Nerve injury inhibits Oprd1 and Cnr1 transcription through REST in primary sensory neurons.

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1, Oprd1, Oprl1, Oprk1) and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression of Rest and downregulated mRNA levels of all 4 opioid receptor and Cnr1 genes, but Oprm1 was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription of Oprd1 and Cnr1 via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.

Side Chain Programming Synchronously Enhances the Photothermal Conversion Efficiency and Photodynamic Activity of A-D-A Photosensitizers.

Synchronously improving the photothermal conversion efficiency and photodynamic activity of organic small molecule photosensitizers is crucial for their further wide application in cancer treatment. Recently, the emerging A-D-A photosensitizer-based phototherapy systems have attracted great interest due to their plentiful inherent merits. Herein, we propose a design strategy for A-D-A photosensitizers with synchronously enhanced photothermal conversion and reactive oxygen species (ROS) generation efficiencies. Side chain programming is carried out to design three A-D-A photosensitizers (IDT-H, IDT-Br, IDT-I) containing hexyl, bromohexyl, and iodohexyl side chains, respectively. Theoretical calculations confirm that a bulky iodine atom could weaken the intermolecular π-π stacking and enhance spin-orbit coupling constants of IDT-I. These molecular mechanisms enable IDT-I nanoparticles (NPs) to exhibit 2.4-fold and 1.7-fold higher ROS generation efficiency than that of IDT-H NPs and IDT-Br NPs, respectively, as well as the highest photothermal conversion efficiency. Both the experimental results in vitro and in vivo verify that IDT-I NPs are perfectly qualified for the mission of photothermal and photodynamic synergistic therapy. Therefore, in this contribution, we provide a promising perspective for the design of A-D-A photosensitizers with simultaneously improved photothermal and photodynamic therapy ability.

Prognostic Model Associated with Necroptosis in Colorectal Cancer based on Transcriptomic Analysis and Experimental Validation.

PURPOSE: Numerous studies have emphasised the importance of necroptosis in the malignant progression of colorectal cancer (CRC). However, whether necroptosis-related genes (NRGs) can be used to predict the prognosis of CRC remains to be revealed. METHODS: Patients with CRC were divided into two clusters based on the expression of NRGs, and prognosis was compared between the two clusters. A prognostic model was established based on NRGs, and its predictive efficiency was validated using Kaplan-Meier (K-M) curves, receiver operating characteristic (ROC) curves and a nomogram. Immune infiltration, single-cell and drug sensitivity analyses were used to examine the effects of NRGs on the prognosis of CRC. RESULTS: The prognostic model served as a valid and independent predictor of CRC prognosis. Immune infiltration and single-cell analyses revealed that the unique immune microenvironment of CRC was regulated by NRGs. Drug sensitivity analysis showed that patients in the high- and low-risk groups were sensitive to different drugs. In addition, H2BC18 was found to play an important role in regulating the malignant progression of CRC. CONCLUSION: This study provides novel insights into precision immunotherapy based on NRGs in CRC. The NRG-based prognostic model may help to identify targeted drugs and develop more effective and individualised treatment strategies for patients with CRC.

Recent advances in swine wastewater treatment technologies for resource recovery: A comprehensive review.

Swine wastewater (SW), characterized by highly complex organic and nutrient substances, poses serious impacts on aquatic environment and public health. Furthermore, SW harbors valuable resources that possess substantial economic potential. As such, SW treatment technologies place increased emphasis on resource recycling, while progressively advancing towards energy saving, sustainability, and circular economy principles. This review comprehensively encapsulates the state-of-the-art knowledge for treating SW, including conventional (i.e., constructed wetlands, air stripping and aerobic system) and resource-utilization-based (i.e., anaerobic digestion, membrane separation, anaerobic ammonium oxidation, microbial fuel cells, and microalgal-based system) technologies. Furthermore, this research also elaborates the key factors influencing the SW treatment performance, such as pH, temperature, dissolved oxygen, hydraulic retention time and organic loading rate. The potentials for reutilizing energy, biomass and digestate produced during the SW treatment processes are also summarized. Moreover, the obstacles associated with full-scale implementation, long-term treatment, energy-efficient design, and nutrient recovery of various resource-utilization-based SW treatment technologies are emphasized. In addition, future research prospective, such as prioritization of process optimization, in-depth exploration of microbial mechanisms, enhancement of energy conversion efficiency, and integration of diverse technologies, are highlighted to expand engineering applications and establish a sustainable SW treatment system.

