Review of soil dissolved organic nitrogen cycling: Implication for groundwater nitrogen contamination.

Dissolved organic nitrogen (DON) in groundwater is derived from soil DON transformation and migration processes, which has been considered an emerging nitrogen (N) pollutant. However, due to the limitations of the analytical methods and the complexity of the involved transformation process, the role of DON in soil N cycling remains unclear. Therefore, this review aims to critically examine previous related studies on DON and highlight the knowledge gaps related to DON transformations and molecular characteristics in soils. In addition, the DON distributions and key transformation processes, as well as their influencing factors, were summarized. About 60% of DON components have not been determined due to the limited analytical techniques and methodologies. The depolymerization process of polymers into DON is the rate-limiting step of N mineralization. Furthermore, DON leaching amounts accounted for 7-1500% of soil nitrate (NO3--N) amounts, becoming the dominate pathway of N loss. Further studies are required to provide accurate information on DON compositions and transformation mechanisms, as well as their influencing factors, in soils. The suggested studies can provide further insights into the role of DON in soil N cycling, thereby controlling effectively groundwater N contamination.

Traceability of atmospheric ammonia in a suburban area of the Beijing-Tianjin-Hebei region.

Ammonia (NH3) is one of the most important sources that have been linked to the formation of PM2.5. Therefore, it is important to study the source contributions to atmospheric NH3 for air pollution control. Here we used 15N natural abundance (expressed by δ15N) values to quantify the source contributions to atmospheric NH3 in the Beijing-Tianjin-Hebei (BTH) region, which suffers from the country's worst air pollution. Results showed that from 2017 to 2019, the annual mean δ15N-NH3 value at the livestock site (-27.5 ± 6.0 ‰) was lower than at cropland (-20.7 ± 6.0 ‰) and rural residential sites (-22.1 ± 7.4 ‰), while their concentrations were the opposite. Seasonal mean δ15N-NH3 values were the highest in winter and lowest in summer, whereas monthly mean δ15N-NH3 values were the highest in January and lowest in June. The isotope mixing model results showed that agricultural sources account for 64.5 ± 13.5 % of year-round total NH3 emissions, while industrial and other sources contributed 27.4 and 8.1 %, respectively. However, the contribution of industrial sources was higher than that of agricultural sources in January. Our results indicated that the contribution of agricultural sources has decreased after the implementation of air pollution control policies in this region suggesting that NH3 abatement from agricultural sources is effective. However, further refinement of agricultural emission abatement measures will be required, accompanied by a greater focus on controlling winter non-agricultural sources.

Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages.

Purpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism. Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models. Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia. Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.

Immunoglobulin superfamily 6 is a molecule involved in the anti-tumor activity of macrophages in lung adenocarcinoma.

BACKGROUND: Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily and has been implicated in various diseases. However, the specific role of IGSF6 in the anti-tumor immunity within lung adenocarcinoma (LUAD) remains unclear. METHODS: We analyzed the IGSF6 expression in LUAD using data from TCGA, and we performed qRT-PCR and western blotting to validate these findings using tissue samples obtained from LUAD patients. Images of IHC staining were obtained from HPA. To assess the clinical relevance of IGSF6 expression, we utilized UALCAN and SPSS to analyze its association with major clinical features of LUAD. Additionally, we employed ROC curves and survival analysis to evaluate the potential diagnostic and prognostic value of IGSF6 in LUAD. To gain insights into the functional implications of IGSF6, we performed enrichment analysis using the R software clusterProfiler package. Moreover, we utilized TIMER2.0 and TISIDB to investigate the relationship between IGSF6 and immune infiltrates in LUAD. The proportion of tumor-infiltrating immune cells in LUAD was assessed using FCM, and their correlation with IGSF6 expression in tumor tissues was analyzed. The localization of IGSF6 protein on macrophages was confirmed using the HPA and FCM. To determine the regulatory role of IGSF6 on macrophage activity in LUAD, we employed ELISA, FCM, and tumor-bearing models. RESULTS: We discovered that both IGSF6 mRNA and protein levels were significantly decreased in LUAD. Additionally, we observed a negative correlation between IGSF6 expression and TNM stages as well as pathologic stages in LUAD. Notably, IGSF6 exhibited high sensitivity and specificity in diagnosing LUAD, and was positively associated with the survival rate of LUAD patients. Furthermore, IGSF6 expression was closely linked to gene sets involved in immune response. IGSF6 expression showed a positive correlation with immune infiltrates exhibiting anti-tumor activity, particularly M1 macrophages. We confirmed the predominant localization of the IGSF6 protein on the membrane of M1 macrophages. Importantly, the knockdown of IGSF6 resulted in a reduction in the anti-tumor activity of M1 macrophages, thereby promoting tumor progression. CONCLUSION: IGSF6 is a molecule that is essential for the anti-tumor activity of macrophages in LUAD.

