Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy.

Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" or "down" conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2's epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2's therapeutic potential in treating COVID-19.

NEK2 contributes to radioresistance in esophageal squamous cell carcinoma by inducing protective autophagy via regulating TRIM21.

BACKGROUND: Radiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms. METHODS: Human esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM). RESULTS: In the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21. CONCLUSION: These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.

Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux.

Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5 mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis.

Preparation and properties of two-dimensional Ti2CTxMXene based on electroetching method.

The continuous advancements in wearable electronics have drawn significant attention toward 2D MXenes materials for energy storage owing to their abundant availability, adaptability, and distinctive physicochemical properties. Two unresolved concerns currently revolve around environmental pollution by F-containing etching and finite kinetics caused because of re-stacking of nanosheets. In this study, Al was electrochemically etched from porous Ti2AlC electrodes without the use of fluorine, through a selective electrochemical etching process in dilute hydrochloric acid. Subsequently, Ti2CTxMXene was vertically grown on carbon fiber (CF) substrates. The resulting Ti2CTx@CF electrodes are lightweight, thin, and flexible, exhibiting a surface capacitance of 330 mF cm-2at a constant current density of 1 mA cm-2after 2000 cycles. They display a surface capacitance retention of 96.16% and a high energy density of 45.3µWh cm-2at a power density of 0.497 mW cm-2. These metrics underscore the Ti2CTx@CF electrode's commendable multifunctionality, electrochemical performance, ion transport efficiency, and charge storage capacity. Moreover, a flexible energy storage electrode material with a high area capacity was developed by combining Ti2CTxMXene nanosheets, possessing a large specific surface area, with a flexible carbon fabric substrate.

Advanced detection of cervical cancer biomarkers using engineered filamentous phage nanofibers.

Cervical cancer is a major global health concern, characterized by its high incidence and mortality rates. The detection of tumor markers is crucial for managing cancer, making treatment decisions, and monitoring disease progression. Vascular endothelial growth factor (VEGF) and programmed death-ligand 1 (PDL-1) are key targets in cervical cancer therapy and valuable biomarkers in predicting treatment response and prognosis. In this study, we found that combining the measurement of VEGF and soluble PDL-1 can be used for diagnosing and evaluating the progression of cervical cancer. To explore a more convenient approach for detecting and assessing cervical cancer, we designed and prepared an engineered fd bacteriophage, a human-safe viral nanofiber, equipped with two peptides targeting VEGF and PD-L1. The dual-display phage nanofiber specifically recognizes and binds to both proteins. Utilizing this nanofiber as a novel capture agent, we developed a new enzyme-linked immunosorbent assay (ELISA) method. This method shows significantly enhanced detection sensitivity compared to conventional ELISA methods, which use either anti-VEGF or anti-PD-L1 antibodies as capture agents. Therefore, the phage dual-display nanofiber presents significant potential in detecting cancer markers, evaluating medication efficacy, and advancing immunotherapy drug development. KEY POINTS: • The combined measurement of VEGF and soluble Programmed Death-Ligand 1(sPD-L1) demonstrates an additive effect in the diagnosis of cervical cancer. Fd phage nanofibers have been ingeniously engineered to display peptides that bind to VEGF and PD-L1, enabling the simultaneous detection of both proteins within a single assay • Genetically engineered phage nanofibers, adorned with two distinct peptides, can be utilized for the diagnosis and prognosis of cancer and can be mass-produced cost-effectively through bacterial infections • Employing dual-display fd phage nanofibers as capture probes, the phage ELISA method exhibited significantly enhanced detection sensitivity compared to traditional sandwich ELISA. Furthermore, phage ELISA facilitates the detection of a single protein or the simultaneous detection of multiple proteins, rendering them powerful tools for protein analysis and diagnosis across various fields, including cancer research.

Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance.

