Cyclophilin J limits linear ubiquitin signaling and controls colorectal cancer progression.

Exorbitant sustained inflammation is closely linked to inflammation-associated disorders, including cancer. The initiation of gastrointestinal cancers such as colorectal cancer (CRC) is frequently accelerated by uncontrollable chronic inflammation which is triggered by excessive activation of nuclear factor kappa-B (NF-κB) signaling. Linear ubiquitin chains play an important role in activating canonical NF-κB pathway. The only known E3 complex, linear ubiquitin assembly complex (LUBAC) is responsible for the synthesis of linear ubiquitin chains, thus leading to the activation of NF-κB axis and promoting the development of inflammation and inflammation-associated cancers. We report here cyclophilin J (CYPJ) is a negative regulator of the LUBAC. The N-terminus of CYPJ binds to the second Npl4-like zinc finger (NZF2) domain of HOIP and the ubiquitin-like (UBL) domain of SHARPIN to disrupt the interaction between HOIP and SHARPIN and thus restrains linear ubiquitin chain synthesis and NF-κB activation. Cypj-deficient mice are highly susceptible to dextran sulfate sodium (DSS)-induced colitis and DSS plus azoxymethane (AOM)-induced colon cancer. Moreover, CYPJ expression is induced by hypoxia. Patients with high expression of both CYPJ and hypoxia-inducible factor-1α (HIF-1α) have longer overall survival and progression-free survival. These results implicate CYPJ as an unexpected robust attenuator of inflammation-driven tumorigenesis that exerts its effects by controlling linear ubiquitin chain synthesis in NF-κB signal pathway.

Inhibition of DKC1 induces telomere-related senescence and apoptosis in lung adenocarcinoma.

BACKGROUND: Lung cancer is one of the most widely spread cancers in the world and half of the non-small cell lung cancers are lung adenocarcinoma (LUAD). Although there were several drugs been approved for LUAD therapy, a large portion of LUAD still cannot be effectively treated due to lack of available therapeutic targets. Here, we investigated the oncogenic roles of DKC1 in LUAD and its potential mechanism and explored the possibility of targeting DKC1 for LUAD therapy. METHODS: The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) databases were used to examine the DKC1 transcript levels. Gene expression with clinical information from tissue microarray of LUAD were analyzed for associations between DKC1 expression and LUAD prognosis. In addition, loss- and gain-of-function assays were used for oncogenic function of DKC1 both in vitro and in vivo. RESULTS: DKC1 is overexpressed in LUAD compared with adjacent normal tissues. High expression of DKC1 predicts the poor overall survival. DKC1 knockdown in LUAD cell lines induced G1 phase arrest and inhibited cell proliferation. Ectopic expression of DKC1 could rescue the growth of LUAD cell lines. In addition, the abundance of DKC1 is positively correlated with telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) levels in LUAD. DKC1 downregulation resulted in decreased TERC expression, reduced telomerase activity and shorten telomere, and thus eventually led to cell senescence and apoptosis. CONCLUSIONS: Our results show that high DKC1 expression indicates poor prognosis of LUAD and DKC1 downregulation could induce telomere-related cell senescence and apoptosis. This study suggests that DKC1 could serve as a candidate diagnostic biomarker and therapeutic target for LUAD.

ARHGEF19 regulates MAPK/ERK signaling and promotes the progression of small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor survival. To identify genes that differentially expressed in SCLC with tumor promotion activity as candidate therapeutic targets, we analyzed the expression of 50 RhoGEFs family genes in published microarray data of SCLC and normal tissues (Gene Expression Omnibus (GEO) dataset GSE43346). We identified ARHGEF19, a member of RhoGEFs family, as an overexpressed oncogene in SCLC. ARHGEF19 is up-regulated in SCLC tissues and ranks first in RhoGEFs family genes. Enforced ARHGEF19 expression promotes SCLC cell proliferation in vitro and its knockdown decreases cell proliferation in vitro and in vivo. ARHGEF19-DH and -PD domain interacts with HRAS and activates the MAPK/ERK pathway in SCLC cells and SCLC xenografts. Our study presents evidences that ARHGEF19 overexpression promotes SCLC cell growth and activates the MAPK/ERK pathway. These findings would shed light on the development of new therapeutics for SCLC management.

