Temporal-spatial Generation of Astrocytes in the Developing Diencephalon.

Astrocytes are the largest glial population in the mammalian brain. However, we have a minimal understanding of astrocyte development, especially fate specification in different regions of the brain. Through lineage tracing of the progenitors of the third ventricle (3V) wall via in-utero electroporation in the embryonic mouse brain, we show the fate specification and migration pattern of astrocytes derived from radial glia along the 3V wall. Unexpectedly, radial glia located in different regions along the 3V wall of the diencephalon produce distinct cell types: radial glia in the upper region produce astrocytes and those in the lower region produce neurons in the diencephalon. With genetic fate mapping analysis, we reveal that the first population of astrocytes appears along the zona incerta in the diencephalon. Astrogenesis occurs at an early time point in the dorsal region relative to that in the ventral region of the developing diencephalon. With transcriptomic analysis of the region-specific 3V wall and lateral ventricle (LV) wall, we identified cohorts of differentially-expressed genes in the dorsal 3V wall compared to the ventral 3V wall and LV wall that may regulate astrogenesis in the dorsal diencephalon. Together, these results demonstrate that the generation of astrocytes shows a spatiotemporal pattern in the developing mouse diencephalon.

8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin.

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)2(8HQ)]PF6 (Ru1), [Ru(dpq)2(8HQ)]PF6 (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC50 = 1.98 ± 0.02 µM) and Ru2 (IC50 = 10.02 ± 0.19 µM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 µM and 60 µM were safe and did not have obvious effect on the normal development of zebrafish embryos.

Krüppel-like factor 7 deficiency disrupts corpus callosum development and neuronal migration in the developing mouse cerebral cortex.

Krüppel-like Factor 7 (KLF7) is a zinc finger transcription factor that has a critical role in cellular differentiation, tumorigenesis, and regeneration. Mutations in Klf7 are associated with autism spectrum disorder, which is characterized by neurodevelopmental delay and intellectual disability. Here we show that KLF7 regulates neurogenesis and neuronal migration during mouse cortical development. Conditional depletion of KLF7 in neural progenitor cells resulted in agenesis of the corpus callosum, defects in neurogenesis, and impaired neuronal migration in the neocortex. Transcriptomic profiling analysis indicated that KLF7 regulates a cohort of genes involved in neuronal differentiation and migration, including p21 and Rac3. These findings provide insights into our understanding of the potential mechanisms underlying neurological defects associated with Klf7 mutations.

Frequent exacerbators of chronic obstructive pulmonary disease have distinguishable sputum microbiome signatures during clinical stability.

Introduction: Frequent exacerbation phenotype of chronic obstructive pulmonary disease (COPD) represents a more concerning disease subgroup requiring better prevention and intervention, of which airway microbiome provides new perspective for further exploration. Methods: To investigate whether frequent exacerbators of COPD have distinguishable sputum microbiome during clinical stability, COPD patients at high disease grades with or without frequent exacerbation were recruited for sputum microbiome analysis. Sputum samples were collected during clinical stability and underwent 16S rRNA sequencing, which was then subjected for amplicon sequence variants (ASVs)-based microbiome analysis. Results: Our results revealed that compared with healthy controls and infrequent exacerbators, frequent COPD exacerbators have distinguishably dysbiotic sputum microbiome, as featured by fewer ASVs features, lower alpha diversity, distinct beta diversity patterns. Further taxonomic compositional analysis illustrated the structural distinctions between frequent COPD exacerbators and infrequent exacerbators at differential taxa levels and highlighted Stenotrephomonas due to its prominent elevation in frequent COPD exacerbators, providing a promising candidate for further exploration of microbiome biomarker. Moreover, we also demonstrated that frequent exacerbation phenotype is distinguishable from infrequent exacerbation phenotype with respect of functional implications. Conclusion: Our study demonstrated the first positive correlation between the frequent exacerbation phenotype of COPD and the sputum microbiome during clinical stability in a single-center Chinese COPD cohort and provide potential diagnostic and therapeutic targets for further investigation.

Conditional knockout of leptin receptor in neural stem cells leads to obesity in mice and affects neuronal differentiation in the hypothalamus early after birth.

