The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that links extracellular signals to the control of cell survival, growth, proliferation and differentiation. Due to its ...frequent overexpression and hyperactivation, EGFR has been a therapeutic target for human malignancies. Unfortunately, the specialized inhibitors of EGFR or EGFR-mediated pathways have not yet achieved the desired clinical effects. Therefore, it is necessary to elucidate the EGFR-mediated molecular basis of tumourigenesis, development and therapeutic resistance and to identify potential therapeutic targets. Interestingly, emerging research has indicated that autophagy is closely related to tumourigenesis, tumour progression and chemoresistance. Both autophagy upregulation and downregulation have been observed in cancers, suggesting its dual oncogenic and tumour suppressor properties during malignant transformation. Importantly, EGFR has been demonstrated to be a critical determinant of whether autophagy has a cytoprotective or cytotoxic effect. Therefore, here, we mainly focus on the function of EGFR in autophagy, especially the potential mechanism. The EGFR-mediated pathways or proteins involved in autophagy regulation include (1) the EGFR-mTOR pathway; (2) the EGFR-RAS pathway; (3) EGFR-Beclin1; (4) the EGFR-STAT3 pathway and (5) EGFR-LAPTM4B (oncoprotein lysosomal-associated transmembrane protein 4B). In addition, we also describe the role of EGFR-mediated autophagy in chemoresistance and tumour therapy. We attempt to summarized the mechanism by which EGFR-mediated signalling pathways participate in regulating autophagy and to investigate how to use the existing knowledge to identify potential cancer therapeutic targets.
•EGFR or EGFR mutation-mediated autophagy plays a critical role in tumorigenesis, tumor progress and therapy resistance.•The role of EGFR-mediated autophagy in tumorigenesis and therapy resistance is highly cell-dependent.•Regulating EGFR-mediated autophagy might be a new strategy for the treatment of EGFR deregulated tumors.
Sequestosome1 (p62/SQSTM 1) is a multidomain protein that interacts with the autophagy machinery as a key adaptor of target cargo. It interacts with phagophores through the LC3-interacting (LIR) ...domain and with the ubiquitinated protein aggregates through the ubiquitin-associated domain (UBA) domain. It sequesters the target cargo into inclusion bodies by its PB1 domain. This protein is further the central hub that interacts with several key signaling proteins. Emerging evidence implicates p62 in the induction of multiple cellular oncogenic transformations. Indeed, p62 upregulation and/or reduced degradation have been implicated in tumor formation, cancer promotion as well as in resistance to therapy. It has been established that the process of autophagy regulates the levels of p62. Autophagy-dependent apoptotic activity of p62 is recently being reported. It is evident that p62 plays a critical role in both autophagy and apoptosis. Therefore in this review we discuss the role of p62 in autophagy, apoptosis and cancer through its different domains and outline the importance of modulating cellular levels of p62 in cancer therapeutics.
Autophagy is a naturally occurring programed cellular catabolic process stimulated by cellular stress for energy homeostasis maintenance and elimination of harmful substances. It mostly works as ...pro‐survival mechanism but on the other hand deregulation of autophagy has been linked to non‐apoptotic cell death known as “type II programed cell death.” Emerging evidences indicate that EGFR (epidermal growth factor receptor)‐mediated RAS/RAF/MEK/ERK signaling pathway plays a critical role in the induction of autophagy in various tumors. It has further been established that this signaling pathway is also involved in several other anti‐proliferative events such as apoptosis and senescence. However, the signaling pathway activity and effects are highly dependent on the cell type and the stimulus. It is currently being evident that autophagy induction by RAS/RAF/MEK/ERK pathway through small molecules may be a potential therapeutic strategy for cancer. However, to our best knowledge, the role of EGFR‐mediated RAS/RAF/MEK/ERK signaling pathway in autophagy‐mediated cell death and survival have not previously been reviewed. In this review, we discuss the current state of knowledge on how RAS/RAF/MEK/ERK signaling pathway regulates autophagy and the role of this EGFR‐mediated autophagy in diseases. We further examine the cross‐talk between this EGFR‐mediated autophagy and apoptosis as well as how this process is currently being utilized for cancer treatment and suggest promoting autophagy‐related cell death by small molecules may be exploited to design better therapeutic strategies for early stage and locally advanced tumors.
Respiratory syncytial virus (RSV) infection is a constant threat to the health of young children, and this is mainly attributed to the lack of effective prevention strategies. This study aimed to ...determine whether
Lactobacillus
(
L.
