A bioinformatics approach to systematically analyze the molecular patterns of monkeypox virus-host cell interactions.

Monkeypox has been spreading worldwide since May 2022, when the World Health Organization (WHO) declared the outbreak a "public health emergency of international concern." The spread of monkeypox has posed a serious threat to the health of people around the world, but few studies have been conducted, and the molecular mechanism of monkeypox after infection remains unclear. We therefore implemented a transcriptome analysis to identify signaling pathways and biomarkers in monkeypox-infected cells to help understand monkeypox-host cell interactions. In this study, datasets GSE36854 and GSE11234 were obtained from GEO. Of these, 84 significantly different genes were identified in the dataset GSE36854, followed by KEGG, GO analysis protein-protein interaction (PPI) construction, and Hub gene extraction. We also analyzed the expression regulation of hub genes and screened for drugs targeting hub genes. The results showed that monkeypox-infected cells significantly activated the cellular immune response. The top 10 hub genes are IER3, IFIT2, IL11, ZC3H12A, EREG, IER2, NFKBIE, FST, IFIT1 and AREG. AP-26113 and itraconazole can be used to counteract the inhibitory effect of monkeypox on IFIT1 and IFIT2 and serve as candidate drugs for the treatment of monkeypox virus infection. IRF1 may also be a transcription factor of IFIT. Our results provide a new entry point for understanding how monkeypox virus interacts with its host.

Drugs targeting CMPK2 inhibit pyroptosis to alleviate severe pneumonia caused by multiple respiratory viruses.

Severe pneumonia caused by respiratory viruses has become a major threat to humans, especially with the SARS-CoV-2 outbreak and epidemic. The aim of this study was to investigate the universal molecular mechanism of severe pneumonia induced by multiple respiratory viruses and to search for therapeutic strategies targeting this universal molecular mechanism. The common differential genes of four respiratory viruses, including respiratory syncytial virus (RSV), rhinovirus, influenza, and SARS-CoV-2, were screened by GEO database, and the hub gene was obtained by Sytohubba in Cytoscape. Then, the effect of hub genes on inflammasome and pyrodeath was investigated in the model of RSV infection in vitro and in vivo. Finally, through virtual screening, drugs targeting the hub gene were obtained, which could alleviate severe viral pneumonia in vitro and in vivo. The results showed that CMPK2 is one of the hub genes after infection by four respiratory viruses. CMPK2 activates the inflammasome by activating NLRP3, and promotes the releases of inflammatory factors interleukin (IL)-1ß and IL-18 to induce severe viral pneumonia. Z25 and Z08 can reduce the expression level of CMPK2 mRNA and protein, thereby inhibiting NLRP3 and alleviating the development of severe viral pneumonia. In conclusion, the inflammatory response mediated by CMPK2 is the common molecular mechanism of severe pneumonia induced by viral infection, and Z25 and Z08 can effectively alleviate viral infection and severe pneumonia through this mechanism.

Hepatitis B virus X protein promotes tumor glycolysis by downregulating lncRNA OIP5-AS1/HKDC1 in HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with Hepatitis B virus (HBV) infection being the leading cause. This study aims to investigate the role of HBV in HCC pathogenesis involving glucose metabolism. Long non-coding RNA (lncRNA) OIP5-AS1 was significantly downregulated in HBV-positive HCC patients, and its low expression indicated a poor prognosis. This lncRNA was primarily localized in the cytoplasm, acting as a tumor suppressor. HBV protein X (HBx) repressed OIP5-AS1 expression by inhibiting a ligand-activated transcriptional factor peroxisome proliferator-activated receptor α (PPARα). Furthermore, mechanistic studies revealed that OIP5-AS1 inhibited tumor growth by suppressing Hexokinase domain component 1 (HKDC1)-mediated glycolysis. The expression of HKDC1 could be enhanced by transcriptional factor sterol regulatory element-binding protein 1 (SREBP1). OIP5-AS1 facilitated the ubiquitination and degradation of SREBP1 to suppress HKDC1 transcription, which inhibited glycolysis. The results suggest that lncRNA OIP5-AS1 plays an anti-oncogenic role in HBV-positive HCC via the HBx/OIP5-AS1/HKDC1 axis, providing a promising diagnostic marker and therapeutic target for HBV-positive HCC patients.