Therapeutic potential of ADSC-EV-derived lncRNA DLEU2: A novel molecular pathway in alleviating sepsis-induced lung injury via the miR-106a-5p/LXN axis.

This study investigates the molecular mechanisms by which extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSCs) promote M2 polarization of macrophages and thus reduce lung injury caused by sepsis. High-throughput sequencing was used to identify differentially expressed genes related to long non-coding RNA (lncRNA) in ADSC-derived EVs (ADSC-EVs) in sepsis lung tissue. Weighted gene co-expression network analysis (WGCNA) was employed to predict the downstream target genes of the lncRNA DLEU2. The RNAInter database predicted miRNAs that interact with DLEU2 and LXN. Functional and pathway enrichment analyses were performed using GO and KEGG analysis. A mouse model of sepsis was established, and treatment with a placebo or ADSC-EVs was administered, followed by RT-qPCR analysis. ADSC-EVs were isolated and identified. In vitro cell experiments were conducted using the mouse lung epithelial cell line MLE-12, mouse macrophage cell line RAW264.7, and mouse lung epithelial cell line (LEPC). ADSC-EVs were co-cultured with RAW264.7 and MLE-12/LEPC cells to study the regulatory mechanism of the lncRNA DLEU2. Cell viability, proliferation, and apoptosis of lung injury cells were assessed using CCK-8, EdU, and flow cytometry. ELISA was used to measure the levels of inflammatory cytokines in the sepsis mouse model, flow cytometry was performed to determine the number of M1 and M2 macrophages, lung tissue pathology was evaluated by H&E staining, and immunohistochemistry was conducted to examine the expression of proliferation- and apoptosis-related proteins. High-throughput sequencing and bioinformatics analysis revealed enrichment of the lncRNA DLEU2 in ADSC-EVs in sepsis lung tissue. Animal and in vitro cell experiments showed increased expression of the lncRNA DLEU2 in sepsis lung tissue after treatment with ADSC-EVs. Furthermore, ADSC-EVs were found to transfer the lncRNA DLEU2 to macrophages, promoting M2 polarization, reducing inflammation response in lung injury cells, and enhancing their viability, proliferation, and apoptosis inhibition. Further functional experiments indicated that lncRNA DLEU2 promotes M2 polarization of macrophages by regulating miR-106a-5p/LXN, thereby enhancing the viability and proliferation of lung injury cells and inhibiting apoptosis. Overexpression of miR-106a-5p could reverse the biological effects of ADSC-EVs-DLEU2 on MLE-12 and LEPC in vitro cell models. Lastly, in vivo animal experiments confirmed that ADSC-EVs-DLEU2 promotes high expression of LXN by inhibiting the expression of miR-106a-5p, further facilitating M2 macrophage polarization and reducing lung edema, thus alleviating sepsis-induced lung injury. lncRNA DLEU2 in ADSC-EVs may promote M2 polarization of macrophages and enhance the viability and proliferation of lung injury cells while inhibiting inflammation and apoptosis reactions, thus ameliorating sepsis-induced lung injury in a mechanism involving the regulation of the miR-106a-5p/LXN axis.

A Recombinant Thermophilic and Glucose-Tolerant GH1 ß-Glucosidase Derived from Hehua Hot Spring.

