Exploring the association of POSTN+ cancer-associated fibroblasts with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis. Cancer-associated fibroblasts (CAFs) play a critical role in regulating TNBC tumor development. This study aimed to identify and characterize a specific subtype of CAFs associated with TNBC. Initially, using high-throughput bulk transcriptomic data in two cohorts, we identified three CAF-related subtypes (CS1, CS2, CS3) in TNBC samples. These three CAFs subtypes were closely linked to the tumor microenvironment. The CS1 subtype exhibited a relatively immune-rich microenvironment and a favourable prognosis, whereas the CS3 subtype displayed an immune-deprived tumor microenvironment and an unfavourable prognosis. Through WGCNA analysis, POSTN was identified as a key biomarker for CAFs associated with TNBC. Then, POSTN+CAFs was identified and characterized. Both POSTN and POSTN+CAFs showed significant positive correlations with stromal molecules HGF and MET at both the transcriptional and protein levels. Specifically co-localized with CAFs in the tumor stromal area, POSTN, produced by POSTN+CAFs, could modulate the HGF-MET axis, serving as a bypass activation pathway to regulate tumor cell proliferation in response to EGFR inhibitor and MET inhibitor. This study underscores the significance of POSTN and POSTN+CAFs as crucial targets for the diagnosis and treatment of TNBC.

PSMC2 knockdown exerts an anti-tumor role in nasopharyngeal carcinoma through regulating AKT signaling pathway.

Nasopharyngeal carcinoma is a major public health problem in several countries, particularly in Southeast Asia and North Africa. However, the mechanism underlying the malignant biological behaviors of nasopharyngeal carcinoma is not fully clear. Our study intended to investigate the functional importance and molecular mechanism of proteasome 26 S subunit ATPase 2 (PSMC2) in the progression of nasopharyngeal carcinoma. We examined the expression of PSMC2 in both nasopharyngeal carcinoma tissues and normal healthy tissues using immunohistochemistry (IHC). Additionally, we conducted a series of cell experiments to verify the functional roles of PSMC2 and to explore the underlying pathway involved. The results revealed that PSMC2 was significantly upregulated in nasopharyngeal carcinoma tissues compared to normal tissues. Moreover, high PSMC2 was shown to closely correlate with the pathological stage and tumor infiltrate in nasopharyngeal carcinoma patients. Functionally, we observed a suppression of nasopharyngeal carcinoma progression upon knocking down PSMC2. This was evidenced by inhibited cell proliferation and migration in vitro, as well as impaired cell growth in vivo, along with increased apoptosis. Mechanistically, the inhibitory effects of PSMC2 silence on nasopharyngeal carcinoma could be reversed by the addition of AKT activator. Overall, our study sheds light on a novel mechanism underlying the development and progression of nasopharyngeal carcinoma, with PSMC2 exerting a positive regulatory role through the modulation of the AKT signaling pathway. A deeper understanding of PSMC2 may contribute to the development of improved treatment strategies for nasopharyngeal carcinoma.

Mutational antigenic landscape of prevailing H9N2 influenza virus hemagglutinin spectrum.

H9N2 influenza viruses are globally endemic in birds, and a sharp increase in human infections with H9N2 occurred during 2021 to 2022. In this study, we assess the antigenic and pathogenic impact of 23 hemagglutinin (HA) amino acid mutations. Our study reveals that three specific mutations, labeled R164Q, N166D, and I220T, are responsible for the binding of antibodies with escape mutations. Variants containing R164Q and I220T mutations increase viral replication in avian and mammalian cells. Furthermore, T150A and I220T mutations are found to enhance viral replication in mice, indicating that these mutations may have the potential to adapt mammals. Structure analysis reveals that residues 164 and 220 bearing R164Q and I220T mutations increase interactions with the surrounding residues. Our findings enrich current knowledge about the risk assessment regarding which predominant HA immune-escape mutations of H9N2 viruses may pose the greatest threat to the emergence of pandemics in birds and humans.

Atypical Sliding and Moiré Ferroelectricity in Pure Multilayer Graphene.

