Cross-Talk between the TGF-ß and Cell Adhesion Signaling Pathways in Cancer.

Transforming growth factor-ß (TGF-ß) is strongly associated with the cell adhesion signaling pathway in cell differentiation, migration, etc. Mechanistically, TGF-ß is secreted in an inactive form and localizes to the extracellular matrix (ECM) via the latent TGF-ß binding protein (LTBP). However, it is the release of mature TGF-ß that is essential for the activation of the TGF-ß signaling pathway. This progress requires specific integrins (one of the main groups of cell adhesion molecules (CAMs)) to recognize and activate the dormant TGF-ß. In addition, TGF-ß regulates cell adhesion ability through modulating CAMs expression. The aberrant activation of the TGF-ß signaling pathway, caused by abnormal expression of key regulatory molecules (such as Smad proteins, certain transcription factors, and non-coding RNAs), promotes tumor invasive and metastasis ability via epithelial-mesenchymal transition (EMT) during the late stages of tumorigenesis. In this paper, we summarize the crosstalk between TGF-ß and cell adhesion signaling pathway in cancer and its underlying molecular mechanisms.

Natural Product Quercetin-3-methyl ether Promotes Colorectal Cancer Cell Apoptosis by Downregulating Intracellular Polyamine Signaling.

Dysregulation of cellular metabolism is a key marker of cancer, and it is suggested that metabolism should be considered as a targeted weakness of colorectal cancer. Increased polyamine metabolism is a common metabolic change in tumors. Thus, targeting polyamine metabolism for anticancer therapy, particularly polyamine blockade therapy, has gradually become a hot topic. Quercetin-3-methyl ether is a natural compound existed in various plants with diverse biological activities like antioxidant and antiaging. Here, we reported that Quercetin-3-methyl ether inhibits colorectal cancer cell viability, and promotes apoptosis in a dose-dependent and time-dependent manner. Intriguingly, the polyamine levels, including spermidine and spermine, in colorectal cancer cells were reduced upon treatment of Quercetin-3-methyl ether. This is likely resulted from the downregulation of SMOX, a key enzyme in polyamine metabolism that catalyzes the oxidation of spermine to spermidine. These findings suggest Quercetin-3-methyl ether decreases cellular polyamine level by suppressing SMOX expression, thereby inducing colorectal cancer cell apoptosis. Our results also reveal a correlation between the anti-tumor activity of Quercetin-3-methyl ether and the polyamine metabolism modulation, which may provide new insights into a better understanding of the pharmacological activity of Quercetin-3-methyl ether and how it reprograms cellular polyamine metabolism.

Micromechanism for Copper-Deficiency Enhanced Stability: A Quasi In Situ TEM Study of Electric-Induced Structural Evolution in Cu2-x(S, Se) Liquid-Like Thermoelectric Materials.

Cu-based liquid-like thermoelectric materials have garnered tremendous attention due to their inherent ultralow lattice thermal conductivity. However, their practical application is hampered by stability issues under a large current or temperature gradient. It has been reported that introduction of copper vacancies can enhance the chemical stability, whereas the micromechanism behind this macroscopic improvement still remains unknown. Here, we have established a quasi in situ TEM method to examine and compare the structural evolution of Cu2-xS0.2Se0.8 (x = 0, 0.05) under external electric fields. It is then found that the preset Cu vacancies could favor the electric-induced formation of a more stable intermediate phase, i.e., the hexagonal CuSe-type structure in the form of either lamellar defects (majorly) or long-range order (minorly), in which ordering of S and Se also occurred. Thereby, copper and chalcogen atoms could largely be solidified into the matrix, and the elemental deposition and evaporation process is mitigated under an electric field.

The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs.

