Recombinant hirudin and PAR-1 regulate macrophage polarisation status in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a malignant tumour. Although some standard therapies have been established to improve the cure rate, they remain ineffective for specific individuals. Therefore, it is meaningful to find more novel therapeutic approaches. Macrophage polarisation is extensively involved in the process of tumour development. Recombinant hirudin (rH) affects macrophages and has been researched frequently in clinical trials lately. Our article validated the regulatory role of rH in macrophage polarisation and the mechanism of PAR-1 by collecting clinical samples and subsequently establishing a cellular model to provide a scientifically supported perspective for discovering new therapeutic approaches. METHOD: We assessed the expression of macrophage polarisation markers, cytokines and PAR-1 in clinical samples. We established a cell model by co-culture with THP-1 and OCI-Ly10 cell. We determined the degree of cell polarisation and expression of validation cytokines by flow cytometry, ELISA, and RT-qPCR to confirm the success of the cell model. Subsequently, different doses of rH were added to discover the function of rH on cell polarisation. We confirmed the mechanism of PAR-1 in macrophage polarisation by transfecting si-PAR-1 and pcDNA3.1-PAR-1. RESULTS: We found higher expression of M2 macrophage markers (CD163 + CMAF+) and PAR-1 in 32 DLBCL samples. After inducing monocyte differentiation into M0 macrophages and co-culturing with OCI-Ly10 lymphoma cells, we found a trend of these expressions in the cell model consistent with the clinical samples. Subsequently, we discovered that rH promotes the polarisation of M1 macrophages but inhibits the polarisation of M2 macrophages. We also found that PAR-1 regulates macrophage polarisation, inhibiting cell proliferation, migration, invasion and angiogenic capacity. CONCLUSION: rH inhibits macrophage polarisation towards the M2 type and PAR-1 regulates polarisation, proliferation, migration, invasion, and angiogenesis of DLBCL-associated macrophages.

Humic acid-mediated mechanism for efficient biodissolution of used lithium batteries.

Resource recovery of valuable metals from spent lithium batteries is an inevitable trend for sustainable development. In this study, external regulation was used to enhance the tolerance and stability of strains in the leaching of spent lithium batteries to radically improve the bioleaching efficiency. The leaching of Li, Ni, Co and Mn increased to 100 %, 85.06 %, 74.25 % and 69.44 % respectively after targeted cultivation with HA as compared to the undomesticated strain. In the process of microbial leaching of spent lithium batteries, the metabolites in the Ⅰ, Ⅳ, and Ⅴ regions of the metabolism of the undomesticated bacterial colony had a positive correlation to the dissolution of spent lithium batteries. The metabolites of Ⅰ, Ⅱ, and Ⅴ regions were directly affected by the HA domesticated flora on the dissolution of spent lithium batteries. The excess metabolism of protein substances can significantly promote the reduction of Ni, Co, Mn leaching, and at the same time in the role of a large number of humic substances complexed the toxic metal ions in the system, to ensure the activity of the bacterial colony. It can be seen that the bacteria were domesticated by humic acid, which promoted the bacteria's own metabolism, and the super-metabolised EPS promoted the solubilisation of spent lithium batteries.

[Determination of the derivatization reactivity between α/ß-dicarbonyl compounds and standard citrullinated peptides based on matrix-assisted laser desorption ionization-time-of-flight mass spectrometry].