Physeal bar resection by modified arthroscopically assisted surgery in a closed osteocavity.

Background: Physeal bar resection has been used for partial growth arrest treatment for a decade while removing the bony bar minimally invasively and accurately is challenging. This research aims to illustrate a modified arthroscopically assisted surgery, by which all the procedure was under all-inside visualization, without the constant exchange between burring under fluoroscopy, followed by irrigation, suction, and arthroscopy of the canal. Methods: We retrospectively reviewed the patients who sustained physeal bar resection under direct all-inside visualization of the arthroscope during 2016-2021. Patients who underwent physeal bar resection with the aid of an arthroscope for identifying the physeal cartilage but not resecting and visualizing the physeal bar simultaneously were excluded from this study. Results: In total, nine patients with ten related joints were included in this study. All the patients were followed up for at least two years. The average following time was 28.5 ± 6.7 months. Eight patients with nine related joints had an improvement of angular deformity, averaging 8.3 ± 6.9 degrees, and one had a worsening of the angular deformity. All the patients had a leg length discrepancy improvement, while four patients still had LLD >1 cm. The surgery time was 3.1 ± 0.7 h. There were no postoperative fractures, infections, or intraoperative complications such as neurovascular injury. Conclusions: Using clamps to form a closed osteocavity could make physeal bar resection under all-inside arthroscopic visualization feasible, which is minimally invasive, accurate, and safe.

Wogonin attenuates inflammation and oxidative stress in lipopolysaccharide-induced mastitis by inhibiting Akt/NF-κB pathway and activating the Nrf2/HO-1 signaling.

Mastitis is a disease involved in inflammation of breast which affects human and animals. Wogonin is one bioactive compound from many Chinese herbal medicines, which have multiple properties, including anti-inflammatory activity. However, the roles of wogonin in mastitis progression are largely undefined. Mastitis models were established using LPS-treated mice and mammary epithelial cells (MECs). Infiltration of inflammatory cells was analyzed by hematoxylin-eosin staining and myeloperoxidase (MPO) activity. Inflammatory cytokine (TNF-α and IL-1ß) levels were detected via ELISA. The phosphorylation and total of Akt and NF-κB levels and content of Nrf2 and HO-1 were measured via western blot. Cell viability was examined by CCK-8 assay. Oxidative stress was assessed by ROS generation and levels of MDA, GSH, and SOD. Wogonin attenuated LPS-induced infiltration of inflammatory cells, increase of MPO activity and levels of TNF-α and IL-1ß, and activation of the Akt/NF-κB pathway in murine mammary gland tissues, and promoted activation of Nrf2/HO-1 signaling. Wogonin did not affect MEC viability, but mitigated LPS-induced inflammation in MECs by reducing TNF-α and IL-1ß levels. Wogonin relieved LPS-induced oxidative stress in MECs through decreasing ROS generation and MDA level and increasing GSH and SOD levels. Wogonin repressed LPS-induced activation of the Akt/NF-κB pathway in MECs and increased Nrf2/HO-1 signaling activation. Activated Akt/NF-κB signaling or Nrf2/HO-1 signaling inactivation reversed the suppressive effects of wogonin on LPS-induced inflammation and oxidative stress in MECs. Wogonin mitigates LPS-induced inflammation and oxidative stress of MECs via suppressing activation of the Akt/NF-κB signaling and activating Nrf2/HO-1 pathway, indicating the therapeutic potential of wogonin in mastitis.

An mRNA vaccine against rabies provides strong and durable protection in mice.

