Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04.

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro's C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.

Trends and Disparities in Treatment and Control of Atherosclerotic Cardiovascular Disease in US Adults, 1999 to 2018.

BACKGROUND: Although cardiovascular mortality continued declining from 2000 to 2019, the rate of this decrease decelerated. We aimed to assess the trends and disparities in risk factor control and treatment among US adults with atherosclerotic cardiovascular disease to find potential causes of the deceleration. METHODS AND RESULTS: A total of 55 ,021 participants, aged ≥20 years, from the 1999 to 2018 National Health and Nutrition Examination Survey were included, of which 5717 were with atherosclerotic cardiovascular disease. Risk factor control was defined as hemoglobin A1c <7%, blood pressure <140/90 mm Hg, and non-high-density lipoprotein cholesterol <100 mg/dL. The prevalence of atherosclerotic cardiovascular disease oscillated between 7.3% and 8.9% from 1999 to 2018. A significant increasing trend was observed in the prevalence of diabetes, obesity, heavy alcohol consumption, and self-reported hypertension within the population with atherosclerotic cardiovascular disease (Ptrend≤0.001). Non-high-density lipoprotein cholesterol <100 mg/dL increased from 7.1% in 1999 to 2002 to 15.7% in 2003 to 2006, before plateauing. Blood pressure control (<140/90 mm Hg) increased until 2011 to 2014, but declined to 70.1% in 2015 to 2018 (Ptrend<0.001, Pjoinpoint=0.14). Similarly, the proportion of participants achieving hemoglobin A1c control began to decrease after 2006 (Pjoinpoint=0.05, Ptrend=0.001). The percentage of participants achieving all 3 targets increased significantly from 4.5% to 18.6% across 1999 to 2018 (Ptrend=0.02), but the increasing trend decelerated after 2005 to 2006 (Pjoinpoint<0.001). Striking disparities in risk factor control and medication use persisted between sexes, and between different racial and ethnic populations. CONCLUSIONS: Worsened control of glycemia, blood pressure, obesity, and alcohol consumption, leveled lipid control, and persistent socioeconomic disparities may be contributing factors to the observed deceleration in decreasing cardiovascular mortality trends.

Morphological Analyses and QTL Mapping of Mottled Leaf in Zucchini (Cucurbita pepo L.).

The mottled leaf is one of the agronomic traits of zucchini and can be applied as a marker trait in aggregation breeding. However, the genetic mechanism responsible for mottled leaf has yet to be elucidated. In the present study, we used two inbred lines (line '19': silver mottled leaf; line '113': normal leaf) as parents for the physiological and genetic analysis of mottled leaf. The synthesis and net photosynthetic rate of chlorophyll were not significantly affected in the mottled areas of leaves. However, we detected a large space between the palisade parenchyma in the leaf mottle area of line '19', which may have caused the mottled leaf phenotype. Light also plays an important role in the formation of mottled leaf, and receiving light during the early stages of leaf development is a necessary factor. Genetic analysis has previously demonstrated that mottled leaf is a quantitative trait that is controlled by multiple genes. Based on the strategy of quantitative trait locus sequencing (QTL-seq), two QTLs were identified on chromosomes 1 and 17, named CpML1.1 and CpML17.1, respectively. Two major loci were identified using R/qtl software version 1.66 under greenhouse conditions in April 2019 (2019A) and April 2020 (2020A) and under open cultivation conditions in May 2020 (2020M). The major QTL, CpML1.1, was located in a 925.2-kb interval on chromosome 1 and explained 10.51%-24.15% of the phenotypic variation. The CpML17.1 was located in a 719.7-kb interval on chromosome 17 and explained 16.25%-38.68% of the phenotypic variation. Based on gene annotation, gene sequence alignment, and qRT-PCR analysis, the Cp4.1LG01g23790 at the CpML1.1 locus encoding a protein of the TPX2 family (target protein of Xklp2) may be a candidate gene for mottled leaf in zucchini. Our findings may provide a theoretical basis for the formation of mottled leaf and provide a foundation for the fine mapping of genes associated with mottled leaf. Molecular markers closely linked to mottled leaf can be used in molecular-assisted selection for the zucchini mottled leaf breeding.

