Wogonoside alleviates microglia-mediated neuroinflammation via TLR4/MyD88/NF-κB signaling axis after spinal cord injury.

Wogonoside (WG) is a natural flavonoid extracted from Scutellariae Radix, recognized for its established anti-inflammatory properties. However, the role of WG in the context of neuroinflammation after spinal cord injury (SCI) remains inadequately elucidated. This study employed in silico, in vitro, and in vivo methodologies to investigate the impact of WG on microglia-mediated neuroinflammation after SCI. In the in silico experiment, we identified 15 potential target genes of WG associated with SCI. These genes were linked to the regulation of inflammatory response and immune defense. Molecular docking maps revealed toll-like receptor 4 as a molecular target for WG, demonstrating binding through a hydrogen bond (Lys263, Ser120). In lipopolysaccharide-stimulated BV2 cells and SCI mice, WG significantly attenuated microglial activation and facilitated a phenotype shift from M1 to M2. This was evidenced by the reversal of the increased expressions of Iba1, GFAP, and iNOS, as well as the decreased expression of Arg1. WG also suppressed the production of pro-inflammatory mediators (NO, TNF-α, IL-6, IL-1α, IL-1ß, C1q). WG exerted these effects by suppressing the TLR4/MyD88/NF-κB signaling axis in microglia. Furthermore, by reducing levels of TNF-α, IL-1α, and C1q in supernatant of LPS-induced microglia, WG indirectly induced astrocytes change to A2 phenotype, evidenced by transcriptome sequencing result of primary mouse astrocytes. All these events above collectively created a favorable microenvironment, contributing to a significant alleviation of weight loss and neuronal damage at the lesion site of SCI mice. Our findings substantiate the efficacy of WG in mitigating neuroinflammation after SCI, thereby warranting further exploration.

Multifaceted nucleic acid probing with a rationally upgraded molecular rotor.

Probing the sequence alterations, structures, interactions, and other important aspects of nucleic acids serves as the cornerstone of understanding nucleic acid-mediated biology and etiology, as well as the development of nucleic acid-based therapeutics. New strategies capable of accommodating these imperatives without necessitating specialized instrument or skills and potentially complementing existing methods are highly desired. Herein, we describe a rationally designed molecular rotor CCVJ-H ((9-(2-carboxy-2-cyanovinyl)julolidine-hydrazide)) and its superior performances compared to the universal base excision reporter probe CCVJ-1 in applications such as nucleic acid detection and DNA glycosylase assays. Furthermore, we showcase that the CCVJ-H probe accurately profiles the interactions between nucleic acids and small molecules, providing binding affinity and binding site information in a single reaction. We subsequently demonstrate the feasibility of applying the CCVJ-H system in high-throughput screening to identify nucleic acid-binding small molecules such as DNA CTG repeat expansion binders, potentially providing therapeutic interventions for myotonic dystrophy type 1. Finally, we profile the recognition difference between DNA/DNA and DNA/RNA against a library of small molecules, uncovering two drug-like molecules that preferentially bind DNA/RNA. We anticipate the versatile CCVJ-H probe will be a useful tool for both fundamental and translational nucleic acid research and application.

RNA Control via Redox-Responsive Acylation.

Incorporating stimuli-responsive components into RNA constructs provides precise spatiotemporal control over RNA structures and functions. Despite considerable advancements, the utilization of redox-responsive stimuli for the activation of caged RNAs remains scarce. In this context, we present a novel strategy that leverages post-synthetic acylation coupled with redox-responsive chemistry to exert control over RNA. To achieve this, we design and synthesize a series of acylating reagents specifically tailored for introducing disulfide-containing acyl adducts into the 2'-OH groups of RNA ("cloaking"). Our data reveal that these acyl moieties can be readily appended, effectively blocking RNA catalytic activity and folding. We also demonstrate the traceless release and reactivation of caged RNAs ("uncloaking") through reducing stimuli. By employing this strategy, RNA exhibits rapid cellular uptake, effective distribution and activation in the cytosol without lysosomal entrapment. We anticipate that our methodology will be accessible to laboratories engaged in RNA biology and holds promise as a versatile platform for RNA-based applications.

