Lactobacillus Firm-5-derived succinate prevents honeybees from having diabetes-like symptoms.

The gut microbiome plays an important role in honeybee hormonal regulation and growth, but the underlying mechanisms are poorly understood. Here, we showed that the depletion of gut bacteria resulted in reduced expression of insulin-like peptide gene (ilp) in the head, accompanied by metabolic syndromes resembling those of Type 1 diabetes in humans: hyperglycemia, impaired lipid storage, and decreased metabolism. These symptoms were alleviated by gut bacterial inoculation. Gut metabolite profiling revealed that succinate, produced by Lactobacillus Firm-5, played deterministic roles in activating ilp gene expression and in regulating metabolism in honeybees. Notably, we demonstrated that succinate modulates host ilp gene expression through stimulating gut gluconeogenesis, a mechanism resembling that of humans. This study presents evidence for the role of gut metabolite in modulating host metabolism and contributes to the understanding of the interactions between gut microbiome and bee hosts.

Up-regulation of RNA m6A methyltransferase like-3 expression contributes to arsenic and benzo[a]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis.

While arsenic or BaP alone exposure can cause lung cancer, studies showed that arsenic plus BaP co-exposure displays a significantly stronger lung tumorigenic effect. However, the underlying mechanism has not been well understood. Studies showed that RNA molecules are chemically modified. The most frequently occurring RNA modification in eukaryotic messenger RNAs is the N6-methyladenosine (m6A) methylation. This study aimed to determine whether arsenic plus BaP exposure alters RNA m6A methylation and its role in lung tumorigenic effect of arsenic plus BaP exposure. Human bronchial epithelial cells transformed by exposure to arsenic or BaP alone, and arsenic plus BaP and mouse xenograft tumorigenesis models were used in this study. It was found that arsenic plus BaP exposure-transformed cells have significantly higher levels of RNA m6A methylation than arsenic or BaP alone exposure-transformed human bronchial epithelial cells. Western blot analysis showed that arsenic plus BaP exposure greatly up-regulates the m6A writer methyltransferase like-3 (METTL3) expression levels in cultured cells and mouse lung tissues. METTL3 knockdown in cells transformed by arsenic plus BaP exposure drastically reduced their RNA m6A methylation levels. Functional studies revealed that METTL3 knockdown in cells transformed by arsenic plus BaP exposure greatly reduces their anchorage-dependent and -independent growth, cancer stem cell characters and tumorigenesis. The findings from this study suggest that arsenic plus BaP co-exposure causes epitranscriptomic dysregulation, which may contribute significantly to arsenic plus BaP co-exposure-caused synergistic lung tumorigenic effect.

Phenotypic drug susceptibility characterization and clinical outcomes of tuberculosis strains with A-probe mutation by GeneXpert MTB/RIF.

BACKGROUND: GeneXpert MTB/RIF (Xpert) assay was applied widely to detect Mycobacterium tuberculosis (MTB) and rifampicin resistance. METHODS: Retrospectively investigated the association among treatment histories, phenotypic drug susceptibility testing (pDST) results, and clinical outcomes of patients infected with probe A absent mutation isolate confirmed by Xpert. RESULTS: 63 patients with only probe A absent mutation and 40 with additional pDST results were analyzed. 24 (60.0%) patients had molecular-phenotypic discordant rifampicin (RIF) susceptibility testing results, including 12 (12/13, 92.3%) new tuberculosis (TB) patients and 12 (12/27, 44.4%) retreated ones. 28 (28/39, 71.8%) retreated patients received first-line treatment regime within two years with failed outcomes. New patients had better treatment outcomes than retreated ones (successful: 83.3% VS. 53.8%; P value = 0.02). The clinical results of RIF-susceptible TB confirmed by pDST were not better than RIF-resistant TB (successful: 62.5% VS. 50.0%; P value = 0.43). INH-resistant TB and INH-susceptible TB had similar treatment outcomes too (successful: 61.5% VS. 50.0%; P value = 0.48). 11 (11/12, 91.7%) new patients treated with the short treatment regimen (STR) had successful outcomes. CONCLUSIONS: More than half of mono probe A absent isolates had RIF molecular-phenotypic discordance results, especially in new patients. Probe A mutations were significantly associated with unsuccessful clinical outcomes, whether the pDST results were RIF susceptible or not. STR was the best choice for new patients. TRIAL REGISTRATION: retrospectively registered in Wuhan Jinyintan Hospital (No. 2021-KY-16).

