Contribution of FOS in neutrophils to venous thromboembolism via miR-144 based on bioinformatic prediction and validation.

The Finkel-Biskis-Jinkins Osteosarcoma (c-Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However, the relationship between FOS and venous thromboembolism (VTE) remains unknown. We identified differentially expressed genes in Gene Expression Omnibus dataset, GSE48000, comprising VTE patients and healthy individuals, and analysed them using CIBERSORT and weighted co-expression network analysis (WGCNA). FOS and CD46 expressions were significantly downregulated (FOS p = 2.26E-05, CD64 p = 8.83E-05) and strongly linked to neutrophil activity in VTE. We used GSE19151 and performed PCR to confirm that FOS and CD46 had diagnostic potential for VTE; however, only FOS showed differential expression by PCR and ELISA in whole blood samples. Moreover, we found that hsa-miR-144 which regulates FOS expression was significantly upregulated in VTE. Furthermore, FOS expression was significantly downregulated in neutrophils of VTE patients (p = 0.03). RNA sequencing performed on whole blood samples of VTE patients showed that FOS exerted its effects in VTE via the leptin-mediated adipokine signalling pathway. Our results suggest that FOS and related genes or proteins can outperform traditional clinical markers and may be used as diagnostic biomarkers for VTE.

Design, synthesis, and anti-inflammatory activity of indole-2-formamide benzimidazole[2,1-b]thiazole derivatives.

Molecular hybridization is a widely employed technique in medicinal chemistry for drug modification, aiming to enhance pharmacological activity and minimize side effects. The combination of an indole ring and imidazole[2,1-b]thiazole has shown promising potential as a group that exhibits potent anti-inflammatory effects. In this study, we designed and synthesized a series of derivatives comprising indole-2-formamide benzimidazole[2,1-b]thiazole to evaluate their impact on LPS-induced production of pro-inflammatory cytokines NO, IL-6, and TNF-α release, as well as iron death in RAW264.7 cells. The findings revealed that most compounds effectively inhibited LPS-induced production of pro-inflammatory cytokines NO, IL-6, and TNF-α release in RAW264.7 cells. Compound 13b exhibited the most potent anti-inflammatory activity among the tested compounds. The results of the cytotoxicity assay indicated that compound 13b was nontoxic. Additionally, compound 13b was found to elevate the levels of ROS, MDA, and Fe2+, while reducing GSH content, thereby facilitating the iron death process. Consequently, compound 13b showed promise for future development as an anti-inflammatory drug.

ANP alleviates motion sickness potentially through regulating endolymph volume in the inner ear increased by AVP.

INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aims to investigate the anti-motion sickness action and inner ear-related mechanisms of ANP. METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method. RESULTS: Both rotational stimulus and intraperitoneal AVP injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour, and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in-vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells. CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.

D-mannose alleviates intervertebral disc degeneration through glutamine metabolism.

BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored. METHODS: The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats. RESULTS: In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes. CONCLUSIONS: In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.

Clinical characteristics and antimicrobial susceptibility profiles of Mycobacterium abscessus and Mycobacterium massiliense pulmonary infection.

