SAMHD1 dysfunction induces IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells.

Dysfunctional mutations in SAMHD1 cause Aicardi-Goutières Syndrome, an autoinflammatory encephalopathy with elevated interferon-α levels in the cerebrospinal fluid. Whether loss of function mutations in SAMHD1 trigger the expression of other cytokines apart from type I interferons in Aicardi-Goutières Syndrome is largely unclear. This study aimed to explore whether SAMHD1 dysfunction regulated the expression of IL-34, a key cytokine controlling the development and maintenance of microglia, in SH-SY5Y neural cells. We found that downregulation of SAMHD1 in SH-SY5Y cells resulted in the upregulation of IL-34 expression. The protein and mRNA levels of NF-κB p65, the transactivating subunit of a transcription factor NF-κB, were also upregulated in SAMHD1-knockdown SH-SY5Y cells. It was further found SAMHD1 knockdown in SH-SY5Y cells induced an upregulation of IL-34 expression through the canonical NF-κB-dependent pathway in which NF-κB p65, IKKα/ß and the NF-κB inhibitor IκBα were phosphorylated. Moreover, knockdown of SAMHD1 in SH-SY5Y cells led to the translocation of NF-κB p65 into the nucleus and promoted NF-κB transcriptional activity. In conclusion, we found SAMHD1 dysfunction induced IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells. This finding could lay the foundation for exploring the role of IL-34-targeting microglia in the pathogenesis of Aicardi-Goutières Syndrome.

Cellular senescence-related genes: predicting prognosis in hepatocellular carcinoma.

Recent studies have shown that the high incidence and low cure rate of hepatocellular carcinoma (HCC) have not improved significantly. Surgery and liver transplantation are the mainstays of prolonging the survival of HCC patients. However, the surgical resection rate of HCC patients is very low, and even after radical surgical resection, the recurrence rate at 5 years postoperatively remains high and the prognosis is very poor, so more treatment options are urgently needed. Increasing evidence suggests that cellular senescence is not only related to cancer development but may also be one of its primary driving factors. We aimed to establish a prognostic signature of senescence-associated genes to predict the prognosis and therapeutic response of HCC patients. The aim of this study was to develop a risk model associated with cellular senescence and to search for potential strategies to treat HCC. We divided HCC patients into two clusters and identified differentially expressed genes (DEGs) between clusters. In this study, low-risk patients had a better prognosis, higher levels of immune cell infiltration, and better efficacy to fluorouracil, Paclitaxel and Cytarabine chemotherapy compared to high-risk patients. To further identify potential biomarkers for HCC, we further validated the expression levels of the four signature genes in HCC and neighbouring normal tissues by in vitro experiments. In conclusion, we identified and constructed a relevant prognostic signature, which performed well in predicting the survival and treatment response of HCC patients. This helps to differentiate between low-score and high-risk HCC, and the results may contribute to precise treatment protocols in clinical practice.

Correction to "Interleukin-34 promotes the proliferation and epithelial-mesenchymal transition of gastric cancer cells".

[This corrects the article on p. 1968 in vol. 14, PMID: 36310707.].

Aicardi-Goutières syndrome: A monogenic type I interferonopathy.

Aicardi-Goutières syndrome (AGS) is a rare monogenic autoimmune disease that primarily affects the brains of children patients. Its main clinical features include encephalatrophy, basal ganglia calcification, leukoencephalopathy, lymphocytosis and increased interferon-α (IFN-α) levels in the patient's cerebrospinal fluid (CSF) and serum. AGS may be caused by mutations in any one of nine genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11 and RNU7-1) that result in accumulation of self-nucleic acids in the cytoplasm or aberrant sensing of self-nucleic acids. This triggers overproduction of type I interferons (IFNs) and subsequently causes AGS, the prototype of type I interferonopathies. This review describes the discovery history of AGS with various genotypes and provides the latest knowledge of clinical manifestations and causative genes of AGS. The relationship between AGS and type I interferonopathy and potential therapeutic methods for AGS are also discussed in this review.

Effects and mechanisms of trifluridine alone or in combination with cryptotanshinone in inhibiting malignant biological behavior of gastric cancer.