Marked-LIEO: Visual Marker-Aided LiDAR/IMU/Encoder Integrated Odometry.

In this paper, we propose a visual marker-aided LiDAR/IMU/encoder integrated odometry, Marked-LIEO, to achieve pose estimation of mobile robots in an indoor long corridor environment. In the first stage, we design the pre-integration model of encoder and IMU respectively to realize the pose estimation combined with the pose estimation from the second stage providing prediction for the LiDAR odometry. In the second stage, we design low-frequency visual marker odometry, which is optimized jointly with LiDAR odometry to obtain the final pose estimation. In view of the wheel slipping and LiDAR degradation problems, we design an algorithm that can make the optimization weight of encoder odometry and LiDAR odometry adjust adaptively according to yaw angle and LiDAR degradation distance respectively. Finally, we realize the multi-sensor fusion localization through joint optimization of an encoder, IMU, LiDAR, and camera measurement information. Aiming at the problems of GNSS information loss and LiDAR degradation in indoor corridor environment, this method introduces the state prediction information of encoder and IMU and the absolute observation information of visual marker to achieve the accurate pose of indoor corridor environment, which has been verified by experiments in Gazebo simulation environment and real environment.

Hydrophobic Interface Starch Nanofibrous Film for Food Packaging: From Bioinspired Design to Self-Cleaning Action.

Starch-derived edible food films have great potential as biodegradable food packaging materials because they reduce the overuse of traditional petroleum-based plastic. Herein, we demonstrate a direct method of mass producing a pure starch food packaging film that consisted of starch nanofibers by using a temperature-assisted electrospinning technique without addition of any nonstarch components. To overcome the major issue of ultralow hydrophobicity of starch nanofibrous film (SNF), we used a facile and low-cost solution immersion approach to create a fiber coating of stearic acid (STA) inspired by biological organisms with superhydrophobic properties, such as lotus leaves. Hierarchical flower-like micronanostructures were obtained on SNF by controlled assembly of STA onto the surface of starch nanofibers. Benefiting from the effective formation of STA self-assembled lamella, the multiscale microstructure surface features, low surface energy, and enhancing thermal stability of SNF were obtained and confirmed to result in the variety of its hydrophobicity, which can be also tailored by simple controlling of the solution concentration of STA. Importantly, the STA-self-assembled coated SNF enabled water to roll freely in all directions, which is a crucial factor for self-cleaning. Our novel strategy based on self-assembly can guide development of bioinspired hydrophobic interfaces for starch-based films for edible hydrophobic materials.

Determination of Differentiating Markers in Coicis Semen From Multi-Sources Based on Structural Similarity Classification Coupled With UPCC-Xevo G2-XS QTOF.

Coicis semen, a medicinal food, is derived from the dried and mature seeds of Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf, a member of the Gramineae family. Lipids are its main constituents. Previous literature reported that coicis semen contains twenty triglycerides and twelve diglycerides. However, we identified thirty-five triglycerides, sixteen diglycerides, four monoglycerides, and two sterols under the preoptimized conditions of UPCC-Xevo G2-XS QTOF combined with a personalized TCM database. Furthermore, we successfully determined glycerol trioleate content to evaluate quality differences. Finally, we identified the fatty acid compositions of seven out of nine differential markers via Progenesis QI using principal component analysis, orthogonal projection to latent structures-discriminant analysis, and the LipidMaps database. In addition, we applied a software-based classification, a method that was previously developed by our team, to verify and predict structurally similar compounds. Our findings confirmed that UPCC-Xevo G2-XS QTOF combined with software-based group classification could be used as an efficient method for exploring the potential lipid markers of seed medicine.

Nephrotoxicity of Herbal Medicine and Its Prevention.

