Dual-Functional AIE Fluorescent Probe for Visualization of Lipid Droplets and Photodynamic Therapy of Cancer.

Abnormal lipid droplets (LDs) are known to be intimately bound with the occurrence and development of cancer, allowing LDs to be critical biomarkers for cancers. Aggregation-induced emission luminogens (AIEgens), with efficient reactive oxygen species (ROS) production performance, are prime photosensitizers (PSs) for photodynamic therapy (PDT) with imaging. Therefore, the development of dual-functional fluorescent probes with aggregation-induced emission (AIE) characteristics that enable both simultaneous LD monitoring and imaging-guided PDT is essential for concurrent cancer diagnosis and treatment. Herein, we reported the development of a novel LD-targeting fluorescent probe (TDTI) with AIE performance, which was expected to realize the integration of cancer diagnosis through LD visualization and cancer treatment via PDT. We demonstrated that TDTI, with typical AIE characteristics and excellent photostability, could target LDs with high specificity, which enables the dynamic tracking of LDs in living cells, specific imaging of LDs in zebrafish, and the differentiation of cancer cells from normal cells for cancer diagnosis. Meanwhile, TDTI exhibited fast ROS generation ability (achieving equilibrium within 60 s) under white light irradiation (10 mW/cm2). The cell apoptosis assay revealed that TDTI effectively induced growth inhibition and apoptosis of HeLa cells. Further, the results of PDT in vivo indicated that TDTI had a good antitumor effect on the tumor-bearing mice model. Collectively, these results highlight the potential utility of the dual-functional fluorescent probe TDTI in the integrated diagnosis and treatment of cancer.

Potentially functional variants of CHMP4A and PANX1 in the pyroptosis-related pathway predict survival of patients with non-oropharyngeal head and neck squamous cell carcinoma.

BACKGROUND: Pyroptosis has been implicated in the advancement of various cancers. Triggering pyroptosis within tumors amplifies the immune response, thereby fostering an antitumor immune environment. Nonetheless, few published studies have evaluated associations between functional variants in the pyroptosis-related genes and clinical outcomes of patients with non-oropharyngeal head and neck squamous cell carcinoma (NON-ORO HNSCC). METHODS: We conducted an association study of 985 NON-ORO HNSCC patients who were randomly divided into two groups: the discovery group of 492 patients and the replication group of 493 patients. We used Cox proportional hazards regression analysis to examine associations between genetic variants of the pyroptosis-related genes and survival of patients with NON-ORO HNSCC. Bayesian false discovery probability (BFDP) was used for multiple testing correction. Functional annotation was applied to the identified survival-associated genetic variants. RESULTS: There are 8254 single-nucleotide polymorphisms (SNPs) located in 82 pyroptosis-related genes, of which 202 SNPs passed multiple testing correction with BFDP < 0.8 in the discovery and six SNPs retained statistically significant in the replication. In subsequent stepwise multivariable Cox regression analysis, two independent SNPs (CHMP4A rs1997996 G > A and PANX1 rs56175344 C > G) remained significant with an adjusted hazard ratios (HR) of 1.31 (95% confidence interval [CI] = 1.09-1.57, p = 0.004) and 0.65 (95% CI = 0.51-0.83, p = 0.0005) for overall survival (OS), respectively. Further analysis of the combined genotypes revealed progressively worse OS associated with the number of unfavorable genotypes (ptrend < 0.0001 and 0.021 for OS and disease-specific survival, respectively). Moreover, both PANX1 rs56175344G and CHMP4A rs1997996A alleles were correlated with reduced mRNA expression levels. CONCLUSIONS: Genetic variants in the pyroptosis pathway genes may predict the survival of NON-ORO HNSCC patients, likely by reducing the gene expression, but our findings need to be replicated by larger studies.

DUSP22 suppresses tumor progression by directly dephosphorylating AKT in non-small cell lung cancer.