Introduction: Rabies is a serious public health problem worldwide for which an effective treatment method is lacking but can be prevented by vaccines. Current vaccines are produced in cell or egg cultures, which are both costly and time consuming. Methods: Here, a non-replicating mRNA vaccine (RV021) encoding the rabies virus glycoprotein was developed in vitro, and its immunogenicity and protective efficacy against live virus was evaluated in mice. Results: A two-dose vaccination with 1 µg of RV021 at 7-day intervals induced a protective level of neutralizing antibody that was maintained for at least 260 days. RV021 induced a robust cellular immune response that was significantly superior to that of an inactivated vaccine. Two doses of 1 µg RV021 provided full protection against challenge with CVS of 30~60-fold lethal dose, 50%. Vaccine potency testing (according to the National Institutes of Health) in vivo revealed that the potency of RV021 at 15 µg/dose was 7.5 IU/dose, which is substantially higher than the standard for lot release of rabies vaccines for current human use. Conclusion: The mRNA vaccine RV021 induces a strong protective immune response in mice, providing a new and promising strategy for human rabies prevention and control.

Ultrasound-mediated delivery of Pik3cb shRNA using magnetic nanoparticles for the treatment of in-stent restenosis in a rat balloon-injured model.

The aim of the present work was to examine the effect of polyethylene glycol (PEG)-coated superparamagnetic iron oxide (SPIO) nanoparticles carrying Pik3cb short hairpin RNA (shRNA) in the prevention of restenosis with the aid of ultrasound and a magnetic field. SPIO is a type of contrast agent used in medical imaging to enhance the visibility of specific tissues or organs. It consists of tiny iron oxide nanoparticles that can be targeted to specific areas of interest in the body. PEG-coated SPIO nanoparticles carrying Pik3cb shRNA (SPIO-shPik3cb) were prepared, and the particle size and zeta potential of PEG-coated SPIO nanoparticles with and without Pik3cb shRNA were examined. After a right common artery balloon-injured rat model was established, the rats were randomly divided into four groups, and the injured arteries were transfected with SPIO-shPik3cb, saline, SPIO-shcontrol and naked shRNA Pik3cb. During the treatment, each group was placed under a magnetic field and was transfected with the aid of ultrasound. Rats were sacrificed, and the tissue was harvested for analysis after 14 days. The results suggested that the mean particle size and zeta potential of SPIO-shPik3cbs were 151.45 ± 11 nm and 10 mV, respectively. SPIO-shPik3cb showed higher transfection efficiency and significantly inhibited the intimal thickening compared with naked Pik3cb shRNA in vascular smooth muscle cells (VSMCs) (*P < 0.05). Moreover, SPIO-shPik3cb could also significantly downregulate the expression of pAkt protein compared with naked Pik3cb shRNA. According to the results, SPIO-shPik3cb can remarkably inhibit the intimal thickening under a combination of magnetic field exposure and ultrasound.

Construction and Application of Fluorescent Probes with Imine Protective Groups for Hypochlorite Detection.

Several fluorescent probes have been designed to detect ClO- in biological systems based on the isomerization mechanism of C = N bonds. Particularly, fluorescein has emerged as an important fluorophore for detecting ClO- because of its unique properties. Previously, we introduced the fluorescein analog F-1 with an active aldehyde group. In this study, two ClO- fluorescent sensors (F-2 and F-3) with imine groups were designed and synthesized using diaminomaleonitrile and 2-hydrazylbenzothiazole as amines. The electron cloud distribution of F-2 and F-3 in ground and excited states was explored via Gaussian calculations, reasonably explaining their photophysical properties. The fluorescence detection of ClO- in solution using the two probes (F-2 and F-3) was realized based on the mechanism of imine deprotection with ClO-. NaClO concentration titration demonstrated that the colorimetric detection of ClO- with the naked eye could be achieved using both F-2 and F-3. However, after adding ClO-, the fluorescence intensity of probe F-2 increased, whereas that of probe F-3 first decreased and then increased. Probes F-2 and F-3 exhibited good selectivity, anti-interference capability, and sensitivity, with the detection limits of 169.95 and 37.30 µM, respectively. Owing to their low cell toxicity, probes F-2 and F-3 can be applied to detect ClO- in vivo. The design approach adopted in this study will further advance the future development of ClO- chemical probes through the removal of C = N bond isomerization.

Direction-Coded Temporal U-Shape Module for Multiframe Infrared Small Target Detection.