Cu-Catalyzed Carbocyclization for General Synthesis of N-Containing Heterocyclics Enabled by BrCF2COOEt as a C1 Source.

A practical and efficient copper-catalyzed carbocyclization of 2-functionalized anilines with ethyl bromodifluoroacetate has been developed. Ethyl bromodifluoroacetate is employed as the C1 source via quadruple cleavage in this transformation. This reaction can afford a variety of N-containing heterocyclics with satisfactory yields and excellent functional group compatibility.

Improved Water Collection from Short-Term Fog on a Patterned Surface with Interconnected Microchannels.

Fog harvesting is considered a promising freshwater collection strategy for overcoming water scarcity, because of its environmental friendliness and strong sustainability. Typically, fogging occurs briefly at night and in the early morning in most arid and semiarid regions. However, studies on water collection from short-term fog are scarce. Herein, we developed a patterned surface with highly hydrophilic interconnected microchannels on a superhydrophobic surface to improve droplet convergence driven by the Young-Laplace pressure difference. With a rationally designed surface structure, the optimized water collection rate from mild fog could reach up to 67.31 g m-2 h-1 (6.731 mg cm-2 h-1) in 6 h; this value was over 130% higher than that observed on the pristine surface. The patterned surface with interconnected microchannels significantly shortened the startup time, which was counted from the fog contact to the first droplet falling from the fog-harvesting surface. The patterned surface was also facilely prepared via a controllable strategy combining laser ablation and chemical vapor deposition. The results obtained in outdoor environments indicate that the rationally designed surface has the potential for short-term fog harvesting. This work can be considered as a meaningful attempt to address the practical issues encountered in fog-harvesting research.

The impact of the time factors on the exercise-based cardiac rehabilitation outcomes of the patients with acute myocardial infarction after percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Cardiac rehabilitation (CR) has been demonstrated to improve outcomes in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). However, the optimal CR initiation time and duration remain to be determined. This study aimed to explore the impact of the time factors on the CR outcomes in AMI patients who received PCI by the method of meta-regression analysis. METHODS: We searched five databases (PubMed, Embase, Cochrane Library, Web of Science and Google scholar) up to October 31, 2023. Meta-regression analysis was utilized to explore the impact of the time factors on the effect sizes. Subgroups with more than 3 studies were used for meta-regression analysis. RESULTS: Our analysis included 16 studies and a total of 1810 patients. The meta-regression analysis revealed that the initiation time and duration of CR had no significant impact on the occurrence of arrhythmia, coronary artery restenosis and angina pectoris. The initiation time and duration of CR also had no significant impact on the changes in left ventricular ejection fraction (LVEF, starting time: estimate = 0.160, p = 0.130; intervention time: estimate = 0.017, p = 0.149), left ventricular end-diastolic volume (LVEDV, starting time: estimate = - 0.191, p = 0.732; intervention time: estimate = - 0.033, p = 0.160), left ventricular end-systolic volume (LVESV, starting time: estimate = - 0.301, p = 0.464; intervention time: estimate = 0.015, p = 0.368) and 6-minute walk test (6MWT, starting time: estimate = - 0.108, p = 0.467; intervention time: estimate = 0.019, p = 0.116). CONCLUSION: Implementation of CR following PCI in patients with AMI is beneficial. However, in AMI patients, there is no significant difference in the improvement of CR outcomes based on different CR starting times within 1 month after PCI or different durations of the CR programs. It indicates that it is feasible for patients with AMI to commence CR within 1 month after PCI and continue long-term CR, but the time factors which impact CR are intricate and further clinical research is still needed to determine the optimal initiation time and duration of CR.

