Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma.

Hepatocellular carcinoma is the third leading cause of deaths from cancer worldwide. Infection with the hepatitis B virus is one of the leading risk factors for developing hepatocellular carcinoma, particularly in East Asia1. Although surgical treatment may be effective in the early stages, the five-year overall rate of survival after developing this cancer is only 50-70%2. Here, using proteomic and phospho-proteomic profiling, we characterize 110 paired tumour and non-tumour tissues of clinical early-stage hepatocellular carcinoma related to hepatitis B virus infection. Our quantitative proteomic data highlight heterogeneity in early-stage hepatocellular carcinoma: we used this to stratify the cohort into the subtypes S-I, S-II and S-III, each of which has a different clinical outcome. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)-high expression of which is a signature specific to the S-III subtype-alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumour xenograft mouse model of hepatocellular carcinoma, we found that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumours that had high levels of SOAT1 expression. The proteomic stratification of early-stage hepatocellular carcinoma presented in this study provides insight into the tumour biology of this cancer, and suggests opportunities for personalized therapies that target it.

Bioinformatics analysis of the prognosis and biological significance of N6 methyladenine regulators in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common type of cancer. We performed the present study to explore the function and specific regulatory mechanism of m6A in OSCC and to find a new diagnosis and treatment strategy for OSCC. METHODS: Using bioinformatics, we examined the associations between 20 genes associated with methylation and the epidemiological data about OSCC tumor samples. RESULTS: We created two subgroup curves based on the gene expression levels related to m6A methylation. In total, 14 genes were found to be differentially expressed. Significant differences in terms of survival rates, Grade and gender were found among subgroups with different m6A expression levels. Nine genes had areas under the curves greater than 0.7. Therefore, these genes may be utilized for the clinical diagnosis and prognosis of OSCC. Because of their high individual predictive value, HNRNPC and IGF2BP2 were chosen as the two potential predictors. The two regulatory elements were used to create the prognostic signals for OSCC. The developed prognostic signals made it possible to discern between the samples with good and poor prognoses without potential confounding factors. Four genes (HNRNPC, METTL14, YTHDF2 and ALKBH5) combined well with compounds, which had an anti-cancer effect. CONCLUSIONS: Our findings suggested that OSCC-related genes with m6A methylation could be beneficial treatment targets or prognostic indicators.

Salvianolic Acid B Alleviates High Glucose-Induced Vascular Smooth Muscle Cell Inflammation by Upregulating the miR-486a-5p Expression.

The macrovascular complications of diabetes cause high mortality and disability in patients with type 2 diabetes mellitus (T2DM). The inflammatory response of vascular smooth muscle cell (VSMC) runs through its pathophysiological process. Salvianolic acid B (Sal B) exhibits beneficial effects on the cardiovascular system. However, its role and mechanism in diabetic vascular inflammatory response remain unclear. In this study, we found that Sal B reduced vascular inflammation in diabetic mice and high glucose- (HG-) induced VSMC inflammation. Subsequently, we found that Sal B reduced HG-induced VSMC inflammation by downregulating FOXO1. Furthermore, miR-486a-5p expression was obviously reduced in HG-treated VSMC. Sal B attenuated HG-induced VSMC inflammation by upregulating miR-486a-5p. Loss- and gain-of-function experiments had proven that the transfection of the miR-486a-5p mimic inhibited HG-induced VSMC inflammation whereas that of the miR-486a-5p inhibitor promoted HG-induced VSMC inflammation, thereby leading to the amelioration of vascular inflammation in the diabetic mice. Furthermore, studies had shown that miR-486a-5p inhibited FOXO1 expression by directly targeting its 3'-UTR. In conclusion, Sal B alleviates the inflammatory response of VSMC by upregulating miR-486a-5p and aggravating its inhibition of FOXO1 expression. Sal B exerts a significant anti-inflammatory effect in HG-induced VSMC inflammation by modulating the miR-486a-5p/FOXO1 axis.

Functional preference of the left inferior parietal lobule to second language reading.