Leptin, secreted by peripheral adipocytes, binds the leptin receptor (Lepr) in the hypothalamus, thereby contributing to the regulation of satiety and body weight. Lepr is expressed in the embryonic brain as early as embryonic day 12.5. However, the function of Lepr in neural precursor cells in the brain has not been resolved. To address this issue, we crossed the Leprflox/flox mice with each of Shh-Cre mice (Shh, sonic hedgehog) and Nestin (Nes)-Cre mice. We found that deletion of Lepr specifically in nestin-expressing cells led to extreme obesity, but the conditional null of Lepr in Shh-expressing cells had no obvious phenotype. Moreover, the level of leptin-activated pSTAT3 decreased in the anterior and central subregions of the arcuate hypothalamus of Shh-Cre; Leprflox/flox mice compared with the controls. By contrast, in Nes-Cre; Leprflox/flox mice, the level of leptin-activated pSTAT3 decreased in all subregions including the anterior, central, and posterior arcuate hypothalamus as well as the dorsomedial, ventromedial, and median eminence of the hypothalamus, revealing that the extensive lack of Lepr in the differentiated neurons of the hypothalamus in the conditional null mice. Notably, conditional deletion of Lepr in nestin-expressing cells enhanced the differentiation of neural precursor cells into neurons and oligodendroglia but inhibited differentiation into astrocytes early in postnatal development of hypothalamus. Our results suggest that Lepr expression in neural precursor cells is essential for maintaining normal body weight as well as the differentiation of neural precursor cells to the neural/glial fate in the hypothalamus shortly after birth.

Berberine alleviates endothelial glycocalyx degradation and promotes glycocalyx restoration in LPS-induced ARDS.

In the pathogenesis of acute respiratory distress syndrome (ARDS), an increase in vascular endothelial permeability may trigger pulmonary edema and ultimately lead to respiratory failure. Endothelial glycocalyx damage is an important factor that causes an increase in vascular endothelial permeability. Berberine (BBR) is an isoquinoline alkaloid extracted from Coptis chinensis, a plant used in traditional Chinese medicine that exerts multiple pharmacological effects. In this study, pretreatment with BBR inhibited the increase in vascular endothelial permeability in mice with lipopolysaccharide (LPS)-induced ARDS. BBR pretreatment inhibited the shedding of syndecan-1 (SDC-1) and heparan sulfate (HS), which are important components of the endothelial glycocalyx that lessen endothelial glycocalyx damage. BBR further significantly inhibited increases in important endothelial glycocalyx damage factors, including reactive oxygen species (ROS), heparanase (HPA), and matrix metalloproteinase 9 (MMP9) in LPS-induced ARDS mice and in LPS-stimulated human umbilical vein endothelial cells. BBR pretreatment also decreased the production of pro-inflammatory cytokines TNF-α, IL-1ß, IL-6, and inhibited NF-κB signaling pathway activation in LPS-induced ARDS. In addition, BBR promoted the recovery of SDC-1 and HS content in injured endothelial glycocalyx after LPS treatment and accelerated its restoration. This is the first report of BBR maintaining the integrity of endothelial glycocalyx. These results provide a new theoretical basis for the use of BBR in the treatment of ARDS and other diseases related to endothelial glycocalyx damage.

Natural Sugar: A Green Assistance To Efficiently Exfoliate Inorganic Layered Nanomaterials.

We have demonstrated that natural sugars can efficiently exfoliate inorganic layered nanomaterials with direct stirring. The representative transition-metal dichalcogenides (MoS2 and WS2), transition-metal oxide (MoO3), and graphene were explored, and the formation of ultrathin nanosheets was verified. Glucose and MoS2 selected each other as the perfect partner with superior exfoliation and excellent properties. The obtained inorganic layered nanosheets possess favorable stability and dispersity, which renders it suitable for direct homogeneous liquid applications, such as catalytic activities and sensors. With a high-throughput and green process, the sugar-assisted method may offer new ideas for inorganic layered nanomaterials synthesis and applications in a more ecofriendly way.

New beta-caryophyllene-derived terpenoids from the soft coral Sinularia nanolobata.

Two new norsesquiterpenoids, nanonorcaryophyllenes A (1) and B (2), two new diterpenoids, nanolobatins A (3) and B (4), and a novel norditerpenoid, nanolobatin C (5), were isolated from the n-hexane extract of the Taiwanese soft coral Sinularia nanolobata. Also, two new furanone derivatives, 6 and 7, were isolated for the first time from natural sources. The structures of 1-5 were elucidated on the basis of extensive spectroscopic analyses and by comparison of the spectral data with those of the related metabolites. Nanonorcaryophyllenes A (1) and B (2) were characterized as 13-norcaryophyllenes that lack a methyl group at C-11, while nanolobatin C (5) represents the first example of a xeniaphyllane-based 17-norditerpenoid. The cytotoxicity of 1-6 against the growth of a limited panel of cancer cell lines is also described.