Unlocking the secrets: the power of methylation-based cfDNA detection of tissue damage in organ systems.

BACKGROUND: Detecting organ and tissue damage is essential for early diagnosis, treatment decisions, and monitoring disease progression. Methylation-based assays offer a promising approach, as DNA methylation patterns can change in response to tissue damage. These assays have potential applications in early detection, monitoring disease progression, evaluating treatment efficacy, and assessing organ viability for transplantation. cfDNA released into the bloodstream upon tissue or organ injury can serve as a biomarker for damage. The epigenetic state of cfDNA, including DNA methylation patterns, can provide insights into the extent of tissue and organ damage. CONTENT: Firstly, this review highlights DNA methylation as an extensively studied epigenetic modification that plays a pivotal role in processes such as cell growth, differentiation, and disease development. It then presents a variety of highly precise 5-mC methylation detection techniques that serve as powerful tools for gaining profound insights into epigenetic alterations linked with tissue damage. Subsequently, the review delves into the mechanisms underlying DNA methylation changes in organ and tissue damage, encompassing inflammation, oxidative stress, and DNA damage repair mechanisms. Next, it addresses the current research status of cfDNA methylation in the detection of specific organ tissues and organ damage. Finally, it provides an overview of the multiple steps involved in identifying specific methylation markers associated with tissue and organ damage for clinical trials. This review will explore the mechanisms and current state of research on cfDNA methylation-based assay detecting organ and tissue damage, the underlying mechanisms, and potential applications in clinical practice.

Molecular targets and mechanisms of Guanxinning tablet in treating atherosclerosis: Network pharmacology and molecular docking analysis.

BACKGROUND: Guanxinning tablet (GXNT), a Chinese patent medicine, is composed of salvia miltiorrhiza bunge and ligusticum striatum DC, which may play the role of endothelial protection through many pathways. We aimed to explore the molecular mechanisms of GXNT against atherosclerosis (AS) through network pharmacology and molecular docking verification. METHODS: The active ingredients and their potential targets of GXNT were obtained in traditional Chinese medicine systems pharmacology database and analysis platform and bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. DrugBank, TTD, DisGeNET, OMIM, and GeneCards databases were used to screen the targets of AS. The intersection targets gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were performed in DAVID database. GXNT-AS protein-protein interaction network, ingredient-target network and herb-target-pathway network were constructed by Cytoscape. Finally, we used AutoDock for molecular docking. RESULTS: We screened 65 active ingredients of GXNT and 70 GXNT-AS intersection targets. The key targets of protein-protein interaction network were AKT1, JUN, STAT3, TNF, TP53, IL6, EGFR, MAPK14, RELA, and CASP3. The Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling pathway were the main pathways. The ingredient-target network showed that the key ingredients were luteolin, tanshinone IIA, myricanone, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone. The results of molecular docking showed that tanshinone IIA, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone all had good binding interactions with AKT1, EGFR and MAPK14. CONCLUSION: The results of network pharmacology and molecular docking showed that the multiple ingredients within GXNT may confer protective effects on the vascular endothelium against AS through multitarget and multichannel mechanisms. AKT1, EGFR and MAPK14 were the core potential targets of GXNT against AS.

The impact of carbon-biased technological progress on carbon haze coordinated governance: insights from China.

