Chemotherapy can eradicate a majority of cancer cells. However, a small population of tumor cells often survives drug treatments through genetic and/or non-genetic mechanisms, leading to tumor ...recurrence. Here we report a reversible chemoresistance phenotype regulated by the mTOR pathway. Through a genome-wide CRISPR knockout library screen in pancreatic cancer cells treated with chemotherapeutic agents, we have identified the mTOR pathway as a prominent determinant of chemosensitivity. Pharmacological suppression of mTOR activity in cancer cells from diverse tissue origins leads to the persistence of a reversibly resistant population, which is otherwise eliminated by chemotherapeutic agents. Conversely, activation of the mTOR pathway increases chemosensitivity in vitro and in vivo and predicts better survival among various human cancers. Persister cells display a senescence phenotype. Inhibition of mTOR does not induce cellular senescence per se, but rather promotes the survival of senescent cells through regulation of autophagy and G2/M cell cycle arrest, as revealed by a small-molecule chemical library screen. Thus, mTOR plays a causal yet paradoxical role in regulating chemotherapeutic response; inhibition of the mTOR pathway, while suppressing tumor expansion, facilitates the development of a reversible drug-tolerant senescence state.
PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained ...benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM‐induced production of ROS‐mediated activation of Akt and extracellular signal‐regulated kinase (ERK) pathways and inhibits nuclear piling‐up of nuclear factor kappa B (NF‐κB) and HIF‐1α. On the basis of time and dose‐dependent manner, our data demonstrated that GEM‐induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N‐acetyl‐l‐cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time‐dependent escalation of NF‐κB and HIF‐1α in the nucleus resulted from phosphorylation‐induced degradation of IκBα, whereas HIF‐1α upregulation was NF‐κB‐dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF‐κB and HIF‐1α and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF‐κB and HIF‐1α and their pharmacological inhibition suppressed GEM‐induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM‐induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF‐κB downregulation in lung cancer.
An undesired effect of chemotherapy: Gemcitabine (GEM) promotes invasiveness through upregulation of PTX3 in lung cancer. GEM‐induced ROS enhances nuclear localization of nuclear factor kappa B (NF‐κB)/p65; HIF‐1α and both are involved in PTX3 expression in lung cancer cells NF‐κB/p65 enhances expression of HIF‐1α. Rg3 abrogates GEM‐induced production of ROS and inhibits nuclear piling‐up of NF‐κB and HIF‐1α. Rg3 inhibits GEM‐induced PTX3 activation through inhibition of IκB‐α Kinase and Akt.
DNA offers excellent programming properties to nanomaterials syntheses. Host–guest interaction between DNA nanostructures and inorganic nanoparticles (NPs) is of particular interest because the ...resulting complexes would possess both programming properties intrinsic to DNA and physical properties associated with inorganic NPs, such as plasmonic and magnetic features. Here, we report a class of core–shell complexes (AuNP@DNA cages): hard gold NPs (AuNPs) are encapsulated in geometrically well-defined soft DNA nanocages. The AuNP guest can be further controllably released from the host (DNA nanocages), pointing to potential applications in surface engineering of inorganic NPs and cargo delivery of DNA nanocages.
Cucumber green mottle mosaic virus (CGMMV) causes substantial global losses in cucurbit crops, especially watermelon. N6-methyladenosine (m
A) methylation in RNA is one of the most important ...post-transcriptional modification mechanisms in eukaryotes. It has been shown to have important regulatory functions in some model plants, but there has been no research regarding m
A modifications in watermelon.
We measured the global m
A level in resistant watermelon after CGMMV infection using a colorimetric method. And the results found that the global m
A level significantly decreased in resistant watermelon after CGMMV infection. Specifically, m
A libraries were constructed for the resistant watermelon leaves collected 48 h after CGMMV infection and the whole-genome m
A-seq were carried out. Numerous m
A modified peaks were identified from CGMMV-infected and control (uninfected) samples. The modification distributions and motifs of these m
A peaks were highly conserved in watermelon transcripts but the modification was more abundant than in other reported crop plants. In early response to CGMMV infection, 422 differentially methylated genes (DMGs) were identified, most of which were hypomethylated, and probably associated with the increased expression of watermelon m
A demethylase gene ClALKBH4B. Gene Ontology (GO) analysis indicated quite a few DMGs were involved in RNA biology and stress responsive pathways. Combined with RNA-seq analysis, there was generally a negative correlation between m
A RNA methylation and transcript level in the watermelon transcriptome. Both the m
A methylation and transcript levels of 59 modified genes significantly changed in response to CGMMV infection and some were involved in plant immunity.
