Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies.

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.

Effects of Sjogren's syndrome and high sugar diet on oral microbiome in patients with rampant caries: a clinical study.

OBJECTIVE: The purpose of this study was to assess the composition of the oral microbial flora of adults with rampant caries in China to provide guidance for treatment. PATIENTS AND METHODS: Sixty human salivary and supragingival plaque samples were collected. They were characterized into four groups: patients with rampant caries with Sjogren's syndrome (RC-SS) or high-sugar diet (RC-HD), common dental caries (DC), and healthy individuals (HP). The 16S rRNA V3-V4 region of the bacterial DNA was detected by Illumina sequencing. PCoA based on OTU with Bray-Curtis algorithm, the abundance of each level, LEfSe analysis, network analysis, and PICRUSt analysis were carried out between the four groups and two sample types. Clinical and demographic data were compared using analysis of variance (ANOVA) or the nonparametric Kruskal-Wallis rank-sum test, depending on the normality of the data, using GraphPad Prism 8 (P < 0.05). RESULTS: OTU principal component analysis revealed a significant difference between healthy individuals and those with RC-SS. In the saliva of patients with rampant caries, the relative abundance of Firmicutes increased significantly at the phylum level. Further, Streptocpccus, Veillonella, Prevotella, and Dialister increased, while Neisseria and Haemophilus decreased at the genus level. Veillonella increased in the plaque samples of patients with rampant caries. CONCLUSION: Both salivary and dental plaque composition were significantly different between healthy individuals and patients with rampant caries. This study provides a microbiological basis for exploring the etiology of rampant caries. CLINICAL RELEVANCE: This study provides basic information on the flora of the oral cavity in adults with rampant caries in China. These findings could serve as a reference for the treatment of this disease.

Identification of N-(3-(methyl(3-(orotic amido)propyl)amino)propyl) oleanolamide as a novel topoisomerase I catalytic inhibitor by rational design, molecular dynamics simulation, and biological evaluation.

DNA topoisomerase I (TOP1) catalytic inhibitors are a promising class of antitumor agents. Oleanolic acid derivatives are potential TOP1 catalytic inhibitors. However, their inhibitory activity still needs to be enhanced, and the stability and hotspot residue sites of their interaction with TOP1 remain to be elucidated. Herein, a novel oleanolic acid derivative, OA4 (N-(3-(methyl(3-(orotic amido)propyl)amino)propyl)oleanolamide), was identified by rational design. Subsequently, molecular dynamics simulations were performed to explore the stability and conformational dynamics of the TOP1-OA4 complex. The molecular mechanics/generalized Born surface area method calculated the binding free energy and predicted Arg488, Ile535, and His632 to be hotspot residues. Biological experiments verified that OA4 is a nonintercalative TOP1 catalytic inhibitor. OA4 exhibits better proliferation inhibitory activity against tumor cells than normal cells. Furthermore, OA4 can induce apoptosis and effectively suppress the proliferation and migration of cancer cells. This work provides new insights for the development of novel TOP1 catalytic inhibitors.

Single-cell RNA sequencing reveals the local cell landscape in mouse epididymal initial segment during aging.

