Variants of the promoter of MYH6 gene in congenital isolated and sporadic patent ductus arteriosus: case-control study and cellular functional analyses.

Patent ductus arteriosus (PDA) is a common form of congenital heart disease. The MYH6 gene has important effects on cardiovascular growth and development, but the effect of variants in the MYH6 gene promoter on ductus arteriosus is unknown. DNA was extracted from blood samples of 721 subjects (428 patients with isolated and sporadic PDA and 293 healthy controls) and analyzed by sequencing for MYH6 gene promoter region variants. Cellular function experiments with three cell lines (HEK-293, HL-1, and H9C2 cells) and bioinformatics analyses were performed to verify their effects on gene expression. In the MYH6 gene promoter, 11 variants were identified. Four variants were found only in patients with PDA and 2 of them (g.3434G>C and g.4524C>T) were novel. Electrophoretic mobility shift assay showed that the transcription factors bound by the promoter variants were significantly altered in comparison to the wild-type in all three cell lines. Dual luciferase reporter showed that all the 4 variants reduced the transcriptional activity of the MYH6 gene promoter (P < 0.05). Prediction of transcription factors bound by the variants indicated that these variants alter the transcription factor binding sites. These pathological alterations most likely affect the contraction of the smooth muscle of ductus arteriosus, leading to PDA. This study is the first to focus on variants at the promoter region of the MYH6 gene in PDA patients with cellular function tests. Therefore, this study provides new insights to understand the genetic basis and facilitates further studies on the mechanism of PDA formation.

ARHGAP4 promotes colon cancer metastasis through the TGF-ß signaling pathway and may be associated with T cell exhaustion.

BACKGROUND: Colon cancer is a prevalent invasive neoplasm in the gastrointestinal system with a high degree of malignancy. Despite extensive research, the underlying mechanisms of its recurrence and metastasis remain elusive.Rho GTPase activating protein 4 (ARHGAP4), a member of the small GTPases protein family, may be closely related to tumor metastasis, and its expression is increased in colon cancer. However, the role of ARHGAP4 in colon cancer metastasis is uncertain. This study investigates the impact of ARHGAP4 on the metastasis of colon cancer cells. Our objective is to determine the role of ARHGAP4 in regulating the invasive behavior of colon cancer cells. METHODS: We downloaded colon adenocarcinoma (COAD) data from the Cancer Genome Atlas (TCGA), and performed differential analysis and survival analysis. By using the CIBERSORT algorithm, we evaluated the proportion of infiltrating immune cells in colon cancer. We further analyzed whether ARHGAP4 is associated with T cell exhaustion. Finally, we investigated the impact of ARHGAP4 knockdown on the migration and invasion of colon cancer cells through in vitro cell experiments. Additionally, we utilized western blotting to assess the expression of protein related to the TGF-ß signaling pathway and epithelial-mesenchymal transition (EMT). RESULTS: We found that ARHGAP4 is upregulated in colon cancer. Subsequent survival analysis revealed that the high-expression group had significantly lower survival rates compared to the low-expression group. Immune infiltration analysis showed that ARHGAP4 was not only positively correlated with CD8+ T cells, but also positively correlated with T cell exhaustion markers programmed cell death 1 (PDCD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte activating 3 (LAG-3). In vitro cell experiments, the knockdown of ARHGAP4 inhibited the migration and invasion of colon cancer cells. Among EMT-related proteins, when ARHGAP4 was knocked down, the expression of E-cadherin was increased, while the expression of N-cadherin and Vimentin was decreased. Meanwhile, the expression of TGF-ß1, p-Smad2, and p-Smad3, which are associated with the TGF-ß/Smad pathway, all decreased. CONCLUSION: ARHGAP4 promotes colon cancer metastasis through the TGF-ß/Smad signaling pathway and may be associated with T cell exhaustion. It plays an important role in the progression of colon cancer and may serve as a potential target for diagnosis and treatment of colon cancer.

OLFM2 promotes epithelial-mesenchymal transition, migration, and invasion in colorectal cancer through the TGF-ß/Smad signaling pathway.

