Cryoprotective effect of soybean oil on surimi gels and the mechanism based on molecular dynamics simulation.

The effect of soybean oil (SO) on freeze-thaw (F-T)-treated surimi was investigated and its related mechanism was revealed by molecular dynamics (MD) simulations. The results displayed that SO has a disrupting effect on the structure of fresh samples. However, in the F-T-treated samples, surimi gels supplemented with SO had a more uniform microstructure. Simultaneously, when SO was added from 0% to 7% in the F-T-treated samples, the gel strength increased from 46.66 to 51.86 N · mm $$ 46.66\ \mathrm{to}\ 51.86\;\mathrm{N}\cdotp \mathrm{mm} $$ (p < .05), the physically bound water was increased from 92.90% to 94.15% (p < .05), and storage modulus was increased from 5939 to 6523 Pa. Triglycerides of SO generated hydrophobic interactions with myosin mainly in carbon chains. Computational results from MD simulations illustrated that the structure of myosin combined with triglycerides was more stable than that of myosin alone during temperature fluctuations (-20 to 4°C). During ice crystal growth, triglycerides absorbed on the myosin surface inhibited the growth of surrounding ice crystals and mitigated the ice crystal growth rate (from 7.54 to 5.99 cm/s). The addition of SO during the F-T treatments allowed myosin to be less negatively affected by ice crystal formation and temperature fluctuations and ultimately contributed to the formation of a more uniform network gel structure.

Effects of diets with different amino acid release characteristics on the gut microbiota and barrier function of weaned pigs.

BACKGROUND: The absorption and utilization of proteins by animals is affected by the amino acid (AA) release characteristics of their diets. In the present study, we aimed to determine the effects of diets with various amino acid release characteristics on the intestinal barrier function and diversity of gut microbiota of weaned pigs. RESULTS: Forty-eight pigs (7.45 ± 0.58 kg) were fed with diets having different amino acid release characteristics during a period of 28 days. We used a 2 × 3 full-factor (two protein levels and three protein sources with differing amino acid release characteristics) experimental design, with normal (standard terminal ileal digestibility of 17.5%) or low (standard terminal ileal digestibility of 14.9%) protein levels as the first factor. Casein (CAS), corn gluten meal (CGM) and a MIX diet were used as protein sources. Due to the more balanced release of amino acids, the diamine oxidase (DAO) concentrations in the CAS and MIX groups were significantly lower than those in the CGM group (P < 0.05); Reducing the dietary protein content from 17.5% to 14.9% had no significant effects on the levels of serum DAO or D-lactic acid. By contrast, it increased the microbial diversity (chao1 and ACE values) and the number of Lactobacillus in the jejunum (P < 0.05). The CAS-containing diet and the MIX diet resulted in significantly higher microbial diversity (Simpson and Shannon) than the CGM-containing diet in the jejunum. CONCLUSION: The balanced release of amino acids in CAS and MIX diets maintained intestinal barrier function and increased gut microbiota diversity. These findings could potentially provide a scientific reference for the rational preparation of piglet feed.

Trapezoidal pile-up nuclear pulse parameter identification method based on deep learning transformer model.

Pile-up between adjacent nuclear pulses is unavoidable in the actual detection process. Some scholars have tried to apply deep learning techniques to identify pile-up nuclear pulse parameters. However, traditional deep learning recurrent neural networks (RNNs) suffer from inefficient pulse recognition and poor recognition of pile-up nuclear pulses with short intervals between adjacent pulses. In this paper, a Transformer model with an attention mechanism as the core to recognize pile-up nuclear pulses is innovatively applied, aiming to provide a more accurate and efficient method for pile-up nuclear pulse recognition. Thus, it gives a better help for the spectrum correction with a high count rate.

Hierarchical microtubes constructed using Fe-doped MoS2 nanosheets for biosensing applications.

