ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains ...elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of patients with lung cancer. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-to-mesenchymal transition regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt coreceptor LRP5/6. Activation of these signaling axes decreased GSK3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. In addition, we generated a chimeric anti-ENO1 mAb (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and support the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer. SIGNIFICANCE: This study shows that ENO1 promotes lung cancer metastasis via HGFR and WNT signaling and introduces a novel anti-ENO1 antibody for potential therapeutic use in lung cancer.
Development of specific antiviral agents is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infection. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike ...protein, critical for its fusion after binding to angiotensin-converting enzyme 2 (ACE2), as antiviral targets. We first validate cleavage at a putative furin substrate motif at SARS-CoV-2 spikes by expressing it in VeroE6 cells and find prominent syncytium formation. Cleavage and the syncytium are abolished by treatment with the furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein, but not by the transmembrane protease serine 2 (TMPRSS2) inhibitor camostat. CMK and naphthofluorescein show antiviral effects on SARS-CoV-2-infected cells by decreasing virus production and cytopathic effects. Further analysis reveals that, similar to camostat, CMK blocks virus entry, but it further suppresses cleavage of spikes and the syncytium. Naphthofluorescein acts primarily by suppressing viral RNA transcription. Therefore, furin inhibitors may be promising antiviral agents for prevention and treatment of SARS-CoV-2 infection.
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•The furin cleavage site in the SARS-CoV-2 spike protein mediates syncytium formation•The SARS-CoV-2 spike-mediated syncytium is suppressed by specific furin inhibitors•Furin inhibitors block SARS-CoV-2 virus entry and virus replication•Furin inhibitors are potential antiviral agents for SARS-CoV-2 infection and pathogenesis
Development of effective antiviral agents is an urgent unmet need for SARS-CoV-2 infection. Cheng et al. find that cleavage of the furin substrate site in the viral spike protein is critical for virus production and cytopathic effects. Two inhibitors targeting furin are potential antiviral agents to control SARS-CoV-2 infection and pathogenesis.
In this paper, we propose a novel joint data-hiding and compression scheme for digital images using side match vector quantization (SMVQ) and image inpainting. The two functions of data hiding and ...image compression can be integrated into one single module seamlessly. On the sender side, except for the blocks in the leftmost and topmost of the image, each of the other residual blocks in raster-scanning order can be embedded with secret data and compressed simultaneously by SMVQ or image inpainting adaptively according to the current embedding bit. Vector quantization is also utilized for some complex blocks to control the visual distortion and error diffusion caused by the progressive compression. After segmenting the image compressed codes into a series of sections by the indicator bits, the receiver can achieve the extraction of secret bits and image decompression successfully according to the index values in the segmented sections. Experimental results demonstrate the effectiveness of the proposed scheme.
An approach for enzyme therapeutics is elaborated with cell‐implanted nanoreactors that are based on multiple enzymes encapsulated in hollow silica nanospheres (HSNs). The synthesis of HSNs is ...carried out by silica sol–gel templating of water‐in‐oil microemulsions so that polyethyleneimine (PEI) modified enzymes in aqueous phase are encapsulated inside the HSNs. PEI‐grafted superoxide dismutase (PEI‐SOD) and catalase (PEI‐CAT) encapsulated in HSNs are prepared with quantitative control of the enzyme loadings. Excellent activities of superoxide dismutation by PEI‐SOD@HSN are found and transformation of H2O2 to water by PEI‐CAT@HSN. When PEI‐SOD and PEI‐CAT are co‐encapsulated, cascade transformation of superoxide through hydrogen peroxide to water was facile. Substantial fractions of HSNs exhibit endosome escape to cytosol after their delivery to cells. The production of downstream reactive oxygen species (ROS) and COX‐2/p‐p38 expression show that co‐encapsulated SOD/CAT inside the HSNs renders the highest cell protection against the toxicant N,N′‐dimethyl‐4,4′‐bipyridinium dichloride (paraquat). The rapid cell uptake and strong detoxification effect on superoxide radicals by the SOD/CAT‐encapsulated hollow mesoporous silica nanoparticles demonstrate the general concept of implanting catalytic nanoreactors in biological cells with designed functions.
