Selective binding and periodic arrangement of magic boron clusters on monolayer borophene.

The synthesis and characterization of small boron clusters with unique size and regular arrangement are crucial for boron chemistry and two-dimensional borophene materials. In this study, together with theoretical calculations, the joint molecular beam epitaxy and scanning tunneling microscopy experiments achieve the formation of unique B5 clusters on monolayer borophene (MLB) on a Cu(111) surface. The B5 clusters tend to selectively bind to specific sites of MLB with covalent boron-boron bonds in the periodic arrangement, which can be ascribed to the charge distribution and electron delocalization character of MLB and also prohibits nearby co-adsorption of B5 clusters. Furthermore, the close-packed adsorption of B5 clusters would facilitate the synthesis of bilayer borophene, exhibiting domino effect-like growth mode. The successful growth and characterization of uniform boron clusters on a surface enrich the boron-based nanomaterials and reveal the essential role of small clusters during the growth of borophene.

Oncoprotein-induced transcript 3 protein-enriched extracellular vesicles promotes NLRP3 ubiquitination to alleviate acute lung injury after cardiac surgery.

Acute lung injury (ALI) including acute respiratory distress syndrome (ARDS) is a major complication and increase the mortality of patients with cardiac surgery. We previously found that the protein cargoes enriched in circulating extracellular vesicles (EVs) are closely associated with cardiopulmonary disease. We aimed to evaluate the implication of EVs on cardiac surgery-associated ALI/ARDS. The correlations between "oncoprotein-induced transcript 3 protein (OIT3) positive" circulating EVs and postoperative ARDS were assessed. The effects of OIT3-overexpressed EVs on the cardiopulmonary bypass (CPB) -induced ALI in vivo and inflammation of human bronchial epithelial cells (BEAS-2B) were detected. OIT3 enriched in circulating EVs is reduced after cardiac surgery with CPB, especially with postoperative ARDS. The "OIT3 positive" EVs negatively correlate with lung edema, hypoxemia and CPB time. The OIT3-overexpressed EVs can be absorbed by pulmonary epithelial cells and OIT3 transferred by EVs triggered K48- and K63-linked polyubiquitination to inactivate NOD-like receptor protein 3 (NLRP3) inflammasome, and restrains pro-inflammatory cytokines releasing and immune cells infiltration in lung tissues, contributing to the alleviation of CPB-induced ALI. Overexpression of OIT3 in human bronchial epithelial cells have similar results. OIT3 promotes the E3 ligase Cbl proto-oncogene B associated with NLRP3 to induce the ubiquitination of NLRP3. Immunofluorescence tests reveal that OIT3 is reduced in the generation from the liver sinusoids endothelial cells (LSECs) and secretion in liver-derived EVs after CPB. In conclusion, OIT3 enriched in EVs is a promising biomarker of postoperative ARDS and a therapeutic target for ALI after cardiac surgery.

Moderating Effect of Coping Strategies on the Association Between the Infodemic-Driven Overuse of Health Care Services and Cyberchondria and Anxiety: Partial Least Squares Structural Equation Modeling Study.

BACKGROUND: The COVID-19 pandemic has led to a substantial increase in health information, which has, in turn, caused a significant rise in cyberchondria and anxiety among individuals who search for web-based medical information. To cope with this information overload and safeguard their mental well-being, individuals may adopt various strategies. However, the effectiveness of these strategies in mitigating the negative effects of information overload and promoting overall well-being remains uncertain. OBJECTIVE: This study aimed to investigate the moderating effect of coping strategies on the relationship between the infodemic-driven misuse of health care and depression and cyberchondria. The findings could add a new dimension to our understanding of the psychological impacts of the infodemic, especially in the context of a global health crisis, and the moderating effect of different coping strategies on the relationship between the overuse of health care and cyberchondria and anxiety. METHODS: The data used in this study were obtained from a cross-sectional web-based survey. A professional survey company was contracted to collect the data using its web-based panel. The survey was completed by Chinese individuals aged 18 years or older without cognitive problems. Model parameters of the relationships between infodemic-driven overuse of health care, cyberchondria, and anxiety were analyzed using bootstrapped partial least squares structural equation modeling. Additionally, the moderating effects of coping strategies on the aforementioned relationships were also examined. RESULTS: A total of 986 respondents completed the web-based survey. The mean scores of the Generalized Anxiety Disorder-7 and Cyberchondria Severity Scale-12 were 8.4 (SD 3.8) and 39.7 (SD 7.5), respectively. The mean score of problem-focused coping was higher than those of emotion- and avoidant-focused coping. There was a significantly positive relationship between a high level of infodemic and increased overuse of health care (bootstrapped mean 0.21, SD 0.03; 95% CI 0.1581-0.271). The overuse of health care resulted in more severe cyberchondria (bootstrapped mean 0.107, SD 0.032) and higher anxiety levels (bootstrapped mean 0.282, SD 0.032) in all the models. Emotion (bootstrapped mean 0.02, SD 0.008 and 0.037, SD 0.015)- and avoidant (bootstrapped mean 0.026, SD 0.009 and 0.049, SD 0.016)-focused coping strategies significantly moderated the relationship between the overuse of health care and cyberchondria and that between the overuse of health care and anxiety, respectively. Regarding the problem-based model, the moderating effect was significant for the relationship between the overuse of health care and anxiety (bootstrapped mean 0.007, SD 0.011; 95% CI 0.005-0.027). CONCLUSIONS: This study provides empirical evidence about the impact of coping strategies on the relationship between infodemic-related overuse of health care services and cyberchondria and anxiety. Future research can build on the findings of this study to further explore these relationships and develop and test interventions aimed at mitigating the negative impact of the infodemic on mental health.

