HYOU1 facilitates proliferation, invasion and glycolysis of papillary thyroid cancer via stabilizing LDHB mRNA.

HYOU1 is upregulated in many kinds of cancer cells, and its high expression is associated with tumour invasiveness and poor prognosis. However, the role of HYOU1 in papillary thyroid cancer (PTC) development and progression remains to be elucidated. Here, we reported that HYOU1 was highly expressed in human PTC and associated with poor prognosis. HYOU1 silencing suppressed the proliferation, migration and invasion of PTC cells. Mechanistic analyses showed that HYOU1 silencing promoted oxidative phosphorylation while inhibited aerobic glycolysis via downregulating LDHB at the posttranscriptional level. We further confirmed that the 3'UTR of LDHB mRNA is the indirect target of HYOU1 silencing and HYOU1 silencing increased miR-375-3p levels. While LDHB overexpression significantly suppressed the inhibitory effects of HYOU1 silencing on aerobic glycolysis, proliferation, migration and invasion in PTC cells. Taken together, our findings suggest that HYOU1 promotes glycolysis and malignant progression in PTC cells via upregulating LDHB expression, providing a potential target for developing novel anticancer agents.

Temporal Differences in Interneuron Invasion of Neocortex and Piriform Cortex during Mouse Cortical Development.

Establishing a balance between excitation and inhibition is critical for brain functions. However, how inhibitory interneurons (INs) generated in the ventral telencephalon integrate with the excitatory neurons generated in the dorsal telencephalon remains elusive. Previous studies showed that INs migrating tangentially to enter the neocortex (NCx), remain in the migratory stream for days before invading the cortical plate during late corticogenesis. Here we show that in developing mouse cortices, INs in the piriform cortex (PCx; the major olfactory cortex) distribute differently from those in the NCx. We provide evidence that during development INs invade and mature earlier in PCx than in NCx, likely owing to the lack of CXCR4 expression in INs from PCx compared to those in NCx. We analyzed IN distribution patterns in Lhx2 cKO mice, where projection neurons in the lateral NCx are re-fated to generate an ectopic PCx (ePCx). The PCx-specific IN distribution patterns found in ePCx suggest that properties of PCx projection neurons regulate IN distribution. Collectively, our results show that the timing of IN invasion in the developing PCx fundamentally differs from what is known in the NCx. Further, our results suggest that projection neurons instruct the PCx-specific pattern of IN distribution.

p53-dependent transcriptional suppression of BAG3 protects cells against metabolic stress via facilitation of p53 accumulation.

Solid tumour frequently undergoes metabolic stress during tumour development because of inadequate blood supply and the high nutrient expenditure. p53 is activated by glucose limitation and maintains cell survival via triggering metabolic checkpoint. However, the exact downstream contributors are not completely identified. BAG3 is a cochaperone with multiple cellular functions and is implicated in metabolic reprogramming of pancreatic cancer cells. The current study demonstrated that glucose limitation transcriptionally suppressed BAG3 expression in a p53-dependent manner. Importantly, hinderance of its down-regulation compromised cellular adaptation to metabolic stress triggered by glucose insufficiency, supporting that BAG3 might be one of p53 downstream contributors for cellular adaptation to metabolic stress. Our data showed that ectopic BAG3 expression suppressed p53 accumulation via direct interaction under metabolic stress. Thereby, the current study highlights the significance of p53-mediated BAG3 suppression in cellular adaptation to metabolic stress via facilitating p53 accumulation.

Transgelin interacts with PARP1 in human colon cancer cells.