Additional neural substance for reading in a second language has been reported by prior studies. However, to date, there has been little investigation into whether and how the brain's adaptation to a second language is induced by specific linguistic tasks or is a general effect during reading in a new language. To address this issue, our study investigated Chinese children learning English as a second language by combining cross-sectional and longitudinal Functional Magnetic Resonance Imaging (fMRI) studies. We compared brain activation across four reading tasks, orthographic tasks and phonological tasks in Chinese (the first language, L1) and English (the second language, L2). By comparing the activation pattern across languages, we observed greater activation in the left inferior parietal lobule (LIPL) in English compared to Chinese, suggesting a functional preference of the LIPL to L2. In addition, greater correlation between LIPL-related FC and L2 was mainly observed in the phonological task, indicating that LIPL could be associated with phonological processing. Moreover, a proportion of the children were enrolled in an 8-week phonological-based reading-training program. We observed significant functional plasticity of the LIPL elicited by this training program only in the English phonological task and not in the orthographic task, further substantiating that the additional requirements of the LIPL in L2 are mainly associated with phonological processing. The findings provide new insights into understanding the functional contribution of the LIPL to reading in a second language.

A Recombinant VSV-Based Bivalent Vaccine Effectively Protects against Both SARS-CoV-2 and Influenza A Virus Infection.

COVID-19 and influenza are both highly contagious respiratory diseases that have been serious threats to global public health. It is necessary to develop a bivalent vaccine to control these two infectious diseases simultaneously. In this study, we generated three attenuated replicating recombinant vesicular stomatitis virus (rVSV)-based vaccine candidates against both SARS-CoV-2 and influenza viruses. These rVSV-based vaccines coexpress SARS-CoV-2 Delta spike protein (SP) bearing the C-terminal 17 amino acid (aa) deletion (SPΔC) and I742A point mutation, or the SPΔC with a deletion of S2 domain, or the RBD domain, and a tandem repeat harboring four copies of the highly conserved influenza M2 ectodomain (M2e) that fused with the Ebola glycoprotein DC-targeting/activation domain. Animal immunization studies have shown that these rVSV bivalent vaccines induced efficient humoral and cellular immune responses against both SARS-CoV-2 SP and influenza M2 protein, including high levels of neutralizing antibodies against SARS-CoV-2 Delta and other variant SP-pseudovirus infections. Importantly, immunization of the rVSV bivalent vaccines effectively protected hamsters or mice against the challenges of SARS-CoV-2 Delta variant and lethal H1N1 and H3N2 influenza viruses and significantly reduced respiratory viral loads. Overall, this study provides convincing evidence for the high efficacy of this bivalent vaccine platform to be used and/or easily adapted to produce new vaccines against new or reemerging SARS-CoV-2 variants and influenza A virus infections. IMPORTANCE Given that both COVID-19 and influenza are preferably transmitted through respiratory droplets during the same seasons, it is highly advantageous to develop a bivalent vaccine that could simultaneously protect against both COVID-19 and influenza. In this study, we generated the attenuated replicating recombinant vesicular stomatitis virus (rVSV)-based vaccine candidates that target both spike protein of SARS-Cov-2 Delta variant and the conserved influenza M2 domain. Importantly, these vaccine candidates effectively protected hamsters or mice against the challenges of SARS-CoV-2 Delta variant and lethal H1N1 and H3N2 influenza viruses and significantly reduced respiratory viral loads.

The nature of stability and adsorption interactions of binary Au-Li clusters with bridge adsorption structures.

Earlier findings have confirmed that CO molecules have propensities to adsorb on low-coordinated gold atoms (top sites) of Au-based clusters, which can be treated by the Blyholder model wherein the σ donation and π-back donation take place. Here, the structural features and stability of (AuLi)n (n = 1-9) clusters were first analyzed using the GA-DFT method. The new adsorption modes, vibration frequencies and electronic interactions for Au-Li clusters with CO were investigated in detail. More excitingly, we found that CO prefers to adsorb on the bridge sites of the Au-Li clusters rather than on the top sites, which are much lower in energies than the top adsorptions, and the C-O stretching frequencies are also red-shifted. AIMD simulations show that the adsorption structures still have good thermal stability at 500 K. The density of states reveals that the electronic structures of Au-Li clusters have excellent stability for the bridge adsorptions of CO molecules. The ETS-NOCV analysis and NPA charges show that the direction of charge flow is from Au-Li clusters → CO. Our study provides an idea to elucidate the new adsorption mechanism on Au-Li clusters and the connection between the geometries and reaction properties.

Planar σ-Aromaticity in Ga-Doped Au Clusters.