INTRODUCTION: Mycobacterium abscessus complex (MABC) is the most common rapidly growing Mycobacterium species in structural pulmonary diseases and can be life-threatening. This study aimed to assess the clinical characteristics and drug susceptibility statuses of different Mycobacterium abscessus (MAB) subspecies. METHODS: DNA sequencing was used to differentiate clinical MABC subspecies isolates. The Clinical and Laboratory Standards Institute guidelines were used to determine vitro susceptibility of imipenem-relebactam, omadacycline, and other conventional antibiotics. Patient's clinical characteristics were collected and analysed. RESULTS: There were 139 M. abscessus, 39 M. massiliense, and 1 M. bolletii, accounting for 77.7%, 21.8%, and 0.5% of the MABC isolates, respectively. Patients with M. abscessus pulmonary disease (M.ab-PD) had higher proportions of older adults, tuberculosis history, chronic pulmonary disease, and malignancy than those with M. massiliense pulmonary disease (M.ma-PD). Patients with M.ab-PD had higher rates of bilateral middle- and lower-lobe involvement than patients with M.ma-PD. Both subspecies showed high resistance rates to doxycycline and moxifloxacin, and clarithromycin-induced resistance was more common in M.ab than in M.ma. Relebactam with imipenem resulted in a 2-fold reduction in the minimum inhibitory concentration (MIC) value compared to imipenem alone among MAB; furthermore, the MIC was lower in M.ab than in M.ma. Omadacycline and tigecycline had comparable in vitro susceptibility, and the MIC showed no statistically significant difference between M.ab and M.ma. CONCLUSIONS: M.ab is the most prevalent MABC subspecies in the Zhejiang Province. Patients with M.ab-PD have complex underlying diseases and broader lobar lesions. Imipenem-relebactam and omadacycline are promising antibiotics for MABC infection treatment.

Molecular Mechanistic Insights into Dipeptidyl Peptidase-IV Inhibitory Peptides to Decipher the Structural Basis of Activity.

Dipeptidyl peptidase-IV (DPP-IV) inhibiting peptides have attracted increased attention because of their possible beneficial effects on glycemic homeostasis. However, the structural basis underpinning their activities has not been well understood. This study combined computational and in vitro investigations to explore the structural basis of DPP-IV inhibitory peptides. We first superimposed the Xaa-Pro-type peptide-like structures from several crystal structures of DPP-IV ligand-protein complexes to analyze the recognition interactions of DPP-IV to peptides. Thereafter, a small set of Xaa-Pro-type peptides was designed to explore the effect of key interactions on inhibitory activity. The intramolecular interaction of Xaa-Pro-type peptides at the first and third positions from the N-terminus was pivotal to their inhibitory activities. Residue interactions between DPP-IV and residues of the peptides at the fourth and fifth positions of the N-terminus contributed significantly to the inhibitory effect of Xaa-Pro-type tetrapeptides and pentapeptides. Based on the interaction descriptors, quantitative structure-activity relationship (QSAR) studies with the DPP-IV inhibitory peptides resulted in valid models with high R2 values (0.90 for tripeptides; 0.91 for tetrapeptides and pentapeptides) and Q2 values (0.33 for tripeptides; 0.68 for tetrapeptides and pentapeptides). Taken together, the structural information on DPP-IV and peptides in this study facilitated the development of novel DPP-IV inhibitory peptides.

Comparison of the Protective Effects of Casein Hydrolysate Containing Tyr-Pro-Val-Glu-Pro-Phe and Casein on the Behaviors and Peripheral and Brain Functions in Mice with Chronic-Stress-Induced Anxiety and Insomnia.

Chronic stress is a major inducer of anxiety and insomnia. Milk casein has been studied for its stress-relieving effects. We previously prepared a casein hydrolysate (CP) rich in the sleep-enhancing peptide YPVEPF, and this study aims to systemically investigate the different protective effects of CP and casein on dysfunction and anxiety/insomnia behavior and its underlying mechanisms in chronically stressed mice. Behavioral results showed that CP ameliorated stress-induced insomnia and anxiety more effectively than milk casein, and this difference in amelioration was highly correlated with an increase in GABA, 5-HT, GABAA, 5-HT1A receptors, and BDNF and a decrease in IL-6 and NMDA receptors in stressed mice. Furthermore, CP restored these dysfunctions in the brain and colon by activating the HPA response, modulating the ERK/CREB-BDNF-TrκB signaling pathway, and alleviating inflammation. The abundant YPVEPF (1.20 ± 0.04%) and Tyr-based/Trp-containing peptides of CP may be the key reasons for its different effects compared to casein. Thus, this work revealed the main active structures of CP and provided a novel dietary intervention strategy for the prevention and treatment of chronic-stress-induced dysfunction and anxiety/insomnia behaviors.