Protein citrullination is an irreversible post-translational modification process regulated by peptidylarginine deiminases (PADs) in the presence of Ca2+. This process is closely related to the occurrence and development of autoimmune diseases, cancers, neurological disorders, cardiovascular and cerebrovascular diseases, and other major diseases. The analysis of protein citrullination by biomass spectrometry confronts great challenges owing to its low abundance, lack of affinity tags, small mass-to-charge ratio change, and susceptibility to isotopic and deamidation interferences. The methods commonly used to study the protein citrullination mainly involve the chemical derivatization of the urea group of the guanine side chain of the peptide to increase the mass-to-charge ratio difference of the citrullinated peptide. Affinity-enriched labels are then introduced to effectively improve the sensitivity and accuracy of protein citrullination by mass spectrometry. 2,3-Butanedione or phenylglyoxal compounds are often used as derivatization reagents to increase the mass-to-charge ratio difference of the citrullinated peptide, and the resulting derivatives have been observed to contain α-dicarbonyl structures. To date, however, no relevant studies on the reactivity of dicarbonyl compounds with citrullinated peptides have been reported. In this study, we determined whether six α-dicarbonyl and two ß-dicarbonyl compounds undergo derivatization reactions with standard citrullinated peptides using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Among the α-dicarbonyl compounds, 2,3-butanedione and glyoxal reacted efficiently with several standard citrullinated peptides, but yielded a series of by-products. Phenylglyoxal, methylglyoxal, 1,2-cyclohexanedione, and 1,10-phenanthroline-5,6-dione also derivated efficiently with standard citrullinated peptides, generating a single derivative. Thus, a new derivatization method that could yield a single derivative was identified. Among the ß-dicarbonyl compounds, 1,3-cyclohexanedione and 2,4-pentanedione successfully reacted with the standard citrullinated peptides, and generated a single derivative. However, their reaction efficiency was very low, indicating that the ß-dicarbonyl compounds are unsuitable for the chemical derivatization of citrullinated peptides. The above results indicate that the α-dicarbonyl structure is necessary for realizing the efficient and specific chemical derivatization of citrullinated peptides. Moreover, the side chains of the α-dicarbonyl structure determine the structure of the derivatives, derivatization efficiency, and generation (or otherwise) of by-products. Therefore, the specific enrichment and precise identification of citrullinated peptides can be achieved by synthesizing α-dicarbonyl structured compounds containing affinity tags. The proposed method enables the identification of citrullinated proteins and their modified sites by MS, thereby providing a better understanding of the distribution of citrullinated proteins in different tissues. The findings will be beneficial for studies on the mechanism of action of citrullinated proteins in a variety of diseases.

Hepatic Oxidative Stress and Cell Death Influenced by Dietary Lipid Levels in a Fresh Teleost.

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation, affecting physiological and pathological processes. Fatty liver disease associated with metabolic dysfunction is a common pathological condition in aquaculture. However, the exact role and mechanism of ferroptosis in its pathogenesis and progression remains unclear. In this study, an experiment was conducted using different dietary lipid levels in the feeding of largemouth bass (Micropterus salmoides) for 11 weeks. The results revealed that the growth performance and whole-body protein content significantly increased with the elevation of dietary lipid levels up to 12%. The activities of antioxidant enzymes as well as the content of GSH (glutathione) in the liver initially increased but later declined as the lipid levels increased; the contents of MDA (malondialdehyde) and GSSG (oxidized glutathione) demonstrated an opposite trend. Moreover, elevating lipid levels in the diet significantly increased liver Fe2+ content, as well as the expressions of TF (Transferrin), TFR (Transferrin receptor), ACSL4 (acyl-CoA synthetase long-chain family member 4), LPCAT3 (lysophosphatidylcholine acyltransferase 3), and LOX12 (Lipoxygenase-12), while decreasing the expressions of GPX4 (glutathione peroxidase 4) and SLC7A11 (Solute carrier family 7 member 11). In conclusion, the optimal lipid level is 12.2%, determined by WG-based linear regression. Excess lipid-level diets can up-regulate the ACSL4/LPCAT3/LOX12 axis, induce hepatic oxidative stress and cell death through a ferroptotic-like program, and decrease growth performance.

Genome-Wide Identification and Bioinformatics Analysis of the FK506 Binding Protein Family in Rice.

