Enhancing the therapeutic potential of isoliensinine for hypertension through PEG-PLGA nanoparticle delivery: A comprehensive in vivo and in vitro study.

BACKGROUND: Hypertension, a highly prevalent chronic disease, is known to inflict severe damage upon blood vessels. In our previous study, isoliensinine, a kind of bibenzyl isoquinoline alkaloid which isolated from a TCM named Lotus Plumule (Nelumbo nucifera Gaertn), exhibits antihypertensive and vascular smooth muscle proliferation-inhibiting effects, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare isoliensinine loaded by PEG-PLGA polymer nanoparticles to increase its efficacy METHOD: We synthesized and thoroughly characterized PEG-PLGA nanoparticles loaded with isoliensinine using a nanoprecipitation method, denoted as, PEG-PLGA@Isoliensinine. Additionally, we conducted comprehensive investigations into the stability of PEG-PLGA@Isoliensinine, in vitro drug release profiles, and in vivo pharmacokinetics. Furthermore, we assessed the antihypertensive efficacy of this nano-system through in vitro experiments on A7R5 cells and in vivo studies using AngII-induced mice. RESULT: The findings reveal that PEG-PLGA@Isoliensinine significantly improves isoliensinine absorption by A7R5 cells and enhances targeted in vivo distribution. This translates to a more effective reduction of AngII-induced hypertension and vascular smooth muscle proliferation. CONCLUSION: In this study, we successfully prepared PEG-PLGA@Isoliensinine by nano-precipitation, and we confirmed that PEG-PLGA@Isoliensinine surpasses free isoliensinine in its effectiveness for the treatment of hypertension, as demonstrated through both in vivo and in vitro experiments. SIGNIFICANCE: This study lays the foundation for isoliensinine's clinical use in hypertension treatment and vascular lesion protection, offering new insights for enhancing the bioavailability of traditional Chinese medicine components. Importantly, no toxicity was observed, affirming the successful implementation of this innovative drug delivery system in vivo and offers a promising strategy for enhancing the effectiveness of Isoliensinine and propose an innovative avenue for developing novel formulations of traditional Chinese medicine monomers.

Platelet-derived TGF-ß1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia.

Platelet α-granules are rich in TGF-ß1 which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and re-balancing T cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-ß/Smad pathways in TPO-RA-corrected-MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-ß1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that ITP patients achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-ß1 induces the expansion and functional reprogramming of MDSCs via the TGF-ß/Smad pathway. These data indicate that platelet recovery not only serves as an endpoint of treatment response, but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.

Mechanistic investigation of Pb2+ adsorption on biochar modified with sodium alginate composite zeolitic imidazolate framework-8.

For the serious situation of heavy metal pollution, the use of cheap, clean, and efficient biochar to immobilize heavy metals is a good treatment method. In this paper, SA@ZIF-8/BC was prepared for the adsorption of Pb2+ in solution using sodium alginate (SA) and zeolitic imidazolate framework-8 (ZIF-8) modified corn cob biochar. The results showed that the specific surface area of modified biochar was greatly improved, with good adsorption capacity for Pb2+, strong anti-interference ability, and good economy. At the optimal adsorption pH of 5, the adsorption model of Pb2+ by SA@ZIF-8/BC was more consistent with the pseudo-second-order kinetic model and Langmuir isotherm model. This indicates that the adsorption of Pb2+ by SA@ZIF-8/BC is chemisorption and monolayer adsorption. The maximum adsorption of modified biochar was 300 mg g-1, which was 2.38 times higher than that of before modified BC (126 mg g-1). The shift in binding energy of functional groups before and after adsorption of SA@ZIF-8/BC was studied by XPS, and it was found that hydroxyl and carboxyl groups played an important role in the adsorption of Pb2+. It was demonstrated that this novel adsorbent can be effectively used for the treatment of Pb pollution in wastewater.

Transcriptome data reveal beneficial effects of Rickettsia (Rickettsiales: Rickettsiaceae) on Bemisia tabaci (Hemiptera: Aleyrodidae) through nutritional factors and defense mechanisms.

Whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) is a destructive insect pest of many crops. Rickettsia infection in different cryptic species of B. tabaci has been observed worldwide. Understanding the interactions between these 2 organisms is critical to developing Rickettsia-based strategies to control B. tabaci and thereby reduce the transmission of related vector-borne viruses. In this study, we investigated the effects of Rickettsia infection on the biological characteristics of the Middle East Asia Minor 1 (MEAM1) strain of B. tabaci through biological analysis of infected and uninfected individuals. The results of this study suggest that Rickettsia may confer fitness benefits. These benefits include increased fertility, improved survival rates, accelerated development, and resulted in female bias. We also investigated the transcriptomics impact of Rickettsia infection on B. tabaci by performing a comparative RNA-seq analysis of nymphs and adult females, both with and without the infection. Our analysis revealed 218 significant differentially expressed genes (DEGs) in infected nymphs compared to uninfected ones and 748 significant DEGs in infected female adults compared to their uninfected whiteflies. Pathway analysis further revealed that Rickettsia can affect many important metabolic pathways in whiteflies. The results suggest that Rickettsia plays an essential role in energy metabolism, and nutrient synthesis in the B. tabaci MEAM1, and depends on metabolites obtained from the host to ensure its survival. Overall, our findings suggest that Rickettsia has beneficial effects on B. tabaci and offered insights into the potential molecular mechanisms governing the interactions between Rickettsia and B. tabaci MEAM1.

KP177R-based visual assay integrating RPA and CRISPR/Cas12a for the detection of African swine fever virus.

Introduction: Early detection of the virus in the environment or in infected pigs is a critical step to stop African swine fever virus (ASFV) transmission. The p22 protein encoded by ASFV KP177R gene has been shown to have no effect on viral replication and virulence and can serve as a molecular marker for distinguishing field virus strains from future candidate KP177R deletion vaccine strains. Methods: This study established an ASFV detection assay specific for the highly conserved ASFV KP177R gene based on recombinase polymerase amplification (RPA) and the CRISPR/Cas12 reaction system. The KP177R gene served as the initial template for the RPA reaction to generate amplicons, which were recognized by guide RNA to activate the trans-cleavage activity of Cas12a protein, thereby leading to non-specific cleavage of single-stranded DNA as well as corresponding color reaction. The viral detection in this assay could be determined by visualizing the results of fluorescence or lateral flow dipstick (LFD) biotin blotting for color development, and was respectively referred to as fluorescein-labeled RPA-CRISPR/Cas12a and biotin-labeled LFD RPA-CRISPR/Cas12a. The clinical samples were simultaneously subjected to the aforementioned assay, while real-time quantitative PCR (RT-qPCR) was employed as a control for determining the diagnostic concordance rate between both assays. Results: The results showed that fluorescein- and biotin-labeled LFD KP177R RPA-CRISPR/Cas12a assays specifically detected ASFV, did not cross-react with other swine pathogens including PCV2, PEDV, PDCoV, and PRV. The detection assay established in this study had a limit of detection (LOD) of 6.8 copies/µL, and both assays were completed in 30 min. The KP177R RPA-CRISPR/Cas12a assay demonstrated a diagnostic coincidence rate of 100% and a kappa value of 1.000 (p < 0.001), with six out of ten clinical samples testing positive for ASFV using both KP177R RPA-CRISPR/Cas12a and RT-qPCR, while four samples tested negative in both assays. Discussion: The rapid, sensitive and visual detection assay for ASFV developed in this study is suitable for field application in swine farms, particularly for future differentiation of field virus strains from candidate KP177R gene-deleted ASFV vaccines, which may be a valuable screening tool for ASF eradication.

Isoalantolactone exerts anti-melanoma effects via inhibiting PI3K/AKT/mTOR and STAT3 signaling in cell and mouse models.

BACKGROUND AND AIM: Although the anti-cancer activity of isoalantolactone (IATL) has been extensively studied, the anti-melanoma effects of IATL are still unknown. Here, we have investigated the anti-melanoma effects and mechanism of action of IATL. MTT and crystal violet staining assays were performed to detect the inhibitory effect of IATL on melanoma cell viability. Apoptosis and cell cycle arrest induced by IATL were examined using flow cytometry. The molecular mechanism of IATL was explored by Western blotting, confocal microscope analysis, molecular docking, and cellular thermal shift assay (CETSA). A B16F10 allograft mouse model was constructed to determine the anti-melanoma effects of IATL in vivo. The results showed that IATL exerted anti-melanoma effects in vitro and in vivo. IATL induced cytoprotective autophagy in melanoma cells by inhibiting the PI3K/AKT/mTOR signaling. Moreover, IATL inhibited STAT3 activation both in melanoma cells and allograft tumors not only by binding to the SH2 domain of STAT3 but also by suppressing the activity of its upstream kinase Src. These findings demonstrate that IATL exerts anti-melanoma effects via inhibiting the STAT3 and PI3K/AKT/mTOR signaling pathways, and provides a pharmacological basis for developing IATL as a novel phytotherapeutic agent for treating melanoma clinically.

