CCL28 promotes progression of hepatocellular carcinoma through PDGFD-regulated MMP9 and VEGFA pathways.

Hepatocellular carcinoma (HCC) remains a major global health concern with limited therapeutic options and poor prognosis. Chemokines have emerged as critical regulators in the progression and metastasis of HCC. This study aims to investigate the mechanisms involved in CCL28-promoted progression of HCC and provide novel therapeutic targets for HCC treatment. Relationship between CCL28 expression and HCC progression were investigated by bioinformatic analysis and immunohistochemical staining assays. CCK-8, Transwell, and colony formation assay were conducted to explore the impact of CCL28 on the growth, migration and invasion of HCC cells. Quantitative real-time PCR and western blotting assays were performed to learn potential molecular mechanisms underlying the transformation of HCC driven by CCL28. The results showed that there was a direct link between increased CCL28 levels and the advancement of HCC, leading to a worse outcome. CCL28 significantly augmented malignant transformation of HCC cells, containing proliferation, migration, invasion, and clonogenicity, via activation of PDGFD-regulated MMP9 and VEGFA pathways. CCL28 emerges as a pivotal contributor to HCC tumorigenesis, propelling HCC development through the PDGFD signaling pathway. Our findings unveil potential therapeutic targets for HCC treatment.

Native language advantage in electrical brain responses to speech sound changes in passive and active listening condition.

It is not clear whether the brain can detect changes in native and non-native speech sounds in both unattended and attended conditions, but this information would be important to understand the nature of potential native language advantage in speech perception. We recorded event-related potentials (ERPs) for changes in duration and in Chinese lexical tone in a repeated vowel /a/ in native speakers of Finnish and Chinese in passive and active listening conditions. ERP amplitudes reflecting deviance detection (mismatch negativity; MMN and N2b) and attentional shifts towards changes in speech sounds (P3a and P3b) were investigated. In the passive listening condition, duration changes elicited increased amplitude in the MMN latency window for both standard and deviant sounds in the Finnish speakers compared to the Chinese speakers, but no group differences were observed for P3a. In passive listening to lexical tones, P3a was increased in amplitude for both standard and deviant stimuli in Chinese speakers compared to Finnish speakers, but the groups did not differ in MMN. In active listening, both tone and duration changes elicited N2b and P3b, but the groups differed only in pattern of results for the deviant type. The results thus suggest an overall increased sensitivity to native speech sounds, especially in passive listening, while the mechanisms of change detection and attentional shifting seem to work well for both native and non-native speech sounds in the attentive mode.

Exosomes derived from mesenchymal stem cells containing berberine for ulcerative colitis therapy.

Berberine (Ber), an isoquinoline alkaloid, is a potential drug therapy for ulcerative colitis (UC) because of its anti-inflammatory activity, high biological safety, and few side effects. Nevertheless, its clinical application is hindered by its limited water solubility and low bioavailability. Currently, compared to synthetic nanocarriers, exosomes as carriers possess advantages such as low toxicity, high stability, and high specificity. Human placental mesenchymal stem cell-derived exosomes (HplMSC-Exos) have emerged as a promising drug delivery system, offering intrinsic anti-inflammatory and antioxidant activities. Therefore, we engineered MSC-Exos loaded with Ber (Exos-Ber) to enhance the solubility and bioavailability of Ber and for colon targeting, revealing a novel approach for treating UC with natural compounds. Structurally and functionally, Exos-Ber closely resembled unmodified Exos. Both in vitro and in vivo investigations confirmed the antioxidant and anti-inflammatory properties of Exos-Ber. Notably, Exos-Ber exhibited reparative effects on injured epithelial cells and reduced cellular apoptosis. Furthermore, Exos-Ber concurrently demonstrated anti-inflammatory and antioxidant activities, contributing to the mitigation of UC, possibly through its modulation of the MAPK signaling pathway. Overall, our findings demonstrate the potential of Exos-Ber as a promising therapeutic option for alleviating UC, highlighting its capacity to enhance the clinical applicability of Ber.

Dictyophora indusiata polysaccharide mediates priming of the NLRP3 inflammasome activation via TLR4/ NF-κB signaling pathway to exert immunostimulatory effects.