The structural design of multiple functional components could enhance the synergistic catalytic performance of MoS2-based composites in enzyme-like catalysis. Herein, one-dimensional (1D) Fe-MoS2 microtubes were designed to prepare tubular Fe-doped MoS2 composites with MoO3 microrods as self-sacrificing precursors. Remarkably, the results indicated that the generated ammonia released from the sulfidation process led to the dissolution of MoO3 cores and the generation of a tubular structure. The Fe-MoS2 composites integrated the synergistic effects of Fe-doped MoS2 nanosheets (NSs) and the 1D tubular structure. Thus, a higher catalytic activity was observed in peroxidase-like catalysis than in other components, such as MoO3@FeOOH, FeOOH and MoS2 NSs. The peroxidase-like mechanism originated from the generation of the ˙OH radical. The Fe-MoS2 microtube-based colorimetric assay was used to detect H2O2 with a detection limit (LOD) of 0.51 µM in a linear range from 1.25 to 50 µM. The colorimetric method was simple, selective, and sensitive for glutathione (GSH) detection in the range of 0.25-125 µM with a detection limit (LOD) of 0.12 µM. Thus, we provide a facile synthetic strategy for simultaneously integrating electronic modulation and structural design to develop an efficient MoS2-based functional catalyst.

PET imaging of hepatocellular carcinoma by targeting tumor-associated endothelium using [68Ga]Ga-PSMA-617.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality rates. In many non-prostate solid tumors such as HCC, prostate-specific membrane antigens (PSMA) are overexpressed in tumor-associated endothelial cells. Therefore, the aim of this study was to evaluate the performance of [68Ga]Ga-PSMA-617 PET imaging on HCC with different animal models, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX), and to explore its mechanisms of function. METHODS: [68Ga]Ga-PSMA-617 was prepared. The expression level of PSMA in two human hepatocellular cancer cells (HepG2 and HuH-7) was evaluated, and the cellular uptakes of [68Ga]Ga-PSMA-617 were assayed. HepG2 and HuH-7 subcutaneous xenograft models, HepG2 orthotopic xenograft models, and four different groups of PDX models were prepared. Preclinical pharmacokinetics and performance of [68Ga]Ga-PSMA-617 were evaluated in different types of HCC xenografts models using small animal PET and biodistribution studies. RESULTS: Low PSMA expression level of HepG2 and HuH-7 cells was observed, and the cellular uptake and blocking study confirmed the non-specificity of the PSMA-targeted probe binding to HepG2 and HuH-7 cells. In the subcutaneous xenograft models, the tumor uptakes at 0.5 h were 0.76 ± 0.12%ID/g (HepG2 tumors) and 0.78 ± 0.08%ID/g (HuH-7 tumors), respectively, which were significantly higher than those of the blocking groups (0.23 ± 0.04%ID/g and 0.20 ± 0.04%ID/g, respectively). In the orthotopic xenograft models, PET images clearly displayed the tumor locations based on the preferential accumulation of [68Ga]Ga-PSMA-617 in tumor tissue versus normal liver tissue, suggesting the possibility of using [68Ga]Ga-PSMA-617 PET imaging to detect primary HCC lesions in deep tissue. In the four different groups of HCC PDX models, PET imaging with [68Ga]Ga-PSMA-617 provided clear tumor uptakes with prominent tumor-to-background contrast, further demonstrating its potential for the clinical imaging of PSMA-positive HCC lesions. The staining of tumor tissue sections with CD31- and PSMA-specific antibodies visualized the tumor-associated blood vessels and PSMA expression on endothelial cells in subcutaneous, orthotopic tissues, and PDX tissues, confirming the imaging with [68Ga]Ga-PSMA-617 might be mediated by targeting tumor associated endothelium. CONCLUSION: In this study, in vivo PET on different types of HCC xenograft models illustrated high uptake within tumors, which confirmed that [68Ga]Ga-PSMA-617 PET may be a promising imaging modality for HCC by targeting tumor associated endothelium.

Syndrome of inappropriate antidiuretic hormone secretion is associated with different proton pump inhibitor use: a pharmacovigilance study.