Preparation and evaluation of the PD0721­DOX antibody­drug conjugate targeting EGFRvIII to inhibit glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is prominently expressed in various epithelial tumors. PD0721, a single-chain antibody (scFv), has been developed to specifically target EGFRvIII. Although doxorubicin (DOX) is an essential treatment approach for glioblastoma (GBM), its toxic effects and limited targeting capabilities are a challenge. To overcome the above limitations, antibody-drug conjugates (ADCs) have been developed to exploit the specificity of monoclonal antibodies in directing potent cytotoxic drugs to tumor cells expressing the target antigens. The present study aimed to conjugate DOX with PD0721 scFv to construct a PD0721-DOX ADC targeting EGFRvIII and examine its targeting effect and in vitro anti-GBM activity. PD0721-DOX ADC was generated by combining PD0721 scFv with DOX, using dextran T-10 as a linker. The drug-to-antibody ratio (DAR) was measured by ultraviolet and visible spectrophotometry (UV-Vis). A series of techniques, including cytotoxicity assays, immunofluorescence, cell internalization and flow cytometry assays were employed to evaluate the targeting efficacy and anti-GBM activity of the PD0721-DOX ADC. Following the conjugation of PD0721 scFv with DOX, the UV-Vis results showed a noticeable red shift in the maximum absorbance. The DAR of PD0721 scFv and DOX was 9.23:1. Cytotoxicity assays demonstrated that DK-MG cells treatment with PD0721-DOX ADC at 10 and 20 µg/ml significantly increased cytotoxicity compared with U-87MG ATCC cells (all P<0.01). Confocal microscopy revealed distinct green and red fluorescence in EGFRvIII-expressing DK-MG cells, while no fluorescence was observed in EGFRvIII negative U-87MG ATCC cells. Furthermore, compared with U-87MG ATCC cells, DK-MG cells showed effective internalization of the PD0721-DOX ADC (P<0.001). Finally, flow cytometric analyses indicated that the PD0721-DOX ADC significantly promoted the apoptosis of DK-MG cells compared with U-87MG ATCC cells (P<0.01). In summary, the current study suggested that the PD0721-DOX ADC could exhibit a notable targeting efficacy and potent anti-GBM activity.

Herb-drug interactions: Quantitative analysis of levofloxacin absorption and transporter expression in the rat intestine following combined treatment with Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross.

Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, a traditional Chinese medicinal plant, is often used to treat various urologic disorders in China. P. capitata extracts (PCE) have been used in combination with levofloxacin (LVFX) to treat urinary tract infections (UTIs) for a long time. However, little is known about the absorption of LVFX and transporter expression in the intestine after combined treatment with PCE, restricting the development and utilization of PCE. In view of this, a UPLC-MS/MS method was established for the determination of LVFX in intestinal sac fluid samples and in situ intestinal circulation perfusate samples to explore the effect of PCE on the intestinal absorption characteristics of LVFX ex vivo and in vivo. To further evaluate the interaction between LVFX and PCE, western blotting, immunohistochemistry, and RT-qPCR were utilized to determine the expression levels of drug transporters (OATP1A2, P-gp, BCRP, and MRP2) involved in the intestinal absorption of LVFX after combined treatment with PCE. Using the everted intestinal sac model, the absorption rate constant (Ka) and cumulative drug absorption (Q) of LVFX in each intestinal segment were significantly lower in groups treated with PCE than in the control group. Ka at 2 h decreased most in the colon segment (from 0.088 to 0.016 µg/h·cm2), and Q at 2 h decreased most in the duodenum (from 213.29 to 33.92 µg). Using the intestinal circulation perfusion model, the Ka value and percentage absorption rate (A) of LVFX in the small intestine decreased significantly when PCE and LVFX were used in combination. These results showed that PCE had a strong inhibitory effect on the absorption of LVFX in the rat small intestine (ex vivo and in vivo intestinal segments). In addition, PCE increased the protein and mRNA expression levels of efflux transporters (P-gp, BCRP, and MRP2) and decreased the expression of the uptake transporter OATP1A2 significantly. The effects increased as the PCE concentration increased. These findings indicated that PCE changed the absorption characteristics of levofloxacin, possibly by affecting the expression of transporters in the small intestine. In addition to revealing a herb-drug interaction (HDI) between PCE and LVFX, these results provide a basis for further studies of their clinical efficacy and mechanism of action.