The FK506 Binding Protein (FKBP), ubiquitously present across diverse species, is characterized by its evolutionarily conserved FK506 binding domain (FKBd). In plants, evidence suggests that this gene family plays integral roles in regulating growth, development, and responses to environmental stresses. Notably, research on the identification and functionality of FKBP genes in rice remains limited. Therefore, this study utilized bioinformatic tools to identify 30 FKBP-encoding genes in rice. It provides a detailed analysis of their chromosomal locations, evolutionary relationships with the Arabidopsis thaliana FKBP family, and gene structures. Further analysis of the promoter elements of these rice FKBP genes revealed a high presence of stress-responsive elements. Quantitative PCR assays under drought and heat stress conditions demonstrated that genes OsFKBP15-2, OsFKBP15-3, OsFKBP16-3, OsFKBP18, and OsFKBP42b are inducible by these adverse conditions. These findings suggest a significant role for the rice FKBP gene family in stress adaptation. This research establishes a critical foundation for deeper explorations of the functional roles of the OsFKBP genes in rice.

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

Melatonin-Induced Chromium Tolerance Requires Hydrogen Sulfide Signaling in Maize.

Both melatonin and hydrogen sulfide (H2S) mitigate chromium (Cr) toxicity in plants, but the specific interaction between melatonin and H2S in Cr detoxification remains unclear. In this study, the interaction between melatonin and H2S in Cr detoxification was elucidated by measuring cell wall polysaccharide metabolism and antioxidant enzyme activity in maize. The findings revealed that exposure to Cr stress (100 µM K2Cr2O7) resulted in the upregulation of L-/D-cysteine desulfhydrase (LCD/DCD) gene expression, leading to a 77.8% and 27.3% increase in endogenous H2S levels in maize leaves and roots, respectively. Similarly, the endogenous melatonin system is activated in response to Cr stress. We found that melatonin had a significant impact on the relative expression of LCD/DCD, leading to a 103.3% and 116.7% increase in endogenous H2S levels in maize leaves and roots, respectively. In contrast, NaHS had minimal effects on the relative mRNA expression of serotonin-Nacetyltransferase (SNAT) and endogenous melatonin levels. The production of H2S induced by melatonin is accompanied by an increase in Cr tolerance, as evidenced by elevated gene expression, elevated cell wall polysaccharide content, increased pectin methylesterase activity, and improved antioxidant enzyme activity. The scavenging of H2S decreases the melatonin-induced Cr tolerance, while the inhibitor of melatonin synthesis, p-chlorophenylalanine (p-CPA), has minimal impact on H2S-induced Cr tolerance. In conclusion, our findings suggest that H2S serves as a downstream signaling molecule involved in melatonin-induced Cr tolerance in maize.

Timing of immunotherapeutic strategies for first-episode Isolated Anti-Myelin Oligodendrocyte Glycoprotein-IgG Associated Optic Neuritis: A single-centre retrospective study.

Background: There is no consensus on the timing of immunotherapeutic strategies for the first-episode anti-myelin oligodendrocyte glycoprotein-IgG (MOG-IgG) associated disorders (MOGAD) presenting with isolated optic neuritis (ON). Objective: To investigate the optimal timing of intravenous methylprednisolone therapy (IVMP) and necessity of immunosuppressive therapy for the first-episode isolated MOG-IgG associated ON (iMOG-ON). Methods: Adult patients with the first-episode iMOG-ON were enrolled. Primary outcomes were best-corrected visual acuity (BCVA) at last follow-up (i.e. final BCVA) and relapse, and their predictors were assessed by multivariate analysis. Results: 62 patients were included. Logistic regression analysis revealed BCVA at the time of IVMP (odds ratio: 0.463 (95 % confidence interval (CI) 0.310-0.714) was a factor predictive of regaining a final BCVA of 0.0 logMAR vision, and its Youden optimal criterion was <0.175 logMAR by plotting the receiver operating characteristic curve. The time-dependent cox proportional hazards model exhibited MMF therapy was not associated with a high likelihood of relapse-free survival (HR = 1.099, 95 % CI 0.892-1.354, P = 0.376) after adjusting for age of onset, gender, and baseline MOG serum titers. Similar analysis exhibited evidently negative association between high MOG-IgG serum titers at baseline and relapse-free survival after adjusting for age of onset, gender, and MMF therapy (HR = 0.339, 95 % CI 0.155-0.741, P = 0.007). Conclusions: During the first episode of iMOG-ON, the optimal timing of IVMP may be a short timeframe before visual acuity decreasing to 0.175 logMAR, and MMF therapy may not be recommended for patients with low MOG-IgG serum titers. Further long-term follow-up studies are required to validate these findings.

