A novel heterozygous HTRA1 mutation in an Asian family with CADASIL-like disease.

BACKGROUND: HTRA1 gene mutations are related to the pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). However, heterozygous HTRA1 mutations at specific sites can also lead to rare autosomal dominant cerebral artery disease (CADASIL-like disease). To date, 28 heterozygous mutations in the HTRA1 gene have been reported to be related to CADASIL-like diseases. Only one case of this disease was caused by a heterozygous mutation of c.497G>T in exon 2 of the HTRA1 gene. METHODS: In this case, we report on an Asian family with CADASIL-like disease caused by a heterozygous mutation of c.497G>T in exon 2 of the HTRA1 gene. The clinical and imaging characteristics of the proband were summarized, and gene mutations were verified by whole-exome sequencing (WES) and direct Sanger sequencing. RESULTS: The result of the gene sequencing showed a heterozygous missense mutation at the c.497G>T locus of the HTRA1 gene in the proband of one sick family member, resulting in a change in amino acid (p.arg166leu). CONCLUSION: This is the first reported pathogenic mutation at the c.497G>T locus of the HTRA1 gene in an Asian population. It provides an important theoretical basis for the specific gene-based diagnosis and treatment of CADASIL-like diseases.

Association of an insertion mutation in PRRT2 with hereditary spastic paraplegia accompanied by polyneuropathy.

BACKGROUND: Hereditary spastic paraplegia is a rare familial hereditary neurodegenerative disease caused by multiple autosomal dominant mutations. More than 50 mutant genes have been reported to be associated with this disease. METHODS: In this study, we have reported a rare insertion mutation site in PRRT2 that caused a familial disorder of hereditary spastic paraplegia accompanied by polyneuropathy. RESULTS: We used second-generation sequencing of samples of the proband's familial genome and found an insertion mutation of C/CC in NM_001256443:c.641dupC that was localized to the second exon of PRRT2. This functional mutation can cause an amino acid sequence change (arginine >proline) and dysfunctional neuronal transmembrane proteins, which might have been related to the onset of hereditary spastic paraplegia accompanied by polyneuropathy in the family reported in this study. CONCLUSION: The discovery of this mutation site provides an important theoretical basis for specific gene-based diagnosis and treatment of hereditary spastic paraplegia.

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation.

BACKGROUND: Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebrovascular disease closely related to the NOTCH3 gene. More than 200 mutations in this gene have been reported to be associated with this disease. METHODS: The NOTCH3 gene from CADASIL patient was screened for mutations by whole-exome sequencing (WES). PCR amplification and direct Sanger sequencing were used to verify the suspicious gene mutation sites detected by WES. RESULTS: We performed second-generation sequencing on a sample of the patient's genome and found a heterozygous deletion-insertion mutation c.512_605delinsA in exon 4 of NOTCH3, which resulted in amino acid changes p.G171_A202delinsE. This variation was confirmed by the direct Sanger sequencing. It may be rated as a CADASIL clinical variation. CONCLUSION: Discovery of this mutation site provides an important theoretical basis for specific gene-based diagnosis and treatment of CADASIL.

Long non-coding RNAs involved in cancer metabolic reprogramming.

Metabolic reprogramming has now been accepted as a hallmark of cancer. Compared to normal cells, cancer cells exhibit different metabolic features, including increased glucose uptake, aerobic glycolysis, enhanced glutamine uptake and glutaminolysis, altered lipid metabolism, and so on. Cancer metabolic reprogramming, which supports excessive cell proliferation and growth, has been widely regulated by activation of oncogenes or loss of tumor suppressors. Here, we review that long non-coding RNAs (lncRNAs) can affect cancer metabolism by mutual regulation with oncogenes or tumor suppressors. Additionally, the interaction of lncRNAs with crucial transcription factors, metabolic enzymes or microRNAs can also effectively modulate the processes of cancer metabolism. LncRNAs-derived metabolism reprogramming allows cancer cells to maintain deregulated proliferation and withstand hostile microenvironment such as energy stress. Understanding the functions of lncRNAs in cancer metabolic reprogramming that contributes to carcinogenesis and cancer development may help to develop novel and effective strategies for cancer diagnosis, prognosis and treatment.

Guidance of circular RNAs to proteins' behavior as binding partners.

Circular RNAs (circRNAs) are single-stranded and covalently closed back-splicing products of pre-mRNAs. They can be derived from exons, introns, or exons with intron retained between exons of transcripts, as well as antisense transcripts. CircRNAs have been reported to function as microRNA sponges, regulate gene transcription mediated by RNA polymerase II, and modulate the splicing or stability of mRNA. However, emerging studies demonstrate that they affect the behavior of proteins via direct interactions with them. Here, we summarize that by binding directly with proteins; circRNAs can facilitate their nuclear or cytoplasmic localizations, regulate their functions or stability, promote or inhibit the interactions between them, or influence the interactions between them and DNA. Furthermore, these circRNA-binding proteins contain transcription factors, RNA processing proteins, proteases, and some other RNA-binding proteins. As a consequence, circRNAs are involved in the regulation of multiple physiological or pathological processes, including tumorigenesis, atherosclerosis, wound repair, cardiac senescence, myocardial ischemia/reperfusion injury, and so forth. Nonetheless, it is worthwhile to further explore more types of proteins that interact with circRNAs, which would be helpful in revealing other unknown biological functions of circRNAs that guide the variation in behavior of cellular proteins.

Regulation of RNA decay and cellular function by 3'-5' exoribonuclease DIS3L2.

