Mitofilin in cardiovascular diseases: Insights into the pathogenesis and potential pharmacological interventions.

The impact of mitochondrial dysfunction on the pathogenesis of cardiovascular disease is increasing. However, the precise underlying mechanism remains unclear. Mitochondria produce cellular energy through oxidative phosphorylation while regulating calcium homeostasis, cellular respiration, and the production of biosynthetic chemicals. Nevertheless, problems related to cardiac energy metabolism, defective mitochondrial proteins, mitophagy, and structural changes in mitochondrial membranes can cause cardiovascular diseases via mitochondrial dysfunction. Mitofilin is a critical inner mitochondrial membrane protein that maintains cristae structure and facilitates protein transport while linking the inner mitochondrial membrane, outer mitochondrial membrane, and mitochondrial DNA transcription. Researchers believe that mitofilin may be a therapeutic target for treating cardiovascular diseases, particularly cardiac mitochondrial dysfunctions. In this review, we highlight current findings regarding the role of mitofilin in the pathogenesis of cardiovascular diseases and potential therapeutic compounds targeting mitofilin.

Identification and validation of SLCO4C1 as a biological marker in hepatocellular carcinoma based on anoikis classification features.

BACKGROUND: Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a strong correlation between anoikis resistance and tumor progression, invasion, and metastasis. Nevertheless, the classification of anoikis in HCC and the investigation of novel biological target mechanisms in this context continue to pose challenges, requiring further exploration. METHODS: Combined with HCC samples from TCGA, GEO and ICGC databases, cluster analysis was conducted on anoikis genes, revealing novel patterns among different subtypes. Significant gene analysis of different gene subtypes was performed using WCGNA. The anoikis prognostic risk model was established by Lasso-Cox. Go, KEGG, and GSEA were applied to investigate pathway enrichment primarily observed in risk groups. We compared the disparities in immune infiltration, TMB, tumor microenvironment (TME), and drug sensitivity between the two risk groups. RT-qPCR and Western blotting were performed to validate the expression levels of SLCO4C1 in HCC. The biological functions of SLCO4C1 in HCC cells were assessed through various experiments, including CCK8 assay, colony formation assay, invasion migration assay, wound healing assay, and flow cytometry analysis. RESULTS: HCC was divided into 2 anoikis subtypes, and the subtypeB had a better prognosis. An anoikis prognostic model based on 12 (COPZ2, ACTG2, IFI27, SPP1, EPO, SLCO4C1, RAB26, STC2, RAC3, NQO1, MYCN, HSPA1B) risk genes is important for survival and prognosis. Significant differences were observed in immune cell infiltration, TME, and drug sensitivity analysis between the risk groups. SLCO4C1 was downregulated in HCC. SLCO4C1 downregulation promoted the proliferation, invasion, migration, and apoptosis of HCC cells. The tumor-suppressive role of SLCO4C1 in HCC has been confirmed. CONCLUSIONS: Our study presents a novel anoikis classification method for HCC that reveals the association between anoikis features and HCC. The anoikis feature is a critical biomarker bridging tumor cell death and tumor immunity. In this study, we provided the first evidence of SLCO4C1 functioning as a tumor suppressor in HCC.

Disulfidptosis classification of hepatocellular carcinoma reveals correlation with clinical prognosis and immune profile.

A new mode of cell death, disulfidptosis, has been discovered. Clinical prognostic significance of disulfidptosis related pattern in hepatocellular carcinoma(HCC). In this study, a risk score model was established based on disulfidptosis model to analyze the role of risk score in clinical prognosis, immune cell infiltration, drug sensitivity and immunotherapy response. Disulfidptosis subtype were constructed based on the transcriptional profiles of 15 disulfidptosis-related genes(DRGs). All 601 samples were defined as high risk group(HRG) and low risk group(LRG) based on the disulfidptosis risk score. Drug sensitivity and response to immunotherapy were calculated by immunophenotypic score(IPS), tumor prediction, tumor immune dysfunction and rejection(TIDE). RT-qPCR was used to determine the mRNA level of disulfidptosis prognostic gene. Risk groups was identified as potential predictors of immune cell infiltration, drug sensitivity, and immunotherapy responsiveness. HRG may benefit from immunotherapy. Classification is very effective in predicting the prognosis and therapeutic effect of patients, and provides a reference for accurate individualized treatment. This study suggests that new biomarkers related to Disulfidptosis can be used in clinical diagnosis of liver cancer to predict prognosis and treatment targets.