CONTEXT: Sepsis can result in critical organ failure, and notoginsenoside R1 (NGR1) offers mitochondrial protection. OBJECTIVE: To determine whether NGR1 improves organ function and prognosis after sepsis by protecting mitochondrial quality. MATERIALS AND METHODS: A sepsis model was established in C57BL/6 mice using cecum ligation puncture (CLP) and an in vitro model with lipopolysaccharide (LPS, 10 µg/mL)-stimulated primary intestinal microvascular endothelial cells (IMVECs) and then determine NGR1's safe dosage. Groups for each model were: in vivo-a control group, a CLP-induced sepsis group, and a CLP + NGR1 treatment group (30 mg/kg/d for 3 d); in vitro-a control group, a LPS-induced sepsis group, and a LPS + NGR1 treatment group (4 µM for 30 min). NGR1's effects on survival, intestinal function, mitochondrial quality, and mitochondrial dynamic-related protein (Drp1) were evaluated. RESULTS: Sepsis resulted in approximately 60% mortality within 7 days post-CLP, with significant reductions in intestinal microvascular perfusion and increases in vascular leakage. Severe mitochondrial quality imbalance was observed in IMVECs. NGR1 (IC50 is 854.1 µM at 30 min) targeted Drp1, inhibiting mitochondrial translocation, preventing mitochondrial fragmentation and restoring IMVEC morphology and function, thus protecting against intestinal barrier dysfunction, vascular permeability, microcirculatory flow, and improving sepsis prognosis. DISCUSSION AND CONCLUSIONS: Drp1-mediated mitochondrial quality imbalance is a potential therapeutic target for sepsis. Small molecule natural drugs like NGR1 targeting Drp1 may offer new directions for organ protection following sepsis. Future research should focus on clinical trials to evaluate NGR1's efficacy across various patient populations, potentially leading to novel treatments for sepsis.

Ascidian-Inspired Temperature-Switchable Hydrogels with Antioxidant Fullerenols for Protecting Radiation-Induced Oral Mucositis and Maintaining the Homeostasis of Oral Microbiota.

A key characteristic of radiation-induced oral mucositis (RIOM) is oxidative stress mediated by the "reactive oxygen species (ROS) storm" generated from water radiolysis, resulting in severe pathological lesions, accompanied by a disturbance of oral microbiota. Therefore, a sprayable in situ hydrogel loaded with "free radical sponge" fullerenols (FOH) is developed as antioxidant agent for RIOM radioprotection. Inspired by marine organisms, 3,4,5-trihydroxyphenylalanine (TOPA) which is enriched in ascidians is grafted to clinically approved temperature-switchable Pluronic F127 to produce gallic acid (containing the TOPA fragment)-modified Pluronic F127 (MGA) hydrogels to resist the fast loss of FOH via biomimetic adhesion during oral movement and saliva erosion. Based on this, progressive RIOM found in mice is alleviated by treatment of FOH-loaded MGA hydrogels whether pre-irradiation prophylactic administration or post-irradiation therapeutic administration, which contributes to maintaining the homeostasis of oral microbiota. Mechanistically, FOH inhibits cell apoptosis by scavenging radiation-induced excess ROS and up-regulates the inherent enzymatic antioxidants, thereby protecting the proliferation and migration of mucosal epithelial cells. In conclusion, this work not only provides proof-of-principle evidence for the oral radioprotection of FOH by blocking the "ROS storm", but also provides an effective and easy-to-use hydrogel system for mucosal in situ administration.

High-speed measurement of retinal arterial blood flow in the living human eye with adaptive optics ophthalmoscopy.

We present a technique to measure the rapid blood velocity in large retinal vessels with high spatiotemporal resolution. Red blood cell motion traces in the vessels were non-invasively imaged using an adaptive optics near-confocal scanning ophthalmoscope at a frame rate of 200 fps. We developed software to measure blood velocity automatically. We demonstrated the ability to measure the spatiotemporal profiles of the pulsatile blood flow with a maximum velocity of 95-156 mm/s in retinal arterioles with a diameter >100 µm. High-speed and high-resolution imaging increased the dynamic range, enhanced sensitivity, and improved the accuracy when studying retinal hemodynamics.

