Multichiral Mesoporous Silica Screws with Chiral Differential Mucus Penetration and Mucosal Adhesion for Oral Drug Delivery.

In the harsh gastrointestinal tract, helical bacteria with hierarchical chiral architectures possess strong abilities. Taking inspirations from nature, we developed a multichiral mesoporous silica nanoscrew (L/D-MCNS) as an efficient oral drug delivery platform by modifying the structural chiral silica nanoscrew (CNS) with L/D-alanine (L/D-Ala) enantiomers via the sequential application of a chiral template and postmodification strategies. We demonstrated that L-MCNS showed differential biological behaviors and superior advantages in oral adsorption compared to those of CNS, D-MCNS, and DL-MCNS. During the delivery, helical L/D-MCNS presenting distinctive topological structures, including small section area, large rough external surface, and a screw-like body, displayed multiple superiorities in mucus diffusion and mucosal adhesion. Meanwhile, the grafted chiral enantiomers enabled positive or negative chiral recognition with the biosystems. Once racemic flurbiprofen (FP) was encapsulated into the nanopores of L/D-MCNS (FP@L/D-MCNS), L/D-MCNS providing highly cross-linked and mesoscopic chiral nanochannels was beneficial for controlling the drug loading/release kinetics with chiral microenvironment sensitivity. Particularly, we noticed enantioselective absorption of FP in vivo, which could be attributed to the differential biological behaviors of L/D-MCNS. By simple design and regulation of the multilevel chirality of nanocarriers, L/D-MCNS can be employed for efficient oral drug delivery from the perspectives of material science, pharmacy, and bionics.

Natural products as the therapeutic strategies for addiction.

World Drug Report 2023 concluded that 296 million people abused drugs, 39.5 million became addiction and 494,000 died as a direct or indirect result of addiction. Addiction has become a growing problem that affects individuals, their families, societies, countries and even the world. However, treatment for addiction is only limited to some developed countries because of the high cost, difficult implementation, and time consuming. Therefore, there is an urgent need to develop a low-cost, effective drug for the development of addiction treatment in more countries, which is essential for the stability and sustainable development of the world. In this review, it provided an overview of the abuse of common addictive drugs, related disorders, and current therapeutic regimen worldwide, and summarized the mechanisms of drug addiction as reward circuits, neuroadaptation and plasticity, cognitive decision-making, genetics, and environment. According to their chemical structure, 43 natural products and 5 herbal combinations with potential to treat addiction were classified, and their sources, pharmacological effects and clinical trials were introduced. It was also found that mitragine, ibogine, L-tetrahydropalmatine and crocin had greater potential for anti-addiction.

CircRNA: a rising therapeutic strategy for lung injury induced by pulmonary toxicants.

Lung injury has been a serious medical problem that requires new therapeutic approaches and biomarkers. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) that exist widely in eukaryotes. CircRNAs are single-stranded RNAs that form covalently closed loops. CircRNAs are significant gene regulators that have a role in the development, progression, and therapy of lung injury by controlling transcription, translating into protein, and sponging microRNAs (miRNAs) and proteins. Although the study of circRNAs in lung injury caused by pulmonary toxicants is just beginning, several studies have revealed their expression patterns. The function that circRNAs perform in relation to pulmonary toxicants (severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2), drug abuse, PM2.5, and cigarette smoke) is the main topic of this review. A variety of circRNAs can serve as potential biomarkers of lung injury. In this review, the biogenesis, properties, and biological functions of circRNAs were concluded, and the relationship between circRNAs and pulmonary toxicants was discussed. It is expected that the new ideas and potential treatment targets that circRNAs provide would be beneficial to research into the molecular mechanisms behind lung injury.

Development and validation of nomograms predicting postoperative survival in patients with chromophobe renal cell carcinoma.

