Total Syntheses of Rhodomollins A and B.

The first and asymmetric total syntheses of rhodomollins A and B, two rhodomollane type grayanoids featuring a d-homograyanane carbon skeleton and an oxa-bicyclo[3.2.1] core, were accomplished via a convergent strategy. A Stille coupling and a lithium-halogen exchange/intramolecular nucleophilic addition to the aldehyde sequence were employed to assemble two enantioenriched fragments. The oxa-bicyclo[3.2.1] core was achieved through an intramolecular SN2 substitution of cyclic sulfate of 1,2-diols (Williamson ether synthesis). The A ring oxidation states were adjusted by a Payne/Meinwald rearrangement sequence and subsequent redox transformations.

BODIPY-Based NO Probe for Macrophage-Targeted Immunotherapy Response Monitoring.

Precise and rapid detection of immune responses is critical for timely therapeutic regimen adjustment. Immunomodulation of tumor-associated macrophages (TAMs) from a protumorigenic phenotype (M2) to an antitumorigenic phenotype (M1) is crucial in macrophage-targeted immunotherapy. Herein, we developed a boron dipyrromethene (BODIPY)-based fluorescence probe BDP3 to detect the immune responses after immunotherapy by monitoring the nitric oxide (NO) released by M1 TAMs. With an aromatic primary monoamine structure and a p-methoxyanilin electron donor in the meso-position, BDP3 not only specifically activates stable and sensitive fluorescence by NO via a photoinduced electron transfer (PET) process but also achieves a long emission wavelength for efficient in vitro and in vivo imaging. Such NO-induced fluorescence signals of BDP3 are validated to correlate well with the phenotypes of TAMs detected in macrophage cell lines and tumor tissues. The distinct sensing effects toward two types of clinically used immunotherapeutic drugs further confirm the ability of BDP3 for specific monitoring of the M1/M2 switch in response to the macrophage-targeted immunotherapy. By virtue of good biocompatibility and appropriate tumor retention time, BDP3 could be a potential fluorescent probe for noninvasive evaluation of the immunotherapeutic efficacy of macrophage-targeted immunotherapy in living animals.

Synthesis, structure-activity relationship, and biological evaluation of quinolines for development of anticancer agents.

Tetrahydro-ß-carbolines (THßCs) are a kind of natural alkaloids with multiple pharmaceutical activities. Herein, a focused compound library derived from THßCs was synthesized and their anticancer activities were studied in several cancer cell lines. Among them, three compounds showed considerable anticancer activities with low micromolar to submicromolar IC50 values. The abilities to induce apoptosis and alter mitochondrial membrane potential levels, which are comparable to those of the commercial anticancer drug adriamycin, were confirmed by one representative compound (21) on the B16/F10 cell line. Our preliminary structure-activity relationship studies indicated that alkylamines with suitable lengths are very important for potency improvement.

Total Synthesis of Mollanol A.

Mollanol A is the first isolated member of the mollane-type grayanoids which possesses an unprecedented C-nor-D-homograyanane carbon skeleton and an 5,8-epoxide. Due to its transcriptional activation effects on the Xbp1 upstream promoters in different cell types, it has a potential therapeutic effect on inflammatory bowel disease. Here we report the first total synthesis of mollanol A, which constitutes a 15-step synthesis from commercially available materials via a convergent strategy. The synthesis involves an InCl3-catalyzed Conia-ene cyclization reaction to construct the bicyclo[3.2.1]octane moiety and a vinylogous aldol reaction/intramolecular oxa-Michael addition sequence to rapidly assemble the oxa-bicyclo[3.2.1] core.

Chemical Modification of Chitosan for Developing Cancer Nanotheranostics.

Cancer is a worldwide public health issue that has not been conquered. Theranostics, the combination of a therapeutic drug and imaging agent in one formulation using nanomaterials, has been developed to better cure cancer in recent years. Although diverse biomaterials have been applied in cancer theranostics, chitosan (CS), a natural polysaccharide bearing easy modification sites with excellent biocompatibility and biodegradability, shows great potential for developing cancer nanotheranostics. In this review, we seek to describe the chemical functionalities of CS used in cancer theranostics and their synthesis methods. We also present recent discoveries and research progresses on how the CS functionalization could improve the delivery efficiency of CS-based nanotheranostics. Finally, we report several case studies about the application of CS-based nanotheranostics. This paper focuses on the strategies to construct CS-based theranostics systems via chemical routes and highlights their applications in cancer treatment, which can provide useful references for further studies.