BACKGROUND: Morphological and functional alterations in aging reproductive organs result in decreased male fertility. The epididymis functions as the transition region for post-testicular sperm maturation. And we have previously demonstrated that the epididymal initial segment (IS), a region of the reproductive tract essential for sperm maturation and capacitation, undergoes considerable histological changes and chronic immune activation in mice during aging. However, the local aging-associated cellular and molecular changes in the aged epididymal IS are poorly understood. RESULTS: We conducted single-cell RNA sequencing analysis on the epididymal IS of young (3-month-old) and old (21-month-old) mice. In total, 10,027 cells from the epididymal IS tissues of young and old mice were obtained and annotated. The cell composition, including the expansion of a principal cell subtype and Ms4a4bHiMs4a6bHi T cells, changed with age. Aged principal cells displayed multiple functional gene expression changes associated with acrosome reaction and sperm maturation, suggesting an asynchronous process of sperm activation and maturation during epididymal transit. Meanwhile, aging-related altered pathways in immune cells, especially the "cell chemotaxis" in Cx3cr1Hi epididymal dendritic cells (eDCs), were identified. The monocyte-specific expression of chemokine Ccl8 increased with age in eDCs. And the aged epididymal IS showed increased inflammatory cell infiltration and cytokine secretion. Furthermore, cell-cell communication analysis indicated that age increased inflammatory signaling in the epididymal IS. CONCLUSION: Contrary to the general pattern of lower immune responses in the male proximal genital tract, we revealed an inflammaging status in mouse epididymal initial segment. These findings will allow future studies to enable the delay of male reproductive aging via immune regulation.

Prevalence of preconception TORCH infections and its influential factors: evidence from over 2 million women with fertility desire in southern China.

BACKGROUND: TORCH (Toxoplasma gondii [TOX], Cytomegalovirus [CMV], Rubella virus [RV], and Herpes simplex virus [HSV]) represents pathogens known to traverse the maternal-fetal barrier and cause severe neonatal anomalies. We aimed to assess the prevalence of preconception TOX, CMV, and RV infections among women with fertility desire in southern China, and identify related risk factors. METHODS: Data were obtained from a population-based cross-sectional study conducted as part of the National Free Preconception Health Examination Project. Women planning to conceive within the next 6 months in Guangdong Province were enrolled between 2014 and 2019. Information on sociodemographic, gynecological, and obstetric characteristics was collected. Sera were analyzed for TOX IgG, CMV IgG, and RV IgG antibodies using an enzyme-linked immunosorbent assay. Descriptive, univariate, and multivariate logistic regression analyses were performed to assess the association between TORCH infections and related factors. RESULTS: Among 2,409,137 participants, the prevalence of IgG antibodies for TOX, CMV, and RV was 3.20% (95% CI: 3.18-3.22%), 77.67% (95% CI: 77.62-77.71%) and 76.03% (95% CI: 75.98-76.07%), respectively. Of all participants, 141,047 women (5.85%, 95% CI:5.83-5.88%) reported a history of immunization for RV. Women living in the Pearl River Delta, a more developed region, have significantly lower vaccination rates than those living in other regions. The seropositivity of TOX IgG was highest among women aged 35 years and above, with primary or lower education levels, and rural registration. Factors such as being older, having a higher educational level, and being of other ethnicities were associated with a higher prevalence of naturally acquired CMV and RV infections. Women living in the Pearl River Delta showed a higher risk of TOX, CMV, and RV infections, with aORs of 2.21, 4.45, and 1.76, respectively. A history of pregnancy, gynecological diseases, and sexually transmitted infections were potentially associated with TORCH infections, but this association varied across pathogens. CONCLUSION: The findings of this study update the baseline of preconception TORCH infections among women with fertility desire in southern China, helping to estimate the risk of congenital infection and guide the development and implementation of effective prevention measures for preconception TORCH infections.

Activating Blood Circulation, Anti-Inflammatory and Diuretic Effects of Leonurus japonicus Extract on a Rat Model of Trauma Blood Stasis and Its Phytochemical Profiling.