AIM: The objective of this study was to evaluate the reported associations between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a variety of proton pump inhibitors (PPI) through analysis of the reports extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: FAERS reports from January 2004 to March 2020 were used to conduct disproportionality and Bayesian analyses. The definition of SIADH relied on the preferred terms provided by the Medical Dictionary for Regulatory Activities. The time to onset, mortality, and hospitalization rates of PPI-related SIADH were also investigated. RESULTS: The study identified a total of 273 reports of PPI-associated SIADH, which appeared to influence more elderly than middle-aged patients (71.1% vs. 12.5%). Women were more affected than men (48.7% vs. 41.8%). Rabeprazole had a stronger SIADH association than other PPIs based on the highest reporting odds ratio (reporting odds ratio = 13.3, 95% confidence interval (CI) = 7.2, 24.9), proportional reporting ratio (proportional reporting ratio = 13.3, χ2 = 113.7), and empirical Bayes geometric mean (empirical Bayes geometric mean = 13.3, 95% CI = 7.9). The median time to SIADH onset was 22 (interquartile range 6-692) days after PPI administration. PPI-associated SIADH generally led to a 2.95% fatality rate and a 79.7% hospitalization rate. The highest hospitalization death rate occurred in esomeprazole (91.2%). CONCLUSION: According to our findings, more attention should be paid to SIADH within the first several months after the administration of PPIs. For women older than 65 years, dexlansoprazole may reduce the incidence of PPI-associated SIADH. Nonetheless, larger epidemiological studies are suggested to verify this conclusion.

Effects of protein content and the inclusion of protein sources with different amino acid release dynamics on the nitrogen utilization of weaned piglets.

OBJECTIVE: We aimed to investigate the effect of the differing amino acid (AA) release dynamics of two protein sources on the growth performance, nitrogen deposition, plasma biochemical parameters, and muscle synthesis and degradation of piglets when included in their diets at normal and low concentrations. METHODS: Forty-eight piglets (Duroc×Landrace×Large White) with initial body weight of 7.45±0.58 kg were assigned to six groups and fed one of 6 diets. The 6 dietary treatments were arranged by 3×2 factorial with 3 protein sources and 2 dietary protein levels. They are NCAS (a normal protein content with casein), NBlend (a normal protein content with blend of casein and corn gluten meal), NCGM (a normal protein content with corn gluten meal), LCAS (a low protein content with casein), LBlend (a low protein content with blend of casein and corn gluten meal), LCGM (a low protein content with corn gluten meal). The release dynamics of AA in these diets were determined by in vitro digestion. The digestibility, utilization and biological value of nitrogen in piglets were determined by micro Kjeldahl method. Plasma insulin was measured by enzyme-linked immunosorbent assay kits. The protein expression of mediators of muscle synthesis and degradation was determined by western blotting. RESULTS: Although the consumption of a low-protein diet supplemented with crystalline AA was associated with greater nitrogen digestion and utilization (p<0.05), the final body weight, growth performance, nitrogen deposition, and phosphorylation of ribosomal protein S6 kinase 1 and eIF4E binding protein 1 in the muscle of pigs in the low-protein diet-fed groups were lower than those of the normal-protein diet-fed groups (p<0.05) because of the absence of non-essential AA. Because of the more balanced release of AA, the casein (CAS) and Blend-fed groups showed superior growth performance, final body weight and nitrogen deposition, and lower expression of muscle ring finger 1 and muscle atrophy F-box than the CGM-fed groups (p<0.05). CONCLUSION: We conclude that the balanced release of AA from CAS containing diets and mixed diets could reduce muscle degradation, favor nitrogen retention, % intake and improve growth performance in pigs consuming either a normal- or low-protein diet.

Aneurysm and Artery Dissection Following the Use of Vascular Endothelial Growth Factor Inhibitor: A Real-World Analysis Using a Spontaneous Reporting System.

