Nickel-catalyzed C(sp2)-C(sp3) coupling via photoactive electron donor-acceptor complexes.

We have developed a novel Ni-catalyzed reductive cross-coupling reaction of aryl bromides and alkyl iodides via a photoactive electron donor-acceptor (EDA) complex. This photo-induced process enables the efficient construction of C(sp2)-C(sp3) bonds in the absence of an external photocatalyst. Electronically and structurally diverse aryl bromides, as well as secondary and primary alkyl iodides could undergo this transformation smoothly. Natural product derivatives were employed successfully, and UV-vis spectroscopy was utilized to gain mechanistic insight.

Endocrine disrupting effects of parabens in zebrafish (Danio rerio): New insights from transcriptomics, metabolomics, and molecular dynamics simulation.

Parabens (PBs), a group of widely used synthetic preservatives with potential endocrine disrupting activity, have been detected with increasing frequency in organisms and environmental matrices. This study assessed the hormone interference effects of four typical PBs, namely methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP), in zebrafish and elucidated the probable underlying mechanisms. Transcriptomic and metabolomic analyses showed that the differentially expressed genes and metabolites were associated with the tyrosine metabolism, arachidonate metabolism, and glycerophospholipid metabolism, indicating they were essential precursors of steroid hormone biosynthesis and metabolism. Histopathological analysis revealed impaired gonad development in the zebrafish exposed to PBs, as evidenced by the significantly increased vitellogenin (VTG) and estradiol (E2) levels. Furthermore, molecular dynamics simulation suggested that the four PBs could preferentially activate the zebrafish estrogen receptor, zfERß2, to regulate the downstream pathways. Disruption of the amino acid metabolism and lipid metabolism, and activation of zfERß2 signaling pathway were found to be the key mechanisms for the endocrine disrupting effects of PBs. The hormone interference effects of PBs were apparently dependent on the shared oxybenzene on their structures, with the degree of interference determined largely by the length of their alkyl chains. These findings provide new insights into the endocrine disrupting effects of PBs and could help better assess their risk to human health.

Nontargeted Identification of Organic Components in Fine Particulate Matter Related to Lung Tumor Metastasis Based on an Adverse Outcome Pathway Strategy.

Emerging studies implicate fine particulate matter (PM2.5) and its organic components (OCs) as urgent hazard factors for lung cancer progression in nonsmokers. Establishing the adverse outcome pathway (AOP)-directed nontargeted identification method, this study aimed to explore whether PM2.5 exposure in coal-burning areas promoted lung tumor metastasis and how we identify its effective OCs to support traceability and control of regional PM2.5 pollution. First, we used a nude mouse model of lung cancer for PM2.5 exposure and found that the exposure significantly promoted the hematogenous metastases of A549-Luc cells in lung tissues and the adverse outcomes (AOs), with key events (KEs) including the changed expression of epithelial-mesenchymal transition (EMT) markers, such as suppression of E-cad and increased expression of Fib. Subsequently, using AOs and KEs as adverse outcome directors, we identified a total of 35 candidate chemicals based on the in vitro model and nontargeted analysis. Among them, tributyl phosphate (C12H27O4P), 2-bromotetradecane (C14H29Br), and methyl decanoate (C11H22O2) made greater contributions to the AOs. Finally, we clarified the interactions between these OCs and EMT-activating transcription factors (EMT-ATFs) as the molecular initiation event (MIE) to support the feasibility of the above identification strategy. The present study updates a new framework for identifying tumor metastasis-promoting OCs in PM2.5 and provides solid data for screening out chemicals that need priority control in polluted areas posing higher lung cancer risk.

Lung injuries induced by ozone exposure in female mice: Potential roles of the gut and lung microbes.