Origin of thermally activated Er3+ emission in GeGaSe films and waveguides.

The origin of the dead or active emission from Er in various Er-doped films has been unclear. Here we took Er-doped GeGaSe as examples and investigated the correlation between the intensity of the photoluminescence (PL) spectra, the content of the activated Er ions, and the intensity of the absorption spectra in the waveguides. We found the linear correlation between the content of Er ions, photoluminescence, and absorption intensity. This provides clear evidence that thermal annealing can promote the conversion of Er metals into Er ions, and such a conversion is essential for practical applications, in which the number of the activated Er ions rather than the nominal Er contents in the materials plays an important role in achieving emission and thus effective optical amplification and lasing.

On-chip Er-doped Ta2O5 waveguide amplifiers with a high internal net gain.

We designed and fabricated a double-layered structure Er3+:Ta2O5 waveguide and investigated its optical amplification performance in C band. The pump laser threshold for zero gain at 1533 nm was 2.5 mW, and the internal net gain was ∼4.63 dB/cm for a lunched pump power of 36.1 mW at 980 nm and signal input power of -30.0 dBm (1 µW). The relationship between the internal gain and the signal input power was also investigated, and a large internal net gain of 10.58 dB/cm was achieved at a signal input power of ∼-47.1 dBm. The results confirm the potentials of the use of Ta2O5 as a host material for optical waveguide amplification.

Modeling the Breakup of Oil-Particle Aggregates in Turbulent Environments for Projectile Penetration.

After an oil spill incident, the spilled oil slicks are observed to migrate to the shoreline area. Under the turbulent conditions, they break into small droplets and are suspended in the water column. The dispersed droplets are expected to interact with the suspended particles and form the oil-particle aggregates (OPAs), which significantly changes the transport of the oil. Instead of an earlier assumption that particles cover the oil surface, thus preventing further breakage or aggregation of OPAs, recent studies demonstrated that particles act like projectiles penetrating the oil droplets, resulting in the breakage of OPAs over a longer period of time. A model looking into the OPA breakup through two breakup mechanisms was proposed for the first time. The first method depicted the breakup of one large OPA into two daughter droplets owing to the turbulent nature, while the second method demonstrated the tear of the OPA surface layer caused by particle uprooting. The model was then calibrated by an experimental study targeting crude oil with varied viscosities, along with previous experimental investigations. Three key factors were identified accounting for the breakage of OPAs, where the increase in particle concentration in the natural environment and the increase in turbulent energy of the surrounding flows benefited the breakage of OPAs, and the increase in oil viscosity suppressed the breakage due to large resistance to shear stress. Besides these elements, the impact of the particle shape on the penetration depth was discussed. The model serves as a fundamental theory to describe the evolution of OPAs for fragmentation behavior.

Radiotherapy combined with nano-biomaterials for cancer radio-immunotherapy.

Radiotherapy (RT) plays an important role in tumor therapy due to its noninvasiveness and wide adaptation. In recent years, radiation therapy has been discovered to induce an anti-tumor immune response, which arouses widespread concern among scientists and clinicians. In this review, we highlight recent advances in the applications of nano-biomaterials for radiotherapy-activated immunotherapy. We first discuss the combination of different radiosensitizing nano-biomaterials and immune checkpoint inhibitors to enhance tumor immune response and improve radiotherapy efficacy. Subsequently, various nano-biomaterials-enabled tumor oxygenation strategies are introduced to alleviate the hypoxic tumor environment and amplify the immunomodulatory effect. With the aid of nano-vaccines and adjuvants, radiotherapy refreshes the host's immune system. Additionally, ionizing radiation responsive nano-biomaterials raise innate immunity-mediated anti-tumor immunity. At last, we summarize the rapid development of immune modulatable nano-biomaterials and discuss the key challenge in the development of nano-biomaterials for tumor radio-immunotherapy. Understanding the nano-biomaterials-assisted radio-immunotherapy will maximize the benefits of clinical radiotherapy and immunotherapy and facilitate the development of new combinational therapy modality.