Dysregulations of long non-coding RNAs - The emerging "lnc" in environmental carcinogenesis.

Long non-coding RNAs (lncRNAs) refer to a class of RNA molecules that are more than 200 nucleotides in length and usually lack protein-coding capacity. LncRNAs play important roles in regulating gene expression as well as many aspects of normal physiological processes. Dysregulations of lncRNA expressions and functions are considered to be critically involved in the development and progression of many diseases especially cancer. The lncRNA research in the field of cancer biology over the past decade reveals that a large number of lncRNAs are dysregulated in various types of cancer and that dysregulated lncRNAs may play important roles in cancer initiation, metastasis and therapeutic responses. Metal carcinogens and other common environmental carcinogens such as polycyclic aromatic hydrocarbons, fine particular matters, cigarette smoke, ultraviolet and ionizing radiation are important cancer etiology factors. However, the mechanisms of how metal carcinogens and other common environmental carcinogen exposures initiate cancer and promote cancer progression remain largely unknown. Accumulating evidence show that exposure to metal carcinogens and other common environmental carcinogens dysregulate lncRNA expression in various model systems, which may offer novel mechanistic insights for environmental carcinogenesis. This review will first provide a brief introduction about lncRNA biology and the mechanisms of lncRNA functions, followed by summarizing and discussing recent studies about lncRNA dysregulation by metal carcinogen and other common environment carcinogen exposures and the potential roles of dysregulated lncRNAs in environmental carcinogenesis. A perspective for future studies in this emerging and important field is also presented.

The Epitranscriptomic Mechanism of Metal Toxicity and Carcinogenesis.

Metals are common toxic environmental pollutants. Acute or chronic exposure to metal pollutants causes severe adverse health effects in animals and humans, such as developmental retardation, abnormal metabolism, and disorders of cardiovascular, neurologic, respiratory, reproductive, and urologic systems. Moreover, several metals (arsenic, cadmium, chromium, and nickel) are classified as potent Group I carcinogens and cause various types of cancer in humans. Although the toxicity and carcinogenicity of metal pollutants are well recognized, the underlying mechanisms have not been clearly defined. The epitranscriptome includes all kinds of chemical modifications of all forms of RNA molecules inside a cell. Recent progresses in demonstrating the reversible pattern of RNA modifications and their roles in physiology and pathogenesis represent a breakthrough in the field of RNA biology and function study. The epitranscriptomic study is now an exciting emerging field in toxicology research. While few studies have been conducted so far to determine the epitranscriptomic effects of metal pollutants, they offer novel insights for understanding the mechanisms of metal toxicity and carcinogenesis. The goal of this review is to discuss recent studies on the epitranscriptomic effects of metals and propose some thoughts for future studies in the field.

NAC Transcription Factor GmNAC12 Improved Drought Stress Tolerance in Soybean.