)
mucosae
, a potential probiotic, could protect against respiratory viral infection in a mouse model. Naive 3–4-week-old BALB/c mice were orally administered with three
L. mucosae
strains (2.5 × 10
8
CFU/mouse) 7 days before RSV infection (10
5
TCID
50
/mouse). Results showed that all three strains inhibited RSV replication and reduced the proportions of inflammatory cells, including granulocytes and monocytes in the blood. The
L. mucosae
M104R01L3 treatment maintained stable weight in mice and increased interferon (IFN)-β and tumor necrosis factor (TNF)-α levels. The
L. mucosae
DCC1HL5 treatment increased interleukin (IL)-1β and IL-10 levels. Moreover, the M104R01L3 and DCC1HL5 strains increased the proportions of
Akkermansia
,
Alistipes
, and
Anaeroplasma
which contributed to the advantageous modulation of the gut microbiota. Besides,
L. mucosae
affected the gut levels of short-chain fatty acids (SCFAs) that are important for the antiviral response.
L. mucosae
1,025 increased acetate, propionate, and butyrate levels, whereas
L. mucosae
M104R01L3 increased the level of acetate in the gut.
L. mucosae
M104R01L3 may protect against viral infection by upregulating the IFN-β levels in the lungs and its antiviral effect may be related to the increase of acetate levels in the gut. In conclusion, the three
L. mucosae
strains exerted antiviral effects against RSV infection by differentially regulating immune responses and intestinal micro-ecological balance. This study can provide a reference for studying the mechanisms underlying the antiviral effects of
L. mucosae
.
Microbiota-derived desaminotyrosine (DAT) protects the host from influenza by modulating the type I interferon (IFN) response. The aim of this study was to investigate the antivirus effects of a ...DAT-producing bacteria strain. A comparative genomics analysis and UHPLC Q-Exactive MS were used to search for potential strains and confirm their ability to produce DAT, respectively. The anti-influenza functions of the DAT producer were evaluated using an antibiotic-treated mouse model by orally administering the specific strain before viral infection. The results showed the Lactiplantibacillus pentosus CCFM1227 contained the phy gene and produced DAT by degrading phloretin. In vivo, L. pentosus CCFM1227 re-inoculation increased the DAT level in feces, and protected from influenza through inhibiting viral replication and alleviating lung immunopathology. Furthermore, CCFM1227-derived DAT was positively correlated with the IFN-β level in the lung. The transcriptome results showed that CCFM1227 activated gene expression in the context of the defense response to the virus, and the response to interferon-beta. Moreover, CCFM1227 treatment upregulated the expression of MHC-I family genes, which regulate the adaptive immune response. In conclusion, L. pentosus CCFM1227 exerted antiviral effects by producing DAT in the gut, and this may provide a potential solution for creating effective antiviral probiotics.
In the present work, seven Mg-Zn-Ag alloys with the nominal composition of Mg96-xZnxAg4 (x = 17, 20, 23, 26, 29, 32, 35 in at.%) were prepared by induction melting and single-roller melt-spinning. ...The X-ray diffraction (XRD) analyses indicate the metallic glasses with three composition of Mg73Zn23Ag4, Mg70Zn26Ag4, and Mg67Zn29Ag4 were obtained successfully. The differential scanning calorimetry (DSC) measurement was used to obtain the characteristic temperature of Mg-Zn-Ag metallic glasses for the glass-forming ability analysis. The maximum glass transition temperature (Trg) was found to be 0.525 with a composition close to Mg67Zn29Ag4, which results in the best glass-forming ability. Moreover, the immersion test in simulated body fluid (SBF) demonstrate the relative homogeneous corrosion behavior of the Mg-Zn-Ag metallic glasses. The corrosion rate of Mg-Zn-Ag metallic glasses in SBF solution decreases with the increase of Zn content. The sample Mg67Zn29Ag4 has the lowest corrosion rate of 0.19 mm/yr, which could meet the clinical application requirement well. The in vitro cell experiments show that the Madin-Darby canine kidney (MDCK) cells cultured in sample Mg67Zn29Ag4 and its extraction medium have higher activity. However, the Mg-Zn-Ag metallic glasses exhibit obvious inhibitory effect on human rhabdomyosarcoma (RD) tumor cells. The present investigations on the glass-forming ability, corrosion behavior, cytocompatibility and tumor inhibition function of the Mg-Zn-Ag based metallic glass could reveal their biomedical application possibility.