BACKGROUND: The incidence of gastric cancer (GC) ranks fourth among all malignant tumors worldwide, and the fatality rate ranks second among all malignant tumors. Several Chinese traditional medicines have been used in the treatment of advanced gastric cancer. This study aims to investigate the effect of combinational use of natural product cryptotanshinone (CTS) with anti-cancer drug trifluorothymidine (FTD) in GC. METHODS: Cell Counting Kit-8 assay was used to detect the inhibitory effect of the combinational or separate use of FTD and CTS on the growth of HGC-27 and AGS GC cells. The combined index of FTD and CTS was calculated using CompuSyn software. To understand the mechanism, we applied flow cytometry to study the cell cycle and cell apoptosis after treatment. We also investigated the amount of FTD incorporated into the DNA by immunofluorescence assay. The expression of relevant proteins was monitored using western blot. Furthermore, the effect of using TAS-102 in combination with CTS was studied in xenograft tumor nude mice model. RESULTS: FTD and CTS inhibited the growth of GC cells in a dose-dependent manner, respectively. They both exhibited low to sub-micromolar potency in HGC-27 and AGS cells. The combination of FTD and CTS showed synergistic anticancer effect in HGC-27 cells and AGS cells. Our mechanism studies indicate that FTD could block HGC-27 cells at G2/M phase, while CTS could block HGC-27 cells at G1/G0 phase, while FTD combined with CTS could mainly block HGC-27 cells at G2 phase. FTD in combination with CTS significantly increased the apoptosis of HGC-27 cells. We observed that CTS treatment increased the incorporation of FTD into the DNA HGC-27 cell. FTD treatment activated STAT3 phosphorylation in HGC-27 cells, while CTS treatment down-regulated the concentration of p-STAT3. Interestingly, the combination of CTS and FTD reduced STAT3 phosphorylation induced by FTD. In the in vivo experiments, we observed that the combination of TAS-102 with CTS was significantly more potent than TAS-102 on tumor growth inhibition. CONCLUSIONS: FTD combined with CTS has a synergistic anti-gastric cancer effect as shown by in vitro and in vivo experiments, and the combined treatment of FTD and CTS will be a promising treatment option for advanced gastric cancer.

Sp1 Controls the Basal Level of Interleukin-34 Transcription.

Interleukin-34 (IL-34) is a cytokine that plays important roles at steady state and in diseases. The induced or inhibited expression of IL-34 by stimuli has been deeply investigated. However, the regulation of IL-34 basal expression is largely unknown. The aim of this study is to investigate whether IL-34 expression is regulated by a general transcription factor Specificity Protein 1 (Sp1) at transcription level. By using bioinformatic software, four putative Sp1-binding sites overlapping GC boxes were found in the core promoter region of IL-34. Alignment of the core promoter sequences of mammalian IL-34 showed GC box-C (-62/-57) and D (-11/-6) were conserved in some mammals. Luciferase assay results showed that only deletion of GC box-C (-62/-57) significantly reduced luciferase activities of IL-34 core promoter in SH-SY5Y cells. By using electrophoretic mobility shift assay (EMSA), it was found that Sp1 specifically interacted with GC box-C sequence CCCGCC (-62/-57) in the core promoter of IL-34. By using chromatin immunoprecipitation (ChIP), it was discovered that Sp1 bound to the core promoter of IL-34 in living cells. In addition, silencing of Sp1 expression by its specific siRNA reduced IL-34 mRNA and protein levels significantly in SH-SY5Y cells. Likewise, IL-34 expression was inhibited in a dose-dependent manner by a Sp1 inhibitor Plicamycin. Furthermore, silencing of Sp1 also downregulated mRNA and protein expression of IL-34 in GES-1 and 293T cell lines, suggesting that IL-34 transcription regulated by Sp1 was not cell-type specific. Taken together, these results indicate that Sp1 controls the basal level of IL-34 transcription.

Identification of necroptosis-related genes for predicting prognosis and exploring immune infiltration landscape in colon adenocarcinoma.

