = 0.004). Micronodules (< 5 mm) were more common in the TBP patients (P < 0.001), and masses (> 3 cm) were more common in the PC patients (P = 0.001). Smudged and nodular patterns occurred more frequently in the TBP patients than in the PC patients (P < 0.001 and P = 0.003, respectively), and the caked pattern occurred more frequently in the PC patients (P < 0.001). There was no significant difference in the FDG uptake intensity and the boundary of soft-tissue lesions between the TBP and PC patients (P = 0.191 and P = 0.061, respectively). CONCLUSION: Diffuse FDG uptake, an apron-like pattern, micronodules, and a smudged and nodular pattern might be significant differential features of TBP. Absent and/or focal FDG uptake, mass, and a caked pattern might be significant differential features of PC.

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.

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.

[Beneficial effects of liver X receptor agonist on adipose-derived mesenchymal stem cells transplantation in mice with myocardial infarction].

OBJECTIVE: To investigate the effects of liver X receptor (LXR) agonist on adipose-derived mesenchymal stem cells (AD-MSCs) implantation into infarcted hearts of mice. METHOD: AD-MSC(Fluc+) which stably expressed firefly luciferase (Fluc) were isolated from ß-actin-Fluc transgenic mice and characterized by flow cytometry. Male FVB mice were randomly allocated into the following four groups (n = 10 each): (1) sham group; (2) MI + PBS group; (3) MI + AD-MSC(Fluc+) group; (4) MI + AD-MSC(Fluc+) + LXR agonist (T0901317) group. AD-MSC(Fluc+) or PBS were injected intramyocardial into peri-infarcted region of mice heart after permanent left anterior descending (LAD) artery ligation. Bioluminescence imaging (BLI) was performed for quantification of injected cells retention and survival. Cardiac function was evaluated by echocardiography. RESULTS: The AD-MSC(Fluc+) were positive for CD44 and CD90 by flow cytometry. BLI evidenced the firefly luciferase expression of AD-MSC(Fluc+) which was positively correlated with cell numbers (r(2) = 0.98). The results of BLI in vivo revealed that LXR agonist could improve the survival of AD-MSC(Fluc+) at day 7, 14 and 21 after transplantation compared with AD-MSC(Fluc+) alone group. Cardiac function was further improved in combination therapy group compared with AD-MSC(Fluc+) alone group (P < 0.05). CONCLUSIONS: LXR agonist T0901317 can improve the retention and survival of intramyocardial injected AD-MSC(Fluc+) post-MI, and the combination therapy of T0901317 and AD-MSC(Fluc+) has a synergetic effect on improving cardiac function in this model.