Cardiac adverse events associated with lacosamide: a disproportionality analysis of the FAERS database.

Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide.

Pyrotinib and trastuzumab plus palbociclib and fulvestrant in HR+/HER2+ breast cancer patients with brain metastasis.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8-64.9%), with a CNS-ORR of 28.6% (95% CI: 8.4-58.1%). The median follow-up period was 6.3 months (range, 2.1-14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3-16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9-11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

Salvianolic acid B alleviates autoimmunity in Treg-deficient mice via inhibiting IL2-STAT5 signaling.

Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.

Clinicopathological characteristics and genomic profiling of pure mucinous breast cancer.

PURPOSE: Pure mucinous breast cancer (PMC) is a rare histological type with a favourable prognosis. However, cases with recurrence have been reported and diagnosed in clinical practice. The mechanisms underlying PMC recurrence remain unknown. In this study, we aimed to identify the prognostic factors associated with PMC. MATERIALS AND METHODS: A total of 166 patients diagnosed with PMC were included. We compared the clinicopathological characteristics between patients with and without recurrence. The 21-gene assay was performed in 10 patients with recurrence and 20 TNM stage-matched patients without recurrence. Whole-exon sequencing was performed in 12 PMC primary tumours and four positive lymph nodes (LNs). RESULTS: Tumour size, lymph node status and TNM staging differed significantly between recurrent group and non-recurrent group. And the 21-gene recurrence scores did not differ significantly between recurrent group and its TNM stage-matched non-recurrent group. The most frequently mutated genes in the primary tumours of regional LN-positive PMCs were ADCY10 (3/6) and SHANK3 (3/6), and they more recurrently harboured gains of 15q23, 17q23.2 and 20p11.21, and loss of 21p11.2. And these alterations were not detected in primary tumours of regional LN-negative PMCs. CONCLUSION: TNM stage is an important prognostic factor in PMC. Although we revealed that regional LN-positive PMCs show increased occurrence of duplication variants at 15q23, 17q23.2 and 20p11.21, and deletion variants at 21p11.2. Further investigation, including multi-omics studies, are needed and may provide additional insights into the nature of PMC.

Advancements in Solid-State Hydrogen Storage: A Review on the Glass Microspheres.

Glass microspheres, with their unique internal structure and chemical stability, offer a promising solution for the challenges of hydrogen storage and transmission, potentially advancing the utility of hydrogen as a safe and efficient energy source. In this review, we systematically evaluate various treatment and modification strategies, including fusion, sol-gel, and chemical vapor deposition (CVD), and compare the performance of different types of glass microspheres. Our synthesis of current research findings reveals that specific low-cost and environmentally friendly modification techniques can significantly enhance the hydrogen storage efficiency of glass microspheres, with some methods increasing storage capacity by up to 32% under certain conditions. Through a detailed life-cycle and cost-benefit assessment, our study highlights the economic and sustainability advantages of using modified glass microspheres. For example, selected alternative materials used in lightweight vehicles have been shown to reduce density by approximately 10% while reducing costs. This review not only underscores the contributions of modified glass microspheres to overcoming the limitations of current hydrogen storage technologies but also provides a systematic framework for improving their performance in hydrogen storage applications. Our research suggests that modified glass microspheres could help to make hydrogen energy more commercially viable and environmentally friendly.

Effects of Bacillus coagulans TBC169 on gut microbiota and metabolites in gynecological laparoscopy patients.