As a crucial enzyme for cellulose degradation, ß-glucosidase finds extensive applications in food, feed, and bioethanol production; however, its potential is often limited by inadequate thermal stability and glucose tolerance. In this study, a functional gene (lq-bg5) for a GH1 family ß-glucosidase was obtained from the metagenomic DNA of a hot spring sediment sample and heterologously expressed in E. coli and the recombinant enzyme was purified and characterized. The optimal temperature and pH of LQ-BG5 were 55 °C and 4.6, respectively. The relative residual activity of LQ-BG5 exceeded 90% at 55 °C for 9 h and 60 °C for 6 h and remained above 100% after incubation at pH 5.0-10.0 for 12 h. More importantly, LQ-BG5 demonstrated exceptional glucose tolerance with more than 40% activity remaining even at high glucose concentrations of 3000 mM. Thus, LQ-BG5 represents a thermophilic ß-glucosidase exhibiting excellent thermal stability and remarkable glucose tolerance, making it highly promising for lignocellulose development and utilization.

[DNA barcode screening, identification of germplasm resources, and analysis of genetic diversity of Anemarrhena asphodeloides].

Anemarrhena asphodeloides is a common medicinal material used in clinical prescriptions and Chinese patent medicine. In this study, the Illumina platform was used to obtain the chloroplast genome sequences of seven kinds of A. asphodeloides from different areas. The specific DNA barcodes were screened by comparative genomics analysis, and the DNA barcodes were used to identify the germplasm resources and analyze the genetic diversity of A. asphodeloides samples from different areas in China. All the seven chloroplast genomes had a ring structure. The total length was 156 801-156 930 bp, and 113 genes were annotated, including 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. The comparative genomics analysis showed that rps16, trnG-GCC, atpF, rpoB, ycf3, rpl16, ndhF, trnS-GCU＿trnG-GCC, petN-psbM, and ndhF-rpl32 were potential candidates for specific DNA barcodes of A. asphodeloides. In this study, the second intron of ycf3 and atpF intron sequences with a sequence length of 700-800 bp and easy amplification were selected for polymerase chain reaction(PCR) amplification and sequencing of 594 samples from 26 areas. The sequence analysis showed that six and eight haplotypes of ycf3 and atpF sequences could be identified, respectively, and 17 haplotypes could be identified by combined analysis of the two sequences, which were named Hap1-Hap17. The haplotype diversity(H_d), nucleotide diversity(P_i), and genetic distance of A. asphodeloides in 26 populations were 0.68, 0.93×10~(-3), and 0-0.003 1, respectively, indicating that the genetic diversity within the species of A. asphodeloides is rich. The intermediary adjacent network analysis showed that Hap5 was the oldest haplotype, which was mainly distributed in Yixian county of Baoding, Hebei province, Hequ county of Xinzhou, Shanxi province, and Xiangfen county of Linfen, Shanxi province. This study has important guiding significance for the identification of A. asphodeloides species, the protection and development of germplasm resources, and the identification of production areas, and it provides a research basis for further revealing the genetic evolution law of A. asphodeloides.

PnNAC2 promotes the biosynthesis of Panax notoginseng saponins and induces early flowering.

KEY MESSAGE: PnNAC2 positively regulates saponin biosynthesis by binding the promoters of key biosynthetic genes, including PnSS, PnSE, and PnDS. PnNAC2 accelerates flowering through directly associating with the promoters of FT genes. NAC transcription factors play an important regulatory role in both terpenoid biosynthesis and flowering. Saponins with multiple pharmacological activities are recognized as the major active components of Panax notoginseng. The P. notoginseng flower is crucial for growth and used for medicinal and food purposes. However, the precise function of the P. notoginseng NAC transcription factor in the regulation of saponin biosynthesis and flowering remains largely unknown. Here, we conducted a comprehensive characterization of a specific NAC transcription factor, designated as PnNAC2, from P. notoginseng. PnNAC2 was identified as a nuclear-localized protein with transcription activator activity. The expression profile of PnNAC2 across various tissues mirrored the accumulation pattern of total saponins. Knockdown experiments of PnNAC2 in P. notoginseng calli revealed a significant reduction in saponin content and the expression level of pivotal saponin biosynthetic genes, including PnSS, PnSE, and PnDS. Subsequently, Y1H assays, dual-LUC assays, and electrophoretic mobility shift assays (EMSAs) demonstrated that PnNAC2 exhibits binding affinity to the promoters of PnSS, PnSE and PnDS, thereby activating their transcription. Additionally, an overexpression assay of PnNAC2 in Arabidopsis thaliana witnessed the acceleration of flowering and the induction of the FLOWERING LOCUS T (FT) gene expression. Furthermore, PnNAC2 demonstrated the ability to bind to the promoters of AtFT and PnFT genes, further activating their transcription. In summary, these results revealed that PnNAC2 acts as a multifunctional regulator, intricately involved in the modulation of triterpenoid saponin biosynthesis and flowering processes.