Most nonferroelectric two-dimensional materials can be endowed with so-called sliding ferroelectricity via nonequivalent homobilayer stacking, which is not applicable to monoelement systems like pure graphene bilayer with inversion symmetry at any sliding vector. Herein, we show first-principles evidence that multilayer graphene with N>3 can all be ferroelectric, where the polarizations of polar states stem from the symmetry breaking in stacking configurations of across layer instead of adjacent layer, which are electrically switchable via interlayer sliding. The nonpolar states can also be electrically driven to polar states via sliding, and more diverse states with distinct polarizations will emerge in more layers. In contrast to the ferroelectric moiré domains with opposite polarization directions in twisted bilayers reported previously, the moiré pattern in some multilayer graphene systems (e.g., twisted monolayer-trilayer graphene) possess nonzero net polarizations with domains of the same direction separated by nonpolar regions, which can be electrically reversed upon interlayer sliding. The distinct moiré bands of two polar states should facilitate electrical detection of such sliding moiré ferroelectricity during switching.

tRNA-Derived RNA Fragments Are Novel Biomarkers for Diagnosis, Prognosis, and Tumor Subtypes in Prostate Cancer.

BACKGROUND: tRNA-derived RNA fragments (tRFs) are a novel class of small ncRNA that are derived from precursor or mature tRNAs. Recently, the general relevance of their roles and clinical values in tumorigenesis, metastasis, and recurrence have been increasingly highlighted. However, there has been no specific systematic study to elucidate any potential clinical significance for these tRFs in prostate adenocarcinoma (PRAD), one of the most common and malignant cancers that threatens male health worldwide. Here, we investigate the clinical value of 5'-tRFs in PRAD. METHODS: Small RNA sequencing data were analyzed to discover new 5'-tRFs biomarkers for PRAD. Machine learning algorithms were used to identify 5'-tRF classifiers to distinguish PRAD tumors from normal tissues. LASSO and Cox regression analyses were used to construct 5'-tRF prognostic predictive models. NMF and consensus clustering analyses were performed on 5'-tRF profiles to identify molecular subtypes of PRAD. RESULTS: The overall levels of 5'-tRFs were significantly upregulated in the PRAD tumor samples compared to their adjacent normal samples. tRF classifiers composed of 13 5'-tRFs achieved AUC values as high as 0.963, showing high sensitivity and specificity in distinguishing PRAD tumors from normal samples. Multiple 5'-tRFs were identified as being associated with the PRAD prognosis. The tRF score, defined by a set of eight 5'-tRFs, was highly predictive of survival in PRAD patients. The combination of tRF and Gleason scores showed a significantly better performance than the Gleason score alone, suggesting that 5'-tRFs can offer PRAD patients additional and improved prognostic information. Four molecular subtypes of the PRAD tumor were identified based on their 5'-tRF expression profiles. Genetically, these 5'-tRFs PRAD tumor subtypes exhibited distinct genomic landscapes in tumor cells. Clinically, they showed marked differences in survival and clinicopathological features. CONCLUSIONS: 5'-tRFs are potential clinical biomarkers for the diagnosis, prognosis, and classification of tumor subtypes on a molecular level. These can help clinicians formulate personalized treatment plans for PRAD patients and may have similar potential applications for other disease types.

Key amino acid position 272 in neuraminidase determines the replication and virulence of H5N6 avian influenza virus in mammals.

Avian influenza H5N6 virus not only wreaks economic havoc in the poultry industry but also threatens human health. Strikingly, as of August 2022, 78 human beings were infected with H5N6, and the spike in the number of human infections with H5N6 occurred during 2021. In the life cycle of influenza virus, neuraminidase (NA) has numerous functions, especially viral budding and replication. Here, we found that NA-D272N mutation became predominant in H5N6 viruses since 2015 and significantly increased the viral replication and virulence in mice. D272N mutation in NA protein increased viral release from erythrocytes, thermostability, early transcription, and accumulation of NA protein. Particularly, the dominant 272 residue switch from N to S has occurred in wild bird-origin H5N6 viruses since late 2016 and N272S mutation induced significantly higher levels of inflammatory cytokines in infected human cells. Therefore, comprehensive surveillance of bird populations needs to be enhanced to monitor mammalian adaptive mutations of H5N6 viruses.

