SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway.

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

Comparative physiological, biochemical, metabolomic, and transcriptomic analyses reveal the formation mechanism of heartwood for Acacia melanoxylon.

Acacia melanoxylon is well known as a valuable commercial tree species owing to its high-quality heartwood (HW) products. However, the metabolism and regulatory mechanism of heartwood during wood development remain largely unclear. In this study, both microscopic observation and content determination proved that total amount of starches decreased and phenolics and flavonoids increased gradually from sapwood (SW) to HW. We also obtained the metabolite profiles of 10 metabolites related to phenolics and flavonoids during HW formation by metabolomics. Additionally, we collected a comprehensive overview of genes associated with the biosynthesis of sugars, terpenoids, phenolics, and flavonoids using RNA-seq. A total of ninety-one genes related to HW formation were identified. The transcripts related to plant hormones, programmed cell death (PCD), and dehydration were increased in transition zone (TZ) than in SW. The results of RT-PCR showed that the relative expression level of genes and transcription factors was also high in the TZ, regardless of the horizontal or vertical direction of the trunk. Therefore, the HW formation took place in the TZ for A. melanoxylon from molecular level, and potentially connected to plant hormones, PCD, and cell dehydration. Besides, the increased expression of sugar and terpenoid biosynthesis-related genes in TZ further confirmed the close connection between terpenoid biosynthesis and carbohydrate metabolites of A. melanoxylon. Furthermore, the integrated analysis of metabolism data and RNA-seq data showed the key transcription factors (TFs) regulating flavonoids and phenolics accumulation in HW, including negative correlation TFs (WRKY, MYB) and positive correlation TFs (AP2, bZIP, CBF, PB1, and TCP). And, the genes and metabolites from phenylpropanoid and flavonoid metabolism and biosynthesis were up-regulated and largely accumulated in TZ and HW, respectively. The findings of this research provide a basis for comprehending the buildup of metabolites and the molecular regulatory processes of HW formation in A. melanoxylon.

Intermittent high altitude hypoxia induced liver and kidney injury leading to hyperuricemia.

About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1ß and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.

Meta Analysis of the Effects of Thalassemia Minor on the Incidence of Amniotic Fluid Abnormalities and the Amount of Bleeding During Delivery.

Objective: To analyze the effects of thalassemia minor on the incidence of amniotic fluid abnormalities and the blood loss of pregnant women during delivery based on the database. Methods: PubMed, EMBASE, EBSCO, Web of Knowledge and Ovid databases were searched for articles on the incidence of amniotic fluid abnormalities and the amount of bleeding during delivery in pregnant women with mild thalassemia; it can also be combined with manual retrieval for literature review. The data retrieval period was from the establishment of the database to June 2022. According to the Newcastle Ottawa scale score, the quality of the six included literature was evaluated, and the Revman processing software was used for meta-analysis. Results: The 6 included articles are all high-quality literature, including 364 cases in the case group and 689 cases in the control group. The publication years of the literature are mainly from 2013 to 2021, and they are all high-quality literature. All literature was blinded, and a total of 4 pregnancy outcomes were extracted from the 6 included literature, including oligohydramnios/oligohydramnios, postpartum hemorrhage, preterm delivery, and cesarean section. Compared to normal pregnant women, the level of postpartum bleeding in thalassemia pregnant women was significantly increased [RR = 2.40, 95% CI (1.63-3.54), P < .05], and the difference was statistically significant. Compared to normal pregnant women, thalassemia pregnant women have a significantly higher risk of developing excessive/insufficient amniotic fluid [RR = 2.71, 95% CI (2.52-2.81), P < .01], and the difference is statistically significant. Compared to normal pregnant women, pregnant women with thalassemia have a significantly higher risk of premature birth [RR = 3.02, 95% CI (1.84~4.96), P < .05], and the difference is statistically significant. Compared to normal pregnant women, the risk of cesarean section in thalassemia pregnant women is significantly increased [RR = 1.68, 95% CI (1.39-2.02), P < .05], and the difference is statistically significant. Conclusion: Thalassemia minor can increase the incidence of amniotic fluid abnormalities and the amount of bleeding during labor. In the future, we should strengthen the health education of pregnant women, improve the understanding of the disease, avoid or reduce the impact of thalassemia on newborns, improve the pregnancy outcome, and provide a more reliable basis for clinical decision-making.However, there are still certain limitations: (1) the literature selected in the study for the past 5 years is relatively small, and they are all single center, retrospective studies, and have a small sample size, resulting in insufficient accuracy of the results of the meta-analysis; (2) Some literature lacks blind methods, which may lead to language bias and implementation bias in the results; (3) The research time is still short, and it has not been clear how different types of thalassemia affect abnormal amniotic fluid volume and postpartum bleeding.