A simplified viral RNA extraction method based on magnetic nanoparticles for fast and high-throughput detection of SARS-CoV-2.

The ongoing outbreak of the novel coronavirus disease 2019 (COVID-19) draws worldwide concerns due to its long incubation period and strong infectivity. Although RT-PCR-based methods are being widely applied for clinical diagnosis, timely and accurate diagnosis towards COVID-19 causing virus, the SARS-CoV-2, is still limited due to labor-intensive and time-consuming operations. Herein, we report a new viral RNA extraction method based on poly-(amino ester) with carboxyl group (PC)-coated magnetic nanoparticles (pcMNPs) for the sensitive detection of SARS-CoV-2. This method combines the lysis and binding steps into one step, and refines multiple washing steps into one step, giving a turnaround time of less than 9 min. Furthermore, the extracted pcMNP-RNA complexes can be directly introduced into subsequent RT-PCR reactions without elution. This simplified viral RNA method could be well adapted in fast manual and automated high-throughput nucleic acids extraction protocols suitable for different scenarios. A high sensitivity down to 100 copies/mL and a linear correlation between 100 and 106 copies/mL of SARS-CoV-2 pseudovirus particles are achieved in both protocols. Benefitting from the simplicity and excellent performances, this new method can dramatically improve the efficiency and reduce operational requirements for the early clinical diagnosis and large-scale SARS-CoV-2 nucleic acid screening.

Kaempferol modulates IFN-γ induced JAK-STAT signaling pathway and ameliorates imiquimod-induced psoriasis-like skin lesions.

Immune-mediated inflammation contributes to the development of psoriasis. However, long-term treatment with global immunosuppressive agents may cause a variety of side effects including recurrent infections. Kaempferol (KP), a natural flavonol, present in various plants is proposed to be useful for the treatment of psoriasis patients. Nevertheless, an explicit understanding of KP induced mechanisms is a prerequisite for its use in clinics. Therefore, we investigated the therapeutic effects and potential mode of action of KP using IFN-γ induced HaCaT cells and imiquimod-induced psoriasis-like skin lesions in mice. In this study, we found KP reduced intracellular ROS production, inhibited rhIFN-γ-induced IFN-γR1 expression, and up-regulated SOCS1 levels in HaCaT cells. In addition, KP inhibited rhIFN-γ-induced phosphorylation of JAK-STAT signaling molecules in HaCaT cells. Most importantly, KP alleviated imiquimod-induced psoriasis-like skin lesions in mice, histopathology and proportion of DCs in the skin. Besides, it reduced the population of γδT17 cells in the lymph nodes of the psoriatic mice and also decreased the gene expression of many proinflammatory cytokines, including interleukin IL-23, IL-17A, TNF-α, IL-6, and IL-1ß in addition to down-regulation of the proinflammatory JAK-STAT signaling pathway. Thus, KP modulated IFN-γ induced JAK-STAT signaling pathway by inducing IFN-γR1 expression and up-regulating SOCS1 expression. In addition, KP also ameliorated imiquimod-induced psoriasis by reducing the dendritic cell numbers, and γδT17 cell population, along with down- modulation of the JAK-STAT pathway.

Stochastic simulation of seawater intrusion in the Longkou area of China based on the Monte Carlo method.

Seawater intrusion is a common groundwater pollution problem, which has a great impact on ecological environment and economic development. In this paper, a numerical simulation model of variable density groundwater was constructed to simulate and predict the future seawater intrusion in Longkou city, Shandong Province of China. The influence of the sensitive parameter uncertainty of the model on the simulation results was evaluated by using the Monte Carlo method. In order to reduce the computational load from repeatedly calling the simulation model, the surrogate model was established by using the support vector regression (SVR) method. After training, the correlation coefficient R2 of the input-output relationship between the SVR surrogate model and the seawater intrusion simulation model reached 0.9957, with an average relative error of 0.2%, indicating that the surrogate model has a high fitting accuracy. Stochastic simulations of seawater intrusion showed that the seawater intrusion in the Longkou area will gradually aggravate at a slow rate, and the increase of seawater intrusion in the study area after 30 years was expected to range from - 6.03% to 7.37% at the 80% confidence level.