The trends in death of primary liver cancer caused by specific etiologies worldwide: results from the Global Burden of Disease Study 2019 and implications for liver cancer management.

BACKGROUND: Over past decades, epidemiological patterns of liver cancer (LC) have changed dramatically. The Global Burden of Disease (GBD) study provides an opportunity for tracking the progress in cancer control with its annual updated reports at national, regional and global level, which can facilitate the health decision-making and the allocation of health resources. Therefore, we aim to estimate the global, regional and national trends of death caused by liver cancer due to specific etiologies and attributable risks from 1990 to 2019. MATERIALS AND METHODS: Data was collected from the GBD study 2019. Estimated annual percentage changes (EAPC) were used to quantify the trends of age-standardized death rate (ASDR). We applied a linear regression for the calculation of estimated annual percentage change in ASDR. RESULTS: From 1990 to 2019, the ASDR of liver cancer decreased globally (EAPC = - 2.23, 95% confidence interval [CI]: - 2.61 to - 1.84). Meanwhile, declining trends were observed in both sexes, socio-demographic index (SDI) areas, and geographies, particularly East Asia (EAPC = - 4.98, 95% CI: - 5.73 to - 4.22). The ASDR for each of the four major etiologies fell globally, while liver cancer caused by hepatitis B had the largest drop (EPAC = - 3.46, 95% CI: - 4.01 to - 2.89). China has had dramatic decreases in death rates on a national scale, particularly when it comes to the hepatitis B etiology (EAPC = - 5.17, 95% CI: - 5.96 to - 4.37). However, certain nations, such as Armenia and Uzbekistan, saw a rise in liver cancer mortality. Controlling smoking, alcohol, and drug use contributed to a drop in LC-related mortality in the majority of socio-demographic index areas. Nevertheless, the excessive body mass index (BMI) was portrayed as the underlying cause for LC fatalities. CONCLUSION: From 1990 to 2019, there was a worldwide decrease in deaths caused by liver cancer and its underlying causes. However, rising tendencies have been observed in low-resource regions and countries. The trends in drug use- and high BMI-related death from liver cancer and its underlying etiologies were concerning. The findings indicated that efforts should be increased to prevent liver cancer deaths through improved etiology control and risk management.

Simultaneous separation of glycyrrhizic acid, baicalein and wogonin from Radix Glycyrrhizae and Radix Scutellariae using foam fractionation and in vitro activity evaluation.