Superficial or cosmetic measures are unlikely to solve the complex challenges of carbon haze governance. Carbon-biased technological progress plays a significant role in low-carbon technology and economic sustainable development. This study introduces carbon resources as a production factor in the transcendental logarithmic function to calculate the biased technological progress index of 30 provinces in China between 2010 and 2020. Subsequently, this study constructs the spatial Durbin model to empirically investigate the spatial spillover effect of carbon-biased technology progress on carbon haze coordinated governance. The findings reveal that China's technological progress is primarily characterized by carbon bias, particularly in terms of labor-using carbon-saving technological progress and capital-using carbon-saving technological progress. Additionally, both levels of carbon haze coordinated governance and carbon-biased technological progress have significant spatial agglomeration characteristics. Moreover, the carbon-biased technological progress can facilitate synergy degree of carbon haze governance through energy-saving effects but can also hinder the carbon haze coordinated governance through rebound effects. Therefore, it is imperative to improve labor productivity, augment green capital investment, and stimulate the induction of technological progress towards carbon saving to achieve sustainable and high-quality economic development. The primary contribution is identifying the uncertainty surrounding the impact of carbon-biased technological progress on coordinated governance of carbon haze, while also providing theoretical explanations for the influence channels of carbon-biased technological progress.

Effect of eIF2α in Neuronal Injury Induced by High Glucose and the Protective Mechanism of Resveratrol.

Diabetes mellitus (DM) is a type of metabolic disease characterized by chronic hyperglycemia, which can lead to different degrees of cognitive decline. Therefore, it is crucial to explore the molecular biological mechanisms of neuronal injury. In this study, we investigated the effect of high glucose on eIF2α expression and the mechanism of neuronal injury, and on this basis, the protective mechanism of resveratrol is explored. Treatment with 50 mM high glucose in cortical neurons increased the levels of eIF2α phosphorylation; the expressions of ATF4 and CHOP increased. ISRIB alleviated high glucose-induced neuronal injury by reducing eIF2α phosphorylation when neurons were pretreated with ISRIB before high glucose treatment. Compared with the high glucose-treated group, resveratrol pretreatment reduced eIF2α phosphorylation, the levels of its downstream molecules ATF4 and CHOP, and LDH release. Resveratrol reduced the level of cortical eIF2α phosphorylation and the expression of its downstream molecules in DM mice and improved the ability of spatial memory and learning in DM mice without affecting anxiety and motor performance. Meanwhile, resveratrol modulated the expression of Bcl-2 protein and also effectively decreased the DM-induced up-regulation of Bax, caspase-3, p53, p21, and p16. Taken together, these results suggested that high glucose caused neuronal injury through the eIF2α/ATF4/CHOP pathway which was inhibited by ISRIB and resveratrol. The present study indicates that eIF2α is the new target for the treatment of high glucose-induced neuronal injury, and resveratrol is a potential new medicine to treat diabetes encephalopathy.

Erchen Decoction alleviates obesity-related hepatic steatosis via modulating gut microbiota-drived butyric acid contents and promoting fatty acid ß-oxidation.

ETHNOPHARMACOLOGICAL RELEVANCE: Erchen decoction (ECD) is a traditional Chinese medicine formula comprising six distinct herbs and has been documented to possess a protective effect against obesity. The study conducted previously demonstrated that ECD has the potential to effectively modulate the composition of gut microbiota and levels of short-chain fatty acids (SCFAs) in obese rat. However, the regulatory mechanism of ECD on gut microbiota and SCFAs and further improvement of obesity have not been thoroughly explained. AIM OF THE STUDY: The objective of this study was to examine the therapeutic effect and molecular mechanism of ECD in a rat model of high-fat diet (HFD) feeding. MATERIALS AND METHODS: Rats with HFD-induced obesity were treated with ECD. Upon completion of the study, serum and liver samples were procured to conduct biochemical, pathological, and Western blotting analyses. The investigation of alterations in the gut microbiota subsequent to ECD treatment was conducted through the utilization of 16S rRNA sequencing. The metabolic alterations in the cecal contents were examined through the utilization of mass spectrometry-ultraperformance liquid chromatography. RESULTS: ECD treatment improved lipid metabolic disorders and reduced hepatic steatosis in HFD-induced obese rats. Obese rat treated with ECD showed a higher abundance of SCFA-producing bacteria, including Lactobacillus, Bifidobacterium, and Butyricicoccus, and lower abundance of disease-related bacteria, such as Bacteroides, Parabacteroides, and Sediminibacterium. Additionally, ECD caused an increase in total SCFAs levels; in particular, butyric acid was dramatically increased in the HFD group. Rats treated with ECD also exhibited significantly increased butyric acid concentrations in the serum and liver. The subsequent reduction in histone deacetylase 1 expression and increase in acetyl-histone 3-lysine 9 (H3K9ac) levels contributed to the promotion of fatty acid ß-oxidation (FAO) in liver by ECD. CONCLUSION: This study demonstrates that ECD regulates the gut microbiota and promotes butyric acid production to ameliorate obesity-related hepatic steatosis. The mechanism might be related to the promotion of FAO via a butyric acid-mediated increase in H3K9ac levels in the liver.