Physiological, Biochemical, and Molecular Analyses Reveal Dark Heartwood Formation Mechanism in Acacia melanoxylon.

Acacia melanoxylon is highly valued for its commercial applications, with the heartwood exhibiting a range of colors from dark to light among its various clones. The underlying mechanisms contributing to this color variation, however, have not been fully elucidated. In an effort to understand the factors that influence the development of dark heartwood, a comparative analysis was conducted on the microstructure, substance composition, differential gene expression, and metabolite profiles in the sapwood (SW), transition zone (TZ), and heartwood (HW) of two distinct clones, SR14 and SR25. A microscopic examination revealed that heartwood color variations are associated with an increased substance content within the ray parenchyma cells. A substance analysis indicated that the levels of starches, sugars, and lignin were more abundant in SP compared to HW, while the concentrations of phenols, flavonoids, and terpenoids were found to be higher in HW than in SP. Notably, the dark heartwood of the SR25 clone exhibited greater quantities of phenols and flavonoids compared to the SR14 clone, suggesting that these compounds are pivotal to the color distinction of the heartwood. An integrated analysis of transcriptome and metabolomics data uncovered a significant accumulation of sinapyl alcohol, sinapoyl aldehyde, hesperetin, 2', 3, 4, 4', 6'-peptahydroxychalcone 4'-O-glucoside, homoeriodictyol, and (2S)-liquiritigenin in the heartwood of SR25, which correlates with the up-regulated expression of CCRs (evm.TU.Chr3.1751, evm.TU.Chr4.654_667, evm.TU.Chr4.675, evm.TU.Chr4.699, and evm.TU.Chr4.704), COMTs (evm.TU.Chr13.3082, evm.TU.Chr13.3086, and evm.TU.Chr7.1411), CADs (evm.TU.Chr10.2175, evm.TU.Chr1.3453, and evm.TU.Chr8.1600), and HCTs (evm.TU.Chr4.1122, evm.TU.Chr4.1123, evm.TU.Chr8.1758, and evm.TU.Chr9.2960) in the TZ of A. melanoxylon. Furthermore, a marked differential expression of transcription factors (TFs), including MYBs, AP2/ERFs, bHLHs, bZIPs, C2H2s, and WRKYs, were observed to be closely linked to the phenols and flavonoids metabolites, highlighting the potential role of multiple TFs in regulating the biosynthesis of these metabolites and, consequently, influencing the color variation in the heartwood. This study facilitates molecular breeding for the accumulation of metabolites influencing the heartwood color in A. melanoxylon, and offers new insights into the molecular mechanisms underlying heartwood formation in woody plants.

Association between oxidative stress, mitochondrial function of peripheral blood mononuclear cells and gastrointestinal cancers.

BACKGROUND: The incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated. METHODS: A total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated. RESULTS: The imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer. CONCLUSION: Our study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.

The regulatory roles of DDIT4 in TDCIPP-induced autophagy and apoptosis in PC12 cells.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate-based flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy. However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4 (DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot (WB) and Flow cytometry (FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II (LC3II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the mTOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.

Expression and significance of SOX B1 genes in glioblastoma multiforme patients.