Two-photon endomicroscopy with microsphere-spliced double-cladding antiresonant fiber for resolution enhancement.

We demonstrate a miniature fiber-optic two two-photon endomicroscopy with microsphere-spliced double-cladding antiresonant fiber for resolution enhancement. An easy-to-operate process for fixing microsphere permanently in an antiresonant fiber core, by arc discharge, is proposed. The flexible fiber-optic probe is integrated with a parameter of 5.8 mm × 49.1 mm (outer diameter × rigid length); the field of view is 210 µm, the resolution is 1.3 µm, and the frame rate is 0.7 fps. The imaging ability is verified using ex-vivo mouse kidney, heart, stomach, tail tendon, and in-vivo brain neural imaging.

A water-soluble membrane for SARS-CoV-2 viral nucleic acid sampling and detection.

This communication describes a novel water-soluble membrane prepared from chitosan intended for SARS-CoV-2 viral nucleic acid collection and detection. The CSH membrane formed from nanofibers shows promising potential in the quantitative determination of the SARS-CoV-2 viral nucleic acids at a concentration of 102 copies per L in air. The sponge-like structure which allows gas to pass through for collection of viral nucleic acids potentially provides simple, fast, and reliable sampling as well as detection of various types of airborne viruses.

Carrier-Free Cellular Transport of CRISPR/Cas9 Ribonucleoprotein for Genome Editing by Cold Atmospheric Plasma.

A carrier-free CRISPR/Cas9 ribonucleoprotein delivery strategy for genome editing mediated by a cold atmospheric plasma (CAP) is described. The CAP is promising in many biomedical applications due to efficient production of bioactive ionized species. The MCF-7 cancer cells after CAP exposure exhibit increased extracellular reactive oxygen and nitrogen species (RONS) and altered membrane potential and permeability. Hence, transmembrane transport of Ca2+ into the cells increases and accelerates ATP hydrolysis, resulting in enhanced ATP-dependent endocytosis. Afterwards, the increased Ca2+ and ATP contents promote the release of cargo into cytoplasm due to the enhanced endosomal escape. The increased membrane permeability also facilitates passive diffusion of foreign species across the membrane into the cytosol. After CAP exposure, the MCF-7 cells incubated with Cas9 ribonucleoprotein (Cas9-sgRNA complex, Cas9sg) with a size of about 15 nm show 88.9% uptake efficiency and 65.9% nuclear import efficiency via passive diffusion and ATP-dependent endocytosis pathways. The efficient transportation of active Cas9sg after the CAP treatment leads to 21.7% and 30.2% indel efficiencies in HEK293T and MCF-7 cells, respectively. This CAP-mediated transportation process provides a simple and robust alternative for the delivery of active CRISPR/Cas9 ribonucleoprotein. Additionally, the technique can be extended to other macro-biomolecules and nanomaterials to cater to different biomedical applications.

Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.

From Octahedron Crystals to 2D Silicon Nanosheets: Facet-Selective Cleavage and Biophotonic Applications.

2D silicon nanosheets (SiNSs) are promising materials for biomedicine but facile synthesis of SiNSs remains a challenge. Herein, by means of a sulfur-iodine co-assisted chemical vapor transport method, octahedron silicon (oct-Si) crystals with fully exposed {111} planes are prepared as precursors for efficient synthesis of SiNSs by facet-selective exfoliation. The 13 nm thick SiNSs have good biocompatibility and the sharp Raman scattering signal facilitates intracellular Raman imaging upon exposure to a near-infrared (NIR) laser. Furthermore, the SiNSs have excellent NIR photothermal characteristics such as a large extinction coefficient of 11.3 L g-1 cm-1 and high photothermal conversion efficiency of 21.4% at 1064 nm. In vitro experiments demonstrate superior NIR-II photothermal therapeutic effects in killing cancer cells. Comparing to conventional methods, the novel facet-selective cleavage strategy is more controllable and environmentally friendly boding well for the fabrication of non-van der Waals 2D materials. The multimodal photonic behavior also suggests large potential of the SiNSs pertaining to integrated multi-NIR biophotonic techniques using single nanomaterials.

Sensitive and selective ctDNA detection based on functionalized black phosphorus nanosheets.