Analysis of the dissipation kinetics of thiophanate-methyl and its metabolite carbendazim in apple leaves using a modified QuEChERS-UPLC-MS/MS method.

As one of the main fungicides for the apple leaf disease control, thiophanate-methyl (TM) mainly exerts its fungicidal activity in the form of its metabolite carbendazim (MBC), whose dissipation kinetics is very distinct from that of its parent but has been paid little attention. The aim of this work was to investigate the dissipation kinetics of TM and its active metabolite MBC in apple leaves using a modified QuEChERS-UPLC-MS/MS method. The results showed that TM and MBC could be quickly extracted by this modified QuEChERS procedure with recoveries of 81.7-96.5%. The method linearity was in the range of 0.01-50.0 mg kg-1 with the quantification limit of 0.01 mg kg-1 . Then this method was applied to the analysis of fungicide dissipation kinetics in apple leaves. The results showed that the dissipation kinetics of TM for the test in 3 months can be described by a first-order kinetics model with a DT50 (dissipation half-life) range of 5.23-6.03 days and the kinetics for MBC can be described by a first-order absorption-dissipation model with the Tmax (time needed to reach peak concentration) range of 4.78-7.09 days. These models can scientifically describe the behavior of TM and MBC in apple leaves, which provides necessary data for scientific application.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

[Production and mechanism of CCL5 by macrophages in U14 cervical cancer-bearing mice during infection].

OBJECTIVE: To investigate the production and mechanism of chemokine (C-C motif) ligand 5 (CCL5) by macrophages in U14 cervical cancer-bearing mice during infection. METHODS: The U14 cervical cancer cells were injected in C57BL/6 mice to induce tumor-bearing condition. Lipopolysaccharide (LPS) was injected into C57BL/6 mice to induce infection. The protein expression of CCL5 in the serum and the CCL5 mRNA expression in inflammatory cells were measured by ELISA and fluorescence quantitative-PCR in four groups. Macrophages were induced in the tumor conditioned medium (TCM) which extracted from mice serum. The protein expression levels of CCL5, prostaglandin E2 (PGE2) and cyclic adenosine monophosphate (cAMP) in the medium and CCL5, PGE2 and cAMP mRNA expression in the macrophages were detected in different groups. In order to determine whether the inhibition was related to PGE2, selective cyclooxygenase 2(COX-2) inhibitor NS398 was used to reverse this phenomenon and protein kinase A (PKA) inhibitor H89 demonstrated the mechanism through blocking cAMP/PKA signaling pathway. RESULTS: (1) The protein and mRNA level of CCL5 in tumor-bearing mice were respectively (151 ± 35) pg/ml and 1.0, which were lower than those in the tumor-free mice (691 ± 85) pg/ml and 4.5 ± 0.8, there were significant difference between them (all P < 0.05). The protein and mRNA level of PGE2 in tumor-bearing mice were (1 198 ± 83) pg/ml and 5.8 ± 0.8, which were higher than those in the tumor-free mice (187 ± 25) pg/ml and 1.0, the difference were significant (all P < 0.05). The protein and mRNA level of CCL5 in tumor-free + LPS mice were (4 049 ± 141) pg/ml and 31.5 ± 2.0, which were higher than those in the tumor-bearing + LPS mice (1 951 ± 71) pg/ml and 12.1 ± 2.8, the difference were also significant (P < 0.05). The protein and mRNA level of PGE2 in tumor-free + LPS mice were (676 ± 70) pg/ml and 3.4 ± 0.4, which were lower than those in tumor-bearing + LPS mice (2 550 ± 382) pg/ml and 11.6 ± 0.9, the difference were also significant (all P < 0.05). (2) Macrophages were cultured in vitro using TCM derived from mice. The protein and mRNA level of CCL5 in tumor-bearing mice TCM were respectively (1 626 ± 177) pg/ml and 28.6 ± 1.2, which were higher than those in the tumor-free mice TCM [(27 ± 3) pg/ml and 1.0], there were significant difference (P < 0.05). The protein and mRNA level of PGE2 in tumor-bearing mice TCM were (790 ± 156) pg/ml and 1.7 ± 0.3, which were higher than those in the tumor-free mice TCM [(448 ± 115) pg/ml, 1.0], the difference were significant (all P < 0.05). The protein and mRNA level of cAMP in tumor-bearing mice TCM were (164 ± 30) pg/ml and 1.6 ± 0.3, which weres higher than those in the tumor-free mice TCM [(118 ± 25) pg/ml,1.0], the difference were significant (all P < 0.05). The protein and mRNA level of CCL5 in tumor-free + LPS mice TCM were (10 475 ± 742) pg/ml and 212.0 ± 5.7, which were higher than those in the tumor-bearing + LPS mice TCM [(6 375 ± 530) pg/ml, 142.3 ± 2.5], the difference were significant (all P < 0.05). The protein and mRNA level of PGE2 in tumor-free + LPS mice TCM were (2 438 ± 95) pg/ml and 4.3 ± 0.7, which weres lower than those in the tumor-bearing + LPS mice TCM [(3 441 ± 163) pg/ml, 5.9 ± 0.3], the difference were significant (all P < 0.05). The protein and mRNA level of cAMP in tumor-free + LPS mice TCM were (340 ± 13) pg/ml and 4.1 ± 0.4, which were lower than those in the tumor-bearing + LPS mice TCM [(542 ± 42) pg/ml, 5.4 ± 0.5], the difference were significant (all P < 0.05). (3) Using COX-2 inhibitor NS398 in the tumor-bearing + LPS mice, the protein and mRNA level of CCL5, PGE2 and cAMP were (7 691 ± 269) pg/ml and 159.0 ± 8.9, (2 820 ± 152) pg/ml and 4.9 ± 0.3, (465 ± 8) pg/ml and 4.3 ± 0.4, respectively, and there were significant difference (all P < 0.05), compared to before treatment. Using PKA inhibitor H89 in the tumor-bearing + LPS mice, the protein and mRNA level of CCL5, PGE2 and cAMP were (8 375 ± 520) pg/ml and 177.0 ± 8.8, (2 650 ± 35) pg/ml and 4.7 ± 0.4, (368 ± 13) pg/ml and 3.1 ± 0.7, respectively, and there were significant difference (all P < 0.05), compared to before treatment. CONCLUSION: TCM of U14 cells activated macrophages to release PGE2 could inhibit the expression of CCL5 levels by cAMP/PKA signaling pathway.