Dictyophora indusiata, commonly known as bamboo fungus, is a type of edible mushroom that is highly popular worldwide for its rich flavor and nutritional value. It is also recognized for its pharmaceutical efficacy, with medicinal benefits attributed to its consumption. One of the most important components of Dictyophora indusiata is polysaccharide, which has been acknowledged as a promising regulator of biological response due to its immunostimulatory and anti-inflammatory properties. However, the specific roles of polysaccharide in modulating the NOD-like receptor protein 3 (NLRP3) inflammasome activation within macrophages remain relatively under-researched. To investigate this further, the mechanism by which Dictyophora indusiata polysaccharide (DIP) exerts its immunostimulatory activity in RAW 264.7 macrophages was analyzed. Results indicated that DIP has the potential to facilitate the priming of NLRP3 inflammasome activation by enhancing TLR4 expression, phosphorylation of IκB-α, and nuclear translocation of NF-κB p65 subunit. It was noted that DIP was unable to mediate the second step of NLRP3 inflammasome activation. The findings of this study provide compelling evidence that DIP has immunomodulatory effects by modulating the NLRP3 inflammasome in RAW264.7 macrophages.

Dimethyl Sulfoxide: An Ideal Electrochemical Probe for Hydroxyl Radical Detection.

In situ and real-time determination of hydroxyl radicals (•OH) in physiological and pathological processes is a great challenge due to their ultrashort lifetime. Herein, an electrochemical method was developed by using dimethyl sulfoxide (DMSO) as a trapping probe for rapid determination of •OH in aqueous solution. When DMSO reacted with •OH, an intermediate product methane sulfinic acid (MSIA) was formed, which can be electrochemically oxidized to methanesulfonic acid (MSA) on the glassy carbon electrode (GCE), resulting in a distinct voltammetric signal that is directly proportional to the concentration of •OH. Other commonly encountered reactive oxygen species (ROS), including hypochlorite anions (ClO-), superoxide anions (O2•-), sulfate radicals (SO4•-), and singlet oxygen (1O2), have showed no interference for •OH determination. Thus, an electrochemical method was developed for the determination of •OH, which exhibits a wide linear range (0.4-5120 µM) and a low limit detection of 0.13 µM (S/N = 3) and was successfully applied for the quantification of •OH in aqueous extracts of cigarette tar (ACT). Alternatively, the same reaction mechanism is also applicable for the determination of DMSO, in which a linear range of 40-320 µM and a detection limit 13.3 µM (S/N = 3) was achieved. The method was used for the evaluation of DMSO content in cell cryopreservation medium. This work demonstrated that DMSO can serve as an electrochemical probe and has valuable application potential in radical study, biological research, and environmental monitoring.

ASIC1 promotes migration and invasion of hepatocellular carcinoma via the PRKACA/AP-1 signaling pathway.

Hepatocellular carcinoma (HCC) exhibits a high mortality rate due to its high invasion and metastatic nature, and the acidic microenvironment plays a pivotal role. Acid-sensing ion channel 1 (ASIC1) is upregulated in HCC tissues and facilitates tumor progression in a pH-dependent manner, while the specific mechanisms therein remain currently unclear. Herein, we aimed to investigate the underlying mechanisms by which ASIC1 contributes to the development of HCC. Using bioinformatics analysis, we found a significant association between ASIC1 expression and malignant transformation of HCC, such as poor prognosis, metastasis and recurrence. Specifically, ASIC1 enhanced the migration and invasion capabilities of Li-7 cells in the in vivo experiment using an HCC lung metastasis mouse model, as well as in the in vitro experiments such as wound healing assay and Transwell assay. Furthermore, our comprehensive gene chip and molecular biology experiments revealed that ASIC1 promoted HCC migration and invasion by activating the PRKACA/AP-1 signaling pathway. Our findings indicate that targeting ASIC1 could have therapeutic potential for inhibiting HCC progression.

Directed Modification of a GHF11 Thermostable Xylanase AusM for Enhancing Inhibitory Resistance towards SyXIP-I and Application of AusMPKK in Bread Making.