Deep resource utilization of hazardous arsenic-alkali slag: Thermodynamic analysis, mechanism investigation and process optimization.

The best solution to address environmental pollution caused by arsenic-containing hazardous waste is to prepare high-purity elemental arsenic from such waste. The key to this approach lies in the efficient separation of arsenic from various impurities. This paper presents a viable solution for producing high-purity elemental arsenic from arsenic-alkali slag, and the keylies in utilizing the selective precipitation of magnesium ammonium arsenate (MgNH4AsO4) to achieve efficient separation of arsenic from alkali, antimony, and other impurities. Thermodynamic analysis and hydrometallurgical condition experiments indicate that in complex alkaline arsenic-containing solutions, over 90% of arsenic components can selectively precipitate in the form of MgNH4AsO4. The content of arsenic in the resulting precipitate reaches approximately 30%, while the content of antimony is below 0.1%. This achieves efficient enrichment of arsenic and preliminary separation of impurities in complex arsenic-alkali slag. Thermodynamic analysis and pyrometallurgical condition experiments demonstrate that the precipitate of MgNH4AsO4 can be reduced to elemental arsenic with an arsenic content reaching 99.85%, and an antimony content as low as 0.05%. This achieves a profound separation of arsenic from impurities. Based on the research presented in this paper, a production line was established that enables the deep resource utilization of arsenic-alkali slag.

Urbanization-driven forest soil greenhouse gas emissions: Insights from the role of soil bacteria in carbon and nitrogen cycling using a metagenomic approach.

Increasing population densities and urban sprawl have induced greenhouse gas (GHG) emissions from the soil, and the soil microbiota of urban forests play a critical role in the production and consumption of GHGs, supporting green development. However, the function and potential mechanism of soil bacteria in GHG emissions from forests during urbanization processes need to be better understood. Here, we measured the fluxes of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) in Cinnamomum camphora forest soils along an urbanization gradient. 16S amplicon and metagenomic sequencing approaches were employed to examine the structure and potential functions of the soil bacterial community involved in carbon (C) and nitrogen (N) cycling. In this study, the CH4 and CO2 emissions from urban forest soils (sites U and G) were significantly greater than those from suburban soils (sites S and M). The N2O emissions in the urban center (site U) were 24.0 % (G), 13.8 % (S), and 13.5 % (M) greater than those at the other three sites. These results were related to the increasing bacterial alpha diversity, interactions, and C and N cycling gene abundances (especially those involved in denitrification) in urban forest soils. Additionally, the soil pH and metal contents (K, Ca, Mg) affected key bacterial populations (such as Methylomirabilota, Acidobacteriota, and Proteobacteria) and indicators (napA, nosZ, nrfA, nifH) involved in reducing N2O emissions. The soil heavy metal contents (Fe, Cr, Pb) were the main contributors to CH4 emissions, possibly by affecting methanogens (Desulfobacterota) and methanotrophic bacteria (Proteobacteria, Actinobacteriota, and Patescibacteria). Our study provides new insights into the benefits of conservation-minded urban planning and close-to-nature urban forest management and construction, which are conducive to mitigating GHG emissions and supporting urban sustainable development by mediating the core bacterial population.

Social and demographic factors associated with receipt of a COVID-19 vaccine initial booster dose and with interval between primary series completion and initial booster dose uptake among persons aged ≥ 12 years, United States, August 2021-October 2022.

COVID-19 booster dose vaccination has been crucial in ensuring protection against COVID-19 including recently predominant Omicron variants. Because vaccines against newer SARS-CoV- 2 variants are likely to be recommended in future, it will be valuable to understand past booster dose uptake among different demographic groups. Using U.S. vaccination data, this study examined intervals between primary series completion and receipt of first booster dose (monovalent or bivalent) during August 2021 - October 2022 among persons ≥12 years of age who had completed a COVID-19 vaccine primary series by October 2021. Sub-populations who were late booster recipients (received a booster dose ≥12 months after the primary series) or received no booster dose included persons <35 years old, Johnson & Johnson/Janssen vaccine primary dose recipients, persons in certain racial and ethnic groups, and persons living in rural and more socially vulnerable areas, and in the South region of the United States; these groups may benefit the most from public health outreach efforts to achieve timely COVID-19 vaccination completion in future.

