Impressive progress has been made in the copper‐catalyzed asymmetric propargylic substitution (APS) reaction, but its use in remote asymmetric yne‐allylic substitution remains a challenging topic. ...Herein, we report the first remote enantioselective copper‐catalyzed sulfonylation of yne‐allylic esters with sodium sulfinates. The reaction is assumed to occur via a copper‐vinylvinylidene species as the key reactive intermediate. The use of readily available starting materials, the mild reaction conditions, and the excellent regio‐, enantio‐ and stereoselectivity, as well as broad substrate scope (>70 examples), show the practicality and attractiveness of this method.
An enantioselective copper‐catalyzed reaction was developed for the sulfonylation of yne‐allylic esters with sodium sulfinates. Salient features of this practical method include readily available starting materials, mild reaction conditions, excellent regio‐, enantio‐ and diastereoselectivity, as well as broad substrate scope.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Purpose
Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe ...that A‐kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive‐like behaviours in mice via a palmitoylation‐dependent mechanism.
Experimental Approach
Depressive‐like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl‐biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2‐mediated AKAP150 palmitoylation signalling pathway in depressive‐like behaviours. Electrophysiological recording, western blotting and co‐immunoprecipitation were performed to define the mechanistic pathway.
Key Results
Chronic stress successfully induced depressive‐like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150‐PKA interaction with the peptide Ht‐31 abolished the CRS‐induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS‐induced depressive‐like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS‐treated mice.
Conclusion and Implications
These results delineate that DHHC2 modulates chronic stress‐induced depressive‐like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Purpose
Hepatic mitochondrial pyruvate carrier (MPC) transports pyruvate into mitochondria. This study investigated the involvement of MPC1 in hepatic glucagon response, in order to ...identify a possible pharmacological intervention.
Experimental Approach
The correlation between hepatic glucagon response and MPC1 induction was investigated in fasted mice and primary hepatocytes. The effects of ginsenoside Rb1 on MPC1 function were observed.
Key Results
Glucagon challenge raised blood glucose with hepatic MPC1 induction, and inhibition of MPC induction coincided with a reduced rise in blood glucose. cAMP‐responsive element‐binding protein (CREB) knockdown blocked glucagon‐induced MPC1 expression, while CREB overexpression increased MPC1 expression. Luciferase reporter, chromatin immunoprecipitation assay, and promoter mutation confirmed that CREB increased MPC1 transcription through gene promoter induction. CREB regulated transcription co‐activator 2 nuclear translocation was also required for CREB to promote MPC1 induction. Glucagon shifted mitochondrial pyruvate towards carboxylation for gluconeogenesis via the opposite regulation of pyruvate dehydrogenase and carboxylase with respect to MPC1 induction. MPC1 induction was necessary for glucagon to promote pyruvate‐driven hepatic glucose production (HGP), but glucagon failed to influence HGP from other gluconeogenic substrates routed into the tricarboxylic acid cycle, independent of MPC. Rb1 blocked cAMP signalling by inhibiting AC activity and deactivated CREB by dephosphorylation, possibly contributing to inhibiting MPC1 induction to reduce HGP.
Conclusions and Implications
CREB transcriptionally up‐regulates MPC1 to provide pyruvate for gluconeogenesis. Rb1 reduced cAMP formation which consequently reduced CREB‐mediated MPC1 induction and thereby might contribute to limiting pyruvate‐dependent HGP. These results suggest a therapeutic strategy to reduce hyperglycaemia in diabetes.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Diabetic wounds are recalcitrant to healing. However, the mechanism causing this dysfunction is not fully understood. High expression of matrix metalloproteinase-9 (MMP-9) is indicative of poor wound ...healing. In this study, we show that specificity protein-1 (Sp1), a regulator of MMP-9, binds directly to its promoter and enhances its expression. Additionally, we demonstrated that Sp1 is the direct target of two microRNAs (miRNAs), miR-129 and -335, which are significantly downregulated in diabetic skin tissues. In vitro experiments confirmed that miR-129 or -335 overexpression inhibits MMP-9 promoter activity and protein expression by targeting Sp1, whereas the inhibition of these miRNAs has the opposite effect. The beneficial role of miR-129 or miR-335 in diabetic wound healing was confirmed by the topical administration of miRNA agomirs in diabetic animals. This treatment downregulated Sp1-mediated MMP-9 expression, increased keratinocyte migration, and recovered skin thickness and collagen content. The combined treatment with miR-129 and miR-335 induced a synergistic effect on Sp1 repression and MMP-9 downregulation both in vitro and in vivo. This study demonstrates the regulatory mechanism of Sp1-mediated MMP-9 expression in diabetic wound healing and highlights the potential therapeutic benefits of miR-129 and -335 in delayed wound healing in diabetes.