To reduce the inhibition sensitivity of a thermoresistant xylanase AusM to xylanase inhibitor protein (XIP)-type in wheat flour, the site-directed mutagenesis was conducted based on the computer-aided redesign. First, fourteen single-site variants and one three-amino acid replacement variant in the thumb region of an AusM-encoding gene (AusM) were constructed and expressed in E. coli BL21(DE3), respectively, as predicted theoretically. At a molar ratio of 100:1 between SyXIP-I/xylanase, the majority of mutants were nearly completely inactivated by the inhibitor SyXIP-I, whereas AusMN127A retained 62.7% of its initial activity and AusMPKK retained 100% of its initial activity. The optimal temperature of the best mutant AusMPKK was 60 °C, as opposed to 60-65 °C for AusM, while it exhibited improved thermostability, retaining approximately 60% of its residual activity after heating at 80 °C for 60 min. Furthermore, AusMPKK at a dosage of 1000 U/kg was more effective than AusM at 4000 U/kg in increasing specific bread loaf volume and reducing hardness during bread production and storage. Directed evolution of AusM significantly reduces inhibition sensitivity, and the mutant enzyme AusMPKK is conducive to improving bread quality and extending its shelf life.

A large-scale fMRI dataset for the visual processing of naturalistic scenes.

One ultimate goal of visual neuroscience is to understand how the brain processes visual stimuli encountered in the natural environment. Achieving this goal requires records of brain responses under massive amounts of naturalistic stimuli. Although the scientific community has put a lot of effort into collecting large-scale functional magnetic resonance imaging (fMRI) data under naturalistic stimuli, more naturalistic fMRI datasets are still urgently needed. We present here the Natural Object Dataset (NOD), a large-scale fMRI dataset containing responses to 57,120 naturalistic images from 30 participants. NOD strives for a balance between sampling variation between individuals and sampling variation between stimuli. This enables NOD to be utilized not only for determining whether an observation is generalizable across many individuals, but also for testing whether a response pattern is generalized to a variety of naturalistic stimuli. We anticipate that the NOD together with existing naturalistic neuroimaging datasets will serve as a new impetus for our understanding of the visual processing of naturalistic stimuli.

A large-scale fMRI dataset for human action recognition.

Human action recognition is a critical capability for our survival, allowing us to interact easily with the environment and others in everyday life. Although the neural basis of action recognition has been widely studied using a few action categories from simple contexts as stimuli, how the human brain recognizes diverse human actions in real-world environments still needs to be explored. Here, we present the Human Action Dataset (HAD), a large-scale functional magnetic resonance imaging (fMRI) dataset for human action recognition. HAD contains fMRI responses to 21,600 video clips from 30 participants. The video clips encompass 180 human action categories and offer a comprehensive coverage of complex activities in daily life. We demonstrate that the data are reliable within and across participants and, notably, capture rich representation information of the observed human actions. This extensive dataset, with its vast number of action categories and exemplars, has the potential to deepen our understanding of human action recognition in natural environments.

Functional integration of anterior insula related to meaning in life and loneliness.

BACKGROUND: Meaning in life (MIL), defined as people's feelings of life's meaningfulness, plays a vital role in buffering loneliness - an important indicator of depression and other psychological disorders. Considerable evidence shows that MIL arises from widely distributed brain activity; however, how such activity is functionally integrated and how it influences loneliness is still understudied. METHODS: We here examined how the functional integration of brain regions is related to individual MIL based on resting-state functional magnetic resonance imaging data from the Human Connectome Project (N = 970). RESULTS: We found that the global brain connectivity (GBC) of the right anterior insula (rAI) can significantly predict individual MIL. Moreover, mediation analyses were conducted to investigate how the brain influences loneliness with MIL's mediation, which revealed that MIL fully mediates the effect of this hub on loneliness. CONCLUSIONS: These findings suggest that the rAI is a key hub for MIL and loneliness. Its functional integration can be used as a biomarker to predict individual MIL and loneliness.

An Integrated Strategy for Investigating Antioxidants from Ribes himalense Royle ex Decne and Their Potential Target Proteins.