Objective: The primary objective of this study is to investigate the mechanism by which Bacillus coagulans TBC169 accelerates intestinal function recovery in patients who have undergone gynecological laparoscopic surgery, using metabolomics and gut microbiota analysis. Methods: A total of 20 subjects were selected and randomly divided into two groups: the intervention group (n = 10) receiving Bacillus coagulans TBC169 Tablets (6 pills, 1.05 × 108 CFU), and the control group (n = 10) receiving placebos (6 pills). After the initial postoperative defecation, fecal samples were collected from each subject to analyze their gut microbiota and metabolic profiles by high-throughput 16S rRNA gene sequencing analysis and untargeted metabonomic. Results: There were no statistically significant differences observed in the α-diversity and ß-diversity between the two groups; however, in the intervention group, there was a significant reduction in the relative abundance of unclassified_Enterobacteriaceae at the genus level. Furthermore, the control group showed increased levels of Holdemanella and Enterobacter, whereas the intervention group exhibited elevated levels of Intestinimonas. And administration of Bacillus coagulans TBC169 led to variations in 2 metabolic pathways: D-glutamine and D-glutamate metabolism, and arginine biosynthesis. Conclusion: This study demonstrated that consuming Bacillus coagulans TBC169 after gynecological laparoscopic surgery might inhibit the proliferation of harmful Enterobacteriaceae; mainly influence 2 pathways including D-glutamine and D-glutamate metabolism, and arginine biosynthesis; and regulate metabolites related to immunity and intestinal motility; which can help regulate immune function, maintain intestinal balance, promote intestinal peristalsis, and thus accelerate the recovery of intestinal function.

Optimized decomposition of fresh tomato remnants in facility soil.

To return vegetable remnants to soil in situ and understand parameters that determine their decomposition efficiency, the tomato remnant length, soil moisture, soil temperature and dosage of a microbial decomposer (MD) have been evaluated through a laboratory experiment using a nylon mesh bag in this study. The results showed that the residual remnant weight, and total carbon content increased 28.49 % and 32.65 %, respectively with two different remnant lengths (∼0.5 cm and ∼2.5 cm), while the decay rate and organic carbon breakdown rate decreased by 6.14 % and 7.48 %, respectively. When the relative water content in soil increased, the residual remnant weight and total carbon content first decreased and then increased, while the trend of the decay rate (16.94 % with 80 % soil water content) and organic carbon breakdown rate (9.96 % with 60 % soil water content) were opposite. At a high MD dosage (7 % or 9 % of the total compost weight), both rates of remnants were greater than those at the low dosage (1 %), with an increase of 38.63 % or 36.19 % and 15.89 % or 15.78 %, respectively. With an increase in soil temperature, both residual remnant weight and total carbon content decreased first and then increased, while both decomposition rate and organic carbon breakdown rate increased first and then decreased by 27.35 % and 22.78 %, respectively at 45 °C, compared with those at 30 °C. It was concluded that the decomposition rate was significantly correlated with the remnant length and the MD dosage, while the organic carbon breakdown rate was significantly associated with all four parameters evaluated. The optimal decomposing efficiency was achieved through cutting tomato remnants to a length of ∼0.5 cm, maintaining soil relative moisture content at 89 %, keeping soil temperature at 50 °C, and adding 7 % microbial decomposer MD to chopped tomato cuttings.

Pan-cancer transcriptional atlas of minimal residual disease links DUSP1 to chemotherapy persistence.

Chemotherapy is a commonly effective treatment for most types of cancer. However, many patients experience a relapse due to minimal residual disease (MRD) after chemotherapy. Previous studies have analyzed the changes induced by chemotherapy for specific types of cancer, but our study is the first to comprehensively analyze MRD across various types of cancer. We included both bulk and single-cell RNA sequencing datasets. We compared the expression of the entire genome and calculated scores for canonical pathway signatures and immune infiltrates before and after chemotherapy across different types of cancer. Our findings revealed that DUSP1 was the most significantly and widely enriched gene in pan-cancer MRD. DUSP1 was found to be essential for MRD formation and played a role in T cell-fibroblast communications and the cytotoxic function of CD4 + T cells. Overall, our analysis provides a comprehensive understanding of the changes caused by chemotherapy and identifies potential targets for preventing and eliminating MRD, which could lead to long-term survival benefits for patients.

Effect of the red uniform on the judgment of position or movement used in Wushu Routine, evaluated by practitioners of the modality.