ABBREVIATIONS: AMBRA1 autophagy and beclin 1 regulator 1; ATG14 autophagy related 14; ATG5 autophagy related 5; ATG7 autophagy related 7; BECN1 beclin 1; BECN2 beclin 2; CC coiled-coil; CQ chloroquine CNR1/CB1R cannabinoid receptor 1 DAPI 4',6-diamidino-2-phenylindole; dCCD delete CCD; DRD2/D2R dopamine receptor D2 GPRASP1/GASP1 G protein-coupled receptor associated sorting protein 1 GPCR G-protein coupled receptor; ITC isothermal titration calorimetry; IP immunoprecipitation; KD knockdown; KO knockout; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; NRBF2 nuclear receptor binding factor 2; OPRD1/DOR opioid receptor delta 1 PIK3C3/VPS34 phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15 phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K class III phosphatidylinositol 3-kinase; PtdIns3P phosphatidylinositol-3-phosphate; RUBCN rubicon autophagy regulator; SQSTM1/p62 sequestosome 1; UVRAG UV radiation resistance associated; VPS vacuolar protein sorting; WT wild type.

The upregulation of peripheral blood polyamine metabolites spermidine and spermine in children with hand, foot, mouth disease is related to enterovirus 71 capsid protein VP1, but not VP4.

Background: Hand, foot, and mouth disease (HFMD) is a common viral childhood illness caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16. The pathogenesis of EV71 has been extensively studied, and the regulation of the host immune response is suspected to aggravate the serious complications induced by EV71. Our previous research showed that EV71 infection significantly increased the release of circulating interleukin (IL)-6, IL-10, IL-13, and IL-27. Notably, these cytokines are related to the EV71 infection risk and clinical stage. Polyamines are compounds that are ubiquitous in mammalian cells and play a key role in various cellular processes. Several studies have shown that targeting polyamine metabolic pathways can reduce infections caused by viruses. However, the significance of polyamine metabolism in EV71 infection remains largely unknown. Methods: Serum samples from 82 children with HFMD and 70 healthy volunteers (HVs) were collected to determine the polyamine metabolites spermidine (SPD) and spermine (SPM), and IL-6 levels. In addition, peripheral blood mononuclear cells (PBMCs) were treated with EV71 viral protein 1 (VP1) and EV71 VP4, and the cells and supernatant were then collected to analyze the expression of polyamine metabolism-related enzymes by western blot. The data were analyzed using GraphPad Prism 7.0 software (USA). Results: The serum polyamine metabolites SPD and SPM were elevated in the HFMD patients, especially in the EV71-infected children. Further, a positive correlation was found between serum SPD and IL-6 levels in the EV71-infected children. We also found that the upregulation of peripheral blood polyamine metabolites in the EV71-infected HFMD children was related to EV71 capsid protein VP1, but not VP4. VP1 may promote the expression of polyamine metabolism-related enzymes and promote the production of polyamine metabolites, thereby upregulating the SPD/nuclear factor kappa B/IL-6 signaling pathway. However, VP4 has the opposite effect in this process. Conclusions: Our results suggest that EV71 capsid protein may regulate the polyamine metabolic pathways of infected cells in a variety of ways. This study provides insights into the mechanism of EV71 infection and polyamine metabolism and has good reference value for the development of EV71 vaccine.

Incommensurately Modulated Structure in AgCuSe-Based Thermoelectric Materials for Intriguing Electrical, Thermal, and Mechanical Properties.

AgCuSe-based materials have attracted great attentions recently in thermoelectric (TE) field due to their extremely high electron mobility, ultralow lattice thermal conductivity, and abnormal "brittle-ductile" transition at room temperature. However, although the investigation on the crystal structure of AgCuSe low-temperature phase (named as ß-AgCuSe) was started more than half a century before, it is still in controversy yet, which greatly limits the understanding of its intriguing electrical, thermal, and mechanical performance. In this work, via adopting the advanced three-dimensional electron diffraction technique, this study finds that the AgCuSe-based materials crystalize in an incommensurately modulated structure with an orthorhombic Pmmn(0ß1/2)s00 superspace group. The local lattice distortion in the incommensurately modulated structure has weak effects on the conduction band minimum due to the delocalized and isotropic feature of Ag 5s states, leading to high carrier mobility. Likewise, the inhomogeneous, weak, and anisotropic Ag-Se bonds result in the high degree of anharmonicity and ultralow lattice thermal conductivity. Furthermore, alloying S in AgCuSe reinforces the interaction between the adjacent Ag-Se layers, yielding the "brittle-ductile" transition at room temperature. This work well interprets the structure-performance relationship of AgCuSe-based materials and sheds light on the future investigation of this class of promising TE materials.