Ozone (O3) is one of the most harmful pollutants affecting health. However, the potential effects of O3 exposure on microbes in the gut-lung axis related to lung injuries remain elusive. In this study, female mice were exposed to 0-, 0.5- and 1-ppm O3 for 28 days, followed by routine blood tests, lung function tests and histopathological examination of the colon, nasal cavity and lung. Mouse faeces and lungs were collected for 16s rRNA sequencing to assess the overall microbiological profile and screen for key differential enriched microbes (DEMs). The key DEMs in faecal samples were Butyricimonas, Rikenellaceae RC9 and Escherichia-Shigella, whereas those in lung samples were DNF00809, Fluviicola, Bryobacter, Family XII AD3011 group, Sharpea, MND1 and unclassified Phycisphaeraceae. After a search in microbe-disease databases, these key DEMs were found to be associated with lung diseases such as lung neoplasms, cystic fibrosis, pneumonia, chronic obstructive pulmonary disease, respiratory distress syndrome and bronchiectasis. Subsequently, we used transcriptomic data from Gene Expression Omnibus (GEO) with exposure conditions similar to those in this study to cross-reference with Comparative Toxicogenomic Database (CTD). Il-6 and Ccl2 were identified as the key causative genes and were validated. The findings of this study suggest that exposure to O3 leads to significant changes in the microbial composition of the gut and lungs. These changes are associated with increased levels of inflammatory factors in the lungs and impaired lung function, resulting in an increased risk of lung disease. Altogether, this study provides novel insights into the role of microbes present in the gut-lung axis in O3 exposure-induced lung injury.

Invisible Hand behind Female Reproductive Disorders: Bisphenols, Recent Evidence and Future Perspectives.

Reproductive disorders are considered a global health problem influenced by physiological, genetic, environmental, and lifestyle factors. The increased exposure to bisphenols, a chemical used in large quantities for the production of polycarbonate plastics, has raised concerns regarding health risks in humans, particularly their endocrine-disrupting effects on female reproductive health. To provide a basis for future research on environmental interference and reproductive health, we reviewed relevant studies on the exposure patterns and levels of bisphenols in environmental matrices and humans (including susceptible populations such as pregnant women and children). In addition, we focused on in vivo, in vitro, and epidemiological studies evaluating the effects of bisphenols on the female reproductive system (the uterus, ovaries, fallopian tubes, and vagina). The results indicate that bisphenols cause structural and functional damage to the female reproductive system by interfering with hormones; activating receptors; inducing oxidative stress, DNA damage, and carcinogenesis; and triggering epigenetic changes, with the damaging effects being intergenerational. Epidemiological studies support the association between bisphenols and diseases such as cancer of the female reproductive system, reproductive dysfunction, and miscarriage, which may negatively affect the establishment and maintenance of pregnancy. Altogether, this review provides a reference for assessing the adverse effects of bisphenols on female reproductive health.

Group†14 Elements Hetero-Difunctionalizations via Nickel-Catalyzed Electroreductive Cross-Coupling.

The difunctionalization of unsaturated bonds plays a vital role in the enrichment of molecular complexity. While various catalytic methods for alkene and alkyne difunctionalization have been developed in recent years, hetero-functionalization the introduction of two different atoms has been less explored. This is mainly due to the challenges associated with achieving high chemo-, regio-, and stereoselectivity, especially when adding two similar atoms from the same group across unsaturated bonds. In this study, we describe a nickel-catalyzed, three-component reductive protocol for group 14 element hetero-difunctionalization of 1,3-enynes using electrochemistry. This new method is mild, selective, and general, allowing for the silyl-, germanyl-, and stannyl-alkylation of enynes. Various chlorosilanes as well as chlorogermans, and chlorostannanes can be successfully used in combination with aryl/alkyl-substituted 1,3-enynes and primary, secondary, and tertiary alkyl bromides in the electroreductive coupling.

Bisphenol B and bisphenol AF exposure enhances uterine diseases risks in mouse.