Insights into the tolerant function of VWA proteins in terms of expression analysis and RGLG5-VWA crystal structure.

The VWA domain commonly functions as a crucial component of multiprotein complexes, facilitating protein-protein interactions. However, limited studies have focused on the systemic study of VWA proteins in plants. Here, we identified 28 VWA protein genes in Arabidopsis thaliana, categorized into three clades, with one tandem duplication event and four paralogous genes within collinearity blocks. Then, we determined their expression patterns under abiotic stresses by transcriptomic analysis. All five RGLG genes were found to be responsive to at least one kind of abiotic stress, and RGLG5 was identified as a multiple stress-responsive gene, coding an E3 ubiquitin ligase with a VWA domain and a C-terminal RING domain. Subsequently, we explored tolerant function of RGLG5 by determining the crystal structure of its VWA domain. The structural comparison revealed the allosteric regulation mechanism of RGLG5-VWA, wherein the deflection of α7 led to displacement of key residue binding metal ion within MIDAS motif. Our findings provide full-scale knowledge on VWA proteins, and insights into tolerant function of RGLG5-VWA in terms of crystal structure.

Carboxyl-Modified Quantum Dots for NIR-IIb Bone Marrow Imaging.

Real-time, noninvasive, and nonradiative bone imaging can directly visualize bone health but requires bone-targeted probes with high specificity. Herein, we propose that carboxyl-rich fluorescent nanoprobes are easily absorbed by macrophages in bone marrow during circulation, enabling optical bone marrow imaging in vivo. We used PbS/CdS core-shell quantum dots with NIR-IIb (1500-1700 nm) emission as substrates to prepare the carboxyl-rich nanoprobe. In vivo NIR-IIb fluorescence imaging with the nanoprobes showed high resolution and penetration depth in bone tissues and allowed for imaging-guided fracture diagnosis. Bone tissue slices showed substantial accumulation of carboxyl nanoprobes in the bone marrow and strong colocalization with macrophages. Similar results with CdSe quantum dots and an organic nanofluorophore suggest that carboxyl surface modification is effective to achieve bone marrow targeting, providing a novel strategy for developing bone/bone marrow imaging probes.