Our study represents the first comprehensive characterization of m
A patterns in the watermelon transcriptome and helps to clarify the roles and regulatory mechanisms of m
A modification in watermelon in early responses to CGMMV.
The aim of this study was to elucidate the application of ultrasound examination of umbilical artery (UA) hemodynamics with urine microalbumin (UmA) determination in evaluating the outcomes of sPE ...patients. Altogether 80 sPE patients and 75 healthy pregnant women were recruited. UmA, RI (resistance index) and PI (pulsatility index) were separately measured by ELISA and the ultrasonic Doppler flow detector. The correlation between parameters was analysed using Pearson's coefficient method. The independent risk factors of sPE were identified using the Logistic regression model. sPE patients had increased UmA, RI and PI (all p < 0.05). UmA level was positively correlated with RI and PI in sPE patients. RI, PI and UmA were independent risk factors of sPE (all p < 0.05). sPE can predict adverse pregnancy outcomes. High UmA levels may increase the risk of poor prognosis. Overall, ultrasound examination of UA hemodynamics with UmA determination can predict the adverse pregnancy outcomes of sPE patients.
IMPACT STATEMENT
What is already known on this subject? Doppler ultrasound and urine microalbumin (UmA) measurement are important tools in assessing the clinical severity of severe preeclampsia (sPE).
What do the results of this study add? This study aims to unravel the application of ultrasound examination of hemodynamics in the umbilical artery (UA) combined with the determination of UmA in evaluating the outcomes of sPE patients.
What are the implications of these findings for clinical practice and/or further research? Ultrasound examination of hemodynamics in UA combined with the determination of UmA can predict the adverse pregnancy outcomes of sPE patients.
PANoptosis plays a crucial role in cancer initiation and progression. However, the roles of PANoptosis-related genes (PARGs) in the prognosis and immune landscape of head and neck squamous cell ...carcinoma (HNSCC) remain unclear. Integrated bioinformatics analyses based on the data of HNSCC patients in the TCGA database were conducted. We extracted 48 PARGs expression profile and then conducted differentially expressed analysis, following building a Cox model to predict the survival of HNSCC patients. Subsequently, the relationships between the risk score, immune landscape, chemo-, and immune-therapy responses were analyzed, respectively. Moreover, we investigated the prognostic value, and further predicted the pathways influenced by PARGs. Finally, we identified the biological function of crucial PARGs. A total of 18 differentially expressed PARGs were identified in HNSCC, and a Cox model including CASP8, FADD, NLRP1, TNF, and ZBP1 was constructed, which showed that the risk score was associated with the prognosis as well as immune infiltration of HNSCC patients, and the risk score could be regarded as an independent biomarker. Additionally, patients with high-risk score might be an indicator of lymph node metastasis and advanced clinical stage. High-risk scores also contributed to the chemotherapy resistance and immune escape of HNSCC patients. In addition, FADD and ZBP1 played a crucial role in various cancer-related pathways, such as the MAPK, WNT, and MTOR signaling pathways. On the other hand, we suggested that FADD facilitated the progression and 5-fluorouracil (5-FU) resistance of HNSCC cells. A signature based on PANoptosis showed great predictive power for lymph node metastasis and advanced stage, suggesting that the risk score might be an independent prognostic biomarker for HNSCC. Meanwhile, FADD, identified as a prognostic biomarker, may represent an effective therapeutic target for HNSCC.
Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Here we show that complement is activated in skeletal muscle injury and plays a key role during ...regeneration. Genetic ablation of complement C3 or its inactivation with Cobra Venom Factor (CVF) result in impaired muscle regeneration following cardiotoxin-induced injury in mice. The effect of complement in muscle regeneration is mediated by the alternative pathway and C3a receptor (C3aR) signaling, as deletion of Cfb, a key alternative pathway component, or C3aR leads to impaired regeneration and reduced monocyte/macrophage infiltration. Monocytes from C3aR-deficient mice express a reduced level of adhesion molecules, cytokines and genes associated with antigen processing and presentation. Exogenous administration of recombinant CCL5 to C3aR-deficient mice rescues the defects in inflammatory cell recruitment and regeneration. These findings reveal an important role of complement C3a in skeletal muscle regeneration, and suggest that manipulating complement system may produce therapeutic benefit in muscle injury and regeneration.