Infrared small target (IRST) detection aims at separating targets from cluttered background. Although many deep learning-based single-frame IRST (SIRST) detection methods have achieved promising detection performance, they cannot deal with extremely dim targets while suppressing the clutters since the targets are spatially indistinctive. Multiframe IRST (MIRST) detection can well handle this problem by fusing the temporal information of moving targets. However, the extraction of motion information is challenging since general convolution is insensitive to motion direction. In this article, we propose a simple yet effective direction-coded temporal U-shape module (DTUM) for MIRST detection. Specifically, we build a motion-to-data mapping to distinguish the motion of targets and clutters by indexing different directions. Based on the motion-to-data mapping, we further design a direction-coded convolution block (DCCB) to encode the motion direction into features and extract the motion information of targets. Our DTUM can be equipped with most single-frame networks to achieve MIRST detection. Moreover, in view of the lack of MIRST datasets, including dim targets, we build a multiframe infrared small and dim target dataset (namely, NUDT-MIRSDT) and propose several evaluation metrics. The experimental results on the NUDT-MIRSDT dataset demonstrate the effectiveness of our method. Our method achieves the state-of-the-art performance in detecting infrared small and dim targets and suppressing false alarms. Our codes will be available at https://github.com/TinaLRJ/Multi-frame-infrared-small-target-detection-DTUM.

Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma.

Osteosarcoma is a highly aggressive cancer and lacks effective therapeutic targets. We found that L3MBTL2 acts as a tumor suppressor by transcriptionally repressing IFIT2 in osteosarcoma. L3MBTL2 recruits the components of Polycomb repressive complex 1.6 to form condensates via both Pho-binding pockets and polybasic regions within carboxyl-terminal intrinsically disordered regions; the L3MBTL2-induced condensates are required for its tumor suppression. Multi-monoubiquitination of L3MBTL2 by UBE2O results in its proteasomal degradation, and the UBE2O/L3MBTL2 axis was crucial for osteosarcoma growth. There is a reverse correlation between L3MBTL2 and UBE2O in osteosarcoma tissues, and higher UBE2O and lower L3MBTL2 are associated with poorer prognosis in osteosarcoma. Pharmacological blockage of UBE2O by arsenic trioxide can enhance L3MBTL2-induced condensates and consequently suppress osteosarcoma growth. Our findings unveil a crucial biological function of L3MBTL2-induced condensates in mediating tumor suppression, proposing the UBE2O-L3MBTL2 axis as a potential cancer therapeutic target in osteosarcoma.

Substance P Increases STAT6-Mediated Transcription Activation of Lymphocyte Cytosolic Protein 2 to Sustain M2 Macrophage Predominance in Pediatric Asthma.

Substance P (SP) is a neuropeptide released by neurons and participates in various biological processes, including inflammation. M2 macrophages are major immune cells associated with type 2 inflammation in asthma. This study investigates the effect of SP on macrophage phenotype in pediatric asthma and the underpinning factors. Asthmatic children exhibited an increased level of SP, along with a higher proportion of M2 macrophages in their bronchoalveolar lavage fluid. Flow cytometry revealed that SP treatment enhanced the M2 polarization of 12-O-tetradecanoylphorbol 13-acetate-treated THP-1 cells (macrophages) in vitro. By contrast, the administration of a neutralizing antibody of SP reduced the M2 macrophage population, mitigated inflammatory cell infiltration in mouse lung tissues, and decreased the population of immune cells in the mouse bronchoalveolar lavage fluid. SP up-regulated the expression of STAT6, which, in turn, activated the transcription of lymphocyte cytosolic protein 2 (LCP2). The population of macrophages and allergic inflammatory responses in mice were reduced by STAT6 inhibition but restored by LCP2 overexpression. Collectively, the present study demonstrates that SP sustains M2 macrophage predominance and allergic inflammation in pediatric asthma by enhancing STAT6-dependent transcription activation of LCP2.

Global myocardial work in coronary artery disease patients without regional wall motion abnormality: Correlation with Gensini-score.