Bisphenol A (BPA) analogs, bisphenol B (BPB) and bisphenol AF (BPAF) have been widely detected in the environment and human products with increasing frequency. However, uterine health risks caused by BPB and BPAF exposure need to be further elucidated. The study aimed to explore whether BPB or BPAF exposure will induce adverse outcomes in uterus. Female CD-1 mice were continuously exposed to BPB or BPAF for 14 and 28 days. Morphological examination showed that BPB or BPAF exposure caused endometrial contraction, decreased epithelial height, and increased number of glands. Bioinformatics analysis indicated that both BPB and BPAF disturbed the immune comprehensive landscape of the uterus. In addition, survival and prognosis analysis of hub genes and tumor immune infiltration evaluation were performed. Finally, the expression of hub genes was verified by quantitative real-time PCR (qPCR). Disease prediction found that eight of the BPB and BPAF co-response genes, which participated in the immune invasion of the tumor microenvironment, were associated with uterine corpus endometrial carcinoma (UCEC). Importantly, the gene expression levels of Srd5a1 after 28-day BPB and BPAF exposure were 7.28- and 25.24-fold higher than those of the corresponding control group, respectively, which was consistent with the expression trend of UCEC patients, and its high expression was significantly related to the poor prognosis of patients (p = 0.003). This indicated that Srd5a1 could be a valuable signal of uterus abnormalities caused by BPA analogs exposure. Our study revealed the key molecular targets and mechanisms of BPB or BPAF exposure induced uterine injury at the transcriptional level, providing a perspective for evaluating the safety of BPA substitutes.

Exploration of the damage and mechanisms of BPS exposure on the uterus and ovary of adult female mice.

Bisphenol S (BPS) has been followed with interest for its endocrine disrupting effects, but exploration on the reproductive system of adult females is lack of deep investigation. In the present study, adult female CD-1 mice were treated with BPS for 28 days at 300 µg/kg/day. After that, uteruses and ovaries were harvested for histopathological examination, RNA-seq analysis, and diseases risk prediction. Hematoxylin-eosin (H&E) staining results showed significant histological alterations in the uterus and ovary of the BPS-exposed mice. Bioinformatics analysis of the RNA-seq screened a certain number of differentially expressed genes (DEGs) in both uterus and ovary between BPS group and their corresponding vehicle control groups (Veh), respectively. Functional enrichment analysis of DEGs found that hormone metabolism and immunoinflammatory related pathways were enriched. Disease risk evaluation of the hub genes was performed and the results indicated that diseases associated with uterus and ovary were mainly related to tumors and cancers. Further pan cancer and ovarian cancer survival analysis based on human diseases database pointed out, Foxa1, Gata3, S100a8 and Shh for uterus, Itgam, Dhcr7, Fdps, Hmgcr, Hsd11b1, Hsd3b1, Ptges, F3, Fn1, Ptger4 and Srd5a1 for ovary were significant correlation with cancer. The findings suggest that BPS causes some histopathological changes, alters the expressions of hub genes, enhances uterine and ovarian tumors or even cancer risks.

New Insights into Prenatal NO2 Exposure and Behavioral Abnormalities in Male Offspring: Disturbed Serotonin Metabolism and Delayed Oligodendrocyte Development.

Epidemiological studies show that prenatal exposure to nitrogen dioxide (NO2) might cause behavioral abnormalities in childhood. However, toxicological mechanisms for such effects remain unclear, and it is still difficult to define adverse outcome pathways linking exposures to behavioral phenotypes. In this study, by exposing pregnant mice to NO2 (2.5 ppm, 5 h/day) throughout gestation, we provided the first experimental evidence that prenatal NO2 exposure did cause anxiety- and depression-like behaviors in weaning male offspring but not females. Specifically, the behavioral abnormalities were associated with abnormal myelination and the alterations attributed to the delayed oligodendrocyte (OL) development in the fetus and the early stage after birth. The expression of platelet-derived growth factor receptor α (Pdgfr-α) and Olig2 significantly decreased in the NO2 group at E13.5 and E15.5, and the expression of Olig2, adenomatous polyposis coli colon (Cc1), and myelin basic protein (Mbp) was reduced in offspring at PNDs 1, 7, and 21. We performed the targeted metabolomic analysis of neurotransmitters in the placenta and found that prenatal exposure to NO2 disturbed the metabolism of placental neurotransmitters. Serotonin (5-HT) was transferred from the placenta to the fetus at E10.5, and its accumulation in the fetal forebrain might affect oligodendrocyte progenitor cell (OPC) differentiation and OL maturation and eventually be involved in behavioral abnormalities. Our findings provide new insights into the association between prenatal NO2 exposure with anxiety- and depression-like behaviors in male offspring.