Background Pharmacological inhibition of angiogenesis via the vascular endothelial growth factor pathway is an important therapeutic target that prevents tumor growth and the formation of metastases. Although vascular endothelial growth factor inhibitor (VPI) is well understood as a well-defined safety profile, few real-world studies are comparing the incidence, clinical features, and prognosis of the aneurysm and artery dissection. Methods and Results To evaluate and compare the links between different VPIs and aneurysm and artery dissection, we identified 634 reports with VPIs in the US Food and Drug Administration Adverse Event Reporting System database ranging between January 2004 to March 2020. We used the reporting odds ratio for the association between the use of VPIs and aneurysm and artery dissection. The reporting odds ratio (3.68, 95%, 2.18‒6.23) shows that ramucirumab has a stronger correlation than other VPIs. The results show a significant difference in onset time (P<0.001). The median time to aneurysm and artery dissection was 79.5 (interquartile interval, 19.0-273.5) days after VPI administration. The results also show that VPI-associated aneurysm and artery dissection was reported more often in men (n=336, 59.68% versus n=227, 40.32%), and there were more cases in patients aged between 45 to 74 years than those <45 years (n=312, 68.12% versus n=18, 3.93%); patients aged ≥75 years accounted for 27.95% (n=128). Finally, the suspected drugs generally led to 19.98% deaths and 29.81% hospitalizations. Conclusions We identified signals for aneurysm and artery dissection following various VPIs in real-world practice via the Food and Drug Administration Adverse Event Reporting System, which represents the first step for continued pharmacovigilance investigation.

Association between anxiety symptoms and atrial fibrillation in a community cohort of Chinese older adults: a case-control study.

BACKGROUND: The association between anxiety and atrial fibrillation (AF) remains unclear. Moreover, this association has rarely been studied in Chinese individuals aged 60 years or older. This study investigated the association between anxiety and AF in a community-based case-control study of older adult residents in urban China. METHODS: The cases and controls were from a community-based study conducted in the Jingansi community in Shanghai, China, between January 2010 and December 2012. A total of 3622 residents aged 60 years or older without severe vision, hearing, or speaking impairments were eligible to participate in the physical examinations and questionnaire survey. AF was assessed based on a previous physician's diagnosis, electrocardiogram, ambulatory electrocardiogram, or echocardiogram. Anxiety was evaluated using the Zung Self-Rating Anxiety Scale (ZSAS). Using the AF group as a reference, the control group consisted of randomly selected age- and sex-matched individuals in a 1:5 ratio (case:control = 1:5). The association between anxiety and AF in the AF group and the multifactor-matched control group was explored using logistic regression. RESULTS: In the AF and control groups, after adjusting for a history of coronary heart disease, valvular heart disease, hypertension, stroke, hyperlipidemia, and diabetes, as well as depression score, ZSAS scores (odds ratio 1.07; 95% confidence interval 1.02-1.12; p = 0.003), and anxiety symptoms (odds ratio 3.94; 95% confidence interval 1.06-14.70; p = 0.041) were associated with AF. CONCLUSIONS: Anxiety symptoms were associated with AF in a Chinese older population. This suggests that older adults who have anxiety symptoms may need psychological intervention or treatment in daily life and care.

Dexmedetomidine Ameliorates Postoperative Cognitive Dysfunction in Aged Mice.

Neuroinflammation and oxidative stress coexist and interact in the progression of postoperative cognitive dysfunction (POCD) and other neurodegenerative disease. Mounting studies reveal that Dexmedetomidine (Dex) possesses anti-inflammatory and antioxidant properties. Nevertheless, whether Dex exerts neuroprotective effect on the cognitive sequelae of oxidative stress and inflammatory process remains unclear. A mouse model of abdominal exploratory laparotomy-induced cognitive dysfunction was employed to explore the underlying mechanism of neuroprotective effects exerted by Dex in POCD. Aged mice were treated with Dex (20 µg/kg) 20 min prior to surgery. Open field test (OFT) and Morris water maze (MWM) were employed to examine the cognitive function on postoperative day 3 (POD 3) or POD 7. In the present study, mice underwent surgery exhibited cognitive impairment without altering spontaneous locomotor activity, while the surgery-induced cognitive impairment could be alleviated by Dex pretreatment. Dex inhibited surgery-induced pro-inflammatory cytokines accumulation and microglial activation in the hippocampi of mice. Furthermore, Dex decreased MDA levels, enhanced SOD activity, modulated CDK5 activity and increased BDNF expression in the hippocampus. In addition, Dex remarkably reduced the surgery-induced increased ratio of Bax/Bcl-2 and apoptotic neurons in the hippocampi of aged mice. Collectively, our study provides evidence that Dex may exert neuroprotective effects against surgery-induced cognitive impairment through mechanisms involving its anti-inflammatory and antioxidant properties, as well as the suppression on the mitochondrial permeability transition pore and apoptosis-related pathway.