BACKGROUND: Transgelin, an actin-binding protein, is associated with cytoskeleton remodeling. Findings from our previous studies demonstrated that transgelin was up-regulated in node-positive colorectal cancer (CRC) versus node-negative disease. Over-expression of TAGLN affected the expression of 256 downstream transcripts and increased the metastatic potential of colon cancer cells in vitro and in vivo. This study aims to explore the mechanisms through which transgelin participates in the metastasis of colon cancer cells. METHODS: Immunofluorescence and immunoblotting analysis were used to determine the cellular localization of endogenous and exogenous transgelin in colon cancer cells. Co-immunoprecipitation and subsequently high-performance liquid chromatography/tandem mass spectrometry were performed to identify the proteins that were potentially interacting with transgelin. The 256 downstream transcripts regulated by transgelin were analyzed with bioinformatics methods to discriminate the specific key genes and signaling pathways. The Gene-Cloud of Biotechnology Information (GCBI) tools were used to predict the potential transcription factors (TFs) for the key genes. The predicted TFs corresponded to the proteins identified to interact with transgelin. The interaction between transgelin and the TFs was verified by co-immunoprecipitation and immunofluorescence. RESULTS: Transgelin was found to localize in both the cytoplasm and nucleus of the colon cancer cells. Approximately 297 proteins were identified to interact with transgelin. The overexpression of TAGLN led to the differential expression of 184 downstream genes. Network topology analysis discriminated seven key genes, including CALM1, MYO1F, NCKIPSD, PLK4, RAC1, WAS and WIPF1, which are mostly involved in the Rho signaling pathway. Poly (ADP-ribose) polymerase-1 (PARP1) was predicted as the unique TF for the key genes and concurrently corresponded to the DNA-binding proteins potentially interacting with transgelin. The interaction between PARP1 and transgelin in human RKO colon cancer cells was further validated by immunoprecipitation and immunofluorescence assays. CONCLUSIONS: Our results suggest that transgelin binds to PARP1 and regulates the expression of downstream key genes, which are mainly involved in the Rho signaling pathway, and thus participates in the metastasis of colon cancer.

AUF1 modulates TGF-ß signal in renal tubular epithelial cells via post-transcriptional regulation of Nedd4L expression.

Posttranscriptional regulation process plays important roles in renal disease pathogenesis. AU-rich element RNA-binding protein (AUF1) interacts with and destabilizes mRNAs containing AU-rich elements (AREs) in their 3'UTR. The current study demonstrated that AUF1 was increased in unilateral ureteral obstruction (UUO) animal models. While proliferation and migration of HK2 cells was unaltered by AUF1 downregulation under normal condition, proliferative inhibition and migratory promotion mediated by TGF-ß was significantly compromised. Mechanically, AUF1 downregulation decreased phosphorylated Smad2/3 via increasing their E3 ligase Nedd4L at the posttranscriptional level. In addition, the current study identified Nedd4L as a previously unreported target of AUF1. AUF1 regulates Nedd4L expression at the posttranscriptional level by interaction with AREs in the 3'UTR of the Nedd4L mRNA. Collectively, the current study indicates that AUF1 might be a potential player in renal tubulointerstitial fibrosis through modulation of TGF-ß signal transduction via posttranscriptional regulation of Nedd4L.

MicroRNA-1271 functions as a potential tumor suppressor in hepatitis B virus-associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1.

Hepatocellular carcinoma (HCC) is mainly associated with hepatitis B virus (HBV) infection and characterized by metastasizing and infiltrating adjacent and distant tissues. Notably, microRNA-1271 (miR-1271) is a tumor suppressor in various cancers. Therefore, we evaluate the ability of miR-1271 to influence cell proliferation, migration, invasion, and apoptosis in HBV-associated HCC through the Adenosine monophosphate-activated protein kinase (AMPK) signaling pathway via targeting CCNA1. HBV-associated HCC and adjacent normal tissues were collected to identify the expression of miR-1271 and CCNA1. To verify the relationship between miR-1271 and CCNA1, we used bioinformatics prediction and the dual-luciferase reporter gene assay. The effects of miR-1271 on HBV-associated HCC cell behaviors were investigated by treatment of the miR-1271 mimic, the miR-1271 inhibitor, or small interfering RNA against CCNA1. The HBV-DNA quantitative assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromid assay, scratch test, transwell assay, and flow cytometry were used to detect HBV-DNA replication, cell proliferation, invasion, migration, and apoptosis. MiR-1271 showed a low expression, whereas CCNA1 showed a high expression in HBV-associated HCC tissues. We identified that miR-1271 targeted and negatively regulated CCNA1. Upregulated miR-1271 and downregulated CCNA1 inhibited the HBV-associated HCC cell HBV-DNA replication, proliferation, migration, and invasion, while accelerating apoptosis by activating the AMPK signaling pathway. MiR-1271 promotes the activation of the AMPK signaling pathway by binding to CCNA1, whereby miR-1271 suppresses HBV-associated HCC progression. This study points to a potential therapeutic approach of downregulation of miR-1271 in HBV-associated HCC treatment.

Sestrin 2 protects against metabolic stress in a p53-independent manner.