Objective: The purpose of our study is to construct and validate nomograms that effectively predict postoperative overall survival and cancer-specific survival for patients with chromophobe renal cell carcinoma (chRCC). Method: Clinical, social, and pathological data from 6016 patients with chRCC collected from the SEER database were screened from 2004 to 2015. They were randomly assigned to a training cohort (n = 4212) and a validation cohort (n = 1804) at a 7:3 ratio. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were used to identify the prognostic factors affecting overall survival (OS) and cancer-specific survival (CSS) and establish nomograms. Their performance was validated internally and externally by calculating Harrell's C-indexes, area under the curve (AUC), calibration, and decision curves. For external validation, samples from postoperative patients with chRCC at 3 independent centers in Xuzhou, China, were collected. Risk stratification models were built according to the total scores of each patient. Kaplan-Meier curves were generated for the low-risk, intermediate-risk, and high-risk groups to evaluate survival. Results: The C-indexes, AUC curves, and decision curves revealed the high ability of the nomograms in predicting OS and CSS, overall better than that of AJCC and TNM staging. Moreover, in internal and external validation, the calibration curves of 5-, 8-, and 10-year OS agreed with the actual survival. Kaplan-Meier curves indicated significant differences in survival rates among the 3 risk groups in OS or CSS. Conclusion: The nomograms showed favourable predictive power for OS and CSS. Thus, they should contribute to evaluating the prognosis of patients with chRCC. Furthermore, the risk stratification models established on the nomograms can guide the prognosis of patients and further treatment.

Long Non-coding RNA HOTAIR in Central Nervous System Disorders: New Insights in Pathogenesis, Diagnosis, and Therapeutic Potential.

Central nervous system (CNS) disorders, such as ischemic stroke, neurodegenerative diseases, multiple sclerosis, traumatic brain injury, and corresponding neuropathological changes, often lead to death or long-term disability. Long non-coding RNA (lncRNA) is a class of non-coding RNA with a transcription length over 200 nt and transcriptional regulation. lncRNA is extensively involved in physiological and pathological processes through epigenetic, transcription, and post-transcriptional regulation. Further, dysregulated lncRNA is closely related to the occurrence and development of human diseases, including CNS disorders. HOX Transcript antisense RNA (HOTAIR) is the first discovered lncRNA with trans-transcriptional regulation. Recent studies have shown that HOTAIR may participate in the regulation of the occurrence and development of CNS disorders. In addition, HOTAIR has the potential to become a new biomarker for the diagnosis and prognosis assessment of CNS disorders and even provide a new therapeutic target for CNS disorders. Here, we reviewed the research results of HOTAIR in CNS disorders to provide new insights into the pathogenesis, diagnostic value, and therapeutic target potential of HOTAIR in human CNS disorders.

Cocaine in Different Matrices: Recent Updates on Pretreatment and Detection Techniques.

Cocaine abuse has attracted increased attention in the recent past since it can cause addiction and great harm to the normal human body. Due to cocaine exists in various complex matrices, the detection of it in different matrices is helpful to prevent abuse. It is thus imperative to establish efficient and accurate methods for pretreatment and detection of cocaine in different samples. The present study provides a summary of the research progress of cocaine pretreatment methods (such as different microextraction methods, QuEChERS, and solid phase extraction based on novel extraction materials) and detection approaches (such as liquid chromatography coupled with different detectors, gas chromatography and related techniques, capillary electrophoresis and sensors). A comparison of the pros and cons of different pretreatment and detection methods is presented. The findings of this study will provide a reference for selection of the most suitable cocaine pretreatment and detection techniques.

Tasks Integrated Networks: Joint Detection and Retrieval for Image Search.