The overall survival of glioblastoma multiforme (GBM) patients remains poor. To improve patient outcomes, effective diagnostic and prognostic biomarkers for GBM are needed. In this study, we first applied bioinformatic analyses to identify biomarkers for GBM, focusing on SOX (sex-determining region on the Y chromosome (SRY)-related high mobility group (HMG) box) B1 family members. The ONCOMINE, GEPIA, LinkedOmics and CCLE databases were used to assess mRNA expression levels of the SOX B1 family members in different cancers and normal tissue. Further bioinformatic analysis was performed using the ONCOMINE database in combination with the LinkedOmics data set to identify the prognostic value of SOX B1 family members for GBM. We found mRNA expression levels of all tested SOX B1 genes were significantly increased in GBM. In the LinkedOmics database, increased expression of SOX3 indicated a better overall survival. In GEPIA databases, increased expression of all SOX B1 family members suggested an improved overall survival, but none of them were statistically different. Then, Transwell assays and wound healing were employed to evaluate the motility and invasive captivity of U251 cells when silencing SOX2 and SOX3. We found exogenous inhibition of SOX2 appeared to reduce the migration and invasion of U251 cells in vitro. Collectively, our research suggested that SOX2 might serve as a cancer-promoting gene to identify high-risk GBM patients, and SOX3 had the potential to be a prognostic biomarker for GBM patients.

S100A1 is Involved in Myocardial Injury Induced by Exhaustive Exercise.

Many studies have confirmed that exhaustive exercise has adverse effects on the heart by generating reactive oxygen species (ROS). S100A1 calcium-binding protein A1 (S100A1) is a regulator of myocardial contractility and a protector against myocardial injury. However, few studies have investigated the role of S100A1 in the regulation of myocardial injury induced by exhaustive exercise. In the present study, we suggested that exhaustive exercise led to increased ROS, downregulation of S100a1, and myocardial injury. Downregulation of S100a1 promoted exhaustive exercise-induced myocardial injury and overexpression of S100A1 reversed oxidative stress-induced cardiomyocyte injury, indicating S100A1 is a protective factor against myocardial injury caused by exhaustive exercise. We also found that downregulation of S100A1 promoted damage to critical proteins of the mitochondria by inhibiting the expression of Ant1, Pgc1a, and Tfam under exhaustive exercise. Our study indicated S100A1 as a potential prognostic biomarker or therapeutic target to improve the myocardial damage induced by exhaustive exercise and provided new insights into the molecular mechanisms underlying the myocardial injury effect of exhaustive exercise.

Resveratrol Ameliorates High Altitude Hypoxia-Induced Osteoporosis by Suppressing the ROS/HIF Signaling Pathway.

Hypoxia at high-altitude leads to osteoporosis. Resveratrol (RES), as an antioxidant, has been reported to promote osteoblastogenesis and suppress osteoclastogenesis. However, the therapeutic effect of RES against osteoporosis induced by high-altitude hypoxia remains unclear. Thus, this study was intended to investigate the potential effects of RES on high-altitude hypoxia-induced osteoporosis both in vivo and in vitro. Male Wistar rats were given RES (400 mg/kg) once daily for nine weeks under hypoxia, while the control was allowed to grow under normoxia. Bone mineral density (BMD), the levels of bone metabolism-related markers, and the changes on a histological level were measured. Bone marrow-derived mesenchymal stem cells (BMSCs) and RAW264.7 were incubated with RES under hypoxia, with a control growing under normoxia, followed by the evaluation of proliferation and differentiation. The results showed that RES inhibited high-altitude hypoxia-induced reduction in BMD, enhanced alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT) and runt-related transcription factor 2 (RUNX2) levels, whereas it reduced cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) levels and tartrate-resistant acid phosphatase (TRAP) activity in vivo. In addition, RES attenuated histological deteriorations in the femurs. In vitro, RES promoted osteoblastogenesis and mineralization in hypoxia-exposed BMSCs, along with promotion in RUNX2, ALP, OCN and osteopontin (OPN) levels, and inhibited the proliferation and osteoclastogenesis of RAW264.7. The promotion effects of RES on osteoblastogenesis were accompanied by the down-regulation of reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α) induced by hypoxia. These results demonstrate that RES can alleviate high-altitude hypoxia-induced osteoporosis via promoting osteoblastogenesis by suppressing the ROS/HIF-1α signaling pathway. Thus, we suggest that RES might be a potential treatment with minimal side effects to protect against high-altitude hypoxia-induced osteoporosis.

Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia-related diseases.