Vimentin as a potential target for diverse nervous system diseases.

Vimentin is a major type III intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout (GFAP-/-VIM-/-) mice. However, attenuated glial scar formation in post-stroke in GFAP-/- VIM-/- mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIM-/- mice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination.

The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment.

The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.

Phase Transition Behaviors and Thermoelectric Properties of CuAgTe1-xSex near 400 K.

Phase transition is an effective strategy to engineer thermal conductivity and electrical transports. Recently, p-type CuAgTe1-xSex materials were reported to show excellent thermoelectric performance at 300-450 K, but the data are controversial due to the cooccurrence of phase transition in this temperature range. Accurately measuring and analyzing the electrical and thermal transport properties in the narrow phase transition temperature range is a quite challenging task. In this work, we systemically investigate the phase transition behavior, and electrical and thermal transport properties of p-type CuAgTe1-xSex (x = 0.3, 0.4, and 0.5) near 400 K. CuAgTe1-xSex (x = 0.3, 0.4, and 0.5) materials show similar phase transition temperatures but quite different phase transition speeds. The phase transition has a weak influence on the electrical transport properties of CuAgTe0.7Se0.3 and CuAgTe0.6Se0.4, but a strong influence on those of CuAgTe0.5Se0.5. Likewise, an obvious underestimation of thermal diffusivity, with a maximum deviation about 20% off the real value, is observed during the phase transition temperature range for CuAgTe1-xSex. Finally, CuAgTe0.7Se0.3 shows a peak zT around 0.9 at 390 K. The present study proves that CuAgTe1-xSex solid solutions are one kind of promising near-room-temperature thermoelectric material.

Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells.

Beclin 1 is an essential autophagy gene and a haploinsufficient tumor suppressor. Beclin 1 is the scaffolding member of the Class III phosphatidylinositol-3-kinase complex (PI3KC3) and recruits two positive regulators Atg14L and UVRAG through its coiled-coil domain to upregulate PI3KC3 activity. Our previous work has shown that hydrocarbon-stapled peptides targeted to the Beclin 1 coiled-coil domain reduced Beclin 1 homodimerization and promoted the Beclin 1-Atg14L/UVRAG interaction. These peptides also induced autophagy and enhanced the endolysosomal degradation of cell surface receptors like EGFR. Here, we present the optimization of these Beclin 1-targeting peptides by staple scanning and sequence permutation. Placing the hydrocarbon staple closer to the Beclin 1-peptide interface enhanced their binding affinity by ∼10- to 30-fold. Optimized peptides showed potent antiproliferative efficacy in cancer cells that overexpressed EGFR and HER2 by inducing necrotic cell death but not apoptosis. Our Beclin 1-targeting stapled peptides may serve as effective therapeutic candidates for EGFR- or HER2-driven cancer.

Beta-1 syntrophin (SNTB1) regulates colorectal cancer progression and stemness via regulation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Beta-1 syntrophin (SNTB1) is an intracellular scaffold protein that provides a platform for the formation of signal transduction complexes, thereby modulating and coordinating various intracellular signaling events and crucial cellular processes. However, the physiological role of SNTB1 is poorly understood. This study aims to explore the role of SNTB1 in colorectal cancer (CRC) tumorigenesis and progression, with particular focus on SNTB1's expression pattern, clinical relevance, and possible molecular mechanism in CRC development. METHODS: SNTB1 expression was analyzed in both clinical tissues and The Cancer Genome Atlas (TCGA) database. Real-time polymerase chain reaction (PCR), Western blot, and immunohistochemical assays were used to detect the relative mRNA and protein levels of SNTB1. Statistical analysis was performed to examine the correlation between SNTB1 expression and the clinicopathological characteristics of patients with CRC. Bioinformatics gene set enrichment analysis (GSEA), Western blot, luciferase assay, and agonist recovery assays were conducted to evaluate the relevance of SNTB1 and the ß-catenin signaling pathway in CRC. A flow cytometry-based Hoechst 33342 efflux assay was applied to assess the proportion of the side population (SP) within total CRC cells. RESULTS: Elevated levels of SNTB1 were identified in CRC tissues and cell lines. The elevation of SNTB1 was positively correlated with the degree of malignancy and poor prognosis in CRC. We further revealed that, by modulating the ß-catenin signaling pathway, silencing SNTB1 expression suppressed tumor growth and cancer stemness in vitro, as well as tumorigenesis in vivo. CONCLUSIONS: These findings suggest that SNTB1 plays a crucial role in colorectal tumorigenesis and progression by modulating ß-catenin signaling and the stemness maintenance of cancer cells.