Glucose limitation activates p53, which functions as an adaptive response to maintain cell survival. However, p53 is frequently deleted or mutated in a variety of tumors, while most cancer cells can acclimatize themselves to metabolically unfavorable surrounding, indicating that alternative mechanisms other than p53 transactivation underly adaptive response of cancer cells with p53 deletion or mutation to metabolically hostile environment. Sestrin 2 (SESN2) is a p53 downstream target, which plays a protective role against various stressful stimuli, such as genotoxic, energetic, and oxidative stress. In the current study, we demonstrated that SESN2 transcript was stabilized by glucose limitation at the posttranscriptional level irrespective of p53 status. Importantly, SESN2 also protected cells from metabolic stress triggered by glucose limitation in a p53-independent manner. Our data indicated that stabilization of SESN2 transcript might be an alternative adaptive response to metabolic stress other than p53 activation. Thereby, the current study highlights the significance of stabilization of SESN2 transcript in adaptation of cells with p53 deletion or mutation to metabolic stress.

Evaluation of serum free fatty acids in chronic renal failure: evidence from a rare case with undetectable serum free fatty acids and population data.

BACKGROUND: Free fatty acid (FFA) accumulation in proximal tubules plays a fundamental role in the progress of kidney disease. Here, we reported a rare case with undetectable serum FFAs and further evaluated the changes of serum FFAs in patients with chronic renal failure (CRF). METHODS: We analyzed the clinical data of a rare case and 574 CRF patients. The mRNA expression of lipoprotein lipase (LPL), hepatic lipase (HL) and fatty acid synthase (FASN) were determined in the rare case and 30 age-matched healthy males with qPCR. RESULTS: This rare case had serious proteinuria, hyperglycemia, lipid disorders and bilateral renal glomerular filtration dysfunction. Compared with healthy males, this case showed a 1.49-fold increase of LPL expression (P < 0.01), a 3.38-fold reduction of HL expression (P < 0.001), and no significant change of FASN expression (P > 0.05). In total, 21.6% of CRF patients showed abnormal FFAs. Biochemical parameters such as blood urea nitrogen (BUN) and creatinine (CREA) significantly differed among groups with low-, normal- or high-level-FFAs. Moreover, serum FFAs was found to be associated with BUN. FFAs decreased in the group with higher BUN (> 17.4 mmol/L) and in the group with lower estimated glomerular filtration rate (eGFR) (< 15 mL/min/1.73m2). CONCLUSIONS: The proteinuria, HL low expression and renal function failure may contribute to the FFA reduction, which might imply that the renal function is severely damaged.

Integrating CNVs into meta-QTL identified GBP4 as positional candidate for adult cattle stature.

Copy number variation (CNV) of DNA sequences, functionally significant but yet fully ascertained, is believed to confer considerable increments in unexplained heritability of quantitative traits. Identification of phenotype-associated CNVs (paCNVs) therefore is a pressing need in CNV studies to speed up their exploitation in cattle breeding programs. Here, we provided a new avenue to achieve this goal that is to project the published CNV data onto meta-quantitative trait loci (meta-QTL) map which connects causal genes with phenotypes. Any CNVs overlapping meta-QTL therefore will be potential paCNVs. This study reported potential paCNVs in Bos taurus autosome 3 (BTA3). Notably, overview indexes and CNVs both highlighted a narrower region (BTA3 54,500,000-55,000,000 bp, named BTA3_INQTL_6) within one constructed meta-QTL. Then, we ascertained guanylate-binding protein 4 (GBP4) among the nine positional candidate genes was significantly associated with adult cattle stature, including body weight (BW, P < 0.05) and withers height (WHT, P < 0.05), fitting GBP4 CNV either with three levels or with six levels in the model. Although higher copy number downregulated the mRNA levels of GBP2 (P < 0.05) and GBP4 (P < 0.05) in 1-Mb window (54.0-55.0 Mb) in muscle and adipose, additional analyses will be needed to clarify the causality behind the ascertained association.

A comprehensive investigation of starch degradation process and identification of a transcriptional activator MabHLH6 during banana fruit ripening.