BACKGROUND: In this study, the optimal conditions for the extraction and purification of glycyrrhizic acid from Radix Glycyrrhizae (RG) and baicalein and wogonin from Radix Scutellariae (RS) by foam fractionation were studied on the basis of central composite design (CCD) and response surface methodology. RESULTS: The results showed that herbal proportion (RG:RS), gas flow and ethanol concentration were the main factors guiding the foam fractionation of RG and RS. The optimum technological parameters were obtained as follows: herbal proportion (RG:RS), 1.86:1.14; gas flow, 109 mL min-1 ; and ethanol concentration, 53%. Under the optimal operating conditions, the maximal extraction yields of baicalein, glycyrrhizic acid and wogonin were 56.67, 13.25 and 9.51 mg g-1 , respectively, which were 2.32-, 1.22- and 1.84-fold higher than those of ultrasonic extraction and 17.28-, 1.15- and 9.91-fold higher than those of ultrasonic extraction without hydrolysis, respectively. Investigations on the antioxidant activity showed that the foam-fractionated extract exhibited better free radical scavenging activity (IC50 13.80 µg mL-1 ) than that of the ultrasonic extract (IC50 223.00 µg mL-1 ). Antibacterial activity showed that the minimum inhibitory concentrations of the foam fractionated extract against Staphylococcus aureus, Candida albicans, Group A Streptococcus and Pseudomonas aeruginosa were 1.38, 1.38, 0.69 and 5.50 mg mL-1 , respectively. CONCLUSION: The results indicate that the foam fractionated extract exhibited better extraction yields and free radical scavenging activity than did the ultrasonic extract. Therefore, this fast and eco-friendly method was established and could be a basis for the extraction and separation of other active constituents from herbal medicines. © 2022 Society of Chemical Industry.

Effect of the "Normalized Epidemic Prevention and Control Requirements" on hospital-acquired and community-acquired infections in China.

BACKGROUND: No studies have yet reported the effect of prevention and control measures, which were implemented to combat COVID-19, on the prevention and control of common HAIs. We aimed to examine the effect of the "Normalized Epidemic Prevention and Control Requirements" (implemented in May 2020) by comparison of hospital-acquired infections (HAIs) and community-acquired infections (CAIs) in China during 2018, 2019, and 2020. METHODS: Data of inpatients before and after implementation of new requirements were retrospectively analyzed, including infection rate, use of alcohol-based hand cleaner, anatomical sites of infections, pathogen species, infection by multi-drug resistant species, and use of different antibiotics. RESULTS: The HAI rate was significantly higher in 2020 than in 2018 and 2019 (P < 0.05), and the CAI rate was significantly higher in 2019 and 2020 than in 2018 (P < 0.001). Lower respiratory tract infections were the most common HAI during all years, with no significant changes over time. Lower respiratory tract infections were also the most common CAI, but were significantly more common in 2018 and 2019 than 2020 (P < 0.001). There were no changes in upper respiratory tract infections among HAIs or CAIs. Most HAIs and CAIs were from Gram-negative bacteria, and the percentages of fungal infections were greater in 2019 and 2020 than 2018. MRSA infections were more common in 2020 than in 2018 and 2019 (P < 0.05). The utilization rate and usage days of antibiotics decreased over time (P < 0.001) and the culture rate of microbial specimens before antibiotic usage increased over time (P < 0.001). CONCLUSIONS: The new prevention and control requirements provided important benefits during the COVID-19 pandemic. However, their effects on HAIs were not obvious.

Circulating extracellular vesicles from patients with valvular heart disease induce neutrophil chemotaxis via FOXO3a and the inhibiting role of dexmedetomidine.

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.

Dynamics of Single-Molecule Dissociation by Selective Excitation of Molecular Phonons.

Breaking bonds selectively in molecules is vital in many chemistry reactions and custom nanoscale device fabrications. The scanning tunneling microscope (STM) has proved to be an ideal tool to initiate and view bond-selective chemistry at the single-molecule level, offering opportunities for the further study of the dynamics in single molecules on metal surfaces. We demonstrate H─HS and H─S bond breaking on Au(111) induced by tunneling electrons using low-temperature STM. An experimental study combined with theoretical calculations shows that the dissociation pathway is facilitated by vibrational excitations. Furthermore, the dissociation probabilities of the two different dissociation processes are bias dependent due to different inelastic-tunneling probabilities, and they are also closely linked to the lifetime of inelastic-tunneling electrons. Combined with time-dependent ab initio nonadiabatic molecular dynamics simulations, the dynamics of the injected electron and the phonon-excitation-induced molecule dissociation can be understood at the atomic scale, demonstrating the potential application of STM for the investigation of excited-state dynamics of single molecules on surfaces.

Molecular determinants of cytochrome C oxidase IV mRNA axonal trafficking.