BACKGROUND: Early detection of coronary atherosclerotic diseases (CAD) without regional wall motion abnormality (RWMA) is important for improving the outcome of cardiovascular events. Global myocardial work (GMW), including global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global myocardial work efficiency (GWE), offer comprehensive quantitative assessment of myocardial function in CAD. HYPOTHESIS: We hypothesized that GMW could provide incremental value in detecting CAD without RWMA. METHODS: One hundred and twenty-four patients referred for coronary angiography (CAG) without resting RWMA were enrolled in this study. Global longitudinal strain (GLS), GWI, GCW, GWW, GWE were quantified. The severity of coronary lesions was evaluated by Gensini score (GS) based on CAG. We further divided CAG-confirmed CAD patients into three subgroups according to the tertiles of GS: low 0 < GS ≤ 17, mid 17 < GS ≤ 38, and high GS > 38. RESULTS: Compared with control, CAD patients showed decreased GLS, GWE, GWI, GCW but an increased GWW. Compared to low-GS group, GWW was increased in the mid-GS group. GLS, GWE, GWI and GCW were decreased in the high-GS group while GWW was increased. Receiver operator characteristic curve analysis demonstrated that GWE was the most powerful predictor of high-GS and was superior to GLS. GWE under 92.0% had the optimal sensitivity and specificity for identifying high-GS. CONCLUSION: The proposed GWE, which outperformed the conventional GLS, could be considered as a potential predictive indicator to help to detect severe coronary disease in non-RWMA CAD patients.

The nonstructural protein 1 of respiratory syncytial virus hijacks host mitophagy as a novel mitophagy receptor to evade the type I IFN response in HEp-2 cells.

Mitochondria are good targets for viruses to manipulate their hosts. However, it remains obscure whether respiratory syncytial virus (RSV) target mitochondria to suppress the type I interferon (IFN) responses. Here, we show that nonstructural protein 1 (NS1) protein of RSV interacts with Tu translation elongation factor mitochondrial (TUFM), which can lead to its localization in mitochondria and finally induce TUFM-dependent mitophagy and inhibition of IFNß. Mechanically, NS1-mediated TUFM-dependent mitophagy does not depend on the PINK1-PARKIN pathway and classic mitophagy receptors. Importantly, NS1 may act as a new receptor protein to bridge mitochondria and autophagosomes by interacting with TUFM and LC3B. The LIR motif of NS1 protein is essential for its interaction with LC3B and is of great importance for its mitophagy induction and IFNß suppression. Finally, NS1-induced TUFM-dependent mitophagy was essential for its attenuated IFNß response using autophagy-deficient cells and mice. Our study provides a novel mitophagy receptor molecular and a new antiviral option by suppressing antiviral innate immune via targeting TUFM-dependent mitophagy. IMPORTANCE It is a worthy concern for us to understand virus-host interactions which affect progression and prognosis of disease. We demonstrated that the non-structural protein 1 of respiratory syncytial virus (RSV NS1) may act as a novel mitophagy receptor to induce mitophagy by binding LC3B and mitochondrial protein TUFM, and finally dampen interferon (IFN) responses induced by RIG1 and RSV infection. TUFM is beneficial for RSV replication in vivo and vitro. It is new and interesting that RSV NS1 may function as a mitophagy receptor to interact with LC3B. The LIR motif of NS1 protein is essential for its interaction with LC3B. We further confirm that RSV NS1 inhibited IFNß response and promoted RSV replication in autophagy-dependent mechanisms in vivo and vitro. Our study contributes to understanding virus-host interaction, enriching our insights into RSV pathogenic mechanism and exploiting new antiviral treatments targeting TUFM.

Unlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering.

Allogeneic Vγ9Vδ2 (Vδ2) T cells have emerged as attractive candidates for developing cancer therapy due to their established safety in allogeneic contexts and inherent tumor-fighting capabilities. Nonetheless, the limited clinical success of Vδ2 T cell-based treatments may be attributed to donor variability, short-lived persistence, and tumor immune evasion. To address these constraints, we engineer Vδ2 T cells with enhanced attributes. By employing CD16 as a donor selection biomarker, we harness Vδ2 T cells characterized by heightened cytotoxicity and potent antibody-dependent cell-mediated cytotoxicity (ADCC) functionality. RNA sequencing analysis supports the augmented effector potential of Vδ2 T cells derived from CD16 high (CD16Hi) donors. Substantial enhancements are further achieved through CAR and IL-15 engineering methodologies. Preclinical investigations in two ovarian cancer models substantiate the effectiveness and safety of engineered CD16Hi Vδ2 T cells. These cells target tumors through multiple mechanisms, exhibit sustained in vivo persistence, and do not elicit graft-versus-host disease. These findings underscore the promise of engineered CD16Hi Vδ2 T cells as a viable therapeutic option for cancer treatment.