Unveiling the Structural Origins of Dynamic Diversity in Pd-Based Metallic Glasses.

The ß-relaxation is one of the major dynamic behaviors in metallic glasses (MGs) and exhibits diverse features. Despite decades of efforts, the understanding of its structural origin and contribution to the overall dynamics of MG systems is still unclear. Here two palladium-based Pd─Cu─P and Pd─Ni─P MGs are reported with distinct different ß-relaxation behaviors and reveal the structural origins for the difference using the advanced X-ray photon correlation spectroscopy and absorption fine structure techniques together with the first-principles calculations. The pronounced ß-relaxation and fast atomic dynamics in the Pd─Cu─P MG mainly come from the strong mobility of Cu atoms and their locally favored structures. In contrast, the motion of Ni atoms is constrained by P atoms in the Pd─Ni─P MG, leading to the weakened ß-relaxation peak and sluggish dynamics. The correlation of atomic dynamics with microscopic structures provides a way to understand the structural origins of different dynamic behaviors as well as the nature of aging in disordered materials.

Olmsted Syndrome.

This case report describes a 6-year-old girl who presented with symmetrical massive keratotic plaques on the palms, soles, and perioral area, as well as hair loss for 4 years.

Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review).

RNA methylation modifications are closely linked to tumor development, migration, invasion and responses to various therapies. Recent studies have shown notable advancements regarding the roles of RNA methylation in tumor immunotherapy, the tumor microenvironment and metabolic reprogramming. However, research on the association between tumor chemoresistance and N6­methyladenosine (m6A) methyltransferases in specific cancer types is still scarce. Colorectal cancer (CRC) is among the most common gastrointestinal cancers worldwide. Conventional chemotherapy remains the predominant treatment modality for CRC and chemotherapy resistance is the primary cause of treatment failure. The expression levels of m6A methyltransferases, including methyltransferase­like 3 (METTL3), METTL14 and METTL16, in CRC tissue samples are associated with patients' clinical outcomes and chemotherapy efficacy. Natural pharmaceutical ingredients, such as quercetin, have the potential to act as METTL3 inhibitors to combat chemotherapy resistance in patients with CRC. The present review discussed the various roles of different types of key RNA methylation enzymes in the development of CRC, focusing on the mechanisms associated with chemotherapy resistance. The progress in the development of certain inhibitors is also listed. The potential of using natural remedies to develop antitumor medications that target m6A methylation is also outlined.

Effect and its mechanism of potassium persulfate on aerobic composting process of vegetable wastes.

Vegetable waste (VW) is a potential organic fertilizer resource. As an important way to utilize vegetable wastes, aerobic composting of VW generally has the problems of long fermentation cycle and incomplete decomposition of materials. In this study, 0.3-1.2% of potassium persulfate (KPS) was added to promote the maturity of compost. The results showed that the addition of KPS promoted the degradation of materials, accelerated the temperature rise of compost. KPS also promoted the formation of humic substances (HS). Compared with the control, HS contents of treatments with KPS addition increased by 7.81 ~ 17.52%. Fourier transform infrared (FTIR) spectroscopy and scanning electron microscope (SEM) analysis reveal the mechanism of KPS affecting the composting process: KPS stimulated the degradation of various organic substances such as lignin at high temperature stage, and the degradation of lignin could accelerate the release and decomposition of other components; KPS made the structure of the material looser, with more voids and pores, and more specific surface area of the material, which was more suitable for microbial degradation activities. Therefore, the addition of KPS can promote the decomposition of organic matter in the early stage of composting, accelerate the process of thermophilic phase, and shorten the composting process and improve product maturity.