The traditional object (person) retrieval (re-identification) task aims to learn a discriminative feature representation with intra-similarity and inter-dissimilarity, which supposes that the objects in an image are manually or automatically pre-cropped exactly. However, in many real-world searching scenarios (e.g., video surveillance), the objects (e.g., persons, vehicles, etc.) are seldom accurately detected or annotated. Therefore, object-level retrieval becomes intractable without bounding-box annotation, which leads to a new but challenging topic, i.e., image-level search with multi-task integration of joint detection and retrieval. In this paper, to address the image search issue, we first introduce an end-to-end Integrated Net (I-Net), which has three merits: 1) A Siamese architecture and an on-line pairing strategy for similar and dissimilar objects in the given images are designed. Benefited by the Siamese structure, I-Net learns the shared feature representation, because, on which, both object detection and classification tasks are handled. 2) A novel on-line pairing (OLP) loss is introduced with a dynamic feature dictionary, which alleviates the multi-task training stagnation problem, by automatically generating a number of negative pairs to restrict the positives. 3) A hard example priority (HEP) based softmax loss is proposed to improve the robustness of classification task by selecting hard categories. The shared feature representation of I-Net may restrict the task-specific flexibility and learning capability between detection and retrieval tasks. Therefore, with the philosophy of divide and conquer, we further propose an improved I-Net, called DC-I-Net, which makes two new contributions: 1) two modules are tailored to handle different tasks separately in the integrated framework, such that the task specification is guaranteed. 2) A class-center guided HEP loss (C 2HEP) by exploiting the stored class centers is proposed, such that the intra-similarity and inter-dissimilarity can be captured for ultimate retrieval. Extensive experiments on famous image-level search oriented benchmark datasets, such as CUHK-SYSU dataset and PRW dataset for person search and the large-scale WebTattoo dataset for tattoo search, demonstrate that the proposed DC-I-Net outperforms the state-of-the-art tasks-integrated and tasks-separated image search models.

MicroRNA-124: A Key Player in Microglia-Mediated Inflammation in Neurological Diseases.

Neurological disorders are mainly characterized by progressive neuron loss and neurological deterioration, which cause human disability and death. However, many types of neurological disorders have similar pathological mechanisms, including the neuroinflammatory response. Various microRNAs (miRs), such as miR-21, miR-124, miR-146a, and miR-132 were recently shown to affect a broad spectrum of biological functions in the central nervous system (CNS). Microglia are innate immune cells with important roles in the physiological and pathological activities of the CNS. Recently, abnormal expression of miR-124 was shown to be associated with the occurrence and development of various diseases in CNS via regulating microglia function. In addition, miR-124 is a promising biomarker and therapeutic target. Studies on the role of miR-124 in regulating microglia function involved in pathogenesis of neurological disorders at different stages will provide new ideas for the use of miR-124 as a therapeutic target for different CNS diseases.

Heterogeneous miRNA-mRNA Regulatory Networks of Visceral and Subcutaneous Adipose Tissue in the Relationship Between Obesity and Renal Clear Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urologic cancer. Associations of both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with ccRCC have been reported, and underlying mechanisms of VAT perhaps distinguished from SAT, considering their different structures and functions. We performed this study to disclose different miRNA-mRNA networks of obesity-related ccRCC in VAT and SAT using datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA); and find out different RNAs correlated with the prognosis of ccRCC in VAT and SAT. Methods: We screened out different expressed (DE) mRNAs and miRNAs of obesity, in both VAT and SAT from GEO datasets, and constructed miRNA-mRNA networks of obesity-related ccRCC. To evaluate the sensitivity and specificity of RNAs in networks of obesity-related ccRCC in both VAT and SAT, Receiver Operating Characteristic (ROC) analyses were conducted using TCGA datasets. Spearman correlation analyses were then performed to find out RNA pairs with inverse correlations. We also performed Cox regression analyses to estimate the association of all DE RNAs of obesity with the overall survival. Results: 136 and 185 DE mRNAs of obesity in VAT and SAT were found out. Combined with selected DE miRNAs, miRNA-mRNA networks of obesity-related ccRCC were constructed. By performing ROC analyses, RNAs with same trend as shown in networks and statistically significant ORs were selected to be paired. Three pairs were finally remained in Spearman correlation analyses, including hsa-miR-182&ATP2B2, hsa-miR-532&CDH2 in VAT, and hsa-miR-425&TFAP2B in SAT. Multivariable Cox regression analyses showed that several RNAs with statistically significant adjusted HRs remained consistent trends as shown in DE analyses of obesity. Risk score analyses using selected RNAs showed that the overall survival time of patients in the low-risk group was significantly longer than that in the high-risk group regardless of risk score models. Conclusions: We found out different miRNA-mRNA regulatory networks of obesity-related ccRCC for both VAT and SAT; and several DE RNAs of obesity-related ccRCC were found to remain consistent performance in terms of ccRCC prognosis. Our findings could provide valuable evidence on the targeted therapy of obesity-related ccRCC.