Protein kinase B (AKT) plays a pivotal in regulating cell migration, proliferation, apoptosis, and survival, making it a prominent target for anticancer therapy. While the kinase activity of AKT has been extensively explored, its dephosphorylation have largely remained uncharted. Herein, we aimed to unravel the molecular mechanisms governing AKT dephosphorylation, with a specific emphasis on dual-specificity phosphatases DUSP22. Our investigation sought to shed light on the potential of DUSP22 as a potential therapeutic target for non-small cell lung cancer (NSCLC). To determine the expression level of DUSP22 in NSCLC cell lines, the gene expression profiling interactive analysis (GEPIA) and Oncomine database were searched. Additionally, the effect of DUSP22 on patient survival was analyzed with Kaplan-Meier database. Antitumor effects of DUSP22 were tested in A549 and H1299 cell lines. Experiments are based on: (1) cell viability determined by the cell counting kit-8 assay and colony-formation assay; (2) cell migratory ability assessed through the scratch assay and the transwell migration assay; (3) the mechanism behind the antitumor effects of DUSP22 dissected with co-immunoprecipitation (Co-IP) and in vitro kinase assays. Our study revealed a significant downregulation of DUSP22 in both NSCLC cell lines and tissues. Meanwhile, survival rate analysis results demonstrated that reduced DUSP22 expression was correlated with poorer overall survival in lung cancer patients. Moreover, DUSP22 exhibited an inhibitory effect on the cell viability and migratory capacity of A549 and H1299 cells. This inhibition was accompanied by the decrease in the phosphorylation of AKT and p38. Mechanistically, the phosphatase domain of DUSP22 interacted with AKT, resulting in the inhibition of AKT phosphorylation. This inhibitory effect was contingent upon the phosphatase activity of DUSP22. These findings provide compelling evidence that DUSP22 directly interacted with AKT, leading to the dephosphorylation of AKT at S473 and T308 residues, ultimately curbing the proliferation and migration of lung cancer cells. Additionally, our results also highlight a preclinical rationale for utilizing DUSP22 as a prognostic marker in NSCLC.

Wheel Running During Pregnancy Alleviates Anxiety-and Depression-Like Behaviors During the Postpartum Period in Mice: The Roles of NLRP3 Neuroinflammasome Activation, Prolactin, and the Prolactin Receptor in the Hippocampus.

Despite the increase in the prevalence of postpartum depression among maternal disorder, its treatment outcomes remain suboptimal. Studies have shown that exercise can reduce postpartum depressive episodes in the mother, but the effects of exercise during pregnancy on maternal behavior and the potential mechanisms involved remain poorly understood. From the second day of pregnancy to the day of birth, dams exercised for 1 h a day by running on a controlled wheel. The maternal behaviors of the dams were assessed on postpartum day 2 to postpartum day 8. Chronic restraint stress was applied from postpartum day 2 to day 12. Blood was collected on postpartum days 3 and 8, then subjected to ELISA to determine the serum concentration of prolactin. The weight of each dam and the food intake were recorded. Anxiety- and depression-like behavioral tests were conducted, and hippocampal neuroinflammation and prolactin receptor levels were measured. The dams exhibited elevated levels of anxiety and depression, decreased serum prolactin levels, decreased prolactin receptor expression, and activation of NLRP3-mediated neuroinflammation in the hippocampus following the induction of postpartum chronic restraint stress, which were reversed with controlled wheel running during pregnancy. Overall, the findings of this study revealed that the preventive effects of exercise during pregnancy on postpartum anxiety-and depression-like behaviors were accompanied by increased serum prolactin levels, hippocampal prolactin receptor expression and hippocampal NLRP3-mediated neuroinflammation.

Brief Pup Separation in Lactation Confers Stress Resistance with Increased Prolactin and Adult Hippocampal Neurogenesis in Postpartum C57BL/6J Dams.