Untargeted metabolomic reveals the changes in muscle metabolites of mice during exercise recovery and the mechanisms of whey protein and whey protein hydrolysate in promoting muscle repair.

Our previous study indicated that whey protein hydrolysate (WPH) showed effective anti-fatigue properties, but its regulatory mechanism on recovery from exercise in mice is unclear. In the present study, we divided the mice into control, WP, and WPH groups and allowed them to rest for 1 h and 24 h after exercise, respectively. The changes in muscle metabolites of mice in the recovery period were investigated using metabolomics techniques. The results showed that the WPH group significantly up-regulated 94 muscle metabolites within 1 h of rest, which was 1.96 and 2.61 times more than the control and WP groups, respectively. In detail, significant decreases in TCA cycle intermediates, lipid metabolites, and carbohydrate metabolites were observed in the control group during exercise recovery. In contrast, administration with WP and WPH enriched more amino acid metabolites within 1 h of rest, which might provide a more comprehensive metabolic environment for muscle repair. Moreover, the WPH group remarkably stimulated the enhancement of lipid, carbohydrate, and vitamin metabolites in the recovery period which might provide raw materials and energy for anabolic reactions. The result of the western blot further demonstrated that WPH could promote muscle repair via activating the Sestrin2/Akt/mTOR/S6K signaling pathway within 1 h of rest. These findings deepen our understanding of the regulatory mechanisms by WPH to promote muscle recovery and may serve as a reference for comprehensive assessments of protein supplements on exercise.

Identification of Key Immune Infiltration Related Genes Involved in Aortic Dissection Using Bioinformatic Analyses and Experimental Verification.

Purpose: Immune microenvironment plays an important role in aortic dissection (AD). Therefore, novel immune biomarkers may facilitate AD prevention, diagnosis, and treatment. This study aimed at mining key immune-related genes and relevant mechanisms involved in AD pathogenesis. Patients and Methods: Key immune cells in AD were identified by ssGESA algorithm. Next, genes associated with key immune cells were screened by weighted gene coexpression network analysis (WGCNA). Then hub immune genes were picked from protein-protein interaction network of overlapped genes from differential expression and WGCNA analyses by cytohubba plug-in. Their diagnostic potential was evaluated in two independent cohorts from GEO database. In addition, the expressions of hub immune genes were determined by quantitative RT-PCR, immunohistochemistry, and Western blotting in dissected and normal aortic tissues. Results: Activated B cells, CD56dim natural killer cells, eosinophils, gamma delta T cells, immature B cells, natural killer cells and type 17 T helper cells were identified as key immune cells in AD. Thereafter, a gene module significantly correlated with key immune cells were found by WGCNA method. Subsequently, KDR, IGF1, NOS3, PECAM1, GAPDH, FLT1, DLL4, CDH5, VWF, and TEK were identified as hub immune cell related genes by PPI network analysis, which may be potential diagnostic markers for AD, as evidenced by ROC curves. Moreover, the decreased expression of VWF in AD was validated at both mRNA and protein levels, and its expression was significantly positive correlated with the marker of smooth muscle cells, ACTA2, in AD. Further immunofluorescent results showed that VWF was colocalized with ACTA2 in aortic tissues. Conclusion: We identified key immune cells and hub immune cell-related genes involved in AD. Moreover, we found that VWF was co-expressed with the smooth muscle cell marker ACTA2, indicating the important role of VWF in smooth muscle cell loss in AD pathogenesis.

