Liver cancer is one of the leading causes of cancer mortality worldwide. Inspired by the biological structure and function of low-density lipoprotein (LDL), in this study, an ApopB-100 based targeted ...lipid nanoparticles was synthesized to improve the therapeutic efficacy in liver cancer treatment.
The biological composition of ApopB is similar to LDL which can effectively increase the targeting efficiency of nanoparticles in LDL receptor (LDLR)-overexpressed liver tumors.
We have demonstrated that the co-administration of sorafenib (SRF) and Dihydroartemisinin (DHA) could exhibit synergistic anticancer effect in HepG2 liver cancer cells. DHA produced excessive cellular reactive oxygen species (ROS) and induced greater apoptosis of cancer cells. LDL-based SRF/DHA-loaded lipid nanoparticles (LD-SDN) showed remarkable decrease in the cell viability compared to that of either of single drug treated cancer cells. Combination of SRF+DHA resulted in predominant SubG1 proportion of cells. LD-SDN exhibited the highest SubG1 (%) of cells compared to that of any of the individual drugs. Most importantly, robust antitumor response and delayed tumor growth was observed for LD-SDN treated xenograft tumor model. Ki67 proliferation index of LD-SDN (22.1 ± 5.6%) is significantly lesser compared to that of either control (86.2 ± 6.9%) or SRF (75.4 ± 4.89%) or DHA (69.4 ± 6.9%).
These data provide strong evidence that LDL-mimetic lipid nanoformulations could be utilized as a biocompatible and tumor targeted platform for the delivery of multiple anticancer drugs in cancer treatment.
Long-term visualization of the dynamic interactions between intracellular structures throughout the three-dimensional space of whole live cells is essential to better understand their functions, but ...this task remains challenging due to the limitations of existing three-dimensional fluorescence microscopy techniques, such as an insufficient axial resolution, low volumetric imaging rate and photobleaching. Here, we present the combination of a progressive deep-learning super-resolution strategy with a double-ring-modulated selective plane illumination microscopy design capable of visualizing the dynamics of intracellular structures in live cells for hours at an isotropic spatial resolution of roughly 100 nm in three dimensions at speeds up to roughly 17 Hz. Using this approach, we reveal the complex spatial relationships and interactions between endoplasmic reticulum (ER) and mitochondria throughout live cells, providing new insights into ER-mediated mitochondrial division. We also examined the motion of Drp1 oligomers involved in mitochondrial fission and revealed the dynamic interactions between Drp1 and mitochondria in three dimensions.
Despite the prevalence of superresolution (SR) microscopy, quantitative live-cell SR imaging that maintains the completeness of delicate structures and the linearity of fluorescence signals remains ...an uncharted territory. Structured illumination microscopy (SIM) is the ideal tool for live-cell SR imaging. However, it suffers from an out-of-focus background that leads to reconstruction artifacts. Previous post hoc background suppression methods are prone to human bias, fail at densely labeled structures, and are nonlinear. Here, we propose a physical model-based Background Filtering method for living cell SR imaging combined with the 2D-SIM reconstruction procedure (BF-SIM). BF-SIM helps preserve intricate and weak structures down to sub-70 nm resolution while maintaining signal linearity, which allows for the discovery of dynamic actin structures that, to the best of our knowledge, have not been previously monitored.
Golgi-derived PI4P-containing vesicles play important roles in mitochondrial division, which is essential for maintaining cellular homeostasis. However, the mechanism of the PI4P-containing vesicle ...effect on mitochondrial division is unclear. Here, we found that actin appeared to polymerize at the contact site between PI4P-containing vesicles and mitochondria, causing mitochondrial division. Increasing the content of PI4P derived from the Golgi apparatus increased actin polymerization and reduced the length of the mitochondria, suggesting that actin polymerization through PI4P-containing vesicles is involved in PI4P vesicle-related mitochondrial division. Collectively, our results support a model in which PI4P-containing vesicles derived from the Golgi apparatus cooperate with actin filaments to participate in mitochondrial division by contributing to actin polymerization, which regulates mitochondrial dynamics. This study enriches the understanding of the pathways that regulate mitochondrial division and provides new insight into mitochondrial dynamics.
The development of super-resolution technology has made it possible to investigate the ultrastructure of intracellular organelles by fluorescence microscopy, which has greatly facilitated the ...development of life sciences and biomedicine. To realize super-resolution imaging of living cells, both advanced imaging systems and excellent fluorescent probes are required. Traditional fluorescent probes have good availability, but that is not the case for probes for live-cell super-resolution imaging. In this review, we first introduce the principles of various super-resolution technologies and their probe requirements, then summarize the existing designs and delivery strategies of super-resolution probes for live-cell imaging, and finally provide a brief conclusion and overview of the future.