Mechanism of astragalus injection to relieve symptoms of preeclampsia rat model by inhibiting MMP-9/sFlt-1/TNF-α.

Objective: The aim of this study was to observe the effect of astragalus injection on rats with preeclampsia. Methods: A total of 30 pregnant Sprague Dawley (SD) rats were randomly assigned to the model group (MG), the astragalus group (AG) or the control group (CG), with 10 rats in each group. The rat model of preeclampsia was established by subcutaneous injection of 50 mg/(kg∙d) of N-nitro-L-arginine methyl ester (L-NAME), and 0.024 ml/(g∙d) astragalus injection was administered intraperitoneally. The arterial pressure, urinary protein, placental mass, fetal weight, inflammatory factors in peripheral blood of pregnant rats, protein and mRNA levels of nuclear factor- κB (NF-κB), matrix metalloproteinase-9 (MMP-9), nuclear transcription factor 5 (NFAT-5), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and reactive oxygen species (ROS) activity, malondialdehyde (MDA) and nitric oxide (NO) levels in placental tissues were compared in the 3 groups. Results: After treatment, the arterial pressure and urinary protein levels in pregnant rats in the MG group were significantly higher than in the CG and AG groups (P < .05). The placental mass in the MG group was lower than in the CG and AG groups (P < .05). The messenger RNA (mRNA) and protein levels of sFlt-1, NFAT-5 and NF-κB, as well as ROS activity, MDA, inerleukin (IL)-6, tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ) in the AG group were significantly lower than in the MG group, and mRNA and protein expression of MMP-9 and PlGF, as well as the NO level in the AG group, were significantly higher than in the MG (P < .05). Conclusions: Astragalus injection can effectively inhibit the expression of sFlt-1, NFAT-5, NF-κB and enhance the expression of PlGF and MMP-9 in the placental tissue of rats with preeclampsia, which may be the mechanism of preeclampsia treatment.

Clinical and Genetic Study of Three Inherited Microdeletions of Chromosome 16p11.2.

Copy number variations (CNVs) in chromosome 16p11.2 are not rare. 16p11.2 microdeletion is among the most commonly known genetic etiologies of overweightness, autism spectrum disorder (ASD), and related neurodevelopmental disorders. We report the prenatal diagnosis and genetic counseling of three cases with inherited 16p11.2 microdeletions. In these families, mother/father and fetus have the same microdeletion. Following the use of molecular genetic techniques including array-based methods, the number of reported cases has rapidly increased. A combination of prenatal three-dimensional ultrasound, karyotype analysis, chromosomal microarray analysis (CMA), copy number variation sequencing (CNV-seq), whole-exome sequencing (WES), and genetic counseling is helpful for the prenatal diagnosis of chromosomal microdeletions/microduplications.

[Outcomes and measurements of randomized controlled trial for traditional Chinese medicine in treatment of endometriosis].