The lncRNA GATA3-AS1/miR-495-3p/CENPU axis predicts poor prognosis of breast cancer via the PLK1 signaling pathway.

The function of centromere protein U (CENPU) gene in breast cancer has not been well understood. Therefore, we explored the expression profiles of CENPU gene in breast carcinoma to better understand the functions of this gene, as well as the relationship between CENPU expression and the prognosis of breast carcinoma patients. Our results indicate that CENPU was expressed at significantly higher levels in cancerous tissues than in normal tissues. Furthermore, CENPU expression correlated significantly with many clinicopathological characteristics of breast cancer. In addition, we discovered that high levels of CENPU expression predicted poor prognosis in patients with breast cancer. Functional investigation revealed that 180 genes exhibited co-expression with CENPU. Functional annotation indicated that 17 of these genes were involved in the PLK1 signaling pathway, with most of them (16/17) being expressed at significantly higher levels in malignant tissues compared with normal controls and correlating with a poor prognosis. Subsequently, we found that four miRNAs, namely hsa-miR-543, hsa-miR-495-3p, hsa-miR-485-3p, and hsa-miR-337-3p, could be regarded as potential CENPU expression regulators. Then, five lncRNAs were predicted to potentially bind to the four miRNAs. Combination of the results from expression, survival, correlation analysis and functional experiments analysis demonstrated the link between lncRNA GATA3-AS1/miR-495-3p/CENPU axis and prognosis of breast cancer. In conclusion, CENPU could be involved in cell cycle progression through PLK1 signaling pathway.

Phosphoproteome Profiling Revealed the Importance of mTOR Inhibition on CDK1 Activation to Further Regulate Cell Cycle Progression.

The mammalian target of rapamycin (mTOR) functions as a critical regulator of cell cycle progression. However, the underlying mechanism by which mTOR regulates cell cycle progression remains elusive. In this study, we used stable isotope labeling of amino acids in cell culture with a two-step strategy for phosphopeptide enrichment and high-throughput quantitative mass spectrometry to perform a global phosphoproteome analysis of mTOR inhibition by rapamycin. By monitoring the phosphoproteome alterations upon rapamycin treatment, downregulation of mTOR signaling pathway was detected and enriched. Further functional analysis of phosphoproteome revealed the involvement of cell cycle events. Specifically, the elevated profile of cell cycle-related substrates was observed, and the activation of CDK1, MAPK1, and MAPK3 kinases was determined. Second, pathway interrogation using kinase inhibitor treatment confirmed that CDK1 activation operated downstream from mTOR inhibition to further regulate cell cycle progression. Third, we found that the activation of CDK1 following 4-12 h of mTOR inhibition was accompanied by the activation of the Greatwall-endosulfine complex. In conclusion, we presented a high-confidence phosphoproteome map inside the cells upon mTOR inhibition by rapamycin. Our data implied that mTOR inhibition could contribute to CDK1 activation for further regulating cell cycle progression, which was mediated by the Greatwall-endosulfine complex.

Improved Stability and Targeted Cytotoxicity of Epigallocatechin-3-Gallate Palmitate for Anticancer Therapy.

Although with high antioxidant activity, epigallocatechin-3-gallate (EGCG) was restricted by its poor chemical stability in practical applications. One of EGCG derivatives, EGCG palmitate, was synthesized with EGCG and palmitoyl chloride to overcome instability of EGCG. However, uncertainties still exist in chemical stability and cytotoxicity of EGCG palmitate, which are essential for further exploration in anticancer therapy. Our work aims to analyze the resistance of EGCG palmitate to oxidation and summarize its targeted inhibition efficiency on cancerous cells and normal cells. High-performance liquid chromatography analysis confirmed that EGCG palmitate remained stable in air and Dulbecco's modified eagle medium (DMEM) for a longer time than EGCG. Antioxidative and pro-oxidative effects of EGCG palmitate on treated cells are proposed through reactive oxygen species (ROS) detection, respectively. It reveals that pro-oxidants by H2O2 production can exert antiproliferative and proapoptotic effects on cancerous cells and stimulate autophagy, while an antioxidant relieves oxidative stress caused by superoxide as compared to normal cells. Consequently, targeted cytotoxicity is adopted by EGCG palmitate-treated cancerous cells. Results above manifest that EGCG palmitate possesses potential to serve as a promising prodrug in anticancer treatment.