End Group Engineering for Constructing A-D-A Fused-Ring Photosensitizers with Balanced Phototheranostics Performance.

Phototheranostics continues to flourish in cancer treatment. Due to the competitive relationships between these photophysical processes of fluorescence emission, photothermal conversion, and photodynamic action, it is critical to balance them through subtle photosensitizer designs. Herein, it is provided a useful guideline for constructing A-D-A photosensitizers with superior phototheranostics performance. Various cyanoacetate group-modified end groups containing ester side chains of different length are designed to construct a series of A-D-A photosensitizers (F8CA1 ∼ F8CA4) to study the structure-property relationships. It is surprising to find that the photophysical properties of A-D-A photosensitizers can be precisely regulated by these tiny structural changes. The results reveal that the increase in the steric hindrance of ester side chains has positive impacts on their photothermal conversion capabilities, but adverse impacts on the fluorescence emission and photodynamic activities. Notably, these tiny structural changes lead to their different aggregation behavior. The molecule mechanisms are detailedly explained by theoretical calculations. Finally, F8CA2 nanoparticles with more balanced photophysical properties perform well in fluorescence imaging-guided photothermal and type I&II photodynamic synergistic cancer therapy, even under hypoxic conditions. Therefore, this work provides a novel practicable construction strategy for desired A-D-A photosensitizers.

Formononetin ameliorates airway inflammation by suppressing ESR1/NLRP3/Caspase-1 signaling in asthma.

Since inhaled glucocorticoids are the first-line treatment for asthma, asthma management becomes extremely difficult when asthma does not react well to glucocorticoids. Formononetin, a bioactive isoflavone and typical phytoestrogen, has been shown to have an anti-inflammatory impact while alleviating epithelial barrier dysfunction, which plays a role in the pathogenesis of allergic illnesses like asthma. However, the biological mechanisms behind this impact are unknown. As a result, we set out to investigate the effects of formononetin on airway inflammation and epithelial barrier repair in house dust mite (HDM)-induced asthmatic mice. We further expanded on formononetin's putative mode of action in reducing airway inflammation by modifying epithelial barrier dysfunction. In the current study, researchers discovered that formononetin significantly lowered total IgE levels in serum and interleukin (IL)-4, IL-6, and IL-17A levels in bronchoalveolar lavage fluid (BALF) in HDM-challenged asthmatic mice. Experiments on cell proliferation, migration, and apoptosis were performed in vitro to determine the effect of formononetin on bronchial epithelial barrier repair. Furthermore, in lipopolysaccharide (LPS)-stimulated 16HBE cells, formononetin increased cell proliferation and migration while preventing apoptosis and lowering the Bax/Bcl-2 ratio. In vitro and in vivo, formononetin significantly inhibited toll-like receptor 4 (TLR4) and estrogen receptor (ESR1)/Nod-like receptor family pyrin domain-containing protein 3 (NLRP3)/Caspase-1 signaling. These findings show that formononetin can reduce airway inflammation in HDM-challenged asthmatic mice by promoting epithelial barrier repair and possibly by inhibiting ESR1/NLRP3/Caspase-1 signaling as the underlying mechanism; formononetin could be a promising alternative treatment for asthma.

Emissive Nanoparticles from Co-assembly of Metallatetragon and Amphiphilic Tetraphenylethylene for Cancer Theranostics.

Platinum(II)-based metallacycles/cages have obtained tremendous attention due to their fascinating topology and wide range of applications, such as fluorescent materials, cell imaging, and tumor treatment. In this work, a metallatetragon (1) was constructed from 4-(4-(1,2,2-triphenylvinyl)phenyl)pyridine (2) and 90° cis-Pt(II) (Pt) in acetone through the strategy called "coordination driven self-assembly". Interestingly, through co-assembly of 1 and poly(ethylene glycol)-modified tetraphenylethylene (TPE-PEG22), fluorescent nanotheranostics, which could generate singlet oxygen (1O2) under the NIR irradiation and release Pt drugs under a low-pH microenvironment, were prepared successfully. The obtained theranostics could realize living cell imaging and synergistic chemo-photodynamic therapy in vitro and in vivo.