An autophagy-related protein Becn2 regulates cocaine reward behaviors in the dopaminergic system.

Drug abuse is a foremost public health problem. Cocaine is a widely abused drug worldwide that produces various reward-related behaviors. The mechanisms that underlie cocaine-induced disorders are unresolved, and effective treatments are lacking. Here, we found that an autophagy-related protein Becn2 is a previously unidentified regulator of cocaine reward behaviors. Becn2 deletion protects mice from cocaine-stimulated locomotion and reward behaviors, as well as cocaine-induced dopamine accumulation and signaling, by increasing presynaptic dopamine receptor 2 (D2R) autoreceptors in dopamine neurons. Becn2 regulates D2R endolysosomal trafficking, degradation, and cocaine-induced behaviors via interacting with a D2R-bound adaptor GASP1. Inactivating Becn2 by upstream autophagy inhibitors stabilizes striatal presynaptic D2R, reduces dopamine release and signaling, and prevents cocaine reward in normal mice. Thus, the autophagy protein Becn2 is essential for cocaine psychomotor stimulation and reward through regulating dopamine neurotransmission, and targeting Becn2 by autophagy inhibitors is a potential strategy to prevent cocaine-induced behaviors.

ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway.

Anaplastic lymphoma kinase (ALK) has been described in a range of human cancers and is involved in cancer initiation and progression via activating multiple signaling pathways, such as the PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5, JAK-STAT and MAPK signal pathways. Recently ALK and LTK ligand 1 (ALKAL1) also named "augmentor-ß" or "FAM150A" is identified as a potent activating ligands for human ALK that bind to the extracellular domain of ALK. However, due to its poor stability, the mechanisms of ALKAL1 underlying the tumor progression in the human cancers including colorectal cancer have not been well documented. Herein, ALKAL1 expression was evaluated by RNA sequencing datasets from The Cancer Genome Atlas (TCGA) of 625 cases colorectal cancer, immunohistochemical analysis of 377 cases colorectal cancer tissues, and Western blotting even Real-time PCR of 10 pairs of colorectal cancer tissues and adjacent normal tissues, as well as 8 colorectal cancer cell lines. Statistical analysis was performed to explore the correlation between ALKAL1 expression and clinicopathological features in colorectal cancer. Univariate and multivariate Cox regression analysis were performed to examine the association between ALKAL1 expression and overall survival. In vitro and in vivo assays were performed to assess the biological roles of ALKAL1 in colorectal cancer. Gene set enrichment analysis (GSEA), Western blotting and luciferase assays were used to identify the underlying signal pathway involved in the tumor progression role of ALKAL1. As a result, we showed that ALKAL1 was upregulated in colorectal cancer tissues and cell lines. Upregulation of ALKAL1 correlated with tumor malignancy and poor prognosis in colorectal cancer. ALKAL1 silencing inhibited tumorigenesis, metastasis and invasion of colorectal cancer cells, and inhibited SHH signaling pathway, which is essential for ALKAL1 induced migration. Our findings reveal a new mechanism by which ALKAL1 participates in colorectal cancer migration and invasion via activating the SHH signaling pathway.

Ectodysplasin A receptor (EDAR) promotes colorectal cancer cell proliferation via regulation of the Wnt/ß-catenin signaling pathway.