BACKGROUND: Colorectal cancer (CRC) is an aggressive tumor of the gastrointestinal tract, which is a major public health concern worldwide. Despite numerous studies, the precise mechanism of metastasis behind its progression remains elusive. As a member of the containing olfactomedin domains protein family, olfactomedin 2 (OLFM2) may play a role in tumor metastasis. It is highly expressed in colorectal cancer, and its role in the metastasis of CRC is still unclear. As such, this study seeks to explore the function of OLFM2 on CRC metastasis and its potential mechanisms. METHODS: Real-time fluorescence quantitative PCR and western blotting were used to study the expression of OLFM2 in human CRC and adjacent normal tissues. Knockdown and overexpression OLFM2 cell lines were constructed using siRNA and overexpression plasmids to explore the role of OLFM2 in the migration and invasion of CRC through transwell, and wound healing experiments. Finally, the expression of epithelial-mesenchymal transition (EMT) -related proteins and TGF-ß/Smad signaling pathway-related proteins was investigated using western blotting. RESULTS: In this study, we observed an elevation of OLFM2 expression levels in CRC tissues. To investigate the function of OLFM2, we overexpressed and knocked down OLFM2. We discovered that OLFM2 knockdown inhibited migration and invasion of colon cancer cells. Furthermore, E-cadherin expression increased while N-cadherin and Vimentin expression were opposite. It is no surprise that overexpressing OLFM2 had the opposite effects. We also identified that OLFM2 knockdown resulted in reduced TGF-ßR1 and downstream molecules p-Smad2 and p-Smad3, which are related to the TGF-ß / Smad pathway. In contrast, overexpressing OLFM2 significantly boosted their expression levels. CONCLUSION: The protein OLFM2 has been identified as a crucial determinant in the progression of CRC. Its mechanism of action involves the facilitation of EMT through the TGF-ß/Smad signaling pathway. Given its pivotal role in CRC, OLFM2 has emerged as a promising diagnostic and therapeutic target for the disease. These results indicate the potential of OLFM2 as a valuable biomarker for CRC diagnosis and treatment and highlight the need for further research exploring its clinical significance.

Tetralogy of Fallot: variants of MYH6 gene promoter and cellular functional analyses.

BACKGROUND: Tetralogy of Fallot (TOF) is a common form of congenital heart disease. The MYH6 gene has important effects on cardiovascular growth and development. METHODS: In 608 subjects, including 315 TOF patients, we investigated the MYH6 gene promoter variants and verified the effect on gene expression by using cellular functional experiments with three cell lines (HEK-293, HL-1, and H9C2 cells) and bioinformatics analysis. RESULTS: In the MYH6 gene promoter, 12 variants were identified from 608 subjects. Five variants were found only in patients with TOF and two of them (g.3384G>T and g.4518T>C) were novel. Electrophoretic mobility shift assay with three cell lines (HEK-293, HL-1, and H9C2) showed significant changes in the transcription factors bound by the promoter variants compared to the wild-type. Dual luciferase reporter showed that four of the five variants reduced the transcriptional activity of the MYH6 gene promoter (p < 0.05). CONCLUSIONS: This study is the first to test the cellular function of variants in the promoter region of the MYH6 gene in patients with TOF, which provides new insights into the genetic basis of TOF and provides a basis for further study of the mechanism of TOF formation. IMPACT: DNA from 608 human subjects was sequenced for MYH6 gene promoter region variants with five variants found only in TOF patients and two were novel. EMSA and dual luciferase reporter experiments in three cell lines found these variants pathological. Prediction by JASPAR database indicated that these variants alter the transcription factor binding sites. The study, for the first time, confirmed that there are variants at the MYH6 gene promoter region and these variants alter the cellular function. The variants found in this study suggest the possible pathological role in the formation of TOF.

Leveraging the Proximity and Distribution of Cu-Cs Sites for Direct Conversion of Methanol to Esters/Aldehydes.