In previous studies, we identified a putative 38-nucleotide stem-loop structure (zipcode) in the 3' untranslated region of the cytochrome c oxidase subunit IV (COXIV) mRNA that was necessary and sufficient for the axonal localization of the message in primary superior cervical ganglion (SCG) neurons. However, little is known about the proteins that interact with the COXIV-zipcode and regulate the axonal trafficking and local translation of the COXIV message. To identify proteins involved in the axonal transport of the COXIV mRNA, we used the biotinylated 38-nucleotide COXIV RNA zipcode as bait in the affinity purification of COXIV zipcode binding proteins. Gel-shift assays of the biotinylated COXIV zipcode indicated that the putative stem-loop structure functions as a nucleation site for the formation of ribonucleoprotein complexes. Mass spectrometric analysis of the COXIV zipcode ribonucleoprotein complex led to the identification of a large number RNA binding proteins, including fused in sarcoma/translated in liposarcoma (FUS/TLS), and Y-box protein 1 (YB-1). Validation experiments, using western analyses, confirmed the presence of the candidate proteins in the COXIV zipcode affinity purified complexes obtained from SCG axons. Immunohistochemical studies show that FUS, and YB-1 are present in SCG axons. Importantly, RNA immunoprecipitation studies show that FUS, and YB-1 interact with endogenous axonal COXIV transcripts. siRNA-mediated downregulation of the candidate proteins FUS and YB-1 expression in the cell-bodies diminishes the levels of COXIV mRNA in the axon, suggesting functional roles for these proteins in the axonal trafficking of COXIV mRNA.

PP2A catalytic subunit silence by microRNA-429 activates AMPK and protects osteoblastic cells from dexamethasone.

Activation of AMP-activated protein kinase (AMPK) could efficiently protect osteoblasts from dexamethasone (Dex). Here, we aim to induce AMPK activation through miRNA-mediated downregulating its phosphatase, protein phosphatase 2A (PP2A). We discovered that microRNA-429 ("miR-429") targets the catalytic subunit of PP2A (PP2A-c). Significantly, expression of miR-429 downregulated PP2A-c and activated AMPK (p-AMPKα1 Thr172) in human osteoblastic cells (OB-6 and hFOB1.19 lines). Remarkably, miR-429 expression alleviated Dex-induced osteoblastic cell death and apoptosis. On the other hand, miR-429-induced AMPK activation and osteoblast cytoprotection were almost abolished when AMPKα1 was either silenced (by targeted shRNA) or mutated (T172A inactivation). Further studies showed that miR-429 expression in osteoblastic cells increased NADPH (nicotinamide adenine dinucleotide phosphate) content to significantly inhibit Dex-induced oxidative stress. Such effect by miR-429 was again abolished with AMPKα1 silence or mutation. Together, we propose that PP2A-c silence by miR-429 activates AMPK and protects osteoblastic cells from Dex.

Axonal localization and mitochondrial association of precursor microRNA 338.

MicroRNAs (miRNAs) selectively localize to subcompartments of the neuron, such as dendrites, axons, and presynaptic terminals, where they regulate the local protein synthesis of their putative target genes. In addition to mature miRNAs, precursor miRNAs (pre-miRNAs) have also been shown to localize to somatodendritic and axonal compartments. miRNA-338 (miR-338) regulates the local expression of several nuclear-encoded mitochondrial mRNAs within axons of sympathetic neurons. Previous work has shown that precursor miR-338 (pre-miR-338) introduced into the axon can locally be processed into mature miR-338, where it can regulate local ATP synthesis. However, the mechanisms underlying the localization of pre-miRNAs to the axonal compartment remain unknown. In this study, we investigated the axonal localization of pre-miR-338. Using proteomic and biochemical approaches, we provide evidence for the localization of pre-miR-338 to distal neuronal compartments and identify several constituents of the pre-miR-338 ribonucleoprotein complex. Furthermore, we found that pre-miR-338 is associated with the mitochondria in axons of superior cervical ganglion (SCG) neurons. The maintenance of mitochondrial function within axons requires the precise spatiotemporal synthesis of nuclear-encoded mRNAs, some of which are regulated by miR-338. Therefore, the association of pre-miR-338 with axonal mitochondria could serve as a reservoir of mature, biologically active miRNAs, which could coordinate the intra-axonal expression of multiple nuclear-encoded mitochondrial mRNAs.

MHY1485 activates mTOR and protects osteoblasts from dexamethasone.