Circulating tumor DNA (ctDNA) identification is one of the most meaningful approaches towards early cancer diagnosis. However, effective and practical methods for analyzing this emerging class of biomarkers are still lacking. In this work, a biosensor based on nitrophenyl functionalized black phosphorus nanosheets (NP-BPs) is fabricated for sensitive and selective detection of ctDNA. In this work, a nitrophenyl functionalized black phosphorus nanosheets (NP-BPs) biosensor is fabricated for sensitive and selective detection of ctDNA. Due to the successful nitrophenyl functionalization, the NP-BPs biosensor shows higher quenching efficiency and stronger affinity towards single-stranded DNA (ssDNA), as compared with double-stranded DNA (dsDNA). Therefore, the NP-BPs biosensor exhibits 5.4-fold fluorescence enhancement when dye-labelled ssDNA probe forms dsDNA in the presence of its specific ctDNA target. This biosensor exhibits a detection limit of 50 fM and a wide linear detection range of 50 fM-80 pM, provides reliable readout in a short time (15 min). Moreover, the NP-BPs-based biosensor could be applied to discriminate single nucleotide polymorphisms in clinical serum samples. It is envisioned that the NP-BPs-based sensing platform has great potentials in early cancer diagnosis and monitoring cancer progression.

Bioactive phospho-therapy with black phosphorus for in vivo tumor suppression.

Background and Purpose: Although inorganic nanomaterials have been widely used in multimodal cancer therapies, the intrinsic contributions of the materials are not well understood and sometimes underestimated. In this work, bioactive phospho-therapy with black phosphorus nanosheets (BPs) for in vivo tumor suppression is studied. Methods: Orthotopic liver tumor and acute myeloid leukemia are chosen as the models for the solid tumor and hematological tumor, respectively. BPs are injected into mice through the tail vein and tumor growth is monitored by IVIS bioluminescence imaging. Tumor tissues and serum samples are collected to determine the suppression effect and biosafety of BPs after treatment. Results: The in vitro studies show that BPs with high intracellular uptake produce apoptosis- and autophagy-mediated programmed cell death of human liver carcinoma cells but do not affect normal cells. BPs passively accumulate in the tumor site at a high concentration and inhibit tumor growth. The tumor weight is much less than that observed from the doxorubicin (DOX)-treated group. The average survival time is extended by at least two months and the survival rate is 100% after 120 days. Western bolt analysis confirms that BPs suppress carcinoma growth via the apoptosis and autophagy pathways. In addition, administration of BPs into mice suffering from leukemia results in tumor suppression and long survival. Conclusions: This study reveals that BPs constitute a type of bioactive anti-cancer agents and provides insights into the application of inorganic nanomaterials to cancer therapy.

InSe Nanosheets for Efficient NIR-II-Responsive Drug Release.

Near-infrared-II (NIR-II) biowindow is appealing from the perspectives of larger maximum permissible exposure in comparison with the near-infrared-I biowindow, so the NIR-II-responsive drug-delivery nanoplatform is highly desirable. In this work, two-dimensional InSe nanosheets (InSe NSs) are modified with poly(ethylene glycol) and evaluated as an effective NIR-II-responsive cancer treatment nanoplatform. The InSe NSs synthesized by liquid exfoliation exhibit prominent NIR-II-responsive photothermal conversion efficiency (39.5%) and photothermal stability. Moreover, the InSe NSs have a doxorubicin (DOX) loading capacity as high as 93.6%, along with excellent NIR-II-responsive DOX release characteristic. The superior synergistic chemo/photothermal effects have also been demonstrated by the in vitro experiments in killing cancer cells. In combination with good biocompatibility, the InSe NSs have great potential in therapeutic applications.

Black Phosphorus: Bioactive Nanomaterials with Inherent and Selective Chemotherapeutic Effects.

Black phosphorus nanosheets (BPs) are demonstrated to be highly bioactive anti-cancer agents because of their inherent and selective chemotherapeutic effects. Fast intracellular biodegradation of BPs and acute elevation of phosphate anions were observed from different types of cancer cells due to the stronger intracellular oxidative stress and accelerated energy metabolism, but normal cells are not affected. Selective biodegradation of BPs induced G2/M phase arrest and subsequent apoptosis- and autophagy-mediated cell death in cancer cells but not normal cells. The selectivity was superior to that of the traditional chemotherapeutic agent, doxorubicin (DOX). In vivo assessment confirmed the efficiency of BPs in suppressing tumor growth. This study provides insights into nanostructured bioactive anti-cancer agents and reveals a new direction for nanomedicine research.