SHISA3 Reprograms Tumor-Associated Macrophages Toward an Antitumoral Phenotype and Enhances Cancer Immunotherapy.

The main challenge for immune checkpoint blockade (ICB) therapy lies in immunosuppressive tumor microenvironment (TME). Repolarizing M2-like tumor-associated macrophages (TAMs) into inflammatory M1 phenotype is a promising strategy for cancer immunotherapy. Here, this study shows that the tumor suppressive protein SHISA3 regulates the antitumor functions of TAMs. Local delivery of mRNA encoding Shisa3 enables cancer immunotherapy by reprogramming TAMs toward an antitumoral phenotype, thus enhancing the efficacy of programmed cell death 1 (PD-1) antibody. Enforced expression of Shisa3 in TAMs increases their phagocytosis and antigen presentation abilities and promotes CD8+ T cell-mediated antitumor immunity. The expression of SHISA3 is induced by damage/pathogen-associated molecular patterns (DAMPs/PAMPs) in macrophages via nuclear factor-κB (NF-κB) transcription factors. Reciprocally, SHISA3 forms a complex with heat shock protein family A member 8 (HSPA8) to activate NF-κB signaling thus maintaining M1 polarization of macrophages. Knockout Shisa3 largely abolishes the antitumor efficacy of combination immunotherapy with Toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and PD-1 antibody. It further found that higher expression of SHISA3 in antitumoral TAMs is associated with better overall survival in lung cancer patients. Taken together, the findings describe the role of SHISA3 in reprogramming TAMs that ameliorate cancer immunotherapy.

Changes in sulfur in soybean rhizosphere soil and the response of microbial flora in a continuous cropping system mediated by Funneliformis mosseae.

Soybean is an S-loving crop, and continuous cropping might cause soil sulfur shortage. The primary objectives of this study are to determine whether Funneliformis mosseae (F. mosseae) can enhance the content of available S in S-deficient soil and thereby improve the sulfur utilization rate in soybean. The experiment used Heinong 48 (HN48), a soybean variety with a vast planting area in Heilongjiang Province, and F. mosseae was inoculated in the soil of soybean that had been continuously cropped for 0 and 3 years. The results of the barium sulfur turbidimetric assay show that the sulfur content in the soil and soybean was reduced by continuous cropping and increased by inoculation with F. mosseae; the results of the macro-genome sequencing technology, show that the diversity and abundance of bacteria in the soil was decreased by continuous cropping and increased by inoculation with F. mosseae. The sulfur-oxidizing bacteria (SOB) activity and sulfur-related gene expression levels were lower in the continuous crop group compared to the control group and higher in the F.mosseae-inoculated group compared to the control group. Continuous cropping reduced the sulfur content and ratio of soybean rhizosphere soil, affecting soil flora activity and thus soybean growth; F. mosseae inoculation increased the sulfur content of soybean root-perimeter soil and plants, increased the diversity and abundance of rhizosphere soil microorganisms, increased the expression of genes for sulfur transport systems, sulfur metabolism, and other metabolic functions related to elemental sulfur, and increased the species abundance and metabolic vigor of most SOB. In summary, continuous cropping inhibits soil sulfur uptake and utilization in soybean while the inoculation with F. mosseae can significantly improve this situation. This study offers a theoretical research foundation for using AMF as a bio-fungal agent to enhance soil sulfur use. It also supports the decrease of chemical fertilizers, their substitution, and the protection of native soil.

The Source and Distribution of Tetracycline Antibiotics in China: A Review.

