Expression of RNautophagy/DNautophagy-related genes is regulated under control of an innate immune receptor.

Double-stranded RNA (dsRNA) is a molecular pattern uniquely produced in cells infected with various viruses as a product or byproduct of replication. Cells detect such molecules, which indicate non-self invasion, and induce diverse immune responses to eliminate them. The degradation of virus-derived molecules can also play a role in the removal of pathogens and suppression of their replication. RNautophagy and DNautophagy are cellular degradative pathways in which RNA and DNA are directly imported into a hydrolytic organelle, the lysosome. Two lysosomal membrane proteins, SIDT2 and LAMP2C, mediate nucleic acid uptake via this pathway. Here, we showed that the expression of both SIDT2 and LAMP2C is selectively upregulated during the intracellular detection of poly(I:C), a synthetic analog of dsRNA that mimics viral infection. The upregulation of these two gene products upon poly(I:C) introduction was transient and synchronized. We also observed that the induction of SIDT2 and LAMP2C expression by poly(I:C) was dependent on MDA5, a cytoplasmic innate immune receptor that directly recognizes poly(I:C) and induces various antiviral responses. Finally, we showed that lysosomes can target viral RNA for degradation via RNautophagy and may suppress viral replication. Our results revealed a novel degradative pathway in cells as a downstream component of the innate immune response and provided evidence suggesting that the degradation of viral nucleic acids via RNautophagy/DNautophagy contributes to the suppression of viral replication.

A Simple and Convenient Method for Preparing Fluorine-Free Durable Superhydrophobic Coatings Suitable for Multiple Substrates.

Superhydrophobic coatings have attracted a lot of attention due to their excellent self-cleaning and anti-fouling capabilities. However, the preparation processes for several superhydrophobic coatings are intricate and expensive, which restricts their usefulness. In this work, we present a straightforward technique for creating durable superhydrophobic coatings that can be applied to a variety of substrates. The addition of C9 petroleum resin to a styrene-butadiene-styrene (SBS) solution lengthens the SBS backbone and undergoes a cross-linking reaction to form a dense spatial cross-linked structure, improving the storage stability, viscosity, and aging resistance of the SBS. The combined solution functions as a more stable and effective adhesive. Using a two-step spraying technique, the hydrophobic silica (SiO2) nanoparticles solution was applied to the surface to create durable nano-superhydrophobic coatings. Additionally, the coatings have excellent mechanical, chemical, and self-cleaning stability. Furthermore, the coatings have wide application prospects in the fields of water-oil separation and corrosion prevention.

MiR-4763-3p targeting RASD2as a Potential Biomarker and Therapeutic Target for Schizophrenia.

Existing diagnostic methods are limited to observing appearance and demeanor, even though genetic factors play important roles in the pathology of schizophrenia. Indeed, no molecular-level test exists to assist diagnosis, which has limited treatment strategies. To address this serious shortcoming, we used a bioinformatics approach to identify 61 genes that are differentially expressed in schizophrenia patients compared with healthy controls. In particular, competing endogenous RNA network revealed the important role of the gene RASD2, which is regulated by miR-4763-3p. Indeed, analysis of blood samples confirmed that RASD2 is downregulated in schizophrenia patients. Moreover, positron emission tomography data collected for 44 human samples identified the prefrontal and temporal lobes as potential key brain regions in schizophrenia patients. Mechanistic studies indicated that miR-4763-3p inhibits RASD2 by base-pairing with the 3' untranslated region of RASD2 mRNA. Importantly, RASD2 has been shown to interact with ß-arrestin2, which contributes to the regulation of the DRD2-dependent CREB response element-binding protein pathway in the dopamine system. Finally, results obtained with a mouse model of schizophrenia revealed that inhibition of miR-4763-3p function alleviated anxiety symptoms and improved memory. The dopamine transporters in the striatal regions were significantly reduced in schizophrenia model mice as compared with wild-type mice, suggesting that inhibition of miR-4763-3p can lessen the symptoms of schizophrenia. Our findings demonstrate that miR-4763-3p may target RASD2 mRNA and thus may serve as a potential biomarker and therapeutic target for schizophrenia, providing a theoretical foundation for further studies of the molecular basis of this disease.

