Visually induced γ band rhythm in spatial summation beyond the receptive field in mouse primary visual cortex.

Recent studies in many kinds of mammals have established the existence of multiple γ rhythms in the cerebral cortex subserving different functions. In the primary visual cortex (V1), visually induced γ rhythms are dependent on stimulus features. However, experimental findings of γ power induced by varying the size of the drifting grating are inconsistent. Here, we reinvestigated the spatial summation properties of visually induced spike and γ rhythm activities in mouse V1. Our results show that drifting sinusoidal grating stimuli mainly induce 2 γ band rhythms, including a low-frequency band (25-45 Hz) and a high-frequency band (55-75 Hz). Unlike previous findings, we discovered that visually induced γ power could also exhibit extrareceptive field (ERF) modulatory properties. The modulation by ERF stimulation could be either suppressive, countersuppressive, or nonsuppressive, mostly similar to the local spike activity. Moreover, further analysis of the neuron group exhibiting surround suppression in both spike and γ activity revealed that the strength of the surround suppression and the receptive field size showed moderate correlations between measurements by spike and γ rhythm activity. Our findings improve the understanding of the characteristics and neural mechanisms of induced γ rhythms in visual spatial summation.

Novel application potential of cinaciguat in the treatment of mixed hyperlipidemia through targeting PTL/NPC1L1 and alleviating intestinal microbiota dysbiosis and metabolic disorders.

Mixed hyperlipidemia, characterized by high levels of triglycerides and cholesterol, is a key risk factor leading to atherosclerosis and other cardiovascular diseases. Existing clinical drugs usually only work on a single indicator, decreasing either triglyceride or cholesterol levels. Developing dual-acting agents that reduce both triglycerides and cholesterol remains a great challenge. Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as crucial proteins in the transport of triglycerides and cholesterol. Here, cinaciguat, a known agent used in the treatment of acute decompensated heart failure, was identified as a potent dual inhibitor targeting PTL and NPC1L1. We presented in vitro evidence from surface plasmon resonance analysis that cinaciguat interacted with PTL and NPC1L1. Furthermore, cinaciguat exhibited potent PTL-inhibition activity. Fluorescence-labeled cholesterol uptake analysis and confocal imaging showed that cinaciguat effectively inhibited cholesterol uptake. In vivo evaluation showed that cinaciguat significantly reduced the plasma levels of triglycerides and cholesterol, and effectively alleviated high-fat diet-induced intestinal microbiota dysbiosis and metabolic disorders. These results collectively suggest that cinaciguat has the potential to be further developed for the therapy of mixed hyperlipidemia.

Hsa_circ_0006732 regulates colorectal cancer cell proliferation, invasion and EMT by miR-127-5p/RAB3D axis.

Colorectal cancer (CRC) remains a malignancy tumor with high metastasis and poor prognosis. We aimed to explore the effect of circular RNA (circRNA) hsa_circ_0006732 in the progression of CRC. Hsa_circ_0006732 expression in CRC tissues and cell lines were detected using qRT-PCR. The relationship between hsa_circ_0006732 expression and clinicopathologic characteristics of patients with CRC was analyzed. Loss-of-function assay was conducted to determine the regulatory effect of hsa_circ_0006732 on CRC cell proliferation, migration and invasion by using the CCK-8, wound-healing assay and transwell assays. Protein expression changes on epithelial mesenchymal transition (EMT)-related factors were detected by western blotting. The downstream signaling pathway was investigated by bioinformatics, dual-luciferase reporter assay. Rescue assay was further examined for prediction validation. It was found that hsa_circ_0006732 was highly expressed in CRC tissues and cell lines. Downregulation of hsa_circ_0006732 suppressed the proliferation, migration, invasion and EMT of CRC cells. Further mechanistic investigations proved that hsa_circ_0006732 functioned as a competitive endogenous RNA (ceRNA) by directly sponging of miR-127-3p, which further affected the expression of Ras-related protein Rab-3D (Rab3D). Taken together, these findings indicated that hsa_circ_0006732 might be an oncogene in CRC through the regulation of the miR-127-5p/RAB3D axis. Thus, hsa_circ_0006732 might serve as a potential therapeutic target for the treatment of CRC.

miR-199a-3p suppresses progression of esophageal squamous cell carcinoma through inhibiting mTOR/p70S6K pathway.