Recently, the first example of Au-Ga clusters is synthesized and characterized, which can be described by the jellium model as a superatom with 8 valence electrons that come from the joint contribution of Au and Ga atoms, opening a whole new field for further research. Here, the structure features and stability of one Ga-doped Au cluster with magic number electrons (6 and 8) are analyzed in detail. Moreover, the valence electron fillings and chemical bonding of them are also further explored. It is found that Au3Ga and Au5Ga clusters present planar configurations, and they have higher stability than that of neighbor clusters. The AIMD simulations show that these two clusters still have a good thermal stability at 500 K. The molecular orbital analyses show that the Au3Ga and Au5Ga have three and one typical delocalization orbital throughout the whole planar spaces, respectively, following the planar σ-aromaticity rule. The ELF and LOL analyses are further performed, and the results are consistent with the molecular orbital analyses. The NICSzz-scan curves confirm that the Au3Ga is more aromatic than the Au5Ga, and the reason is that the former has more delocalized electrons than the latter. Our work opens up aromaticity studies in the Au-Ga clusters.

Environmental risk assessment near a typical spent lead-acid battery recycling factory in China.

In recent years, environmental pollution and public health incidents caused by the recycling of spent lead-acid batteries (LABs) has becoming more frequent, posing potential risk to both the ecological environment and human health. Accurately assessing the environmental risk associated with the recycling of spent LABs is a prerequisite for achieving pollution control. In this study, a spent LABs recycling factory in Chongqing was investigated through on-site investigation, sample analysis. Exposure assessment and health risk assessment were also conducted. The results showed that: firstly, Pb and As concentrations exceeding the standard limit values were found in the environmental air and vegetables near the spent LABs recycling factory. Secondly, exposure assessment results showed that total average daily exposure to hazardous substances for children (3.46 × 10-2 mg/kg) is higher than for adults (4.80 × 10-2 mg/kg). The main exposure pathways for Pb, Cr, Ni, Cu, Zn, and Hg are ingestion of vegetables, while those for Cd, As, and Sb are through inhalation. Thirdly, health risk assessment results indicate that environmental exposure poses unacceptable non-carcinogenic and carcinogenic risk to both adults and children near the spent LABs recycling factory, with children facing higher risk than adults. Pb and As are the main contributors to non-carcinogenic risk, and Ni and As are the main contributors to unacceptable carcinogenic risk. In particular, As, has a greater contribution to total carcinogenic risk index through inhalation than vegetable ingestion. Overall, vegetable ingestion and inhalation are the main exposure pathways for non-carcinogenic and carcinogenic risk. Consequently, future risk assessment should focus on the impact of hazardous substances on children, as well as the health risk associated with ingestion of vegetables and inhalation. Our findings will provide basic information for proposing measures of environmental risk prevention during the recycling of spent LABs, for example, controlling of As in exhaust gas emissions.

Catalpol ameliorates inflammation and oxidative stress via regulating Sirt1 and activating Nrf2/HO-1 signaling against acute kidney injury.

BACKGROUND: Septic acute kidney injury (SAKI) is usually caused by sepsis. It has been shown that catalpol (Cat) impairs sepsis-evoked organ dysfunction to a certain degree. The current work aims to evaluate the protective effects of Cat on SAKI and potential mechanisms in vivo and in vitro. METHODS: SAKI cellular and murine model were set up using lipopolysaccharide (LPS) in vitro and in vivo. Cell apoptosis in cells was determined by TUNEL assay. Levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA). The levels of the markers of oxidative injury were evaluated by corresponding commercial kits. Protein levels were assayed via western blotting and immunohistochemistry (IHC) staining. RESULTS: The results demonstrated that LPS upregulated TNF-α, IL-6, and malondialdehyde levels, and downregulated superoxide dismutase, whereas Cat treated cells have the opposite results. Functional assays displayed that Cat remarkably reversed the LPS-challenged damage as the impairment of TNF-α and IL-6 levels, oxidative stress, and the apoptosis in HK-2 cells. Moreover, knockdown of Sirtuin 1 (Sirt1) counteracted the suppressive impact of Cat on LPS-triggered inflammatory response, oxidative stress, and renal damage. Further, Cat elevated Sirt1 expression and activated the Nrf2/HO-1 signaling in LPS-engendered SAKI in vivo and in vitro. CONCLUSION: Our study clearly proved that Cat protected against LPS-induced SAKI via synergic antioxidant and anti-inflammatory actions by regulating Sirt1 and Nrf2/HO-1 signaling pathways.

Altered brain network topology during speech tracking in developmental dyslexia.

