Abstract
Many cellular stresses are transduced into apoptotic signals through modification or up-regulation of the BH3-only subfamily of BCL2 proteins. Through direct or indirect mechanisms, these ...proteins activate BAK and BAX to permeabilize the mitochondrial outer membrane. While the BH3-only proteins BIM, PUMA, and tBID have been confirmed to directly activate BAK through its canonical BH3 binding groove, whether the BH3-only proteins BMF, HRK or BIK can directly activate BAK is less clear. Here we show that BMF and HRK bind and directly activate BAK. Through NMR studies, site-directed mutagenesis, and advanced molecular dynamics simulations, we also find that BAK activation by BMF and possibly HRK involves a previously unrecognized binding groove formed by BAK α4, α6, and α7 helices. Alterations in this groove decrease the ability of BMF and HRK to bind BAK, permeabilize membranes and induce apoptosis, suggesting a potential role for this BH3-binding site in BAK activation.
For mass production of high‐purity hydrogen fuel by electrochemical water splitting, seawater electrolysis is an attractive alternative to the traditional freshwater electrolysis due to the abundance ...and low cost of seawater in nature. However, the undesirable chlorine ion oxidation reactions occurring simultaneously with seawater electrolysis greatly hinder the overall performance of seawater electrolysis. To tackle this problem, electrocatalysts of high activity and selectivity with purposely modulated coordination and an alkaline environment are urgently required. Herein, it is demonstrated that atomically dispersed Ni with triple nitrogen coordination (Ni‐N3) can achieve efficient hydrogen evolution reaction (HER) performance in alkaline media. The atomically dispersed Ni electrocatalysts exhibit overpotentials as low as 102 and 139 mV at 10 mA cm–2 in alkaline freshwater and seawater electrolytes, respectively, which compare favorably with those previously reported. They also deliver large current densities beyond 200 mA cm–2 at lower overpotentials than Pt/C, as well as show negligible current attenuation over 14 h. The X‐ray absorption fine structure (XAFS) experimental analysis and density functional theory (DFT) calculations verify that the Ni‐N3 coordination, which exhibits a lower coordination number than Ni‐N4, facilitates water dissociation and hydrogen adsorption, and hence enhances the HER activity.
Seawater electrolysis is an attractive alternative to traditional freshwater electrolysis due to the abundance of seawater. A novel Ni single‐atom catalyst with oxidized Ni‐N3 and Ni‐N4 coordination is developed to achieve efficient hydrogen evolution reaction (HER) performance in alkaline seawater electrolytes. Both experiments and theoretical calculations reveal that the low‐coordinated Ni‐N3 facilitates water dissociation and hydrogen adsorption during HER.
Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills ...cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.
Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) ...remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.
Mitochondria and oxygen homeostasis Mori, Mateus P.; Penjweini, Rozhin; Knutson, Jay R. ...
The FEBS journal,
November 2022, Letnik:
289, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Molecular oxygen possesses a dual nature due to its highly reactive free radical property: it is capable of oxidizing metabolic substrates to generate cellular energy, but can also serve as a ...substrate for genotoxic reactive oxygen species generation. As a labile substance upon which aerobic life depends, the mechanisms for handling cellular oxygen have been fine‐tuned and orchestrated in evolution. Protection from atmospheric oxygen toxicity as originally posited by the Endosymbiotic Theory of the Mitochondrion is likely to be one basic principle underlying oxygen homeostasis. We briefly review the literature on oxygen homeostasis both in vitro and in vivo with a focus on the role of the mitochondrion where the majority of cellular oxygen is consumed. The insights gleaned from these basic mechanisms are likely to be important for understanding disease pathogenesis and developing strategies for maintaining health.
The PO2 of tissues is determined by a balance between the availability of molecular oxygen and its consumption by mitochondria. There is growing evidence that this homeostatic relationship may be an important determinant of both lifespan and health, in part due to the role of oxygen in oxidative stress.
Designing new quantum materials with long-lived electron spin states urgently requires a general theoretical formalism and computational technique to reliably predict intrinsic spin relaxation times. ...We present a new, accurate and universal first-principles methodology based on Lindbladian dynamics of density matrices to calculate spin-phonon relaxation time of solids with arbitrary spin mixing and crystal symmetry. This method describes contributions of Elliott-Yafet and D'yakonov-Perel' mechanisms to spin relaxation for systems with and without inversion symmetry on an equal footing. We show that intrinsic spin and momentum relaxation times both decrease with increasing temperature; however, for the D'yakonov-Perel' mechanism, spin relaxation time varies inversely with extrinsic scattering time. We predict large anisotropy of spin lifetime in transition metal dichalcogenides. The excellent agreement with experiments for a broad range of materials underscores the predictive capability of our method for properties critical to quantum information science.