Microstructure, Mechanical Properties and Oxidation Resistance of Nb-Si Based Ultrahigh-Temperature Alloys Prepared by Hot Press Sintering.

Nb-Si based ultrahigh-temperature alloys with the composition of Nb-22Ti-15Si-5Cr-3Al (atomic percentage, at. %) were prepared by hot press sintering (HPS) at 1250, 1350, 1400, 1450 and 1500 °C. The effects of HPS temperatures on the microstructure, room temperature fracture toughness, hardness and isothermal oxidation behavior of the alloys were investigated. The results showed that the microstructures of the alloys prepared by HPS at different temperatures were composed of Nbss, ßTiss and γ(Nb,X)5Si3 phases. When the HPS temperature was 1450 °C, the microstructure was fine and nearly equiaxed. When the HPS temperature was lower than 1450 °C, the supersaturated Nbss with insufficient diffusion reaction still existed. When the HPS temperature exceeded 1450 °C, the microstructure coarsened obviously. Both the room temperature fracture toughness and Vickers hardness of the alloys prepared by HPS at 1450 °C were the highest. The alloy prepared by HPS at 1450 °C exhibited the lowest mass gain upon oxidation at 1250 °C for 20 h. The oxide film was mainly composed of Nb2O5, TiNb2O7, TiO2 and a small amount of amorphous silicate. The formation mechanism of oxide film is concluded as follows: TiO2 forms by the preferential reaction of ßTiss and O in the alloy; after that, a stable oxide film composed of TiO2 and Nb2O5 forms; then, TiNb2O7 is formed by the reaction of TiO2 and Nb2O5.

PARP inhibition synergizes with CD47 blockade to promote phagocytosis by tumor-associated macrophages in homologous recombination-proficient tumors.

AIMS: PARP inhibitors (PARPi) are known to exert anti-tumor effects in patients with BRCA-mutated (BRCAmut) or homologous recombination (HR)-deficient cancer, but recent clinical investigations have suggested that this treatment may also be beneficial in patients with HR-proficient tumors. In this study, we aimed to investigate how PARPi exerts anti-tumor effects in non-BRCAmut tumors. MAIN METHODS: BRCA wild-type, HR-deficient-negative ID8 and E0771 murine tumor cells were treated in vitro and in vivo with olaparib, a clinically approved PARPi. The effects on tumor growth in vivo were determined in immune-proficient and -deficient mice and alterations of immune cell infiltrations were analyzed with flow cytometry. Tumor-associated macrophages (TAMs) were further investigated with RNA-seq and flow cytometry. In addition, we confirmed olaparib's effect on human TAMs. KEY FINDINGS: Olaparib did not affect HR-proficient tumor cell proliferation and survival in vitro. However, olaparib significantly decreased tumor growth in C57BL/6 and SCID-beige mice (defective in lymphoid development and NK cell activity). Olaparib increased macrophage numbers in the tumor microenvironment, and their depletion diminished the anti-tumor effects of olaparib in vivo. Further analysis revealed that olaparib improved TAM-associated phagocytosis of cancer cells. Notably, this enhancement was not solely reliant on the "Don't Eat Me" CD47/SIRPα signal. In addition, compared to monotherapy, the concomitant administration of αCD47 antibodies with olaparib improved tumor control. SIGNIFICANCE: Our work provides evidence for broadening the application of PARPi in HR-proficient cancer patients and paves the way for developing novel combined immunotherapy to upgrade the anti-tumor effects of macrophages.

