C-Terminal Binding Protein: Regulator between Viral Infection and Tumorigenesis.

C-terminal binding protein (CtBP), a transcriptional co-repressor, significantly influences cellular signaling, impacting various biological processes including cell proliferation, differentiation, apoptosis, and immune responses. The CtBP family comprises two highly conserved proteins, CtBP1 and CtBP2, which have been shown to play critical roles in both tumorigenesis and the regulation of viral infections. Elevated CtBP expression is noted in various tumor tissues, promoting tumorigenesis, invasiveness, and metastasis through multiple pathways. Additionally, CtBP's role in viral infections varies, exhibiting differing or even opposing effects depending on the virus. This review synthesizes the advances in CtBP's function research in viral infections and virus-associated tumorigenesis, offering new insights into potential antiviral and anticancer strategies.

THBS1 promotes angiogenesis and accelerates ESCC malignant progression by the HIF-1/VEGF signaling pathway.

Previously, we demonstrated that the expression of THBS1 is increased in esophageal squamous cell carcinoma (ESCC) tissues and is correlated with lymph node metastasis and poor prognosis, indicating that THBS1 might be a candidate oncogene in ESCC. In this study, we future studied the specific role of THBS1 in ESCC and its molecular mechanism. Silencing THBS1 expression resulted in inhibition of cell migration and cell invasion of ESCC cells, the decrease of colony formation and proliferation. Tube formation of human umbilical vein endothelial cells (HUVECs) in vitro was decreased when cultured with conditioned medium from THBS1-silenced cells. The expression of CD31, a marker for blood vessel endothelial cells, was decreased in tumor tissues derived from THBS1-silenced tumors in vivo. Silencing THBS1 leaded the decreased of hypoxia-inducible factor-1α (HIF-1α), HIF-1ß, and VEGFA protein. The expression of p-ERK and p-AKT were declined in HUVECs following incubation with conditioned medium from THBS1-silenced ESCC cells compared conditioned medium from control cells. Furthermore, the treatment with bevacizumab boosted the decrease of the p-ERK and p-AKT levels in HUVECs incubated with the conditioned medium from THBS1-silenced ESCC cells. THBS1 silencing combined with bevacizumab blocked VEGF, inhibited to the tube formation, colony formation and migration of HUVECs, which were superior to that of bevacizumab alone. We presumed that THBS1 can enhance HIF-1/VEGF signaling and subsequently induce angiogenesis by activating the AKT and ERK pathways in HUVECs, resulting in bevacizumab resistance. THBS1 would be a potential target in tumor antiangiogenesis therapies.

GNA13 inhibits glioblastoma metastasis via the ERKs/FOXO3 signaling pathway.

Glioblastoma (GBM) is a malignant tumor characterized by poor prognosis and low overall survival (OS) rate. Identification of novel biological markers for the diagnosis and treatment of GBM is crucial to developing interventions to improve patient survival. GNA13, a member of the G12 family, has been reported to play important roles in a variety of biological processes involved in tumorigenesis and development. However, its role in GBM is currently unknown. Here, we explored the expression patterns and functions of GNA13 in GBM, as wells its impact on metastasis process. Results showed that GNA13 was downregulated in GBM tissues and correlated with poor prognosis of GBM. Downregulation of GNA13 promoted the migration, invasion and proliferation of GBM cells; whereas its overexpression abolished these effects. Western blots revealed that GNA13 knockdown and overexpression upregulated and inhibited the phosphorylation of ERKs, respectively. Moreover, GNA13 was the upstream of ERKs signaling to regulating ERKs phosphorylation level. Furthermore, U0126 alleviated the metastasis effect induced by GNA13 knockdown. Bioinformatics analyses and qRT-PCR experiments demonstrated that GNA13 could regulate FOXO3, a downstream signaling molecule of ERKs pathway. Overall, our results demonstrate that GNA13 expression is negatively correlated with GBM and can suppress tumor metastasis by inhibiting the ERKs signaling pathway and upregulating FOXO3 expression.

MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.

Glioblastoma (GBM) is a WHO grade 4 tumor and is the most malignant form of glioma. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folate metabolism, has been reported to be highly expressed in several human tumors. However, little is known about the role of MTHFD2 in GBM. In this study, we aimed to explore the biological functions of MTHFD2 in GBM and identify the associated mechanisms. We performed experiments such as immunohistochemistry, Western blot, and transwell assays and found that MTHFD2 expression was lower in high-grade glioma than in low-grade glioma. Furthermore, a high expression of MTHFD2 was associated with a favorable prognosis, and MTHFD2 levels showed good prognostic accuracy for glioma patients. The overexpression of MTHFD2 could inhibit the migration, invasion, and proliferation of GBM cells, whereas its knockdown induced the opposite effect. Mechanistically, our findings revealed that MTHFD2 suppressed GBM progression independent of its enzymatic activity, likely by inducing cytoskeletal remodeling through the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, thereby influencing GBM malignance. Collectively, these findings uncover a potential tumor-suppressor role of MTHFD2 in GBM cells. MTHFD2 may act as a promising diagnostic and therapeutic target for GBM treatment.