Methanol serves as a versatile building-block for various commodity chemicals, and the development of industrially promising strategies for its conversion remains the ultimate goal in methanol chemistry. In this study, we design a dual Cu-Cs catalytic system that enables a one-step direct conversion of methanol and methyl acetate/ethanol into high value-added esters/aldehydes, with customized chain length and saturation by leveraging the proximity and distribution of Cu-Cs sites. Cu-Cs at a millimeter-scale intimacy triggers methanol dehydrogenation and condensation, involving proton transfer, aldol formation, and aldol condensation, to obtain unsaturated esters and aldehydes with selectivities of 76.3 % and 31.1 %, respectively. Cu-Cs at a micrometer-scale intimacy significantly promotes mass transfer of intermediates across catalyst interfaces and their subsequent hydrogenation to saturated esters and aldehydes with selectivities of 67.6 % and 93.1 %, respectively. Conversely, Cu-Cs at a nanometer-scale intimacy alters reaction pathway with a similar energy barrier for the rate-determining step, but blocks the acidic-basic sites and diverts the reaction to byproducts. More importantly, an unprecedented quadruple tandem catalytic production of methyl methacrylate (MMA) is achieved by further tailoring Cu and Cs distribution across the reaction bed in the configuration of Cu-Cs||Cs, outperforming the existing industrial processes and saving at least 15 % of production costs.

MTERF3 contributes to MPP+-induced mitochondrial dysfunction in SH-SY5Y cells.

Parkinson's disease (PD) is a neurodegenerative disorder causing severe social and economic burdens. The origin of PD has been usually attributed to mitochondrial dysfunction. To this end, mitochondrial transcription regulators become attractive subjects for understanding PD pathogenesis. Previously, we found that the expression of mitochondrial transcription termination factor 3 (MTERF3) was reduced in MPP+-induced mice model of PD. In the present study, we probe the function of MTERF3 and its role in MPP+-induced cellular model of PD. Initially, we observe that MTERF3 expression is also reduced in MPP+-induced cellular model of PD, which can be mainly attributed to the increase of MTERF3 degradation. Next, we examine the effect of MTERF3 knockdown and overexpression on the replication, transcription, and translation of mitochondrial DNA (mtDNA). We show that knockdown and overexpression of MTERF3 have opposite effects on mtDNA transcript level but similar effects on mtDNA expression level, in line with MTERF3's dual roles in mtDNA transcription and translation. In addition, we examine the effect of MTERF3 knockdown and overexpression on mitochondrial function with and without MPP+ treatment, and find that MTERF3 seems to play a generally protective role in MPP+-induced mitochondrial dysfunction. Together, this work suggests a regulatory role of MTERF3 in MPP+-induced cellular model of PD and may provide clues in designing novel therapeutics against PD.

A Regulatory Loop Involving miR-200c and NF-κB Modulates Mortalin Expression and Increases Cisplatin Sensitivity in an Ovarian Cancer Cell Line Model.

Ovarian cancer is currently the most lethal gynecological cancer. At present, primary debulking surgery combined with platinum-based chemotherapy is the standard treatment strategy for ovarian cancer. Although cisplatin-based chemotherapy has greatly improved the prognosis of patients, the subsequent primary or acquired drug resistance of cancer cells has become an obstacle to a favorable prognosis. Mortalin is a chaperone that plays an important role in multiple cellular and biological processes. Our previous studies have found that mortalin is associated with the proliferation and migration of ovarian cancer cells and their resistance to cisplatin-based chemotherapy. In this study, microRNA (miR)-200b/c downregulated mortalin expression and inhibited the proliferation and migration of the paired cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CP) epithelial ovarian cancer cell lines. Moreover, miR-200c increased the sensitivity of ovarian cancer cells to cisplatin treatment by regulating mortalin levels. Nuclear factor (NF)-κB directly regulated mortalin and miR-200b/c expression levels, while NF-κB and miR-200b/c jointly regulated the expression of mortalin. The combination of cisplatin and miR-200c significantly enhanced the therapeutic effects on ovarian cancer in vivo, suggesting that miR-200c may serve as a potential therapeutic agent for ovarian cancer.

NF-κB p65 promotes ovarian cancer cell proliferation and migration via regulating mortalin.

Previous studies show that mortalin, a HSP70 family member, contributes to the development and progression of ovarian cancer. However, details of the transcriptional regulation of mortalin remain unknown. We aimed to determine whether NF-κB p65 participates in the regulation of mortalin expression in ovarian cancer cells and to elucidate the underlying mechanism. Chromatin immunoprecipitation and luciferase reporter assay were used to identify mortalin gene sequences, to which NF-κB p65 binds. Results indicated that NF-κB p65 binds to the mortalin promoter at a site with the sequence 'CGGGGTTTCA'. Using lentiviral pLVX-NF-κB-puro and Lentivirus-delivered NF-κB short hairpin RNA (shRNA), we created ovarian cancer cell lines in which NF-κB p65 was stably up-regulated and down-regulated. Using these cells, we found that downregulation of NF-κB p65 inhibits the growth and migration of ovarian cancer cells. Further experimental evidence indicated that downregulation of NF-κB p65 reduced mortalin, and upregulation of mortalin rescued the proliferation and migration of ovarian cancer cells reduced by NF-κB p65 knockdown. In conclusion, NF-κB p65 binds to the mortalin promoter and promotes ovarian cancer cells proliferation and migration via regulating mortalin.