DIS3L2, in which mutations have been linked to Perlman syndrome, is an RNA-binding protein with 3'-5' exoribonuclease activity. It contains two CSD domains and one S1 domain, all of which are RNA-binding domains, and one RNB domain that is responsible for the exoribonuclease activity. The 3' polyuridine of RNA substrates can serve as a degradation signal for DIS3L2. Because DIS3L2 is predominantly localized in the cytoplasm, it can recognize, bind, and mediate the degradation of cytoplasmic uridylated RNA, including pre-microRNA, mature microRNA, mRNA, and some other non-coding RNAs. Therefore, DIS3L2 plays an important role in cytoplasmic RNA surveillance and decay. DIS3L2 is involved in multiple biological and physiological processes such as cell division, proliferation, differentiation, and apoptosis. Nonetheless, the function of DIS3L2, especially its association with cancer, remains largely unknown. We summarize here the RNA substrates degraded by DIS3L2 with its exonucleolytic activity, together with the corresponding biological functions it is implicated in. Furthermore, we discuss whether DIS3L2 can function independently of its 3'-5' exoribonuclease activity, as well as its potential tumor-suppressive or oncogenic roles during cancer progression.

Exosomes in Pathogenesis, Diagnosis, and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of ß-amyloid peptide 1-42 and phosphorylation of tau protein in the brain. Thus far, the transfer mechanism of these cytotoxic proteins between nerve cells remains unclear. Recent studies have shown that nanoscale extracellular vesicles (exosomes) originating from cells may play important roles in this transfer process. In addition, several genetic materials and proteins are also involved in intercellular communication by the secretion of the exosomes. That proposes novel avenues for early diagnosis and biological treatment in AD, based on exosome detection and intervention. In this review, exosome-related pathways of cytotoxic protein intercellular transfer in AD, and the effect of membrane proteins on exosomes targeting cells are first introduced. The advances in exosome-related biomarker detection in AD are summarized. Finally, the advantages and challenges of reducing cytotoxic protein accumulation via exosomal intervention for AD treatment are discussed. It is envisaged that future research in exosomes may well provide new insights into the pathogenesis, diagnosis, and treatment of AD.

Aberrant Regulation of mRNA m6A Modification in Cancer Development.

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs). The m6A modification in RNA can be catalyzed by methyltransferases, or removed by demethylases, which are termed m6A writers and erasers, respectively. Selective recognition and binding by distinct m6A reader proteins lead mRNA to divergent destinies. m6A has been reported to influence almost every stage of mRNA metabolism and to regulate multiple biological processes. Accumulating evidence strongly supports the correlation between aberrant cellular m6A level and cancer. We summarize here that deregulation of m6A modification, resulting from aberrant expression or function of m6A writers, erasers, readers or some other protein factors, is associated with carcinogenesis and cancer progression. Understanding the regulation and functional mechanism of mRNA m6A modification in cancer development may help in developing novel and efficient strategies for the diagnosis, prognosis and treatment of human cancers.

HBV infection effects prognosis and activates the immune response in intrahepatic cholangiocarcinoma.

BACKGROUND: The impact of HBV infection on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains uncertain, and the underlying mechanism has not been elucidated. This study aims to explore the potential mechanism via clinical perspectives and immune features. METHODS: We retrospectively reviewed 1308 patients with ICC treated surgically from January 2007 to January 2015. Then, we compared immune-related markers using immunohistochemistry staining to obtain the gene expression profile GSE107943 and related literature for preliminary bioinformatics analysis. Subsequently, we conducted a drug sensitivity assay to validate the role of TNFSF9 in the ICC organoid-autologous immune cell coculture system and in the patient-derived organoids-based xenograft platform. RESULTS: The analysis revealed that tumors in patients without HBV infection exhibited greater size and a higher likelihood of lymphatic metastasis, tumor invasion, and relapse. After resection, HBV-infected patients had longer survival time than uninfected patients (p<0.01). Interestingly, the expression of immune-related markers in HBV-positive patients with ICC was higher than that in uninfected patients (p<0.01). The percentage of CD8+ T cells in HBV-positive tissue was higher than that without HBV infection (p<0.05). We screened 21 differentially expressed genes and investigated the function of TNFSF9 through bioinformatics analyses. The expression of TNFSF9 in ICC organoids with HBV infection was lower than that in organoids without HBV infection. The growth of HBV-negative ICC organoids was significantly inhibited by inhibiting the expression of TNFSF9 with a neutralizing antibody. Additionally, the growth rate was faster in HbsAg (-) ICC patient-derived organoids-based xenograft model than in HbsAg (+) group. CONCLUSIONS: The activation of the immune response induced by HBV infection makes the prognosis of HBV-positive patients with ICC differ from that of uninfected patients.

Distanct ischemic postconditioning in acute mild to moderate ischemic stroke: A randomized clinical study.

OBJECTIVE: Distant ischemic postconditioning (DIPC) has been confirmed to have a neuroprotective effect in animal models of ischemia. However, there are only a few studies on its efficacy and safety in clinical applications. METHOD: We divided 86 patients with acute non-cardiogenic mild to moderate cerebral infarction into DIPC and control groups. RESULT: After 7 days of using different pressure DIPC therapies, the National Institutes of Health Stroke Scale (NIHSS) scores on the eighth day significantly decreased, and modified Rankin scale significantly increased in the DIPC group, compared to that before treatment. On the eight day of admission, the decrease in the NIHSS scores significantly differed between the two groups. However, there was no change in the early neurological deterioration and platelet aggregation rates between the two groups on the eighth day. CONCLUSION: These results demonstrate that DIPC can safely and effectively improve neurological deficits in acute stages of mild to moderate cerebral infarction without affecting the efficacy of antiplatelet drugs.