Long Non-coding RNA EBLN3P Regulates UHMK1 Expression by Sponging miR-323a-3p and Promotes Colorectal Cancer Progression.

Background: Growing studies have demonstrated that long non-coding RNA (lncRNA) can act as crucial roles during the progression of various tumors, including colorectal carcinoma (CRC). We aimed to determine lncRNA endogenous bornavirus-like nucleoprotein (EBLN3P) expression in CRC and examine its influence on tumor behaviors of CRC cells. Materials and Methods: Quantitative real-time polymerase chain reaction was used to determine the expression levels of EBLN3P and miR-323a-3p in CRC tissues and cell lines. Cell viability, migration, invasion, and apoptosis were assessed by Cell Counting Kit 8, colony formation, Transwell assay, wound healing assays, and flow cytometry. Bioinformatics and dual-luciferase assays were used to investigate the interaction between EBLN3P and miR-323a-3p, as well as between miR-323a-3p and U2AF homology motif kinase 1 (UHMK1). Western blot was applied for detecting the expressions of the related proteins. Results: EBLN3P was highly expressed in CRC, and its high expression was distinctly associated with increased tumor size, histology/differentiation and advanced TNM stage, and poor clinical outcome of CRC patients. EBLN3P silencing significantly inhibited the proliferation and metastasis and induced the apoptosis of CRC cells. Mechanistically, overexpression of EBLN3P exhibited tumorigenic effects through downregulating the inhibitory effects of miR-323a-3p on UHMK1 expression. The correlation analysis confirmed the positive or negative association among EBLN3P, miR-323a-3p, and UHMK1. Conclusion: EBLN3P promoted the development of CRC via targeting miR-323a-3p/UHMK1, which provided a new idea for treating CRC.

Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice.

INTRODUCTION: The incidence of perioperative neurocognitive disorders (PND) is higher in the elderly patients undergoing surgery. Microglia activation-mediated neuroinflammation is one of the hallmarks of PND. Galectin-1 has been identified as a pivotal modulator in the central nervous system (CNS), while the role of galectin-1 in PND induced by microglia-mediated neuroinflammation is still undetermined. METHODS: An exploratory laparotomy model anesthetized with isoflurane was employed to investigate the role of galectin-1 on PND in aged mice. Open field test and Morris water maze were used to test the cognitive function 3- or 7-days post-surgery. The activation of microglia in the hippocampus of aged mice was tested by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the underlying mechanisms. RESULTS: Galectin-1 attenuated the cognitive dysfunction induced by surgery in aged mice and inhibited microglial activity. Moreover, galectin-1 decreased the expression level of inflammatory proteins (interleukin-1ß, interleukin-6, and tumor necrosis factor-α), and prevented neuronal loss in the hippocampus. Galectin-1 inhibited the inflammation of BV2 microglial cells induced by lipopolysaccharide via decreasing the translocation of NF-κB p65 and c-Jun, while this kind of inhibition was rescued when overexpressing IRAK1. CONCLUSION: Our findings provide evidence that galectin-1 may inhibit IRAK1 expression, thus suppressing inflammatory response, inhibiting neuroinflammation, and improving ensuing cognitive dysfunction. Collectively, these findings unveil that galectin-1 may elicit protective effects on surgery-induced neuroinflammation and neurocognitive disorders.