Rod-Shaped Mesoporous Zinc-Containing Bioactive Glass Nanoparticles: Structural, Physico-Chemical, Antioxidant, and Immuno-Regulation Properties.

Bioactive glass nanoparticles (BGNs) are applied widely in tissue regeneration. Varied micro/nanostructures and components of BGNs have been designed for different applications. In the present study, nanorod-shaped mesoporous zinc-containing bioactive glass nanoparticles (ZnRBGNs) were designed and developed to form the bioactive content of composite materials for hard/soft tissue repair and regeneration. The nanostructure and components of the ZnRBGNs were characterized, as were their cytocompatibility and radical-scavenging activity in the presence/absence of cells and their ability to modulate macrophage polarization. The ZnRBGNs possessed a uniform rod shape (length ≈ 500 nm; width ≈ 150 nm) with a mesoporous structure (diameter ≈ 2.4 nm). The leaching liquid of the nanorods at a concentration below 0.5 mg/mL resulted in no cytotoxicity. More significant improvements in the antioxidant and M1-polarization-inhibiting effects and the promotion of M2 polarization were found when culturing the cells with the ZnRBGNs compared to when culturing them with the RBGNs. The doping of the Zn element in RBGNs may lead to improved antioxidant and anti-inflammatory effects, which may be beneficial in tissue regeneration/repair.

NIR-II Emissive Superoxide Radical Photogenerator for Photothermal/Photodynamic Therapy against Hypoxic Tumor.

Due to the "Achilles' heels" of hypoxia, complicated location in solid tumor, small molecular photosensitizers with second near-infrared window (NIR-II) fluorescence, type-I photodynamic therapy (PDT), and photothermal therapy (PTT) have attracted great attention. However, these photosensitizers are still few but yet challenging. Herein, an "all in one" NIR-II acceptor-donor-acceptor fused-ring photosensitizer, Y6-Th, is presented for the in-depth diagnosis and efficient treatment of cancer. Benefiting from the strong intramolecular charge transfer, promoted highly efficient intersystem crossing, largely p-conjugated fused-ring structure, and reduced planarity, the fabricated nanoparticles (Y6-Th nanoparticles) can emit NIR-II fluorescence with the peak located at 1020 nm, exclusively generate O2•- for type-I PDT, and display excellent PTT performance under an 808 nm laser stimulation. These characteristics make Y6-Th a distinguished NIR-wavelength-triggered phototheranostic agent, which can effectively therapy the hypoxic tumor using NIR-II-fluorescence-guided type-I PDT/PTT. This work provides a valuable guideline for fabricating high-performing NIR-II emissive superoxide radical photogenerators.

Relationship between social support and 7-year trajectories of cognitive decline: results from the China Health and Retirement Longitudinal Study.

BACKGROUND: Social support is associated with cognitive function at an older age, but how distinct dimensions of social support affect trajectories of cognitive decline in older Chinese adults remains unclear. METHODS: Using longitudinal data (waves 1-4) from the China Health and Retirement Longitudinal Study, 7-year trajectories of cognitive decline by various social support markers, including family support, financial support, public support and perceived support, were estimated using latent growth curve modelling for adults aged 60 and over (N=6795). RESULTS: After adjusting for baseline sociodemographics, behaviours, body mass index and health conditions, all social support markers were associated with baseline cognitive function, except for living with spouse. Participants living with spouse experienced a slower cognitive decline (0.069 per year, 95% CI 0.006, 0.133) than those who were not. A faster cognitive decline was associated with co-residing with children (-0.053 per year, 95% CI -0.104, -0.003), receiving ≥¥5000 from children (-0.095 per year, 95% CI -0.179, -0.011), receiving financial support from others (-0.108 per year, 95% CI -0.208, -0.008) and perceived support (-0.068 per year, 95% CI -0.123, -0.013). When all markers were mutually adjusted for, the associations of living with spouse and receiving financial support from others with cognitive decline disappeared. Stratifying by rural-urban residence, medical insurance and meeting children 1-3 times per month were associated with a slower rate of cognitive decline in urban residents but not in rural residents. CONCLUSION: Overall, our findings confirm that the effects of distinct domains of social support on cognitive decline vary. More equally good social security systems should be established in urban and rural China.