Graphical Abstract
This article offers an in-depth analysis of the meaning and scope of biosafety and biosecurity in China, thereby relating domestic debates to global developments, exploring notions of safety and ...security in public policy more broadly and embedding a key policy initiative, Chinaʼs new Biosecurity Law, into attempts by Chinaʼs leadership to develop a holistic national security strategy. The article finds that biotic threats have more recently been reframed as matters of national security, in ways that undeniably go beyond conventional understandings of biosecurity and that blur the boundaries to more accident-focused biosafety measures. Given Chinaʼs political and economic importance this apparent trend to securitise biotic risks is likely to impact on global trade relations, international transport and passenger traffic, not the least in the context of the Belt and Road Initiative.
As the most important organ in our bodies, brain plays critical roles in deciding the sex-related differential features; however, the underlying neural circuitry basis remains unclear. Here, we used ...cell-type-specific rabies virus-mediated monosynaptic tracing systems to generate sex differences-related whole-brain input atlas of locus coeruleus noradrenaline (LC-NE) neurons. We developed custom pipelines for brain-wide comparisons of input sources in both sexes with the registration of the whole-brain data set to the Allen Mouse Brain Reference Atlas. Among 257 distinct anatomical regions, we demonstrated the differential proportions of inputs to LC-NE neurons in male and female mice at different levels. LC-NE neurons of two sexes showed general similarity in the input patterns, but with differentiated input proportions quantitatively from major brain regions and diverse sub-regions. For instance, inputs to male LC-NE neurons were dominated in cerebrum, interbrain and cerebellum, whereas inputs to female LC-NE neurons were dominated in midbrain and hindbrain. We further found that specific subsets of nuclei nested within sub-regions contributed to overall sex-related differences in input circuitry. Furthermore, among totaled 123 anatomical regions with proportion of inputs > 0.1%, we also identified 11 sub-regions with significant statistical differences of total inputs between male and female mice, and 7 of them also showed such differences in ipsilateral hemispheres. Our study not only provides a structural basis to facilitate our understanding of sex differences at circuitry level but also provides clues for future sexually differentiated functional studies related to LC-NE neurons.
Background:
Glioma is the most fatal neoplasm among the primary intracranial cancers. Necroptosis, a form of programmed cell death, is correlated with tumor progression and immune response. But, the ...role of necroptosis-related genes (NRGs) in glioma has not been well-uncovered.
Methods:
Single-cell and bulk RNA sequencing data, obtained from publicly accessed databases, were used to establish a necroptosis-related gene signature for predicting the prognosis of glioma patients. Multiple bioinformatics algorithms were conducted to evaluate the efficacy of the signature. The relative mRNA level of each signature gene was validated by quantitative real-time reverse transcription PCR (qRT-PCR) in glioma cell lines compared to human astrocytes.
Results:
In this predicted prognosis model, patients with a high risk score showed a shorter overall survival, which was verified in the testing cohorts. The signature risk score was positively related with immune cell infiltration and some immune check points, such as CD276 (B7-H3), CD152 (CTLA-4), CD223 (LAG-3), and CD274 (PD-L1). Single-cell RNA sequencing analysis confirmed that the glioma microenvironment consists of various immune cells with different markers. The eight NRGs of the signature were detected to be expressed in several immune cells. QRT-PCR results verified that all the eight signature genes were differentially expressed between human astrocytes and glioma cells.
Conclusion:
The eight NRGs correlate with the immune microenvironment of glioma according to our bioinformatics analysis. This necroptosis-related gene signature may evaluate the precise methodology of predicting prognosis of glioma and provide a novel thought in glioma investigation.
As surface flashover discharge limits the performance of hollow-cathode electron beam sources, this work systematically investigates the surface flashover discharge in the hollow-cathode discharge ...process based on electrostatic field simulations. Experimental research is conducted on designing and investigating hollow cathode discharge cavities featuring structures to prevent surface flashover, both single- and multi-gap. Theoretical analysis found that the vacuum surface flashover discharge will cause an abnormal breakdown phenomenon along the wall of the insulating sleeve. The surface flashover, once formed, would develop dramatically, thus suppressing the formation of hollow-cathode discharge and becoming the main form of discharge. To eliminate the abnormal flashover breakdown, an effective suppression structure is designed regarding the triple point of the surface flashover. Through the special design, the triple points in the corners are always hidden by recessing the corner of the insulator in a notch. Moreover, corrugated structures along the insulating surface are studied, and the proper rectangular slots are designed in the inner insulating surface. The experimental results also indicate that after adopting the insulation scheme, the breakdown voltage of the discharge cavity and its working stability are greatly improved.
Purpose
The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a ...inhibition is a promising biological strategy for breast cancer therapy.
Methods
In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system.
Results
The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation.
Conclusion
The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.
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