Bacteremia complicated with pneumonia caused by Corynebacterium diphtheriae.

Due to the use of vaccines, infections caused by Corynebacterium diphtheriae are now rare. Here we describe a case of bacteremia complicated with pneumonia caused by C. diphtheriae in a 69-year-old male patient. The patient presented at the emergency department with a 2 days history of fever of unknown origin. Subsequent examinations revealed pneumonia and bacteremia. Non-toxigenic C. diphtheriae strains were isolated from blood and sputum. The patient had antimicrobial therapy with good improvement. We highlight the important role of C. diphtheriae in causing bacteremia and pneumonia, and its accurate and timely diagnosis is needed to avoid poor visual outcomes.

Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma.

Temozolomide (TMZ), one of the few effective drugs used during adjuvant therapy, could effectively prolong the overall survival (OS) of glioma patients. In our previous study, the mRNA level of G Protein Subunit Alpha 13 (GNA13) was found to be inversely correlated with OS and was therefore identified as a potential biomarker for the prognosis of glioma. Henceforth, this study aims to identify the molecular mechanism of GNA13 in enhancing TMZ sensitization through bioinformatic analyses of GSE80729 and GSE43452 and other experiments. In glioma, overexpression of GNA13 downregulated PRKACA, which is a subunit of PKA, hence reducing phosphorylated RELA and MGMT. Since p-RELA and MGMT were proven to be closely associated with TMZ resistance, we therefore investigated whether thetwo signaling pathways, "GNA13/PRKACA/p-RELA", and "GNA13/PRKACA/MGMT", were involved in the molecular mechanism of GNA13 in TMZ sensitization. Our conclusion was that, GNA13 overexpression in glioma cells were more sensitive in TMZ treatment.

A comparative genomic analysis of small-colony variant and wild-type Burkholderia pseudomallei in a patient with bacterial liver abscess.

OBJECTIVE: To understand the genotypic variations of Burkholderia pseudomallei (B. pseudomallei) small-colony variant (SCV). METHODS: A pair of isogenic wild-type (WT) and SCV B. pseudomallei strains (CX1-1 and CX2-1, respectively) were isolated from a patient with a bacterial liver abscess. They were further identified by multilocus sequence typing (MLST) analysis. To compare their growth speed, the time to detection for the two strains was assessed by BacT/Alert 3D. Antibiotic susceptibility tests were performed by disc diffusion method and Etest assay according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. The whole genomes of the two strains were sequenced. A comparative genome analysis was performed to determine the genotypic variations of the CX2-1 strain. RESULTS: The CX1-1 and CX2-1 strains were both identified as ST70 by MLST. The CX2-1 grew more slowly than the WT strain CX1-1 and was more resistant to imipenem, meropenem, doxycycline, trimethoprim-sulfamethoxazole, and ceftazidime. The comparative genome analysis revealed 38 variations in 30 genes associated with metabolism, drug resistance and virulence. The mutated genes encoded some cell membrane proteins, membrane transporters and synthetases, including: LolB, HisP, PchF, putative polyketide synthetases, probable non-ribosomal peptide synthetases, putative TonB-dependent outer-membrane receptor protein, and putative type III secretion protein. CONCLUSIONS: The reduced growth speed and increased drug resistance of B. pseudomallei SCV strain may be related to those variations in the genome. This provides some clues to their association between the morphotypic and phenotypic characteristics of colony variants, and the potential association of its colony morphotypes with metabolism, antibiotic resistance and virulence.

MiR-506 Suppresses Colorectal Cancer Development by Inhibiting Orphan Nuclear Receptor NR4A1 Expression.