Sestrin2 (SESN2) is a conserved stress-inducible protein (also known as hypoxia-inducible gene 95 (HI95)) that is induced under hypoxic conditions. SESN2 represses the production of reactive oxygen species (ROS) and provides cytoprotection against various noxious stimuli, including hypoxia, oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. In recent years, the determination of the regulation and signalling mechanisms of SESN2 has increased our understanding of its role in the hypoxic response. SESN2 has well-documented roles in hypoxia-related diseases, making it a potential target for diagnosis and treatment. This review discusses the regulatory mechanisms of SESN2 and highlights the significance of SESN2 as a biomarker and therapeutic target in hypoxia-related diseases, such as cancer, respiratory-related diseases, cardiovascular diseases and cerebrovascular diseases.

The effect of different drinking water in culture medium on feces microbiota diversity.

The human gut harbors trillions of microbes, which are extremely important to the health of the host. However, the effect of drinking water on gut microbiota has been poorly understood. In this study, we explored the response of BALB/c mice gut bacterial community (feces) to the different types of drinking water, including commercial bottled mineral water (MW), natural water (NW), purified water (PW) and tap water (TW). Feces were cultured with brain heart infusion broth dissolved in four types of drinking water. 16S rRNA gene analysis was performed. Our results reveal that the microbiota composition is different among culturing with four types of drinking water. As the culture time increases, the number of OTUs significantly decreased, except under the aerobic condition of MW. Under aerobic conditions on the 5th day, the considerable differences of alpha diversity index are found between MW and three others, and these are the most unique taxa in the MW group. Importantly, the LEfSe analysis discovers that the Bacteroidetes taxa dominate the differences between MW and the other water types. Our findings demonstrate that the mineral water as a culture medium may lead to a progressive increase of the gut microbiota diversity by providing the growth convenience to Bacteroidetes.

Quantitative Proteomics Reveals the Effects of Resveratrol on High-Altitude Polycythemia Treatment.

High-altitude polycythemia (HAPC) is a common plateau chronic disease in which red blood cells are compensatory hyperproliferative due to high altitude hypoxic environment. HAPC severely affects the physical and mental health of populations on the plateau. However, the pathogenesis and treatment of HAPC has been rarely investigated. Here, the hypoxia-induced HAPC model of rat is established, in which hemoglobin concentration significantly increases and platelets clearly decrease. The effect of resveratrol upon hypoxia enables HAPC remission and makes hemoglobin and platelet tend to a normal level. Furthermore, quantitative proteomics is applied to investigate the plasma proteome variation and the underlying molecular regulation during HAPC occurrence and treatment with resveratrol. Hypoxia promotes erythrocyte developing and differentiating and disrupts cytoskeleton organization. Notably, the resveratrol administration reverses the proteome change pattern due to hypoxia and contributes to plateau adaption. Quantitative verification of differentially expressed proteins confirms the roles of resveratrol in HAPC. Resveratrol is expected to be useful for HAPC treatment.

Downregulation of miR-541 induced by heat stress contributes to malignant transformation of human bronchial epithelial cells via HSP27.

Environmental factors are one of the important factors affecting the occurrence of lung cancer. However, few studies have been done on the relationship between hot environment and lung cancer. In the present study, we demonstrated that heat stress leads to anchorage-independent proliferation, mitochondrial apoptosis, and autophagy of Beas-2B cells, which are normal lung bronchial epithelial cells. Heat shock protein 27 (HSP27) promoted heat stress-induced anchorage-independent proliferation and autophagy, but suppressed mitochondrial apoptosis, indicating that HSP27 might act as an oncogene in the malignant transformation of lung epithelial cells. We also showed that HSP27 promoted autophagy of these cells under heat stress via autophagy related 7 (ATG7) and ETS Transcription Factor ELK1 (ELK1), a transcription factor of ATG7, under heat stress. In addition, we showed that HSP27 translation could be repressed by microRNA miR-541, and the biological effects of miR-541 were the opposite to HSP27, suggesting that HSP27 is a downstream target of miR-541. In this study, we characterized a new mechanism whereby HSP27 promotes cell transformation during the onset of lung cancer. Our studies provide new insights into the molecular mechanisms underlying the lung carcinogenic effect of heat exposure. Specifically, heat stress promotes translation of HSP27 by inhibiting miR-541 accumulation, ultimately resulting in activation of autophagy, inhibition of mitochondrial apoptotic pathway and malignant transformation of Human Bronchial Epithelial Cells. This study identifies miR-541 as a potential prognostic biomarker or therapeutic target to improve theory of environmental carcinogenesis.