Background: Necroptosis is a recently discovered form of cell death that plays an important role in the occurrence and development of colon adenocarcinoma (COAD). Our study aimed to construct a risk score model to predict the prognosis of patients with COAD based on necroptosis-related genes. Methods: The gene expression data of COAD and normal colon samples were obtained from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to calculate the risk score based on prognostic necroptosis-related differentially expressed genes (DEGs). Based on the risk score, patients were classified into high- and low-risk groups. Then, nomogram models were built based on the risk score and clinicopathological features. Otherwise, the model was verified in the Gene Expression Omnibus (GEO) database. Additionally, the tumor microenvironment (TME) and the level of immune infiltration were evaluated by "ESTIMATE" and single-sample gene set enrichment analysis (ssGSEA). Functional enrichment analysis was carried out to explore the potential mechanism of necroptosis in COAD. Finally, the effect of necroptosis on colon cancer cells was explored through CCK8 and transwell assays. The expression of necroptosis-related genes in colon tissues and cells treated with necroptotic inducers (TNFα) and inhibitors (NEC-1) was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The risk score was an independent prognostic risk factor in COAD. The predictive value of the nomogram based on the risk score and clinicopathological features was superior to TNM staging. The effectiveness of the model was well validated in GSE152430. Immune and stromal scores were significantly elevated in the high-risk group. Moreover, necroptosis may influence the prognosis of COAD via influencing the cancer immune response. In in-vitro experiments, the inhibition of necroptosis can promote proliferation and invasion ability. Finally, the differential expression of necroptosis-related genes in 16 paired colon tissues and colon cancer cells was found. Conclusion: A novel necroptosis-related gene signature for forecasting the prognosis of COAD has been constructed, which possesses favorable predictive ability and offers ideas for the necroptosis-associated development of COAD.

Interleukin-34 promotes the proliferation and epithelial-mesenchymal transition of gastric cancer cells.

BACKGROUND: Interleukin (IL)-34 is a pro-inflammatory cytokine involved in tumor development. The role of IL-34 in the proliferation and epithelial-mesenchymal transition (EMT) of gastric cancer (GC) remains to be investigated. AIM: To investigate whether and how IL-34 affects the proliferation of GC cells and EMT. METHODS: Using immunohistochemical staining, the expression of IL-34 protein was detected in 60 paired GC and normal paracancerous tissues and the relationship between IL-34 and clinicopathological factors was analyzed. The expression of IL-34 mRNA and protein in normal gastric epithelial cell lines and GC was detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Stable IL-34 knockdown and overexpression in AGS cell lines were established by lentiviral infection and validated by qRT-PCR and western blotting. The cholecystokinin-8 assay, clone formation assay, cell scratch assay, and transwell system were used to detect GC cell proliferation, clone formation, migration, and invasion capacity, respectively. The effects of IL-34 on the growth of GC transplant tumors were assessed using a subcutaneous transplant tumor assay in nude mice. The effects of IL-34 on the expression level of EMT-associated proteins in AGS cells were examined by western blotting. RESULTS: Expression of IL-34 protein and mRNA was higher in GC cell lines than in GES-1 cells. Compared to matched normal paraneoplastic tissues, the expression of IL-34 protein was higher in 60 GC tissues, which was correlated with tumor size, T-stage, N-stage, tumor, node and metastasis stage, and degree of differentiation. Knockdown of IL-34 expression inhibited the proliferation, clone formation, migration, and invasion of AGS cells, while overexpression of IL-34 promoted cell proliferation, clone formation, migration, and invasion. Furthermore, the reduction of IL-34 promoted the expression of E-cadherin in AGS cells but inhibited the expression of vimentin and N-cadherin. Overexpression of IL-34 inhibited E-cadherin expression but promoted expression of vimentin and N-cadherin in AGS cells. Overexpression of IL-34 promoted the growth of subcutaneous transplanted tumors in nude mice. CONCLUSION: IL-34 expression is increased in GC tissues and cell lines compared to normal gastric tissues or cell lines. In GC cells, IL-34 promoted proliferation, clone formation, migration, and invasion by regulating EMT-related protein expression cells. Interference with IL-34 may represent a novel strategy for diagnosis and targeted therapy of GC.

SAMHD1, positively regulated by KLF4, suppresses the proliferation of gastric cancer cells through MAPK p38 signaling pathway.

SAMHD1 was reported to be related with the development of tumors, while its function in gastric cancer (GC) has not been elucidated yet. Here, we investigated the role and mechanism of SAMHD1 in regulating the proliferation of GC, as well as the mechanism of its expression regulation. Our results revealed that SAMHD1 was downregulated in GC tissues and cell lines, which was correlated with tumor size, depth of invasion and TNM stage. Overexpression of SAMHD1 inhibited the proliferation, clone formation, DNA synthesis and cell cycle progression, while knockdown of SAMHD1 promoted the proliferation of GC cells in vitro and vivo. Meanwhile, SAMHD1 inhibited the activation of MAPK p38 signaling pathway. Moreover, SB203580, as a MAPK p38 inhibitor, could reverse the proliferation and activation of MAPK p38 signaling pathway caused by knockdown of SAMHD1 in GC cells. Additionally, transcription factor Krüppel-like factor 4 (KLF4) bound to the core promoter of SAMHD1, increasing its transcriptional expression in GC cells. In conclusion, SAMHD1 suppressed the proliferation of GC through negatively regulating the activation of MAPK p38 signaling pathway and was upregulated by KLF4 in GC cells.