Prolactin (PRL) assumes a pivotal role during the postpartum phase, particularly within the hippocampus-a region densely populated with receptors for stress hormones, where stress significantly inhibits adult hippocampal neurogenesis (AHN). The reduction in neurogenesis is implicated in the pathogenesis of anxiety and depression. Mothers are at an increased risk of developing depression when exposed to chronic stress. Therefore, it is imperative to investigate the potential role of PRL in depression-like behaviors stemming from prolonged postpartum stress, and to explore any underlying mechanisms. Despite pup separation (PS) being a natural postpartum care practice, the impact of various PS methods on lactating dams remains uncertain. Lactating C57BL/6J mice, from postpartum day (PPD) 1 to PPD 21, underwent no PS (NPS), brief PS (15 min per day, PS15), or long PS (180 min per day, PS180), followed by 21 days of chronic restraint stress (CRS). Behavioral tests were conducted, and measurements included serum PRL concentration, PRL-R expression, and AHN in the hippocampus. Dams with CRS exhibited cognitive decline, depressive- and anxiety-like behaviors, and reduced PRL secretion, correlating with lower levels of AHN. PS15 dams displayed lower levels of depressive- and anxiety-like behaviors and cognitive decline compared to NPS and PS180 dams. Significantly, PS15 dams exhibited higher levels of AHN, PRL-R expression in the hippocampus, and serum PRL concentration. This study collectively reveals reduced serum PRL and AHN in dams with cognitive decline and depressive- and anxiety-like behaviors after CRS. Brief PS confers resistance to behavioral deficits after CRS, increasing serum PRL concentration and reversing AHN decrease in dams.

Evaluating the Role of Functional Groups in the Selective Capture of Ag(I) onto UiO-66-Type Metal-Organic Frameworks.

UiO-66-type metal-organic frameworks have been considered as promising adsorbents for capturing Ag(I) from wastewater. However, uncertainties persist regarding the specific absorptivity of individual functional groups to the UiO-66 framework structure. In this study, UiO-66-type metal-organic frameworks (UiO-66-X), featuring diverse functional groups (X = -(OH)2, -(COOH)2, -NO2, -NH2, -SO3H, -(SH)2), were synthesized in situ for Ag(I) capture. The findings revealed that functionalization significantly enhanced the adsorption capacity of Ag(I). Notably, quantitative analysis showed that 1 mol of -SH functional group onto the UiO-66 framework structure can adsorb 0.73 mol of Ag(I) ions, surpassing those of -COOH, -OH, -NH2, -SO3H, and -NO2 by 2.4-, 3.5-, 3.8-, 9.1-, and 24.3-fold, respectively. This represents the first assessment of the adsorption capacity of functionalized UiO-66 for Ag(I) based on each effective functional group, addressing limitations in traditional unit mass calculations. Further, the adsorption mechanism of UiO-66-X for selectively capturing Ag(I) was elucidated through experimental and theoretical analyses. Additionally, selectivity and practical applications confirm that UiO-66-(SH)2 exhibits strong anti-interference ability, whether in natural water bodies with complex compositions or in industrial wastewater under harsh conditions. We anticipate that this study will enhance our understanding of structure-performance dependencies of multivariate MOFs for designing novel adsorbents for Ag(I) capture.

Two subtypes of schizophrenia identified by an individual-level atypical pattern of tensor-based morphometric measurement.

Difficulties in parsing the multiaspect heterogeneity of schizophrenia (SCZ) based on current nosology highlight the need to subtype SCZ using objective biomarkers. Here, utilizing a large-scale multisite SCZ dataset, we identified and validated 2 neuroanatomical subtypes with individual-level abnormal patterns of the tensor-based morphometric measurement. Remarkably, compared with subtype 1, which showed moderate deficits of some subcortical nuclei and an enlarged striatum and cerebellum, subtype 2, which showed cerebellar atrophy and more severe subcortical nuclei atrophy, had a higher subscale score of negative symptoms, which is considered to be a core aspect of SCZ and is associated with functional outcome. Moreover, with the neuroimaging-clinic association analysis, we explored the detailed relationship between the heterogeneity of clinical symptoms and the heterogeneous abnormal neuroanatomical patterns with respect to the 2 subtypes. And the neuroimaging-transcription association analysis highlighted several potential heterogeneous biological factors that may underlie the subtypes. Our work provided an effective framework for investigating the heterogeneity of SCZ from multilevel aspects and may provide new insights for precision psychiatry.