Nickel catalyzed multicomponent stereodivergent synthesis of olefins enabled by electrochemistry, photocatalysis and photo-electrochemistry.

Trisubstituted alkenes are important organic synthons and have broad applications in the synthesis of many pharmaceuticals and materials. The stereoselective synthesis of such compounds has long been a research focus for organic researchers. Herein, we report a three-component, reductive cascade, cross-coupling reaction for the arylalkylation of alkynes. A wide range of trisubstituted alkenes are obtained in good to high yields with excellent chemo- and stereoselectivity by switching between electrochemistry and photocatalysis. The E isomer of the product is obtained exclusively when the reaction is conducted with electricity and nickel, while the Z isomer is generated with high stereoselectivity when photo- and nickel dual catalysts are used. Moreover, photo-assisted electrochemically enabled nickel catalyzed protocol is demonstrated to selectively deliver Z-trisubstituted alkenes without the addition of photocatalysts.

Reactivity in Nickel-Catalyzed Multi-component Sequential Reductive Cross-Coupling Reactions.

The nickel-catalyzed three-component reductive carbonylation of alkyl halides, aryl halides, and ethyl chloroformate is described. Ethyl chloroformate is utilized as a safe and readily available source of CO in this multi-component protocol, providing an efficient and practical alternative for the synthesis of aryl-alkyl ketones. The reaction exhibits a wide substrate scope and good functional group compatibility. Experimental and DFT mechanistic studies highlight the complexity of the cross-electrophile coupling and provide insight into the sequence of the three consecutive oxidative additions of aryl halide, chloroformate, and alkyl halide.

Photo-degradation behavior of seven benzoylurea pesticides with C3N4 nanofilm and its aquatic impacts on Scendesmus obliquus.

Present concerns on the residual benzoylurea pesticides (BUPs) are rapidly climbing as their market shares increase and now seven typical compounds were picked to study their photo-degradation behavior and ecological impacts. Carbon nitride (C3N4) nanofilm at a thickness of 50-80 nm was built on the glass slides and utilized to evaluate the photostability of pesticides under visible light. The results showed that the nano-C3N4 can promote the degradation efficiency of BUPs and it follows the first-order dynamic mechanism. They could be divided into three categories with the substituents and their degradations were discriminated in order of chlorofluoro-, chlorofluoroalkoxy- and chlorofluorophenoxy- substituted ones. Analyzing the intermediates by UHPLC-MS, it can be speculated that the similar pathways came to BUPs such as cleavage of urea-bridge, hydroxylation and dehalogenation. It is attractive that they all passed into a same molecule, 2-fluorobenzamide (m/z, 301.14). Moreover Scendesmus obliquus was applied to indicate the ecological impacts of originals and their photoproducts. Exposed to pesticides, the levels of chlorophyll a demonstrated much more inhibition than chlorophyll b. Lufenuron and chlorfuazuron among seven showed the higher toxicity for algal cells and finally the photodegradation products showed the lowest toxicity. The activities of antioxidant enzymes happened to a significant remedy after photodegradation. It can be concluded that the residual BUPs under visible-light irradiation may degrade through similar pathways and reduce the aquatic toxicity with the presence of C3N4 nanofilm.

Maternal smoking-induced lung injuries in dams and offspring via inflammatory cytokines.

