Innate radioresistance substantially limits the effectiveness of radiotherapy for colorectal cancer (CRC); thus, a strategy to enhance the radiosensitivity of CRC is urgently needed. Herein, we ...reported that ankyrin repeat and KH domain containing 1 (ANKHD1) serves as a key regulator of radioresistance in CRC. ANKHD1 was highly expressed in CRC tissues and was highly correlated with Yes-associated protein 1 (YAP1) in CRC. Our results first revealed that ANKHD1 knockdown could increase the radiosensitivity of CRC by regulating DNA-damage repair, both in vitro and in vivo. Furthermore, the interactive regulation between ANKHD1 or YAP1 and lncRNA MALAT1 was revealed by RIP and RNA pull-down assays. Moreover, our results also demonstrated that MALAT1 silencing can radiosensitize CRC cells to IR through YAP1/AKT axis, similar to ANKHD1 silencing. Taken together, we report a feedback loop of ANKHD1/MALAT1/YAP1 that synergistically promotes the transcriptional coactivation of YAP1 and in turn enhances the radioresistance of CRC by regulating DNA-damage repair, probably via the YAP1/AKT axis. Our results suggested that targeting the YAP1/AKT axis downstream of ANKHD1/MALAT1/YAP1 may enhance the radiosensitivity of CRC.
The p53‐inducible gene 3 (PIG3) is one of the p53‐induced genes at the onset of apoptosis, which plays an important role in cell apoptosis and DNA damage response. Our previous study reported an ...oncogenic role of PIG3 associated with tumor progression and metastasis in non‐small cell lung cancer (NSCLC). In this study, we further analyzed PIG3 mRNA expression in 504 lung adenocarcinoma (LUAD) and 501 lung squamous cell carcinoma (LUSC) tissues from The Cancer Genome Atlas database and we found that PIG3 expression was significantly higher in LUAD with lymph node metastasis than those without, while no difference was observed between samples with and without lymph node metastasis in LUSC. Gain and loss of function experiments were performed to confirm the metastatic role of PIG3 in vitro and to explore the mechanism involved in its oncogenic role in NSCLC metastasis. The results showed that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, and decreased paxillin, phospho‐focal adhesion kinase (FAK) and phospho‐Src kinase expression, while its overexpression resulted in the opposite effects. Blocking FAK with its inhibitor reverses PIG3 overexpression‐induced cell motility in NSCLC cells, indicating that PIG3 increased cell metastasis through the FAK/Src/paxillin pathway. Furthermore, PIG3 silencing sensitized NSCLC cells to FAK inhibitor. In conclusion, our data revealed a role for PIG3 in inducing LUAD metastasis, and its role as a new FAK regulator, suggesting that it could be considered as a novel prognostic biomarker or therapeutic target in the treatment of LUAD metastasis.
Our data demonstrated that PIG3 might function as a FAK regulator in NSCLC and could serve as a novel prognostic biomarker or therapeutic target in the treatment of NSCLC metastasis. This evidence will further help scientists to understand NSCLC progression and to develop new therapeutic strategies.
Late-onset major depressive disorder (LOD) increases the risk of disability and suicide in elderly patients. However, the complex pathological mechanism of LOD still remains unclear. We selected 10 ...LOD patients and 12 healthy control samples from the GSE76826 dataset for statistical analysis. Under the screening criteria, 811 differentially expressed genes (DEGs) were screened. We obtained a total of two most clinically significant modules through the weighted gene co-expression network analysis (WGCNA). Functional analysis of the genes in the most clinically significant modules was performed to explore the potential mechanism of LOD, followed by protein-protein interaction (PPI) analysis and hub gene identification in the core area of the PPI network. Furthermore, we identified immune infiltrating cells using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm between healthy subjects and LOD patients with the GSE98793 dataset. Next, six hub genes (
,
,
,
,
, and
) were obtained by intersecting hub genes with DEGs, followed by verifying the diagnostic accuracy with the receiver operating characteristic curve (ROC). In addition, we constructed the least absolute shrinkage and selection operator (LASSO) regression model for hub gene cross-validation. Finally, we found that
and
were good diagnostic indicators of LOD, and
may be the key gene of immune function change in LOD. In conclusion, our research shows that the changes in the immune function may be an important mechanism in the development of LOD, which can provide some guidance for the related research of LOD in the future.