In the artistic sports program, the referee' scores directly determine the final results of the athletes. Wushu is a artistic sport that has a Chinese characteristic and has the potential to become an official competition at the Summer Olympic. In this study we tested whether a red uniform color affects Wushu Routine practitioners' ratings of athletes' position or movement of Wushu Routine. We also tested whether the effect varied depending on the gender of the athlete and the practitioner, and depending on whether female practitioners were in the ovulation phase of their menstrual cycle. Male (Experiment 1: N = 72) and female (Experiment 1: N = 72; Experiment 2: N = 52) participants who major in Wushu Routine were recruited to take a referee's perspective and rate the movement quality of male and female athletes wearing red or blue uniforms. The results of Experiment 1 showed that both male and female athletes wearing red uniform (compared to blue uniform) received higher ratings (p = .002, η2 = .066; p = .014, η2 = .043), and the red effect was especially strong when male practitioners rated female athletes (p = .002, η2 = .069). The results of Experiment 2, in an all-female sample, showed that in most cases there was no difference in ratings made by women in the ovulation and non-ovulation phases of their menstrual cycle, with the exception of their ratings of male athletes wearing red; in this condition, women gave higher ratings when they were in the ovulation phase of their cycle (p = .026). The results suggest that there is a red effect in an artistic sport like Wushu Routine, in which gender and the female menstrual cycle play an important role.

Comparison of clinical features and outcomes between two age groups of cryptorchidism testicular torsion in children: a retrospective study in single center.

Objective: The purpose of this study was to compare the clinical characteristics and outcomes of children with cryptorchidism testicular torsion between the younger age group and the older age group. Methods: We collected the clinical data of children with cryptorchidism complicated with testicular torsion in our hospital from January 1, 2013 to January 1, 2023. The patients were divided into two groups: the younger age group (1month∼4 years old, n = 7) and the older age group (4∼18 years old, n = 7). The differences of clinical manifestations and surgical results between the two groups were compared. Results: A total of 14 patients with unilateral cryptorchidism testicular torsion were included in this study, including 9 on the left side and 5 on the right side. The main clinical manifestations were pain /swelling of groin. The rate of crying in the younger age group was significantly higher than those in the older age group [(5,71.4%) vs. (0,0.0%), P < 0.05]. The median duration of symptoms of the younger group was less than the older group [42(7,96) h vs. 70(24, 96) h, P > 0.05]. The ipsilateral testicular salvage rate in the younger age group was 14.3% (1/7), which was lower than the older age group 57.1% [(4/7), P > 0.05]. The degree of testicular torsion in younger age group was more severe than the older age group [720(360, 1,080)° vs. 360(270, 360)°, P > 0.05]. Conclusions: The overall salvage rate of cryptorchidism testicular torsion is low. Although the duration of symptoms in the older age group was longer, the salvage rate of the older age group seemed to be higher than that in the younger age group. In addition, physical and imaging examination of the reproductive system should be carried out in time to identify the children with cryptorchidism testicular torsion in the early stage.

Impact of coconut-fiber biochar on lead translocation, accumulation, and detoxification mechanisms in a soil-rice system under elevated lead stress.

Biochar, an environmentally friendly material, was found to passivate lead (Pb) in contaminated soil effectively. This study utilized spectroscopic investigations and partial least squares path modeling (PLS-PM) analysis to examine the impact of coconut-fiber biochar (CFB) on the translocation, accumulation, and detoxification mechanisms of Pb in soil-rice systems. The results demonstrated a significant decrease (p < 0.05) in bioavailable Pb concentration in paddy soils with CFB amendment, as well as reduced Pb concentrations in rice roots, shoots, and brown rice. Synchrotron-based micro X-ray fluorescence analyses revealed that CFB application inhibited the migration of Pb to the rhizospheric soil region, leading to reduced Pb uptake by rice roots. Additionally, the CFB treatment decreased Pb concentrations in the cellular protoplasm of both roots and shoots, and enhanced the activity of antioxidant enzymes in rice plants, improving their Pb stress tolerance. PLS-PM analyses quantified the effects of CFB on the accumulation and detoxification pathways of Pb in the soil-rice system. Understanding how biochar influences the immobilization and detoxification of Pb in soil-rice systems could provide valuable insights for strategically using biochar to address hazardous elements in complex agricultural settings.