Enhanced Cytosolic Delivery and Release of CRISPR/Cas9 by Black Phosphorus Nanosheets for Genome Editing.

A biodegradable two-dimensional (2D) delivery platform based on loading black phosphorus nanosheets (BPs) with Cas9 ribonucleoprotein engineered with three nuclear localization signals (NLSs) at C terminus (Cas9N3) is successfully established. The Cas9N3-BPs enter cells effectively via membrane penetration and endocytosis pathways, followed by a BPs biodegradation-associated endosomal escape and cytosolic releases of the loaded Cas9N3 complexes. The Cas9N3-BPs thus provide efficient genome editing and gene silencing in vitro and in vivo at a relatively low dose as compared with other nanoparticle-based delivery platforms. This biodegradable 2D delivery platform offers a versatile cytosolic delivery approach for CRISPR/Cas9 ribonucleoprotein and other bioactive macromolecules for biomedical applications.

Synthesis of lipid-black phosphorus quantum dot bilayer vesicles for near-infrared-controlled drug release.

Black phosphorus quantum dots are incorporated into liposomal bilayers to produce a drug delivery system with excellent near-infrared (NIR) photothermal properties and drug release capability controlled by light. In vitro experiments demonstrate its good biocompatibility and NIR-light-induced chemo-photothermal antitumor efficiency.

Fluorine-free preparation of titanium carbide MXene quantum dots with high near-infrared photothermal performances for cancer therapy.

Titanium carbide MXene quantum dots (QDs) were synthesized using an effective fluorine-free method as a biocompatible and highly efficient nanoagent for photothermal therapy (PTT) applications. In contrast to the traditional, hazardous and time-consuming process of HF pretreatment, our fluorine-free method is safe and simple. More importantly, abundant Al oxoanions were found to be modified on the MXene QD surface by the fluorine-free method, which endowed the QDs with strong and broad absorption in the NIR region. As a result, the as-prepared MXene QDs exhibited an extinction coefficient as large as 52.8 Lg-1 cm-1 at 808 nm and a photothermal conversion efficiency as high as 52.2%. Both the values are among the best reported so far. The as-prepared MXene QDs achieved simultaneous photoacoustic (PA) imaging and the remarkable PTT effect of tumors. Moreover, MXene QDs showed great biocompatibility without causing noticeable toxicity in vitro and in vivo, indicating their high potential for clinical applications.

Gold Nanoclusters-Indocyanine Green Nanoprobes for Synchronous Cancer Imaging, Treatment, and Real-Time Monitoring Based on Fluorescence Resonance Energy Transfer.

Well-designed gold nanoclusters-indocyanine green nanoprobes (Au NCs-INPs) have been developed by the conjugation of Au NC assemblies with indocyanine green (ICG) for the therapeutic real-time monitoring based on fluorescence resonance energy transfer (FRET). The synthesized Au NCs-INPs demonstrated the improved cellular uptake and effective tumor targeting because of the enhanced permeability and retention effect and the gp60-mediated secreted protein acidic and rich in cysteine combined transport pathway, suggesting excellent dual-modal near-infrared fluorescence and photoacoustic imaging. Moreover, the simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) of Au NCs-INPs exhibited higher cancer cell killing and tumor removal efficiency than those of PDT or PTT alone. More importantly, a promising therapeutic monitoring strategy was performed based on FRET between Au NCs and ICG, suggesting that Au NCs-INPs could be utilized to evaluate the therapeutic response by real-time monitoring the change in Au NCs in fluorescence intensity together with ICG supersession. Therefore, Au NCs-INPs as a novel photosensitizer have great potentials for combined tumor imaging, therapy, and therapeutic monitoring in real time.

TiL4 -Coordinated Black Phosphorus Quantum Dots as an Efficient Contrast Agent for In Vivo Photoacoustic Imaging of Cancer.

Black phosphorus quantum dots coordinated with a sulfonic ester of the titanium ligand are prepared and exhibit enhanced stability. In vitro and in vivo photoacoustic imaging applications demonstrate that the quantum dots can efficiently accumulate inside the tumor producing tumor profiles with high spatial resolution, demonstrating their potential as an efficient agent for photoacoustic imaging.