Dysregulation of microRNA contributes to multiple tumorigenic processes. Although downregulation of miR-199a-3p has been shown in many cancers, its effects on esophageal squamous cell carcinoma (ESCC) and the regulatory mechanism are still obscure. Here, we aim to evaluate the biological function and underlying mechanisms of miR-199a-3p in ESCC as well as its value to clinical treatment of ESCC. We first analyzed expression of miR-199a-3p in esophageal cancer by bioinformatic analysis and found that there were different opinions about expression of miR-199a-3p in esophageal cancer, and the following qRT-PCR assay demonstrated which was markedly downregulated in ESCC cells. Next, we increased the expression of miR-199a-3p in ESCC cells using miR-199a-3p mimics and demonstrated that overexpression of miR-199a-3p significantly inhibited cell proliferation, migration and invasion, as well as induced cell cycle retard and promoted apoptosis in ESCC. Furthermore, we explored the functional targets of miR-199a-3p and identified that overexpression of miR-199a-3p inhibited mTOR/p70S6K pathway, but stimulated PI3K/Akt pathway. Finally, we demonstrated that overexpression of miR-199a-3p enhanced proliferation-inhibiting effects of MK2206, an inhibitor of Akt, to ESCC cells, which might be related that MK2206 eliminated the activation of miR-199a-3p to p-Akt. These findings discover that miR-199a-3p might participate in the carcinogenesis process of ESCC, which provides a new insight for treatment of ESCC.

Changes in arthropod community but not plant quality benefit a specialist herbivore on plants under reduced water availability.

Plants growing under reduced water availability can affect insect herbivores differently, in some instances benefitting them. However, the forces mediating these positive impacts remain mostly unclear. To identify how water availability impacts plant quality and multi-trophic interactions, we conducted manipulative field studies with two populations of the specialist herbivore Pieris rapae, and its host plant, Rorippa indica. We found that P. rapae larvae experienced higher survival on R. indica growing under low water availability compared with plants grown under high water availability. Higher survival of eggs and larvae was related to the reduced abundance of other herbivores and natural enemies. Water availability had differential impacts on other members of the herbivore community by altering plant quality. Low water availability decreased the quality of R. indica to most herbivores, as indicated by reduced abundance in the field and decreased relative growth rate in laboratory feeding assays. In contrast, P. rapae larval performance was not affected by sympatric R. indica grown under different water availability. These results indicate that local P. rapae populations possess physiological adaptations to overcome fluctuations in host quality. Our findings illustrate that reduced water availability is beneficial to a specialist herbivore but detrimental to most other herbivores. Our work highlights the complex effects of the arthropod communities associated with plants in determining the impacts of water availability on insect herbivores.

OP16 induces deadly autophagy and apoptosis of cells by inhibiting Akt in esophageal squamous cell carcinoma.

BACKGROUND: OP16, a derivative of the novel ent-kaurene diterpenoid compound separated from Rabdosia rubescens, has been confirmed for its efficacy and safety in the treatment of esophageal squamous cell carcinoma (ESCC) in our previous study. However, the precise mechanisms of tumor lethality mediated by OP16 have not yet been fully characterized. AIMS: To investigate the effects and molecular mechanism of OP16 on autophagy and apoptosis of ESCC cells. METHODS: Effects and mechanism of OP16 on autophagy of ESCC cells were first detected by Western blot, immunofluorescence, mRFP-GFP-LC3 adenovirus infection and transmission electron microscope. Next, function of autophagy and apoptosis induced by OP16 on cell death was investigated by flow cytometry and CCK-8 assay. Finally, molecular mechanism of OP16 affecting autophagy and apoptosis of ESCC cells was explored by Western blot. RESULTS: We demonstrated that OP16 could induce autophagy by promoting the formation of autophagosome and autolysosome, and promote autophagic cell death in ESCC. Furthermore, we also found that OP16 could promote cell apoptosis by activating mitochondria apoptosis pathway in ESCC. Finally, we demonstrated that OP16 affecting autophagy and mitochondria apoptosis pathway was mediated by phosphorylation of Akt. CONCLUSION: Our data show that OP16 could promote cell death through affecting autophagy and mitochondria apoptosis pathway mediated by Akt in ESCC, which enriches the theoretical mechanism of anti-tumor effects of OP16 and provides a basis for treatment of OP16 on ESCC.