Resveratrol protects against myocardial ischemic injury in obese mice via activating SIRT3/FOXO3a signaling pathway and restoring redox homeostasis.

BACKGROUND: Increasing global overweight and obesity rates not only increase the prevalence of myocardial infarction (MI), but also exacerbate ischemic injury and result in worsened prognosis. Currently, there are no drugs that can reverse myocardial damage once MI has occurred, therefore discovering drugs that can potentially limit the extent of ischemic damage to the myocardium is critical. Resveratrol is a polyphenol known for its antioxidant properties, however whether prolonged daily intake of resveratrol during obesity can protect against MI-induced damage remains unexplored. METHODS: We established murine models of obesity via high-fat/high-fructose diet, along with daily administrations of resveratrol or vehicle, then performed surgical MI to examine the effects and mechanisms of resveratrol in protecting against myocardial ischemic injury. RESULTS: Daily administration of resveratrol in obese mice robustly protected against myocardial ischemic injury and improved post-MI cardiac function. Resveratrol strongly inhibited oxidative and DNA damage via activating SIRT3/FOXO3a-dependent antioxidant enzymes following MI, which were completely prevented upon administration of 3-TYP, a selective SIRT3 inhibitor. Hence, the cardioprotective effects of prolonged resveratrol intake in protecting obese mice against myocardial ischemic injury was due to reestablishment of intracellular redox homeostasis through activation of SIRT3/FOXO3a signaling pathway. CONCLUSION: Our findings provide important new evidence that supports the daily intake of resveratrol, especially in those overweight or obese, which can robustly decrease the extent of ischemic damage following MI. Our study therefore provides new mechanistic insight and suggests the therapeutic potential of resveratrol as an invaluable drug in the treatment of ischemic heart diseases.

Dopant-additive synergism enhances perovskite solar modules.

Perovskite solar cells (PSCs) are among the most promising photovoltaic technologies owing to their exceptional optoelectronic properties1,2. However, the lower efficiency, poor stability and reproducibility issues of large-area PSCs compared with laboratory-scale PSCs are notable drawbacks that hinder their commercialization3. Here we report a synergistic dopant-additive combination strategy using methylammonium chloride (MACl) as the dopant and a Lewis-basic ionic-liquid additive, 1,3-bis(cyanomethyl)imidazolium chloride ([Bcmim]Cl). This strategy effectively inhibits the degradation of the perovskite precursor solution (PPS), suppresses the aggregation of MACl and results in phase-homogeneous and stable perovskite films with high crystallinity and fewer defects. This approach enabled the fabrication of perovskite solar modules (PSMs) that achieved a certified efficiency of 23.30% and ultimately stabilized at 22.97% over a 27.22-cm2 aperture area, marking the highest certified PSM performance. Furthermore, the PSMs showed long-term operational stability, maintaining 94.66% of the initial efficiency after 1,000 h under continuous one-sun illumination at room temperature. The interaction between [Bcmim]Cl and MACl was extensively studied to unravel the mechanism leading to an enhancement of device properties. Our approach holds substantial promise for bridging the benchtop-to-rooftop gap and advancing the production and commercialization of large-area perovskite photovoltaics.

Exploring the impact of ITGB2 on glioma progression and treatment: Insights from non-apoptotic cell death and immunotherapy.

In the realm of glioma treatment, our groundbreaking research has uncovered the pivotal role of Integrin Beta 2 (ITGB2) in non-apoptotic cell death and its profound implications for immunotherapy efficacy. Gliomas, known for their aggressive and infiltrative nature, demand innovative therapeutic strategies for improved patient outcomes. Our study bridges a critical gap by examining the interplay between non-apoptotic cell death and immunotherapy response in gliomas. Through comprehensive analysis of ten diverse glioma datasets, we developed a unique death enrichment score and identified ITGB2 as a significant risk marker. This study demonstrates that ITGB2 can predict immune activity, mutation characteristics, and drug response in glioma patients. We reveal that ITGB2 not only mediates glioma proliferation and migration but also crucially influences immunotherapy responses by modulating the interaction between gliomas and macrophages by single-cell sequencing analysis (iTalk and ICELLNET). Employing a variety of molecular and cellular methodologies, including in vitro models, our findings highlight ITGB2 as a potent marker in glioma biology, particularly impacting macrophage migration and polarization. We present compelling evidence of ITGB2's dual role in regulating tumor cell behavior and shaping the immune landscape, thereby influencing therapeutic outcomes. The study underlines the potential of ITGB2-targeted strategies in enhancing the efficacy of immunotherapy and opens new avenues for personalized treatment approaches in glioma management. In conclusion, this research marks a significant stride in understanding glioma pathology and therapy, positioning ITGB2 as a key biomarker and a promising target in the quest for effective glioma treatments.