Mechanism understanding of PIKfyve inhibitor YM201636 with human serum albumin: Insights from molecular modeling and multiple spectroscopic techniques.

YM201636 is the potent PIKfyve inhibitor that is being actively investigated for liver cancer efficacy. In this study, computer simulations and experiments were conducted to investigate the interaction mechanism between YM201636 and the transport protein HSA. Results indicated that YM201636 is stably bound between the subdomains IIA and IIIA of HSA, supported by site marker displacement experiments. YM201636 quenched the endogenous fluorescence of HSA by static quenching since a decrease in quenching constants was observed from 7.74 to 2.39 × 104 M-1. UV-vis and time-resolved fluorescence spectroscopy confirmed the YM201636-HSA complex formation and this binding followed a static mechanism. Thermodynamic parameters ΔG, ΔH, and ΔS obtained negative values suggesting the binding was a spontaneous process driven by Van der Waals interactions and hydrogen binding. Binding constants ranged between 5.71 and 0.33 × 104 M-1, which demonstrated a moderately strong affinity of YM201636 to HSA. CD, synchronous, and 3D fluorescence spectroscopy revealed that YM201636 showed a slight change in secondary structure. The increase of Kapp and a decrease of PSH with YM201636 addition showed that YM201636 changed the surface hydrophobicity of HSA. The research provides reasonable models helping us further understand the transportation and distribution of YM201636 when it absorbs into the blood circulatory system.

Disclosing Support-Size-Dependent Effect on Ambient Light-Driven Photothermal CO2 Hydrogenation over Nickel/Titanium Dioxide.

The size of support in heterogeneous catalysts can strongly affect the catalytic property but is rarely explored in light-driven catalysis. Herein, we demonstrate the size of TiO2 support governs the selectivity in photothermal CO2 hydrogenation by tuning the metal-support interactions (MSI). Small-size TiO2 loading nickel (Ni/TiO2 -25) with enhanced MSI promotes photo-induced electrons of TiO2 migrating to Ni nanoparticles, thus favoring the H2 cleavage and accelerating the CH4 formation (227.7 mmol g-1 h-1 ) under xenon light-induced temperature of 360 °C. Conversely, Ni/TiO2 -100 with large TiO2 prefers yielding CO (94.2 mmol g-1 h-1 ) due to weak MSI, inefficient charge separation, and inadequate supply of activated hydrogen. Under ambient solar irradiation, Ni/TiO2 -25 achieves the optimized CH4 rate (63.0 mmol g-1 h-1 ) with selectivity of 99.8 %, while Ni/TiO2 -100 exhibits the CO selectivity of 90.0 % with rate of 30.0 mmol g-1 h-1 . This work offers a novel approach to tailoring light-driven catalytic properties by support size effect.

Transmission Pattern of Measles Virus Circulating in China During 1993-2021: Genotyping Evidence Supports That China Is Approaching Measles Elimination.