Association between depression and stroke and the role of sociodemographic factors: A study among hypertensive populations.

OBJECTIVES: Studies have shown that depression increases the risk of stroke, and that this relationship can be modified by sex. However, few studies have explored this relationship in a hypertensive population, and an examination of sociodemographic factors may be useful in determining whether depression and stroke are related. MATERIALS AND METHODS: We used data from the National Health and Nutrition Examination Survey conducted between 2005-2018. The relationship between depression and stroke was investigated using a multivariate logistic regression. Effect modification by sex was examined using an interaction analysis model. RESULTS: Participants with mild or moderate depression had a 53 % (odds ratio, [OR] 1.53; 95 % confidence interval [CI], 1.15-2.04) higher risk of stroke than those without depression, with 1.76 times (95 % CI, 1.14-2.72) greater risk for major depression. Interaction analysis indicated that sex had no effect on this relationship (OR, 1.30; 95 % CI, 0.85-1.47, P=0.430). In comparison with Hispanics, non-Hispanic blacks and others/mixed-race individuals with depression had a greater risk of stroke (OR, 2.26; 95 % CI, 1.5-3.14; OR, 2.67, 95 % CI, 1.29-5.55). CONCLUSIONS: Our study found that the degree of depression was positively correlated with stroke in a hypertensive population, and that this relationship was not affected by sex.

Recent Advances in RNA-Targeted Cancer Therapy.

Ribonucleic acid (RNA) plays a pivotal role in gene regulation and protein biosynthesis. Interfering the physiological function of key RNAs to induce cell apoptosis holds great promise for cancer treatment. Many RNA-targeted anti-cancer strategies have emerged continuously. Among them, RNA interference (RNAi) has been recognized as a promising therapeutic modality for various disease treatments. Nevertheless, the primary obstacle in siRNA delivery-escaping the endosome and crossing the plasma membrane severely impedes its therapeutic potential. Thus far, a variety of nanosystems as well as carrier-free bioconjugation for siRNA delivery have been developed and employed to enhance the drug delivery and anti-tumor efficiency. Besides, the use of small molecules to target specific RNA structures and disrupt their function, along with the covalent modification of RNA, has also drawn tremendous attention recently owing to high therapeutic efficacy. In this review, we will provide an overview of recent progress in RNA-targeted cancer therapy including various siRNA delivery strategies, RNA-targeting small molecules, and newly emerged covalent RNA modification. Finally, challenges and future perspectives faced in this research field will be discussed.

Combination of eriocalyxin B and homoharringtonine exerts synergistic anti-tumor effects against t(8;21) AML.

Understanding the molecular pathogenesis of acute myeloid leukemia (AML) with well-defined genomic abnormalities has facilitated the development of targeted therapeutics. Patients with t(8;21) AML frequently harbor a fusion gene RUNX1-RUNX1T1 and KIT mutations as "secondary hit", making the disease one of the ideal models for exploring targeted treatment options in AML. In this study we investigated the combination therapy of agents targeting RUNX1-RUNX1T1 and KIT in the treatment of t(8;21) AML with KIT mutations. We showed that the combination of eriocalyxin B (EriB) and homoharringtonine (HHT) exerted synergistic therapeutic effects by dual inhibition of RUNX1-RUNX1T1 and KIT proteins in Kasumi-1 and SKNO-1 cells in vitro. In Kasumi-1 cells, the combination of EriB and HHT could perturb the RUNX1-RUNX1T1-responsible transcriptional network by destabilizing RUNX1-RUNX1T1 transcription factor complex (AETFC), forcing RUNX1-RUNX1T1 leaving from the chromatin, triggering cell cycle arrest and apoptosis. Meanwhile, EriB combined with HHT activated JNK signaling, resulting in the eventual degradation of RUNX1-RUNX1T1 by caspase-3. In addition, HHT and EriB inhibited NF-κB pathway through blocking p65 nuclear translocation in two different manners, to synergistically interfere with the transcription of KIT. In mice co-expressing RUNX1-RUNX1T1 and KITN822K, co-administration of EriB and HHT significantly prolonged survival of the mice by targeting CD34+CD38- leukemic cells. The synergistic effects of the two drugs were also observed in bone marrow mononuclear cells (BMMCs) of t(8;21) AML patients. Collectively, this study reveals the synergistic mechanism of the combination regimen of EriB and HHT in t(8;21) AML, providing new insight into optimizing targeted treatment of AML.