Hepatitis B Virus-mediated m6A demethylation increases hepatocellular carcinoma stemness and immune escape.

Hepatitis B viral (HBV) persistent infection plays a significant role in hepatocellular carcinoma (HCC) tumorigenesis. Many studies have revealed the pivotal roles of N6-methyladenosine (m6A) in multiple cancers, while the regulatory mechanism in stemness maintenance of HBV persistent infection-related HCC remains elusive. Here, we demonstrated that the level of m6A modification was downregulated by HBV in HBV-positive HCC, through enhanced stability of ALKBH5 mRNA. More specifically, we also identified that ALKBH5 mRNA was functionally required for the stemness maintenance and self-renewal in the HBV-positive HCC, but dispensable in HBV-negative HCC. Mechanistically, ALKBH5 demethylated the m6A modification in the 3'UTR region of the oncogenic gene SNAI2 to prevent the recognition of YTHDF2 therewith stabilize SNAI2 transcripts, contributing to cancer stem cell traits in HBV-positive HCC. Moreover, the expression of SNAI2 reversed the suppression of stemness properties by knocking down ALKBH5. Additionally, ALKBH5/SNAI2 axis accelerates tumor immune evasion through activated ligand of immune checkpoint CD155. Our study unveiled that the ALKBH5 induces m6A demethylation of the SNAI2 as a key regulator in HBV-related HCC, and identifies the function of ALKBH5/SNAI2/YTHDF2 axis in promoting the stem-like cells phenotype and immune escape during HBV infection. Implications: HBV promotes hepatocellular carcinoma stemness maintenance through elevate m6A modification of SNAI2 in an ALKBH5-YTHDF2 dependent manner and increases the expression of the ligand of immune checkpoint CD155.

CD74-ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non-small cell lung cancer cells.

The treatment of non-small cell lung cancer (NSCLC) patients harboring a proto-oncogene tyrosine-protein kinase c-ros oncogene 1 (ROS1) fusion gene has greatly benefited from the use of crizotinib. However, drug resistance inevitably occurs after 1 year of treatment. Clinical studies have shown that patients with an L2026M mutation in the ROS1 kinase domain account for about 6% of the total number of crizotinib-resistant cases, which is an important group that cannot be ignored. To explore the mechanism involved, we constructed the HLA class II histocompatibility antigen gamma chain (CD74)-ROS1 L2026M mutant gene by fusion polymerase chain reaction (PCR) and transfected it into H460 and A549 cells. We found that the invasion and metastasis abilities of drug-resistant cells were increased. The results of monodansylcadaverine (MDC) staining, Acridine orange (AO) staining, and western blot indicated that the autophagy level of CD74-ROS1 L2026M mutant NSCLC cells was increased compared with the CD74-ROS1 group, and the inhibition of autophagy could reverse the increased invasion and metastasis abilities caused by the L2026M mutation. In addition, the L2026M mutation led to excessive activation of the MEK/ERK pathway, and MEK inhibitors could reduce the autophagy level, invasion, and metastasis abilities of cells; additionally, this process could be blocked by rapamycin, an activator of autophagy. Furthermore, crizotinib treatment activated expression of Src homology region 2 domain-containing phosphatase-2 (SHP2; also known as PTPN11) to upregulate the MEK/ERK pathway, and the combination of MEK inhibitors and crizotinib increased apoptosis compared with crizotinib alone. In conclusion, our results indicate that the MEK/ERK pathway mediates the induction of invasion, metastasis, and crizotinib resistance through autophagy caused by CD74-ROS1 L2026M mutation in NSCLC cells, and targeting MEK could reverse these processes.

A novel synthesized prodrug of gemcitabine based on oxygen-free radical sensitivity inhibited the growth of lung cancer cells.