BDNF Participates in Chronic Constriction Injury-Induced Neuropathic Pain via Transcriptionally Activating P2X7 in Primary Sensory Neurons.

Neuropathic pain, resulting from the pathological changes of the somatosensory nervous system, remains a severe public health problem worldwide. The effect of treatment targeting neuropathic pain is very limited, as the underlying mechanism of neuropathic pain is largely unknown. In this study, we demonstrated that the expression level of brain-derived neurotrophic factor (BDNF) was remarkably and time-dependently increased in dorsal root ganglion (DRG) neurons. DRG microinjection of BDNF siRNA in DRG ameliorated chronic constriction injury (CCI) induced mechanical, thermal, and cold nociceptive hypersensitivities. Overexpressing BDNF through microinjection of the AAV5-BDNF in DRG caused enhanced responses to basal mechanical, thermal, and cold stimuli in mice exposed to CCI. Mechanically, the P2X7 promoter activity was enhanced by CCI-induced increase of DRG BDNF protein and was involved in the CCI-induced upregulation of DRG P2X7 protein. The overexpression of BDNF also increased P2X7 expression in DRG neurons, which was validated in in vivo and in vitro experiments. BDNF may exert crucial effect via transcriptionally activating the P2X7 gene in primary sensory neurons, since P2X7 acts as a role of endogenous agitator in neuropathic pain and BDNF largely co-expresses with P2X7 in DRG neurons. Therefore, our data provide evidence that BDNF may be a promising therapeutic target for neuropathic pain.

Intravenous versus Volatile Anesthetic Effects on Postoperative Cognition in Elderly Patients Undergoing Laparoscopic Abdominal Surgery.

BACKGROUND: Delayed neurocognitive recovery after surgery is associated with poor outcome. Most surgeries require general anesthesia, of which sevoflurane and propofol are the most commonly used inhalational and intravenous anesthetics. The authors tested the primary hypothesis that patients with laparoscopic abdominal surgery under propofol-based anesthesia have a lower incidence of delayed neurocognitive recovery than patients under sevoflurane-based anesthesia. A second hypothesis is that there were blood biomarkers for predicting delayed neurocognitive recovery to occur. METHODS: A randomized, double-blind, parallel, controlled study was performed at four hospitals in China. Elderly patients (60 yr and older) undergoing laparoscopic abdominal surgery that was likely longer than 2 h were randomized to a propofol- or sevoflurane-based regimen to maintain general anesthesia. A minimum of 221 patients was planned for each group to detect a one-third decrease in delayed neurocognitive recovery incidence in propofol group compared with sevoflurane group. The primary outcome was delayed neurocognitive recovery incidence 5 to 7 days after surgery. RESULTS: A total of 544 patients were enrolled, with 272 patients in each group. Of these patients, 226 in the propofol group and 221 in the sevoflurane group completed the needed neuropsychological tests for diagnosing delayed neurocognitive recovery, and 46 (20.8%) in the sevoflurane group and 38 (16.8%) in the propofol group met the criteria for delayed neurocognitive recovery (odds ratio, 0.77; 95% CI, 0.48 to 1.24; P = 0.279). A high blood interleukin-6 concentration at 1 h after skin incision was associated with an increased likelihood of delayed neurocognitive recovery (odds ratio, 1.04; 95% CI, 1.01 to 1.07; P = 0.007). Adverse event incidences were similar in both groups. CONCLUSIONS: Anesthetic choice between propofol and sevoflurane did not appear to affect the incidence of delayed neurocognitive recovery 5 to 7 days after laparoscopic abdominal surgery. A high blood interleukin-6 concentration after surgical incision may be an independent risk factor for delayed neurocognitive recovery.

Prophylactic Melatonin Treatment Ameliorated Propofol-Induced Cognitive Dysfunction in Aged Rats.