PASS: A Proteomics Alternative Splicing Screening Pipeline.

Alternative splicing (AS) has been well-investigated at the trancriptome level by the application of RNA-seq technology. There is an ongoing debate on the biological importance of AS to proteome complexity. A toolkit for accurately identifying AS from proteome data is urgently needed. Here, a software called PASS is developed to comprehensively detect AS events for the proteomics mass spectrometry (MS) data. Moreover, PASS is well compatible with MS identification by the proteogenomics approach, which provides novel AS candidates for proteome identification. The workflow of PASS mainly contains five core steps: transcripts reconstruction from RNA-Seq data, novel protein sequence generation, MS data searching, proSAM file formatting, and AS detection. Access to the program from either step is supported. PASS is successfully applied to proteome data of mouse hepatocytes and 407 AS events are first identified with proteomics MS evidences. PASS is expected to be widely used to identify AS events on proteome data and provide a deeper understanding of the proteome isoforms. The PASS software is freely available at https://github.com/wupengomics/PASS.

Epigenetic upregulation of miR-126 induced by heat stress contributes to apoptosis of rat cardiomyocytes by promoting Tomm40 transcription.

TOMM40 is the channel-forming subunit of a translocase of the mitochondrial outer membrane (TOM) that is essential for protein transport into mitochondria. TOMM40 plays an important role in maintaining normal mitochondrial function. The correlation between occupational thermal exposure and mitochondria dysfunction has been demonstrated; however, nothing is known about the alteration and role of TOMM40 in response to environmental heat stress. In the present study, we showed that environmental thermal exposure upregulated microRNA miR-126, consequently reducing AU-rich element RNA-binding protein 1 (AUF1)-mediated SP1 mRNA degradation and increasing TOMM40 transcription, which in turn decreased the mitochondria membrane potential and apoptosis of cardiomyocytes. Mechanistically, miR-126 upregulation was attributed to heat stress-induced promoter demethylation via elevated TET2 (Tet methylcytosine dioxygenase 2) expression, while SP1 mRNA degradation was caused by decreased translation of AUF1 induced by miR-126. Moreover, TOMM40 transcription was upregulated via increasing its transcription factor SP1 resulting from AUF1 inhibition in the heat stress responses. The results of the present study increased our understanding of the role of miR-126 and TOMM40 in heat stressed cardiomyocytes.

Efficient replication of blood-borne hepatitis C virus in human fetal liver stem cells.

The development of pathogenic mechanisms, specific antiviral treatments and preventive vaccines for hepatitis C virus (HCV) infection has been limited due to lack of cell culture models that can naturally imitate the entire HCV life cycle. Here, we established an HCV cell culture model based on human fetal liver stem cells (hFLSCs) that supports the entire blood-borne hepatitis C virus (bbHCV) life cycle. More than 90% of cells remained infected by various genotypes. bbHCV was efficiently propagated, and progeny virus were infectious to hFLSCs. The virus could be passed efficiently between cells. The viral infectivity was partially blocked by specific antibodies or small interfering RNA against HCV entry factors, whereas HCV replication was inhibited by antiviral drugs. We observed viral particles of approximately 55 nm in diameter in both cell culture media and infected cells after bbHCV infection. CONCLUSION: Our data show that the entire bbHCV life cycle could be naturally imitated in hFLSCs. This model is expected to provide a powerful tool for exploring the process and the mechanism of bbHCV infection at the cellular level and for evaluating the treatment and preventive strategies of bbHCV infection. (Hepatology 2017;66:1045-1057).

RNA editing is induced by type I interferon in esophageal squamous cell carcinoma.