Overexpression of miR-506-3p reversed doxorubicin resistance in drug-resistant osteosarcoma cells.

Background and objective: Osteosarcoma is a common primary malignant tumor of bone, and doxorubicin is one of the most widely used therapeutic drugs. While the problem of doxorubicin resistance limits the long-term treatment benefits in osteosarcoma patients. The role of miRNAs and their target genes in osteosarcoma have become increasingly prominent. Currently, there is no report on miR-506-3p reversing doxorubicin resistance by targeting STAT3 in osteosarcoma. The purpose of this study was to investigate the molecular mechanism that overexpression of miR-506-3p reverses doxorubicin resistance in drug-resistant osteosarcoma cells. Methods: Doxorubicin-resistant osteosarcoma cells (U-2OS/Dox) were constructed by intermittent stepwise increasing stoichiometry. The target genes of miR-506-3p were predicted by bioinformatics approach and the targeting relationship between miR-506-3p and STAT3 was detected using dual luciferase reporter assay. U-2OS/Dox cells were treated with miR-506-3p overexpression and STAT3 silencing respectively. Then Western blot and RT-qPCR were used to detect the protein and mRNA expression levels of JAK2/STAT3 signaling pathway, drug-resistant and apoptotic associated molecules. The migration and invasion were assessed by cell scratch assay and transwell assay. The cell proliferative viability and apoptosis were investigated by CCK8 assay and flow cytometry assay. Results: U-2OS/Dox cells were successfully constructed with a 14.4-fold resistance. MiR-506-3p is directly bound to the 3'-UTR of STAT3 mRNA. Compared with U-2OS cells, the mRNA expression of miR-506-3p was reduced in U-2OS/Dox cells. Overexpression of miR-506-3p decreased the mRNA expression levels of JAK2, STAT3, MDR1/ABCB1, MRP1/ABCC1, Survivin and Bcl-2, and decreased the protein expression levels of p-JAK2, STAT3, MDR1/ABCB1, MRP1/ABCC1, Survivin and Bcl-2, and conversely increased Bax expression. It also inhibited the proliferation, migration and invasion of U-2OS/Dox cells and promoted cells apoptosis. The results of STAT3 silencing experiments in the above indicators were consistent with that of miR-506-3p overexpression. Conclusion: Overexpression of miR-506-3p could inhibit the JAK2/STAT3 pathway and the malignant biological behaviors, then further reverse doxorubicin resistance in drug-resistant osteosarcoma cells. The study reported a new molecular mechanism for reversing the resistance of osteosarcoma to doxorubicin chemotherapy and provided theoretical support for solving the clinical problems of doxorubicin resistance in osteosarcoma.

Probing Hyperbolic Shear Polaritons in ß-Ga2O3 Nanostructures Using STEM-EELS.

Phonon polaritons, quasiparticles arising from strong coupling between electromagnetic waves and optical phonons, have potential for applications in subdiffraction imaging, sensing, thermal conduction enhancement, and spectroscopy signal enhancement. A new class of phonon polaritons in low-symmetry monoclinic crystals, hyperbolic shear polaritons (HShPs), have been verified recently in ß-Ga2O3 by free electron laser (FEL) measurements. However, detailed behaviors of HShPs in ß-Ga2O3 nanostructures still remain unknown. Here, by using monochromatic electron energy loss spectroscopy in conjunction with scanning transmission electron microscopy, the experimental observation of multiple HShPs in ß-Ga2O3 in the mid-infrared (MIR) and far-infrared (FIR) ranges is reported. HShPs in various ß-Ga2O3 nanorods and a ß-Ga2O3 nanodisk are excited. The frequency-dependent rotation and shear effect of HShPs reflect on the distribution of EELS signals. The propagation and reflection of HShPs in nanostructures are clarified by simulations of electric field distribution. These findings suggest that, with its tunable broad spectral HShPs, ß-Ga2O3 is an excellent candidate for nanophotonic applications.