Autoregulation of RBM10 and cross-regulation of RBM10/RBM5 via alternative splicing-coupled nonsense-mediated decay.

Mutations in the spliceosomal RNA binding protein RBM10 cause TARP syndrome and are frequently observed in lung adenocarcinoma (LUAD). We have previously shown that RBM10 enhances exon skipping of its target genes, including its paralog RBM5. Here, we report that RBM10 negatively regulates its own mRNA and protein expression and that of RBM5 by promoting alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD). Through computational analysis and experimental validation, we identified RBM10-promoted skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 as the underlying AS-NMD events. Importantly, we showed that LUAD-associated mutations affecting splice sites of RBM10 exons 6 or 12 abolished exon inclusion and correlated with reduced expression of RBM10 RNA. Together, our investigations have revealed novel molecular mechanisms underlying RBM10 autoregulation and cross-regulation of RBM5, thereby providing insights concerning the functions of RBM10 under various physiological and pathological conditions. Our combined computational and experimental approach should be useful for elucidating the role of AS-NMD in auto- and cross-regulation by other splicing regulators.

Effects of Chemical State of the Pd Species on H2 Sensing Characteristics of PdOx/SnO2 Based Chemiresistive Sensors.

In this paper, the PdOx nanoparticles modified SnO2 are prepared using sputtering and wet chemical methods. The SnO2 nanoparticles are separately added to a concentration of 0.75% to 10% PdCl2 to obtain a PdCl2/SnO2 composite material, which is calcined for 1 to 2 h at the temperatures of 120 °C, 250 °C, 450 °C and 600 °C. The PdOx/SnO2 nanocomposite was characterized by X-ray photoelectron spectroscopy (XPS), X-ray diffractometry (XRD) and transmission electron microscopy (TEM). Microstructural observations revealed PdOx with different chemical states attached to the surface of SnO2. Hydrogen response change tests were performed on the obtained PdOx/SnO2 gas sensing materials. The results show that the high gas sensing performance may be attributed to the contribution of the PdOx-loaded SnO2. In hydrogen, the best sensitivity response was attained at 80 °C, which is 60 times that of pristine SnO2. It clarifies the role of PdOx in the gas sensing mechanisms.

The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells.

BACKGROUND/AIMS: Circular RNAs (circRNAs), a type of RNA that is widely expressed in human cells, have essential roles in the development and progression of cancer. CircRNAs contain microRNA (miRNA) binding sites and can function as miRNA sponges to regulate gene expression by removing the inhibitory effect of an miRNA on its target gene. METHODS: We used the bioinformatics software TargetScan and miRanda to predict circRNA-miRNA and miRNAi-Mrna interactions. Rate of inhibiting of proliferation was measured using a WST-8 cell proliferation assay. Clone formation ability was assessed with a clone formation inhibition test. Cell invasion and migration capacity was evaluated by performing a Transwell assay. Relative gene expression was assessed using quantitative real-time polymerase chain reaction and relative protein expression levels were determined with western blotting. circRNA and miRNA interaction was confirmed by dual-luciferase reporter and RNA-pull down assays. RESULTS: In the present study, the miRNA hsa-miR-21-5p was a target of circRNA-ACAP2, and T lymphoma invasion and metastasis protein 1 (Tiam1) was identified as a target gene of hsa-miR-21-5p. CircRNA-ACAP2 and Tiam1 were shown to be highly expressed in colon cancer tissue and colon cancer SW480 cells, but miR-21-5p was expressed at a low level. SW480 cell proliferation was suppressed when the expression of circRNA-ACAP2 and Tiam1 was decreased and the expression of miR-21-5p was increased in vivo and in vitro. SW480 cell migration and invasion were also inhibited under the same circumstance. The circRNA-ACAP2 interaction regulated the expression of miR-21-5p, and miR-21-5p regulated the expression of Tiam1. Down-regulation of circRNA-ACAP2 promoted miR-21-5p expression, which further suppressed the transcription and translation of Tiam1. CONCLUSION: The present study shows that the circRNA-ACAP2/hsa-miR-21-5p/Tiam1 regulatory feedback circuit could affect the proliferation, migration, and invasion of colon cancer SW480 cells. This was probably due to the fact that circRNA-ACAP2 could act as a miRNA sponge to regulate Tiam1 expression by removing the inhibitory effect of miR-21-5p on Tiam1 expression. The results from this study have revealed new insights into the pathogenicity of colon cancer and may provide novel therapeutic targets for the treatment of colon cancer.