Natural products have been used extensively around the world for many years as therapeutic, prophylactic, and health-promotive agents. Ribes himalense Royle ex Decne, a plant used in traditional Tibetan medicine, has been demonstrated to have significant antioxidant and anti-inflammatory properties. However, the material basis of its medicinal effects has not been sufficiently explored. In this study, we established an integrated strategy by online HPLC-1,1-diphenyl-2-picrylhydrazyl, medium-pressure liquid chromatography, and HPLC to achieve online detection and separation of antioxidants in Ribes himalense extracts. Finally, four antioxidants with quercetin as the parent nucleus were obtained, namely, Quercetin-3-O-ß-D-glucopyranoside-7-O-α-L-rhamnopyranoside, Quercetin-3-O-ß-D-xylopyranosyl(1-2)-ß-D-glucopyranoside, Quercetin-3-O-ß-D-glucopyranoside, and Quercetin-3-O-ß-D-galactoside. Until now, the four antioxidants in Ribes himalense have not been reported in other literatures. Meanwhile, the free-radical-scavenging ability of them was evaluated by DPPH assay, and potential antioxidant target proteins were explored using molecular docking. In conclusion, this research provides insights into the active compounds in Ribes himalense which will facilitate the advancement of deeper studies on it. Moreover, such an integrated chromatographic strategy could be a strong driver for more efficient and scientific use of other natural products in the food and pharmaceutical industries.

Ferroptosis-Related Gene SLC1A5 Is a Novel Prognostic Biomarker and Correlates with Immune Microenvironment in HBV-Related HCC.

(1) Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is an iron-dependent cell death program that plays a regulatory role in HBV infection and HCC development. It is necessary to classify the roles of ferroptosis or ferroptosis-related genes (FRGs) in HBV-related HCC progression. (2) Methods: We conducted a matched case-control study from the TCGA database, retrospectively collecting demographic data and common clinical indicators from all subjects. The Kaplan-Meier curve, univariate and multivariate cox regression analysis of the FRGs were used to explore the risk factors for HBV-related HCC. The CIBERSORT algorithm and TIDE algorithm were executed to evaluate the functions of FRGs in the tumor-immune environment. (3) Results: A total of 145 HBV-positive HCC patients and 266 HBV-negative HCC patients were enrolled in our study. Four ferroptosis related genes (FANCD2, CS, CISD1 and SLC1A5) were positively correlated with the progression of HBV-related HCC. Among them, SLC1A5 was an independent risk factor for HBV-related HCC, and correlated with poor prognosis, advanced progression and an immunosuppression microenvironment. (4) Conclusions: Here, we revealed that a ferroptosis-related gene, SLC1A5, may be an excellent predictor of HBV-related HCC and may provide insight into the development of innovative possible therapeutic techniques.

Identification of S100A9 as a Potential Inflammation-Related Biomarker for Radiation-Induced Lung Injury.

Radiation-induced lung injury (RILI), a potentially fatal and dose-limiting complication of radiotherapy for thoracic tumors, is divided into early reversible pneumonitis and irreversible advanced-stage fibrosis. Early detection and intervention contribute to improving clinical outcomes of patients. However, there is still a lack of reliable biomarkers for early prediction and clinical diagnosis of RILI. Given the central role of inflammation in the initiation and progression of RILI, we explored specific inflammation-related biomarkers during the development of RILI in this study. Two expression profiles from the Gene Expression Omnibus (GEO) database were downloaded, in which 75 differentially expressed genes (DEGs) were screened out. Combining Gene Oncology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) network analysis, we identified four inflammation-related hub genes in the progression of RILI-MMP9, IL-1ß, CCR1 and S100A9. The expression levels of the hub genes were verified in RILI mouse models, with S100A9 showing the highest level of overexpression. The level of S100A9 in bronchoalveolar lavage fluid (BALF) and the expression of S100A9 in lung tissues were positively correlated with the degree of inflammation in RILI. The results above indicate that S100A9 is a potential biomarker for the early prediction and diagnosis of the development of RILI.

Separation of Antioxidants from Trace Fraction of Ribes himalense via Chromatographic Strategy and Their Antioxidant Activity Supported with Molecular Simulations.