NAC transcription factors (TFs) could regulate drought stresses in plants; however, the function of NAC TFs in soybeans remains unclear. To unravel NAC TF function, we established that GmNAC12, a NAC TF from soybean (Glycine max), was involved in the manipulation of stress tolerance. The expression of GmNAC12 was significantly upregulated more than 10-fold under drought stress and more than threefold under abscisic acid (ABA) and ethylene (ETH) treatment. In order to determine the function of GmNAC12 under drought stress conditions, we generated GmNAC12 overexpression and knockout lines. The present findings showed that under drought stress, the survival rate of GmNAC12 overexpression lines increased by more than 57% compared with wild-type plants, while the survival rate of GmNAC12 knockout lines decreased by at least 46%. Furthermore, a subcellular localisation analysis showed that the GmNAC12 protein is concentrated in the nucleus of the tobacco cell. In addition, we used a yeast two-hybrid assay to identify 185 proteins that interact with GmNAC12. Gene ontology (GO) and KEGG analysis showed that GmNAC12 interaction proteins are related to chitin, chlorophyll, ubiquitin-protein transferase, and peroxidase activity. Hence, we have inferred that GmNAC12, as a key gene, could positively regulate soybean tolerance to drought stress.

The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis.

The m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.

Down-regulation of lncRNA MEG3 promotes chronic low dose cadmium exposure-induced cell transformation and cancer stem cell-like property.

Cadmium (Cd) is a toxic heavy metal and one of carcinogens that cause lung cancer. However, the exact mechanism of Cd carcinogenesis remains unclear. To investigate the mechanism of Cd carcinogenesis, we exposed human bronchial epithelial cells (BEAS-2B) to a low dose of Cd (2.5 µM, CdCl2) for 9 months, which caused cell malignant transformation and generated cancer stem cell (CSC)-like cells. The goal of this study is to investigate the underlying mechanism. The long non-coding RNA (lncRNA) microarray analysis showed that the expression level of a tumor suppressive lncRNA maternally expressed 3 (MEG3) is significantly down-regulated in Cd-transformed cells, which is confirmed by further q-PCR analysis. Mechanistically, it was found that chronic Cd exposure up-regulates the levels of DNA methyltransferases (DNMTs), which increases the methylation of the differentially methylated region (DMR) 1.5 kb upstream of MEG3 transcription start site to reduce MEG3 expression. Functional studies showed that stably overexpressing MEG3 in Cd-transformed cells significantly reduces their transformed phenotypes. Moreover, stably overexpressing MEG3 in parental non-transformed human bronchial epithelial cells significantly impaired the capability of chronic Cd exposure to induce cell transformation and CSC-like property. Further mechanistic studies revealed that the cell cycle inhibitor p21 level is reduced and retinoblastoma protein (Rb) phosphorylation is increased in Cd-transformed cells to promote cell cycle progression. In addition, Cd-transformed cells also expressed higher levels of Bcl-xL and displayed apoptosis resistance. In contrast, stably overexpressing MEG3 increased p21 levels and reduced Rb phosphorylation and Bcl-xL levels in Cd-exposed cells and reduced their cell cycle progression and apoptosis resistance. Together, these findings suggest that MEG3 down-regulation may play important roles in Cd-induced cell transformation and CSC-like property by promoting cell cycle progression and apoptosis resistance.

COL1A1 as a potential new biomarker and therapeutic target for type 2 diabetes.

Type 2 diabetes (T2D) is a public health problem with a rising incidence worldwide. In this study, a potential new biomarker for T2D and mechanisms underlying the hypoglycemic effects of Enteromorpha prolifera oligosaccharide were investigated. Tandem mass tag labeling with LC-MS/MS was used to identify the differentially expressed proteins (DEPs) between the jejunum of diabetic rats and control rats. Correlations between glycometabolic parameters and DEPs were revealed by a network analysis. The expression levels of target genes in key metabolic pathways were further evaluated to identify candidate biomarkers. Among 6810 total proteins, approximately 88 % were quantified, of which 148 DEPs with a fold change of <0.83 or>1.2 and a corrected p-value of <0.05 were identified. A KEGG enrichment analysis indicated that the hypoglycaemic effects of E. prolifera oligosaccharide involved the PI3K/AKT and extracellular matrix receptor interaction signaling pathways. More importantly, Col1a1 was the most significant gene in the extracellular matrix receptor interaction pathway and was linked to hypoglycaemic activity for the first time. Thus, Col1a1 is a novel potential therapeutic target for alleviating T2D.