Arctiin attenuates iron overload­induced osteoporosis by regulating the PI3K/Akt pathway.

Iron overload is a prevalent pathological factor observed among elderly individuals and those with specific hematological disorders, and is frequently associated with an elevated incidence of osteoporosis. Although arctiin (ARC) has been shown to possess antioxidant properties and the ability to mitigate bone degeneration, its mechanism of action in the treatment of iron overload­induced osteoporosis (IOOP) remains incompletely understood. To explore the potential molecular mechanisms underlying the effects of ARC, the MC3T3­E1 cell osteoblast cell line was used. Cell Counting Kit was used to assess MC3T3­E1 cell viability. Alkaline phosphatase staining and alizarin red staining were assessed for osteogenic differentiation. Calcein AM assay was used to assess intracellular iron concentration. In addition, intracellular levels of reactive oxygen species (ROS), lipid peroxides, mitochondrial ROS, apoptosis rate and mitochondrial membrane potential changes in MC3T3­E1 cells were examined using flow cytometry and corresponding fluorescent dyes. The relationship between ARC and the PI3K/Akt pathway was then explored by western blotting and immunofluorescence. In addition, the effects of ARC on IOOP was verified using an iron overload mouse model. Immunohistochemistry was performed to evaluate expression of osteogenesis­related proteins. Micro-CT and H&E were used to analyze bone microstructural parameters and histomorphometric indices in the bone tissue. Notably, ARC treatment reversed the decreased viability and increased apoptosis in MC3T3­E1 cells originally induced by ferric ammonium citrate, whilst promoting the formation of mineralized bone nodules in MC3T3­E1 cells. Furthermore, iron overload induced a decrease in the mitochondrial membrane potential, augmented lipid peroxidation and increased the accumulation of ROS in MC3T3­E1 cells. ARC not only positively regulated the anti­apoptotic and osteogenic capabilities of these cells via modulation of the PI3K/Akt pathway, but also exhibited antioxidant properties by reducing oxidative stress. In vivo experiments confirmed that ARC improved bone microarchitecture and biochemical parameters in a mouse model of iron overload. In conclusion, ARC exhibits potential as a therapeutic agent for IOOP by modulating the PI3K/Akt pathway, and via its anti­apoptotic, antioxidant and osteogenic properties.

Antipyretic and Anti-Inflammatory Effects of Rectal Administration of Reduning Injection in Feverish Rats Induced by Lipopolysaccharide.

This study aimed to explore the antipyretic and anti-inflammatory effects of rectal administration of Reduning injection in feverish rats induced by lipopolysaccharide (LPS), and observe the temperature changes and inflammatory indexes. The selected rats were randomly divided into 6 groups, with 10 rats in each group, named as normal empty group, model group, intravenous group (2 mL/kg), low-dose enema group (1 mL/kg), middle-dose enema group (2 mL/kg), and high-dose enema group (4 mL/kg). The hourly temperature variations in rats injected with LPS in the abdomen were recorded. Five hours later, blood samples from the abdominal aorta were collected to monitor immunoglobulin M (IgM), immunoglobulin A (IgA), interleukin (IL)-6, and tumor necrosis factor (TNF)-α. At 5 hours, the fever peak induced by LPS appeared, and obvious antipyretic effects were observed; the effect was optimal in the medium dose enema group at 4 hours (p < 0.05); the IgM value in the enema groups, the intravenous group, and normal empty group was significantly lower than that in the model group; the IgA value in each group was higher than that in the model group, but there was no statistical significance (p > 0.05); values of IL-6 and TNF-α in each group were lower than those in the model group, and the difference was statistically significant except for the high-dose enema group (p > 0.05). Low-dose and medium-dose rectal administration of Reduning injection have inhibitory effects on IL-6, TNF-α, and IgM in feverish rats induced by LPS, but there is no obvious difference compared to intravenous administration and it could achieve an anti-inflammatory effect. There is a possibility of enhancing IgA immunity with rectal administration, but there is no obvious difference compared to intravenous administration, and rectal administration has no significant effect on mucosal immunity.