Leonurus japonicus Houtt. has been traditionally used to treat many ailments. This study evaluated the activating blood circulation, anti-inflammatory, and diuretic effects of L. japonicus extract (LJ) and identified its phytochemicals. In this work, the phytochemicals in LJ were identified using liquid chromatography mass spectrometry. Rats were randomly assigned to three groups (n=8): Control group was treated with saline, while the Model group (saline) and LJ group (426 mg/kg) had induced traumatic injury. All rats were treated with once by daily oral gavage for one week. The biochemical indices and protein expression were measured. Herein, 79 constituents were identified in LJ, which were effective in elevating body weight, food consumption, water intake, and urinary excretion volume, as well as in ameliorating traumatic muscle tissues in model rats. In addition, LJ prominently decreased the contents of plasma viscosity, platelet aggregation rate, thrombin time, prothrombin time, activated partial thromboplastin time, fibrinogen, thromboxane B2 (TXB2), TXB2/6-keto-prostaglandin F1α (6-keto-PGF1α), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor 1 (PAI-1), PAI-1/tissue-type PA (t-PA), and PAI-1/u-PA, while significantly increasing antithrombin III, 6-keto-PGF1α, and t-PA contents. Furthermore, LJ notably inhibited tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, angiotensin II, antidiuretic hormone, aldosterone, aquaporin 1 (AQP1), AQP2, and AQP3 levels, and markedly elevating IL-10 and natriuretic peptide levels. Finally, LJ markedly reduced the protein expression of AQP1, AQP2, and AQP3 compared to the model group. Collectively, LJ possessed prominent activating blood circulation, anti-inflammatory, and diuretic effects, thus supporting the clinical application of L. japonicus.

Global dynamics of a generalist predator-prey model in open advective environments.

This paper deals with a system of reaction-diffusion-advection equations for a generalist predator-prey model in open advective environments, subject to an unidirectional flow. In contrast to the specialist predator-prey model, the dynamics of this system is more complex. It turns out that there exist some critical advection rates and predation rates, which classify the global dynamics of the generalist predator-prey system into three or four scenarios: (1) coexistence; (2) persistence of prey only; (3) persistence of predators only; and (4) extinction of both species. Moreover, the results reveal significant differences between the specialist predator-prey system and the generalist predator-prey system, including the evolution of the critical predation rates with respect to the ratio of the flow speeds; the take-over of the generalist predator; and the reduction in parameter range for the persistence of prey species alone. These findings may have important biological implications on the invasion of generalist predators in open advective environments.

Inhibitory Effect of Astragalus Polysaccharide Combined with Cisplatin on Cell Cycle and Migration of Nasopharyngeal Carcinoma Cell Lines.

Background Astragalus polysaccharide (APS) had shown great promise in anti-tumour activities in our previous studies. The present study was designed to investigate whether APS has synergistic effect with cisplatin on the growth-inhibitory of human nasopharyngeal carcinoma cell lines and the possible mechanism. Methods Here, nasopharyngeal carcinoma cell lines (CNE-1) were divided into CNE-1 group, Cisplatin treatment group (2 µg/mL Cisplatin), APS treatment group (200 µg/mL APS) and combination group (2 µg/mL Cisplatin and 200 µg/mL APS). The proliferation inhibition rate of CNE-1 cells was determined by Cell Counting Kit-8 (CCK-8) method after treatment with different concentrations of APS for 24, 48, and 72 h. Apoptosis rates and cell cycle retardation of cells were detected by flow cytometry. Cell migration and invasion was evaluated by transwell assay. Western blotting and quantitative (q)RT-PCR were performed to detect the expression of Bcl-2, Bax, caspase-3, matrix metalloproteinase-2 (MMP-2), p53 and matrix metalloproteinase-9 (MMP-9) proteins in CNE-1 cells. Results APS have an inhibition on the proliferation of CNE-1 cells with time and dose dependence manner. Both the APS and combination therapy could promote apoptosis of CNE-1 cells, with the count of cells increased in G0/G1 and S phase while decreased in G2/M phase, and inhibited the migration and invasion of CNE-1 cells. Moreover, co-administration of Cisplatin and APS was more efficacious for the antitumor effect than either agent alone, as evidenced by the significant decrease in MMP-9 level and increase in p53. Conclusion APS, in combination with cisplatin, had significantly synergistic growth-inhibitory effect on nasopharyngeal carcinoma cell lines, which may be related to cell cycle and migration induction.