This study aims to analyze the outcomes and measurements of randomized controlled trial(RCT) for traditional Chinese medicine(TCM) treatment of endometriosis(EM) and provide a basis for the building of the core outcome set(COS) of EM. The RCT for TCM treatment of EM was retrieved from medical literature databases with the time interval from inception to February 3, 2022. The Cochrane risk of bias assessment tool was employed to evaluate the risk of bias of the included RCT, and descriptive analyses of the extracted information were carried out. A total of 519 RCTs were included, with the sample sizes ranging from 28-582 patients and 239 outcome indicators(8 outcome indicators per RCT on average). According to the functional properties, the reported outcome indicators were classified into 7 indicators: clinical efficacy assessment, indicators of clinical symptoms and signs, TCM symptom efficacy indicators, physical and chemical examinations, quality of life, long-term prognosis, and safety events. All the 519 RCTs had problems, such as the lack of differentiation between primary and secondary outcome indicators(1.73% RCTs reported such differen-tiation), poor quality, confused criteria for composite outcome indicators and arbitrary combination of indicators(45 criteria for the single outcome indicator of efficiency), and messy measurements(as many as 18 measurements for TCM symptom score). In addition, as a chronic disease, EM requires long-term management. The outcome indicators vary for the patients in different disease stages, such as EM pain, EM infertility, and post-operative EM, while the specific outcome indicator sets for different EM populations remain to be developed. In addition, the time point of measurement for EM long-term outcomes remains unclear, and the definition of TCM syndromes lacks standards. The RCT for TCM treatment had a variety of problems, such as the lack of differentiation of outcome indicators, confusion in criteria and measurements, lack of specific outcome indicator sets for different EM populations, and unclear time points for long-term outcomes. Therefore, the studies about COS need to be carried out urgently.

Research Progress on the Biological Activities of Metal Complexes Bearing Polycyclic Aromatic Hydrazones.

Due to the abundant and promising biological activities of aromatic hydrazones, it is of great significance to study the biological activities of their metal complexes for the research and development of metal-based drugs. In this review, we focus on the metal complexes of polycyclic aromatic hydrazones, which still do not receive much attention, and summarize the studies related to their biological activities. Although the large number of metal complexes in phenylhydrazone prevent them all from being summarized, the significant value of polycyclic aromatic hydrocarbons themselves (such as naphthalene and anthracene) as pharmacophores are also considered. Therefore, the bioactivities of the metal complexes of naphthylhydrazone and anthrahydrazone are focused on, and the recent research progress on the metal complexes of anthrahydrazone by the authors is also included. In terms of biological activities, these complexes mainly show antibacterial and anticancer activities, along with less bioactivities. The present review demonstrates that the structural design and bioactivities of these complexes are fundamental, which also indicates a certain structure-activity relationship (SAR) in some substructural areas. However, a systematic and comprehensive conclusion of the SAR is still not available, which suggests that more attention should be paid to the bioactivities of the metal complexes of polycyclic aromatic hydrazones since their potential in structural design and biological activity remains to be explored. We hope that this review will attract more researchers to devote their interest and energy into this promising area.

Preparation and Properties of Cyclodextrin Inclusion Complexes of Hyperoside.

In order to improve the aqueous solubility and enhance the bioavailability of Hyperoside (Hyp), three inclusion complexes (ICs) of Hyp with 2-hydroxypropyl-ß-cyclodextrin (2H-ß-CD), ß-cyclodextrin (ß-CD), and methyl-ß-cyclodextrin (M-ß-CD) were prepared using the ultrasonic method. The characterization of the inclusion complexes (ICs) was achieved using Fourier-transform infrared spectroscopy (FTIR), scanning electronic microscopy (SEM), X-ray powder diffraction (XRPD), thin-layer chromatography (TLC), and 1H nuclear magnetic resonance (1H NMR). The effects of the ICs on the solubility and antioxidant activity of Hyp were investigated. A Job's plot revealed that the Hyp formed ICs with three kinds of cyclodextrin (CD), all at a 1:1 stoichiometric ratio. The FTIR, SEM, XRPD, TLC, and 1H NMR results confirmed the formation of inclusion complexes. The water solubility of the IC of Hyp with 2-hydroxypropyl-ß-cyclodextrin was enhanced 9-fold compared to the solubility of the original Hyp. The antioxidant activity tests showed that the inclusion complexes had higher antioxidant activities compared to free Hyp in vitro and the H2O2-RAW264.7 cell model. Therefore, encapsulation with CDs can not only improve Hyp's water solubility but can also enhance its biological activity, which provides useful information for the potential application of complexation with Hyp in a clinical context.

Adsorption and Desorption Characteristics of Total Flavonoids from Acanthopanax senticosus on Macroporous Adsorption Resins.

