Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Multilayer regulatory landscape and new regulators identification for bud dormancy release and bud break in Populus.

For trees originating from boreal and temperate regions, the dormancy-to-active transition, also known as bud dormancy release and bud break, are crucial processes that allow trees to reactive growth in the spring. The molecular mechanisms underlying these two processes remain poorly understood. Here, through integrative multiomics analysis of the transcriptome, DNA methylome, and proteome, we gained insights into the reprogrammed cellular processes associated with bud dormancy release and bud break. Our findings revealed multilayer regulatory landscapes governing bud dormancy release and bud break regulation, providing a valuable reference framework for future functional studies. Based on the multiomics analysis, we have determined a novel long intergenic noncoding RNA named Phenology Responsive Intergenic lncRNA 1 (PRIR1) plays a role in the activation of bud break. that the molecular mechanism of PRIR1 has been preliminary explored, and it may partially promote bud break by activating its neighbouring gene, EXORDIUM LIKE 5 (PtEXL5), which has also been genetically confirmed as an activator for bud break. This study has revealed a lncRNA-mediated regulatory mechanism for the control of bud break in Populus, operating independently of known regulatory pathways.

Enhancing CO catalytic oxidation performance over Cu-doping manganese oxide octahedral molecular sieves catalyst.

The CO oxidation catalytic activity of catalysts is strongly influenced by the oxygen vacancy defects (OVDs) concentration and the valence state of active metal. Herein, a defect engineering approach was implemented to enhance the oxygen vacancy defects and to modify the valence of metal ions in manganese oxide octahedral molecular sieves (OMS-2) by the introduction of copper (Cu). The characterization and theoretical calculation results reveal that the incorporation of Cu2+ ion into the OMS-2 structure led to a rise in specific surface area and pore volume, weakening of Mn-O bonds, higher proportion of the low-coordinated oxygen species adsorbed in oxygen vacancies (Oads) and an increase in the average oxidation state of manganese. These structural modifications were discovered to considerably reduce the apparent activation energy (Ea), thus ultimately significantly enhancing the CO oxidation activity (T99 at 148 ℃at GHSV = 13,200 h-1) than the original OMS-2 (T99 = 215 ℃ at GHSV = 13,200 h-1). Furthermore, In-situ diffuse reflectance infrared Fourier transform (DRIFT) and In-situ near-ambient pressure X-ray photoelectron spectroscopy (in situ NAP-XPS) results indicate that the bimetallic synergy enhanced by doping strategy accelerates the conversion of oxygen to chemisorbed oxygen species and the reaction rate of CO oxidation through Mn3++Cu2+↔Mn4++Cu+ redox cycle. The findings of this study offer novel perspectives on the design of catalysts with exceptional performance in CO oxidation.

A highly sensitive biotin-based probe for small RNA northern blot and its application in dissecting miRNA function in pepper.

Small RNAs play important roles in regulation of plant development and response to various stresses. Northern blot is an important technique in small RNA research. Isotope- and biotin- (or digoxigenin) labeled probes are frequently used in small RNA northern blot. However, isotope-based probe is limited by strict environmental regulation and availability in many places in the world while biotin-based probe is usually suffered from low sensitivity. In this study, we developed a T4 DNA polymerase-based method for incorporation of a cluster of 33 biotin-labeled C in small RNA probe (T4BC33 probe). T4BC33 probe reaches similar sensitivity as 32P-labeled probe in dot blot and small RNA northern blot experiments. Addition of locked nucleic acids in T4BC33 probe further enhanced its sensitivity in detecting low-abundance miRNAs. With newly developed northern blot method, expression of miR6027 and miR6149 family members was validated. Northern blot analysis also confirmed the successful application of virus-based miRNA silencing in pepper, knocking down accumulation of Can-miR6027a and Can-miR6149L. Importantly, further analysis showed that knocking-down Can-miR6027a led to upregulation of a nucleotide binding-leucine rich repeat domain protein coding gene (CaRLb1) and increased immunity against Phytophthora capsici in pepper leaves. Our study provided a highly sensitive and convenient method for sRNA research and identified new targets for genetic improvement of pepper immunity against P. capsici.

Multimodal energy harvesting and catalysis of piezoelectric nanosheets for efficient and round-the-clock wastewater treatment.