Antioxidants from natural sources have long been of interest to researchers. In this paper, taking the traditional Tibetan medicine Ribes himalense as an example, an integrated approach was used to identify and isolate its chemical composition with free-radical-scavenging properties from its ethanol extract. First, the ethanol extract of Ribes himalense was pretreated using polyamide medium-pressure liquid chromatography (polyamide-MPLC), and the target fraction (Fr4) was obtained. Then, a combined HPLC mode was utilized to purify antioxidants in Fr4 under the guidance of an online HPLC-1,1-diphenyl-2-picrylhydrazyl (HPLC-DPPH) activity screening system. Finally, three antioxidants (3-caffeoylquinic acid methyl ester, rutin, and myricetin-3'-α-L-rhamnopyranoside) were isolated, and this is the first report of their presence in R. himalense. Further molecular docking studies showed that the antioxidants exhibited good binding with HO-1, Nrf2, and iNOS. In conclusion, this comprehensive approach is capable of extracting high-purity antioxidants from trace fractions of Ribes himalense and holds promise for future applications in the exploration of the chemical compositions and bioactivity of natural products.

Exosome-Related FTCD Facilitates M1 Macrophage Polarization and Impacts the Prognosis of Hepatocellular Carcinoma.

BACKGROUND: Exosomes are essential for hepatocellular carcinoma (HCC) progression and have garnered significant interest as novel targets for diagnostic, prognostic, and therapeutic approaches. This study aims to identify potential exosome-related biomarkers for the development of useful strategies for HCC diagnosis and therapy. METHODS: Three datasets obtained from the Gene Expression Omnibus (GEO) were utilized to identify differentially expressed genes (DEGs) in HCC. Through Gene Ontology (GO) analysis and protein-protein interaction (PPI) network, overall survival (OS) analysis, Cox analyses, and diethylnitrosamine (DEN)-induced HCC mouse model detection, exosome-related hub gene was screened out, followed by a prognostic value assessment and immune-correlates analysis based on the Cancer Genome Atlas (TCGA) dataset. The hub gene-containing exosomes derived from Hepa1-6 cells were isolated and characterized using differential ultracentrifugation, transmission electron microscopy scanning, and Western blot. Ultrasound-guided intrahepatic injection, cell co-culture, CCK-8, and flow cytometry were performed to investigate the effects of the hub gene on macrophage infiltration and polarization in HCC. RESULTS: A total of 83 DEGs enriched in the extracellular exosome term, among which, FTCD, HRA, and C8B showed the strongest association with the progression of HCC. FTCD was independently associated with a protective effect in HCC and selected as the hub gene. The presence of FTCD in exosomes was confirmed. FTCD-stimulated macrophages were polarized towards the M1 type and suppressed HCC cells proliferation. CONCLUSIONS: FTCD is a potential exosome-related biomarker for HCC diagnosis, prognosis, and treatment. The crosstalk between FTCD-containing exosomes and macrophages in HCC progression deserves further investigation.

Human placental mesenchymal stem cells regulate inflammation via the NF­κB signaling pathway.

Emerging evidence has indicated that mesenchymal stem cells (MSCs) are involved in the modulation of inflammation. Human placenta-derived (HPL)-MSCs exist in sufficient quantities and play a role in immune regulation. However, the exact roles of HPL-MSCs in inflammation and the specific underlying mechanisms are not well defined. In the present study, HPL-MSCs were obtained from human fetal placentas, and further purified using a commercial kit. Using ELISA, reverse transcription-quantitative PCR, western blot, NO detection and other assays, the present study revealed that HPL-MSCs may improve lipopolysaccharide-induced macrophage inflammation by regulating macrophage polarization. Further mechanistic studies demonstrated that HPL-MSCs attenuated the NF-κB signaling pathway by regulating the expression of toll-like receptor 4 and the phosphorylation of IκBα and p65, which resulted in a reduction in the levels of inflammation. The present study indicated that HPL-MSCs may act as a novel target for the treatment of inflammation-related diseases.

The Extended Simple View of Reading in Adult Learners of Chinese as a Second Language.