Cryptotanshinone inhibits cytotoxin-associated gene A-associated development of gastric cancer and mucosal erosions.

BACKGROUND: Approximately 90% of new cases of noncardiac gastric cancer (GC) are related to Helicobacter pylori (H. pylori), and cytotoxin-associated gene A (CagA) is one of the main pathogenic factors. Recent studies have shown that the pharmacological effects of cryptotanshinone (CTS) can be used to treat a variety of tumors. However, the effects of CTS on H. pylori, especially CagA+ strain-induced gastric mucosal lesions, on the development of GC is unknown. AIM: To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells, and determine if CagA+ H. pylori strains causes pathological changes in the gastric mucosa of mice. METHODS: The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8 (CCK-8) assay, and the abnormal growth, migration and invasion caused by CagA were detected by CCK-8 and transwell assays. After transfection with pSR-HA-CagA and treatment with CTS, proliferation and metastasis were evaluated by CCK-8 and transwell assays, respectively, and the expression of Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) and phosphorylated SHP2 (p-SHP2) was detected using western blotting in AGS cells. The enzyme-linked immunosorbent assay was used to determine the immunoglobulin G (IgG) level against CagA in patient serum. Mice were divided into four groups and administered H. pylori strains (CagA+ or CagA-) and CTS (or PBS) intragastrically, and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated strains. Hematoxylin and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and kidney. RESULTS: CTS inhibited the growth of GC cells in dose- and time-dependent manners. Overexpression of CagA promoted the growth, migration, and invasion of GC cells. Importantly, we demonstrated that CTS significantly inhibited the CagA-induced abnormal proliferation, migration, and invasion of GC cells. Moreover, the expression of p-SHP2 protein in tumor tissue was related to the expression of IgG against CagA in the serum of GC patients. Additionally, CTS suppressed the protein expression levels of both SHP2 and p-SHP2 in GC cells. CTS suppressed CagA+ H. pylori strain-induced mucosal erosion in the stomach of mice but had no obvious effects on the CagA- H. pylori strain group. CONCLUSION: CTS inhibited CagA-induced proliferation and the epithelial-mesenchymal transition of GC cells in vitro, and CagA+ H. pylori strains caused mucosal erosions of the stomach in vivo by decreasing the protein expression of SHP2.

Case Report: Aicardi-Goutières Syndrome Caused by Novel TREX1 Variants.

TREX1 (three prime repair exonuclease 1) gene encodes DNA 3' end repair exonuclease that plays an important role in DNA repair. Mutations in TREX1 gene have been identified as the cause of a rare autoimmune neurological disease, Aicardi-Goutières syndrome (AGS). Here, we report an AGS case of a 6-month-old Chinese girl with novel TREX1 variants. The patient had mild rashes on the face and legs, increased muscle tensions in the limbs, and positive cervical correction reflex. Cranial magnetic resonance imaging showed that there were patches of slightly longer T1 and T2 signals in the bilateral cerebral hemisphere and brainstem white matter, mainly in the frontotemporal lobe, together with decreased white matter volume, enlarged ventricles, and widened sulcus fissure. Total exon sequencing showed that the TREX1 gene of the child had mutations of c.137_138insC and c.292_293insA, which had not been reported before. In addition, elevated type I interferons were detected by using enzyme-linked immunosorbent assay in the patient's serum. Together, our study demonstrated that novel TREX1 variants (c.137_138insC and c.292_293insA) cause AGS for the first time.

Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs.

Human sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) has been identified as a GTP or dGTP-dependent deoxynucleotide triphosphohydrolase (dNTPase) and acts as an antiviral factor against certain retroviruses and DNA viruses. Genetic mutation in SAMHD1 causes the inflammatory Aicardi-Goutières Syndrome and abnormal intracellular deoxyribonucleoside triphosphates (dNTPs) pool. At present, the role of SAMHD1 in numerous types of cancer, such as chronic lymphocytic leukemia, lung cancer and colorectal cancer, is highly studied. Furthermore, it has been found that methylation, acetylation and phosphorylation are involved in the regulation of SAMHD1 expression, and that genetic mutations can cause changes in its activities, including dNTPase activity, long interspersed element type 1 (LINE-1) suppression and DNA damage repair, which could lead to uncontrolled cell cycle progression and cancer development. In addition, SAMHD1 has been reported to have a negative regulatory role in the chemosensitivity to anticancer drugs through its dNTPase activity. The present review aimed to summarize the regulation of SAMHD1 expression in cancer and its function in tumor growth and chemotherapy sensitivity, and discussed controversial points and future directions.