Superoxide dismutase and catalase encapsulated in hollow silica nanospheres as a nanoreactor results in cascade reactions converting superoxide ions into water and oxygen. Upon uptake in Hela cells, the nanoreactor protects the cell against reactive oxygen species.
A sudden outbreak of COVID-19 caused by a novel coronavirus, SARS-CoV-2, in Wuhan, China in December 2019 quickly grew into a global pandemic, putting at risk not only the global healthcare system, ...but also the world economy. As the disease continues to spread rapidly, the development of prophylactic and therapeutic approaches is urgently required. Although some progress has been made in understanding the viral structure and invasion mechanism of coronaviruses that may cause severe cases of the syndrome, due to the limited understanding of the immune effects caused by SARS-CoV-2, it is difficult for us to prevent patients from developing acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF), the major complications of coronavirus infection. Therefore, any potential treatments should focus not only on direct killing of coronaviruses and prevention strategies by vaccine development, but also on keeping in check the acute immune/inflammatory responses, resulting in ARDS and PF. In addition, potential treatments currently under clinical trials focusing on killing coronaviruses or on developing vaccines preventing coronavirus infection largely ignore the host immune response. However, taking care of SARS-CoV-2 infected patients with ARDS and PF is considered to be the major difficulty. Therefore, further understanding of the host immune response to SARS-CoV-2 is extremely important for clinical resolution and saving medication cost. In addition to a breif overview of the structure, infection mechanism, and possible therapeutic approaches, we summarized and compared the hematopathologic effect and immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2. We also discussed the indirect immune response caused by SARS and direct infection, replication, and destroying of immune cells by MERS-CoV. The molecular mechanisms of SARS-CoV and MERS-CoV infection-induced lymphopenia or cytokine storm may provide some hint toward fight against SARS-CoV-2, the novel coronavirus. This may provide guidance over using immune therapy as a combined treatment to prevent patients developing severe respiratory syndrome and largely reduce complications.
The convenient cross‐coupling of sp2 or sp3 carbons with a specific boron vertex on carborane cage represents significant synthetic values and insurmountable challenges. In this work, we report an ...Rh‐catalyzed reaction between o‐carborane and N‐acyl‐glutarimides to construct various Bcage−C bonds. Under the optimized condition, the removable imine directing group (DG) leads to B(3)− or B(3,6)−C couplings, while the pyridyl DG leads to B(3,5)−Ar coupling. In particular, an unexpected rearrangement of amide reagent is observed in pyridyl directed B(4)−C(sp3) formation. This scalable protocol has many advantages, including easy access, the use of cheap and widely available coupling agents, no requirement of an external ligand, base or oxidant, high efficiency, and a broad substrate scope. Leveraging the RhI dimer and twisted amides, this method enables straightforward access to diversely substituted and therapeutically important carborane derivatives at boron site, and provides a highly valuable vista for carborane‐based drug screening.
Rh catalysis was used to enable cross‐coupling between o‐carborane and twisted amide. A series of regioselective B(3,6)−C, B(3,5)−Ar and B(4)−C(sp3) coupling products have been obtained. The operationally simple reaction gives rise to diverse carboranyl‐fused organic motifs and accommodates late‐stage diversification, which may pave a new way for medicinal investigations.