[Comparative study on excretion of Shuganning Injection and Scutellariae Radix extract in bile, urine, and feces of rats].

Scutellariae Radix extract is one of the important components in Shuganning Injection. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method was established for simultaneously determining five components in Shuganning Injection and Scutellariae Radix extract in bile, urine, and feces of rats, so as to reveal the difference in the excretion process of Shuganning Injection and Scutellariae Radix extract in rats and explore the law of the excretion process of the five components in vivo before and after the compatibility of Scutellariae Radix. Rats were injected with Shuganning Injection and Scutellariae Radix extract(4.2 mL·kg~(-1)), respectively, and the excretion of baicalin, baicalein, oroxylin A, oroxylin A-7-O-ß-D-glucuronide, and scutellarin in bile, urine, and feces of rats in 24 h was observed. The results showed that except for baicalin, the other four index components were excreted as prototype components in a high proportion after intravenous injection of Shuganning Injection and Scutellariae Radix extract in rats, respectively. The excretion of each component was relatively high in urine and less in feces and bile. After the compatibility of Scutellariae Radix extract, the accumulative excretion of five index components in rats all decreased. Among them, the cumulative excretion of baicalein in bile, urine, and feces significantly decreased by 26.67%, 48.11%, and 31.01%. The cumulative excretion of baicalin in bile, urine, and feces decreased significantly by 70.69%, 19.43%, and 31.22%. The result showed that the five index components in Scutellariae Radix extract were mainly excreted by the kidneys, and other components in Shuganning Injection delayed the excretion process and prolonged the residence time. This study is of great significance for elucidating the compatibility rationality of Shuganning Injection.

Compatible camouflage for dual-band guided-laser radar and infrared via a metamaterial perfect absorber.

Laser-guided detector and infrared detection have attracted increasing attention in a wide range of research fields, including multispectral detection, radiative cooling, and thermal management. Previously reported absorbers presented shortcomings of lacking either tunability or compatibility. In this study, a metamaterial perfect absorber based on a Helmholtz resonator and fractal structure is proposed, which realizes tunable perfect absorptivity (α 1.06µ m >0.99,α 10.6µ m >0.99) of guided-laser radar dual operating bands (1.06 µm and 10.6 µm) and a low infrared average emissivity (ε¯3-5µ m =0.03,ε¯8-14µ m =0.31) in two atmospheric windows for compatible camouflage. The proposed perfect absorber provides a dynamically tunable absorptivity without structural changes and can be applied to optical communication, military stealth or protection, and electromagnetic detection.

Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

BACKGROUND: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

Four New Species and One New Record of Thelephora from China.

Species of the genus Thelephora (Thelephorales, Thelephoraceae) are ectomycorrhizal symbionts of coniferous and broad-leaved plants, and some of them are well-known edible mushrooms, making it an exceptionally important group ecologically and economically. However, the diversity of the species from China has not been fully elucidated. In this study, we conducted a phylogenetic analysis based on the internal transcribed spacer (ITS) regions, using Maximum Likelihood and Bayesian analyses, along with morphological observations of this genus. Four new species from China are proposed, viz., T. dactyliophora, T. lacunosa, T. petaloides, and T. pinnatifida. In addition, T. sikkimensis originally described from India is reported for the first time from China. Thelephora dactyliophora, T. pinnatifida, and T. sikkimensis are distributed in subtropical forests and mainly associated with plants of the families Fagaceae and Pinaceae. Thelephora lacunosa and T. petaloides are distributed in tropical to subtropical forests. Thelephora lacunosa is mainly associated with plants of the families Fagaceae and Pinaceae, while T. petaloides is mainly associated with plants of the family Fagaceae. Line drawings of microstructures, color pictures of fresh basidiomes, and detailed descriptions of these five species are provided.