Arbuscular mycorrhizal colonization rate of an exotic plant, Galinsoga quadriradiata, in mountain ranges changes with altitude.

Arbuscular mycorrhizal fungi (AMF) are suggested to be important for invasions by many exotic plants. However, it is not yet known how associations between AMF and invasive plant populations change in mountains ranges and how changed associations affect further expansion of different populations in new habitats. We conducted a field survey to detect AMF colonization rate of the invasive Galinsoga quadriradiata along an elevational gradient ranging from 223 to 1947 masl in the Qinling and Bashan Mountains, China. Additionally, a greenhouse experiment was conducted to compare plant growth performance among five elevational populations. In the field, total plant mass and seed production, as well as root AMF colonization rate, significantly decreased with elevation. When populations were grown in a novel soil environment in the greenhouse, the high-altitude populations achieved higher seed and total mass at lower AMF colonization rate than the low-altitude populations. Moreover, high AMF association was related to high intraspecific competition within low-altitude populations and limited seed production. Our results revealed that the associations between AMF and G. quadriradiata decrease with altitude in mountain ranges, and this may indicate that differentiation of association between AMF and elevational populations occurs during range expansion of G. quadriradiata. The results of the greenhouse experiment suggest that the high-altitude populations are more aggressive than the low-altitude populations in a non-stressful environment.

Effect of gal/GalNAc regioisomerism in galactosylated liposomes on asialoglycoprotein receptor-mediated hepatocyte-selective targeting in vivo.

In this study, we describe a novel synthesis of galactosylated lipids by lipase catalysis. Lactitol (Lac), galactose (Gal), or N-acetyl galactosamine (GalNAc) was coupled with cholesterol (CHS) as target head groups by enzyme-catalyzed regioselective esterification to produce three kinds of lipids: CHS-1-Gal, CHS-6-Gal, or CHS-6-GalNAc1. The biological effects of galactosylated lipids carrying different constitutional isomers of the pendent sugar species were investigated. LP-1-Gal (liposomes containing 5.0 molar% of CHS-1-Gal) showed strong binding to tetrameric lectins of Ricinus communis agglutinin (RCA120) in vitro, while LP-6-Gal (liposomes containing 5.0 molar% of CHS-6-Gal) and LP-6-GalNAc (liposomes containing 5.0 molar% of CHS-6-GalNAc) did not. After intravenous injection, LP-6-GalNAc, LP-1-Gal and LP-6-Gal rapidly disappeared from the blood and accumulated rapidly in liver (up to 74.88 ± 4.11%, 58.67 ± 5.75%, and 47.66 ± 4.56% of injected dose/g organ within 4 h, respectively). This is significantly higher than the uptake of unmodified liposomes (Unmod-LP) (18.67 ± 6.07%). Pre-injection of asialofetuin significantly inhibits liver uptake of Gal-liposomes (P < 0.01), with the degree of inhibition appearing in the following order: LP-6-GalNAc (73.29%) > LP-1-Gal (67.06%) > LP-6-Gal (53.61%). More importantly, LP-6-GalNAc was preferentially taken up by hepatocytes and the uptake ratio by parenchymal cells (PC) and nonparenchymal cells (NPC) (PC/NPC ratio) was 11.03 higher than LP-1-Gal (7.32), LP-6-Gal (5.83) and Unmod-LP (2.39). We suggest that liposomes containing the novel galactosylated lipid CHS-6-GalNAc have potential as drug delivery carriers for hepatocyte-selective targeting.

Invasion analysis on a predator-prey system in open advective environments.