Diversity of Colletotrichum species associated with anthracnose on Euonymus japonicus and their sensitivity to fungicides.

As an evergreen shrub, Euonymus japonicus plays a crucial role in urban landscape construction, and its growth is affected by severe foliar anthracnose caused by Colletotrichum spp. However, the biodiversity of Colletotrichum species associated with anthracnose on E. japonicus remains undetermined. This study involved a two-year collection of E. japonicus leaf samples with typical anthracnose symptoms from 9 districts in Beijing, China. A total of 194 Colletotrichum isolates were obtained, and eight Colletotrichum species were subsequently identified using morphological characteristics and molecular identification with the ACT, GADPH, CHS, TUB2, and CAL genes, as well as the rDNA-ITS region. These species included Colletotrichum aenigma, C. fructicola, C. gloeosporioides, C. grossum, C. hebeiense, C. karstii, C. siamense, and C. theobromicola with C. siamense being the most prevalent (57%), followed by C. aenigma and C. theobromicola. Furthermore, C. fructicola, C. grossum and C. hebeiense are reported for the first time as causal agents of anthracnose on E. japonicus worldwide, and C. karstii is newly reported to be associated with E. japonicus anthracnose in China. Pathogenicity tests revealed that all tested isolates exhibited pathogenicity in the presence of wounds, emphasizing the need to avoid artificial or mechanical wounds to prevent infection in E. japonicus management. The EC50 values of five fungicides, namely difenoconazole, flusilazole, tebuconazole, hexaconazole, and prochloraz, were found to be less than 10 mg/L, indicating their strong potential for application. Notably, the EC50 of prochloraz was less than 0.05 mg/L for C. theobromicola. These findings offer valuable insights for the management of anthracnose on E. japonicus.

Ecotoxicity of Cadmium along the Soil-Cotton Plant-Cotton Bollworm System: Biotransfer, Trophic Accumulation, Plant Growth, Induction of Insect Detoxification Enzymes, and Immunocompetence.

Cadmium (Cd) is a hazardous element that may jeopardize environmental safety and human health through biotransfer and trophic accumulation. Here, we tested Cd toxicity on cotton plants, cotton bollworms, and their responses. Results demonstrated that Cd accumulated in plant roots, aerial parts, insect larvae, pupae, and frass in a dose-dependent pattern. The ∼9.35 mg kg-1 of Cd in plant aerial parts, ∼3.68 in larvae, ∼6.43 in pupae, and high transfer coefficient (∼5.59) indicate significant mobility. The ∼19.61 mg kg-1 of Cd in larvae frass suggests an effective detoxification strategy, while BAFcotton (∼1.14) and BAFworm (∼0.54) indicated low bioaccumulation. Cadmium exposure resulted in compromised plant growth and yield as well as alterations in photosynthetic pigment contents, antioxidant enzyme activities, and certain life history traits of cotton bollworms. Furthermore, carboxylesterase activity and encapsulation rates of insect larvae decreased with increasing Cd concentrations, whereas acetylcholinesterase, phenol oxidase, glutathione S-transferase, and multifunctional oxidase exhibited hormesis responses.

Circulating GDF-15: a biomarker for metabolic dysregulation and aging in people living with HIV.