Oncogenic role of mortalin contributes to ovarian tumorigenesis by activating the MAPK-ERK pathway.

Mortalin is frequently overexpressed in human malignancies. Previous studies have suggested that mortalin contributes to ovarian cancer development and progression, but further investigation is warranted. The aim of this study is to elucidate the mechanism of mortalin in ovarian cancer development and progression. In this study, lentivirus-delivered mortalin short hairpin RNA (shRNA) was used to knockdown mortalin expression in A2780 and A2780/cis ovarian cancer cell lines, and lentiviral mortalin-pLVX-AcGFP was used to generate mortalin-overexpressing cell lines. The results demonstrated that decreased mortalin expression reduced ovarian cancer cell proliferation, colony formation, migration and invasion by Cell Counting Kit-8 assay, colony formation assay, wounding healing assay and Transwell cell invasion assay, respectively. Flow cytometry results suggested that mortalin promotes the G1 transition, leading to faster restoration of a normal cell-cycle distribution. Cell-cycle proteins, including C-myc and Cyclin-D1, significantly increased, and Cyclin-B1 remarkably decreased upon mortalin down-regulation. Western blot analysis showed that mortalin knockdown significantly decreased p-c-Raf and phospho-extracellular-regulated protein kinases (p-ERK1/2) pathways but not the Jun N-terminal kinase pathway, whereas mortalin overexpression had the opposite effect. Taken together, these results indicate that mortalin is an oncogenic factor, and mitogen-activated protein kinase-ERK signalling pathway activation by mortalin may contribute to ovarian cancer development and progression.

MTERF2 contributes to MPP(+)-induced mitochondrial dysfunction and cell damage.

Parkinson's disease (PD) is a common neurodegenerative disorder whose pathogenesis is under intense investigation. Substantial evidence indicates that mitochondrial dysfunction plays a central role in the pathophysiology of PD. Several mitochondrial internal regulating factors act to maintain the mitochondrial function. However, how these internal regulating factors contribute to mitochondrial dysfunction in PD remains elusive. One of these factors, mitochondrial transcription termination factor 2 (MTERF2), has been implicated in the regulation of oxidative phosphorylation by modulating mitochondrial DNA transcription. Here, we discovered a new role of MTERF2 in regulating mitochondrial dysfunction and cell damage induced by MPP(+) in SH-SY5Y cells. We found that MPP(+) treatment elevated MTERF2 expression, induced mitochondrial dysfunction and cell damage, which was alleviated by MTERF2 knockdown. These findings demonstrate that MTERF2 contributes to MPP(+)-induced mitochondrial disruption and cell damage. This study indicates that MTERF2 is a potential therapeutic target for environmentally induced Parkinson's disease.

MTERF4 regulates the mitochondrial dysfunction induced by MPP(+) in SH-SY5Y cells.

Mitochondrial transcription termination factor 4, MTERF4, a member of the MTERF family, has been implicated in the regulation of mitochondrial translation by targeting NSUN4 to the large mitochondrial ribosome. Here, we found a novel role for MTERF4 in regulating mitochondrial dysfunction induced by MPP(+). We observed that knockdown of MTERF4 in SH-SY5Y cells resulted in increased mitochondrial DNA transcription levels and decreased mitochondrial DNA translation levels. In addition, after treatment with 2 mM MPP(+) for 24 h, the expression levels of MTERF4 were decreased compared to wide-type SH-SY5Y cells. Moreover, after exposure to 2 mM MPP(+) for 24 h, knockdown of MTERF4 in SH-SY5Y cells worsened the mitochondrial dysfunction induced by MPP(+), including increased reactive oxygen species, accumulated cleaved PARP-1, decreased mitochondrial membrane potential and depressed mitochondrial complexes. Furthermore, overexpression of MTERF4 in SH-SY5Y cells partially alleviated the mitochondrial dysfunction induced by MPP(+). Based on these findings, we suggest that the main function of MTERF4 is regulating mtDNA expression, and it is the crucial factor in the mechanism of mitochondrial dysfunction in SH-SY5Y cells induced by MPP(+). MTERF4 probably is the triggering of the pathogenesis of Parkinson's disease induced by environmental toxin.