In the present study, we introduced the H 2O 2-sensitive thiazolidinone moiety at the 4th amino group of gemcitabine (GEM) to synthesize a new target compound named GEM-ZZQ, and then we confirmed its chemical structure by nuclear magnetic resonance spectroscopy. We further confirmed that GEM-ZZQ had a good chemical stability in different pH solutions in vitro and that it could be activated by H 2O 2 to release GEM. Pharmacodynamic studies revealed that the growth inhibition of human normal epithelial cells was weaker by GEM-ZZQ than by GEM treatment and that the inhibition of various lung cancer cell lines by GEM-ZZQ was similar to that of GEM. For the lung cancer cell lines that are resistant to the epidermal growth factor receptor (EGFR)-targeting inhibitor osimertinib, GEM-ZZQ showed less growth inhibition than GEM; however, GEM-ZZQ in combination with cisplatin showed better synergistic effects than GEM in the low-dose groups. In summary, we provided a new anti-cancer compound GEM-ZZQ for treating lung cancer by modifying the GEM structure.

Development of an indirect ELISA for detection of the adaptive immune response of black carp (Mylopharyngodon piceus).

Black carp (Mylopharyngodon piceus) is an important fishery resource and the main breeding target in China. Due to the lack of an assay of immunoglobulin M (IgM) antibodies in black carp, there is no effective method to evaluate adaptive immune response, which limits immunological studies and vaccine development. The present study used mAbs (monoclonal antibodies) against serum IgM of grass carp as capture antibodies. The results of Western blot analysis indicated that these antibodies had strong affinity and specificity to IgM heavy chain in black carp serum and were used to detect the antibody titer, optimize the conditions, perform a sensitivity test, and develop an indirect ELISA (enzyme-linked immunosorbent assay) to detect specific IgM antibodies in the serum. This detection method has good specificity and is effective only for grass carp (Ctenopharyngodon idella) and black carp and not for crucian carp (Carassius aumtus), silver carp (Hypophthalmichthys molitrix), bighead carp (Hypophthalmichthys nobilis), mandarin fish (Siniperca chuatsi), black bream (Megalobrama skolkovii), or yellow catfish (Pseudobagrus fulvidraco). The lowest antigen detection level was 0.05 µg/ml. The error of experimental repetition in the same sample was 1.61-4.61%. The levels of specific IgM in black carp serum were steadily increased after immunization, peaked on day 28, and then slowly decreased. Indirect ELISA can be applied to detect the changes in specific antibodies in black carp serum. Moreover, indirect ELISA provides a convenient and reliable serological detection method for immunological research and evaluation of immune effects of a vaccine in black carp.

Lactobacillus paracasei L9 affects disease progression in experimental autoimmune neuritis by regulating intestinal flora structure and arginine metabolism.

BACKGROUND: Autoimmune neuropathies are common peripheral nervous system (PNS) disorders. Environmental influences and dietary components are known to affect the course of autoimmune diseases. Intestinal microorganisms can be dynamically regulated through diet, and this study combines intestinal microorganisms with diseases to open up new therapeutic ideas. METHODS: In Lewis rats, a model of EAN was established with P0 peptide, Lactobacillus were used as treatment, serum T-cell ratio, inflammatory factors, sciatic neuropathological changes, and pathological inflammatory effects on intestinal mucosa were detected, and fecal metabolomics and 16 s microbiome analysis were performed to further explore the mechanism. RESULTS: In the EAN rat model, Lactobacillus paracasei L9 (LP) could dynamically regulate the CD4+/CD8+T balance in serum, reduce serum IL-1, IL-6 and TNF-α expression levels, improve sciatic nerve demyelination and inflammatory infiltration, and reduce nervous system score. In the rat model of EAN, intestinal mucosa was damaged. Occludin and ZO-1 were downregulated. IL-1, TNF-α and Reg3γ were upregulated. LP gavage induced intestinal mucosa recovery; occludin and ZO-1 upregulation; IL-1, TNF-α and Reg3γ downregulation. Finally, metabolomics and 16 s microbiome analysis were performed, and differential metabolites were enriched with an important metabolic pathway, arginine and proline metabolism. CONCLUSION: LP improved EAN in rats by influencing intestinal community and the lysine and proline metabolism.