Interface contact and modulated electronic properties by in-plain strains in a graphene-MoS2 heterostructure.

Designing a specific heterojunction by assembling suitable two-dimensional (2D) semiconductors has shown significant potential in next-generation micro-nano electronic devices. In this paper, we study the structural and electronic properties of graphene-MoS2 (Gr-MoS2) heterostructures with in-plain biaxial strain using density functional theory. It is found that the interaction between graphene and monolayer MoS2 is characterized by a weak van der Waals interlayer coupling with the stable layer spacing of 3.39 Å and binding energy of 0.35 J m-2. In the presence of MoS2, the linear bands on the Dirac cone of graphene are slightly split. A tiny band gap about 1.2 meV opens in the Gr-MoS2 heterojunction due to the breaking of sublattice symmetry, and it could be effectively modulated by strain. Furthermore, an n-type Schottky contact is formed at the Gr-MoS2 interface with a Schottky barrier height of 0.33 eV, which can be effectively modulated by in-plane strain. Especially, an n-type ohmic contact is obtained when 6% tensile strain is imposed. The appearance of the non-zero band gap in graphene has opened up new possibilities for its application and the ohmic contact predicts the Gr-MoS2 van der Waals heterojunction nanocomposite as a competitive candidate in next-generation optoelectronics and Schottky devices.

Pharmacokinetic and safety profile of PT109B, a novel multi-targeted compound against Alzheimer's disease.

PT109B, 5-(1,2-dithiolan-3-yl)-N-((1r,4r)-4-(isoquinolin-5-ylamino) cyclohexyl) pentanamide, a novel compound structurally related to Fasudil, has been reported as a promising candidate for treating Alzheimer's disease. To investigate the pharmacokinetics and acute toxicity of PT109B in rodents, we first developed and validated a UPLC-MS/MS analytical method to detect PT109B concentration in the biological matrix. The proposed method could separate and quantify the PT109B with good precision and accuracy. The pharmacokinetic results showed that the concentrations of PT109B in rat plasma increased with the dose, but not proportionally. Meanwhile, the double-peak phenomenon disappeared when decreasing the oral administration dosage. In addition, we found that PT109B could be detected in the central nervous system, and highly distributed in the liver and kidney. At the same time, the gender difference of PT109B in rats was observed, and the exposure of PT109B in female rats was significantly higher than that in male rats after oral administration. Finally, we found that oral administration of 750 mg/kg PT109B to C57 BL/6 mice caused significant liver injury in females, which was specifically manifested as hepatomegaly, increased liver coefficient, and hepatocyte ballooning. However, no significant damage was observed in other organs, which may be related to the distribution of PT109B in the liver. In summary, we first established a UPLC-MS/MS method for the analysis of PT109B in a biological matrix and described the characteristics of pharmacokinetics, and acute toxicity of PT109B in rodents, providing a sufficient pharmacokinetic basis for further study of PT109B.

Preoperative and Prognostic Prediction of Microvascular Invasion in Hepatocellular Carcinoma: A Review Based on Artificial Intelligence.

Microvascular invasion of hepatocellular carcinoma is an important factor affecting tumor recurrence after liver resection and liver transplantation. There are many ways to classify microvascular invasion, however, an international consensus is urgently needed. Recently, artificial intelligence has emerged as an important tool for improving the clinical management of hepatocellular carcinoma. Many studies about microvascular invasion currently focus on preoperative and prognosis prediction of microvascular invasion using artificial intelligence. In this paper, we review the definition and staging of microvascular invasion, especially the diagnosis of it by using artificial intelligence. In preoperative prediction, deep learning based on multimodal data modeling of radiomics-screened features, clinical features, and medical images is currently the most effective means. In prognostic prediction, pathology is the gold standard, and the techniques used should more effectively utilize the global features of the pathology images.

Effects of shapes and symmetries of scatterers on acoustic dual-negative refraction.