Astaxanthin inhibits apoptosis in alveolar epithelial cells type II in vivo and in vitro through the ROS-dependent mitochondrial signalling pathway.

Oxidative stress is an important molecular mechanism underlying lung fibrosis. The mitochondrion is a major organelle for oxidative stress in cells. Therefore, blocking the mitochondrial signalling pathway may be the best therapeutic manoeuver to ameliorate lung fibrosis. Astaxanthin (AST) is an excellent antioxidant, but no study has addressed the pathway of AST against pulmonary oxidative stress and free radicals by the mitochondrion-mediated signalling pathway. In this study, we investigated the antioxidative effects of AST against H2 O2 - or bleomycin (BLM)-induced mitochondrial dysfunction and reactive oxygen species (ROS) production in alveolar epithelial cells type II (AECs-II) in vivo and in vitro. Our data show that AST blocks H2 O2 - or BLM-induced ROS generation and dose-dependent apoptosis in AECs-II, as characterized by changes in cell and mitochondria morphology, translocation of apoptotic proteins, inhibition of cytochrome c (Cyt c) release, and the activation of caspase-9, caspase-3, Nrf-2 and other cytoprotective genes. These data suggest that AST inhibits apoptosis in AECs-II cells through the ROS-dependent mitochondrial signalling pathway and may be of potential therapeutic value in lung fibrosis treatment.

Upregulated Parkin expression protects mitochondrial homeostasis in DJ-1 konckdown cells and cells overexpressing the DJ-1 L166P mutation.

Rare genetic mutations in the DJ-1 and Parkin genes cause recessive Parkinsonism, however, the relationship between these two genes is not fully elucidated. Current emerging evidence suggests that these genes are involved in mitochondrial homeostasis, and that a deficiency in either of these two genes is associated with damages in mitochondrial function and morphology. In this study, we demonstrated that knockdown of DJ-1 expression or the overexpression of the DJ-1 L166P mutation results in a damaged phenotype in mitochondria and a hypersensitivity to H2O2-induced cell apoptosis. These phenotypes result from increased levels of endogenous oxidative stress. However, overexpression of wild-type Parkin rescued the phenotypes observed in the mitochondria of DJ-1 knockdown and DJ-1 L166P mutant cells. We also determined that there were differences between the two cell models. Furthermore, both H2O2 treatment and the DJ-1 L166P mutation weakened the interaction between DJ-1 and Parkin. Taken together, these findings suggested that DJ-1 and Parkin were linked through oxidative stress, and that overexpression of Parkin protects DJ-1 protein-deficient and DJ-1 L166P mutant-expressing cells via inhibition of oxidative stress.

Unveiling esophageal cancer treatment mechanisms: network pharmacology and molecular docking of Physcion.

This study investigates the effects of Physcion on esophageal cancer and its possible mechanisms of action. Potential Physcion targets were identified using databases. Transcriptomic data from 17 esophageal cancer and adjacent tissues were analyzed to find differentially expressed genes, intersecting with potential targets to select 16 key genes. Their expression and distribution were evaluated in patient sequencing data. Diagnostic potential was assessed through differential gene expression and ROC curves. Pathway enrichment analysis was performed using KEGG, and molecular docking simulations were conducted to assess Physcion's binding affinity to key genes. In vitro assays complemented these findings. A total of 161 drug targets were identified, narrowing down to 16 pivotal genes. Expression patterns were examined across cell populations, and enrichment analysis showed significant PI3K/AKT pathway involvement. Molecular docking indicated strong binding of Physcion to HSP90AA1 and MMP2. In vitro assays confirmed Physcion's dose- and time-dependent impact on esophageal cancer cells, with significant DAPI staining effects. Physcion shows promise as a therapeutic agent for esophageal cancer. The study supports its potential for clinical development and future research in esophageal cancer treatment.

