Poly(butyl cyanoacrylate) nanoparticles-delivered β-nerve growth factor promotes the neurite outgrowth and reduces the mortality in the rat after traumatic brain injury

Several transport vectors, including nanoparticles, have been reported to be used for the delivery of therapeutic medicines crossing the impermeable blood-brain barrier (BBB) to treat the diseases in the central nerve system (CNS), such as traumatic brain injury (TBI). Poly(n-butyl-2-cyanoacrylate) (PBCA) nanoparticles, made from biocompatible material, are regarded as a better potential delivery tool than others such as gold nanoparticles due to their degradability in vivo. However, little is known whether PBCA nanoparticles can be used to deliver neurotrophic factors into the brain to treat TBI. In this study, we first synthesized PBCA-carried β-nerve growth factor, a neurotrophic agent with a large molecular weight, and then intravenously injected the compound into TBI rats. We found that despite undergoing several synthesis steps and host circulation, β-NGF was able to be successfully delivered into the injured brain by PBCA nanoparticles, still maintain its neurotrophic activity for neurite outgrowth, and could reduce the mortality of TBI rats. Our findings indicate that PBCA nanoparticles, with Tween 80, are an efficient delivery vector and a protective reservoir for large molecular therapeutic agents to treat TBI intravenously.

Identifying the Molecular Cause of Extreme Endoplasmic Reticulum Dilation in Pediatric Osteosarcoma and Its Relationship to the Disease

Pediatric osteosarcoma tumors are characterized by an unusual abundance of grossly dilated endoplasmic reticulum and an immense genomic instability that has complicated identifying new effective molecular therapeutic targets. Here we report a novel molecular signature that encompasses the majority of 108 patient tumor samples, PDXs and osteosarcoma cell lines. These tumors exhibit reduced expression of four critical COPII vesicle proteins that has resulted in the accumulation of procollagen-I protein within ‘hallmark’ dilated ER. Using CRISPR activation technology, increased expression of only SAR1A and SEC24D to physiologically normal levels was sufficient to restore both collagen-I secretion and resolve dilated ER morphology to normal.

Focally amplified long non-coding RNA in epithelial cancer as a potential biomarker and therapeutic target

Deregulation of long non-coding RNAs (lncRNAs) has been implicated in tumorigenesis. FALEC is a lncRNA upregulated in multiple cancer types. FALEC functions as an oncogene through various mechanisms, such as competitively binding miRNAs and regulation of PI3K/AKT, Tp53 and phosphatase and tensin homolog signaling pathways. Pertinent to clinical practice, the use of FALEC as a putative biomarker has been identified. These findings suggested that FALEC might play a pivotal role in human cancers. Further studies are warranted to examine the diagnostic and prognostic performance of FALEC as a noninvasive biomarker in liquid biopsy samples and promote its development to be a clinically utilizable prognostic cancer biomarker and molecular therapeutic target.

Weighted Gene Co-expression Network Analysis Reveals ALDH1B1 As a Prognositc Biomarker Involved in Gastric Cancer Development

BackgroundGastric cancer (GC) is one of the leading cancers associated with high mortality and poor prognosis mainly due to its relatively late diagnosis and the limited therapeutic options. Consequently, screening for prognostic GC biomarkers and novel molecular therapeutic targets is necessary to promote patient outcomes. Methods Weighted gene co-expression network analysis (WGCNA), a systems biology approach, was applied to analyze the mRNA sequencing data and clinical information of GC patients obtained from The Cancer Genome Atlas (TCGA). Gene modules and clinical traits were constructed according to the Pearson correlation analysis, and the gene ontology (GO) and functional enrichment analysis of meaningful modules were carried out. Hub genes from meaningful modules were screened out by two approaches: the intra-modular and protein-protein interaction (PPI) analysis methods. Next, through upstream regulatory analysis, hub genes with high connectivity degree were further validated with differential expression analysis, Kaplan-Meier survival analysis, and the Cox regression model. ResultsWe found that seven modules were associated with the following clinical traits: anatomical location of gastric adenocarcinoma, histological type, histological grade, and pathological stage. The hub gene ALDH1B1 was found to have potential as a biomarker for gastric cancer cells, the relationship between this hub gene and gastric cancer drug treatment is also worthy of attention.Conclusion These findings may contribute to understanding the GC tumourigenic mechanisms, as well as provide new potential prognostic factors and molecular therapeutic targets for GC. The ALDH1B1 hub gene also provides a new vantage point for further clinical experiments and large-scale cohort studies to validate its association with GC patient survival, and provide a new direction for the research of gastric cancer drug treatment.