Helicobacter hepaticus Infection Promotes the Progression of Liver Preneoplasia in BALB/c Mice via the Activation and Accumulation of High-Mobility Group Box-1.

It has been documented that Helicobacter hepaticus (H. hepaticus) infection is linked to chronic hepatitis and fibrosis in male BALB/c mice. However, the mechanism underlying the mice model of H. hepaticus-induced hepatocellular carcinoma is not fully known. In this study, male BALB/c mice were infected with H. hepaticus for 3, 6, 12, and 18 months. H. hepaticus colonization, histopathology, expression of proinflammatory cytokines, key signaling pathways, and protein downstream high-mobility group box-1 (HMGB1) in the liver were examined. Our data suggested that the H. hepaticus colonization level in the colon and liver progressively increased over the duration of the infection. H. hepaticus-induced hepatic inflammation and fibrosis were aggravated during the infection, and hepatic preneoplasia developed in the liver of infected mice at 12 and 18 months post-inoculation (MPI). H. hepaticus infection increased the levels of alanine aminotransferase and aspartate aminotransferase in the infected mice. In addition, the mRNA levels of IL-6, Tnf-α, Tgf-ß, and HMGB1 were significantly elevated in the liver of H. hepaticus-infected mice from 3 to 18 MPI as compared to the controls. In addition, Ki67 was increased throughout the duration of the infection. Furthermore, HMGB1 protein was activated and translocated from the nucleus to the cytoplasm in the hepatocytes and activated the proteins of signal transducers and activators of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) [extracellular regulated protein kinases 1/2 (Erk1/2) and mitogen-activated protein kinase p38 (p38)] upon H. hepaticus infection. In conclusions, these data demonstrated that male BALB/c mice infected with H. hepaticus are prone to suffering hepatitis and developing into hepatic preneoplasia. To verify the effect of HMGB1 in the progression of liver preneoplasia, mice were infected by H. hepaticus for 2 months before additional HMGB1 recombinant adenovirus treatment. All mice were sacrificed at 4 MPI, and the sera and liver tissues from all of the mice were collected. Immunology and histopathology evaluation showed that HMGB1 knockdown attenuated the H. hepaticus-induced hepatic and fibrosis at 4 MPI. Therefore, we showed that H. hepaticus-induced liver preneoplasia is closely correlated with the activation and accumulation of HMGB1.

Characterization of cytokine profile to distinguish latent tuberculosis from active tuberculosis and healthy controls.

BACKGROUND: Tuberculosis (TB) is an infectious disease and its mortality rate ranks first. Latent tuberculosis infection (LTBI) means that a patient is infected with Mycobacterium tuberculosis, but has no relative clinical symptoms. It has been estimated that approximately 10% of patients with LTBI would develop into active tuberculosis. Therefore, it was urgent to search for more efficient biomarkers to discriminate LTBI from healthy population. METHODS: The Luminex assay was employed to detect the quantity of cytokines secreted by mononuclear cells from peripheral blood stimulated with the ESAT6 protein among TB, LTBI and healthy controls. The cytokine profile was analyzed by principal components analysis and the receiver operating characteristic curve analysis. RESULTS: The principal components analysis indicated that LTBI and TB were clearly separated from healthy controls, and that LTBI was also successfully differentiated from healthy controls. The cytokine profiling method to distinguish LTBI from healthy controls has a sensitivity and specificity of 100%. Nine potential biomarkers, including IL-23, IL-21, HGF, Bngf, IL-27, IL-31, IL-1ß, IL-22 and IL-18, were identified, and these cytokines were considered as a potential cytokine complex for more effectively discriminating LTBI from healthy controls. CONCLUSION: IL-23, IL-21, HGF, Bngf, IL-27, IL-31, IL-1ß, IL-22 and IL-18 were demonstrated to be the potential cytokine complex for the assessment between LTBI and healthy controls.