Considering the fact that melatonin acts as protective agent in various cognitive impairment, we decided to explore the precise effect of pretreatment with melatonin on cognitive function, mitochondrial activity, apoptosis and synaptic integrity in aged rats anesthetized by propofol. We first randomly allocated the thirty Sprague Dawley rats into three groups: Control vehicle-treated group (Con), Propofol-treated group (Pro) and Melatonin + Propofol group (Mel + Pro). The Barnes maze, open field and contextual fear conditioning test were employed to evaluate spatial memory, exploratory behavior and general locomotor activity, and hippocampus-dependent learning and memory ability, respectively. Moreover, mitochondrial function (including reactive oxygen species, mitochondrial membrane potential and ATP levels) and apoptosis were detected in the regions of hippocampus (HIP) and prefrontal cortex (PFC). The results of behavioral tests suggested that melatonin improved propofol-induced memory impairment in aged rats. Melatonin mitigated mitochondrial dysfunction and decreased the apoptotic cell counts in the regions of HIP and PFC. Furthermore, prophylactic melatonin treatment also reversed the propofol-induced inactivation of PKA/CREB/BDNF signaling and synaptic dysfunction. On the whole, our results indicated that melatonin ameliorated the propofol-induced cognitive disorders via attenuating mitochondrial dysfunction, apoptosis, inactivation of PKA/CREB/BDNF signaling and synaptic dysfunction.

Long Non-Coding RNA MNX1-AS1 Promotes Progression of Triple Negative Breast Cancer by Enhancing Phosphorylation of Stat3.

Triple negative breast cancer (TNBC) accounts for less than a quarter of breast cancer but has the poorest survival outcome and is prone to relapse as well as metastasis due to its aggressiveness and lack of therapeutic target. Herein, we analyzed the TCGA datasets of lncRNA expressional profiles of breast cancer vs. normal tissue and TNBC vs. Non-TNBC subtypes and screened a long non-coding RNA (lncRNA) MNX1-AS1 overexpressing in TNBC. We found that MNX1-AS1 were upregulated in TNBC tumor tissues and correlated with poor survival outcome in TNBC patients. Silencing MNX1-AS1 reduced the aggressiveness of TNBC in vitro and in vivo. By using RNA pulldown assay followed by western blotting and RNA immunoprecipitation (RIP), we identified Stat3 was the MNX1-AS1 binding protein and MNX1-AS1 upregulated the phosphorylation of Stat3 by enhancing the interaction between p-JAK and Stat3. The present study suggested that targeting MNX1-AS1 may represent a promising therapeutic strategy to TNBC.

HIF-1α Promotes the Metastasis of Esophageal Squamous Cell Carcinoma by Targeting SP1.

Background: In microenvironment of malignant tumors, Hypoxia-Inducible Factors (HIF), most importantly HIF-1α, play an important role in regulation of adaptive biological response to hypoxia, promoting angiogenesis and metastasis. However, the underlying mechanism that HIF-1α regulates metastasis needs to be further clarified. Methods: The expressions of HIF-1α and SP1 were detected in 182 samples of esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues by immunohistochemistry (IHC), and the correlation between the expression levels of HIF-1α and SP1 was analyzed. The expression of HIF-1α in ESCC cell lines TE1 and KYSE30 was then detected using qRT-PCR and western blot. The potential binding sites of HIF-1α on the SP1 promoter were analyzed using UCSC and JASPAR databases, verified by chromosomal immunoprecipitation (ChIP) assay and qRT-PCR. The effects of HIF-1α and SP1 on ESCC cell migration and invasion were then tested with Transwell and Matrigel experiments. Results: The expression of HIF-1α in cancer tissues is higher than adjacent normal tissues, and is correlated with metastasis, recurrence and poor prognosis. Upon silencing HIF-1α by siRNA, the invasion and migration ability of ESCC cells were significantly inhibited, which could be restored by the overexpression of SP1. Hypoxic conditions significantly increased the expression of HIF-1α and SP1 at both protein and mRNA levels in ESCC cells. HIF-1α enhanced SP1 transcription through binding to the promoter region. The expression of protein and mRNA levels of SP1 was decreased by silencing HIF-1α in cells. In contrast, overexpression of HIF-1α significantly increased the mRNA and protein levels of SP1. The expression of SP1 in ESCC was positively correlated with the protein expression of HIF-1α and poor prognosis. Conclusion: The results of our study indicate that HIF-1α promotes metastasis of ESCC by targeting SP1 in a hypoxic microenvironment. Further study on this mechanism may elucidate the possibility of HIF-1α and SP1 as new targets for the treatment of ESCC.