In recent years, antibiotics have been listed as a new class of environmental pollutants. Tetracycline antibiotics (TCs) used in human medical treatment, animal husbandry and agricultural production are the most widely used antibiotics. Due to their wide range of activities and low cost, their annual consumption is increasing. TCs cannot be completely metabolized by humans and animals. They can be abused or overused, causing the continuous accumulation of TCs in the ecological environment and potential negative effects on non-target organisms. These TCs may spread into the food chain and pose a serious threat to human health and the ecology. Based on the Chinese environment, the residues of TCs in feces, sewage, sludge, soil and water were comprehensively summarized, as well as the potential transmission capacity of air. This paper collected the concentrations of TCs in different media in the Chinese environment, contributing to the collection of a TC pollutant database in China, and facilitating the monitoring and treatment of pollutants in the future.

The Food and Drug Administration-approved antipsychotic drug trifluoperazine, a calmodulin antagonist, inhibits viral replication through PERK-eIF2α axis.

Virus-related diseases are seriously threatening human health, but there are currently only 10 viruses with clinically approved antiviral drugs available. As non-cellular organisms, viruses parasitize in living cells and rely on the protein synthesis mechanism of the host cells. In this study, we found that the antipsychotic drug trifluoperazine (TFP), a dual dopamine receptor D2 (DRD2)/calmodulin (CALM) antagonist, increases the phosphorylation of eukaryotic initiation factor 2α (eIF2α), a key factor in the regulation of protein synthesis and significantly inhibits vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) replication. CALM but not DRD2 is involved in the antiviral activity of TFP. By knockdown of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) we found that the antiviral function of TFP is dependent on PERK, a stress response kinase that mediates eIF2α phosphorylation. Furthermore, the results of animal experiments showed that TFP protects mice from lethal VSV attacks, improving the survival rate and reducing lung injury. Taken together, these data suggests that TFP inhibits virus replication through PERK-eIF2α axis, and this broad-spectrum of mechanisms are worth further evaluation in clinical trials in the future.

Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells.

Colorectal cancer, one of the most commonly diagnosed cancers worldwide, is often accompanied by uncontrolled proliferation of tumor cells. Dyskerin pseudouridine synthase 1 (DKC1), screened using the genome-wide RNAi strategy, is a previously unidentified key regulator that promotes colorectal cancer cell proliferation. Enforced expression of DKC1, but not its catalytically inactive mutant D125A, accelerates cell growth in vitro and in vivo. DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation. Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses reveal that DKC1 binds to and stabilizes the mRNA of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34, and RPS3. DKC1 depletion significantly accelerates mRNA decay of these RPs, which mediates the oncogenic function of DKC1. Interestingly, these DKC1-regulated RPs also interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Pyrazofurin and trametinib combination synergistically restrains colorectal cancer cell growth in vitro and in vivo. Furthermore, DKC1 is markedly upregulated in colorectal cancer tissues compared to adjacent normal tissues. Colorectal cancer patients with higher DKC1 expression has consistently poorer overall survival and progression-free survival outcomes. Taken together, these data suggest that DKC1 is an essential gene and candidate therapeutic target for colorectal cancer.

[The effect of rhubarb ethanol-extract on hyperlipidemia and liver fatty in rabbits].

AIM: To observe the effect of rhubarb ethanol-extract on hyperlipidemia and liver fatty in rabbits. METHODS: Thirty healthy male white rabbits were divided randomly into five groups, six rabbits in each group. The rabbits in control group were fed with common forage. The rabbits in model group were fed with high lipid forage. The rabbits in three different rhubarb groups were fed with high lipid forage and treated with different level rhubarb ethanol-extract (REE). In the process of experiment, periodically measured serology index of the rabbits and observed common physiology index. The rabbits were killed at the end of tenth week, liver fatty degeneration degree and liver coefficient were measured and compared. RESULTS: REE could decrease serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), and increase serum high density lipoprotein cholesterol (HDL-C), and reduce liver fatty de generation and protect liver cell function. And the dose-effect relation was showed among different dose REE groups. CONCLUSION: REE can significantly reduce blood lipid, prevent and treat hyperlipidemia and liver fatty.