The placenta is crucial for a successful pregnancy and the health of both the fetus and the pregnant woman. However, how the human trophoblast lineage is regulated, including the categorization of ...the placental cell subtypes is poorly understood. Here we performed single-cell RNA sequencing (RNA-seq) on sorted placental cells from first- and second-trimester human placentas. New subtypes of cells of the known cytotrophoblast cells (CTBs), extravillous trophoblast cells (EVTs), Hofbauer cells, and mesenchymal stromal cells were identified and cell-type-specific gene signatures were defined. Functionally, this study revealed many previously unknown functions of the human placenta. Notably, 102 polypeptide hormone genes were found to be expressed by various subtypes of placental cells, which suggests a complex and significant role of these hormones in regulating fetal growth and adaptations of maternal physiology to pregnancy. These results document human placental trophoblast differentiation at single-cell resolution and thus advance our understanding of human placentation during the early stage of pregnancy.
Extracellular vesicles (EVs) hold great potential in both disease treatment and drug delivery. However, accurate drug release from EVs, as well as the spontaneous treatment effect cooperation of EVs ...and drugs at target tissues, is still challenging. Here, an engineered self‐activatable photo‐EV for synergistic trimodal anticancer therapy is reported. M1 macrophage‐derived EVs (M1 EVs) are simultaneously loaded with bis2,4,5‐trichloro‐6‐(pentyloxycarbonyl) phenyl oxalate (CPPO), chlorin e6 (Ce6), and prodrug aldoxorubicin (Dox‐EMCH). After administration, the as‐prepared system actively targets tumor cells because of the tumor‐homing capability of M1 EVs, wherein M1 EVs repolarize M2 to M1 macrophages, which not only display immunotherapy effects but also produce H2O2. The reaction between H2O2 and CPPO generates chemical energy that activates Ce6, creating both chemiluminescence for imaging and singlet oxygen (1O2) for photodynamic therapy (PDT). Meanwhile, 1O2‐induced membrane rupture leads to the release of Dox‐EMCH, which is then activated and penetrates the deep hypoxic areas of tumors. The synergism of immunotherapy, PDT, and chemotherapy results in potent anticancer efficacy, showing great promise to fight cancers.
Self‐activatable photo‐extracellular vesicles are constructed by loading M1‐macrophage‐derived EVs with bis2,4,5‐trichloro‐6‐(pentyloxycarbonyl)phenyl oxalate, chlorin e6, and prodrug aldoxorubicin. These skillfully engineered extracellular vesicles can actively target tumors owing to their inherent tumor‐homing ability, wherein they exhibit potent trimodal therapy effects in an intersynergistic and self‐controllable way, attributed to the interaction between the engineered EV and the special tumor microenvironment.
Chiral materials have been widely present in people's lives, and their in-depth application research is underway. Generally, the circularly polarized light obtained from nonpolarized light through ...filters would result in brightness loss. Scientists have found that chirality can be introduced into organic compounds to obtain circularly polarized luminescence (CPL). Chiral compounds with CPL properties have attracted great attention and interest in recent years for their wide potential applications in 3D information displays, quantum communication, spintronics information storage, CPL lasers, nonlinear optics, biological probes and other fields. It is worth noting that helicene derivatives with twisted extended π-conjugated molecular structures could exhibit special helical chirality and excellent CPL properties. A chiral helix has also proven to be a valuable structural design for exploring small organic molecules with CPL. This review summarizes the recent development of CPL based on helicene derivatives.
This review summarizes the recent research progress of helicenes and their derivatives with circularly polarized luminescence properties.
Scutellaria baicalensis root is traditionally used for the treatment of common cold, fever and influenza. Flavonoids are the major chemical components of S. baicalensis root.
To evaluate the ...therapeutic effects and action mechanism of flavonoids-enriched extract from S. baicalensis root (FESR) on acute lung injury (ALI) induced by influenza A virus (IAV) in mice.
The anti-influenza, anti-inflammatory and anti-complementary properties of FESR and the main flavonoids were evaluated in vitro. Mice were challenged intranasally with influenza virus H1N1 (A/FM/1/47) 2 h before treatment. FESR (50, 100 and 200 mg/kg) was administrated intragastrically. Baicalin (BG), the most abundant compound in FESR was given as reference control. Survival rates, life spans and lung indexes of IAV-infected mice were measured. Histopathological changes, virus levels, inflammatory markers and complement deposition in lungs were analyzed.
Compared with the main compound BG, FESR and lower content aglycones (baicalein, oroxylin A, wogonin and chrysin) in FESR significantly inhibited H1N1 activity in virus-infected Madin-Darby canine kidney (MDCK) cells and markedly decreased nitric oxide (NO) production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In vitro assays showed that FESR and BG had no anti-complementary activity whereas baicalein, oroxylin A, wogonin and chrysin exhibited obvious anti-complementary activity.
Oral administration of FESR effectively protected the IAV-infected mice, increased the survival rate (FESR: 67%; BG: 33%), decreased the lung index (FESR: 0.90; BG: 1.00) and improved the lung morphology in comparing with BG group. FESR efficiently decreased lung virus titers, reduced haemagglutinin (HA) titers and inhibited neuraminidase (NA) activities in lungs of IAV-infected mice. FESR modulated the inflammatory responses by decreasing the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), and increasing the levels of interferon-γ (IFN-γ) and interleukin-10 (IL-10) in lung tissues. Although showing no anti-complementary activity in vitro, FESR obviously reduced complement deposition and decreased complement activation product level in the lung .