Ferroptosis is a novel form of programmed cell death, and it is characterized by iron-dependent oxidative damage, lipid peroxidation and reactive oxygen species accumulation. Notable studies have ...revealed that ferroptosis plays vital roles in tumor occurrence and that abundant ferroptosis in cells can inhibit tumor progression. Recently, some noncoding RNAs (ncRNAs), particularly microRNAs, long noncoding RNAs, and circular RNAs, have been shown to be involved in biological processes of ferroptosis, thus affecting cancer growth. However, the definite regulatory mechanism of this phenomenon is still unclear. To clarify this issue, increasing studies have focused on the regulatory roles of ncRNAs in the initiation and development of ferroptosis and the role of ferroptosis in progression of various cancers, such as lung, liver, and breast cancers. In this review, we systematically summarized the relationship between ferroptosis-associated ncRNAs and cancer progression. Moreover, additional evidence is needed to identify the role of ferroptosis-related ncRNAs in cancer progression. This review will help us to understand the roles of ncRNAs in ferroptosis and cancer progression and may provide new ideas for exploring novel diagnostic and therapeutic biomarkers for cancer in the future.
The goal of this study was to analyze whether mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction mediated arsenic (As)-evoked pulmonary ferroptosis and acute lung injury (ALI). ...As exposure led to alveolar structure damage, inflammatory cell infiltration and pulmonary function decline in mice. Ferritin, the marker of iron overload, was increased, GPX4, the index of lipid peroxidation, was decreased in As-exposed lungs and pulmonary epithelial cells (MLE-12). Pretreatment with ferrostatin-1 (Fer-1), the inhibitor of ferroptosis, alleviated As-evoked ALI. In addition, As-induced non-heme iron deposition was inhibited in Fer-1 pretreated-mice. Moreover, As-triggered mitochondria damage and ferroptosis were mitigated in Fer-1 pretreated-MLE-12 cells. Mechanistically, PERK phosphorylation and mitofusin-2 (Mfn-2) reduction was observed in As-exposed MLE-12 cells and mice lungs. Additionally, the interaction between PERK and Mfn-2 was downregulated and MAMs dysfunction was observed in As-exposed MLE-12 cells. Intriguingly, PERK inhibitor and Mfn-2-overexpression all mitigated As-induced ferroptosis in MLE-12 cells. Additionally, CLPP and mtHSP70, the markers of mitochondrial stress, were upregulated, mitochondrial ROS (mtROS) was elevated, mitochondrial membrane potential (MMP) and ATP were decreased in As-exposed MLE-12 cells. Mitoquinone mesylate (MitoQ), a novel mitochondrial-targeted antioxidant, alleviated As-induced excess mtROS, mitochondrial stress, MAMs dysfunction in pulmonary epithelial cells. Similarly, in vivo experiments indicated that MitoQ pretreatment countered As-induced pulmonary ferroptosis and ALI. These data indicated that mtROS-initiated MAMs dysfunction is, at least partially, implicated in As-evoked ferroptosis and ALI.
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•Acute As exposure induced pulmonary function decline and ALI in mice.•Acute As exposure caused ferroptosis, MAMs dysfunction and mitochondrial stress in mice lungs and pulmonary epithelial cells.•Pretreatment with ferrostatin-1 alleviated As-induced pulmonary function decline and ALI.•PERK inhibitor and Mfn-2-overexpression inhibited As-evoked ferroptosis in pulmonary epithelial cells.•MitoQ neutralized As-mediated MAMs dysfunction, mtROS production and ferroptosis in pulmonary epithelial cells.•MitoQ abolished As-induced decline of the interaction between PERK and Mfn-2 in pulmonary epithelial cells.•MitoQ attenuated As-caused ferroptosis and ALI in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
N6-methyladenosine (m6A), an epigenetic modification on RNAs, plays an important role in many physiological and pathological processes. However, the involvement of m6A in goat uterus during early ...pregnancy remains largely unknown. In this study, we found that the total m6A level was increasing in goat uterus as early pregnancy progressed. Methyltransferase-like 3 (METTL3) is a core catalytic subunit of the m6A methyltransferase. We thus determined the expression and regulation of METTL3 in goat uterus. METTL3 was highly expressed in the luminal and glandular epithelia from day 16 (D16) to D25 of pregnancy, and it could be up-regulated by estrogen and progesterone in goat uterus and primary endometrial epithelial cells (EECs). In EECs, knockdown or overexpression of METTL3 resulted in a significant decrease or increase of cell proliferation, respectively. METTL3 knockdown reduced the m6A level of not only total RNA but also connective tissue growth factor (CTGF) mRNA. Luciferase assay suggested that METTL3 might target the potential m6A sites in the 3'untranslated region (3'UTR) of CTGF mRNA. Moreover, METTL3 positively regulated CTGF expression, and CTGF knockdown significantly counteracted the promoting effect of METTL3 overexpression on EEC proliferation. Collectively, METTL3 is dynamically expressed in goat uterus and can affect EEC proliferation by regulating CTGF in an m6A-dependent manner. Our results will lay a foundation for further studying the crucial mechanism of METTL3-mediated m6A modification in goat uterus during early pregnancy.