The potential operating conditions of acoustic dual-negative refraction (ADNR) are investigated by band structure theory for scatterers with different shapes and symmetries. Specifically, two types of lattices (triangular and honeycomb) and four different shapes of scatterers (circle, hexagon, square and triangle) are considered. Based on the generation mechanism of the ADNR effect, which is dependent on the frequency of the incident wave at the overlapping second and third Bloch bands, the optimum operating frequencies of ADNR with different crystal structures are given. The calculations demonstrate that the ADNR effect can be generated at the normalized frequency from 0.8 to 1.05.

Broadband acoustic concentrator with multilayered alternative homogeneous materials.

A two-dimensional cylindrical acoustic concentrator is designed with multilayered alternative homogeneous materials, which can focus acoustic field and enhance acoustic energy in a given area. The frequency response analysis of the acoustic concentrator demonstrates that the acoustic energy can be concentrated within the device over a wide frequency band. Meanwhile, there are contradictory relations between the acoustic concentrating performances in the inner region and the scattering properties in the outer region of these concentrators. When the contradictory relations satisfy compromise balance, the concentration ratio can reach at least 70%.

Facile preparation of Au- and BODIPY-grafted lipid nanoparticles for synergized photothermal therapy.

Gold nanoparticles with large size exhibit preferable properties for photothermal therapy (PTT). However, the prolonged tissue retention and slow elimination of gold nanoparticles limit their therapeutic applications. Previously, gold nanoclusters carrying lipid nanoparticles (Au-LNPs) have been reported after simply mixing Au3+ with preformed diethylenetriaminepentaacetic acid lipid nanoparticles to solve this contradiction. Au-LNPs demonstrated enhanced photothermal effects in comparison to neat gold nanoparticles. To further improve the photothermal activity, we introduced the organic photothermal agent boron dipyrromethene (BODIPY) to Au-LNPs for synergistic PTT. Au- and BODIPY-grafted LNPs (AB-LNPs) were formed by simply mixing Au-LNPs with BODIPY. The BODIPY could be associated stably to Au-LNPs, and the release of BODIPY from AB-LNPs could be accelerated by laser irradiation. AB-LNPs are scalable and showed excellent photothermal effects. AB-LNPs showed enhanced cellular uptake efficiency compared to free BODIPY in 4T1 breast cancer cells. Under laser irradiation, AB-LNPs exhibited synergistic photothermal effects with significantly reduced dosage compared to monotherapy (treatments with Au-LNPs or free BODIPY alone). This study thus provides a facile and adaptive strategy for the development of a scalable and safe high-performance nanoplatform for synergistic PTT in the treatment of cancer and other diseases.

Low-molecular-weight heparin in addition to low-dose aspirin for preventing preeclampsia and its complications: A systematic review and meta-analysis.

Background: In this systematic review, we aimed to investigate the efficacy and safety of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin (LDA) started ≤16 weeks'gestation in the prevention of preeclampsia (PE) in high-risk women. Methods: PubMed, Cochrane Library, Embase, and ClinicalTrials.gov databases were searched from their inception to April 2022 for randomized controlled trials (RCTs) that to determine whether the combined treatment of LMWH and LDA is better than single anticoagulant drugs in preventing PE and improving live birth rate of fetus in high-risk women with pregnancy ≤16 weeks. We also searched Embase, OVID MEDLINE and OVID MEDLINE in-process using the OVID platform. Results: 14 RCTs involving 1,966 women were found. The LMWH (or unfractionated heparin) and LDA groups included 1,165 wemen, and the LDA group included 960 women. The meta-analysis showed that the addition of LMWH to LDA reduced the risk of PE (RR: 0.59, 95% CI: 0.44-0.79, P < 0.05), small-for-gestational age (SGA, RR: 0.71, 95% CI: 0.52-0.97, P = 0.03), fetal and neonatal death (RR: 0.45, 95% CI: 0.23-0.88, P = 0.02) and gestational hypertension (RR: 0.47, 95% CI: 0.25-0.90, P = 0.02). It is worth emphasizing that LMWH (or unfractionated heparin) combined with LDA did not increase the risk of bleeding. Conclusions: LMWH combined with LDA can effectively improve the pregnancy outcome of women with high risk factors for PE and its complications. Although this study showed that combined medication also did not increase the risk of bleeding, but such results lack the support of large sample size studies. The clinical safety analysis of LMWH combined with LDA in patients with PE should be more carried out.