BACKGROUND: To provide useful insights into measles elimination progress in China, measles surveillance data were reviewed, and the transmission patterns of measles viruses circulating in China during 1993-2021 were analyzed. METHODS: Measles incidence data from the National Notifiable Disease Reporting System of the China Center for Disease Control and Prevention were analyzed. A total of 17 570 strains were obtained from 30 of 31 provinces in mainland China during 1993-2021. The recommended genotyping window was amplified. Genotyping analysis was conducted for comparison with the reference strains. Phylogenetic analyses were performed to identify genetic relationships among different lineages within the genotypes. RESULTS: With high coverage of routine immunization and intensive supplementary immunization activities, measles incidence has shown a downward trend since 1993, despite 2 resurgences, reaching a historic low level in 2020-2021 (average 0.5 per million). During 1993-2021, 9 genotypes including domestic genotype H1; imported genotypes B3, D4, D8, D9, D11, G3, and H2; and vaccine-associated genotype A were identified. Among them, the genotype H1 strain circulated endemically in China for more than 25 years; the last strain was detected in Yunnan Province in September 2019. Multiple imported genotypes have been identified since 2009 showing different transmission patterns. Since April 2020, no imported strains have been detected, while vaccine-associated genotype A continues to be detected. CONCLUSIONS: The evidence of low incidence during 2020-2021 and virological surveillance data in this study confirm that China is currently approaching measles elimination.

Vacuolar protein sorting 35 (VPS35) acts as a tumor promoter via facilitating cell cycle progression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is insidious and highly malignant with extremely poor prognosis and drug resistance to current chemotherapies. Therefore, there is a critical need to investigate the molecular mechanism underlying PDAC progression to develop promising diagnostic and therapeutic interventions. In parallel, vacuolar protein sorting (VPS) proteins, involved in the sorting, transportation, and localization of membrane proteins, have gradually attracted the attention of researchers in the development of cancers. Although VPS35 has been reported to promote carcinoma progression, the specific molecular mechanism is still unclear. Here, we determined the impact of VPS35 on the tumorigenesis of PDAC and explored the underlying molecular mechanism. We performed a pan-cancer analysis of 46 VPS genes using RNAseq data from GTEx (control) and TCGA (tumor) and predicted potential functions of VPS35 in PDAC by enrichment analysis. Furthermore, cell cloning experiments, gene knockout, cell cycle analysis, immunohistochemistry, and other molecular and biochemical experiments were used to validate the function of VPS35. Consequently, VPS35 was found overexpressed in multiple cancers and correlated with the poor prognosis of PDAC. Meanwhile, we verified that VPS35 could modulate the cell cycle and promote tumor cell growth in PDAC. Collectively, we provide solid evidence that VPS35 facilitates the cell cycle progression as a critical novel target in PDAC clinical therapy.

One single-person bicycling enhances interpersonal cooperation via increasing interpersonal neural synchronization in left frontal cortex.

Previous findings have shown a strong relationship between sports and interpersonal cooperative behavior. Physical activity is the basic form of sport. In this study, we investigated the effect of physical activity on interpersonal cooperative behavior and its inter-brain correlates. Eighty college students were recruited and randomly divided into the experimental or control group (20 dyads per each). The experimental group performed a 30-min of moderate intensity single-person cycling exercise, while the control group performed a 30-min single-person sitting. Interpersonal cooperative behavior was measured by a Prisoner's Dilemma task before and after the intervention, while neural activities in the frontal cortex in each dyad were measured by the near-infrared spectroscopy-based hyperscanning approach. The results showed that the average cooperation rate and cooperation efficiency of the experimental dyads were significantly higher after the exercise intervention compared to that before intervention, but not in control group. Meanwhile, the interpersonal neural synchronization (INS) in the left frontal cortex was significantly increased after intervention only in experimental dyads. Moreover, the INS increased in left frontal cortex was positively correlated with the cooperation improvement. Taken together, these results indicate that one single-person bicycling can improve interpersonal cooperation behavior, which may be associated with enhanced interpersonal neural synchronization in the left frontal cortex.

Neo-peripheral adaptive immune score predicts neoadjuvant chemotherapy for locally advanced breast cancer.