This study investigates the synthesis of mesophase pitch using low-cost fluid catalytic cracking (FCC) slurry and waste fluid asphaltene (WFA) as raw materials through the co-carbonization method. ...The resulting mesophase pitch product and its formation mechanism were thoroughly analyzed. Various characterization techniques, including polarizing microscopy, softening point measurement, Fourier-transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA), were employed to characterize and analyze the properties and structure of the mesophase pitch. The experimental results demonstrate that the optimal optical texture of the mesophase product is achieved under specific reaction conditions, including a temperature of 420 °C, pressure of 1 MPa, reaction time of 6 h, and the addition of 2% asphaltene. It was observed that a small amount of asphaltene contributes to the formation of mesophase pitch spheres, facilitating the development of the mesophase. However, excessive content of asphaltene may cover the surface of the mesophase spheres, impeding the contact between them and consequently compromising the optical texture of the mesophase pitch product. Furthermore, the inclusion of asphaltene promotes polymerization reactions in the system, leading to an increase in the average molecular weight of the mesophase pitch. Notably, when the amount of asphaltene added is 2%, the mesophase pitch demonstrates the lowest I
/I
value, indicating superior molecular orientation and larger graphite-like microcrystals. Additionally, researchers found that at this asphaltene concentration, the mesophase pitch exhibits the highest degree of order, as evidenced by the maximum diffraction angle (2θ) and stacking height (Lc) values, and the minimum d
value. Moreover, the addition of asphaltene enhances the yield and aromaticity of the mesophase pitch and significantly improves the thermal stability of the resulting product.
Although doxorubicin (Dox) has been widely used in the treatment of different types of cancer, its insufficient cellular uptake and intracellular release is still a limitation. Herein, we report an ...easy process for the preparation of redox-sensitive nanogels that were shown to be highly efficient in the intracellular delivery of Dox. The nanogels (AG/Cys) were obtained through in situ cross-linking of alginate (AG) using cystamine (Cys) as a cross-linker via a miniemulsion method. Dox was loaded into the AG/Cys nanogels by simply mixing it in aqueous solution with the nanogels, that is, by the establishment of electrostatic interactions between the anionic AG and the cationic Dox. The results demonstrated that the AG/Cys nanogels are cytocompatible, have a high drug encapsulation efficiency (95.2 ± 4.7%), show an in vitro accelerated release of Dox in conditions that mimic the intracellular reductive conditions, and can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in higher Dox intracellular accumulation and a remarkable cell death extension when compared with free Dox. The developed nanogels can be used as a tool to overcome the problem of Dox resistance in anticancer treatments and possibly be used for the delivery of other cationic drugs in applications beyond cancer.
Angiotensin II induces cardiovascular injury, in part, by activating inflammatory response; however, the initial factors that trigger the inflammatory cascade remain unclear. Microarray analysis of ...cardiac tissue exposed to systemic angiotensin II infusion revealed that extracellular heterodimeric proteins S100a8/a9 were highly upregulated. The increase in S100a8/a9 mRNA of CD11b(+)Gr1(+) neutrophils isolated from both the peripheral blood and heart was highest on day 1 of angiotensin II infusion and decreased to baseline at day 7. Immunostaining showed that S100a8/a9 was primarily present in infiltrating CD11b(+)Gr1(+) neutrophils in the heart. The receptor for advanced glycation end products, an S100a8/a9 receptor, was expressed in cardiac fibroblasts (CFs). Microarray analysis and Bio-Plex protein array showed that treatment of CFs with recombinant S100a8/a9 activated multiple chemokine and cytokines released. Luciferase reporter assay indicated S100a8/a9-activated nuclear factor-κ B pathway in CFs. Consequently, recombinant S100a8/a9-treated CFs promoted migration of monocytes and CFs, whereas neutralizing S100a9 antibody blocked S100a9 or receptor for advanced glycation end products-suppressed cellular migration. Finally, administration of a neutralizing S100a9 antibody prevented angiotensin II infusion-induced nuclear factor-κ B activation, inflammatory cell infiltration, cytokine production, subsequent perivascular and interstitial fibrosis, and hypertrophy in heart. Our findings identify neutrophil-produced S100a8/a9 as an initial proinflammatory factor needed to trigger inflammation and cardiac injury during acute hypertension.
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