Maternal smoking during pregnancy can induce permanent changes in neonatal inflammation, which will result in lifelong implications. An original study of data from GSE96978, composed of 2 subseries (GSE96976 and GSE96977), investigated genome-wide changes in ELT cells, the lungs of mouse dams and their juvenile offspring and focused on finding an in vitro alternative as a human tissue-based replacement for the use of animals. Therefore, the study only analyzed the similarities of GO terms between ELT cells and dams. However, the relationship between differentially expressed genes (DEGs) in dams and offspring was not investigated. The present study aimed to identify the key molecules involved in maternal smoking-induced dam and offspring lung injuries. Data from GSE96977 were downloaded from Gene Expression Omnibus (GEO) data sets. In our study, differentially expressed genes (DEGs) in dams and offspring were reanalyzed using the limma package. The results of Gene Set Enrichment Analysis (GSEA) showed that the DEGs in the lungs of dams were significantly enriched in immune-related functions and those in the lungs of offspring were enriched in cell growth. Furthermore, a total of 90 DEGs shared in the dam and offspring datasets were screened out. In addition, most of these DEGs were enriched in cytokine and cytokine receptor interaction KEGG pathways. Furthermore, protein-protein interaction (PPI) network analysis screened out 4 core genes in cluster 1. In addition, the miRNAs related to these core genes were predicted, and mmu-miR-1903 was screened out. Taken together, our data indicate that inflammatory responses may play an important role in maternal smoking induced lung injuries in dams and offspring. Furthermore, mmu-miR-1903 is a potential epigenetic biomarker of lung inflammation in the offspring of dams who smoked during pregnancy. In conclusion, by screening shared differential genes, we only need to detect maternal genes to predict maternal smoking-induced lung injuries in offspring.

Nickel-Catalyzed C-Heteroatom Cross-Coupling Reactions under Mild Conditions via Facilitated Reductive Elimination.

The formation of C-heteroatom bonds represents an important type of bond-forming reaction in organic synthesis and often provides a fast and efficient access to privileged structures found in pharmaceuticals, agrochemical and materials. In contrast to conventional Pd- or Cu-catalyzed C-heteroatom cross-couplings under high-temperature conditions, recent advances in homo- and heterogeneous Ni-catalyzed C-heteroatom formations under mild conditions are particularly attractive from the standpoint of sustainability and practicability. The generation of NiIII and excited NiII intermediates facilitate the reductive elimination step to achieve mild cross-couplings. This review provides an overview of the state-of-the-art approaches for mild C-heteroatom bond formations and highlights the developments in photoredox and nickel dual catalysis involving SET and energy transfer processes; photoexcited nickel catalysis; electro and nickel dual catalysis; heterogeneous photoredox and nickel dual catalysis involving graphitic carbon nitride (mpg-CN), metal organic frameworks (MOFs) or semiconductor quantum dots (QDs); as well as more conventional zinc and nickel dual catalyzed reactions.

Mechanistic Insight into the Photoredox-Nickel-HAT Triple Catalyzed Arylation and Alkylation of α-Amino Csp3-H Bonds.

We report here a comprehensive computational analysis of the mechanisms of the photoredox-nickel-HAT (HAT: hydrogen atom transfer) catalyzed arylation and alkylation of α-amino Csp3-H bonds developed by MacMillan and co-workers. Different alternatives for the three catalytic cycles were tested to identify unambiguously the operative reaction mechanism. Our analysis indicated that the IrIII photoredox catalyst, upon irradiation with visible light, can be either reduced or oxidized by the HAT and nickel catalysts, respectively, indicating that both reductive and oxidative quenching catalytic cycles can be operative, although the reductive cycle is favored. Our analysis of the HAT cycle indicated that activation of a α-amino Csp3-H bond of the substrate is facile and selective relative to activation of a ß-amino Csp3-H bond. Finally, our analysis of the nickel cycle indicated that both arylation and alkylation of α-amino Csp3-H bonds occurs via the sequence of nickel oxidation states NiI-NiII-NiI-NiIII and of elementary steps: radical addition-SET-oxidative addition-reductive elimination.

Recent advances in photoredox and nickel dual-catalyzed cascade reactions: pushing the boundaries of complexity.

Cascade reactions that produce multiple chemical bonds in one synthetic operation are important in the efficient construction of complex molecules. In addition, photoredox and nickel dual catalysis opens a new and powerful avenue for transition-metal-catalyzed cross-coupling reactions. By combining these two concepts, photoredox and nickel dual-catalyzed cascade reactions have been recently established, and they provide an efficient and mild method for accessing a series of valuable organic compounds.

Prenatal NO2 exposure and neurodevelopmental disorders in offspring mice: Transcriptomics reveals sex-dependent changes in cerebral gene expression.