MicroRNA Regulation of Breast Cancer Stemness.

Recent advances in our understanding of breast cancer have demonstrated that cancer stem-like cells (CSCs, also known as tumor-initiating cell (TICs)) are central for progression and recurrence. CSCs are a small subpopulation of cells present in breast tumors that contribute to growth, metastasis, therapy resistance, and recurrence, leading to poor clinical outcome. Data have shown that cancer cells can gain characteristics of CSCs, or stemness, through alterations in key signaling pathways. The dysregulation of miRNA expression and signaling have been well-documented in cancer, and recent studies have shown that miRNAs are associated with breast cancer initiation, progression, and recurrence through regulating CSC characteristics. More specifically, miRNAs directly target central signaling nodes within pathways that can drive the formation, maintenance, and even inhibition of the CSC population. This review aims to summarize these research findings specifically in the context of breast cancer. This review also discusses miRNAs as biomarkers and promising clinical therapeutics, and presents a comprehensive summary of currently validated targets involved in CSC-specific signaling pathways in breast cancer.

Metal carcinogen exposure induces cancer stem cell-like property through epigenetic reprograming: A novel mechanism of metal carcinogenesis.

Arsenic, cadmium, nickel and hexavalent chromium are among the most common environmental pollutants and potent carcinogens. Chronic exposure to these metals causes various types of cancer in humans, representing a significant environmental health issue. Although under active investigation, the mechanisms of metal carcinogenesis have not been clearly defined. One common feature of these metal carcinogens is that they are all able to cause various epigenetic dysregulations, which are believed to play important roles in their carcinogenicity. However, how metal carcinogen-caused epigenetic dysregulation contributes to metal carcinogenesis remains largely unknown. The evolution of cancer stem cell (CSC) theory has opened exciting new avenues for studying the mechanism of metal carcinogenesis. Increasing evidence indicates that chronic metal carcinogen exposure produces CSC-like cells through dysregulated epigenetic mechanisms. This review will first provide some brief introductions about CSC, epigenetics and epigenetic regulation of CSCs; then summarize progresses in recent studies on metal carcinogen-induced CSC-like property through epigenetic reprograming as a novel mechanism of metal carcinogenesis. Some perspectives for future studies in this field are also presented.

Integrin α9 depletion promotes ß-catenin degradation to suppress triple-negative breast cancer tumor growth and metastasis.

Although integrin α9 (ITGA9) is known to be involved in cell adhesion and motility, its expression in cancer and its role in tumor growth and metastasis remain largely unknown. Our study was designed to investigate the role of ITGA9 in triple-negative breast cancer (TNBC). ITGA9 expression in TNBC cells was knocked out (KO) using CRISPR/Cas9 technology. Four orthotopic mouse mammary xenograft tumor models coupled with cell culture studies were performed to determine the effect of ITGA9 depletion on TNBC tumor growth and metastasis and the underlying mechanism. Bioinformatics analysis showed that ITGA9 level is significantly higher in TNBC than other breast cancer subtypes, and higher ITGA9 level is associated with significantly worse distant metastasis-free survival and recurrence-free survival in TNBC patients. Experimentally, ITGA9 KO significantly reduced TNBC cell cancer stem cell (CSC)-like property, tumor angiogenesis, tumor growth and metastasis by promoting ß-catenin degradation. Further mechanistic studies revealed that ITGA9 KO causes integrin-linked kinase (ILK) relocation from the membrane region to the cytoplasm, where it interacts with protein kinase A (PKA) and inhibits PKA activity leading to increased activity of glycogen synthase kinase 3 (GSK3) and subsequent ß-catenin degradation. Overexpressing ß-catenin in ITGA9 KO cells reversed the inhibitory effect of ITGA9 KO on tumor growth and metastasis. Furthermore, ITGA9 downregulation in TNBC tumors by nanoparticle-mediated delivery of ITGA9 siRNA drastically decreased tumor angiogenesis, tumor growth and metastasis. These findings indicate that ITGA9 depletion suppresses TNBC tumor growth and metastasis by promoting ß-catenin degradation through the ILK/PKA/GSK3 pathway.