Crosstalk between the lung microbiome and lung cancer.

The human microbiome is a complex ecosystem that mediates interaction between the human host and the environment. All of the human body is colonized by microorganisms. The lung as an organ used to be considered sterile. Recently, however, there has been a growing number of reports with evidence that the lungs are also in a state of carrying bacteria. The pulmonary microbiome is associated with many lung diseases and is increasingly reported in current studies. These include; chronic obstructive pulmonary disease (COPD), asthma, acute chronic respiratory infections, and cancers. These lung diseases are associated with reduced diversity and dysbiosis. It directly or indirectly affects the occurrence and development of lung cancer. Very few microbes directly cause cancer, while many are complicit in cancer growth, usually working through the host's immune system. This review focuses on the correlation between lung microbiota and lung cancer, and investigates the mechanism of action of lung microorganisms on lung cancer, which will provide new and reliable treatments and diagnosis of lung cancer in the future.

Construction of crizotinib resistant models with CD74-ROS1 D2033N and CD74-ROS1 S1986F point mutations to explore resistance mechanism and treatment strategy.

Targeted therapy is an essential treatment for non-small cell lung cancer (NSCLC) that is always associated with the drug resistance. c-ros oncogene 1 (ROS1) gene point mutation is one of the leading factors causing drug resistance. However, the point mutation cell models of crizotinib are challenging to obtain, causing few reports on the drug resistance mechanism and the treatment strategy. We constructed CD74-ROS1 D2033N and CD74-ROS1 S1986F point mutant plasmids by fusion PCR technology and transfected them into A549 cells. Western blot and MTT assay proved that the drug-resistant cell lines were successfully transfected. The transwell assay confirmed that the mutant cells' motor abilities were significantly increased compared with the wild-type group. In addition, focal adhesion kinase (FAK) was significantly increased in mutant cells. Moreover, crizotinib resistance occurred in the mutant cells through the activation of FAK / phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) pathway. Next, crizotinib was combined with defactinib, a FAK inhibitor, to further explore its therapeutic effect. The results showed that the combination could significantly inhibit the proliferation, invasion and migration of mutant cells. In conclusion, we proved that CD74-ROS1 D2033N and CD74-ROS1 S1986F point mutant NSCLC cells were resistant to crizotinib through the activation of FAK/PI3K/AKT signaling pathway, and inhibiting FAK/PI3K/AKT signaling pathway activation by defactinib could overcome drug resistance in mutant cells.

Exogenous abscisic acid alleviates Cd toxicity in Arabidopsis thaliana by inhibiting Cd uptake, translocation and accumulation, and promoting Cd chelation and efflux.

Exogenous abscisic acid (ABA) has been implicated in plant response to cadmium (Cd) stress, but the underlying mechanism remains unclear. In the present study, we found that exogenous ABA application decreased Cd fixation in wild type (WT) root cell wall through reducing the hemicelluloses content, in parallel with the decreased expression of IRT1, ZIP1, ZIP4, HMA2 and HMA4, which are related to Cd uptake and translocation, and the increased expression of PDF2.6, PDR8 and AIT1, which are related to Cd chelation, efflux, and accumulation inhibition. These changes might be associated with the reduced Cd accumulation in roots and shoots and the alleviated Cd toxicity. In contrast, the mutation of ABI4, a transcription factor in ABA signaling pathway, significantly increased the expression of IRT1, ZIP1, ZIP4, HMA2 and HMA4, while decreased the expression of AIT1, PDF2.6 and PDR8, enhancing Cd accumulation in roots and shoots of abi4. The enhanced Cd-sensitivity in abi4 mutant could not be rescued by exogenous ABA addition compared with WT. In a word, we conclude that exogenous ABA mitigates Cd toxicity in Arabidopsis thaliana via inhibiting Cd uptake, translocation and accumulation, promoting Cd chelation and efflux, a pathway that might be regulated by ABI4.

Applications of Artificial Intelligence Based on Medical Imaging in Glioma: Current State and Future Challenges.