Over-expression of GRP75 inhibits liver injury induced by oxidative damage.

It has been reported that over-expression of GRP75 can protect cells under different types of stress. In this study, we investigated the protective effect of GRP75 on the liver both in vivo and in vitro. To evaluate the effect of GRP75 over-expression on oxidative damage in the liver in vitro, cell viability and the mitochondrial function of GRP75-overexpressing HL-7702 cells and control transfected cells were monitored during H(2)O(2) treatment. In vivo, liver fibrosis was induced in rats by carbon tetrachloride (CCl(4)) injection for 8 weeks. The GRP75-overexpressing vector was randomly injected into rats before fibrosis was established to study the inhibitory effect of GRP75 on hepatic fibrosis. Liver injury and mitochondrial function were assessed. On H(2)O(2) treatment, GRP75-overexpressing HL-7702 cells exhibited more moderate cell damage than control HL-7702 cells. Both groups of cells showed a decrease in ATP following an early increase on H(2)O(2) treatment, and the mitochondrial membrane potential also decreased similarly in these two groups of cells. Control HL-7702 cells showed an immediate and rapid increase in reactive oxygen species accumulation after the onset of H(2)O(2) treatment, and this accumulation was slowed and reduced in GRP75-overexpressing cells. Western blotting revealed that cytochrome c was greater in control HL-7702 cells than in GRP75-overexpressing HL-7702 cells. Compared with the CCl(4)-only rats, serum alanine transaminase and aspartate aminotransferase were significantly lower in CCl(4)-treated rats transfected with the GRP75 vector (P < 0.01). ATP concentrations decreased in both groups of rats treated with CCl(4), but were higher in the GRP75-overexpressing CCl(4)-treated group than in CCl(4)-only rats. Cytochrome c expression was lower in GRP75-overexpressing rats than in CCl(4)-only rats.

Exogenous taurine attenuates mitochondrial oxidative stress and endoplasmic reticulum stress in rat cardiomyocytes.

Taurine, a conditionally essential amino acid, plays a critical role in cardiovascular function. Here we examined the effect of taurine on mitochondria and endoplasmic reticulum in rat cardiomyocytes during glucose deprivation (GD). Data showed that cell viability, intracellular taurine contents, and taurine transporter expression were decreased during GD. In contrast, an increase in reactive oxygen species and intracellular Ca(2+) contents was observed. GD also caused disrupted mitochondrial membrane potential, apoptotic cell death, and dissociation of unfolded protein response (UPR)-relative proteins in cardiomyocytes. Signal transduction analysis showed that Bcl-2 family protein balance was disturbed, caspase-12 was activated and UPR-relative protein levels were up-regulated. Moreover, pre-treatment with 80 mM exogenous taurine attenuated GD effect in cardiomyocytes. Our results suggest that taurine have beneficial effects on inhibiting mitochondria-dependent cell apoptosis and UPR-associated cell apoptosis and might have clinical implications on acute myocardial infarction in future.

Serum miR-146a level is a potential biomarker in predicting the outcome of diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with heterogenicity in clinical manifestation and prognosis. Some microRNAs can influence the development of tumors and may be related to the response of therapy or prognosis. This study aims to explore the role of serum miR-146a in predicting the prognosis of DLBCL. METHODS: A total of 72 de novo DLBCL patients received 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab combined CHOP (R-CHOP) regimen, and their serum samples were collected before treatment and after 4 cycles of chemotherapy. RESULTS: The results show that a high level of miR-146a is significantly associated with a good outcome in baseline and is more obvious in post-chemotherapy. In addition, a high level of miR-146a was associated with better progression-free survival and overall survival in patients treated with R-CHOP but has not been related to a superior outcome in patients treated with CHOP. Rituximab may improve the efficacy of therapy, especially in patients with high miR-146a levels. The level of miR-146a decreased in more patients after chemotherapy, and it seems patients with a decreased expression of miR-146a after chemotherapy tended a better outcome, but it is not statistically significant. CONCLUSION: Our results suggest that the level of serum miR-146a can serve as a potential prognostic biomarker for DLBCL patients.