Solar-driven pollutants degradation is an important way for green wastewater treatment, but it is still limited by the intermittent solar flux. Here, we have prepared piezoelectric Bi4Ti3O12 (BTO) nanosheets with abundant physical properties, which can convert extensive solar energy, mechanical energy and temperature variation energy into electrical and chemical energy. It can be used for round-the-clock wastewater treatment by harvesting multi-modal energy. More importantly, the degradation rate of piezoelectric nanosheets can reach 153.4 × 10-3 min-1, and nanosheets can degrade many organic pollutants. In addition, we fabricate porous foam catalysts based on BTO-polydimethylsiloxane (PDMS) composite to prevent secondary contamination. Our results suggest that BTO nanosheets with photoelectric, piezoelectric and pyroelectric catalysis offer a potential approach for round-the-clock wastewater degradation by harvesting solar energy, ambient mechanical energy, and cyclic thermal energy.

Extending the optical temperature sensing range of Cr3+ by synchronously tuning 2E and 4T2 emission.

Due to the different sensitivities of the 2E and 4T2 energy levels of Cr3+ to the local environment, Cr3+-doped fluorescent materials appear as excellent candidates for highly sensitive temperature sensing based on luminescence intensity ratio technology. However, a way to broaden the strict Boltzmann temperature measuring range is rarely reported. In this work, through Al3+ alloying strategy, a series of SrGa12-xAlxO19:0.5%Cr3+(x = 0, 2, 4, and 6) solid-solution phosphors were synthesized. Remarkably, the introduction of Al3+ can play a role in regulating the crystal field around Cr3+ and the symmetry of [Ga/AlO6] octahedron, realizing the synchronous tuning of 2E and 4T2 energy levels when the temperature changes in a wide range, achieving the purpose of increasing the intensity difference of 2E → 4A2 and 4T2 → 4A2 transitions, so as to extend the temperature sensing range. Among all samples, SrGa6Al6O19:0.5%Cr3+ showed the widest temperature measuring range from 130 K to 423 K with Sa of 0.0066 K-1 and Sr of 1% K-1@130 K. This work proposed a feasible way to extend the temperature sensing range for transition metal-doped LIR-mode thermometers.

Phase stability and electronic structure of CsPbCl3 under hydrostatic stress and anion substitution.

Perovskites based on CsPbX3 (X = Cl, Br, I) have promising applications in solar cells, light-emitting diodes, and photodetectors. In this paper, the phase stability of inorganic metal halide perovskite CsPbCl3 under hydrostatic pressure and anion substitution is studied using density functional theory (DFT), and this modification is explained by the interaction of the octahedrons and transformation of the bond-orbital coupling. In addition, two space groups, P4/mbm and Amm2, which are stable under stress, are subjected to anion substitution; then, the structural stability and band gap change of CsPbCl3-yXy (X = Br, I; y = 0, 1, 2, 3) are analyzed after applying stress; finally, the electronic structures and optical properties of the six most stable components are presented. The effect of stress and anions on the components' optoelectronic properties is closely linked with the crystal's structural alteration mechanism. These results show that stress and anion modulation can significantly change the optoelectronic properties of materials, which make these materials have broad application prospects. Furthermore, stress can be used as an effective tool for screening the most stable material structure.

Rubidium ions doping to improve the photoluminescence properties of Mn doped CsPbCl3perovskite quantum dots.

All-inorganic cesium lead halide CsPbX3(X = Cl, Br, I) perovskite quantum dots (PQDs) have shown promising potential in current Mini/Micro-LED display applications due to their excellent photoluminescence performance. However, lead ions in PQDs are easily to leak owing to the unstable structure of PQDs, which hinders their commercial applications. Herein, we adopt Rb+ions co-doping strategy to regulate the doping characteristics of Mn2+ions in CsPbCl3PQDs. The synthesized CsPbCl3:(Rb+, Mn2+) PQDs possess enhanced photoluminescence quantum yield of 71.1% due to the reduction of intrinsic defect states and Mn-Mn or Mn-traps in co-doped PQDs. Moreover, the white light emission of CsPb(Cl/Br)3:(Rb+, Mn2+) PQDs is achieved by anion exchange reaction and the constructed WLED exhibits the CIE coordinate of (0.33, 0.29) and the correlated color temperature of 5497 K. Benefiting from the substitution strategy, these doped CsPbX3PQDs can be widely used as fluorescence conversion materials for the construction of Mini/Micro-LED.

Biological Effects of EGCG@MOF Zn(BTC)4 System Improves Wound Healing in Diabetes.

Tea contains high levels of the compound epigallocatechin gallate (EGCG). It is considered an important functional component in tea and has anti-cancer, antioxidant, and anti-inflammatory effects. The eight phenolic hydroxyl groups in EGCG's chemical structure are the basis for EGCG's multiple biological effects. At the same time, it also leads to poor chemical stability, rendering EGCG prone to oxidation and isomerization reactions that change its original structure and biological activity. Learning how to maintain the activity of EGCG has become an important goal in understanding the biological activity of EGCG and the research and development of tea-related products. Metal-organic frameworks (MOFs) are porous materials with a three-dimensional network structure that are composed of inorganic metals or metal clusters together with organic complexes. MOFs exploit the porous nature of the material itself. When a drug is an appropriate size, it can be wrapped into the pores by physical or chemical methods; this allows the drug to be released slowly, and MOFs can also reduce drug toxicity. In this study, we used MOF Zn(BTC)4 materials to load EGCG and investigated the sustained release effect of EGCG@MOF Zn(BTC)4 and the biological effects on wound healing in a diabetic mouse model.