Duo of (-)-epigallocatechin-3-gallate and doxorubicin loaded by polydopamine coating ZIF-8 in the regulation of autophagy for chemo-photothermal synergistic therapy.

To achieve highly systemic therapeutic efficacy, chemotherapy is combined with photothermal therapy for chemo-photothermal synergistic therapy; however, this strategy suffers from high toxicity and unsatisfactory sensitivity for cancer cells. Herein, we developed a pH- and photothermal-responsive zeolitic imidazolate framework (ZIF-8) compound for loading a dual-drug in the tumor site and improving their curative effects. Since autophagy always accompanies tumor progression and metastasis, there is an unmet need for an anticancer treatment related to the regulation of autophagy. Green tea polyphenols, namely, (-)-epigallocatechin-3-gallate (EGCG) and doxorubicin (DOX), both of which exhibit anticancer activity, were dual-loaded via polydopamine (PDA) coating ZIF-8 (EGCG@ZIF-PDA-PEG-DOX, EZPPD for short) through hierarchical self-assembly. PDA could transfer photothermal energy to increase the temperature under near-infrared (NIR) laser irradiation. Due to its pH-response, EZPPD released EGCG and DOX in the tumor microenvironment, wherein the temperature increased with the help of PDA and NIR laser irradiation. The duo of DOX and EGCG induced autophagic flux and accelerated the formation of autophagosomes. In a mouse HeLa tumor model, photothermal-chemotherapy could ablate the tumor with a significant synergistic effect and potentiate the anticancer efficacy. Thus, the results indicate that EZPPD renders the key traits of a clinically promising candidate to address the challenges associated with synergistic chemotherapy and photothermal utilization in antitumor therapy.

Comprehensive Analysis of Lysine Acetylome Reveals a Site-Specific Pattern in Rapamycin-Induced Autophagy.

Protein acetylation reportedly acts as a key regulator of autophagy. However, up to now, the relationship between acetylome and autophagy has remained unclear. Here stable isotope labeling of amino acids in cell culture and high-throughput quantitative mass spectrometry were used to perform an acetylome analysis of rapamycin-induced autophagy in vitro. Our data revealed that 2135 sites were quantified on 1081 proteins. During autophagy, 421 sites were significantly regulated on 296 proteins, with 80.8% of sites downregulated and 19.2% upregulated. Motif enrichment analysis revealed five main motifs. Most of the downregulated sites conformed to the classical functional motif of p300/CBP [G-AcK]. Furthermore, acetylation targeted proteins involved mainly in ribosomes, spliceosomes, and AcCoA-related metabolic process. In-depth analysis indicated that most of the acetylation sites were in the critical domain, were functional sites, or could change their enzymatic activity by acetylation, highlighting the importance of site-specific acetylation patterns. Subsequently, we demonstrated that K1549 of p300 was also a functional site that could regulate the autophagic process in vitro. In conclusion, our data reveal a deacetylation-preponderant profile with autophagy. The specificity of the related motifs and the identification of site-specific acetylation patterns will assist searches for potential targets or subsequent mechanism-focused studies to elucidate site-specific protein networks in autophagy.

FA-PEG decorated MOF nanoparticles as a targeted drug delivery system for controlled release of an autophagy inhibitor.

