The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection Microglia use a defined armamentarium of genes to perform these tasks In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons Injury to neurons in Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy

Microglia in neurodegeneration.

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

/pdf/colorectal-carcinoma-a-general-overview-and-future-2e96vugrtz.pdf

Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts that are processed by RNase III-endonucleases DROSHA and DICER into small RNAs of approximately 21 nucleotides. All miRNAs are loaded into Argonaute proteins in the RNA-induced silencing complex (RISC) and act as post-transcriptional regulators by binding to the 3′- untranslated region (UTR) of mRNAs. This seed-dependent miRNA binding inhibits the translation and/or promotes the degradation of mRNA targets. Surprisingly, recent data presents evidence for a target-mediated decay mechanism that controls the level of specific miRNAs. In addition, several non-canonical miRNA-containing genes have been recently described and unexpected functions of miRNAs have been identified. For instance, several miRNAs are located in the nucleus, where they are involved in the transcriptional activation or silencing of target genes. These epigenetic modifiers are recruited by RISC and guided by miRNAs to specific loci in the genome. Here, we will review non-canonical aspects of miRNA biology, including novel regulators of miRNA expression and functions of miRNAs in the nucleus.

https://www.mdpi.com/2073-4409/8/11/1465/pdf

The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation.

Deep analysis of next-generation sequencing data unveils numerous small non-coding RNAs with distinct functions. Recently, fragments derived from tRNA, named as tRNA-derived small RNA (tsRNA), have attracted broad attention. There are mainly two types of tsRNAs, including tRNA-derived stress-induced RNA (tiRNA) and tRNA-derived fragment (tRF), which differ in the cleavage position of the precursor or mature tRNA transcript. Emerging evidence has shown that tsRNAs are not merely tRNA degradation debris but have been recognized to play regulatory roles in many specific physiological and pathological processes. In this review, we summarize the biogeneses of various tsRNAs, present the emerging concepts regarding functions and mechanisms of action of tsRNAs, highlight the potential application of tsRNAs in human diseases, and put forward the current problems and future research directions.

tRNA-Derived Small RNA: A Novel Regulatory Small Non-Coding RNA

The number of studies on non-coding RNAs has increased substantially in recent years owing to their importance in gene regulation However, the biological functions of small RNAs from abundant species of housekeeping non-coding RNAs (rRNA, tRNA, etc) remain a highly studied topic tRNA-derived small RNAs (tsRNAs) refer to the specific cleavage of tRNAs by specific nucleases [eg, Dicer and angiogenin (ANG)] in particular cells or tissues or under certain conditions such as stress and hypoxia tsRNAs are a type of non-coding small RNA that are widely found in the prokaryotic and eukaryotic transcriptomes and are generated from mature tRNAs or precursor tRNAs at different sites There are two main types of tsRNAs, tRNA-derived fragments (tRFs) and tRNA halves tRFs are 14–30 nucleotides (nt) long and mainly consist of three subclasses: tRF-5, tRF-3, and tRF-1 tRNA halves, which are 31–40 nt long, are generated by specific cleavage in the anticodon loops of mature tRNAs There are two types of tRNA halves, 5′-tRNA halves and 3′-tRNA halves tsRNAs have multiple biological functions including acting as signaling molecules in stress responses and as regulators of gene expression Additionally, they have been considered to be involved in RNA processing, cell proliferation, translation suppression, the modulation of DNA damage response, and neurodegeneration More importantly, they are closely related to the occurrence of many human diseases such as tumors, infectious diseases, metabolic diseases, and neurological diseases Moreover, tsRNAs have the potential to become new biomarkers for disease diagnosis Continuous investigations will help us to understand their generation and regulatory mechanisms as well as the possible roles of tRFs and tRNA halves

Transfer RNA-derived fragments and tRNA halves: biogenesis, biological functions and their roles in diseases

Metastasis of colorectal cancer (CRC) is the leading cause of CRC-associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA-derived stress-induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG-promoted CRC metastasis. Moreover, higher level of a 5'-tiRNA from mature tRNA-Val (5'-tiRNA-Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG-tiRNAs-cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.32245

Angiogenin promotes colorectal cancer metastasis via tiRNA production.