Developmental dyslexia is often accompanied by altered phonological processing of speech. Underlying neural changes have typically been characterized in terms of stimulus- and/or task-related responses within individual brain regions or their functional connectivity. Less is known about potential changes in the more global functional organization of brain networks. Here we recorded electroencephalography (EEG) in typical and dyslexic readers while they listened to (a) a random sequence of syllables and (b) a series of tri-syllabic real words. The network topology of the phase synchronization of evoked cortical oscillations was investigated in four frequency bands (delta, theta, alpha and beta) using minimum spanning tree graphs. We found that, compared to syllable tracking, word tracking triggered a shift toward a more integrated network topology in the theta band in both groups. Importantly, this change was significantly stronger in the dyslexic readers, who also showed increased reliance on a right frontal cluster of electrodes for word tracking. The current findings point towards an altered effect of word-level processing on the functional brain network organization that may be associated with less efficient phonological and reading skills in dyslexia.

17ß-estradiol reduces NF-κB expression induced by increased crosstalk between KLF5 and ERα in murine vascular smooth muscle cells.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17ß-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

Adsorption properties of pyramidal superatomic molecules based on the structural framework of the Au20 cluster.

The pyramidal Au20 cluster is a highly inert and stable superatomic molecule, but it is not suitable as a potential catalyst for covalent bond activations, e.g., CO oxidation reaction. Herein, the adsorption and electronic properties of CO molecules on various pyramidal clusters based on the structural framework of Au20 are investigated using density functional theory. According to the SVB model, we constructed isoelectronic superatomic molecules with different pyramid configurations by replacing the vertex atoms of the Au20 using metal M atoms (M = Li, Be, Ni, Cu, and Zn group atoms). After the CO molecules are adsorbed on the vertex atoms of these metal clusters, we analyzed the CO adsorption energies, C-O bond stretching frequencies, and electronic properties of the adsorption structures. It was found that the adsorption of CO molecules results in minimal changes in the parent geometries of the pyramidal clusters, and most adsorption structures are consistent with the geometry of CO adsorption at the vertex site of the Au20 cluster. There are significant red shifts when CO molecules are adsorbed on the Ni/Pd/Pt atoms of the clusters, and their CO adsorption energies were also greater. The molecular orbitals and density of states reveal that there are overlaps between the frontier orbitals of the clusters and CO, and the electronic structure of NiAu19- is not sensitive to CO. The ETS-NOCV analysis shows that the increase in the density of the bonding area caused by the orbital interactions between the fragments is higher than the decrease in the density of the bonding area caused by Pauli repulsion, presenting that the direction of charge flow in the deformation density is from CO → clusters. From energy decomposition analysis (EDA) and NPA charge, we find a predominant covalent nature of the contributions in CO⋯M interactions (σ-donation). Our study indicates that the SVB model provides a new direction to expand the superatomic catalysts from the superatom clusters, which also provides inference for the extension of the single atom catalysis.

Characterization of ß-Glucan-Peanut Protein Isolate/Soy Protein Isolate Conjugates and Their Application on Low-Fat Sausage.

Polysaccharide-protein conjugates can improve the functional properties and expand the application field. The emulsifying, thermal properties of WSG-PPI conjugates and WSG-SPI conjugates were improved, compared to WSG, PPI and SPI. The Maillard reaction was confirmed by Fourier transform infrared spectroscopy (FT-IR). Circular dichroism (CD) exhibited that the structure of the conjugates was more expanded. Cryo-SEM and AFM demonstrated that the WSG, WSG-PPI and WSG-SPI conjugates had a morphology of a chain. When the conjugates were added as fat substitutes to low-fat sausage, the cooking yield, hardness and chewiness increased. The objective of this research was to study the emulsifying property, thermal property and structural changes of ß-glucan-peanut protein isolate (WSG-PPI) conjugates and ß-glucan-soy protein isolate (WSG-SPI) conjugates prepared through wet-heated Maillard reaction, and their effect on the texture of low-fat sausage.

An Effective Chromatography Process for Simultaneous Purification and Separation of Total Lignans and Flavonoids from Valeriana amurensis.