MiR-122-5p suppresses the proliferation, migration, and invasion of gastric cancer cells by targeting LYN.

Gastric cancer (GC) is one of malignant tumors with high mortality and morbidity in the world. MicroRNA-122 (miR-122) acts as a tumor suppressor in a variety of cancers and has been found to be dominant in gastric adenocarcinoma. However, the specific biological function of miR-122-5p in GC is not completely clear. In this study, we found that miR-122-5p was low-expressed in GC tissues and cell lines by using qRT-PCR. Overexpression of miR-122-5p inhibited the proliferation, migration, and invasion of GC cells by using CCK-8 and transwell assays. On the contrary, downregulation of miR-122-5p promoted the proliferation, migration, and invasion of GC cells. In addition, we found that the expression of LYN, an Src family tyrosine kinase, was inversely correlated with miR-122-5p expression in GC tissues by using western blot analysis, immunohistochemistry, and qRT-PCR assays. Meanwhile, luciferase assay results indicated that LYN is a direct target of miR-122-5p in GC cells. Moreover, silencing LYN expression by its siRNA inhibited the proliferation, migration, and invasion of GC cells. Importantly, overexpression of LYN restored miR-122-5p-mediated inhibition of the proliferation, migration, and invasion of GC cells. Taken together, our results indicated miR-122-5p inhibited the proliferation, migration, and invasion by targeting LYN in GC.

Voltage-gated sodium channel Nav1.5 promotes proliferation, migration and invasion of oral squamous cell carcinoma.

The protein voltage-gated sodium channel Nav1.5 is highly upregulated in various types of cancer and, in general, promotes cancer cell invasiveness and metastatic progression. A previous study found that Nav1.5 was highly expressed in poorly differentiated oral squamous cell carcinoma (OSCC). However, whether Nav1.5 enhances invasiveness and metastasis of OSCC are still unknown. In this study, we found that Nav1.5 was highly expressed in OSCC cell lines compared with normal oral keratinocyte HOK cell line by using western blot analysis. CCK-8 assay results revealed that downregulation of Nav1.5 expression by its specific siRNA reduced proliferation of OSCC HSC-3 cells. Moreover, transwell assay results showed Nav1.5 knockdown significantly inhibited migration and invasion of HSC-3 cells. Meanwhile, qRT-PCR and western blot analysis results showed that epidermal growth factor (EGF) induced Nav1.5 expression in a time- and dose-dependent manner. In addition, EGF promoted proliferation, migration and invasion of HSC-3 cells. Importantly, the Nav1.5 inhibitor tetrodotoxin significantly inhibited the proliferation of HSC-3 cells and impeded the migration and invasion of HSC-3 cells. Furthermore, it was found that siRNA-mediated knockdown of Nav1.5 also lessened the proliferation of HSC-3 cells and blocked the migration and invasion of HSC-3 cells. Taken together, these results indicate that Nav1.5 is involved in the progression of OSCC and Nav1.5 promotes the proliferation, migration and invasion of OSCC cells.

MicroRNA-31 Negatively Regulates Interleukin-34 Expression In Vitro.

Interleukin-34 (IL-34) is a recently discovered cytokine that promotes tissue macrophage maturation and differentiation. We previously found that 1α,25-Dihydroxyvitamin D3 up-regulated IL-34 expression in SH-SY5Y neural cells. However, whether microRNA regulates IL-34 expression is not completely clear. By using on-line TargetScan and MiRanda software, we found that there was only one conserved microRNA-31 (miR-31) binding site in the 3' untranslated region (3'UTR) of IL-34 mRNA. Intriguingly, using qPCR we demonstrated that miR-31 levels were negatively correlated to IL-34 mRNA levels in different cell lines. By examining the effect of miR-31 on IL-34 3' UTR reporter luciferase activity and on IL-34 mRNA and argonaute RISC catalytic component 2 (AGO2) binding, it was found that miR-31 bound directly to IL-34 3'UTR and regulated the post-transcriptional expression of IL-34 in MGC-803 cells. Moreover, a miR-31 mimic significantly reduced IL-34 expression levels while a miR-31 inhibitor up-regulated IL-34 expression in KYSE-45 and HT-29 cells. Taken together, these results show that miR-31 negatively regulates IL-34 expression by directly binding to the IL-34 3' UTR in vitro.