The Synaptic Vesicle Protein 2A Interacts With Key Pathogenic Factors in Alzheimer's Disease: Implications for Treatment.

Alzheimer's disease (AD), a serious neurodegenerative disease, is pathologically characterized by synaptic loss and dysfunction. Synaptic vesicle protein 2A (SV2A) is an indispensable vesicular protein specifically expressed in synapses and can be used as a biomarker for synaptic density. We found that the expression of SV2A was down-regulated in the hippocampus of AD patients, yet the relation of SV2A to other hallmarks of AD pathology such as amyloid precursor protein (APP), ß-amyloid (Aß), and Tau protein is not thoroughly clear. In addition, SV2A colocalized with APP and was down-regulated at Aß deposition. Moreover, we found that SV2A deficiency leads to a simultaneous increase in Aß and Tau hyperphosphorylation, while SV2A overexpression was associated with downregulation of ß-site APP cleaving enzyme 1 and apolipoprotein E genes. In addition, evidence gained in the study points to the phosphatidylinositol 3-kinase signaling pathway as a possible mediator in SV2A regulation influencing the incidence and development of AD. With limited effective diagnostic methods for AD, a close interplay between SV2A and AD-related proteins demonstrated in our study may provide novel and innovative diagnostic and therapeutic opportunities.

Preparation of Colored Microcapsule Phase Change Materials with Colored SiO2 Shell for Thermal Energy Storage and Their Application in Latex Paint Coating.

This article reports the design and manufacture of colored microcapsules with specific functions and their application in architectural interior wall coating. Utilizing reactive dyes grafted SiO2 shell to encapsulate paraffin through interfacial polymerization and chemical grafting methods, this experiment successfully synthesized paraffin@SiO2 colored microcapsules. The observations of surface morphology demonstrated that the colored microcapsules had a regular spherical morphology and a well-defined core-shell structure. The analysis of XRD and FT-IR confirmed the presence of amorphous SiO2 shell and the grafting reactive dyes, and the paraffin possessed high crystallinity. Compared with pristine paraffin, the thermal conductivity of paraffin@SiO2 colored microcapsules was significantly enhanced. The results of DSC revealed that the paraffin@SiO2 colored microcapsules performed high encapsulation efficiency and desirable latent heat storage capability. Besides, the examinations of UV-vis and TGA showed that the paraffin@SiO2 colored microcapsules exhibited good thermal reliability, thermal stability, and UV protection property. The analysis of infrared imaging indicated that the prepared latex paint exhibited remarkable temperature-regulated property. Compared with normal interior wall coatings, the temperature was reduced by about 2.5 °C. With such incomparable features, the paraffin@SiO2 colored microcapsules not only appeared well in their solar thermal energy storage and temperature-regulated property, but also make the colored latex paint coating have superb colored fixing capabilities.

In silico prediction of bioequivalence of Isosorbide Mononitrate tablets with different dissolution profiles using PBPK modeling and simulation.

AIM: The waiver of bioequivalence (BE) studies is well accepted for Biopharmaceutics Classification System (BCS) class I drugs in form of immediate-release solid oral products. This study aimed to assess whether the rapid dissolution profiles (≥85% in 30 min) was crucial to guarantee bioequivalence of isosorbide mononitrate (ISMN) and then established a clinically relevant dissolution specification (CRDS) for screening BE or non-BE batches. METHOD: A physiologically based pharmacokinetic (PBPK) model was constructed by integrating clinical and non-clinical data by B2O simulator. The model was verified by an actual clinical study (NMPA registration number: CTR20191360) with 28 healthy Chinese subjects. Then a virtual BE study was simulated to evaluate the bioequivalence of 7 virtual batches of ISMN tablets with different dissolution profiles, and the CRDS was established by integrating the results. RESULT: The simulated PK behavior of ISMN was comparable to the observed. Even though the batches with slower dissolution were not equivalent to a rapid dissolution profile (≥85% in 30 min), it was demonstrated these batches would exhibit the similar in vivo performance. Meanwhile, the in vitro dissolution specification time point and the percentage of drug release (75% in 45 min) proved to have clinical relevance. CONCLUSION: The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations.