Regulation of glucose metabolism by bioactive phytochemicals for the management of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is the most prevalent disease and becoming a serious public health threat worldwide. It is a severe endocrine metabolic disorder that has the ability to induce serious complications in all kinds of organs. Although mechanisms of anti-diabetics have been described before, we focus here on the cellular and physiological mechanisms involved in the modulation of insulin and glucose blood levels. As obesity and inflammation are intimately associated with the development of T2DM, their possible relationships are also described. The effects of gut microbiota on insulin resistance have been recently investigated in clinical trials, and we discuss the potential mechanisms by which gut microbiota may improve glucose handling, especially via the metabolism of ingested phytochemicals. Among the historically supported effects of phytochemicals, their therapeutic potential for T2DM leads to consider these natural products as an important pool for the identification of novel anti-diabetic drug leads. This current research extends the descriptions of anti-diabetic effects of plants that are used in traditional medicines or as nutraceuticals. The objective of the present review is to make a systematic report on glucose metabolism in T2DM as well as to explore the relationships between natural phytochemicals and glucose handling.

Bacterial spoilage profiles in the gills of Pacific oysters (Crassostrea gigas) and Eastern oysters (C. virginica) during refrigerated storage.

Microorganisms harbored in oyster gills are potentially related to the spoilage and safety of oyster during storage. In this study, the microbial activities and pH changes of the gills of the two species, Crassostrea gigas and C. virginica, harvested from three different sites were determined and sensory evaluation was conducted during refrigerated storage. The bacteria in gills with an initial aerobic plate count (APC) of 3.1-4.5 log CFU/g rose remarkably to 7.8-8.8 log CFU/g after 8-days of storage. The APC of Enterobacteriaceae increased from 2.5 to 3.6 log CFU/g to 4.5-4.8 log CFU/g, and that of lactic acid bacteria (LAB) fluctuated in the range of 1.4-3.0 log CFU/g during the whole storage period. The results of sensory analysis indicated that the oysters had 8-days of shelf-life and that the gill presented the fastest deterioration rate. The pH of all samples showed a decrease in the early stages followed by an increased after 4-days of storage. The dynamic changes in microbial profiles were depicted to characterize gill spoilage by Illumina Miseq sequencing to characterize gill spoilage. The results revealed that oysters harvested at different sites showed common bacterial profiles containing Arcobacter, Spirochaeta, Pseudoalteromonas, Marinomonas, Fusobacterium, Psychrobacter, Psychromonas, and Oceanisphaera when spoiled, especially, among which Psychrobacter and Psychromonas (psychrotrophic genus) were represented as the most important gill spoiled bacteria during refrigerated storage, and Arcobacter with pathogenic potential was the dominated bacteria in all spoiled oysters. The consumption quality and safety of refrigerated oysters could be greatly improved by targeted control of bacteria in oyster gills according to the results the present study provided.

RNA-binding protein trinucleotide repeat-containing 6A regulates the formation of circular RNA circ0006916, with important functions in lung cancer cells.