In recent years, abnormal RNA editing has been shown to play an important role in the development of esophageal squamous cell carcinoma, as such abnormal editing is catalyzed by ADAR (adenosine deaminases acting on RNA). However, the regulatory mechanism of ADAR1 in esophageal squamous cell carcinomas remains largely unknown. In this study, we investigated ADAR1 expression and its association with RNA editing in esophageal squamous cell carcinomas. RNA sequencing applied to esophageal squamous cell carcinoma clinical samples showed that ADAR1 expression was correlated with the expression of STAT1, STAT2, and IRF9. In vitro experiments showed that the abundance of ADAR1 protein was associated with the induced activation of the JAK/STAT pathway by type I interferon. RNA sequencing results showed that treatment with type I interferon caused an increase in the number and degree of RNA editing in esophageal squamous cell carcinoma cell lines. In conclusion, the activation of the JAK/STAT pathway is a regulatory mechanism of ADAR1 expression and causes abnormal RNA editing profile in esophageal squamous cell carcinoma. This mechanism may serve as a new target for esophageal squamous cell carcinoma therapy.

Postoperative survival of EGFR-TKI-targeted therapy in non-small cell lung cancer patients with EGFR 19 or 21 mutations: a retrospective study.

BACKGROUND: The aim of this retrospective study is to identify epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer patients and to compare the long-term postoperative outcomes in different EGFR-TKI-targeted therapy effects between the different EGFR mutation groups. METHODS: A total of 2094 postoperative non-small cell lung cancer (NSCLC) patients with EGFR gene detection were collected in the Department of Pathology in the Cancer Hospital Chinese Academy of Medical Sciences from January 2003 to January 2014. Three hundred sixty-three patients were treated with EGFR tyrosine kinase inhibitor (TKI) after surgery: 184 harbored the exon 19 deletion mutation and 179 cases carried the exon 21 L858R point mutation. The end points included progression-free survival (PFS), overall survival (OS), and the response rate. RESULTS: OS was increased in the EGFR exon 19 deletion group compared with the exon 21 L858R point mutation group (92 vs. 65 months; P < 0.001). But the median PFS did not differ between two groups (12 vs 14 months). The objective response rate (ORR) in 19 deletion group was increased compared with L858R mutation patients (28.35 vs. 22.73%). The disease control rate (DCR) of patients with 19 deletion benefited more from targeted therapy, compared with L858R group (93.71 vs. 84.31%, P = 0.014). In 19 deletion group, a high ORR and DCR were noted in patients treated with icotinib, 16 out of 18 achieved stable disease (SD), and the DCR in this population was 100%. CONCLUSIONS: EGFR subtypes could influence the postoperative survival of NSCLC patients with TKI-targeted therapy.

Combination of platelet count and mean platelet volume (COP-MPV) predicts postoperative prognosis in both resectable early and advanced stage esophageal squamous cell cancer patients.

The aim of this study is to search the most powerful prognostic factor from routine blood test for esophageal squamous cell cancer (ESCC) patients. Multiple laboratory tests were evaluated including those reflecting red blood cell parameters (hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red blood cell distribution width (RDW)), platelet morphological parameters (mean platelet volume (MPV) and platelet count (PLT)), blood coagulation status (D-dimer), and tumor biomarker (CA19-9). Known inflammatory indices (NLR and PLR) were also calculated. A total of 468 patients who were diagnosed with ESCC between December 2005 and December 2008 were retrospectively analyzed in this study. By utilizing univariate and multivariate Cox proportional hazard analyses, we found that PLT and MPV were significantly associated with overall survival (OS) and disease-free survival (DFS) of ESCC patients, with optimal cutoff values of 212 and 10.6, respectively. Moreover, the combination of the preoperative PLT and MPV (COP-MPV) was calculated as follows: patients with both PLT (≥212 × 10(9) L(-1)) and MPV (≥10.6 fL) elevation were assigned a score of 2, and patients with one or neither were assigned a score of 1 and 0. The COP-MPV was an independent prognostic factor for OS (hazard ratio (HR) 0.378, 95 % confidence interval (CI) 0.241 to 0.593, P < 0.001, 0/2) and DFS (HR 0.341, 95 % CI 0.218 to 0.534, P < 0.001, 0/2) in multivariate analyses. In subgroup analyses for early (stages I and II) and locally (stage III) advanced stage patients, COP-MPV was found significantly associated with OS and DFS in each group (P = 0.025 and P = 0.018 for OS and P = 0.029 and P = 0.002 for DFS). In conclusion, we considered that COP-MPV is a promising predictor for postoperative survival in ESCC patients.