Inhibition of autophagy improves resistance and enhances sensitivity of gastric cancer cells to cisplatin.

Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the sensitivity and resistance of gastric cancer cells to cisplatin (DDP). We firstly demonstrated that there was stronger autophagy activity in gastric cancer SGC-7901 cells than that in DDP-resisting SGC-7901/DDP cells. Then, we discovered that inhibiting autophagy by chloroquine (CQ) significantly enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP to SGC-7901 and SGC-7901/DDP cells. Moreover, CQ could partially reverse the resistance of SGC-7901/DDP cells to DDP in a concentration-dependent manner. However, the autophagy inducer everolimus (RAD001) had no obvious effects on the sensitivity of gastric cells to DDP. Mechanistically, we demonstrated that CQ might enhance the sensitivity of SGC-7901cells and improve the resistance of SGC-7901/DDP cells to DDP through inhibiting the mTORC1 pathway, especially to SGC-7901/DDP cells. Additionally, we found interfering Beclin-1 using Beclin-1 shRNA also enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP on gastric cancer cells by inhibiting phosphorylation of Akt. Our study shows that inhibiting autophagy could improve the chemoresistance and enhanced sensitivity of gastric cancer cells to DDP and provide a rationale for the administration of cisplatin combined with CQ for treating patients with gastric cancer.

Hyaluronic acid-based prodrug nanomedicines for enhanced tumor targeting and therapy: A review.

Hyaluronic acid (HA) represents a natural polysaccharide which has attracted significant attention owing to its improved tumor targeting capacity, enzyme degradation capacity, and excellent biocompatibility. Its receptors, such as CD44, are overexpressed in diverse cancer cells and are closely related with tumor progress and metastasis. Accordingly, numerous researchers have designed various kinds of HA-based drug delivery platforms for CD44-mediated tumor targeting. Specifically, the HA-based nanoprodrugs possess distinct advantages such as good bioavailability, long circulation time, and controlled drug release and retention ability and have been extensively studied during the past years. In this review, the potential strategies and applications of HA-modified nanoprodrugs for drug molecule delivery in anti-tumor therapy are summarized.

NRG1 promotes tumorigenesis and metastasis and afatinib treatment efficiency is enhanced by NRG1 inhibition in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC and its contribution to aggressiveness remain unknown. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC as well as the treatment strategy for ESCC with overexpression of NRG1. We firstly demonstrated the upregulation of NRG1 and a negative correlation trend between patients' overall survival (OS) and the expression level of NRG1 in esophageal cancer. And then we found NRG1 promoted cell proliferation, migration, inhibited apoptosis, and accelerated tumorigenesis and metastasis in ESCC using cell lines and xenograft models. Furthermore, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway, contributing to the metastatic phenotype in ESCC. Finally, we show that afatinib (FDA approved cancer growth blocker) could inhibit ESCC with overexpressed NRG1 and down-regulation of NRG1 along with afatinib treatment provides higher efficient strategy. This study uncovers the critical role and molecular mechanism of NRG1 in ESCC tumorigenesis and metastasis, suggesting its potential as a novel biomarker for ESCC treatment.

Electronic structure and interaction in CH4@C60: a first-principle investigation.

CH4@C60 was the first example within which an organic molecule has been embedded in C60. CH4 can rotate freely in the molecular cage, and the carbon skeleton structure of the C60 has no obvious deformation. The electronic structure of CH4@C60 and interaction between C60 and CH4 were studied under quantum mechanical calculation method. The different reaction sites on C-C bonds in C60 and the weak Van der Waals interaction between CH4 and C60 were shown clearly. These results and the orbital interaction between CH4 and C60 were helpful for understanding and further application of this unique biggest organic molecule CH4 contained in C60 structure so far.

ARHGAP9 inhibits colorectal cancer cell proliferation, invasion and EMT via targeting PI3K/AKT/mTOR signaling pathway.