Herbal medicine (HM) has been widely used to treat diseases for thousands of years and has greatly contributed to the health of human beings. Many new drugs have been developed from HM, such as artemisinin. However, artemisinin has adverse effects, such as renal toxicity. In 1993, a study conducted in Belgium reported for the first time that the root extracts of Aristolochia obliqua S. M. Hwang led to progressive interstitial renal fibrosis. The nephrotoxicity of HM has attracted worldwide attention. More than 100 kinds of HM induce renal toxicity, including some herbs, animal HMs, and minerals. This paper aimed to summarize the HM compounds that cause nephrotoxicity, the mechanisms underlying the toxicity of these compounds, biomarkers of renal injury, and prevention strategies. These findings provide a basis for follow-up studies on the prevention and treatment of HM nephrotoxicity.

Designer Fluorescent Adenines Enable Real-Time Monitoring of MUTYH Activity.

The human DNA base excision repair enzyme MUTYH (MutY homolog DNA glycosylase) excises undamaged adenine that has been misincorporated opposite the oxidatively damaged 8-oxoG, preventing transversion mutations and serving as an important defense against the deleterious effects of this damage. Mutations in the MUTYH gene predispose patients to MUTYH-associated polyposis and colorectal cancer, and MUTYH expression has been documented as a biomarker for pancreatic cancer. Measuring MUTYH activity is therefore critical for evaluating and diagnosing disease states as well as for testing this enzyme as a potential therapeutic target. However, current methods for measuring MUTYH activity rely on indirect electrophoresis and radioactivity assays, which are difficult to implement in biological and clinical settings. Herein, we synthesize and identify novel fluorescent adenine derivatives that can act as direct substrates for excision by MUTYH as well as bacterial MutY. When incorporated into synthetic DNAs, the resulting fluorescently modified adenine-release turn-on (FMART) probes report on enzymatic base excision activity in real time, both in vitro and in mammalian cells and human blood. We also employ the probes to identify several promising small-molecule modulators of MUTYH by employing FMART probes for in vitro screening.

The Phytochemistry, Pharmacology, and Quality Control of Tetrastigma hemsleyanum Diels & Gilg in China: A Review.

Tetrastigma hemsleyanum Diels & Gilg (TDG), the family member of Vitaceae, is a traditional herbal medicine in China. The root of TDG can be immediately used after cleaning the muddy soil, and can be dehydrated for dry use. TDG is able to be collected all year round, which is commonly used in the treatment of hepatitis, infantile high fever, snake bite, etc. Based on phytochemistry, the chemical components of TDG are divided into flavonoids, phenolic acids, terpenes, steroids, polysaccharide, and other compounds, showing many pharmacological effects which include anti-tumor, anti-oxidation, anti-inflammatory, antipyretic, analgesic, and immunomodulatory activity, as well as other activities. Currently, TDG involves some problems of the reduction of wild resources, the backward processing methods, and storage difficulties as well as the imperfection of detection methods. Therefore, this review summarizes the literature of the past 20 years, and the purpose of this review is to summarize the recent researches on the phytochemistry, pharmacology, quality control, and clinical application of TDG. The above discussions provide new insights for the future research on TDG.

Distal γ-C(sp3 )-H Olefination of Ketone Derivatives and Free Carboxylic Acids.

Reported herein is the distal γ-C(sp3 )-H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino-acid directing group and using the ligand combination of a mono-N-protected amino acid (MPAA) and an electron-deficient 2-pyridone were critical for the γ-C(sp3 )-H olefination of ketone substrates. In addition, MPAAs enabled the γ-C(sp3 )-H olefination of free carboxylic acids to form diverse six-membered lactones. Besides alkyl carboxylic acids, benzylic C(sp3 )-H bonds also could be functionalized to form 3,4-dihydroisocoumarin structures in a single step from 2-methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ-C(sp3 )-H olefinated products.