Diabetic cardiomyopathy is a diabetic complication with complicated pathophysiological changes and pathogenesis and difficult treatment. Sodium houttuyfonate is the adduct of sodium bisulfite and ...houttuynin, the main volatile component in Houttuynia cordata Thunb, possesses a variety of activities including multiple interventions on inhibiting ventricular remodeling. The study aims to explore effect of sodium houttuyfonate on diabetic myocardial injury and its underlying mechanisms. The diabetes model was established by intraperitoneal injection of streptozotocin at a dose of 85 mg/kg. By intragastric administration for 26 days, sodium houttuyfonate (50 and 100 mg/kg/d) reversed the abnormal serum levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, improved the abnormal levels of serum aspartate aminotransferase and brain natriuretic peptide, reduced electrocardiogram P-R and QRS interval extension, accelerated the heart rate, decreased serum malondialdehyde content, up-regulated the myocardial energy metabolism including elevated the contents of ATP, ADP, total adenine nucleotides and phosphocreatine in myocardium, decreased AMP/ATP ratio, elevated myocardial Ca2+-Mg2+-ATPase activity, and down-regulated the mRNA expressions of AMP protein activation kinase α2 (AMPK-α2) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). In a conclusion, these results suggest that sodium houttuyfonate can improve cardiac energy metabolism disorder caused by diabetes by increasing cardiac Ca2+-Mg2+-ATPase activity and regulating AMPK signaling pathway, and then attenuates cardiac injury caused by hyperglycemia. In addition, sodium houttuyfonate also has the effects of anti-oxidation and improving abnormal levels of blood lipid.
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Cancer-associated fibroblasts (CAFs) produce a critical tumor-promoting effect by cellular crosstalk with cancer cells and remodel the extracellular matrix (ECM) to form a protective physical ...barrier. The simple elimination of CAFs is not sufficient to govern the CAF-shaped aggressive tumor microenvironment (TME) because of the complexity of tumors. Herein, a CAF-targeted poly (lactic-
-glycolic acid) (PLGA) nanoemulsion is tailored to simultaneously deliver doxorubicin (DOX) and small interfering RNA (siRNA) targeting hepatocyte growth factor (HGF) for the combination of chemotherapy and gene therapy. The nanoemulsion (apt-Si/DNPs) shows a high specificity towards CAFs due to the aptamer modification and efficiently induces the apoptosis of CAFs, thus decreasing ECM deposition in the TME. Importantly, the delivered siRNA reduces the expression of the HGF in the remaining CAFs, which overcomes chemotherapy-induced upregulation of HGF mRNA and prevents the reproduction of CAFs through the autocrine HGF closed-loop. Owing to these synergetic effects, tumor proliferation, migration and invasion are prominently inhibited and tumor permeability is improved significantly. Overall, these results emphasize the potential of CAF-targeted combination treatments to inhibit tumor progression and metastasis, as well as overcome therapeutic resistance.
Background: Cordyceps sinensis (CS), a traditional Chinese herbal medicine, has many pharmacological effects. Doxorubicin (DOX) is a spectrum antitumor drug, but it has toxicity to multiple organs. ...Objective: The objective of this study was to evaluate the effect of fermented CS on regulating hepatic energy metabolism against DOX-treated hepatic toxicity in rats. Materials and Methods: Male Sprague-Dawley rats were randomly divided into six groups and administrated orally for 23 days as follows: normal control group, CS (1.50 g/kg/d) control group, DOX control group, and DOX + CS (0.75 g/kg/d, 1.5 g/kg/d, 3.00 g/kg/d) groups. Rats in DOX-treated groups were intraperitoneally injected with DOX at a dose of 2.5 mg/kg at every 48 h, and repeated for six times. At the end of the experiment, the mortality and liver index, blood biomarkers about the hepatic injury, hepatic histopathological changes, hepatic energy metabolism, and hepatic cyclic adenosine monophosphate (AMP) were measured. Results: DOX-induced a higher mortality, the damage of the liver manifests itself in the increase of liver weight index and the activity of serum aspartate aminotransferase, the decrease of serum contents of total protein and albumin, and histopathological changes, and the disorders of energy metabolism including the decrease of phosphocreatine, adenosine-triphosphate, adenosine diphosphate, AMP, and total adenine nucleotides in hepatic tissues. Fermented CS not only could attenuate those changes but also could increase the content of hepatic cAMP. Conclusion: DOX induces hepatic injury accompanying hepatic energy metabolism disorders. Fermented CS regulates the disorders of hepatic energy metabolism, thereby attenuating liver injury caused by DOX.