Pyrotinib Combined with Vinorelbine in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Single-Arm, Prospective Study.

PURPOSE: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. MATERIALS AND METHODS: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. RESULTS: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). CONCLUSION: Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.

An ultrasensitive and selective near-infrared fluorescent probe for tracking carboxylesterases with large Stokes shift in living cells and mice.

Carboxylesterases (CEs) play great role in CEs-related diseases and drug metabolism. Selectively monitoring its activity is important to explore its role in CEs-related diseases and drug combination. Herein, a new "turn-on" near-infrared (NIR) fluorescent probe (CHY-1) was reported with large Stokes shift (145 nm) for CEs detection. Dicyanoisophorone-based derivative was chosen as NIR fluorophore and 4-bromobutyrate was the identifying group. What's more, CHY-1 exhibited ultra-sensitivity (LOD âˆ¼ 9.2 × 10-5 U/mL), high selectivity against Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE) and Chymotrypsin for CEs fluorescence detection under physiological pH and temperature. Furthermore, CHY-1 showed little effect on cell viability at high concentration and featured good optical imaging character for the slight change of CEs activity induced by 5-Fu (5-Fluorouridine, anti-tumor drug) and CEs inhibitor in living cells. Moreover, CHY-1 was also used to detect the activity and distribution of CEs in mice. Taken together, CHY-1 had widely applicable value in the diagnosis of CEs-related diseases and drug combination.

Nomogram for the prediction of tigecycline-induced hypofibrinogenaemia in a Chinese population.

BACKGROUND: Tigecycline has been widely used for multi-drug-resistant bacterial infections in China. Although many studies have reported the risk factors for tigecycline-induced hypofibrinogenaemia, it remains unknown whether valproic acid or voriconazole in combination with tigecycline is associated with the decrease in fibrinogen, as both drugs could lead to coagulation disorders. The aim of this study was to develop a nomogram for the prediction of tigecycline-induced hypofibrinogenaemia. METHODS: This was a multi-centre retrospective case-control study. The primary outcome was the accurate prediction of tigecycline-induced hypofibrinogenaemia. Nomograms were developed from logistic regression models with least absolute shrinkage and selection operator regression for variable selection. Model performance was assessed via calibration plots, and models were validated internally using bootstrapping on a validation cohort. RESULTS: In total, 2362 patients were screened, of which 611 were eligible for inclusion in this study. These 611 patients were divided into the training cohort (n=488) and the validation cohort (n=123). Predictors included in the nomogram for the total population were total dose, age, fibrinogen, prothrombin time (PT), comorbidity, and concomitant use of voriconazole. Total dose, fibrinogen, PT, activated partial thromboplastin time, white blood cell count, and concomitant use of voriconazole were selected to predict hypofibrinogenaemia in patients with malignant haematologic diseases. Both models were calibrated adequately, and their predictions were correlated with the observed outcome. The cut-offs for treatment duration in the total population and the subgroup were 10 and 6 days, respectively. CONCLUSIONS: Tigecycline in combination with voriconazole could increase the risk of hypofibrinogenaemia, and tigecycline-induced hypofibrinogenaemia is more likely to occur in patients with malignant haematologic diseases.

[Effect of Coconut Fiber Biochar and Its Nitrate Modification on Pb Passivation in Paddy Soils].