Despite effective control of HIV replication by antiretroviral therapy (ART), a significant number of people living with HIV (PLWH) fail to achieve complete immune reconstitution and thus are deemed immune non-responders (INRs). Compared with immune responders (IRs) who have restored their CD4 T cell numbers and functions, CD4 T cells from these INRs exhibit prominent mitochondrial dysfunction and premature aging, which play a major role in increasing the incidence of non-AIDS, non-communicable diseases (NCDs). To date, there are no reliable biomarkers that can be used to typify and manage PLWH, especially INRs with non-AIDS NCDs. Growth differential factor-15 (GDF-15) is a transforming growth factor-ß (TGF-ß) family member known to regulate several biological processes involved in cell aging and stress responses. Since PLWH exhibit premature aging and metabolic dysregulation, here we measured the plasma levels of GDF-15 by ELISA and metabolic proteins by proteomic array and correlated the results with clinical parameters in ART-controlled PLWH (including INRs and IRs) and healthy subjects (HS). We found that GDF-15 levels were significantly elevated in PLWH compared to HS. GDF-15 levels were positively correlated with age and negatively associated with body mass and LDL cholesterol levels in the study subjects. Also, elevated GDF-15 levels were correlated with differential dysregulation of multiple metabolic proteins in PLWH. These results suggest that GDF-15 protein may serve as a biomarker of metabolic dysregulation and aging, and this biomarker will be useful in clinical trials targeting aging and metabolic disorders in ART-treated PLWH.

Single-cell transcriptome atlas of testes from mice with high-fat diets.

Obesity is accompanied by multiple known health risks and increased morbidity, and obese men display reduced reproductive health. However, the impact of obesity on the testes at the molecular levels remain inadequately explored. This is partially attributed to the lack of monitoring tools for tracking alterations within cell clusters in testes associated with obesity. Here, we utilized single-cell RNA sequencing to analyze over 70,000 cells from testes of obese and lean mice, and to study changes related to obesity in non-spermatogenic cells and spermatogenesis. The Testicular Library encompasses all non-spermatogenic cells and spermatogenic cells spanning from spermatogonia to spermatozoa, which will significantly aid in characterizing alterations in cellular niches and the testicular microenvironment during high-fat diet (HFD)-induced obesity. This comprehensive dataset is indispensable for studying how HFD disrupts cell-cell communication networks within the testis and impacts alterations in the testicular microenvironment that regulate spermatogenesis. Being the inaugural dataset of single-cell RNA-seq in the testes of diet-induced obese (DIO) mice, this holds the potential to offer innovative insights and directions in the realm of single-cell transcriptomics concerning male reproductive injury associated with HFD.

Comparison of the therapeutic effects of photodynamic therapy, transpupillary thermotherapy, and their combination on circumscribed choroidal haemangioma.

OBJECTIVE: To characterize the clinical and imaging features of circumscribed choroidal hemangioma (CCH), and to evaluate individualized treatment efficiency of photodynamic therapy (PDT), transpupillary thermotherapy (TTT), or their combination, followed by retrobulbar injection of betamethasone on CCH resolvement. METHODS: Forty-nine patients with CCHs who underwent PDT, TTT or PDT+TTT treatments were retrospectively analyzed. Their treatment efficacy was compared by analyzing the change of best corrected visual acuity (BCVA), subretinal fluid (SRF) and CCH lesion characteristics. RESULTS: PDT, TTT and PDT+TTT were respectively administrated in 17, 11 and 21 patients. No significant difference in age, gender, affected eyes and tumor location across the three groups. Baseline BCVA were 0.41 ± 0.28, 0.62 ± 0.30 and 0.24 ± 0.24 for PDT, TTT and PDT+TTT groups, respectively (F = 6.572, P = 0.003). CCH treated by three strategies showed significant difference in maximum tumor basal diameter, SRF areas and macula involvement prior to the treatment (P < 0.05). Patients receiving PDT+TTT exhibited larger tumor basal diameter, more SRF, higher ratio of macular involvement than other groups. A total of 38 (77.6 %) cases had good visual acidity with final BCVA ≥0.5 after treatments. PDT and PDT+TTT treatment groups acquired more vision improvement (0.27 ± 0.23 and 0.31 ± 0.26) in BCVA than TTT group (0.09 ± 0.13). All SRF were resolved within two weeks of treatment and no recurrent SRF were found. CONCLUSION: The three treatments showed good performance in improving visual function and controlling SRF, and individualized treatment should be selected primarily by the tumor location, and then the tumor size and presence of SRF.