Progress of RAGE Molecular Imaging in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by senile plaques (SPs), which are caused by amyloid beta (Aß) deposition and neurofibrillary tangles (NFTs) of abnormal hyperphosphorylated tau protein. The receptor for advanced glycation end products (RAGE) binds to advanced glycation end products deposited during vascular dysfunction. Alzheimer's disease may occur when RAGE binds to Aß and releases reactive oxygen species, further exacerbating Aß deposition and eventually leading to SPs and NFTs. As it is involved in early AD, RAGE may be considered as a more potent biomarker than Aß. Positron emission tomography provides valuable information regarding the underlying pathological processes of AD many years before the appearance of clinical symptoms. Thus, to further reveal the role of RAGE in AD pathology and for early diagnosis of AD, a tracer that targets RAGE is needed. In this review, we first describe the early diagnosis of AD and then summarize the interaction between RAGE and Aß and Tau that is required to induce AD pathology, and finally focus on RAGE-targeting probes, highlighting the potential of RAGE to be used as an effective target. The development of RAGE probes is expected to aid in AD diagnosis and treatment.

Pathological Mechanisms Linking Diabetes Mellitus and Alzheimer's Disease: the Receptor for Advanced Glycation End Products (RAGE).

Diabetes and Alzheimer's disease (AD) place a significant burden on health care systems in the world and its aging populations. These diseases have long been regarded as separate entities; however, advanced glycation end products (AGEs) and the receptors for AGEs (RAGE) may be a link between diabetes and AD. In our study, mice injected with AGEs through stereotaxic surgery showed significant AD-like features: behavior showed decreased memory; immunofluorescence showed increased phosphorylated tau and APP. These results suggest links between diabetes and AD. Patients with diabetes are at a higher risk of developing AD, and the possible underlying molecular components of this association are now beginning to emerge.

Determination of Isosorbide-5-Mononitrate in Human Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Its Application to a Bioequivalence Study.

Isosorbide-5-mononitrate (5-ISMN), an organic nitrate vasodilator, has been widely used worldwide to prevent angina pectoris for more than two decades. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the determination of 5-ISMN in human plasma. 13C6-5-ISMN is an internal standard, and 5-ISMN was extracted from human plasma (50 µL) with ethyl acetate (200 µL) by a simple liquid-liquid extraction method. The chromatographic separation was carried out on LC-20A (Shimadzu, Japan) using an analytical column ZORBAX XDB-C18 (4.6 × 50 mm, 5 µm), coupled with API 4000 tandem mass spectrometers in a multiple reaction monitoring (MRM) mode. The mobile phase was composed of acetonitrile (organic phase A) and 2 mM ammonium acetate in water (aqueous phase B) with an isocratic elution of A/B = 90 : 10 (v/v). The total run time was 3.5 min with a small injection volume (5 µL). This method was fully validated in every aspect of selectivity, linearity, accuracy, precision, matrix effect, extraction recovery, and different stabilities. It was proved that the calibration standards within the 5.00-1000 ng/mL concentration range were linear. The lower limit of quantification was 5.00 ng/mL for 5-ISMN. The intrabatch and interbatch accuracy (RE) ranged from -8.8% to 7.1% with precision between 2.4% and 6.6%. The mean values of 5-ISMN extraction recovery and matrix effect were 87.0% and 102.0%, respectively. The fully validated method was successfully applied for a bioequivalence clinical trial of oral 20 mg 5-ISMN tablets in healthy Chinese subjects.

Development and validation of a UPLC-MS/MS method for simultaneous determination of LBPT and its metabolites in human plasma.

Aim: A UPLC-MS/MS method was developed to determine LBPT as well as its four metabolites in human plasma to support the clinical study aiming to evaluate the efficacy of LBPT tablet in patients undergoing hip/knee replacement. Methodology: Plasma samples were prepared by protein precipitation and then separated on a C18 analytical column using (A) acetonitrile (B) 0.1% formic acid and 10 mM ammonium formate in water. The detection was performed on a triple quadrupole tandem mass spectrometer in positive electrospray ionization using multiple reactions monitoring mode. Results & conclusion: The method has been validated in accordance with the US FDA guidelines and was applied to the measurement of five analytes in human plasma samples from a Phase II clinical trial.