Treatment of Rheumatoid Arthritis Based on the Inherent Bioactivity of Black Phosphorus Nanosheets.

Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.

DRTerHGAT: A drug repurposing method based on the ternary heterogeneous graph attention network.

Drug repurposing is an effective method to reduce the time and cost of drug development. Computational drug repurposing can quickly screen out the most likely associations from large biological databases to achieve effective drug repurposing. However, building a comprehensive model that integrates drugs, proteins, and diseases for drug repurposing remains challenging. This study proposes a drug repurposing method based on the ternary heterogeneous graph attention network (DRTerHGAT). DRTerHGAT designs a novel protein feature extraction process consisting of a large-scale protein language model and a multi-task autoencoder, so that protein features can be extracted accurately and efficiently from amino acid sequences. The ternary heterogeneous graph of drug-protein-disease comprehensively considering the relationships among the three types of nodes, including three homogeneous and three heterogeneous relationships. Based on the graph and the extracted protein features, the deep features of the drugs and the diseases are extracted by graph convolutional networks (GCN) and heterogeneous graph node attention networks (HGNA). In the experiments, DRTerHGAT is proven superior to existing advanced methods and DRTerHGAT variants. DRTerHGAT's powerful ability for drug repurposing is also demonstrated in Alzheimer's disease.

Blastocyst-Derived Lactic Acid May Regulate S100A6 Expression and Function in Mouse Decidualization via Stimulation of Uterine Epithelial Arachidonic Acid Secretion.

(1) Background: Inflammatory responses are implicated in embryo implantation, decidualization, pregnancy maintenance and labor. Both embryo implantation and decidualization are essential to successful pregnancy in rodents and primates. S100A6 is involved in inflammation, tumor development, apoptosis and calcium homeostasis. S100A6 is strongly expressed in mouse decidua, but the underlying mechanisms of how S100A6 regulates implantation and decidualization are poorly defined. (2) Methods: Mouse endometrial stromal and epithelial cells are isolated from day 4 pseudopregnant mouse uteri. Both immunofluorescence and Western blotting are used to analyze the expression and localization of proteins. The molecular mechanism is verified in vitro by Western blotting and the quantitative polymerase chain reaction. (3) Results: From days 4 to 8 of pregnancy, S100A6 is specifically expressed in mouse subluminal stromal cells. Blastocyst-derived lactic acid induces AA secretion by activating the luminal epithelial p-cPLA2. The epithelial AA induces stromal S100A6 expression through the COX2/PGI2/PPAR δ pathway. Progesterone regulates S100A6 expression through the progesterone receptor (PR). S100A6/RAGE signaling can regulate decidualization via EGFR/ERK1/2 in vitro. (4) Conclusions: S100A6, as an inflammatory mediator, is important for mouse implantation and decidualization.

One-pot solvothermal preparation of the porous NiS2//MoS2 composite catalyst with enhanced low-temperature hydrodesulfurization activity.

The simple preparation of mesoporous NiS2//MoS2 composite catalyst through a one-pot solvothermal method is presented. The improvement of the specific surface area (220 m2/g) and the construction of the porous structure are realized by this method in the case of no support. The organics acts as a microscopic binder contribute to uniform stacking of MoS2 with NiS2 clusters. The composite structure including NiS2 and MoS2 was obtained (proved by XRD, XPS, TEM, IR, UV-vis and RAMAN) and changed the microelectronic environment of the active metal surface (DFT calculation). The mesoporous NiS2//MoS2 catalyst (Ni1Mo1-200) showed an excellent hydrodesulfurization performance of dibenzothiophene (DBT conversion: 78 % at 260 °C) and a high ratio of direct desulfurization pathway (SDDS/HYD = 16.6) at a low reaction temperature. By combining the characterization and theoretical calculation results, the advantages of this NiS2//MoS2 composite structure in synergistic catalysis was further confirmed.

Molecular Mechanisms of AMPA Receptor Trafficking in the Nervous System.

Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.

Aronia melanocarpa Prevents Alcohol-Induced Chronic Liver Injury via Regulation of Nrf2 Signaling in C57BL/6 Mice.

Aronia melanocarpa (AM), which is rich in anthocyanins and procyanidins, has been reported to exert antioxidative and anti-inflammatory effects. This study aimed to systematically analyze the components of AM and explore its effects on alcohol-induced chronic liver injury in mice. A component analysis of AM revealed 17 types of fatty acids, 17 types of amino acids, 8 types of minerals, and 3 types of nucleotides. Chronic alcohol-induced liver injury was established in mice via gradient alcohol feeding over a period of 6 months, with test groups orally receiving AM in the last 6 weeks. AM administration yielded potential hepatoprotective effects by alleviating weight gain and changes in organ indexes, decreasing the ratio of alanine aminotransferase/aspartate aminotransferase, reducing lipid peroxidation, enhancing antioxidant activities, decreasing oxidation-related factor levels, and regulating inflammatory cytokine levels. Histological analyses suggest that AM treatment markedly prevented organ damage in alcohol-exposed mice. Furthermore, AM activated nuclear factor erythroid 2-like 2 (Nrf2) by downregulating the expression of Kelch-like ECH-associated protein 1, resulting in elevated downstream antioxidative enzyme levels. AM activated Nrf2 via modulation of the phosphatidylinositol-3-hydroxykinase/protein kinase B signaling pathway. Altogether, AM prevented alcohol-induced liver injury, potentially by suppressing oxidative stress via the Nrf2 signaling pathway.

Warburg-like Glycolysis and Lactate Shuttle in Mouse Decidua during Early Pregnancy.

Decidualization is an essential process of maternal endometrial stromal cells to support pregnancy. Although it is known that enhanced glucose influx is critical for decidualization, the underlying mechanism in regulating glucose metabolism in decidua remains insufficiently understood. Here, we demonstrate that aerobic glycolysis-related genes and factors are all substantially induced during decidualization, indicating the existence of Warburg-like glycolysis in decidua. In vitro, progesterone activates hypoxia-inducible factor 1α (Hif1α) and c-Myc through Pi3k-Akt signaling pathway to maintain aerobic glycolysis in decidualizing cells. Knocking down of pyruvate kinase M2 (Pkm2) attenuates the induction of decidual marker gene. Decidual formation in vivo is also impaired by glycolysis inhibitor 3-bromopyruvate. Besides, lactate exporter monocarboxylate transporter 4 (Mct4) is induced in newly formed decidual cells, whereas lactate importer Mct1 and proliferation marker Ki-67 are complementarily located in the surrounding undifferentiated cells, which are supposed to consume lactate for proliferation. Hif1α activation is required for lactate-dependent proliferation of the undifferentiated cells. Inhibition of lactate flux leads to compromised decidualization and decelerated lactate-dependent proliferation. In summary, we reveal that Warburg-like glycolysis and local lactate shuttle are activated in decidua and play important roles for supporting early pregnancy.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization.

Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans.

Progesterone regulates secretin expression in mouse uterus during early pregnancy.

Secretin, a classical gastrointestinal and neuroendocrine peptide, plays an important role in maintaining the body fluid balance. However, the expression and regulation of secretin in the reproductive system are still unknown. In our study, secretin is specifically expressed in the decidua on days 5 to 8 of pregnancy. Secretin expression is not detected under delayed implantation but is stimulated after estrogen activation and under artificial decidualization. Progesterone induces secretin expression in ovariectomized mice and cultured stromal cells, which is abrogated by specific LY294002. Because secretin is mainly localized in the decidua and also strongly expressed during in vitro decidualization, secretin may play a role during mouse decidualization through regulating cyclic adenosine monophosphate level.