Although starch degradation has been well studied in model systems such as Arabidopsis leaves and cereal seeds, this process in starchy fruits during ripening, especially in bananas, is largely unknown. In this study, 38 genes encoding starch degradation-related proteins were identified and characterized from banana fruit. Expression analysis revealed that 27 candidate genes were significantly induced during banana fruit ripening, with concomitant conversion of starch-to-sugars. Furthermore, iTRAQ-based proteomics experiments identified 18 starch degradation-associated enzymes bound to the surface of starch granules, of which 10 were markedly up-regulated during ripening. More importantly, a novel bHLH transcription factor, MabHLH6, was identified based on a yeast one-hybrid screening using MaGWD1 promoter as a bait. Transcript and protein levels of MabHLH6 were also increased during fruit ripening. Electrophoretic mobility shift assays, chromatin immunoprecipitation and transient expression experiments confirmed that MabHLH6 activates the promoters of 11 starch degradation-related genes, including MaGWD1, MaLSF2, MaBAM1, MaBAM2, MaBAM8, MaBAM10, MaAMY3, MaAMY3C, MaISA2, MaISA3 and MapGlcT2-2 by recognizing their E-box (CANNTG) motifs present in the promoters. Collectively, these findings suggest that starch degradation during banana fruit ripening may be attributed to the complex actions of numerous enzymes related to starch breakdown at transcriptional and translational levels, and that MabHLH6 may act as a positive regulator of this process via direct activation of a series of starch degradation-related genes.

Association of IL-28B, TBX21 gene polymorphisms and predictors of virological response for chronic hepatitis C.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. The outcomes of both spontaneous HCV clearance and response to therapy depend on both viral and host factors. To investigate the influence of polymorphisms of IL-28B rs12979860 and TBX21 rs17250932, rs4794067 as well as viral factors (HCV genotype, F protein) on the outcome of HCV infection, we genotyped 565 patients with chronic HCV infection, 191 patients spontaneously resolved from HCV infection, 359 healthy controls and 383 treatment-naïve CHC patients with pegylated interferon-α and ribavirin (PEG IFN-α/RBV). Results showed that TBX21 rs4794067 variant genotypes significantly correlated with increased risk of HCV chronic infection (dominant model: OR = 5.690, 95% CI = 2.024-16.000) and susceptibility (dominant model: OR = 5.658, 95% CI = 2.514-12.735). We also found that the rs12979860, rs2227982 and rs36084323 polymorphisms showed no significant associations with susceptibility or spontaneous clearance of HCV in the anti-F antibody subgroup; however, the anti-F antibody positive subgroup might show an increased risk of N-SVR (all P < 0.001). Our results demonstrate that variant factors in both the host and pathogen are commonly important for HCV clearance. In addition rs4794067 and F protein status may be strong predictive markers in the Chinese population.

[Rapid analysis of compounds in leaves of Chinese seabuckthorn and Tibetan seabuckthorn by UPLC/Q-TOF-MS].

The study is aimed to analyze the chemical components in leaves of Chinese seabuckthorn and Tibetan seabuckthorn qualitatively and compare the differences between them by using ultra performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS).The chromatographic separation of the components was achieved ona Waters ACQUITY UPLC-T3 column (2.1 mm×100 mm, 1.7 µm）using gradient mobile phase consisting of acetonitrile (A) and aqueous solution (B). The identification of the separated compounds was performed on atandem mass spectrometry (MS/MS)by fragmentation patterns under the negative electrospray ionization. The parameters of ion source were as follows：capillary voltage, 2 000 V; Cone voltage, 40 V. The ion source temperature, 100 ℃; collision gas argon; sheath gas flow rate, 900 L•h⁻¹; sheath gas temperature, 450 ℃. Through the analysis of mass spectrometry data and with the help of literature data, a total of 35 compounds were detected and most of them were flavonoids. Among these compounds, 29 were common components for the two species, two components were unique to Chinese seabuckthorn and 4 were characteristic components of Tibetan seabuckthorn. The results indicated that the compositions of the two kinds of seabuckthorn leaves were quite similar. It is also demonstrated that UPLC/Q-TOF-MS method could be applied to rapidly and effectively analyze and speculate the compounds in leaves of Chinese seabuckthorn and Tibetan seabuckthorn.

Advanced glycation end products promote proliferation and suppress autophagy via reduction of Cathepsin D in rat vascular smooth muscle cells.