Dendritic spines, the tiny and actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain that control synaptic activity and ...plasticity. Dendritic spines contain a specialized form of endoplasmic reticulum (ER), i.e., the spine apparatus, required for local calcium signaling and that is involved in regulating dendritic spine enlargement and synaptic plasticity. Many autism-linked genes have been shown to play critical roles in synaptic formation and plasticity. Among them, KLHL17 is known to control dendritic spine enlargement during development. As a brain-specific disease-associated gene,
KLHL17
is expected to play a critical role in the brain, but it has not yet been well characterized. In this study, we report that KLHL17 expression in mice is strongly regulated by neuronal activity and KLHL17 modulates the synaptic distribution of synaptopodin (SYNPO), a marker of the spine apparatus. Both KLHL17 and SYNPO are F-actin-binding proteins linked to autism. SYNPO is known to maintain the structure of the spine apparatus in mature spines and contributes to synaptic plasticity. Our super-resolution imaging using expansion microscopy demonstrates that SYNPO is indeed embedded into the ER network of dendritic spines and that KLHL17 is closely adjacent to the ER/SYNPO complex. Using mouse genetic models, we further show that
Klhl17
haploinsufficiency and knockout result in fewer dendritic spines containing ER clusters and an alteration of calcium events at dendritic spines. Accordingly, activity-dependent dendritic spine enlargement and neuronal activation (reflected by extracellular signal-regulated kinase (ERK) phosphorylation and C-FOS expression) are impaired. In addition, we show that the effect of disrupting the KLHL17 and SYNPO association is similar to the results of
Klhl17
haploinsufficiency and knockout, further strengthening the evidence that KLHL17 and SYNPO act together to regulate synaptic plasticity. In conclusion, our findings unravel a role for KLHL17 in controlling synaptic plasticity via its regulation of SYNPO and synaptic ER clustering and imply that impaired synaptic plasticity contributes to the etiology of KLHL17-related disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Measurement of real-ear-to-coupler differentials (RECDs) is a critical part of the hearing aid (HA) verification process. This study examines the validity of reference RECD values preset by the HA ...analyzer, Audioscan RM500, for deaf-and-hard-of-hearing (DHH) children in Taiwan. RECD measurements were performed on 658 ears of DHH children. A linear mixed model was used to analyze the reference and measured RECD values. The findings revealed slight disparities between normative RECD values from North America and those observed in Taiwanese DHH children. While generally small (less than 5 dB), these differences imply potential challenges in achieving optimal HA fitting in specific scenarios. Therefore, we recommend individualized RECD/REM measurements for cases of poor auditory performance, certain frequency ranges, or notable variations in ear canal volume. From a clinical perspective, while broadly applicable, the use of North American RECD normative data in Taiwan requires cautious consideration of potential minor variations. This study contributes to current knowledge by affirming the use of a Western RECD database for Taiwanese DHH children. However, we underscore the ongoing importance of individualized HA fitting strategies, particularly for cases with stagnant intervention progress. While built-in RECD reference values can offer preliminary fitting guidance, especially in busy clinical settings, our study sheds light on the circumstances where caution is essential. Audiologists can efficiently allocate their time and effort by focusing on personalized RECD measurements for cases exhibiting suboptimal intervention outcomes, thereby effectively optimizing HA gain settings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal ...degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic
mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.
A major challenge to end the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to develop a broadly protective vaccine that elicits long-term immunity. As the key ...immunogen, the viral surface spike (S) protein is frequently mutated, and conserved epitopes are shielded by glycans. Here, we revealed that S protein glycosylation has site-differential effects on viral infectivity. We found that S protein generated by lung epithelial cells has glycoforms associated with increased infectivity. Compared to the fully glycosylated S protein, immunization of S protein with N-glycans trimmed to the mono-GlcNAc-decorated state (S
) elicited stronger immune responses and better protection for human angiotensin-converting enzyme 2 (hACE2) transgenic mice against variants of concern (VOCs). In addition, a broadly neutralizing monoclonal antibody was identified from S
-immunized mice that could neutralize wild-type SARS-CoV-2 and VOCs with subpicomolar potency. Together, these results demonstrate that removal of glycan shields to better expose the conserved sequences has the potential to be an effective and simple approach for developing a broadly protective SARS-CoV-2 vaccine.
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