We investigate a reaction-diffusion-advection system which characterizes the interactions between the predator and prey in advective environments, such as streams or rivers. In contrast with non-advective environments, the dynamics of this system is more complicated. It turns out that there exists a critical mortality rate of the predator and two critical advection rates, which classify the dynamic behavior of this system into two or three scenarios, that is, (i) both populations go extinct; (ii) the predator can not invade and the prey survives in the long run; (iii) the predator can invade successfully when rare and it will coexist permanently with the prey. Specially, the predator can invade successfully when rare if both the mortality rate of the predator and the advection rate are suitably small. Furthermore, by the global bifurcation theory and some auxiliary techniques, the existence and uniqueness of coexistence steady states of this system are established. Finally, by means of numerical simulations, the effects of diffusion on the dynamics of this system are investigated. The numerical results show that the random dispersals of both populations favor the invasion of the predator.

Spreading speed for a West Nile virus model with free boundary.

The purpose of this paper is to determine the precise asymptotic spreading speed of the virus for a West Nile virus model with free boundary, introduced recently in Lin and Zhu (J Math Biol 75:1381-1409, 2017), based on a model of Lewis et al. (Bull Math Biol 68:3-23, 2006). We show that this speed is uniquely defined by a semiwave solution associated with the West Nile virus model. To find such a semiwave solution, we firstly consider a general cooperative system over the half-line [Formula: see text], and prove the existence of a monotone solution by an upper and lower solution approach; we then establish the existence and uniqueness of the desired semiwave solution by applying this method together with some other techniques including the sliding method. Our result indicates that the asymptotic spreading speed of the West Nile virus model with free boundary is strictly less than that of the corresponding model in Lewis et al. (2006).

Five New Alkaloids from the Roots of Sophora flavescens.

Five new quinolizidine alkaloids, including three sparteine-type alkaloids (1 - 3) and two cytisine-type alkaloids (4 and 5), along with four known ones, were isolated from the roots of Sophora flavescens. Their structures were determined by extensive spectroscopic techniques including IR, UV, NMR, and HR-ESI-MS. All the compounds were evaluated for their antibacterial activities against Staphylococcus aureus and Escherichia coli.

Algal competition in a water column with excessive dioxide in the atmosphere.

This paper deals with a resource competition model of two algal species in a water column with excessive dioxide in the atmosphere. First, the uniqueness of positive steady state solutions to the single-species model with two resources is established by the application of the degree theory and the strong maximum principle for the cooperative system. Second, some asymptotic behavior of the single-species model is given by comparison principle and uniform persistence theory. Third, the coexistence solutions to the competition system of two species with two substitutable resources are obtained by global bifurcation theory, various estimates and the strong maximum principle for the cooperative system. Numerical simulations are used to illustrate the outcomes of coexistence and competitive exclusion.

High-Yield Spreading of Water-Miscible Solvents on Water for Langmuir-Blodgett Assembly.

Langmuir-Blodgett (LB) assembly is a classical molecular thin-film processing technique, in which the material is spread onto water surface from a volatile, water-immiscible solvent to create floating monolayers that can be later transferred to solid substrates. LB has also been applied to prepare colloidal thin films with an unparalleled level of microstructural control and thickness, which has enabled the discovery of many exciting collective properties of nanoparticles and the construction of bulk nanostructured materials. To maximize the benefits of LB assembly, the nanoparticles should be well dispersed in both the spreading solvent and on water. This is quite challenging since colloids usually need contrasting surface properties in order to be stable in the water-hating organic solvents and on water surface. In addition, many organic and polymeric nanostructures dissolve in those organic solvents and cannot be processed directly. Using water-liking spreading solvents can avoid this dilemma. However, spreading of water-miscible solvents on water surface is fundamentally challenging due to extensive mixing, which results in significant material loss. Here we report a conceptually simple strategy and a general technique that allows nearly exclusive spreading of such solvents on water surface using electrospray. Since the volume of these aerosolized droplets is reduced by many orders of magnitude, they are readily depleted during the initial spreading step before any significant mixing could occur. The new strategy drastically reduces the burden of material processing prior to assembly and broadens the scope of LB assembly to previously hard-to-process materials. It also avoids the use of toxic volatile organic spreading solvents, improves the reproducibility, and can be readily automated, making LB assembly a more robust tool for colloidal assembly and thin-film fabrication.