LncRNA GAPLINC Promotes Renal Cell Cancer Tumorigenesis by Targeting the miR-135b-5p/CSF1 Axis

BackgroundLong noncoding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Gastric adenocarcinoma-associated, positive CD44 regulator, long intergenic noncoding RNA (GAPLINC) is a recently identified lncRNA that can actively participate in the tumorigenesis of various cancers. Here, we investigated the functional roles and mechanism of GAPLINC in renal cell carcinoma (RCC) development.MethodsDifferentially expressed lncRNAs between RCC tissues and normal kidney tissues were detected by using a microarray technique. RNA sequencing was applied to explore the mRNA expression profile changes after GAPLINC silencing. After gain- and loss-of-function approaches were implemented, the effect of GAPLINC on RCC in vitro and in vivo was assessed by cell proliferation and migration assays. Moreover, rescue experiments and luciferase reporter assays were used to study the interactions between GAPLINC, miR-135b-5p and CSF1.ResultsGAPLINC was significantly upregulated in RCC tissues and cell lines and was associated with a poor prognosis in RCC patients. Knockdown of GAPLINC repressed RCC growth in vitro and in vivo, while overexpression of GAPLINC exhibited the opposite effect. Mechanistically, we found that GAPLINC upregulates oncogene CSF1 expression by acting as a sponge of miR-135b-5p.ConclusionTaken together, our results suggest that GAPLINC is a novel prognostic marker and molecular therapeutic target for RCC.

The SF3B1R625H Mutation Promotes Prolactinoma Tumor Progression Through Aberrant Splicing Of DLG1

Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and mechanisms are poorly understood. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. Quantitative PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components of relevant signaling pathways were detected by western blot, immunohistochemistry, and immunofluorescence, and were knocked down by siRNA-mediated silencing. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. Consistently between rat cells and human tumor samples, mutant SF3B1 promoted aberrant splicing and the suppression of DLG1. Additionally, mutant SF3B1 with knockdown of DLG1 expression promoted cell migration, invasion, and epithelial-mesenchymal transition by activating the PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.

The Perspective of Dysregulated LncRNAs in Alzheimer's Disease: A Systematic Scoping Review

LncRNAs act as part of non-coding RNAs at high levels of complex and stimulatory configurations in basic molecular mechanisms. Their extensive regulatory activity in the CNS continues on a small scale, from the functions of synapses to large-scale neurodevelopment and cognitive functions, aging, and can be seen in both health and disease situations. One of the vast consequences of the pathological role of dysregulated lncRNAs in the CNS due to their role in a network of regulatory pathways can be manifested in Alzheimer's as a neurodegenerative disease. The disease is characterized by two main hallmarks: amyloid plaques due to the accumulation of β-amyloid components and neurofibrillary tangles (NFT) resulting from the accumulation of phosphorylated tau. Numerous studies in humans, animal models, and various cell lines have revealed the role of lncRNAs in the pathogenesis of Alzheimer's disease. This scoping review was performed with a six-step strategy and based on the Prisma guideline by systematically searching the publications of seven databases. Out of 1,591 records, 69 articles were utterly aligned with the specified inclusion criteria and were summarized in the relevant table. Most of the studies were devoted to BACE1-AS, NEAT1, MALAT1, and SNHG1 lncRNAs, respectively, and about one-third of the studies investigated a unique lncRNA. About 56% of the studies reported up-regulation, and 7% reported down-regulation of lncRNAs expressions. Overall, this study was conducted to investigate the association between lncRNAs and Alzheimer's disease to make a reputable source for further studies and find more molecular therapeutic goals for this disease.

Current Molecular Therapeutic Agents and Drug Candidates for Mycobacterium abscessus

Mycobacterium abscessus has been recognised as a dreadful respiratory pathogen among the non-tuberculous mycobacteria (NTM) because of misdiagnosis, prolonged therapy with poor treatment outcomes and a high cost. This pathogen also shows extremely high antimicrobial resistance against current antibiotics, including the anti-tuberculosis agents. Therefore, current chemotherapies require a long curative period and the clinical outcomes are not satisfactory. Thus, there is an urgent need for discovering and developing novel, more effective anti-M. abscessus drugs. In this review, we sum the effectiveness of the current anti-M. abscessus drugs and drug candidates. Furthermore, we describe the shortcomings and difficulties associated with M. abscessus drug discovery and development.

Genetic alterations and functional networks of m6A RNA methylation regulators in pancreatic cancer based on data mining

Background Pancreatic cancer is a fatal malignancy of the digestive system and the 5-year survival rate remains low. Therefore, new molecular therapeutic targets are required to improve treatments, prognosis, and the survival of patients. N6-methyladenosine (m6A) is the most prevalent reversible methylation in mammalian messenger RNA (mRNA) and has critical roles in the tumorigenesis and metastasis of various malignancies. However, the role of m6A in pancreatic cancer is still unclear. Exploring genetic alterations and functional networks of m6A regulators in pancreatic cancer may provide new strategies for its treatment. Methods In this study, we used data from the Cancer Genome Atlas (TCGA) database and other public databases through cBioPortal, LinkedOmics, UALCAN, GEPIA, STRING, and the database for annotation, visualization, and integrated discovery (DAVID) to systematically analyze the molecular alterations and functions of 20 main m6A regulators in pancreatic cancer. Results We found that m6A regulators had widespread genetic alterations, and that their expression levels were significantly correlated with pancreatic cancer malignancy. Moreover, m6A regulators were associated with the prognosis of pancreatic cancer patients. Conclusions m6A regulators play a crucial part in the occurrence and development of pancreatic cancer. Our study will guide further studies of m6A RNA modification in pancreatic cancer and could potentially provide new strategies for pancreatic cancer treatment.