Circular RNAs (circRNAs) are widespread and diverse endogenous RNAs distinct from traditional linear RNAs, which may regulate gene expression in eukaryotes. However, the function of human circRNAs, including their potential role in lung cancer, remains largely unknown. We screened the circRNA circ0006916, which was evidently down-regulated in 16HBE-T cells (anti-benzopyrene-trans-7, 8-dihydrodiol-9, 10-epoxide-transformed human bronchial epithelial cells), and in A549 and H460 cell lines. Silencing of circ0006916, but not its parental gene homer scaffolding protein 1 (HOMER1), promoted cell proliferation via speeding up the cell cycle process rather than by inhibiting apoptosis; conversely, overexpression of circ0006916 had the opposite effect. Luciferase-screening assay indicated that circ0006916 bound to miR-522-3p and inhibited pleckstrin homology domain and leucine rich repeat protein phosphatase 1 (PHLPP1) activity. We also explored the effect of the RNA-binding protein trinucleotide repeat-containing 6A (TNRC6A) on circ0006916 production. Circ0006916 expression was decreased after silencing TNRC6A. TNRC6A bound to the intron regions around the circRNA-forming exons of circ0006916, as shown by RNA immunoprecipitation assay combined with sequencing analysis. The association of circ0006916 with TNRC6A was further verified by RNA pull-down assays. We then constructed a carrier and confirmed that TNRC6A binding to the flanked intron region of circ0006916 was necessary for generation of circ0006916. These results demonstrate that TNRC6A regulates the biogenesis of the circRNA circ0006916, which has a regulatory role in cell growth.

Upregulation of histone-lysine methyltransferases plays a causal role in hexavalent chromium-induced cancer stem cell-like property and cell transformation.

While hexavalent chromium [Cr(VI)] is generally considered as a genotoxic environmental carcinogen, studies showed that Cr(VI) exposure also causes epigenetic changes. However, whether Cr(VI)-caused epigenetic dysregulations plays an important role in Cr(VI) carcinogenicity remain largely unknown. The aim of this study was to determine if chronic low dose Cr(VI) exposure causes epigenetic changes, the underlying mechanism and whether chronic low dose Cr(VI) exposure-caused epigenetic dysregulation contributes causally to Cr(VI)-induced cancer stem cell (CSC)-like property and cell transformation. Two immortalized human bronchial epithelial cell lines (BEAS-2B and 16HBE) were exposed to 0.25 µM of K2Cr2O7 for 20 and 40 weeks to induce cell transformation, respectively. Cr(VI)-induced epigenetic changes were examined in Cr(VI)-transformed cells and Cr(VI) exposure-caused human lung cancer tissues. Pharmacological inhibitors and gene knockdown experiments were used to determine the role of epigenetic dysregulation in Cr(VI) carcinogenicity. We found that chronic Cr(VI) exposure causes epigenetic dysregulation as evidenced by the increased levels of histone H3 repressive methylation marks (H3K9me2 and H3K27me3) and the related histone-lysing methyltransferases (HMTases). Pharmacological inhibition or knockdown of HMTases reduces H3 repressive methylation marks and malignant phenotypes of Cr(VI)-transformed cells. Moreover, knockdown of HMTases in parental cells significantly reduces chronic Cr(VI) exposure-induced CSC-like property and cell transformation. Further mechanistic study revealed that knockdown of HMTases decreases Cr(VI) exposure-caused DNA damage. Our findings indicate that chronic Cr(VI) exposure increases H3 repressive methylation marks by increasing the related HMTases expression; and that increased expression of HMTases plays a causal role in Cr(VI)-induced CSC-like property and cell transformation.

Determinative Surface-Wrinkling Microstructures on Polypyrrole Films by Laser Writing.

We report a simple and efficient laser-writing strategy to fabricate hierarchical nested wrinkling microstructures on conductive polypyrrole (PPy) films, which enables us to develop advanced functional surfaces with diverse applications. The present strategy adopts the photothermal effect of PPy films to mimick the formation of hierarchical nested wrinkles observed in nature and design controlled microscale wrinkling patterns. Here, the PPy film is grown on a poly(dimethylsiloxane) (PDMS) substrate via oxidation polymerization of pyrrole in an acidic solution, accompanied by in situ self-wrinkling with wavelengths of two different scales (i.e., λ1 and λ2). Subsequent laser exposure of the PPy/PDMS bilayer induces a new surface wrinkling with a larger wavelength (i.e., λ3). Owing to the retention of the initial λ1 wrinkles, we obtain hierarchical nested wrinkles with the smaller λ1 wrinkles nested in the larger λ3 ones. Importantly, we realize the large-scale path-determinative fabrication of complex oriented wrinkling microstructures by controlling the relative motion between the bilayer and the laser. Combined with the induced changes in surface color, surface-wrinkling microstructures, and conductivity in the PPy films, the laser-writing strategy can find broad applications, for example, in modulation of surface wetting properties and fabrication of microcircuits, as demonstrated in this work.

Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer.

While the small GTPase Rac1 and its effectors are well-established mediators of mitogenic and motile signaling by tyrosine kinase receptors and have been implicated in breast tumorigenesis, little is known regarding the exchange factors (Rac-GEFs) that mediate ErbB receptor responses. Here, we identify the PIP(3)-Gßγ-dependent Rac-GEF P-Rex1 as an essential mediator of Rac1 activation, motility, cell growth, and tumorigenesis driven by ErbB receptors in breast cancer cells. Notably, activation of P-Rex1 in breast cancer cells requires the convergence of inputs from ErbB receptors and a Gßγ- and PI3Kγ-dependent pathway. Moreover, we identified the GPCR CXCR4 as a crucial mediator of P-Rex1/Rac1 activation in response to ErbB ligands. P-Rex1 is highly overexpressed in human breast cancers and their derived cell lines, particularly those with high ErbB2 and ER expression. In addition to the prognostic and therapeutic implications, our findings reveal an ErbB effector pathway that is crucial for breast cancer progression.

Role of Green Macroalgae Enteromorpha Prolifera Polyphenols in the Modulation of Gene Expression and Intestinal Microflora Profiles in Type 2 Diabetic Mice.

Effects of green macroalgae 55% ethanolic extract Enteromorpha prolifera through an ultrafiltration membrane of 3 kDa (EPE3k) on antidiabetic activity, gut microbiota, and regulation mechanism were investigated in high-fat/high-sucrose diet and streptozocin-induced diabetic mice. The structural characterizations of its major compounds in EPE3k were determined by ultra-performance liquid chromatography-quadrupole/time of flight mass spectrometry. Furthermore, the intestinal microflora modulation in diabetic mice was also investigated with high-throughput 16S rRNA gene sequencing. The proposed presence of polyphenols in EPE3k was confirmed. EPE3k could significantly decrease the fasting blood glucose and improve fasting glucose tolerance. The hypoglycemic effect of EPE3k was via activation of phosphatidylinositol 3-kinase and suppression of c-Jun N-terminal kinase in liver. EPE3k treatment significantly increased the relative abundance of Akkermansia and decreased the proportion of Alistipes and Turicibacter. The above results indicated that EPE3k could be provided as a new potential therapy for the treatment of type 2 diabetic mellitus.

Characterizations of the Interactions between Escherichia coli Periplasmic Chaperone HdeA and Its Native Substrates during Acid Stress.

The bacterial acid-resistant chaperone HdeA is a "conditionally disordered" protein that functions at low pH when it undergoes a transition from a well-folded dimer to an unfolded monomer. The dimer dissociation and unfolding processes result in exposure of hydrophobic surfaces that allows binding to a broad range of client proteins. To fully elucidate the chaperone mechanism of HdeA, it is crucial to understand how the activated HdeA interacts with its native substrates during acid stress. Herein, we present a nuclear magnetic resonance study of the pH-dependent HdeA-substrate interactions. Our results show that the activation of HdeA is not only induced by acidification but also regulated by the presence of unfolded substrates. The variable extent of unfolding of substrates differentially regulates the HdeA-substrate interaction, and the binding further affects the HdeA conformation. Finally, we show that HdeA binds its substrates heterogeneously, and the "amphiphilic" model for HdeA-substrate interaction is discussed.