A novel self-assembling peptide with UV-responsive properties.

A novel heptapeptide comprising Ile-Gln-Ser-Pro-His-Phe-Phe (IQSPHFF) identified and found to undergo self-assembly into microparticles in solution. To understand the effects of ultraviolet (UV) irradiation on the self-assembly process, IQSPHFF solutions were exposed to the UV light of 365 nm at room temperature. This exposure was found to have a profound effect on the morphology of the self-assembled aggregates, converting the microparticles to nanorod shapes. Circular dichroism and FTIR studies indicated distinct structural differences in the arrangements of the peptide moieties before and after UV irradiation. However, Mass spectrum analysis and high performance liquid chromatography of the peptide molecules before and after UV irradiation demonstrated that the chemical structure of IQSPHFF was not changed. UV-visible spectroscopy and fluorescence spectroscopy studies showed that the absorption peak both increased after UV irradiation. Overall, our data show that the heptapeptide with UV-responsive properties.

Dynamical analysis of a diffusive population-toxicant model with toxicant-taxis in polluted aquatic environments.

This paper deals with a diffusive population-toxicant model in polluted aquatic environments, with a toxicant-taxis term describing a toxicant-induced behavior change, that is, the population tends to move away from locations with high-level toxicants. The global existence of solutions is established by the techniques of the semigroup estimation and Moser iteration. Based on a detailed study on the properties of the principal eigenvalue for non-self-adjoint eigenvalue problems, we investigated the local and global stability of the toxin-only steady-state solution and the existence of positive steady state, which yields sufficient conditions that lead to population persistence or extinction. Finally, by numerical simulations, we studied the effects of some key parameters, such as toxicant-taxis coefficient, advection rate, and effect coefficient of the toxicant on population growth, on population persistence. Both numerical and analytical results show that a weak chemotaxis effect, a small advection rate of the population, and a weak effect of the toxicant on population growth are favorable for population persistence.

Neural epidermal growth factor-like 1 protein (Nell-1) alleviates periodontal tissue destruction in periodontitis by regulating the ratio of M2/M1 macrophage phenotypes.

BACKGROUND: Periodontitis is a common oral disease with high prevalence worldwide. Neural epidermal growth factor-like 1 protein (Nell-1) has recently been reported to have anti-inflammation effects and may be a drug candidate for osteoarthritis. However, its immunotherapeutic effects in periodontitis remain unknown. Therefore, this study aimed to investigate the effects of Nell-1 on periodontitis in terms of macrophage polarization and analyze its possible underlying mechanism. METHODS: A rat ligation-induced experimental periodontitis model was established and locally injected with Nell-1 (n = 6/group). Periodontal tissue destruction and macrophage polarization in vivo were analyzed using micro-CT, histology analysis, and western blot. Enzyme-linked immunosorbent assay was used to evaluate serum inflammatory cytokines. Then, the RAW 264.7 macrophage cells were treated with lipopolysaccharide (LPS), Nell-1, and the c-Jun N-terminal kinases (JNK) inhibitor (SP600125). RT-PCR, western blot, and flow cytometry were performed to further analyze the effect of Nell-1 on macrophage polarization and the underlying mechanism in vitro. RESULTS: Local treatment with Nell-1 significantly alleviated the destruction of alveolar bone and fibers in periodontitis, and upregulated the ratio of M2/M1 macrophages in periodontal tissues (P < 0.05). In vitro, Nell-1 at the concentrations of 200 and 500 ng/mL could significantly inhibit the expression of M1-related inflammatory factors in LPS-stimulated macrophages, and increase the expression of M2-related markers, regulating the macrophage phenotype switch into M2 (P < 0.05). The mRNA of JNK and relative protein level of phospho-JNK/JNK were also upregulated by Nell-1 (P < 0.05). Additionally, the JNK inhibitor (SP600125) could reverse the effect of Nell-1 on macrophage polarization (P < 0.05). CONCLUSIONS: Nell-1 could modulate the ratio of M2/M1 macrophages possibly through the JNK/MAPK signaling pathway, subsequently attenuating the inflammation and destruction of periodontal tissues caused by periodontitis.