Cooperative ETM-Based Adaptive Neural Network Tracking Control for Nonlinear Pure-Feedback MASs: A Special-Shaped Laplacian Matrix Method.

This article solves the cooperative adaptive tracking control problem for nonlinear pure-feedback multi-agent systems (MASs). Compared with the previous achievements of adaptive control of pure-feedback MASs, the partial derivative of the nonaffine function may not exist by using decoupling technology. In the controller design framework based on the backstepping technique, the additional state variables are processed using the special properties of the radial basis function neural networks (RBF NNs). A special-shaped Laplacian matrix is proposed to unify the leader gain form in the tracking error design process (the coefficient in the second term of tracking error). Furthermore, an event trigger mechanism (ETM) is introduced to save resources. The constructed controller under the ETM can not only stabilize the system states but also make the tracking error reach a small accuracy. Finally, the simulation results demonstrated the feasibility of the proposed method.

Expression, purification, and kinetic characterization of the human strep-IDO1.

Background: Tryptophan catabolism leading to T cell suppression mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of tumor immune escape, and IDO1 inhibitors have attracted increasing attention as anticancer therapeutics. However, the phase III clinical trial (ECHO-301/KEYNOTE-252) of epacadostat (INCB024360) had disappointing outcomes. This revealed that purification of IDO1 with high purity is one of the major constraints that limit the development of its inhibitors. Methods: Pan-cancer analysis was used to elucidate the relationship between IDO1 function in tumor immunology. The recombinant pET28a-IDO1-strep plasmid and E. coli Rosetta (DE3) strain were used to express and strep-tactin beads to purify the strep-IDO1 protein. High performance liquid chromatography (HPLC) was used to detect enzymatic activity of IDO1. Ten female C57BL/6 mice was used to prepared polyclonal antibody. Enzyme linked immunosorbent assay (ELISA), Western blot, and immunofluorescence were used to measure polyclonal antibody. Results: We described an improved method for the purification of recombinant IDO1 protein based on the strep-tag using an E. coli expression system. We obtained large amount of IDO1 with enhanced purity by employing one-step purification through strep-tactin beads. The polyclonal antibody acquired immunized mice could specifically recognize both recombinant and endogenous IDO1. Conclusions: Purified human strep-IDO1 using the protocol described in our study could be used for further biochemical and structural analyses, which may facilitate functional research and further drug screening study on IDO1.

Gasdermin E mediates resistance of pancreatic adenocarcinoma to enzymatic digestion through a YBX1-mucin pathway.

Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape autodigestion by digestive enzymes. Here we show that human PDAC tumour cells use gasdermin E (GSDME), a pore-forming protein, to mediate digestive resistance. GSDME facilitates the tumour cells to express mucin 1 and mucin 13, which form a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME-/- PDAC cells results in subcutaneous but not orthotopic tumour formation in mice. Inhibition or knockout of mucin 1 or mucin 13 abrogates orthotopic PDAC growth in NOD-SCID mice. Mechanistically, GSDME interacts with and transports YBX1 into the nucleus where YBX1 directly promotes mucin expression. This GSDME-YBX1-mucin axis is also confirmed in patients with PDAC. These findings uncover a unique survival mechanism of PDAC cells in pancreatic microenvironments.

SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterol-increased endosomal pH of alveolar macrophages.

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

Adaptive fixed-time tracking control for a class of nonlinear pure-feedback systems: A relative threshold event-triggered strategy.

In this paper, a fixed-time controller under the mechanism of event-trigger is designed for a class of nonlinear pure-feedback systems with non-differentiable non-affine functions. By properly modeling non-affine terms, the limitation of the partial derivatives of non-affine functions is eliminated. In our design process, we first develop a fixed-time adaptive controller using decoupling method. Then, a relative threshold event-trigger mechanism (ETM) is introduced in Section 3.1. The proposed controller can not only stabilize the system within a fixed-time, but also save communication resources more effectively. Lastly, the feasibility of the proposed control scheme is verified by two simulation examples.

Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.

Proliferation of MDA-MB-231 can be suppressed by dimeric-epigallocatechin gallate through competitive inhibition of amphiregulin-epidermal growth factor receptor signaling.