Glioma is one of the most fatal primary brain tumors, and it is well-known for its difficulty in diagnosis and management. Medical imaging techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), and spectral imaging can efficiently aid physicians in diagnosing, treating, and evaluating patients with gliomas. With the increasing clinical records and digital images, the application of artificial intelligence (AI) based on medical imaging has reduced the burden on physicians treating gliomas even further. This review will classify AI technologies and procedures used in medical imaging analysis. Additionally, we will discuss the applications of AI in glioma, including tumor segmentation and classification, prediction of genetic markers, and prediction of treatment response and prognosis, using MRI, PET, and spectral imaging. Despite the benefits of AI in clinical applications, several issues such as data management, incomprehension, safety, clinical efficacy evaluation, and ethical or legal considerations, remain to be solved. In the future, doctors and researchers should collaborate to solve these issues, with a particular emphasis on interdisciplinary teamwork.

The role of glycolysis and lactate in the induction of tumor-associated macrophages immunosuppressive phenotype.

Growing evidence highlights that glycolysis and tumor-derived lactate could skew tumor-associated macrophages (TAMs) toward an immunosuppressive phenotype. However, the updated research has not been systematically summarized yet. TAMs are educated by the tumor microenvironment (TME) and exert immunosuppressive functions and tumorigenic effects via multiple biological processes. It is well known that lactate generated by aerobic glycolysis is significantly accumulated in TME and promotes tumor progression in solid tumors. Moreover, some recent research demonstrated that glycolysis is activated in TAMs to support M2-like polarization, which is absolutely in contrast with the metabolic profile of M2 macrophages in inflammation. Notably, lactate produced by high levels of glycolysis is not only a metabolic by-product but also an oncometabolite. TAMs could access the biological information delivered by lactate and further enhance protumor functions such as immunosuppression and angiogenesis. Here, we outline the connection between glycolysis and TAM phenotype to elucidate the metabolic characteristics of TAMs. Further, insights into the specific molecular mechanisms of lactate-induced TAM polarization and potential therapeutic targets are summarized. We sought to discuss the reciprocal interaction between tumor cells and TAMs mediated by lactate, which will lay a foundation for the research aiming to elucidate the complex functions of TAMs.

LncNSPL facilitates influenza A viral immune escape by restricting TRIM25-mediated K63-linked RIG-I ubiquitination.

Long noncoding RNAs (lncRNAs) participate in host antiviral responses; however, how viruses exploit host lncRNAs for immune evasion remains largely unexplored. Functional screening of differentially expressed lncRNA profile in patients infected with influenza A virus (IAV) revealed that lncNSPL (Gene Symbol: LOC105370355) was highly expressed in monocytes. Deregulated lncNSPL expression in infected monocytes significantly increased type I interferon (IFN-I) production and inhibited IAV replication. Moreover, lncNSPL overexpression in mice increased the susceptibility to IAV infection and impaired IFN-I production. LncNSPL directly bound to retinoic acid-inducible gene I (RIG-I) and blocked the interaction between RIG-I and E3 ligase tripartite interaction motif 25 (TRIM25), reducing TRIM25-mediated lysine 63 (K63)-linked RIG-I ubiquitination and limiting the downstream production of antiviral mediators during the late stage of IAV infection. Our findings provide mechanistic insights into the means by which lncNSPL promotes IAV replication and immune escape via restricting the TRIM25-mediated RIG-I K63-linked ubiquitination. Thus, lncNSPL may represent a promising pharmaceutical target for anti-IAV therapy.

The Role of Nitric Oxide Signaling in Plant Responses to Cadmium Stress.