The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology.

Voltage-gated sodium channels (VGSCs) are transmembrane proteins which function as gates that control the flux of ions across the cell membrane. They are key ion channels for action potentials in excitable tissues and have important physiological functions. Abnormal function of VGSCs will lead to dysfunction of the body and trigger a variety of diseases. Various studies have demonstrated the participation of VGSCs in the progression of different tumors, such as prostate cancer, cervical cancer, breast cancer, and others, linking VGSC to the invasive capacity of tumor cells. However, it is still unclear whether the VGSC regulate the malignant biological behavior of tumors. Therefore, this paper systematically addresses the latest research progress on VGSCs subunits and tumors and the underlying mechanisms, and it summarizes the potential of VGSCs subunits to serve as potential targets for tumor diagnosis and treatment.

Inhibitory effects of isocryptotanshinone on gastric cancer.

Gastric cancer (GC) is one of the most common digestive malignancies globally, and the prognosis of patients with advanced tumors remains poor. Isocryptotanshinone (ICTS), isolated from Salvia miltiorrhiza, was found to inhibit the proliferation of lung and breast cancer cells. However, whether ICTS has anticancer activities against GC is unknown. In the present study, we reported that the proliferation of GC cells was inhibited by ICTS in a dose- and time-dependent manner. After treatment with ICTS, GC cells were arrested in the G1/G0 phase of cell cycle and the apoptotic cells were induced in a dose-dependent manner. Additionally, ICTS suppressed the expression of cell cycle- and apoptosis-associated proteins (e.g., Cyclin D1, phosphorylated Rb, E2F1, Mcl-1, Bcl-2, and Survivin). ICTS inhibited the phosphorylation of STAT3 in a dose-dependent manner. Down-regulated STAT3 attenuated the expression of Cyclin D1, p-Rb, and Survivin, which remarkably increased the sensitivity of ICTS in GC cells; overexpression of STAT3 restored the cell growth and proliferation and the protein expression suppressed by ICTS. ICTS also suppressed the xenograft tumor growth in BALB/c nude mice. Together, these data indicate that ICTS inhibits GC proliferation by inducing G1/G0 cell cycle arrest and apoptosis via inhibiting the STAT3 signaling pathway.

1α,25-Dihydroxyvitamin D3 up-regulates IL-34 expression in SH-SY5Y neural cells.

Vitamin D supplementation is regarded as a novel approach to treat Alzheimer's disease, but the underlying mechanism remains elusive. The cytokine IL-34 provides strong neuroprotective and survival signals in brain injury and neurodegeneration and could be an immunological mediator for the vitamin D-induced protection. The aim of this study was to investigate whether human IL-34 is up-regulated in neuronal cells by the hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. We found that IL-34 was detectable in a variety of cell lines and its expression was strongly induced in SH-SY5Y neural cells in a dose- and time-dependent manner by 1α,25(OH)2D3 through the vitamin D receptor (VDR). Furthermore, we identified the core promoter of IL-34 gene and a VDR binding site (CGCCCT) that was required for 1α,25(OH)2D3-induced IL-34 expression. These findings suggest that the induction of IL-34 expression by 1α,25(OH)2D3 may constitute a mechanism that explains the protective function of vitamin D in Alzheimer's disease.

Roles of SAMHD1 in antiviral defense, autoimmunity and cancer.

The enzyme, sterile α motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) diminishes infection of human immunodeficiency virus type 1 (HIV-1) by hydrolyzing intracellular deoxynucleotide triphosphates (dNTPs) in myeloid cells and resting CD4+ T cells. This dNTP degradation reduces the dNTP concentration to a level insufficient for viral cDNA synthesis, thereby inhibiting retroviral replication. This antiviral enzymatic activity can be inhibited by viral protein X (Vpx). The HIV-2/SIV Vpx causes degradation of SAMHD1, thus interfering with the SAMHD1-mediated restriction of retroviral replication. Recently, SAMHD1 has been suggested to restrict HIV-1 infection by directly digesting genomic HIV-1 RNA through a still controversial RNase activity. Here, we summarize the current knowledge about structure, antiviral mechanisms, intracellular localization, interferon-regulated expression of SAMHD1. We also describe SAMHD1-deficient animal models and an antiviral drug on the basis of disrupting proteasomal degradation of SAMHD1. In addition, the possible roles of SAMHD1 in regulating innate immune sensing, Aicardi-Goutières syndrome and cancer are discussed in this review.