Fasting plasma glucose and fetal ultrasound predict the occurrence of neonatal macrosomia in gestational diabetes mellitus.

OBJECTIVE: The cause of fetal overgrowth during pregnancy is still unclear. This study aimed to analyze and predict the risk of macrosomia in pregnant women with gestational diabetes mellitus (GDM). METHODS: This study was a retrospective study collected from October 2020 to October 2021. A total of 6072 pregnant women with a routine 75-g oral glucose tolerance test (OGTT) during 24-28 gestational weeks were screened. Nearly equal numbers of pregnant women with gestational diabetes and with normal glucose tolerance (NGT) were included in the study. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curve were performed to determine the index and inflection point for predicting macrosomia occurrence. RESULTS: The data of perinatal outcomes of 322 GDM and 353 NGT who had given birth to single live babies at term were analyzed. We found that significant cut-off values for the prediction of macrosomia are 5.13mmol/L in fasting plasma glucose (FPG), 12.25kg in gestational weight gain (GWG), 3,605g in ultrasound fetal weight gain (FWG) and 124mm in amniotic fluid index (AFI).The area under the ROC curve of this predictive model combined all variables reached 0.953 (95% CI: 0.914 ~ 0.993) with a sensitivity of 95.0% and a specificity of 85.4%. CONCLUSIONS: FPG is positively associated with newborn birth weight. An early intervention to prevent macrosomia may be possible by combining maternal GWG, FPG, FWG, and AFI in gestational diabetes.

IFNγ blockade in capillary leak site improves tumour chemotherapy by inhibiting lactate-induced endocytosis of vascular endothelial-cadherins.

IFNγ has long been recognised as a key mediator of tumour immunity and angiostasis. However, IFNγ modulation for cancer therapy is still unsuccessful due to its complex effects on various host cells. In this study, we found that treatment of Lewis lung carcinoma transplants with cisplatin often caused IFNγ-dependent tumour vascular damage. IFNγ induced endothelial glycolysis and lactate production, leading to enhanced endocytosis of vascular endothelial (VE)-cadherin and vessel leakage. We have also developed anti-IFNγ nanoparticles coated with a clot-binding peptide CREKA (CREKA-lipo-anti-IFNγ), which targets the fibrin-fibronectin complex that appears in the leaky site of damaged tumour blood vessels. Blocking IFNγ activity in the leakage site of capillaries using nanoparticles rescued VE-cadherin distribution on the endothelial cellular surface, promoted blood vessel integrity, and improved drug delivery. In conclusion, IFNγ blockade in capillary leak site protected tumour blood vessels from lactate-dependent VE-cadherin loss and enhanced drug delivery during chemotherapy, which provides a basis for tissue-specific IFNγ blockade for tumour therapy.

Emerging trends and hotspots evolution in cardiotoxicity: A bibliometric and knowledge-Map analysis From 2010 to 2022.

Background: There is growing emphasis on the cardiotoxicity research over the past 12 years. To look for the hotspots evolution and to explore the emerging trends in the field of cardiotoxicity, publications related to cardiotoxicity were acquired from the Web of Science Core Collection on August 2, 2022. Methods: We used the CiteSpace 5.8 R3 and VOSviewer 1.6.18 to perform bibliometric and knowledge-map analysis. Results: A total of 8,074 studies by 39,071 authors from 6,530 institutions in 124 countries or regions were published in different academic journals. The most productive country was absolutely the United States, and the University of Texas MD Anderson Cancer Center was the institution with the largest output. Zhang, Yun published the most articles, and the author who had the most frequent co-citations was Moslehi, Javid. New England Journal of Medicine was the most frequently cited journals in this field. Mechanisms of cardiotoxicity have received the most attention and was the main research directions in the field. The disease of cardiotoxicity together with the related risk factors are potential research hotspots. Immune checkpoint inhibitor and myocarditis are two recently discussed and rapidly expanding research topic in the areas of cardiotoxicity. Conclusions: This bibliometric analysis provided a thorough analysis of the cardiotoxicity, which would provide crucial sources of information and concepts for academics studying this area. As a rapidly expanding field in cardiology, the related field of cardiotoxicity will continue to be a focus of research.