Targeted liposomes encapsulated iridium(III) compound greatly enhance anticancer efficacy and induce cell death via ferroptosis on HepG2 cells.

In this study, ligands 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (PIP), 2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (NPIP), 2-(2-nitronaphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NNIP) and their iridium(III) metal compounds [Ir(ppy)2(PIP)](PF6) (ppy = 2-phenylpyridine, 1a), [Ir(ppy)2(NPIP)](PF6) (1b), [Ir(ppy)2(NNIP)](PF6) (1c) were designed and synthesized. The anti-cancer activities of 1a, 1b and 1c on BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 were detected using MTT method. 1a shows moderate, 1b and 1c display low or no anti-cancer activities. To elevate the anti-cancer effectiveness, encapsulating the compounds 1a, 1b and 1c into the ordinary or targeted liposomes to produce 1alip, 1blip, 1clip, or targeted 1aTlip, 1bTlip and 1cTlip. The IC50 values of 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against HepG2 cells are 7.9 ± 0.1, 8.6 ± 0.2, 16.9 ± 0.5, 5.9 ± 0.2, 7.3 ± 0.1 and 9.7 ± 0.7 µM, respectively. Specifically, the anti-tumor activity assays in vivo found that the inhibitory rates are 23.24 % for 1a, 61.27 % for 1alip, 76.06 % for 1aTlip. It is obvious that the targeted liposomes entrapped iridium(III) compound greatly enhance anti-cancer efficacy. Additionally, 1alip, 1blip and 1clip or targeted 1aTlip, 1bTlip and 1cTlip can effectively restrain the cell colony and proliferation in the G0/G1 period. 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip can increase reactive oxygen species (ROS) concentration, arouse a decline in the mitochondrial membrane potential and promote Ca2+ release. RNA-sequence was applied to examine the signaling pathways. Taken together, the liposomes or targeted liposomes encapsulated compounds trigger cell death by way of apoptosis, autophagy, ferroptosis, disruption of mitochondrial function and PI3K/AKT/mTOR signaling pathways.

Maternal Hypertension and Fecundability: A Population-Based Cohort Study.

BACKGROUND: The association of hypertension and blood pressure control with fecundability among women is not yet elucidated. The purpose of this study was to evaluate the hypothesis that maternal preconception hypertension would be associated with reduced fecundability and that blood pressure control could reduce excess risk. METHODS: Using the National Free Preconception Checkup Projects in Guangdong Province, China, 1422 couples whose female partners had been diagnosed with hypertension and 997 703 reference couples whose female partners were without hypertension were included in this prospective cohort study. Fecundability was measured by time to pregnancy (TTP) and infertility (TTP >12 months). RESULTS: Compared with women without hypertension, those with controlled hypertension (time ratio, 1.47 [95% CI, 1.24-1.73]) or uncontrolled hypertension (time ratio, 1.59 [95% CI, 1.34-1.90]) were associated with prolonged TTP and increased risk of infertility (relative risk, 1.19 [95% CI, 1.09-1.31]; relative risk, 1.24 [95% CI, 1.14-1.34]). However, using instrumental variable analyses, there was no significant association between blood pressure control and TTP (time ratio, 0.68 [95% CI, 0.34-1.36]; P=0.270) or infertility (relative risk, 0.97 [95% CI, 0.70-1.34]; P=0.849) among women with hypertension. These results were consistent in the propensity score matching and inverse probability of treatment weighting analyses. CONCLUSIONS: Maternal hypertension, with or without controlled blood pressure, was independently associated with prolonged TTP and an increased risk of infertility. These findings may provide insights for the implementation of preconception hypertension screening and the design of future trials.