Various functions of detoxification enzymes against insecticides in Nilaparvata lugens selected by toxicity assays and RNAi methods.

The brown planthopper (BPH), Nilaparvata lugens is a devastating agricultural pest of rice, and they have developed resistance to many pesticides. In this study, we assessed the response of BPH nymphs to nitenpyram, imidacloprid, and etofenprox using contact and dietary bioassays, and investigated the underlying functional diversities of BPH glutathione-S-transferase (GST), carboxylesterase (CarE) and cytochrome P450 monooxygenase (P450) against these insecticides. Both contact and ingestion toxicity of nitenpyram to BPH were significantly higher than either imidacloprid or etofenprox. Under the LC50 concentration of each insecticide, they triggered a distinct response for GST, CarE, and P450 activities, and each insecticide induced at least one detoxification enzyme activity. These insecticides almost inhibited the expression of all tested GST, CarE, and P450 genes in contact bioassays but induced the transcriptional levels of these genes in dietary bioassays. Silencing of NlGSTD2 expression had the greatest effect on BPH sensitivity to nitenpyram in contact test and imidacloprid in dietary test. The sensitivities of BPH to insecticide increased the most in the contact test was etofenprox after silencing of NlCE, while the dietary test was nitenpyram. Knockdown of NlCYP408A1 resulted in BPH sensitivities to insecticide increasing the most in the contact test was nitenpyram, while the dietary test was imidacloprid. Taken together, these findings reveal that NlGSTD2, NlCE, and NlCYP408A1 play an indispensable role in the detoxification of the contact and ingestion toxicities of different types of insecticides to BPH, which is of great significance for the development of new strategies for the sucking pest control.

Comparison of sea buckthorn fruit oil nanoemulsions stabilized by protein-polysaccharide conjugates prepared using ß-glucan from various sources.

To understand the influence of ß-glucans structure on the emulsifying properties of protein-polysaccharide conjugates, sodium caseinate (NaCas) was utilized to form glycosylation conjugates with varying degrees of glycosylation (10.68-17.50%) using three ß-glucans from bacteria, yeast, and oats. This process induced alterations in the secondary structure of protein. The nanoemulsions prepared with the glycosylated conjugates exhibited superior stability compared to those formulated solely with NaCas, particularly under conditions of drastic pH fluctuations and extended storage periods. The nanoemulsion prepared with the NaCas-Salecan conjugate demonstrated exceptional stability at pH 4 and 6, or storage for 20 days. Additionally, it significantly attenuated the oxidation of unsaturated fatty acids and exhibited the lowest levels of aggregation, flocculation, and free fatty acid release rate during in vitro digestion. This study suggested the potential of the NaCas-Salecan conjugates in enhancing the stability of nanoemulsions and facilitating the colorectal-targeted delivery of sea buckthorn fruit oil.

[Role of COX-2/PGE2/EP4 Axis-induced Macrophage Functional Activation 
in NSCLC Development].

BACKGROUND: Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. RESULTS: EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. CONCLUSIONS: During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC.

Titanium dioxide nanoparticles alleviates polystyrene nanoplastics induced growth inhibition by modulating carbon and nitrogen metabolism via melatonin signaling in maize.