Spleen-selective co-delivery of mRNA and TLR4 agonist-loaded LNPs for synergistic immunostimulation and Th1 immune responses.

Spleen is an ideal site for initiating and amplifying antigen-specific immune response. However, spleen-selective antigen delivery has limited tumor therapeutic efficacy owing to an inadequate cytotoxic T-cell immune response. In this study, we designed a spleen-selective mRNA vaccine that delivered unmodified mRNA and Toll-like Receptor (TLR) agonists to the spleen after systemic administration, resulting in a sufficient and persistent antitumor cellular immune response with potent tumor immunotherapeutic efficacy. To establish potent tumor vaccines (sLNPs-OVA/MPLA), we co-loaded stearic acid doped lipid nanoparticles with ovalbumin (OVA)-coding mRNA and TLR4 agonists (MPLA). We found that sLNPs-OVA/MPLA facilitated tissue-specific mRNA expression in the spleen after intravenous injection and elicited enhanced adjuvant activity with Th1 immune responses by activating multiple TLRs. In a prophylactic mouse model, sLNPs-OVA/MPLA induced a potent antigen-specific cytotoxic T cell immune response and ultimately prevented the growth of EG.7-OVA tumors with persistent immune memory protection. In addition, sLNPs-OVA/MPLA effectively delayed the tumor growth of EG.7-OVA subcutaneously transplanted lymphoma and lung metastasis formation of B16F10-OVA intravenously injected melanoma. This study showed that the co-delivery of mRNA antigens and appropriate TLR agonists could significantly improve the antitumor immunotherapeutic efficacy of spleen-targeted mRNA vaccines via synergistic immunostimulation and Th1 immune responses.

Rapidly separable microneedle patch for the controlled and sustained release of 5-fluorouracil.

5-Fluorouracil (5-FU) is frequently used in the treatment of tumors and swollen tissues. However, traditional administration methods can result in poor patient compliance and require to administrate frequently due to the short T1/2 of 5-FU. Herein, the 5-FU@ZIF-8 loaded nanocapsules were prepared using multiple emulsion solvent evaporation methods to enable the controlled and sustained release of 5-FU. To decrease the drug release rate and enhance patient compliance, the obtained pure nanocapsules were added to the matrix to fabricate rapidly separable microneedles (SMNs). The entrapment efficiency (EE%) of 5-FU@ZIF-8 loaded nanocapsules was in the range of 41.55-46.29 %, and the particle size of ZIF-8, 5-FU@ZIF-8, and 5-FU@ZIF-8 loaded nanocapsules were 60 nm, 110 nm, and 250 nm respectively. According to the release study in vivo and in vitro, we concluded that 5-FU@ZIF-8 nanocapsules could achieve the sustained release of 5-FU and that the burst release of nanocapsules could be elegantly handled by incorporating nanocapsules into the SMNs. What's more, the use of SMNs could improve patient compliance due to the rapid separation of needles and backing of SMNs. The pharmacodynamics study also revealed that the formulation would be a better choice for the treatment of scars due to the advantages of painlessness, separation ability, and high delivery efficiency. In conclusion, the SMNs containing 5-FU@ZIF-8 loaded nanocapsules could serve as a potential strategy for some skin diseases therapy with controlled and sustained drug release behavior.

Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.