An effective chromatography process was developed and validated for simultaneous purification and separation of total lignans and flavonoids from Valeriana amurensis. The total lignans and flavonoids in Valeriana amurensis extract were prepurified with macroporous resin column chromatography, and the conditions were optimized as follows: 40 mg/mL Valeriana amurensis extract (2.0 g) solution was loaded onto an AB-8 resin column with a diameter-to-height ratio of 1:7, followed by adsorption for 6 h; then, the column was eluted successively with 5 BV water and 10% and 50% ethanol at a flow rate 2 BV/h. The obtained 50% ethanol fraction was further repurified and separated by polyamide resin column chromatography to obtain the total lignans and flavonoids, respectively. The chromatography conditions were optimized as follows: a 50% ethanol fraction (1.0 g) was mixed with 1.0 g polyamide resin and loaded onto a polyamide resin (60-100 mesh) column with a diameter-to-height ratio of 1:3; then, the column was eluted successively with 6 BV water and 40% and 80% ethanol at a flow rate of 4 BV/h. The total lignans and flavonoids were obtained from water and 80% ethanol fraction, respectively. The content and recovery of standard compounds in total lignans and flavonoids were analyzed with HPLC-PDA, and the feasibility of the process was confirmed.

Failure of resting-state frontal-occipital connectivity in linking visual perception with reading fluency in Chinese children with developmental dyslexia.

It is widely accepted that impairment in visual perception impedes children's reading development, and further studies have demonstrated significant enhancement in reading fluency after visual perceptual training. However, the mechanism of the neural linkage between visual perception and reading is unclear. The purpose of this study was to examine the intrinsic functional relationship between visual perception (indexed by the texture discrimination task,TDT) and reading ability (character reading and reading fluency) in Chinese children with developmental dyslexia (DD) and those with typical development (TD). The resting-state functional connectivity (RSFC) between the primary visual cortex (V1, BA17) and the entire brain was analyzed. In addition, how RSFC maps are associated with TDT performance and reading ability in the DD and TD groups was examined. The results demonstrated that the strength of the RSFC between V1 and the left middle frontal gyrus (LMFG, BA9/BA46) was significantly correlated with both the threshold (SOA) of the TDT and reading fluency in TD children but not in DD children. Moreover, LMFG-V1 resting-state connectivity played a mediating role in the association of visual texture discrimination and reading fluency, but not in character reading, in TD children. In contrast, this mediation was absent in DD children, albeit their strengths of RSFC between V1 and the left middle frontal gyrus (LMFG) were comparable to those for the TD group. These findings indicate that typically developing children use the linkage of the RSFC between the V1 and LMFG for visual perception skills, which in turn promote fluent reading; in contrast, children with dyslexia, who had higher TDT thresholds than TD children, could not take advantage of their frontal-occipital connectivity to improve reading fluency abilities. These findings suggest that visual perception plays an important role in reading skills and that children with developmental dyslexia lack the ability to use their frontal-occipital connectivity to link visual perception with reading fluency.

Triglyceride-glucose index and the incidence of atherosclerotic cardiovascular diseases: a meta-analysis of cohort studies.

BACKGROUND: Insulin resistance has been demonstrated to be involved in the pathogenesis of atherosclerotic cardiovascular diseases (ASCVDs). This study evaluated the association between the triglyceride-glucose (TyG) index, a novel surrogate indicator of insulin resistance, and the incidence of ASCVDs in people without ASCVDs at baseline by performing a meta-analysis. METHODS: Cohort studies reporting the multivariate-adjusted association between the TyG index and the incidence of ASCVDs were obtained by searching the PubMed and Embase databases. A random-effects model incorporating intra-study heterogeneity was applied to combine the results. RESULTS: Eight cohort studies comprising 5,731,294 participants were included in this meta-analysis. The results showed that compared to those with the lowest TyG index category, participants with the highest TyG index category were independently associated with a higher risk of ASCVDs [hazard ratio (HR): 1.61, 95% confidence interval (CI) 1.29-2.01, I2 = 80%, P < 0.001]. This finding was consistent with the meta-analysis results with the TyG index analyzed as a continuous variable (HR per 1-unit increment of the TyG index: 1.39, 95% CI 1.18-1.64, I2 = 89%, P < 0.001). Subgroup analyses suggested that the age, sex, and diabetic status did not significantly affect the association (for subgroup analyses, all P > 0.05). Moreover, participants with the highest TyG index category were independently associated with a higher risk of coronary artery disease [(CAD), HR: 1.95, 95% CI 1.47-2.58, I2 = 92%, P < 0.001] and stroke (HR: 1.26, 95% CI 1.23-1.29, I2 = 0%, P < 0.001). CONCLUSIONS: A higher TyG index may be independently associated with a higher incidence of ASCVDs, CAD, and stroke in people without ASCVDs at baseline.

Combined exome sequencing and deep phenotyping in highly selected fetuses with skeletal dysplasia during the first and second trimesters improves diagnostic yield.