Erratum: [Corrigendum] Pien Tze Huang inhibits hypoxia­induced epithelial­mesenchymal transition in human colon carcinoma cells through suppression of the HIF­1 pathway.

[This corrects the article DOI: 10.3892/etm.2014.1549.].

Neural radiance fields-based multi-view endoscopic scene reconstruction for surgical simulation.

PURPOSE: In virtual surgery, the appearance of 3D models constructed from CT images lacks realism, leading to potential misunderstandings among residents. Therefore, it is crucial to reconstruct realistic endoscopic scene using multi-view images captured by an endoscope. METHODS: We propose an Endoscope-NeRF network for implicit radiance fields reconstruction of endoscopic scene under non-fixed light source, and synthesize novel views using volume rendering. Endoscope-NeRF network with multiple MLP networks and a ray transformer network represents endoscopic scene as implicit field function with color and volume density at continuous 5D vectors (3D position and 2D direction). The final synthesized image is obtained by aggregating all sampling points on each ray of the target camera using volume rendering. Our method considers the effect of distance from the light source to the sampling point on the scene radiance. RESULTS: Our network is validated on the lung, liver, kidney and heart of pig collected by our device. The results show that the novel views of endoscopic scene synthesized by our method outperform existing methods (NeRF and IBRNet) in terms of PSNR, SSIM, and LPIPS metrics. CONCLUSION: Our network can effectively learn a radiance field function with generalization ability. Fine-tuning the pre-trained model on a new endoscopic scene to further optimize the neural radiance fields of the scene, which can provide more realistic, high-resolution rendered images for surgical simulation.

Neoadjuvant savolitinib targeted therapy for stage IIIB-N3 lung adenocarcinoma harboring mesenchymal-epithelial transition exon 14 skipping mutation: a case report and literature review.

Savolitinib is a selective inhibitor that specifically targets the phosphorylation of mesenchymal-epithelial transition (MET) kinase. It has demonstrated significant inhibitory effects on the proliferation of tumor cells with METex14 skipping mutation, making it a promising treatment option. While it is the first approved small-molecule inhibitor specifically targeting MET kinase in China, there is limited information about its efficacy as neoadjuvant therapy for patients with supraclavicular lymph node metastasis (N3). In this case report, we presented the successful outcome of a 48-year-old male patient who was diagnosed with stage IIIB (T2bN3M0) lung adenocarcinoma originating from the left upper lobe. The patient exhibited the METex14 skipping alteration. Following two months of neoadjuvant savolitinib treatment, the patient achieved partial remission, with a significant reduction in the size of the primary tumor and metastatic lymph nodes. Postoperative pathological confirmation revealed a pathological complete response, and subsequent imaging examinations, including computed tomography scan and circulating tumor DNA-based molecular residual disease detection, showed no sign of recurrence at 7 months after surgery. Based on this case, neoadjuvant and adjuvant savolitinib therapy may be considered as a favorable alternative to chemotherapy for marginally resectable nonsmall cell lung cancer patients with METex14 skipping mutation.

Astaxanthin Inhibits STING Carbonylation and Enhances Antiviral Responses.

STING-mediated DNA sensing pathway plays a crucial role in the innate antiviral immune responses. Clarifying its regulatory mechanism and searching STING agonists has potential clinical implications. Although multiple STING agonists have been developed to target cancer, there are few for the treatment of infectious diseases. Astaxanthin, a natural and powerful antioxidant, serves many biological functions and as a potential candidate drug for many diseases. However, how astaxanthin combats viruses and whether astaxanthin regulates the cyclic GMP-AMP synthase-STING pathway remains unclear. In this study, we showed that astaxanthin markedly inhibited HSV-1-induced lipid peroxidation and inflammatory responses and enhanced the induction of type I IFN in C57BL/6J mice and mouse primary peritoneal macrophages. Mechanistically, astaxanthin inhibited HSV-1 infection and oxidative stress-induced STING carbonylation and consequently promoted STING translocation to the Golgi apparatus and oligomerization, which activated STING-dependent host defenses. Thus, our study reveals that astaxanthin displays a strong antiviral activity by targeting STING, suggesting that astaxanthin might be a promising STING agonist and a therapeutic target for viral infectious diseases.