NR4A1 acts as an oncogene and plays an important role in colorectal cancer development and progression, but little is known about the regulatory mechanism of NR4A1 expression. MicroRNA (miRNA) is involved in the progression of various tumors, affecting proliferation, apoptosis or migration. We aimed to elucidate whether miRNA regulates NR4A1 expression and determine its underlying significance in colorectal cancer. By using the TargetScan database, we identified a miR-506 binding site in the NR4A1 3'-UTR. Examination of colorectal cancer tissues and cells revealed that NR4A1 mRNA and protein were up-regulated, while miR-506 expression was down-regulated. Spearman correlation analysis revealed that expression of NR4A1 mRNA was negatively correlated with miR-506 levels in colorectal cancer tissue. Further studies indicated that miR-506 decreased NR4A1 expression through directly targeting the NR4A1 mRNA 3'-UTR. Functional experiments showed that rescue of NR4A1 expression in cells reversed the inhibitory effects of miR-506 on proliferation, migration and invasion of colorectal cancer cells. In conclusion, miR-506 acts as a tumor suppressor and inhibits proliferation, migration and invasion in colorectal cancer cells partly through decreasing NR4A1 expression.

A novel lncRNA NR4A1AS up-regulates orphan nuclear receptor NR4A1 expression by blocking UPF1-mediated mRNA destabilization in colorectal cancer.

Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression. The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as an oncogene, and is involved in colorectal cancer (CRC) development. However, the mechanism through which lncRNA regulates NR4A1 expression remains unknown. We aimed to identify lncRNAs that regulate NR4A1 and assess their underlying mechanisms in CRC. We first identified an antisense lncRNA of NR4A1 that was up-regulated in CRC tissues and cells with rapid amplification of cDNA ends (RACE), and designated it as NR4A1AS. Spearman correlation analysis showed that NR4A1AS was positively correlated with NR4A1 mRNA levels in 37 CRC tissues. Mechanistically, NR4A1AS stabilized NR4A1 mRNA by forming RNA-RNA complexes via partial base-pairing and up-regulated NR4A1 expression in CRC cells. RNA immunoprecipitation (RIP) assays revealed that knockdown of NR4A1AS expression by siRNA enhanced up-frameshift 1 (UPF1) recruitment to NR4A1 mRNA, thereby decreasing NR4A1 mRNA stability. Moreover, depletion of NR4A1AS was found to mimic the effect of NR4A1 knockdown, specifically by suppressing cell proliferation, migration and invasion, and inducing apoptosis and cell cycle arrest. Accordingly, restoring NR4A1 expression ameliorated the effects of NR4A1AS knockdown on tumor growth and metastasis of CRC cells in vitro and in vivo Thus, we conclude that NR4A1AS up-regulates NR4A1 expression by forming RNA-RNA complexes and blocking UPF1-mediated mRNA destabilization, and it functions in tumor growth and metastasis of CRC cells at least partly through regulating NR4A1, suggesting that NR4A1AS might be as a potential target for RNA-based anti-CRC drug studies.

Orphan nuclear receptor NR4A1 suppresses hyperhomocysteinemia-induced hepatic steatosis in vitro and in vivo.

Homocysteine (Hcy) is associated with nonalcoholic fatty liver disease (NAFLD). orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) is involved in hepatic lipid metabolism. However, the potential role of NR4A1 in Hcy-associated NAFLD remains elusive. We aimed to elucidate the regulation of NR4A1 and its significance in Hcy-induced NAFLD. Hcy induced steatosis and elevated the expression of CD36 and FATP2 in HepG2 cells. Furthermore, Hcy enhanced p300 and decreased HDAC7 recruitment to the NR4A1 promoter, resulting in histone H3K27 hyperacetylation and NR4A1 upregulation. Moreover, NR4A1 depletion not only mimicked but also exaggerated the effects of Hcy on steatosis, whereas NR4A1 agonist Cytosporone B (CsnB) blocked Hcy-induced steatosis. In hyperhomocysteinemia (HHcy) mice, CsnB attenuated HHcy-induced hepatic steatosis. Thus, Hcy transiently and rapidly induces NR4A1 expression to reduce Hcy-induced steatosis.

Dehydrogenation of Formic Acid Catalyzed by a Ruthenium Complex with an N,N'-Diimine Ligand.

We report a ruthenium complex containing an N,N'-diimine ligand for the selective decomposition of formic acid to H2 and CO2 in water in the absence of any organic additives. A turnover frequency of 12 000 h-1 and a turnover number of 350 000 at 90 °C were achieved in the HCOOH/HCOONa aqueous solution. Efficient production of high-pressure H2 and CO2 (24.0 MPa (3480 psi)) was achieved through the decomposition of formic acid with no formation of CO. Mechanistic studies by NMR and DFT calculations indicate that there may be two competitive pathways for the key hydride transfer rate-determining step in the catalytic process.

Aluminium complexes of bidentate N,O- and N,N-ligands derived from oxidative functionalization of amido phosphines: synthesis, structure and reactivity.