The Simple View of Reading (SVR) designates that reading comprehension is the product of decoding and listening comprehension and this conclusion has been supported by studies on school-aged native and nonnative speakers. However, it remains unknown whether SVR can be applied to adult second language (L2) learners. The current study addressed this issue by testing adult learners of Chinese as a second language with various proficiency levels and further extended the model by including word segmentation and word-meaning access, both of which are particularly crucial in reading Chinese. The results showed that listening comprehension only contributed to reading comprehension for the advanced learners, while decoding accuracy predicted reading comprehension regardless of Chinese proficiency. However, the total proportion of variance accounted for was relatively low, especially for the lower proficiency groups. Interestingly, word segmentation and word-meaning access explained a large proportion of the total variance and concomitantly decreased the apparent influence of word decoding. Taken together, these findings highlight that the individual characteristics of a given language can modulate the contributions of decoding and listening comprehension to predicting reading comprehension.

Implication of human endogenous retrovirus W family envelope in hepatocellular carcinoma promotes MEK/ERK-mediated metastatic invasiveness and doxorubicin resistance.

Human endogenous retrovirus (HERVs), originating from exogenous retroviral infections of germ cells millions of years ago, have the potential for human diseases. Syncytin-1, an envelope protein encoded by the HERV W family, participates in the contexts of schizophrenia, multiple sclerosis, diabetes, and several types of cancers. Nevertheless, there is no report on the expression pattern and potential mechanism of Syncytin-1 in HCC. Here we found Syncytin-1 expression was up-regulated in HCC compared to adjacent non-tumorous tissues, especially in advanced HCC. Syncytin-1 was an independent risk factor to predict vascular invasion, metastasis, larger tumor size, and poor prognosis in HCC patients. Further analysis discovered that Syncytin-1 overexpression positively associated with HCC patients with serum HBsAg positive. Functional experiments in vitro and in vivo demonstrated that Syncytin-1 enhanced cell proliferation, metastasis, and tumorigenicity in HCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the mitogen-activated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK) pathway was involved in HCC. Our clinical data indicated that the levels of phosphorylation MEK1/2 and ERK1/2 were increased in HCC comparing with adjacent non-tumorous tissues. It showed the linear correlation between Syncytin-1 expression and upregulated MEK1/2 and ERK1/2 phosphorylation levels in HCC. Furthermore, Syncytin-1 activated MEK/ERK pathway in HCC cells. In-depth research showed that the inflammation-activated MEK/ERK pathway was essential in Syncytin-1 promoted hepatocarcinogenesis. Syncytin-1 suppressed doxorubicin-induced apoptosis via MEK/ERK cascade. In conclusion, Syncytin-1 promoted HCC progression and doxorubicin resistance via the inflammation-activated MEK/ERK pathway. Our findings revealed that Syncytin-1 was a potential prognostic biomarker and therapeutic target for HCC.

Nearly perfect kinetic resolution of racemic o-nitrostyrene oxide by AuEH2, a microsomal epoxide hydrolase from Aspergillus usamii, with high enantio- and regio-selectivity.

Only a few known epoxide hydrolases (EHs) displayed activity towards o-nitrostyrene oxide (4a), presumably owing to the large steric hindrance caused by o-nitro substituent. Therefore, excavating EHs with high activity and enantio- and/or regio-selectivity towards racemic (rac-) 4a is essential but challenging. Here, AuEH2 from Aspergillus usamii was expressed in E. coli BL21(DE3). E. coli/Aueh2, an E. coli transformant expressing AuEH2, possessed EH activities of 16.2-184 U/g wet cell towards rac-styrene oxide (1a) and its derivatives (2a-13a), and the largest enantiomeric ratio of 96 towards rac-4a. The regioselectivity coefficients, ßR and ßS, of AuEH2 were determined to be 99.2% and 98.9%, suggesting that it regiopreferentially attacks the Cß in the oxirane rings of (R)- and (S)-4a. Then, the nearly perfect kinetic resolution of 20 mM rac-4a in pure water was carried out using 20 mg/mL wet cells of E. coli/Aueh2 at 25 °C for 50 min, retaining (S)-4a with over 99% ees and 48.9% yields, while producing (R)-o-nitrophenyl-1,2-ethanediol (4b) with 95.3% eep and 49.8% yieldp. To elucidate the molecular mechanism of AuEH2 with high enantiopreference for (R)-4a, its crystal structure was solved by X-ray diffraction and the molecular docking of AuEH2 with (R)- or (S)-4a was simulated.