PURPOSE: Whether peripheral immune cell subsets can predict pathological complete response (pCR) in breast cancer patients remains to be elucidated. We aimed to dissect the relationship between peripheral immune cell subsets and pCR. METHODS: Two hundred and twenty-six eligible patients from two prospective clinical trials (SHPD001 and SHPD002) in China were randomly divided into a training cohort and a validation cohort. The breast cancer subtypes in this study included hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 95), HER2-positive (n = 100), and triple negative (n = 31) breast cancer. We defined the "Neo-Peripheral Adaptive Immune Score" for neoadjuvant chemotherapy (neoPAI Score) based on the percentages of CD4 + T cells, CD8 + T cells, B cells, and the CD4 + /CD8 + ratio in peripheral blood. We also evaluated the ability of the neoPAI Score derived from tumor-infiltrating immune cells (TIICs) to predict survival by employing The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) database. RESULTS: In the training cohort, multivariate analysis showed that HR status [odds ratio (OR) 0.325; 95% confidence interval (CI) 0.135-0.761; P = 0.010], HER2 status (OR 2.657; 95% CI 1.266-5.730; P = 0.011), Ki67 index (OR 3.191; 95% CI 1.509-6.956; P = 0.003), histological grade (OR 2.297; 95% CI 1.031-5.290; P = 0.045) and neoPAI Score (OR 4.451; 95% CI 1.608-13.068; P = 0.005) were independent predictors of pCR. In the validation cohort, histological grade (OR 3.779; 95% CI 3.793-1.136 × 103; P = 0.008) and neoPAI Score (OR 90.828; 95% CI 3.827-9.843 × 103; P = 0.019) were independent predictors of pCR. The Immune Model that integrated the neoPAI Score was more accurate in predicting pCR than the Clinical Model that exclusively contained clinicopathological parameters in both cohorts. In TCGA-BRCA database, the neoPAI Score constructed from TIICs can predict the progression-free interval (P = 0.048) of breast cancer. CONCLUSION: The neoPAI Score defined by the percentages of peripheral immune cell subsets could be used as a potential biomarker for neoadjuvant chemotherapy efficacy.

Brief pup separation during lactation confers resilience in behavioural deficits induced by chronic restraint stress in postpartum C57BL/6J dams.

BACKGROUND: The postpartum period is a complex time for females that affects health recovery. Stress during this period is one of the main risk factors for depression. Therefore, preventing stress-induced depression in the postpartum period is of great importance. Pup separation (PS) is a natural paradigm of postpartum care; however, the effect of different PS protocols during lactation on stress-induced depressive behaviours in dams is unknown. METHODS: Lactating C57BL/6J mice were subjected to no pup separation (NPS), brief PS (15 min/day, PS15) or long PS (180 min/day, PS180) from postpartum day 1 to postpartum day 21 and were then subjected to chronic restraint stress (CRS) for 21 days. Behavioural tests, specifically the open field test (OFT), elevated plus maze (EPM) test and tail suspension test (TST), were performed. The expression of mRNA and protein in the hippocampus and microbiota composition were also assessed. RESULTS: We observed CRS-induced anxiety- and depression-like behaviours in NPS dams. In addition, in NPS dams, microglial activation and the levels of NOD-like receptor pyrin domain containing 3, caspase-1 and interleukin-1ß were increased, whereas expression levels of collapsing response mediator protein 2 (CRMP2) and α-tubulin were decreased. However, immobility time in the TST was lower in PS15+CRS dams than in NPS+CRS dams, and time spent in the centre during the OFT and in the open arms during the EPM test was higher in PS15+CRS dams, indicating resilience. Expression of hippocampal biomarkers of neuroinflammation was inhibited and levels of CRMP2-mediated neuroplasticity were increased in PS15+CRS dams. Notably, we observed taxonomic changes in the cecal microbiota across different PS groups, as well as relationships between gut microbiota composition and some biomarkers of hippocampal neuroinflammation and neuroplasticity. LIMITATIONS: The sample size for gut microbiota analysis in this study was small. CONCLUSION: Collectively, the results of this study confirm that brief PS confers stress resilience in CRS-induced behavioural deficits and reverses hippocampal neuroinflammation-neuroplasticity injury and gut microbiota imbalance.