BACKGROUND: Nanoplastics, are emerging pollutants, present a potential hazard to food security and human health. Titanium dioxide nanoparticles (Nano-TiO2), serving as nano-fertilizer in agriculture, may be important in alleviating polystyrene nanoplastics (PSNPs) toxicity. RESULTS: Here, we performed transcriptomic, metabolomic and physiological analyzes to identify the role of Nano-TiO2 in regulating the metabolic processes in PSNPs-stressed maize seedlings (Zea mays L.). The growth inhibition by PSNPs stress was partially relieved by Nano-TiO2. Furthermore, when considering the outcomes obtained from RNA-seq, enzyme activity, and metabolite content analyses, it becomes evident that Nano-TiO2 significantly enhance carbon and nitrogen metabolism levels in plants. In comparison to plants that were not subjected to Nano-TiO2, plants exposed to Nano-TiO2 exhibited enhanced capabilities in maintaining higher rates of photosynthesis, sucrose synthesis, nitrogen assimilation, and protein synthesis under stressful conditions. Meanwhile, Nano-TiO2 alleviated the oxidative damage by modulating the antioxidant systems. Interestingly, we also found that Nano-TiO2 significantly enhanced the endogenous melatonin levels in maize seedlings. P-chlorophenylalanine (p-CPA, a melatonin synthesis inhibitor) declined Nano-TiO2-induced PSNPs tolerance. CONCLUSIONS: Taken together, our data show that melatonin is involved in Nano-TiO2-induced growth promotion in maize through the regulation of carbon and nitrogen metabolism.

Advancements in artificial intelligence for pelvic floor ultrasound analysis.

Pelvic floor ultrasound provides a clear depiction of pelvic floor structures and their spatial anatomical relationships, enabling enhanced observation of pelvic organ function and position. The integration of artificial intelligence (AI) into medical imaging has revolutionized the automatic analysis of imaging data, offering efficient and accurate preprocessing and analysis. This technological advance addresses challenges associated with traditional pelvic floor ultrasound, such as reliance on operator's experience, time-intensive manual measurements, and significant potential for human error. Current AI applications in pelvic floor ultrasound encompass automatic measurement of the angle of progress (AOP), automatic segmentation of the levator hiatus (LH), and automatic identification of the levator ani muscle (LAM). AI excels in mimicking human analysis, distilling patterns from reorganized data. This paper, grounded in a comprehensive literature review, outlines the principal aspects of pelvic floor ultrasound and its augmentation through AI, highlighting the application value and progress of AI in this field.

A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy.

OBJECTIVE: The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors. METHODS: Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions. RESULTS: 1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05). CONCLUSION: Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020.

Machine learning-based characterization of the gut microbiome associated with the progression of primary biliary cholangitis to cirrhosis.

BACKGROUND: Primary biliary cholangitis (PBC) is associated closely with the gut microbiota. This study aimed to explore the characteristics of the gut microbiota after the progress of PBC to cirrhosis. METHOD: This study focuses on utilizing the 16S rRNA gene sequencing method to screen for differences in gut microbiota in PBC patients who progress to cirrhosis. Then, we divided the data into training and verification sets and used seven different machine learning (ML) models to validate them respectively, calculating and comparing the accuracy, F1 score, precision, and recall, and screening the dominant intestinal flora affecting PBC cirrhosis. RESULT: PBC cirrhosis patients showed decreased diversity and richness of gut microbiota. Additionally, there are alterations in the composition of gut microbiota in PBC cirrhosis patients. The abundance of Faecalibacterium and Gemmiger bacteria significantly decreases, while the abundance of Veillonella and Streptococcus significantly increases. Furthermore, machine learning methods identify Streptococcus and Gemmiger as the predominant gut microbiota in PBC patients with cirrhosis, serving as non-invasive biomarkers (AUC = 0.902). CONCLUSION: Our study revealed that PBC cirrhosis patients gut microbiota composition and function have significantly changed. Streptococcus and Gemmiger may become a non-invasive biomarker for predicting the progression of PBC progress to cirrhosis.