Abbreviation used: CS: Cordyceps sinensis; DOX: Doxorubicin; cAMP: Cyclic adenosine monophosphate; AST: Aspartate aminotransferase; TP: Total protein; ALB: Albumin; ATP: Adenosine triphosphate; ADP: Adenosine diphosphate; AMP: Adenosine monophosphate; TAN: Total adenine nucleotides.
Abstract
Pain-related aversive memory is common in chronic pain patients. Electroacupuncture has been demonstrated to block pain-related aversive memory. The insular cortex is a key region closely ...related to aversive behaviors. In our study, a potential mechanism underlying the effect of electroacupuncture treatment on pain-related aversive memory behaviors relative to the insular cortex was investigated. Our study used the chemogenetic method, pharmacological method, electroacupuncture intervention, and behavioral detection. Our study showed that both inhibition of gamma-aminobutyric acidergic neurons and activation of the kappa opioid receptor in the insular cortex blocked the pain-related aversive memory behaviors induced by 2 crossover injections of carrageenan in mice; conversely, both the activation of gamma-aminobutyric acidergic neurons and inhibition of kappa opioid receptor in the insular cortex play similar roles in inducing pain-related aversive memory behaviors following 2 crossover injections of carrageenan. In addition, activation of gamma-aminobutyric acidergic neurons in the insular cortex reversed the effect of kappa opioid receptor activation in the insular cortex. Moreover, electroacupuncture effectively blocked pain-related aversive memory behaviors in model mice, which was reversed by both activation of gamma-aminobutyric acidergic neurons and inhibition of kappa opioid receptor in the insular cortex. The effect of electroacupuncture on blocking pain-related aversive memory behaviors may be related to the activation of the kappa opioid receptor and inhibition of gamma-aminobutyric acidergic neurons in the insular cortex.
Background: The studies about the protective effect on the heart of single Atractylodes macrocephala rhizoma (AMR) herb and mechanisms have not been reported. Objective: The purpose of this study was ...to assess the effects of AMR on attenuating myocardial hypertrophy induced by isoproterenol (ISO) in mice. Materials and Methods: Mice were randomly divided into normal control group, ISO control group, ISO plus metoprolol (60 mg/kg) group, ISO plus AMR (2, 4, and 8 g/kg) groups, and AMR (4 g/kg) control group. The mice with myocardial hypertrophy were established by subcutaneous (s.c.) injection with ISO (2 mg/kg/d) and administered intragastrically with the corresponding drugs in the volume of 0.2 mL/10 g/d for 7 days. In the normal and AMR control groups, mice were injected (s.c.) with physiological saline (the solvent for ISO) and administered intragastrically with drinking water for 7 days. Results: Compared with the ISO-induced group, AMR significantly decreased heart weight index, left ventricular weight index, and average transverse area of cardiomyocytes, significantly increased the activity of total superoxide dismutase in serum and the level of the angiotensin II receptor type (AT) gene expression in myocardium and significantly decreased the contents of malondialdehyde, cyclic adenosine monophosphate , and aldosterone in serum and angiotensin II (Ang II) in myocardium. Conclusion: The ability of AMR to mitigate myocardial hypertrophy is partly associated with its anti-oxidative effect, restraining excessive secretion or activation of neuroendocrine factors, and the stronger upward effect on AT2gene expression than AT1.
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