Fatigue damage accumulation will not only cause the degradation of material performance but also lead to the growth of effective stress and critical stiffness. However, the existing fatigue ...reliability models usually ignore the effective stress growth and its influence on the critical stiffness of a composite material. This study considers the combined effects of performance degradation and effective stress growth, and a pair of fatigue reliability models for a composite material are presented. Firstly, the fatigue damage in a composite material is quantified by its performance degradation, and the fitting accuracy of several typical fatigue damage models is compared. Subsequently, the uncertainties of initial strength and initial stiffness are considered, and a pair of probabilistic models of residual strength and residual stiffness are proposed. The performance degradation data of Gr/PEEK 0/45/90/−452S laminates are utilized to verify the proposed probabilistic models. Finally, the effective stress growth mechanism and its influence on the failure threshold are elaborated, and a pair of fatigue reliability models for composite materials are developed. Moreover, the differences between the strength-based and stiffness-based reliability analysis results of composite materials are compared and discussed.
Functional constipation (FC) in children affects their growth, development and quality of life. L-pipecolic acid (L-PA) was decreased in FC children based on gut microbiome and serum metabolomic. In ...this study, loperamide-induced constipation in mice was used to evaluate the effects of L-PA on constipated mice.
26 FC and 28 healthy children were recruited. Stool samples and serum samples were subjected to 16S rDNA sequencing and ultra-performance liquid chromatography/quadrupole time of flight (UPLC-Q/TOF-MS) approach, respectively. A loperamide-induced mouse constipation model was developed, and all mice were randomly divided into control (Con), loperamide (Lop) and L-PA (Lop + L-PA) treatment groups (6 mice per group). The mice in the Lop + L-PA group were given L-PA (250 mg/kg, once a day) and loperamide; the Lop group was given loperamide for 1 week, and the Con group was given saline. The fecal parameters and intestinal motility of mice in each group were detected. serum 5-HT levels and colon 5-HT expression were detected by ELISA and immunohistochemistry, respectively; qRT-PCR was used to detect the expression of AQP3 and 5-HT4R mRNA in each group.
45 differential metabolites and 18 significantly different microbiota were found in FC children. The α and β diversity of gut microbiota in FC children was significantly reduced. Importantly, serum L-PA was significantly reduced in FC children. The KEGG pathway enrichment were mainly enriched in fatty acid biosynthesis, lysine degradation, and choline metabolism. L-PA was negatively associated with Ochrobactrum, and N6, N6, N6-trimethyl-l-lysine was positively associated with Phascolarcrobacterium. In addition, L-PA improved the fecal water content, intestinal transit rate, and increased the serum 5-HT levels in constipated mice. Moreover, L-PA increased the expression of 5-HT4R, reduced AQP3, and regulated constipation-associated genes.
Gut microbiota and serum metabolites were significantly altered in children with FC. The abundance of Phascolarctobacterium and Ochrobactrum and serum L-PA content were decreased in FC children. L-PA was found to alleviate the fecal water content, increase intestinal transit rate and the first black stool defecation time. L-PA improved constipation by increasing 5-HT and 5-HT4R expression while down-regulating AQP3 expression.
The catalytic activity of Au-embedded graphene is investigated by the first-principle method using the CO oxidation as a benchmark probe. The first step of CO oxidation catalyzed by the Au-embedded ...graphene is most likely to proceed with the Langmuir−Hinshelwood reaction (CO + O2 → OOCO → CO2 +O), and the energy barrier is as low as 0.31 eV. The second step of the oxidation would be the Eley−Rideal reaction (CO + O → CO2) with a much smaller energy barrier (0.18 eV). The partially filled d states of Au are localized around the Fermi level due to the interactions between Au and the neighboring carbon atoms. The high activity of Au-embedded graphene may be attributed to the electronic resonance among electronic states of CO, O2, and the Au atom, particularly, among the d states of the Au atom and the antibonding 2π* states of CO and O2. This opens a new avenue to fabricate low cost and high activity carbon-based catalyst.
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