The changes of serum zinc, copper, and selenium levels in epileptic patients: a systematic review and meta-analysis.

INTRODUCTION: It is widely accepted that trace elements have been implicated in various metabolic processes. Valproic acid (VPA) is a remarkably safe and effective antiepileptic drug. There is no consensus option regarding the fluctuations in serum zinc (Zn), copper (Cu), and selenium (Se) in epileptic patients treated with VPA. We applied a meta-analysis to systematically assess the effects of VPA on serum ions in these patients. AREAS COVERED: In this study, we performed a meta-analysis of the changes in serum Zn, Cu, and Se levels in human samples of healthy controls, epileptic patients, and patients treated with VPA. Twenty-two published analyzable studies were selected by searching the databases of PubMed, China National Knowledge Infrastructure (CNKI), Google Scholar, Web of Science, EMBASE, WAN FANG and Vip. EXPERT OPINION: Serum Se levels in epileptic patients were decreased compared to healthy controls. Serum Zn levels in patients with VPA treatment were significantly lower than those in epileptic patients. The results of this meta-analysis are instructive for the intake of trace elements such as Zn, Cu, and Se in the diet balance of patients with epilepsy treated with VPA. Meanwhile, this study provides a theoretical basis for the combined use of other drugs that affect the intake and absorption of trace elements and VPA.

FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma.

BACKGROUND: Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis. METHODS: The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins . RESULTS: We demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop. CONCLUSION: Our data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

Cell Recognition Molecule L1 Regulates Cell Surface Glycosylation to Modulate Cell Survival and Migration.

Background: Cell recognition molecule L1 (L1) plays an important role in cancer cell differentiation, proliferation, migration and survival, but its mechanism remains unclear. Methodology/Principal: Our previous study has demonstrated that L1 enhanced cell survival and migration in neural cells by regulating cell surface glycosylation. In the present study, we show that L1 affected cell migration and survival in CHO (Chinese hamster ovary) cell line by modulation of sialylation and fucosylation at the cell surface via the PI3K (phosphoinositide 3-kinase) and Erk (extracellularsignal-regulated kinase) signaling pathways. Flow cytometry analysis indicated that L1 modulated cell surface sialylation and fucosylation in CHO cells. Activated L1 upregulated the protein expressions of ST6Gal1 (ß-galactoside α-2,6-sialyltransferase 1) and FUT9 (Fucosyltransferase 9) in CHO cells. Furthermore, activated L1 promoted CHO cells migration and survival as shown by transwell assay and MTT assay. Inhibitors of sialylation and fucosylation blocked L1-induced cell migration and survival, while decreasing FUT9 and ST6Gal1 expressions via the PI3K-dependent and Erk-dependent signaling pathways. Conclusion : L1 modulated cell migration and survival by regulation of cell surface sialylation and fucosylation via the PI3K-dependent and Erk-dependent signaling pathways.

Differential expression of circulating microRNAs in blood and haematoma samples from patients with intracerebral haemorrhage.

OBJECTIVE: To measure the differential expression of microRNAs (miRNAs) in peripheral blood samples from patients with intracerebral haemorrhage (ICH) and to measure the levels of hsa-miR-21-5p in peripheral blood and haematoma samples from patients with ICH. METHODS: This case-control study enrolled individuals with ICH in the putamen treated by craniotomy and age- and sex-matched healthy control subjects. Serum miRNA expression profiles were determined in the patient and control groups using miRNA polymerase chain reaction (PCR) arrays. The ICH-related miRNA hsa-miR-21-5p was selected and its differential expression was assessed in peripheral blood and haematoma specimens from patients with ICH compared with peripheral blood samples controls using real-time PCR. RESULTS: Seven patients and five control subjects were included in the miRNA expression profile analysis; and 31 patients and 22 control subjects provided samples for the real-time PCR of hsa-miR-21-5p expression. A total of 59 miRNAs were significantly downregulated in patients with ICH. Relative hsa-miR-21-5p levels of 0.43 and 0.31 for peripheral blood and haematoma samples, respectively, were obtained in the patient group compared with the control subjects. CONCLUSION: Hsa-miR-21-5p levels were significantly reduced in both peripheral blood and haematoma samples in patients with ICH.