A zeolitic imidazolate framework (ZIF-8) with high loading capacity and pH-responsive properties, an important subclass of metal-organic frameworks (MOFs), has become a promising material for drug delivery. A multifunctional drug delivery system (DDS) was designed in this work for effective targeting delivery of chloroquine diphosphate (CQ) as an autophagy inhibitor. The ZIF-8 nanoparticles encapsulating CQ (CQ@ZIF-8 NPs) were fabricated by a simple one-pot method and were then decorated with methoxy poly(ethylene glycol)-folate (FA-PEG), a special identifier of cancer cells, to form FA-PEG/CQ@ZIF-8. The target identification of FA-PEG/CQ@ZIF-8 NPs, compared with CQ@ZIF-8 NPs, leads to an increasing number of NPs being internalized into HeLa cells, which decreases the loss of drugs and results in high cytotoxicity of CQ for cancer cells. The lower viabilities of HeLa cells (cancer cells) and higher viabilities of HEK293 cells (healthy cells) treated with FA-PEG/CQ@ZIF-8 NPs show that the special target for cancer cells results from the combinations of folic acid and folate receptors on the surface of HeLa cells. The quantitative measurements of autophagy-related proteins and the detection of autophagy flux in HeLa cells suggest that the autophagosome formation and autophagy flux are appreciably blocked after the cells are treated with FA-PEG/CQ@ZIF-8 NPs. The ZIF-8 can disintegrate only under low pH conditions, resulting in fast and full release of CQ. The pH-responsive and tumor-targeted properties of the NPs can control the drug release and enhance the efficiency of autophagy inhibition. It indicates that the FA-PEG/CQ@ZIF-8 NPs combining target identification with controlled drug release can be used as a novel model for discussing targeted cancer therapy and inhibiting the autophagy of cancer cells.

Derivative of Epigallocatechin-3-gallatea Encapsulated in ZIF-8 with Polyethylene Glycol-Folic Acid Modification for Target and pH-Responsive Drug Release in Anticancer Research.

Epigallocatechin-3-gallatea (EGCG), a key component of tea, has been found to have anticancer activity but poor stability. To improve its antioxidative stability and widen the application of EGCG in anticancer therapy, a kind of EGCG derivative, EGCG palmitate (PEGCG), was synthesized and encapsulated in ZIF-8 nanoparticles with functionalization of folic acid (FA), which is commonly used as pH-responsive drug carrier. PEGCG encapsulated in polyethylene glycol (PEG)-FA/ZIF-8 nanoparticles (PEG-FA/PEGCG@ZIF-8 NPs) exhibits sixfold improvement of stability compared to that of free PEGCG. With target recognition between folic acid (FA) on the surface of NPs and overexpressed FA receptor (FR) in cancer cells, the NPs can be efficiently internalized into cells and present targeted effects of inhibition growth on HeLa cells (cancer cells) compared with HEK 293 cells (normal cells), consistent with the regulation of reactive oxygen species (ROS) level and the induction of autophagy. The detection of autophagy flux and the measurement of autophagy marked proteins in cells suggest that autophagy flux and the autophagosome formation are appreciably induced when the cells were treated with PEG-FA/PEGCG@ZIF-8 NPs. It indicates that pH-responsive PEG-FA/PEGCG@ZIF-8 NPs with target identification for cancer cells can be used as highly efficient drug carriers in targeting cancer chemotherapy.

MOF Nanoparticles with Encapsulated Autophagy Inhibitor in Controlled Drug Delivery System for Antitumor.

High porosities, large surface areas, and tunable functionalities made metal-organic frameworks (MOFs) as effective carriers for drug delivery. One of the most promising MOFs is the zeolitic imidazolate framework (ZIF-8) crystal, an advanced functional material for small-molecule delivery, due to its high loading ability and pH-sensitive degradation. As a novel carrier, ZIF-8 nanoparticles were used in this work to control the release of an autophagy inhibitor, 3-methyladenine (3-MA), and prevent it from dissipating in a large quantity before reaching the target. The cellular uptake in HeLa cells of 3-MA encapsulated in ZIF-8 (3-MA@ZIF-8 NPs) is facilitated through the nanoparticle internalization with reference to TEM observations and the quantitative analyses of zinc by ICP-MS. The autophagy-related proteins and autophagy flux in HeLa cells treated with 3-MA@ZIF-8 NPs show that the autophagosome formation is significantly blocked, which reveals that the pH-sensitive dissociation increases the efficiency of autophagy inhibition at the equivalent concentration of 3-MA. In vivo experiments, when compared to free 3-MA, 3-MA@ZIF-8 NPs show a higher antitumor efficacy and repress the expression of autophagy-related markers, Beclin 1 and LC3. It follows that ZIF-8 is an efficient drug delivery vehicle in antitumor therapy, especially in inhibiting autophagy of cancer cells.