Nitric oxide (NO) is a widely distributed gaseous signaling molecule in plants that can be synthesized through enzymatic and non-enzymatic pathways and plays an important role in plant growth and development, signal transduction, and response to biotic and abiotic stresses. Cadmium (Cd) is a heavy metal pollutant widely found in the environment, which not only inhibits plant growth but also enters humans through the food chain and endangers human health. To reduce or avoid the adverse effects of Cd stress, plants have evolved a range of coping mechanisms. Many studies have shown that NO is also involved in the plant response to Cd stress and plays an important role in regulating the resistance of plants to Cd stress. However, until now, the mechanisms by which Cd stress regulates the level of endogenous NO accumulation in plant cells remained unclear, and the role of exogenous NO in plant responses to Cd stress is controversial. This review describes the pathways of NO production in plants, the changes in endogenous NO levels in plants under Cd stress, and the effects of exogenous NO on regulating plant resistance to Cd stress.

Comparative Analysis of Long Non-Coding RNA Expression and Immune Response in Mild and Severe COVID-19.

Background: Coronavirus disease 2019 (COVID-19) is a worldwide emergency, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Long non-coding RNAs (lncRNAs) do not encode proteins but could participate in immune response. Methods: In our study, 39 COVID-19 patients were enrolled. The microarray of peripheral blood mononuclear cells from healthy and COVID-19 patients was applied to identify the expression profiles of lncRNAs and mRNAs. Identified differentially expressed (DE) lncRNAs were validated by qRT-PCR. Then, the lncRNA-mRNA network was constructed and visualized using Cytoscape (3.6.1) based on the Pearson correlation coefficient. The enrichment of DE mRNAs was analyzed using Metascape. The difference in frequencies of immune cells and cytokines was detected using CIBERSORT and ImmPort based on DE mRNAs. Results: All patients with COVID-19 displayed lymphopenia, especially in T cells, and hyper-inflammatory responses, including IL-6 and TNF-α. Four immune-related lncRNAs in COVID-19 were found and further validated, including AC136475.9, CATG00000032642.1, G004246, and XLOC_013290. Functional analysis enriched in downregulation of the T-cell receptor and the antigen processing and presentation as well as increased apoptotic proteins, which could lead to T-cell cytopenia. In addition, they participated in monocyte remodeling, which contributed to releasing cytokines and chemokines and then recruiting more monocytes and aggravating the clinical severity of COVID-19 patients. Conclusion: Taken together, four lncRNAs were in part of immune response in COVID-19, which was involved in the T-cell cytopenia by downregulating the antigen processing and presentation, the T-cell receptor, and an increased proportion of monocytes, with a distinct change in cytokines and chemokines.

2-Methoxy-5((3,4,5-trimethosyphenyl) seleninyl) phenol causes G2/M cell cycle arrest and apoptosis in NSCLC cells through mitochondrial apoptotic pathway and MDM2 inhibition.

Nonsmall cell lung cancer (NSCLC) is one of the most common malignancies and needs novel and effective chemotherapy. In this study, our purpose is to explore the anticancer effects of 2-methoxy-5((3,4,5-trimethosyphenyl) seleninyl) phenol (SQ) on human NSCLC (A549 and H460) cells. We found that SQ suppressed the proliferation of NSCLC cells in time- and dose-dependent manners, and blocked the cells at G2/M phase, which was relevant to microtubule depolymerization. Additionally, SQ induced A549 and H460 cell apoptosis by activating the mitochondrial apoptotic pathway. Further, we demonstrated that SQ enhanced the generation of reactive oxygen species (ROS), and pretreatment with N-acetyl- L-cysteine (NAC) attenuated SQ-induced cell apoptosis. Meanwhile, SQ mediated-ROS generation caused DNA damage in A549 and H460 cells. Our data also revealed that SQ-induced apoptosis was correlated with the inhibition of mouse double minute 2 (MDM2) in A549 and H460 cells. In summary, our research indicates that the novel compound SQ has great potential for therapeutic treatment of NSCLC in future.

Automatic Detoxification Medicine Delivery by Thermo-Sensitive Poly(ethylene glycol)-Based Nanogels.