Recent advances in the development of bitter gourd seed oil: from chemical composition to potential applications.

Non-conventional seed oils are being considered novelty foods due to the unique properties of their chemical constituents. Numerous such seed oils serve as nutritional and functional supplements, making them a point of interest for scholars. Bitter gourd (Momordica charantia L.) seed oil (BGSO) has been widely used in folk medicine worldwide for the treatment of different pathologies, such as diabetes, cancer, and several inflammatory diseases. Therefore, its nutritional and medicinal value has been extensively studied. Considering the potential use of BGSO, it is imperative to have a comprehensive understanding of this product to develop and use its biologically active ingredients in innovative food and pharmaceutical products. An extensive understanding of BGSO would also help improve the economic feasibility of the bitter gourd seed processing industry and help prevent environmental pollution associated with the raw waste produced during the processing of bitter gourd seeds. This review addresses the potential uses of BGSO in terms of food and pharmaceuticals industry perspectives and comprehensively summarizes the oil extraction process, chemical composition, biological activity, and the application prospects of BGSO in clinical medicine.

Design, synthesis, and antitumor evaluation of morpholine substituted bisnaphthalimides as DNA targeting agents.

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC50 lowered to 0.09 µM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.

Transformation of Mercuric Ions to Mercury Nanoparticles in Diatom Chaetoceros curvisetus.

Particulate HgS play crucial roles in the mercury (Hg) cycle. Approximately 20-90% of dissolved Hg can be transformed into particulate HgS by algae. However, detailed knowledge regarding these particles, including sizes and distribution, remains unknown. The present study explored the formation, distribution, and excretion of mercury nanoparticles (HgNPs) in diatom Chaetoceros curvisetus. The results demonstrated that HgNPs (HgS nanoparticles, 29.6-66.2 nm) formed intracellularly upon exposure to 5.0-100.0 µg L-1 Hg(II), accounting for 12-27% of the total Hg. HgNP concentrations significantly increased with increasing intracellular Hg(II) concentrations, while their sizes remained unaffected. HgNPs formed intracellularly and partly accumulated inside the cells (7-11%). Subsequently, the sizes of intracellular HgNPs gradually decreased to facilitate expulsion, 21-50% of which were excreted. These suggested the vital roles of HgNPs in comprehending marine Hg fate. Their unique physicochemical properties and bioavailability would influence Hg biotransformation in the ocean. Additionally, both intracellular and extracellular HgNPs contributed to Hg settling with cells, ultimately leading to Hg burial in sediments. Overall, these findings further deepened our understanding of Hg biotransformation and posed challenges in accurately estimating marine Hg flux and Hg burial.

Discovery of two biotin-PEG4­diarylidenyl piperidone prodrugs as potent antitumor agents with good efficacy, limited toxicity, and low resistance.

Two biotin-polyethylene glycol (PEG)4­diarylidenyl piperidone (DAP) prodrugs, compounds 3a and 3b, were designed as antineoplastic agents and synthesized by coupling biotin to bifluoro- and binitro-substituted DAP derivatives (DAP-F and DAP-NO2) through a PEG4 linker, respectively. The results of the MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide) assay and a SW480 xenograft model identified compounds 3a and 3b as candidate antitumor agents with good efficacy, limited toxicity, and low resistance, as compared to the original drugs (DAP-F and DAP-NO2), cisplatin, and doxorubicin (dox). The results of a preliminary pharmacokinetic study showed that compounds 3a and 3b slowly released their original drug DAP-F and DAP-NO2 within 12 h after intraperitoneal injection, respectively. Western blot analysis and computer docking simulations indicated that DAP-F, DAP-NO2, and compounds 3a and 3b were indeed inhibitors of signal transducer and activator of transcription 3 (STAT3) and the antitumor effects of compounds 3a and 3b were exerted by sequentially interacting with the SH2-binding domain followed by the DNA-binding domain after releasing the original drugs DAP-F and DAP-NO2, respectively. These results suggest that the targeted prodrug model led to good antitumor efficacy with reduced toxicity, while a dual STAT3-binding model may promote antitumor efficacy and resistance.

Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer.

Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC.

First report of Fusarium concentricum as a causal agent of Fusarium leaf blotch on pecan (Carya illinoinensis) in Southeast China.

The economically important nut crop pecan (Carya illinoinensis (Wangenh.) K. Koch) is seriously affected by increasing incidence of fungal disease worldwide (Xiao et al 2021). The top leaves of the pecan variety 'Pawnee' in the orchard of Zhejiang A&F University, Zhejiang, China were damaged by massive dark brown plaques in summer to autumn 2021. The causal agent was isolated from leaves with target plaques following the steps: sterilized with 70% alcohol (30 s × 2), rinsed with sterilized water (3 ×) before and after 5% sodium hypochlorite (30 s), excised the plaques, and placed on PDA medium at 28℃ in a dark incubator for 3-d. The mycelium on the edge of each colony was transferred to fresh SNA medium in dark for 2 weeks to induce conidia formation. A few conidia-germinated mycelia were transferredand inoculated on new plates containing fresh PDA medium to obtain the purified cultures. Koch's postulates were applied to validate the pathogenicity of the purified isolates. Non-woundedly healthy leaves (disinfected with 5% sodium hypochlorite) of 'Pawnee' seedlings were inoculated with 5 mm 7-d old purified cultures. Dark-brown spots appeared on the leaves 2 days post inoculation at 25℃. The spots became larger accompanied by partially cracking and slight deformation of inoculated leaves from day 2 to day 4, while the control leaves remained asymptomatic. A re-isolated strain ZJ-6 from these infected leaves was identified as the pathogenic isolate with the same symptom as the previous one. Morphologically, aerial mycelia of the pathogenic isolate ZJ-6 cashmere and white. The reverse of colony orange. The edge of the colony appeared gradually thinner, the aerial mycelia loose and flocky, and the matrix mycelium whitened. Hyphae were septate, translucent with smooth wall and 1.47-7.14 µm in width. Microconidia (n = 20) obovoid to fusoid, mainly with 0-septate, 4.45-7.78×4.79-16.25 µm. Macroconidia (n = 20) sickle, mainly with 3-5 septa, 5.56-10.28×56.67-114.54 µm. Simultaneous of monophialidic and polyphialidic conidiophores. Conidiophore width 1.47-3.68 µm, slightly smaller than vegetative hyphae. The morphological characteristics matched with previous descriptions of Fusarium species (Nirenberg and O'Donnell 1998; Wang et al 2013). The identity of ZJ-6 was confirmed by phylogenetic reconstruction using the concatenated sequences of the ATP citrate lyase (ACL1), Calmodulin (CaM), the internal transcribed spacer (ITS) rDNA region, ribosomal RNA gene (LSU), the largest subunit of DNA-dependent RNA polymerase II (RPB1), partial translation elongation factor-1 alpha (TEF) and ß-Tubulin (TUB). To this end, the genomic DNA of ZJ-6 was extracted by the M5 hipermix-MF859 (Mei5 Biotechnology) and submitted to GenBank under the accession numbers OP933646, OP933647, OP925890, OP925889, OP933396, OP933648, and OP933397, respectively. The obtained sequences of ZJ-6 were used for nucleotide BLAST against thetandard databases, respectively, and the strains with sequence identification values above 98% were selected to construct multiple alignment for building a phylogenetic tree. This analyses allowed the identification of ZJ-6 as Fusarium concentricum Nirenberg & O'Donnell, a species with few reports that can cause serious damage to the fruits and branches of other hosts (Hasan et al 2020; Huda-Shakirah et al 2020; Wang et al 2013). This is the first report of pathogenic F. concentricum on pecan in Southeast China that caused no harvest of infected plants.