We examined the application of six different resins with the aim of selecting a macroporous resin suitable for purifying Acanthopanax senticosus total flavonoids (ASTFs) from Acanthopanax senticosus crude extract (EAS) by comparing their adsorption/desorption capacities, which led to the selection of HPD-600. Research on the adsorption mechanism showed that the adsorption process had pseudo-second-order kinetics and fit the Freundlich adsorption model. Moreover, the analysis of thermodynamic parameters indicated that the adsorption process is spontaneous and endothermic. The optimal conditions for purification of ASTFs were determined as sample pH of 3, 60% ethanol concentration, and 3 BV·h-1 flow rate, for both adsorption and desorption, using volumes of 2.5 and 4 BV, respectively. The application of macroporous resin HPD-600 to enrich ASTFs resulted in an increase in the purity of total flavonoids, from 28.79% to 50.57%. Additionally, the antioxidant capacity of ASTFs was higher than that of EAS, but both were lower than that of L-ascorbic acid. The changes in ASTFs compositions were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), with the results illustrating that the levels of seven major flavonoids of ASTFs were increased compared to that in the crude extract.

Long noncoding RNA lnc-RI regulates DNA damage repair and radiation sensitivity of CRC cells through NHEJ pathway.

A percentage of colorectal cancer (CRC) patients display low sensitivity to radiotherapy, which affects its therapeutic effect. Cancer cells DNA double-strand breaks (DSBs) repair capacity is crucial for radiosensitivity, but the roles of long noncoding RNAs (lncRNAs) in this process are largely uncharacterized. This study aims to explore whether lnc-RI regulates CRC cell growth and radiosensitivity by regulating the nonhomologous end-joining (NHEJ) repair pathway. CRC cells in which lnc-RI has been silenced showed lower cell growth and higher apoptosis rates due to increased DSBs and cell cycle arrest. We found that miR-4727-5p targets both lnc-RI and LIG4 mRNA and inhibit their expression. CRC cells showed increased radiosensitivity when lnc-RI was silenced. These results reveal novel roles for lnc-RI in both DNA damage repair and radiosensitivity regulation in CRC cells. Our study revealed that lnc-RI regulates LIG4 expression through lnc-RI/miR-4727-5p/LIG4 axis and regulates NHEJ repair efficiency to participate in DNA damage repair. The level of lnc-RI was negatively correlated with the radiosensitivity of CRC cells, indicates that lnc-RI may be a potential target for CRC therapy. We also present the first report of the function of miR-4727-5p.

Structurally Diverse Labdane Diterpenoids from Leonurus japonicus and Their Anti-inflammatory Properties in LPS-Induced RAW264.7 Cells.

A phytochemical study on the aerial parts of Leonurus japonicus led to the isolation and identification of 38 labdane diterpenoids, including 18 new (1, 2, 11, 12, 16-21, 24, 30-34, 37, 38) and 20 known (3-10, 13-15, 22, 23, 25-29, 35, 36) analogues. Their structures were elucidated based on physical data analysis, including 1D and 2D NMR, HRMS, UV, IR, and X-ray diffraction. The structure of the known compound 4 was confirmed by single-crystal X-ray diffraction data. These compounds can be divided into furanolabdane (1-10), tetrahydrofuranolabdane (11-15), lactonelabdane (16-23), labdane (24-29), and seco-labdane (30-38) type diterpenoids. All compounds were screened by lipopolysaccharide (LPS)-induced nitric acid (NO) production in RAW264.7 cells to evaluate anti-inflammatory effects. Compounds 1, 5, 10-13, 16-19, 31-33, and 38 inhibited NO production with IC50 values lower than 50 µM, with compound 30 being the most active, with an IC50 value of 3.9 ± 1.7 µM. Further studies show that compound 30 inhibits pro-inflammatory cytokine production and IKK α/ß phosphorylation and restores the IκB expression levels in the NF-κB signaling pathway.