Danshensu, a novel indoleamine 2,3-dioxygenase1 inhibitor, exerts anti-hepatic fibrosis effects via inhibition of JAK2-STAT3 signaling.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1), an important intracellular rate-limiting enzyme in the development of Hepatic fibrosis (HF), and has been proposed as a hallmark of HF. Danshensu (DSS) is a major bioactive component that isolated from a edible traditional Chinese medicinal herb Salviae Miltiorrhizae Radix et Rhizoma (Danshen), while, the anti-HF mode and mechanism of action of DSS have not been fully elucidated. METHODS: Carbon tetrachloride (CCl4)-induced rat HF model and TGF-ß1-induced hepatic stellate cell (HSC) model were employed to assess the in vivo and in vitro anti-HF effects of DSS. HSC-T6 cells stably expressing IDO1, a constitutively active IDO1 mutant, was used to determine the role of JAK2-STAT3 signaling in the DSS's anti-HF effects. RESULTS: We found that intragastric administration of DSS potently reduced fibrosis, inhibited IDO1 expression and STAT3 activity both in vitro and in vivo. Using molecular docking and molecular dynamics analysis, DSS was identified as a novel IDO1 inhibitor. Mechanistic studies indicated that DSS inhibited JAK2-STAT3 signaling, it reduced IDO1 expression, STAT3 phosphorylation and STAT3 nuclear localization. More importantly, overexpression of IDO1 diminished DSS's anti-HF effects. CONCLUSION: Our findings provide a pharmacological justification for the clinical use of DSS in treating HF, and suggest that DSS has the potential to be developed as a modern alternative and/or complimentary agent for HF treatment and prevention.

Long noncoding RNA MALAT1 mediates stem cell-like properties in human colorectal cancer cells by regulating miR-20b-5p/Oct4 axis.

Cancer stem cells (CSCs) are crucial components of the tumor microenvironment that take part in tumor initiation, progression, recurrence, metastasis, and resistance to chemotherapy. This study explores the mechanisms through which CSCs maintain their stemness, especially in tumors of colorectal cancer (CRC), which thus far remain uncertain. Our findings indicated that the expression of miR-20b-5p is negatively correlated with that of metastasis-associated lung adenocarcinoma transcript-1 (MALAT1, r = -0.928, p = 0.023) and Oct4 (r = -0.894, p = 0.041) in CRC cells. We hypothesized that there may be some targeted regulatory relationships among MALAT1, miR-20b-5p, and Oct4. We proceeded to show that both si-MALAT1 and miR-20b-5p-mimic attenuated microsphere formation and self-renewal capacity, decreased the proportion of CSCs, and downregulated the expression of proteins associated with tumor cell stemness maintenance (Oct4, Nanog, sex-determining region Y-box 2, and Notch1) and cellular metabolism (glucose transporter 1, lactate dehydrogenase B, hexokinase 2, and pyruvate kinase isozyme M2) in HCT-116 cells in vitro. In addition, a xenograft model based on Balb/c mice demonstrated that the administration of either si-MALAT1 or miR-20b-5p-mimic suppressed the tumorigenicity of HCT-116 cells in vivo. The underlying mechanisms may involve the targeting of the tumor cell stemness maintenance-related factor Oct4 by miR-20b-5p. For the first time, we present the possible underlying effects of MALAT1 in influencing the stem cell-like properties of CRC cells. We propose that microRNAs and long noncoding RNAs have vital functions in mediating tumor stemness, which remain to be fully elucidated.

Inhibition of MALAT1 reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer.