Intracellular Fusobacterium nucleatum infection attenuates antitumor immunity in esophageal squamous cell carcinoma.

Currently, the influence of the tumor microbiome on the effectiveness of immunotherapy remains largely unknown. Intratumoural Fusobacterium nucleatum (Fn) functions as an oncogenic bacterium and can promote tumor progression in esophageal squamous cell carcinoma (ESCC). Our previous study revealed that Fn is a facultative intracellular bacterium and that its virulence factor Fn-Dps facilitates the intracellular survival of Fn. In this study, we find that Fn DNA is enriched in the nonresponder (NR) group among ESCC patients receiving PD-1 inhibitor and that the serum antibody level of Fn is significantly higher in the NR group than in the responder (R) group. In addition, Fn infection has an opposite impact on the efficacy of αPD-L1 treatment in animals. Mechanistically, we confirm that Fn can inhibit the proliferation and cytokine secretion of T cells and that Fn-Dps binds to the PD-L1 gene promoter activating transcription factor-3 (ATF3) to transcriptionally upregulate PD-L1 expression. Our results suggest that it may be an important therapeutic strategy to eradicate intratumoral Fn infection before initiating ESCC immunotherapies.

The design strategy for pillararene based active targeted drug delivery systems.

Pillararenes have columnar architectures with electron-rich cavities to endow themselves with unique host-guest complexation capability. Easy structural modifiability facilitates them to be used in many applications. Currently, pillararene based drug delivery systems (DDSs) have been developed as a powerful tool for precise diagnosis and treatment of cancer. Various functional guest molecules could be integrated with pillararenes to construct nanomaterials for cancer chemotherapy, phototherapy and chemodynamic therapy. In order to improve cancer therapy efficacy, active targeted DDSs have become particularly important. Benefiting from the good host-guest properties and structural variability of pillararenes, tumor targeting groups could be easily introduced into pillararene based DDSs to realize precise drug delivery at tumor sites. In this feature article, we provide a comprehensive summary of the present design strategy for pillararene based active targeted DDSs, which can be classified into three types namely host-guest complexation, charge reversal and targeted group modified pillararenes. Some important examples are selected to for a detailed discussion on their respective strengths and weaknesses.

Mitochondria-Targeting Multimodal Phototheranostics Based on Triphenylphosphonium Cation Modified Amphiphilic Pillararenes and A-D-A Fused-Ring Photosensitizers.

Tumor-targeting phototheranostics has gradually developed as a powerful tool for the precise diagnosis and treatment of cancer. However, the designs of tumor-targeting phototheranostics agents with excellent multimodal phototherapy and fluorescence imaging (FLI) capability, as well as very few components, are still scarce and challenging for cancer treatment. Herein, a mitochondria-targeting multimodal phototheranostics system has been constructed by combining a designed amphiphilic pillararene WP5-2PEG-2TPP and the A-D-A fused-ring photosensitizer F8CA5. WP5-2PEG-2TPP is constructed by attaching the triphenylphosphonium cations to our previously reported dual PEG-functionalized amphiphilic pillararene, which can self-assemble into regular spherical nanocarriers with outstanding mitochondria targeting and water solubility. The A-D-A photosensitizer F8CA5 containing two methyl cyanoacetate group modified end groups displays superior photothermal conversion ability and dual type I/II photodynamic activity as well as strong NIR fluorescence emission. Through their strong union, multifunctional mitochondria-targeting phototheranostics agent F8CA5 NPs were obtained to be applied into FLI-guided synergistic photothermal and type I/II photodynamic therapy. As a result, F8CA5 NPs show good mitochondria-targeting and phototherapy effects in various tumor cells. Not only that, they can combat tumor hypoxia, which hinders the efficacy of photodynamic therapy. Therefore, this work provides a creative ideal for the construction of multifunctional tumor-targeting phototheranostic agents with excellent performance.