A series of amido phosphinoxide and amido phosphinimine ligands that are electronic variations of monoanionic N,O- and N,N-ketiminates have been prepared and employed to examine the coordination chemistry of aluminium. Oxidation of the previously established N-(2-diphenylphosphinophenyl)-2,6-dialkylaniline in the presence of H(2)O(2) or organic azides RN(3) (R = 2,6-C(6)H(3)(i)Pr(2), SiMe(3)) led to phosphinoxides (H[NO] 1a-b) and phosphinimines (H[NN] 1c-d), respectively. Alkane elimination reactions of these protio-ligand precursors with trialkylaluminium in toluene or pentane solutions afforded cleanly the corresponding organoaluminium complexes, including dimethyl 2a-d, diethyl 3a-d and diisobutyl derivatives 4a-b and 4d. Solution NMR studies revealed Cs symmetry for these organoaluminium species, in which the α-hydrogen atoms are all diastereotopic. The correlation between the steric congestion of these molecules and the degree of resolution of the multiplet signals corresponding to the diastereotopic α-hydrogen atoms observed by the (1)H NMR spectroscopy is of particular interest. Dichloroaluminium complexes 5c-d were prepared in high yields by protonolysis of MeAlCl(2) with 1c-d. Single-crystal X-ray diffraction analyses of 2c-d, 3a, 3d, 4a, and 4d elucidated a mononuclear, distorted tetrahedral core for all of these aluminium species. Interestingly, complexes 2c-d are active initiators for catalytic ring-opening oligomerization of ε-caprolactone, whereas 2a-b are rather inactive, highlighting the significance of the steric hindrance imposed by the amido phosphinimine ligands, as compared to that imposed by the phosphinoxide counterparts.

Down-regulation of gp130 in nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to explore the expression and biological functions of glycoprotein 130 (gp130) in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). A prospective study was performed. METHODS: Ten patients with NPC and 10 patients with nasopharyngeal lymphoid hyperplasia (LH) were enrolled in this study. The transcripts of IL-27 receptors (gp130 and WSX-1) in the biopsy specimens derived from NPC were compared with that from LH by using reverse-transcription polymerase chain reaction. Cell lines including EBV(-), Burkitt-like lymphoma (BJAB) cells, human adult peripheral blood mononuclear cells, and lymphoblastoid cell lines were used to provide evidence of the biological function of gp130. In addition, killing assay for natural killer (NK) cells was performed in the presence of gp130. RESULTS: There was significantly stronger expression of gp130 on the LH specimens than on the NPC specimens. The levels of gp130 mRNA were reduced in the EBV-transformed cells. The cytotoxicity ratio against gp130-deficient B cells was diminished compared with gp130-existent B cells. CONCLUSION: The expression of gp130 is down-regulated in patients with NPC. We presume that EBV controls the functions of NK cells through regulation of gp130 cytokine receptor.

Aluminum complexes incorporating bidentate amido phosphine ligands.

A series of aluminum complexes supported by o-phenylene-derived amido phosphine ligands, N-(2-diphenylphosphinophenyl)-2,6-dimethylanilide ([Me-NP]-) and N-(2-diphenylphosphinophenyl)-2,6-diisopropylanilide ([iPr-NP]-), have been prepared. The reactions of trialkylaluminum with H[Me-NP] and H[iPr-NP], respectively, in refluxing toluene produced the corresponding dialkyl complexes [Me-NP]AlR(2) and [iPr-NP]AlR(2) (R = Me, Et). Deprotonation of H[Me-NP] with n-BuLi in THF at -35 degrees C followed by addition of AlCl(3) in toluene at -35 degrees C afforded [Me-NP]AlCl(2), which was subsequently reacted with 2 equiv of trimethylsilylmethyllithium in toluene to give [Me-NP]Al(CH(2)SiMe(3))(2). The aluminum complexes were all characterized by (1)H, (13)C, (31)P, and (27)Al NMR spectroscopy. The solid-state structures of monomeric, four-coordinate [Me-NP]AlEt(2) and [iPr-NP]AlMe(2) and five-coordinate [Me-NP]AlCl(2)(THF) were determined by X-ray crystallography. The (1)H NMR studies of [Me-NP]AlEt(2), [Me-NP]Al(CH(2)SiMe(3))(2), and [iPr-NP]AlEt(2) indicate diastereotopic alpha-hydrogen atoms in these molecules. Heteronuclear COSY and NOE experiments suggest that the phosphorus donor in [Me-NP]Al(CH(2)SiMe(3))(2) and [iPr-NP]AlEt(2) is coupled to only one of the diastereotopic alpha-hydrogen atoms that is virtually antiperiplanar with respect to the phosphorus atom.