BACKGROUND: Early-life exposure to nitrogen dioxide (NO2) is associated with an increased risk of developing a neurodevelopmental disorder during childhood or later in life. OBJECTIVES: We investigated whether prenatal NO2 inhalation causes neurodevelopmental abnormalities and cognitive deficits in weanling offspring without subsequent postnatal NO2 exposure and how this prenatal exposure contributes to postnatal consequences. METHODS: Pregnant C57BL/6 mice were exposed to air or NO2 (2.5 ppm, 5 h/day) throughout gestation, and the offspring were sacrificed on postnatal days (PNDs) 1, 7, 14 and 21. We determined the mRNA profiles of different postnatal developmental windows, detected the long noncoding RNA (lncRNA) profiles and cognitive function in weanling offspring, and analyzed the effects of hub lncRNAs on differentially expressed genes (DEGs). RESULTS: Prenatal NO2 inhalation significantly impaired cognitive function in the weanling male, but not female, offspring. The male-specific response was coupled with abnormal neuropathologies and transcriptional profiles in the cortex during different postnatal developmental windows. Consistently, Gene Ontology (GO) analysis of the DEGs revealed persistent disruptions in neurodevelopment-associated biological processes and cellular components in the male offspring, and Apolipoprotein E (ApoE) was one of key factors contributing to prenatal exposure-induced male-specific neurological dysfunction. In addition, distinct sex-dependent lncRNA expression was identified in the weanling offspring, and metastasis-associated lung adenocarcinoma transcript 1 (Malat1) acted as a hub lncRNA and was coexpressed with most coding genes in the lncRNA-mRNA coexpressed pairs in the male offspring. Importantly, lncRNA Malat1 expression was elevated, and Malat1 modulated ApoE expression through NF-κB activation during this process. CONCLUSIONS: Prenatal NO2 exposure is related to sex-dependent neurocognitive deficits and transcriptomic profile changes in the cortices of the prenatally exposed offspring. Male-specific neurological dysfunction is associated with the constant alteration of genes during postnatal neurodevelopment and their transcriptional modulation by hub lncRNAs.

Sex difference in bronchopulmonary dysplasia of offspring in response to maternal PM2.5 exposure.

The adverse effects of fine particulate matters (PM2.5) on respiratory diseases start in utero. In order to investigate whether maternal PM2.5 exposure could lead to bronchopulmonary dysplasia (BPD) in offspring, PM2.5 was collected in Taiyuan, Shanxi, China during the annual heating period. Mice were mated and gestation day 0 (GD0) was considered the day on which a vaginal plug was observed. The plug-positive mice received 3 mg/kg b.w. PM2.5 by oropharyngeal aspiration every other day starting on GD0 and throughout the gestation period. Offspring were sacrificed at postnatal days (PNDs) 1, 7, 14 and 21. We assessed some typical BPD-like symptoms in offspring. The results showed that maternal PM2.5 exposure caused low birth weight, hypoalveolarization, decreased angiogenesis, suppressed production of secretory and surfactant proteins, and increased inflammation in the lungs of male offspring. However, maternal PM2.5 exposure induced only hypoalveolarization and inflammation in the lungs of female offspring. Furthermore, these alterations were reversed during postnatal development. Our results demonstrated that maternal exposure to PM2.5 caused reversible BPD-related consequences in offspring, and male offspring were more sensitive than females. However, these alterations were reversed during postnatal development.

Regioselective Hydroalkylation and Arylalkylation of Alkynes by Photoredox/Nickel Dual Catalysis: Application and Mechanism.

Alkynes are an important class of organic molecules due to their utility as versatile building blocks in synthesis. Although efforts have been devoted to the difunctionalization of alkynes, general and practical strategies for the direct hydroalkylation and alkylarylation of terminal alkynes under mild reaction conditions are less explored. Herein, we report a photoredox/nickel dual-catalyzed anti-Markovnikov-type hydroalkylation of terminal alkynes as well as a one-pot arylalkylation of alkynes with alkyl carboxylic acids and aryl bromides via a three-component cross-coupling. The results indicate that the transformations proceed via a new mechanism involving a single-electron transfer with subsequent energy-transfer activation pathways. Moreover, steady-state and time-resolved fluorescence-spectroscopy measurements, density functional theory (DFT) calculations, and wavefunction analysis have been performed to give an insight into the catalytic cycle.