Colorectal cancer is the second leading cause of cancer mortality worldwide with poor prognosis and high recurrence. Aberrant Wnt/ß-catenin signaling promotes oncogenesis by transcriptional activation of c-Myc and its downstream signals. EDAR is characterized as an important effector of canonical Wnt signaling in developing skin appendages, but the interplay between EDAR and Wnt signaling in tumorigenesis and progression remains to be elucidated. In this study, we revealed that EDAR expression is prevalently elevated in colorectal cancer tissues compared with normal tissues. Further analysis suggests there is a strict correlation between EDAR expression and colorectal cancer progression. EDAR silencing by shRNA in colorectal cancer cells showed proliferative suppression via retarding cell cycle at G1 phase. Xenograft mice transplanted with shEDAR-transduced tumor cells significantly alleviated tumor burden in comparison with control mice. Furthermore, downregulation of EDAR was accompanied by reduction of ß-catenin, c-Myc and other G1 cell cycle regulators, while ß-catenin agonist restored the expression of these proteins and overrode the proliferative block induced by EDAR knockdown. These findings indicate that EDAR functions as a component of Wnt/ß-catenin signaling pathway, and is a potential modulator in colorectal carcinogenesis.

Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking.

The Beclin 1-Vps34 complex, known as "mammalian class III PI3K," plays essential roles in membrane-mediated transport processes including autophagy and endosomal trafficking. Beclin 1 acts as a scaffolding molecule for the complex and readily transits from its metastable homodimeric state to interact with key modulators such as Atg14L or UVRAG and form functionally distinct Atg14L/UVRAG-containing Beclin 1-Vps34 subcomplexes. The Beclin 1-Atg14L/UVRAG interaction relies critically on their coiled-coil domains, but the molecular mechanism remains poorly understood. We determined the crystal structure of Beclin 1-UVRAG coiled-coil complex and identified a strengthened interface with both hydrophobic pairings and electrostatically complementary interactions. This structure explains why the Beclin 1-UVRAG interaction is more potent than the metastable Beclin 1 homodimer. Potent Beclin 1-UVRAG interaction is functionally significant because it renders UVRAG more competitive than Atg14L in Beclin 1 binding and is critical for promoting endolysosomal trafficking. UVRAG coiled-coil mutants with weakened Beclin 1 binding do not outcompete Atg14L and fail to promote endolysosomal degradation of the EGF receptor (EGFR). We designed all-hydrocarbon stapled peptides that specifically targeted the C-terminal part of the Beclin 1 coiled-coil domain to interfere with its homodimerization. One such peptide reduced Beclin 1 self-association, promoted Beclin 1-Atg14L/UVRAG interaction, increased autophagic flux, and enhanced EGFR degradation. Our results demonstrate that the targeting Beclin 1 coiled-coil domain with designed peptides to induce the redistribution of Beclin 1 among its self-associated form or Atg14L/UVRAG-containing complexes enhances both autophagy and endolysosomal trafficking.

Thermodynamic selectivity of functional agents on zeolite for sodium dodecyl sulfate sequestration.

This study proposes a thermodynamic approach to effectively select functional agents onto zeolite for sodium dodecyl sulfate (SDS) sequestration in greywater reuse. We combine isothermal titration calorimetry (ITC) and quantum chemistry simulation (QCS) to identify the interactions between SDS and agents at the molecular level. Three potential agents, cetyl trimethyl ammonium bromide (CTAB), N,N,N-trimethyltetradecan-1-aminium bromide (C14TAB), and 14-hydroxy-N,N,N-trimethyltetradecan-1-aminium bromide (C14HTAB), differ in carbon chain length and hydrophilic groups. The ITC titration of SDS with CTAB released the highest heat, followed by those with C14TAB and C14HTAB, as was the same trend for the amounts of SDS adsorbed by the respective functionalized-zeolites. Results suggest that the favorable SDS sorption occurred at the bilayer CTAB-zeolite is driven by enthalpy as similar as the SDS…CTAB interaction found, regardless of the contribution from electrostatic and/or hydrophobic behaviors, while the declined sorption is entropy-driven via the predominant hydrophobic interaction onto the monolayer CTAB-zeolite. The data presented here interpret the nature of molecularly thermodynamic quantities and enable the manipulation of sorption capacity optimization.