Autophagy is closely involved in vascular smooth muscle cell (VSMC) function, but little is known about the association between advanced glycation end products (AGEs) and autophagy and its role in AGEs-induced proliferation and migration of VSMCs. The current study investigated the effects of AGEs on the phenotypic modulation and autophagy of VSMCs, as well as the potential underlying mechanisms. Primary rat VSMCs were treated with bovine serum albumin or AGEs. Cell proliferation was detected by MTT assay, real-time cell analyzer and EdU incorporation. Cell cycle was analyzed by Hoechst staining and flow cytometry. The migration of VSMCs was detected by wound-healing assay and transwell migration assay. LC3 transition and p62 accumulation were detected using Western blotting. Acidic vacuoles were measured using AO and MDC staining. Cathepsin D (CatD) was transduced to VSMCs via lentiviral vectors. AGEs enhanced proliferation and migration of primary rat VSMC in a time-dependent manner. AGEs significantly increased LC3-II transition and p62 expression, as well as accumulation of acidic vacuole, which was not further increased by bafilomycin A1. AGEs decreased CatD expression in a time-dependent pattern, and overexpression of CatD prohibited autophagy attenuation mediated by AGEs. CatD overexpression suppressed AGEs-induced proliferation of VSMCs. Nevertheless, CatD exhibited no effects on AGEs-induced migration of VSMCs. AGEs promote proliferation of VSMCs and suppress autophagy, at least in part via CatD reduction.

High-internal-phase-emulsion polymeric monolith coupled with liquid chromatography-electrospray tandem mass spectrometry for enrichment and sensitive detection of trace cytokinins in plant samples.

High-internal-phase-emulsion polymers (polyHIPEs) show great promise as solid-phase-extraction (SPE) materials because of the tremendous porosity and highly interconnected framework afforded by the high-internal-phase-emulsion (HIPE) technique. In this work, polyHIPE monolithic columns as novel SPE materials were prepared and applied to trace enrichment of cytokinins (CKs) from complex plant samples. The polyHIPE monoliths were synthesized via the in-situ polymerization of the continuous phase of a HIPE containing styrene (STY) and divinylbenzene (DVB) in a stainless column, and revealed highly efficient and selective enrichment ability for aromatic compounds. Under the optimized experimental conditions, a method using a monolithic polyHIPE column combined with liquid chromatography-electrospray tandem mass spectrometry (LC-MS-MS) was developed for the simultaneous extraction and sensitive determination of trans-zeatin (tZ), meta-topolin (mT), kinetin (K), and kinetin riboside (KR). The proposed method had good linearity, with correlation coefficients (R (2)) from 0.9957 to 0.9984, and low detection limits (LODs, S/N = 3) in the range 2.4-47 pg mL(-1) for the four CKs. The method was successfully applied to the determination of CKs in real plant samples, and obtained good recoveries ranging from 68.8 % to 103.0 % and relative standard deviations (RSDs) lower than 16 %.

[Study on HPLC specific chromatograms of Lu Dangshen].

In this paper, the RP-HPLC specific chromatography was adopted, with DIKMA-C18 (4.6 mm x 250 mm, 5 µm) as the chromatographic column, with a gradient elution compose of acetonitrile and 0.1% phosphoric acid at flow rate of 0.8 mL · min(-1), the detection wavelength was 220 nm. The difference of the HPLC specific chromatograms between the Lu Dangshen and other different base sources and different producing area of Codonopsis Radix was compared, involved in the similarities and differences of the number and the relative peak area of characteristic peaks in the HPLC specific chromatograms. The HPLC specific chromatograms of Lu Dangshen was established and the relative retention times of seven peaks was determined, and the peaks of codonopyrrolidium B, syringin, lobetyolin, tangshenoside I and atractylenoide III were identified; The HPLC specific chromatograms of Lu Dangshen provided a method for scientific evaluation and effective control the quality of Lu Dangshen from Shanxi famous-region.

BAG3 is upregulated by c-Jun and stabilizes JunD.

BAG3 plays a regulatory role in a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, epithelial-mesenchymal transition (EMT), autophagy activation, and virus infection. The AP-1 transcription factors are implicated in a variety of important biological processes including cell differentiation, proliferation, apoptosis and oncogenesis. Recently, it has been reported that AP-1 protein c-Jun inhibits autophagy and enhances apoptotic cell death mediated by starvation. However, the molecular mechanisms remain unclear. For the first time, the current study demonstrated that serum starvation downregulated BAG3 at the transcriptional level via c-Jun. In addition, the current study reported that BAG3 stabilized JunD mRNA, which was, at least in part, responsible for the promotion of serum starvation mediated-growth inhibition by BAG3.

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport.

BACKGROUND: Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer's, Parkinson's, and Huntington's disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function. METHODS: We generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of techniques, including genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos. RESULTS: We provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide "on-board" ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons. CONCLUSION: NMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

Implication of Nrf2 and ATF4 in differential induction of CHOP by proteasome inhibition in thyroid cancer cells.