The effects of coconut fiber biochar (CFB) and nitrate-modified coconut fiber biochar (NCFB) on the passivation of exogenous lead (Pb) in paddy soils and their underlying mechanisms were investigated using soil incubation experiments combined with spectroscopic techniques such as scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), synchrotron radiation X-ray fluorescence (SRXRF), and Fourier transform infrared absorption spectroscopy (FTIR). The effects of NCFB and CFB on the passivation of exogenous lead (Pb) in paddy soils and its underlying mechanisms were investigated. Compared with that of CFB, the inner wall of NCFB honeycomb pores was rougher, and the amount of alcohol-phenol-ether functional groups containing the C-O structure and the amount of carboxyl groups containing the C[FY=,1]O/O[FY=,1]C-O structure on the surface of CFB was significantly decreased after nitric acid modification. Compared with that in the control (without biochar) paddy soil after 150 d of incubation, the EDTA-extracted Pb content in the paddy soil with CFB and NCFB was reduced by 39.7% and 105.4%, respectively. The carbonate-bound and Fe-Mn oxide-bound Pb contents were significantly lower, and the organic-bound and residue Pb contents were significantly higher in the NCFB-added soil. The SRXRF scans showed that the exogenous Pb was enriched in the microregions of CFB particles rich in Ca and Cu elements and relatively less so in the microregions of soil aggregates rich in the Fe, Mn, and Ti elements. In addition, the characteristic peaks of carboxylates (1384 cm-1) in A-CFBPb and A-NCFBPb were significantly enhanced in the incubation experiment in the presence of exogenous Pb compared to A-CFB and A-NCFB in the absence of exogenous Pb. The addition of CFB or NCFB was more effective in passivating exogenous Pb in paddy soils and promoted the gradual transformation of Pb from unstable to more stable forms in paddy soils to achieve the effect of passivating Pb. The greater amount of carboxyl functional groups in NCFB participated in the passivation of exogenous Pb, which made NCFB more effective than CFB in passivating Pb. NCFB was more effective than CFB in passivating exogenous Pb in paddy soils due to its rougher inner walls of honeycomb pores and abundant carboxyl functional groups. In tropical areas such as Hainan, coconut fiber biochar and its modification can be considered as an environmentally friendly candidate method for the remediation of soil Pb contamination.

In vivo anti-hepatitis B activity of Artemisia argyi essential oil-loaded nanostructured lipid carriers. Study of its mechanism of action by network pharmacology and molecular docking.

BACKGROUND: Hepatitis B virus (HBV) infection remains a major global health burden, due to the increasing risk of complications, such as cirrhosis and hepatocellular carcinoma. Novel anti-HBV agents are critical required. Our previous study suggested that Artemisia argyi essential oil (AAEO) significantly inhibited the replication of HBV DNA and especially the secretion of hepatitis B antigen in vitro. PURPOSE: The aim of this study was to prepare AAEO loaded nanostructured lipid carriers (AAEO-NLCs) for the delivery of AAEO to the liver, investigated the therapeutic benefits of AAEO-NLCs against HBV in a duck HBV (DHBV) model and explored its potential mechanism. STUDY DESIGN AND METHODS: AAEO-NLCs were prepared by hot homogenization and ultrasonication method. The DHBV-infected ducks were treated with AAEO (4 mg/kg), AAEO-NLCs (0.8, 4, and 20 mg/kg of AAEO), and lamivudine (20 mg/kg) for 15 days. The DHBV DNA levels in the serum and liver were measured by quantitative Real-Time PCR. Pharmacokinetics and liver distribution were performed in rats after oral administration of AAEO-NLCs and AAEO suspension. The potential antiviral mechanism and active compounds of AAEO were investigated by network pharmacology and molecular docking. RESULTS: AAEO-NLCs markedly inhibited the replication of DHBV DNA in a dose-dependent manner and displayed a low virologic rebound following withdrawal the treatment in DHBV-infected ducks. Moreover, AAEO-NLCs led to a more pronounced reduction in viral DNA levels than AAEO suspension. Further investigations of pharmacokinetics and liver distribution in rats confirmed that NLCs improved the oral bioavailability and increased the liver exposure of AAEO. The potential mechanisms of AAEO against HBV explored by network pharmacology were associated with signaling pathways related to immune response, such as tumor necrosis factor, nuclear factor kappa B, and sphingolipid signaling pathways. Furthermore, a total of 16 potential targets were obtained, including prostaglandin-endoperoxide synthase-2 (PTGS2), caspase-3, progesterone receptor, etc. Compound-target docking results confirmed that four active compounds of AAEO had strong binding interactions with the active sites of PTGS2. CONCLUSIONS: AAEO-NLCs displayed potent anti-HBV activity with improved oral bioavailability and liver exposure of AAEO. Thus, it may be a potential therapeutic strategy for the treatment of HBV infection.