Human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA known to be highly expressed in several tumors. In colorectal cancer (CRC), MALAT1 promotes cell proliferation, metastasis, and invasion in vitro and in vivo. This study aimed to investigate the effect of MALAT1 on the proliferation, migration, and drug sensitivity of CRC cells in vitro and in vivo and the mechanisms involved therein. We observed increased expression of MALAT1 in six CRC cell lines compared to that in normal cells, suggesting its involvement in CRC progression. Downregulation of MALAT1 inhibited cell migration and induced apoptosis in vitro and inhibited tumor growth and metastasis in nude mice. Furthermore, MALAT1 silencing downregulated the expression of ATP-binding cassette transporters (ABC), breast cancer resistance protein (BCRP), and multi-drug resistance proteins including MDR1 and MRP1, resulting in decreased resistance of cancer cells to 5-FU. In addition, the metastasis and invasion of HCT-116 and HCT-116/5-FU cells were regulated via targeting miR-20b-5p. Based on these observations, we infer that inhibition of MALAT1 suppressed CRC progression and metastasis and improved the sensitivity of cancer cells to 5-FU. The present study proposes a new direction to investigate the molecular mechanisms underlying the invasion and metastasis of CRC, whereby the interaction between MALAT1 and miR-20b-5p could be a novel therapeutic target for CRC.

Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance.

Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn's disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4 + ) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.

Ligand-Enabled γ-C(sp3)-H Activation of Ketones.

We report the first example of Pd(II)-catalyzed γ-C(sp3)-H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2-Pyridone ligands are identified to enable C(sp3)-H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)arylation and vinylation of γ-C(sp3)-H bonds are demonstrated. Sequential ß- and γ-C(sp3)-H (hetero)arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation.

Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts.

Organic molecules are rich in carbon-hydrogen bonds; consequently, the transformation of C-H bonds to new functionalities (such as C-C, C-N, and C-O bonds) has garnered much attention by the synthetic chemistry community. The utility of C-H activation in organic synthesis, however, cannot be fully realized until chemists achieve stereocontrol in the modification of C-H bonds. This Review highlights recent efforts to enantioselectively functionalize C(sp3)-H bonds via transition metal catalysis, with an emphasis on key principles for both the development of chiral ligand scaffolds that can accelerate metalation of C(sp3)-H bonds and stereomodels for asymmetric metalation of prochiral C-H bonds by these catalysts.

Versatile Alkylation of (Hetero)Aryl Iodides with Ketones via ß-C(sp3)-H Activation.

We report Pd(II)-catalyzed ß-C(sp3)-H (hetero)arylation of a variety of ketones using a commercially available 2,2-dimethyl aminooxyacetic acid auxiliary. Facile installation and removal of the auxiliary as well as its superior scope for both ketones and (hetero)aryl iodides overcome the significant limitations of the previously reported ß-C(sp3)-H arylation of ketones. The ready availability of ketones renders this reaction a broadly useful method for alkyl-(hetero)aryl coupling involving both primary and secondary alkyls.

An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary.

A practical method for the removal of a versatile acidic amide auxiliary has been developed. Facile alcoholysis of the amide in the presence of KOAc is enabled by an epoxide, which mechanistically resembles the removal of the Myers' auxiliary. The protocol has been applied to the removal of a variety of amide substrates and their C-H functionalization products with high efficiency and low cost, representing a step forward toward the development of a versatile directing group for C-H activation.

Highly Versatile ß-C(sp3)-H Iodination of Ketones Using a Practical Auxiliary.

The first example of palladium(II)-catalyzed ß-C(sp3)-H iodination of a wide range of ketones using a commercially available aminooxyacetic acid auxiliary has been achieved. This L, X-type directing group overcomes the limitations of the transient directing group approach for C(sp3)-H functionalization of ketones. Practical advantages of this method include simple installation of the auxiliary without chromatography, exceptional tolerance of α-functional groups, as well as alkenes and alkynes, and rapid access to diverse sterically hindered quaternary centers.

Ligand-Enabled Pd(II)-Catalyzed Bromination and Iodination of C(sp3)-H Bonds.

We herein report the palladium(II)-catalyzed bromination and iodination of a variety of α-hydrogen-containing carboxylic acid and amino acid-derived amides. These reactions are exclusively enabled by quinoline-type ligands. The halogenated products obtained in this reaction are highly versatile and rapidly undergo further diversification. Further, we report the first example of a free carboxylic acid-directed Pd(II)-catalyzed C(sp3)-H bromination, enabled by quinoline ligands.