Decades have passed since the first discovery of H10-subtype avian influenza virus (AIV) in chickens in 1949, and it has been detected in many species including mammals such as minks, pigs, seals and ...humans. Cases of human infections with H10N8 viruses identified in China in 2013 have raised widespread attention. Two novel reassortant H10N3 viruses were isolated from chickens in December 2019 in eastern China during routine surveillance for AIVs. The internal genes of these viruses were derived from genotype S (G57) H9N2 and were consistent with H5N6, H7N9 and H10N8, which cause fatal infections in humans. Their viral pathogenicity and transmissibility were further studied in different animal models. The two H10N3 isolates had low pathogenicity in chickens and were transmitted between chickens via direct contact. These viruses were highly pathogenic in mice and could be transmitted between guinea pigs via direct contact and respiratory droplets. More importantly, these viruses can bind to both human-type SAα-2,6-Gal receptors and avian-type SAα-2,3-Gal receptors. Asymptomatic shedding in chickens and good adaptability to mammals of these H10N3 isolates would make it easier to transmit to humans and pose a threat to public health.
(
) is a medicinal fungus that is widely used in East Asia for the adjuvant treatment of cancer. To elucidate the antitumor effective substances and mechanism of
, we designed an approach ...incorporating cytotoxicity screening, phytochemical analysis, network pharmacology construction, and cellular and molecular experiments. The dichloromethane extract of
(DCMPI) was identified as the active portion in HT-29 cells. Nineteen constituents were identified, and 5 were quantified by UPLC-ESI-Q/TOF-MS. Eight ingredients were obtained in the network pharmacology study. In total, 473 putative targets associated with DCMPI and 350 putative targets related to colon cancer were derived from online databases and target prediction tools. Protein-protein interaction networks of drug and disease putative targets were constructed, and 84 candidate targets were identified based on topological features. Pathway enrichment analysis showed that the candidate targets were mostly related to reactive oxygen species (ROS) metabolic processes and intrinsic apoptotic pathways. Then, a cellular experiment was used to validate the drug-target mechanisms predicted by the system pharmacology analysis. Experimental results showed that DCMPI increased intracellular ROS levels and induced HT-29 cell apoptosis. Molecular biology experiments indicated that DCMPI not only increased Bax and Bad protein expression and promoted PARP and caspase-3/9 cleavage but also down-regulated Bcl-2 and Bcl-xl protein levels to induce apoptosis in HT-29 cells. In conclusion, our study provides knowledge on the chemical composition and antitumor mechanism of
, which may be exploited as a promising therapeutic option for colon cancer.
Influenza A virus induces severe respiratory tract infection and results in a serious global health problem. Influenza infection disturbs the cross-talk connection between lung and gut. Probiotic ...treatment can inhibit influenza virus infection; however, the mechanism remains to be explored. The mice received
1025,
CCFM1026, and their mixture MIX for 19 days. Effects of probiotics on clinical symptoms, immune responses, and gut microbial alteration were evaluated.
1025 and MIX significantly reduced the loss of body weight, pathological symptoms, and viral loading.
CCFM1026 significantly reduced the proportion of neutrophils and increased lymphocytes, the expressions of TLR7, MyD88, TRAF6, and TNF-α to restore the immune disorders. MIX increased the antiviral protein MxA expression, the relative abundances of
,
,
,
, and further regulated SCFA metabolism resulting in an enhancement of butyrate. The correlation analysis revealed that the butyrate was positively related to MxA expression (
< 0.001) but was negatively related to viral loading (
< 0.05). The results implied the possible antiviral mechanisms that MIX decreased viral loading and increased the antiviral protein MxA expression, which was closely associated with the increased butyrate production resulting from gut microbial alteration.
Cellular cholesterol plays an important role in influenza A virus (IAV) endocytosis and replication. However, how IAV infection regulates cholesterol biosynthesis remains poorly understood. Here, we ...report that IAV infection activates SREBP2 and induces the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis pathway. SREBP2 deficiency suppresses IAV-induced HMGCR expression and virus replication. Mechanistically, IAV infection activates JAK2 and STAT3, inhibition of JAK2 and STAT3 activity by their inhibitors or by gene knockout downregulates IAV-induced SREBP2 and HMGCR expression and IAV replication, reduces the content of cellular cholesterol and virus binding to host cells. Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis.
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•IAV infection activates SREBP2 to upregulate HMGCR expression•Activation of the JAK2-STAT3 axis increases SREBP2 expression in IAV-infected cells•Inhibition of JAK2 and STAT3 suppresses IAV replication by blocking HMGCR expression•STAT3 activation promotes IAV replication in part by enhancing cholesterol biosynthesis
Genetics; Virology
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