Integrated omics analysis reveals the epigenetic mechanism of visceral hypersensitivity in IBS-D.

Background and objective: IBS-D is a common functional bowel disease with complex etiology and without biomarker. The pathological and physiological basis of IBS-D focuses on visceral hypersensitivity. However, its epigenetic mechanism remains elusive. Our study aimed to integrate the relationship between differentially expressed miRNAs, mRNAs and proteins in IBS-D patients in order to reveal epigenetic mechanism of visceral hypersensitivity from transcription and protein levels and provide the molecular basis for discovering biomarkers of IBS-D. Methods: The intestinal biopsies from IBS-D patients and healthy volunteers were obtained for high-throughput sequencing of miRNAs and mRNAs. The differential miRNAs were selected and verified by q-PCR experiment followed by target mRNA prediction. Biological functions were respectively analyzed for target mRNAs, differential mRNAs and the previously identified differential proteins in order to explore the characteristic involved visceral hypersensitivity. At last, interaction analysis of miRNAs, mRNAs and proteins was performed for the epigenetic regulation mechanism from transcription and protein levels. Results: Thirty-three miRNAs were found to be differentially expressed in IBS-D and five of them were further confirmed, including upregulated hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p and downregulated hsa-miR-219a-5p, hsa-miR-19b-1-5p. In addition, 3,812 differential mRNAs were identified. Thirty intersecting molecules were found from the analysis on the target mRNAs of miRNAs and mRNAs. Fourteen intersecting molecules were obtained from the analysis on the target mRNAs and proteins, and thirty-six intersecting molecules were identified from analysis on the proteins and different mRNAs. According to the integrated analysis of miRNA-mRNA-protein, we noticed two new molecules COPS2 regulated by hsa-miR-19b-1-5p and MARCKS regulated by hsa-miR-641. Meanwhile some critical signaling pathways in IBS-D were found such as MAPK, GABAergic synapse, Glutamatergic synapse, and Adherens junction. Conclusion: The expressions of hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p, hsa-miR-219a-5p, and hsa-miR-19b-1-5p in the intestinal tissues of IBS-D patients were significantly different. Moreover, they could regulate a variety of molecules and signaling pathways, which were involved in the multifaceted and multilevel mechanism of visceral hypersensitivity of IBS-D.

The pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma.

BACKGROUND: Emerging evidences suggest that ARHGEF6 is involved in cancers but the exact significance and underlying mechanism are unclear. This study aimed to elucidate the pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma (LUAD). METHODS: Bioinformatics and experimental methods were used to analyze the expression, the clinical significance, the cellular function and potential mechanisms of ARHGEF6 in LUAD. RESULTS: ARHGEF6 was downregulated in LUAD tumor tissues and correlated negatively with poor prognosis and tumor stemness, positively with the Stromal score, the Immune score and the ESTIMATE score. The expression level of ARHGEF6 was also associated with drug sensitivity, the abundance of immune cells, the expression levels of Immune checkpoint genes and immunotherapy response. Mast cells, T cells and NK cells were the first three cells with the highest expression of ARHGEF6 in LUAD tissues. Overexpression of ARHGEF6 reduced proliferation and migration of LUAD cells and the growth of xenografted tumors, which could be reversed by re-knockdown of ARHGEF6. Results of RNA sequencing revealed that ARHGEF6 overexpression induced significant changes in the expression profile of LUAD cells, and genes encoding uridine 5'-diphosphate-glucuronic acid transferases (UGTs) and extracellular matrix (ECM) components were downregulated. CONCLUSIONS: ARHGEF6 functions as a tumor suppressor in LUAD and may serve as a new prognostic marker and potential therapeutic target. Regulating tumor microenvironment and immunity, inhibiting the expression of UGTs and ECM components in the cancer cells, and decreasing the stemness of the tumors may among the mechanisms underlying the function of ARHGEF6 in LUAD.