Cardiac hypertrophy, a kind of cardiomyopathic abnormality, might trigger heart contractile and diastolic dysfunction, and even heart failure. Currently, bisphenols (BPs) including bisphenol A (BPA), ...and its alternatives bisphenol AF (BPAF), bisphenol F (BPF) and bisphenol S (BPS) are ubiquitously applied in various products and potentially possess high cardiovascular risks for humans. However, the substantial experimental evidences of BPs on heart function, and their structure-related effects on cardiomyocyte hypertrophy are still urgently needed. DNA methylation, a typical epigenetics, play key roles in BPs-induced transcription dysregulation, thereby affecting human health including cardiovascular system. Thus, in this study, we performed RNA-seq and reduced representation bisulfite sequencing (RRBS) to profile the landscapes of BPs-induced cardiotoxicity and to determine the key roles of DNA methylation in the transcription. Further, the capabilities of three BPA analogues, together with BPA, in impacting heart function and changing DNA methylation and transcription were compared. We concluded that similar to BPA, BPAF, BPF and BPS exposure deteriorated heart function in a mouse model, and induced cardiomyocyte hypertrophy in a H9c2 cell line. BPAF, BPF and BPS all played BPA-like roles in both transcriptive and methylated hierarchies. Moreover, we validated the expression levels of four cardiomyocyte hypertrophy related candidate genes, Psmc1, Piptnm2, Maz and Dusp18, which were all upregulated and with DNA hypomethylation. The findings on the induction of BPA analogues on cardiomyocyte hypertrophy and DNA methylation revealed their potential detrimental risks in heart function of humans.
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•BPs exposure disturbed cardiac function and induced cardiomyocyte hypertrophy.•BPs-induced RRBS and RNA-seq landscapes in hearts were profiled.•BPs altered DNA methylation to dysregulate genes’ expression and impaired heart function.•BPAF, BPF and BPS exerted structure-similar cardiotoxicity and mechanisms as BPA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Electrochemical CO
2
-reduction reaction (CO
2
RR) is a promising way to alleviate energy crisis and excessive carbon emission. The Cu-based electrocatalysts have been considered for CO
2
RR to ...generate hydrocarbons and alcohols. However, the application of Cu electrocatalysts has been restricted by a high onset potential for CO
2
RR and low selectivity. In this study, we have designed a series of Cu-based single-atom alloy catalysts (SAAs), denoted as TM
1
/Cu (111), by doping isolated 3d-transition metal (TM) atom onto the Cu (111) surface. We theoretically evaluated their stability and investigated the activity and selectivity toward CO
2
RR. Compared to the pure Cu catalyst, the majority TM
1
/Cu (111) catalysts are more favorable for hydrogenating CO
2
and can efficiently avoid the hydrogen-evolution reaction due to the strong binding of carbonaceous intermediates. Based on the density functional theory calculations, instead of the HCOOH or CO products, the initial hydrogenation of CO
2
on SAAs would form the *CO intermediate, which could be further hydrogenated to produce methane. In addition, we have identified the bond angle of adsorbed *CO
2
can describe the CO
2
activation ability of TM
1
/Cu (111) and the binding energy of *OH can describe the CO
2
RR activity of TM
1
/Cu (111). We speculated that the V/Cu (111) can show the best activity and selectivity for CO
2
RR among all the 3d-TM-doped TM
1
/Cu (111). This work could provide a rational guide to the design of new type of single-atom catalysts for efficient CO
2
RR.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Electroactive asymmetric bis-carbazole small molecules bearing cyano functional group(s) were conveniently synthesized and fully characterized by physicochemical and electrochemical methods. These ...carbazole-based small molecules are colorless in the neutral states and possess reversible redox processes and outstanding thermal stability. The utilization of these bis-carbazole small molecules as the electrochromic materials for the fabrication of electrochromic devices (ECDs) provided high-performance ECDs of high optical contrast up to 99% switching between colorless bleaching state and dark-red colored state and excellent coloration efficiencies of 412 cm2/C. The present work illuminates the excellent qualification of functionalized carbazole-based small molecules in developing efficient ECDs.
•Cyano-modified bis-carbazole molecules show high thermal stability, colorless neutral state, and excellent redox properties.•The bis-carbazoles based electrochromic devices (ECDs) exhibit striking color change from colorless neutral states to red.•The ECDs show high optical contrast up to 94−99% and coloration efficiencies of 225−412 cm2/C.•The performances of ECDs were markedly improved by increasing of the number of cyano groups incorporated in carbazole unit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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