AIM: In digestive system, colorectal cancer (CRC) is a common malignant tumor. The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in CRC, and the aberrant activation of this pathway is associated with tumorigenesis. We aimed to explore the role of Rho GTPase activating protein 9 (ARHGAP9) in the progression of CRC as well as its regulatory effects on the PI3K/AKT/mTOR pathway. METHODS: The expression of ARHGAP9 in CRC tumor tissues and cell lines were detected using reverse transcription-quantitative PCR (qRT-PCR). 5-ethynyl-2'-deoxyuridine (EdU) assay was applied to test the cell proliferation. Cell migration and invasion were both assessed through transwell assay. Xenograft mouse models were constructed to explore the effects of ARHGAP9 on CRC in vivo. The expressions of PI3K/AKT/mTOR-activating factors and epithelial-mesenchymal transition (EMT)-related factors were all determined using western blot. LY294002 was employed to block PI3K/AKT/mTOR pathway in CRC cells. RESULTS: The expression of ARHGAP9 was down-regulated in CRC tumor tissues and cell lines when compared to normal tissues and cells. The over-expression of ARHGAP9 inhibited cell proliferation, invasion, migration and EMT in CRC cell lines while the knockdown of ARHGAP9 promoted them. In addition, ARHGAP9 up-regulation inhibited the activation of PI3K/AKT/mTOR signaling pathway in CRC cell lines while ARHGAP9 down-regulation led to an opposite effect. The over-expression of ARHGAP9 suppressed CRC tumor growth in vivo. When the PI3K/AKT/mTOR pathway was blocked in CRC cells, the effects of ARHGAP9 knockdown on cell proliferation, migration, invasion and EMT were all overturned. CONCLUSION: ARHGAP9 inhibited the malignant phenotypes of CRC cells via interdicting PI3K/AKT/mTOR signaling pathway.

Inhibiting autophagy enhances sulforaphane-induced apoptosis via targeting NRF2 in esophageal squamous cell carcinoma.

Sulforaphane (SFN), a natural anti-tumor compound from cruciferous vegetables, has been reported to induce protective autophagy to cancer cells, which might impair the anti-tumor efficiency of SFN. However, the accurate function and mechanism of SFN inducing autophagy in cancers are still obscure, especially in esophageal squamous cell carcinoma (ESCC), one of malignancies with high incidence in North China. Here, we mainly explored the potential function of autophagy upon SFN treatment in ESCC and molecular mechanism. We demonstrated that SFN could inhibit cell proliferation and induce apoptosis by activating caspase pathway. Moreover, we found activation of NRF2 pathway by SFN was responsible for the induction of autophagy and also a disadvantage element to the anti-tumor effects of SFN on ESCC, indicating that SFN might induce protective autophagy in ESCC. We, therefore, investigated effects of autophagy inhibition on sensitivity of ESCC cells to SFN and found that chloroquine (CQ) could neutralize the activation of SFN on NRF2 and enhance the activation of SFN on caspase pathway, thus improved the anti-tumor efficiency of SFN on ESCC in vitro and in vivo. Our study provides a preclinical rationale for development of SFN and its analogs to the future treatment of ESCC.

miR-219 inhibits the proliferation, migration and invasion of medulloblastoma cells by targeting CD164.

It is known that microRNA-219 (miR-219) expression is downregulated in medulloblastoma. In the present study, we investigated the expression, targets and functional effects of miR-219 in D283-MED medulloblastoma cells. We first demonstrated that miR-219 not only inhibits proliferation, but also suppresses the invasion and migration of D283-MED cells. Moreover, the knockdown of miR-219 promoted the proliferation, migration and invasion of the D283-MED cells. Secondly, we predicted that miR-219 targets the 3' untranslated region (3'UTR) of CD164 and orthodenticle homeobox 2 (OTX2) and then confirmed that it significantly downregulated the protein expression of CD164 and OTX2 in D283-MED cells. Finally, we demonstrated that the proliferation, invasion and migration of D283-MED cells were promoted by theectopic expression of CD164. These results indicate that miR-219 suppresses the proliferation, migration and invasion of medulloblastoma cells by targeting CD164. The results also suggest that miR-219 may serve as a potential therapeutic agent for medulloblastoma.