During the medication-assisted treatment of drug abuse, side effects and addiction liabilities are commonly observed. Thus, control of the medication dose is very important. According to body temperature abnormalities in drug abusers, a thermo-sensitive nanogel was synthesized as a drug carrier to automatically deliver detoxification medicines. This nanogel was prepared through the synthesis of polystyrene (PS) core microspheres, followed by coverage with a nonlinear poly(ethylene glycol)-based copolymer shell. The PS core microspheres were found to be an ideal hydrophobic core for loading the detoxification medicines effectively. The nonlinear poly(ethylene glycol)-based copolymer shell layer consisted of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methyl ether methacrylates (Mn = 300 g mol-1, MEO5MA). The monomer feeding molar ratio n(MEO2MA)/n(MEO5MA) of 1:3 enabled PS@P(MEO2MA-co-MEO5MA) nanogels to exhibit a distinguished colloidal stability and an adjustable volume phase transition temperature which is within the drug addicts' abnormally fluctuating temperature range. Importantly, it was found that the obtained PS@P(MEO2MA-co-MEO5MA) nanogels displayed good biocompatibility with rat aortic endothelial cells in the given concentration range. The nanogels also exhibited a satisfactory loading efficiency and thermo-sensitive/sustained release characteristics for three detoxification medicines: sinomenine, diltiazem and chlorpromazine.

Sulfonylurea receptor 1-expressing cancer cells induce cancer-associated fibroblasts to promote non-small cell lung cancer progression.

Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression; however, how CAFs are induced remains elusive. Sulfonylurea receptor 1 (SUR1) is a tumor-enhancer in non-small cell lung carcinoma (NSCLC). Here, we probed the influence of SUR1-expressing cancer cells on CAFs. Results showed that high SUR1 expression positively correlated with α-SMA positive staining of CAFs in tumor tissues and poor prognosis of NSCLC patients. SUR1 contributed to normal fibroblast (NF) transformation into CAFs and facilitated the growth and metastasis of NSCLC in vivo. Conditioned medium (CM) and exosomes from SUR1-expressing cancer cells induced CAFs and promoted fibroblast migration. In cancer cells, SUR1 promoted p70S6K-induced KH-type splicing regulatory protein (KHSRP) phosphorylation at S395 to inhibit the binding of KHSRP with let-7a precursor (pre-let-7a) and decreasing mature let-7a-5p expression in cancer cells and exosomes. Let-7a-5p delivered by exosomes blocked NF transformation into CAFs by targeting TGFBR1 to inactivate the TGF-ß signaling pathway. Glibenclamide, which targets SUR1, restrained CAFs and suppressed tumor growth in patient-derived xenograft models. Furthermore, we found that let-7a-5p was decreased in the tissues and plasma exosomes of NSCLC patients. In summary, SUR1-expressing cancer cells induce NF transformation into CAFs in the tumor microenvironment and promote NSCLC progression by transferring less exosomal let-7a-5p. Glibenclamide is a promising anti-cancer drug, and plasma exosomal let-7a-5p level is a potential diagnostic biomarker for NSCLC patients. These findings provide new therapeutic strategies by targeting SUR1 in NSCLC.

EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling.

The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene occurs in approximately 5% of non-small-cell lung cancers (NSCLCs). The development of ALK tyrosine kinase inhibitors (ALK-TKIs) is a major advance in treating NSCLC with the ALK fusion gene. Nevertheless, acquired resistance to ALK-TKIs ultimately limits their use. A prevalent mechanism of drug resistance in kinases occurs through the mutation of G1202R in ALK. However, the mechanisms underlying G1202R resistance to ceritinib are not fully understood. Here, we demonstrated that the expression of EML4-ALK G1202R mutation in A549 cells induced an epithelial-mesenchymal transition (EMT) phenotype and significantly increased the migration and invasion abilities. These phenomena may be due to the upregulation of signal transducer and activator of transcription 3 (STAT3), accompanied by the elevated expression of Slug in EML4-ALK G1202R mutant cells. Furthermore, the combination of ALK and STAT3 inhibitors restored the sensitivity of EML4-ALK G1202R mutant cells to ceritinib. In conclusion, these data indicate that the EML4-ALK G1202R mutation mediates the EMT phenotype by activating the STAT3/Slug signaling pathway, resulting in resistance to ceritinib, and that the combination of STAT3 and ALK inhibitors may overcome ALK mutation-driven drug resistance in the clinic.