The purpose of this meta-analysis was to investigate the association between progranulin polymorphism rs5848 and risk of the neurodegenerative diseases frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Published literature from PubMed and other databases were retrieved, and 16 case–control studies were identified as eligible: 5 on FTLD (1,439 cases, 4,461 controls), 5 on AD (2,502 cases, 2,162 controls), 3 on PD (1,605 cases, 1,591 controls), and 3 on ALS (663 cases, 811 controls). The pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated. We found that rs5848 was associated with an increased risk of neurodegenerative diseases in the homozygous (TT vs. CC: OR, 1.24; 95 % CI, 1.10–1.39; P < 0.001) and recessive models (TT vs. CC + CT: OR, 1.23; 95 % CI, 1.10–1.37; P < 0.001). Stratified analyses showed associations of rs5848 with increased risk of AD and PD in the homozygous and recessive models. Our data indicate that rs5848 is associated with risk of AD and PD, suggesting important roles of progranulin in neurodegenerative processes.

Association of progranulin polymorphism rs5848 with neurodegenerative diseases: a meta-analysis

Gene defects have been recognized as prominent factors in the etiology and pathogenesis of neurodegeneration. Among 60 neurodegeneration-related mutations in progranulin (PGRN), a mutation in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of its signal peptide at residue 9 (named PGRN A9D) and results in incorrect cytoplasmic sorting. However, the pathogenesis of this mutation remains elusive. To address this issue, we first examined the subcellular distribution of PGRN A9D in human neuronal-like cells (SH-SY5Y). The results showed that PGRN A9D accumulated in cytosolic stress granules. Interestingly, this mis-sorting associated with a cellular redistribution of angiogenin (ANG), a stress-response factor and neurodegenerative disease-related protein, from nucleus to cytoplasmic stress granules, and there existed protein interaction between PGRN A9D and ANG. Further study revealed that the stress granule localization of PGRN A9D was dependent on ANG. Functionally, PGRN A9D abolished the nuclear ANG-mediated biological roles; on the other hand, the relocation of ANG to stress granules activated its cytoprotective stress-response program by cleaving transfer RNAs (tRNAs) to tiRNAs (tRNA-derived, stress-induced small RNAs), thus promoting PGRN A9D cell survival. Taken together, we hypothesize that PGRN A9D leads to the retention of ANG in the cytoplasm to protect cells from PGRN A9D-induced apoptosis, implying that PGRN and ANG act in concert to regulate the progress of neurodegenerative disease.

Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs

Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) benefit less from traditional therapies; hence, new therapeutic strategies may help improve the treatment response and prognosis of these patients. Ferroptosis is an iron-dependent type of regulated cell death characterized by the accumulation of lipid reactive oxygen species (ROS), distinct from other types of regulated cell death. CRC cells, especially those with drug-resistant properties, are characterized by high iron levels and ROS. This indicates that the induction of ferroptosis in these cells may become a new therapeutic approach for CRC, particularly for eradicating CRC resistant to traditional therapies. Recent studies have demonstrated the mechanisms and pathways that trigger or inhibit ferroptosis in CRC, and many regulatory molecules and pathways have been identified. Here, we review the current research progress on the mechanism of ferroptosis, new molecules that mediate ferroptosis, including coding and non-coding RNA; novel inducers and inhibitors of ferroptosis, which are mainly small-molecule compounds; and newly designed nanoparticles that increase the sensitivity of cells to ferroptosis. Finally, the gene signatures and clusters that have predictive value on CRC are summarized.

/pdf/insights-on-ferroptosis-and-colorectal-cancer-progress-and-16fctqzq.pdf

Insights on Ferroptosis and Colorectal Cancer: Progress and Updates

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