Recycling and Degradation of Polyamides.

As one of the five major engineering plastics, polyamide brings many benefits to humans in the fields of transportation, clothing, entertainment, health, and more. However, as the production of polyamide increases year by year, the pollution problems it causes are becoming increasingly severe. This article reviews the current recycling and treatment processes of polyamide, such as chemical, mechanical, and energy recovery, and degradation methods such as thermal oxidation, photooxidation, enzyme degradation, etc. Starting from the synthesis mechanism of polyamide, it discusses the advantages and disadvantages of different treatment methods of polyamide to obtain more environmentally friendly and economical treatment schemes. Finding enzymes that can degrade high-molecular-weight polyamides, exploring the recovery of polyamides under mild conditions, synthesizing environmentally degradable polyamides through copolymerization or molecular design, and finally preparing degradable bio-based polyamides may be the destination of polyamide.

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated Colorectal Cancer and Associated Pharmacological Interventions.

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

Low TYROBP expression predicts poor prognosis in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is the second most common refractory hematologic cancer. Searching for new targets and prognostic markers for MM is significant. METHODS: GSE39754, GSE6477 and GSE24080 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in MM versus healthy people from GSE39754 and GSE6477 were screened using limma package, and MM-related module genes were chosen with the use of Weighted gene co-expression network analysis (WGCNA), and the two were intersected using ggVennDiagram for obtaining MM-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Then, protein-protein interactions (PPI) analysis in String database was used to obtain hub genes, while prognosis was analyzed by survival package in GSE24080. Receiver operating characteristic (ROC) curve was adopted for evaluating diagnostic value of hub genes. Besides, univariable/multivariable Cox regression were employed to screen independent prognostic biomarkers. Gene set enrichment analysis (GSEA) was used to find possible mechanism. Finally, western-blotting and reverse transcription-polymerase chain reaction (RT-PCR) verify TYROBP expression within MM and healthy people. We performed cell adhesion and transwell assays for investigating TYROBP function in MM cell adhesion and migration. RESULTS: Through differential analyses, 92 MM-related DEGs were obtained. 10 hub genes were identified by PPI and CytoHubba. Their diagnostic and prognostic significance was analyzed. Down-regulation of genes like TYROBP, ELANE, MNDA, and MPO related to dismal MM prognosis. Upon univariable/multivariable Cox regression, TYROBP independently predicted MM prognosis. GSEA pathway was enriched, indicating that TYROBP expression affected MM development via cell adhesion molecular pathway. Upon Western-blotting and RT-PCR assays, TYROBP expression among MM patients decreased relative to healthy donors. Cell adhesion and transwell migration assays revealed increased MM cell adhesion and decreased migration upon TYROBP up-regulation. CONCLUSION: In summary, TYROBP is a potential prognostic marker for MM.

Potential Mechanisms of Casein Hexapeptide YPVEPF on Stress-Induced Anxiety and Insomnia Mice and Its Molecular Effects and Key Active Structure.

The hexapeptide YPVEPF with strong sleep-enhancing effects could be detected in rat brain after a single oral administration as we previously proved. In this study, the mechanism and molecular effects of YPVEPF in the targeted stress-induced anxiety mice were first investigated, and its key active structure was further explored. The results showed that YPVEPF could significantly prolong sleep duration and improve the anxiety indexes, including prolonging the time spent in the open arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing effects by significantly increasing the level of the GABA/Glu ratio, 5-HT, and dopamine in brain and serum and regulating the anabolism of multiple targets, but the effects could be blocked by bicuculline and WAY100135. Moreover, the molecular simulation results showed that YPVEPF could stably bind to the vital GABAA and 5-HT1A receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-, and the electrostatic and van der Waals energy played dominant roles in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing and anxiolytic effects by regulating the GABA-Glu metabolic pathway and serotoninergic system depending on distinctive self-folding structures with Tyr and two Pro repeats.