OBJECTIVE: To investigate the genetic etiology of skeletal dysplasia in highly selected fetuses during the first and second trimesters using deep phenotyping and exome sequencing (ES). METHOD: Fetuses with short femurs were identified using the established prenatal diagnostic approach. A multidisciplinary team reviewed fetal phenotypic information (prenatal ultrasound findings, fetal postmortem, and radiographs) in a cohort of highly selected fetuses with skeletal dysplasia during the first and second trimesters. The affected families underwent multiplatform genetic tests. RESULTS: Of the 27 affected fetuses, 21 (77.8%) had pathogenic or potential pathogenic variations in the following genes: COL1A1, FGFR3, COL2A1, COL1A2, FLNB, DYNC2LI1, and TRIP11. Two fetuses had compound heterozygous mutations in DYNC2LI1 and TRIP11, respectively, and the other 19 carried de novo autosomal dominant variants. Novel variants were identified in COL1A1, COL2A1, COL1A2, DYNC2LI1, and TRIP11 in 11 fetuses. We also included the first description of the phenotype of odontochondrodysplasia in a prenatal setting. CONCLUSIONS: ES or panel sequencing offers a high diagnostic yield for fetal skeletal dysplasia during the first and second trimesters. Comprehensive and complete phenotypic information is indispensable for genetic analysis and the expansion of genotype-phenotype correlations in fetal skeletal abnormalities.

17ß-Estradiol Attenuates LPS-Induced Macrophage Inflammation In Vitro and Sepsis-Induced Vascular Inflammation In Vivo by Upregulating miR-29a-5p Expression.

Excessive release of cytokines such as IL-1ß and other inflammatory mediators synthesized and secreted by macrophages is the fundamental link of uncontrolled inflammatory response in sepsis. 17ß-Estradiol (E2) plays anti-inflammatory and vascular protective effects by regulating leukocyte infiltration and the expression of chemokines or cytokines induced by injury. However, the role of E2 in the inflammatory response of macrophages in sepsis and its mechanism are still not fully understood. In the present study, we show that E2 alleviates vascular inflammation in sepsis mice induced by cecal ligation puncture (CLP). E2 significantly decreases RAW 264.7 cell inflammation response by downregulating the expression of NLRP3. Furthermore, we found that miR-29a-5p was significantly downregulated in LPS-treated macrophages. Treating RAW 264.7 cells with E2 markedly upregulated the miR-29a-5p expression level. More importantly, we demonstrated that miR-29a-5p repressed NLRP3 expression by directly targeting its 3'-UTR. Loss- and gain-of-function experiments revealed that transfection of the miR-29a-5p mimic abrogates LPS-induced macrophage inflammation. Moreover, depletion of miR-29a-5p by its inhibitor largely promotes LPS-induced macrophage inflammation. In summary, miR-29a-5p upregulation induced by E2 alleviated RAW 264.7 cell inflammation response by aggravating miR-29a-5p repression of NLRP3 expression. E2 exerts significant anti-inflammatory efficacy in macrophages by regulating the miR-29a-5p/NLRP3 axis. Targeting miR-29a-5p may be a novel therapeutic strategy to suppress sepsis-induced vascular inflammation.

Inflammatory and Cytotoxic Activities of Abietane Terpenoids from Nepeta bracteata Benth.

Nepeta bracteata Benth. is used clinically to treat tracheal inflammation, coughs, asthma, colds, fevers, adverse urination, and other symptoms, along with functions in clearing heat and removing dampness. However, there have been few studies characterizing the material basis of its efficacy. Therefore, the aim of this study was to screen for compounds with anti-inflammatory activities in N. bracteata Benth. Using silica gel, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, 10 compounds were separated from N. bracteata Benth. extract, including four new diterpenoids (1-4), one amide alkaloid (5), and five known diterpenoids (6-10). The structures of all the isolates were elucidated by HR-ESI-MS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, we investigated the anti-inflammatory activities of compounds 1-10. It is worth noting that all were able to inhibit nitric oxide (NO) production with IC50 values < 50 µM and little effect on RAW 264.7 macrophage viability. Compounds 2 and 4 displayed remarkable inhibition with IC50 values of 19.2 and 18.8 µM, respectively. Meanwhile, screening on HCT-8 cells demonstrated that compounds 2 and 4 also had moderate cytotoxic activities with IC50 values of 36.3 and 41.4 µM, respectively, which is related to their anti-inflammatory effects.

Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer.

Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc finger-homeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-ß, ß-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.