Proteasome inhibition may cause endoplasmic reticulum (ER) stress, which has been reported to be implicated in the antitumoral effects of proteasome inhibitors. CCAAT/enhancer-binding protein homologous protein (CHOP) is induced by a variety of adverse physiological conditions including ER stress and is involved in apoptosis. We have reported that distinct induction of CHOP contributes to the responsiveness of thyroid cancer cells to proteasome inhibitors. However, the mechanism underlying differential induction of CHOP by proteasome inhibitors in thyroid cancer cells has not been well characterized. In the current study, we characterized that proteasome inhibition primarily activated the amino acid response element 1 (AARE1) on the CHOP promoter. We also demonstrated that although proteasome inhibition caused similar accumulation of activating transcription factor 4 (ATF4) in a panel of thyroid cancer cells, distinct amounts of ATF4 were recruited to the AARE1 element of CHOP promoter. In addition, we demonstrated that NF-E2-related factor 2 (Nrf2) was also implicated in the induction of CHOP by precluding the binding of ATF4 to the CHOP promoter. This study highlights the molecular mechanisms by which ATF4 and Nrf2 can control CHOP induction in thyroid cancer cells by proteasome inhibition.

Involvement of JNK and NF-κB pathways in lipopolysaccharide (LPS)-induced BAG3 expression in human monocytic cells.

Lipopolysaccharide (LPS) is an outer-membrane glycolipid component of Gram-negative bacteria known for its fervent ability to activate monocytic cells and for its potent proinflammatory capabilities. Bcl-2-associated athanogene 3 (BAG3) is a survival protein that has been shown to be stimulated during cell response to stressful conditions, such as exposure to high temperature, heavy metals, proteasome inhibition, and human immunodeficiency virus 1 (HIV-1) infection. In addition, BAG3 regulates replication of Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) replication, suggesting that BAG3 could participate in the host response to infection. In the current study, we found that LPS increased the expression of BAG3 in a dose- and time-dependent manner. Actinomycin D completely blocked the LPS-induced BAG3 accumulation, as well as LPS activated the proximal promoter of BAG3 gene, supported that the induction by LPS occurred at the level of gene transcription. LPS-induced BAG3 expression was blocked by JNK or NF-κB inhibition, suggesting that JNK and NF-κB pathways participated in BAG3 induction by LPS. In addition, we also found that induction of BAG3 was implicated in monocytic cell adhesion to extracellular matrix induced by LPS. Overall, the data support that BAG3 is induced by LPS via JNK and NF-κB-dependent signals, and involved in monocytic cell-extracellular matrix interaction, suggesting that BAG3 may have a role in the host response to LPS stimulation.

A case of West syndrome and global developmental delay in a child with a heterozygous mutation in the TBL1XR1 gene: A case report.

BACKGROUND: TBL1XR1, also known as IRA1 or TBLR1, encodes a protein that is localized in the nucleus and is expressed in most tissues. TBL1XR1 binds to histones H2B and H4 in vitro and functions in nuclear receptor-mediated transcription. TBL1XR1 is also involved in the regulation of the Wnt-ß-catenin signaling pathway. Mutations in the TBL1XR1 gene impair the Wnt-ß-catenin signaling pathway's ability to recruit Wnt-responsive element chromatin, affecting brain development. Mutations in this gene cause various clinical phenotypes, including Pierpont syndrome, autism spectrum disorder, speech and motor delays, mental retardation, facial dysmorphism, hypotonia, microcephaly, and hearing impairment. CASE SUMMARY: A 5-month-old female child was admitted with "episodic limb tremors for more than 1 month." At the time of admission, the child had recurrent episodes of limb tremors with motor retardation and a partially atypical and hypsarrhythmic video electroencephalogram. It was determined that a heterozygous mutation in the TBL1XR1 gene caused West syndrome and global developmental delay. Recurrent episodes persisted for 6 months following oral treatment with topiramate; the addition of oral treatment with vigabatrin did not show any significant improvement, and the disease continued to recur. The child continued to have recurrent episodes of limb tremors at follow-up until 1 year and 3 months of age. Additionally, she developed poor eye contact and a poor response to name-calling. CONCLUSION: We report the case of a child with West syndrome and a global developmental delay caused by a heterozygous mutation in the TBL1XR1 gene. This study adds to our understanding of the clinical phenotype of TBL1XR1 mutations and provides a realistic and reliable basis for clinicians.