FESR has a great potential for the treatment of ALI induced by IAV and the underlying action mechanism might be closely associated with antiviral, anti-inflammatory and anti-complementary properties. Furthermore, FESR resulted in more potent therapeutic effect than BG in the treatment of IAV-induced ALI.
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Abstract
Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in ...extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet β-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.
Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted ...tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.
The efficient construction of enantiomerically enriched molecules from simple starting materials via catalytic asymmetric synthesis strategies is a key challenge in synthetic chemistry. Metallated ...azomethine ylides are commonly-used synthons for the preparation of N-heterocycles and α-amino acids. Remarkably, to date, the utilization of azomethine ylides for the facile access to chiral amines has proven elusive. Here, we report that a synergistic Cu/Ir-catalytic system combined with careful tuning of the steric congestion can be used to convert aldimine esters to a variety of chiral homoallylic amines via a cascade allylation/2-aza-Cope rearrangement. The elucidation of the distinct effects of each stereogenic center of the allylation intermediates on the stereochemical outcome and chirality transfer in the rearrangement further guided the selection of catalysts combination.
Follicle dysplasia can cause polycystic ovary syndrome, which can lead to anovulatory infertility. This study explored gene(s) that may contribute to polycystic ovary syndrome.
Three animal models of ...polycystic ovary syndrome were created by treating 3-week-old rats respectively with estradiol valerate, testosterone propionate, or constant illumination for 8 weeks. Granulosa cells from the three disease groups and from healthy controls were transcriptionally profiled to identify differentially expressed genes. The phosphodiesterase-4d (Pde4d) was screened as the most promising candidate pathogenic gene. The Pde4d was overexpressed in rats via intrabursal infection with recombinant lentivirus to see the effect of Pde4d on ovarian morphology. The potential roles of the candidate gene and interactors of the encoded protein were explored using polymerase chain reaction, western blotting, transfection and co-immunoprecipitation.
All three rat models of polycystic ovary syndrome showed polycystic ovary phenotype. Seven promising candidate genes were obtained by transcriptomics and verifications. Pde4d was further investigated because it could trigger downstream signaling pathways. The Pde4d overexpression in rat ovary induced cystic follicles. It inhibited follicle maturation through a mechanism involving inhibition of cAMP-PKA-CREB signaling. The Pde4d also inhibited phosphorylation of c-Jun N-terminal kinase to reduce apoptosis in the ovary, through a mechanism involving interaction of its poly-proline domain with the protein POSH.
Upregulation of Pde4d may contribute to polycystic ovary syndrome by impeding follicle maturation and preventing apoptotic atresia.
•Pde4d is identified as a promising pathogenic gene of polycystic ovary.•The catalytic activity of Pde4d blocks follicle maturation.•The N-terminal poly-proline domain of Pde4d prevents follicle atresia.•Pde4d upregulation allows immature follicles to escape atresia and survive, contributing to polycystic ovary syndrome.
Objective
This study aimed to determine the effects of diet‐induced paternal obesity on cognitive function in mice offspring.
Methods
Male mice (F0) were randomized to receive either a control diet ...(10 kcal% fat) or a high‐fat diet (HFD; 60 kcal% fat) for 10 weeks before being mated with normal females to generate F1 offspring. Male F1 offspring were mated with normal females to generate F2 offspring. Behavioral tests were used to assess cognitive functions in F1 and F2 offspring. Reduced representation bisulfite sequencing was used to the explore mechanisms of epigenetic inheritance.
Results
HFD‐induced paternal obesity resulted in cognitive impairments in F1 offspring, potentially due, at least in part, to increased methylation of the BDNF gene promoter, which was inherited from F0 spermatozoa. BDNF/tyrosine receptor kinase B signaling was associated with cognitive impairments in HFD‐fed F1 offspring. However, there were no significant changes in F2 offspring.
Conclusions
The findings provide evidence of intergenerational effects of paternal obesity on cognitive function in offspring occurring via epigenetic spermatozoan modifications.
Hypoxic microenvironment severely reduces therapeutic efficacy of oxygen‐dependent photodynamic therapy in solid tumor due to the hampered cytotoxic oxygen radicals generation. Herein, a ...biocompatible nanoparticle (NP) is developed by combining bovine serum albumin, indocyanine green (ICG), and an oxygen‐independent radicals generator (AIPH) for efficient sequential cancer therapy, denoted as BIA NPs. Upon near‐infrared irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, such nanosystem provides the highest AIPH loading capacity (14.9%) among all previously reported radical nanogenerators (generally from 5–8%). Additionally, the aggregation‐quenched fluorescence of ICG molecules in the NPs can be gradually released and recovered upon irradiation enabling real‐time drug release monitoring. More attractively, these BIA NPs exhibit remarkable anticancer effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate among 50 days treatment. These results highlight that this albumin‐based nanoplatform is promising for high‐performance cancer therapy circumventing hypoxic tumor environment and possessing great potential for future clinical translation.
A biocompatible free radical nanogenerator is developed based on albumin, indocyanine green, and thermal‐labile molecules for effective hypoxic cancer therapy. Under laser irradiation, this nanoagent can generate toxic free radicals in both normoxia and hypoxia. Meanwhile, the nanogenerator provides a high drug loading capability and real‐time drug release monitoring ability a which enables it with multifunctionality and high therapeutic performance.
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