IL-6 Inhibits Starvation-induced Autophagy via the STAT3/Bcl-2 Signaling Pathway.

IL-6, a pleiotropic cytokine, has been investigated for its role in regulating autophagy. Yet, its mechanism of action remains unclear. Here, we show that IL-6 exerted anti-autophagic effects on U937 cells through the STAT3 signaling pathway in vitro. The addition of IL-6 to starved U937 cells significantly activated the phosphorylation level of STAT3 (p-STAT3) at Tyr705 and reduced the protein levels of microtubule-associated protein 1 light chain 3 of type II (LC3-II) and Beclin 1. By immunoblotting, we also observed a positive correlation between the p-STAT3 level and Bcl-2 level. Furthermore, treatment with a STAT3 inhibitor, LLL12, or overexpression of a mutant form, STAT3Y705F, reversed the inhibitory effect of IL-6 on autophagy. Knockdown of Beclin 1 or Atg14 by siRNA and over-expression of Beclin 1 indicated the involvement of class III PI3K complex in IL-6-mediated inhibition of autophagy. Taken together, these data indicate that IL-6 inhibits starvation-induced autophagy and that p-STAT3 mediates the signal transduction from IL-6 to downstream proteins including Bcl-2 and Beclin1.

Antibacterial Activity, in Vitro Cytotoxicity, and Cell Cycle Arrest of Gemini Quaternary Ammonium Surfactants.

Twelve gemini quaternary ammonium surfactants have been employed to evaluate the antibacterial activity and in vitro cytotoxicity. The antibacterial effects of the gemini surfactants are performed on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with minimum inhibitory concentrations (MIC) ranging from 2.8 to 167.7 µM. Scanning electron microscopy (SEM) analysis results show that these surfactants interact with the bacterial cell membrane, disrupt the integrity of the membrane, and consequently kill the bacteria. The data recorded on C6 glioma and HEK293 human kidney cell lines using an MTT assay exhibit low half inhibitory concentrations (IC50). The influences of the gemini surfactants on the cell morphology, the cell migration ability, and the cell cycle are observed through hematoxylin-eosin (HE) staining, cell wound healing assay, and flow cytometric analyses, respectively. Both the values of MIC and IC50 decrease against the growth of the alkyl chain length of the gemini surfactants with the same spacer group. In the case of surfactants 12-s-12, the MICs and IC50s are found to decrease slightly with the spacer chain length changing from 2 to 8 and again to increase at higher spacer length (s = 10-12). All of the gemini surfactants show great antibacterial activity and cytotoxicity, and they might exhibit potential applications in medical fields.

The miR-30a Negatively Regulates IL-17-Mediated Signal Transduction by Targeting Traf3ip2.

Interleukin-17 (IL-17) has been proved to be involved in the pathogenesis of several autoimmune diseases, including lupus, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. The regulation of IL-17 signal transduction is less studied. miR-30a has been identified to be downregulated in these human autoimmune diseases and their related animal models. However, how it functions in IL-17-mediated inflammation and the pathogenesis of these diseases remain unknown. In this study, we showed that miR-30a inhibits IL-17-mediated NF-κB and MAPK activation, leading to the reduced production of inflammatory cytokines and chemokines. miR-30a also reduced mRNA stability triggered by IL-17 stimulation. These suppressive effects of miR-30a were mediated by directly targeting Traf3ip2 mRNA (coding for Act1). Thus, we concluded that the downregulation of miR-30a in autoimmune diseases may exacerbate IL-17-mediated inflammation, which may serve as a potential target for the therapy of these diseases.