Triple-negative breast cancer (TNBC) is highly aggressive, with high rates of early relapse and very poor overall prognosis. Amphiregulin (AREG) is the most abundant epidermal growth factor receptor (EGFR) agonist in MDA-MB-231 TNBC cells, whose proliferation can be inhibited by (-)-epigallocatechin gallate (EGCG), a constituent of green tea that is prone to oxidative polymerization. The effect of dimeric-EGCG, a dimer of oxidized and polymerized EGCG, on MDA-MB-231 cell the proliferation warrants further exploration. In the present study, MTT, flow cytometry, migration scratch, transwell, western blotting, and surface plasmon resonance assays were used to evaluate the effect of dimeric-EGCG on MDA-MB-231 cells and explore the underlying mechanism. MDA-MB-231 cell proliferation and migration were significantly inhibited by dimeric-EGCG at concentrations as low as 10 µM. Levels of EGFR and p44/42 MAPK phosphorylation in MDA-MB-231 cells were significantly reduced by treatment with 10 µM dimeric-EGCG (P < 0.01). In addition, the levels of phosphorylation induced by exogenous AREG were also inhibited by dimeric-EGCG (P < 0.01); however, no significant effects of dimeric-EGCG were observed on epidermal growth factor or transforming growth factor-alpha signaling. Surface plasmon resonance analysis demonstrated that 10 µM dimeric-EGCG bound directly to the extracellular domain of EGFR, competitively inhibiting the binding of AREG to EGFR. These results suggest a novel mechanism underlying the inhibitory effect of dimeric-EGCG on MDA-MB-231 cells, with potential application in the development of drugs for the treatment of TNBC.

EGCG targeting Notch to attenuate renal fibrosis via inhibition of TGFß/Smad3 signaling pathway activation in streptozotocin-induced diabetic mice.

Renal fibrosis is a characteristic of diabetic nephropathy, which is a serious complication of diabetes. It has been reported that (-)-epigallocatechin gallate (EGCG) attenuates renal fibrosis. However, the molecular mechanism of regulation by EGCG in this process remains unclear. Previous studies showed that abnormal activation of Notch signaling contributes to the development of renal fibrosis. Previous studies have demonstrated that EGCG attenuates Notch1 expression. In this study, we found that the levels of fibronectin and Notch1 expression were decreased in human embryonic kidney cells after treatment with EGCG. We also observed that the type II transforming growth factor beta receptor (TGFßRII) and Smad3 pathway were inhibited in kidney cells by treatment with EGCG. In the diabetic kidney, we found that the activation of Notch signaling was attenuated by administration of EGCG. Moreover, TGFßRII and Smad3 phosphorylation could be inhibited by treatment with EGCG in the kidney. These results indicated that EGCG may improve renal fibrosis by targeting Notch via inhibition of the TGFß/Smad3 pathway in diabetic mice. Our findings provide insight into the therapeutic strategy for diabetes-induced renal fibrosis, and suggest EGCG to be a novel potential medicine for the treatment of chronic kidney disease in patients with diabetes.

IRX5 promotes colorectal cancer metastasis by negatively regulating the core components of the RHOA pathway.

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. As tumor metastasis is the leading cause of death in patients with CRC, it is important to elucidate the molecular mechanisms that drive CRC metastasis. Studies have shown a close relationship between Iroquois homeobox (IRX) family genes and multiple cancers, while the mechanism by which IRX5 promotes CRC metastasis is unclear. Therefore, we focused on the involvement of IRX5 in CRC metastasis. In this study, analyses of clinical data indicated that the expression of IRX5 was coincided with metastatic colorectal tumors tissues and was negatively correlated with the overall survival of patients with CRC. Functional analysis showed that IRX5 promoted the migration and invasion of CRC cells, accompanied by a large number of cellular protrusions. IRX5-overexpressing cells were more likely to form metastatic tumors in nude mice. Further analysis demonstrated that the core components of the RHOA/ROCK1/LIMK1 pathway were significantly inhibited in IRX5-overexpressing cells. Overexpression of LIMK1 effectively reversed the enhanced cellular motility caused by IRX5 overexpression. Moreover, we found that high levels of IRX5 in intestinal tissues were correlated with the inflammatory response. IRX5 was significantly increased in azoxymethane/dextran sodium sulfate intestinal tissue of mice and IRX5-overexpressing may also enhance chemokines CXCL1 and CXCL8. In summary, our findings suggested that IRX5 promoted CRC metastasis by inhibiting the RHOA-ROCK1-LIMK1 axis, which correlates with a poor prognosis.

High glucose upregulates osteopontin expression by FoxO1 activation in macrophages.

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE-/- mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt -1918 ~ -713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.