CCL18-induced HOTAIR upregulation promotes malignant progression in esophageal squamous cell carcinoma through the miR-130a-5p-ZEB1 axis.

Accumulating evidence indicates that CCL18 and the long non-coding RNA, HOTAIR, have critical roles in cancer progression and metastasis, but the correlation between CCL18 and HOTAIR in esophageal squamous cell carcinoma (ESCC) and their downstream molecular mechanisms remain unclear. Overexpression of CCL18 in ESCC tissues was associated with a worse survival in patients with ESCC. CCL18 enhanced the invasiveness of ESCC cells in a dose-dependent manner, whereas CCL18 knockdown inhibited their invasiveness. In particular, CCL18 expression was positively associated with HOTAIR expression in ESCC tissues. Furthermore, CCL18 upregulated the expression of HOTAIR, and knockdown of HOTAIR alleviated the CCL18-induced invasiveness of ESCC cells. HOTAIR may act as a competing endogenous RNA and could effectively becoming a sponge for miR-130a-5p, thereby modulating the derepression of ZEB1 and promoting epithelial-mesenchymal transition in ESCC. Our study suggests that CCL18 contributes to the malignant progression of esophageal cancer by upregulating HOTAIR expression. HOTAIR overexpression may promote tumor invasiveness and progression in ESCC, given that HOTAIR functions as a miR-130a-5p sponge, positively regulating ZEB1. This provides new therapeutic targets for early diagnosis and treatment of ESCC.

Calpain and JNK pathways participate in isoflurane - induced nucleus translocation of apoptosis-inducing factor in the brain of neonatal rats.

Recent studies have demonstrated that volatile anesthetic causes caspase-dependent neuroapoptosis and persistent cognitive deficits in young animals. Apoptosis-inducing factor (AIF) can trigger apoptosis by caspase-independent pathway. Whether isoflurane induces neuroapoptosis by activation of AIF and its possible mechanism are underdetermined. Rats at postnatal day 7 were exposed to 1.1% isoflurane for 4 h and the expression of AIF, cytochrome c, caspase-3, µ-calpain, m-calpain, Bcl-2 and Bax in the mitochondrial, cytosolic, and nuclear fraction, as well as the number of both AIF and TUNEL positive neurons in the cortices of rats were measured. Moreover, the effects of calpain inhibitor MDL-28170 or JNK inhibitor SP600125 on isoflurane-induced AIF release, caspase activation and cognitive deficits were assessed. We found isoflurane activated CytC-caspase-3 dependent apoptosis pathway mainly in the early phase (0-6 h after exposure). Moreover, isoflurane activated mitochondrial µ-calpain, induced AIF truncation during early phase and activated m-calpain, induced AIF release from the mitochondria to cytosol and translocation into the nucleus in the late phase (6-24 h after exposure). MDL-28170 attenuated the isoflurane-induced mitochondrial AIF truncation, release and nuclear translocation, but did not change the expression of cleaved-caspase-3 and mitochondrial Bax and Bcl-2 proteins. SP600125 attenuated isoflurane-induced neuroapoptosis by inhibiting both AIF and caspase-3 pathways and reduced cognitive impairment in neonatal rats. This is the first study to provide the evidence that isoflurane induced AIF-dependent neuroapoptosis by activation of mitochondrial µ-calpain and m-calpain in neonatal rats. JNK inhibition reversed isoflurane-induced neuroapoptosis and subsequent long-term neurocognitive impairment, acting via inhibiting activation of both AIF and caspase-3 pathways.