Dexamethasone (Dex) exerts cytotoxic effects to cultured osteoblasts. The potential effect of MHY1485, a small-molecular mammalian target of rapamycin (mTOR) activator, against the process was studied here. In both osteoblastic MC3T3-E1 cells and primary murine osteoblasts, treatment with MHY1485 significantly ameliorated Dex-induced cell death and apoptosis. mTOR inhibition, through mTOR kinase inhibitor OSI-027 or mTOR shRNAs, abolished MHY1485-mediated osteoblast cytoprotection against Dex. Intriguingly, activation of mTOR complex (mTORC1), but not mTORC2, is required for MHY1485's anti-Dex activity. mTORC1 inhibitors (rapamycin and RAD001) or Raptor knockdown almost reversed MHY1485-induced osteoblast cytoprotection. mTORC2 inhibition, via shRNA knockdown of Rictor, failed to affect MHY1485's activity in MC3T3-E1 cells. Further studies showed that MHY1485 treatment in MC3T3-E1 cells and primary murine osteoblasts significantly inhibited Dex-induced mitochondrial death pathway activation, the latter was tested by mitochondrial depolarization, cyclophilin D-ANT-1 association and cytochrome C cytosol release. Together, these results suggest that MHY1485 activates mTORC1 signaling to protect osteoblasts from Dex.

The ZnSn(OH)6 nanocube-graphene composite as an anode material for Li-ion batteries.

ZnSn(OH)6 (ZSH) nanocubes with a uniform size of 40-80 nm were synthesized by using a simple hydrothermal route and then combined with graphene sheets (rGO) via the electrostatic interaction. The formed composite of ZnSn(OH)6 nanocube-graphene (ZSH-rGO) was used as an anode material for Li-ion batteries and it exhibited significantly enhanced electrochemical performance. For instance, a capacity of 540 mA h g(-1) at 500 mA g(-1) was retained after 40 cycles.

Daptomycin Inhibits Multiple Myeloma Progression through Downregulating the Expression of RPS19.

OBJECTIVES: This study aimed to explore new therapeutic drugs for multiple myeloma (MM). MM is a common plasma cell malignant proliferative disease, accounting for 15% of hematological malignancies. The role of daptomycin (DAP), a potential anti-tumor drug, remains unclear in MM. In the present research, we investigated the anticancer effect of DAP in MM cell line RPMI 8226. METHODS: RPMI 8226 cells were treated with DAP (20 µM, 40 µM, and 80 µM) with 20 nM bortezomib (BZ) as a positive control. Cell function was detected using CCK8, flow cytometry, and transwell assay. RESULTS: In MM cells, DAP inhibited proliferation and induced apoptosis. The cell cycle was arrested at the G1 phase after the treatment of DAP. The migration and invasion abilities were also inhibited by DAP treatment in RPMI 8226 cells. Importantly, the mRNA and protein levels of RPS19 were downregulated in DAP-treated RPMI 8226 cells. CONCLUSION: DAP inhibited the proliferation, migration, and invasion and promoted the apoptosis of MM cells. Mechanistically, the RPS19 expression was significantly decreased in DAPtreated cells. This research provides a potential therapeutic drug for MM therapy.

A smartphone-based fluorescent biosensor with metal-organic framework biocomposites and cotton swabs for the rapid determination of tetrodotoxin in seafood.

BACKGROUND: Tetrodotoxin (TTX) is a potent neurovirulent marine biotoxin that is present in puffer fish and certain marine animals. It is capable of causing severe neurotoxic symptoms and even death when consumed through contaminated seafood. Due to its high toxicity, developing an effective assay for TTX determination in seafood has significant benefits for food safety and human health. Currently, it remains challenging to achieve on-site determination of TTX in seafood. To facilitate mass on-site assays, more affordable technologies utilizing accessible equipment that require no skilled personnel are needed. RESULTS: A smartphone-based portable fluorescent biosensor is proposed for TTX determination by using metal-organic framework (MOF) biocomposites and cotton swabs. Oriented antibody (Ab)-decorated and fluorescent quantum dot (QD)-loaded MOF biocomposites (QD@MOF*Ab) are rapidly synthesized for binding targets and fluorescent responses by utilizing the tunability of zinc-based MOF. Moreover, facile Ab-immobilized household cotton swabs are utilized as TTX capture tools. TTX forms sandwich immune complexes with QD@MOF*Ab probes, achieving signal amplification. These probes are excited by a portable device to generate bright fluorescent signals, which can be detected by the naked eye, and TTX quantitative results are obtained using a smartphone. When observed with the naked eye, the limit of detection (LOD) is 0.4 ng/mL, while intelligent quantitation presents an LOD of 0.13 ng/mL at logarithmic concentrations of 0.2-400 ng/mL. SIGNIFICANCE: This biosensor is convenient to use, and an easy-to-operate analysis is completed within 15 min, thus demonstrating excellent performance in terms of detection speed and portability. Furthermore, it successfully determines TTX contents in puffer fish and clam samples, demonstrating its potential for monitoring seafood. Herein, this work provides a favorable rapid sensing platform that is easily portable.

Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1/FTL/POLQ/RAD51 axis.

Iron is crucial for cell DNA synthesis and repair, but an excess of free iron can lead to oxidative stress and subsequent cell death. Although several studies suggest that cancer cells display characteristics of 'Iron addiction', an ongoing debate surrounds the question of whether iron can influence the malignant properties of ovarian cancer. In the current study, we initially found iron levels increase during spheroid formation. Furthermore, iron supplementation can promote cancer cell survival, cancer spheroid growth, and migration; vice versa, iron chelators inhibit this process. Notably, iron reduces the sensitivity of ovarian cancer cells to platinum as well. Mechanistically, iron downregulates DNA homologous recombination (HR) inhibitor polymerase theta (POLQ) and relieves its antagonism against the HR repair enzyme RAD51, thereby promoting DNA damage repair to resist chemotherapy-induced damage. Additionally, iron tightly regulated by ferritin (FTH1/FTL) which is indispensable for iron-triggered DNA repair. Finally, we discovered that iron chelators combined with platinum exhibit a synergistic inhibitory effect on ovarian cancer in vitro and in vivo. Our findings affirm the pro-cancer role of iron in ovarian cancer and reveal that iron advances platinum resistance by promoting DNA damage repair through FTH1/FTL/POLQ/RAD51 pathway. Our findings highlight the significance of iron depletion therapy, revealing a promising avenue for advancing ovarian cancer treatment.

Structural Simplification of Podophyllotoxin: Discovery of γ-Butyrolactone Derivatives as Novel Antiviral Agents for Plant Protection.

Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin's structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3g demonstrating the most potent in vivo anti-TMV activity. At 500 µg/mL, compound 3g achieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycin and ribavirin. Notably, the syn-diastereomer (syn-3g) exhibited superior antiviral activity compared to the anti-diastereomer (anti-3g). Mechanistic studies revealed that syn-3g could bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g, with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.

Depletion of the N6-Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4.

Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated ferroptosis by modulating the protein expression level of GPX4 through direct binding to a specific motif on GPX4 mRNA. Strikingly, the m6A modification at this motif was found to be critical for GPX4 mRNA stability and translation. Furthermore, IGF2BP3 knockdown glioma cells were incapable of forming tumors in a mouse xenograft model and were more susceptible to phagocytosis by microglia. Our findings shed light on an unrecognized regulatory function of IGF2BP3 in ferroptosis. The identification of a critical m6A site within the GPX4 transcript elucidates the significance of post-transcriptional control in ferroptosis.

METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis.

BACKGROUND: The regulatory role of N6-methyladenosine (m6A) modification in the onset and progression of cancer has garnered increasing attention in recent years. However, the specific role of m6A modification in pulmonary metastasis of colorectal cancer remains unclear. METHODS: This study identified differential m6A gene expression between primary colorectal cancer and its pulmonary metastases using transcriptome sequencing and immunohistochemistry. We investigated the biological function of METTL3 gene both in vitro and in vivo using assays such as CCK-8, colony formation, wound healing, EDU, transwell, and apoptosis, along with a BALB/c nude mouse model. The regulatory mechanisms of METTL3 in colorectal cancer pulmonary metastasis were studied using methods like methylated RNA immunoprecipitation quantitative reverse transcription PCR, RNA stability analysis, luciferase reporter gene assay, Enzyme-Linked Immunosorbent Assay, and quantitative reverse transcription PCR. RESULTS: The study revealed high expression of METTL3 and YTHDF1 in the tumors of patients with pulmonary metastasis of colorectal cancer. METTL3 promotes epithelial-mesenchymal transition in colorectal cancer by m6A modification of SNAIL mRNA, where SNAIL enhances the secretion of CXCL2 through the NF-κB pathway. Additionally, colorectal cancer cells expressing METTL3 recruit M2-type macrophages by secreting CXCL2. CONCLUSION: METTL3 facilitates pulmonary metastasis of colorectal cancer by targeting the m6A-Snail-CXCL2 axis to recruit M2-type immunosuppressive macrophages. This finding offers new research directions and potential therapeutic targets for colorectal cancer treatment.

Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors.

Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most 'cold' tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from 'cold' to 'hot' tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells' ability to recognize and eliminate tumor cells. In 'cold' tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy's efficacy. Concurrently, strategies to convert 'cold' tumors into 'hot' ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting 'cold' tumors.