Heat-shock protein 90 promotes nuclear transport of herpes simplex virus 1 capsid protein by interacting with acetylated tubulin.

Although it is known that inhibitors of heat shock protein 90 (Hsp90) can inhibit herpes simplex virus type 1 (HSV-1) infection, the role of Hsp90 in HSV-1 entry and the antiviral mechanisms of Hsp90 inhibitors remain unclear. In this study, we found that Hsp90 inhibitors have potent antiviral activity against standard or drug-resistant HSV-1 strains and viral gene and protein synthesis are inhibited in an early phase. More detailed studies demonstrated that Hsp90 is upregulated by virus entry and it interacts with virus. Hsp90 knockdown by siRNA or treatment with Hsp90 inhibitors significantly inhibited the nuclear transport of viral capsid protein (ICP5) at the early stage of HSV-1 infection. In contrast, overexpression of Hsp90 restored the nuclear transport that was prevented by the Hsp90 inhibitors, suggesting that Hsp90 is required for nuclear transport of viral capsid protein. Furthermore, HSV-1 infection enhanced acetylation of α-tubulin and Hsp90 interacted with the acetylated α-tubulin, which is suppressed by Hsp90 inhibition. These results demonstrate that Hsp90, by interacting with acetylated α-tubulin, plays a crucial role in viral capsid protein nuclear transport and may provide novel insight into the role of Hsp90 in HSV-1 infection and offer a promising strategy to overcome drug-resistance.

Self-organizing maps for the classification of gallic acylate polyphenols as HSV-1 inhibitors.

Herpes simplex virus type 1 (HSV-1), a member of the Herpesviridae family, is a ubiquitous, contagious, hostadapted pathogen that causes a wide variety of disease states, such as herpes labialis ("cold sores") and encephalitis. Recently, due to the appearance of acyclovir-resistant HSV-1 mutants, a rapidly growing area of research has been the identification of novel small molecules (whether found in traditional medicine or not) with antiviral activity. One group of these novel pre-drugs is gallic acylate polyphenols. Here, detailed insight into the influence of the chemical structure on anti- HSV-1 activity of gallic acylate polyphenols has been provided based on an exploration of structure-function relationships through self-organizing maps and counterpropagation neural networks. A number of descriptors were investigated to construct optimized models. The resulting model exhibits a correct prediction rate of 90.67%, with active molecule classification accuracy higher than 95.00%, demonstrating that the electrostatic effect and distance between atoms are related to HSV-1 inhibition for these gallic acylate polyphenols. The results provide insights into the influence of the chemical structure on anti-HSV-1 activity of gallic acylate polyphenols.

Cofilin 1-mediated biphasic F-actin dynamics of neuronal cells affect herpes simplex virus 1 infection and replication.

Herpes simplex virus 1 (HSV-1) invades the nervous system and causes pathological changes. In this study, we defined the remodeling of F-actin and its possible mechanisms during HSV-1 infection of neuronal cells. HSV-1 infection enhanced the formation of F-actin-based structures in the early stage of infection, which was followed by a continuous decrease in F-actin during the later stages of infection. The disruption of F-actin dynamics by chemical inhibitors significantly reduced the efficiency of viral infection and intracellular HSV-1 replication. The active form of the actin-depolymerizing factor cofilin 1 was found to increase at an early stage of infection and then to continuously decrease in a manner that corresponded to the remodeling pattern of F-actin, suggesting that cofilin 1 may be involved in the biphasic F-actin dynamics induced by HSV-1 infection. Knockdown of cofilin 1 impaired HSV-1-induced F-actin assembly during early infection and inhibited viral entry; however, overexpression of cofilin 1 did not affect F-actin assembly or viral entry during early infection but decreased intracellular viral reproduction efficiently. Our results, for the first time, demonstrated the biphasic F-actin dynamics in HSV-1 neuronal infection and confirmed the association of F-actin with the changes in the expression and activity of cofilin 1. These results may provide insight into the mechanism by which HSV-1 productively infects neuronal cells and causes pathogenesis.