LncRNA CHROMR/miR-27b-3p/MET axis promotes the proliferation, invasion, and contributes to rituximab resistance in diffuse large B-cell lymphoma.

Long non-coding RNAs (LncRNAs) could regulate chemoresistance through sponging microRNAs (miRNAs) and sequestering RNA binding proteins. However, the mechanism of lncRNAs in rituximab resistance in diffuse large B-cell lymphoma (DLBCL) is largely unknown. Here, we investigated the functions and molecular mechanisms of lncRNA CHROMR in DLBCL tumorigenesis and chemoresistance. LncRNA CHROMR is highly expressed in DLBCL tissues and cells. We examined the oncogenic functions of lncRNA CHROMR in DLBCL by a panel of gain-or-loss-of-function assays and in vitro experiments. LncRNA CHROMR suppression promotes CD20 transcription in DLBCL cells and inhibits rituximab resistance. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assay reveal that lncRNA CHROMR sponges with miR-27b-3p to regulate mesenchymal-epithelial transition factor (MET) levels and Akt signaling in DLBCL cells. Targeting the lncRNA CHROMR/miR-27b-3p/MET axis reduces DLBCL tumorigenesis. Altogether, these findings provide a new regulatory model, lncRNA CHROMR/miR-27b-3p/MET, which can serve as a potential therapeutic target for DLBCL.

Hexokinase 2 nonmetabolic function-mediated phosphorylation of IκBα enhances pancreatic ductal adenocarcinoma progression.

Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic function of hexokinase 2 (HK2) plays a role in tumor immune evasion. However, whether HK2, dependent of its nonmetabolic activity, plays a role in human pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains unclear. Here, we demonstrated that HK2 acts as a protein kinase and phosphorylates IκBα at T291 in PDAC cells, activating NF-κB, which enters the nucleus and promotes the expression of downstream targets under hypoxia. HK2 nonmetabolic activity-promoted activation of NF-κB promotes the proliferation, migration, and invasion of PDAC cells. These findings provide new insights into the multifaceted roles of HK2 in tumor development and underscore the potential of targeting HK2 protein kinase activity for PDAC treatment.

MTF1 genetic variants are associated with lung cancer risk in the Chinese Han population.

BACKGROUND: Metal-regulatory transcription factor 1 (MTF1), a conserved metal-binding transcription factor in eukaryotes, regulates the proliferation of cancer cells by activating downstream target genes and then participates in the formation and progression of tumors, including lung cancer (LC). The expression level of MTF1 is down-regulated in LC, and high expression of MTF1 is associated with a good prognosis of LC. However, the association between MTF1 polymorphism and LC risk has not been explored. METHODS: The genotyping of MTF1 Single nucleotide polymorphisms (SNPs) including rs473279, rs28411034, rs28411352, and rs3748682 was identified by the Agena MassARRAY system among 670 healthy controls and 670 patients with LC. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistics regression to assess the association of these SNPs with LC risk. RESULTS: MTF1 rs28411034 (OR 1.22, 95% CI 1.03-1.45, p = 0.024) and rs3748682 (OR 1.24, 95% CI 1.04-1.47, p = 0.014) were associated with higher LC susceptibility overall. Moreover, the effect of rs28411034 and rs3748682 on LC susceptibility was observed in males, subjects with body mass index (BMI) ≥ 24 kg/m2, smokers, drinkers, and patients with lung squamous carcinoma (OR and 95% CI > 1, p < 0.05). Besides, rs28411352 (OR 0.73, 95% CI 0.55-0.97, p = 0.028,) showed protective effect for reduced LC risk in drinkers. CONCLUSIONS: We were first who reported that rs28411034 and rs3748682 tended to be relevant to increased LC susceptibility among the Chinese Han population. These results of this study could help to recognize the pathogenic mechanisms of the MTF1 gene in LC progress.

Thalassotalea psychrophila sp. nov., Thalassotalea nanhaiensis sp. nov. and Thalassotalea fonticola sp. nov., three psychrophilic bacteria isolated from deep-sea sediment.

Three psychrophilic bacteria, designated as strains SQ149T, SQ345T, and S1-1T, were isolated from deep-sea sediment from the South China Sea. All three strains were the most closely related to Thalassotalea atypica RZG4-3-1T based on the 16S rRNA gene sequence analysis (similarity ranged from 96.45 to 96.67 %). Phylogenetic analysis based on the 16S rRNA gene and core-genome sequences showed that three strains formed a cluster within the genus Thalassotalea. The average amino acid identity, average nucleotide identity, and digital DNA-DNA hybridization values among the three strains and closest Thalassotalea species were far below the cut-off value recommended for delineating species, indicating they each represented a novel species. All three strains were Gram-stain-negative, rod-shaped, and contained summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) as the predominant fatty acid, Q-8 as the major respiratory quinone, and phosphatidylethanolamine and phosphatidylglycerol as predominant polar lipids. Based on the genomic, phylogenetic, and phenotypic characterizations, each strain is considered to represent a novel species within the genus Thalassotalea, for which the names Thalassotalea psychrophila sp. nov. (type strain SQ149T=MCCC 1K04231T=JCM 33807T), Thalassotalea nanhaiensis sp. nov. (type strain SQ345T=MCCC 1K04232T=JCM 33808T), and Thalassotalea fonticola sp. nov. (type strain S1-1T=MCCC 1K06879T=JCM 34824T) are proposed.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

The varied restorative values of campus landscapes to students' well-being: evidence from a Chinese University.

BACKGROUND: The literature on therapeutic landscapes highlights that the university campus landscape has restorative effects on students. This deserves more scholarly attention since mental health has become an important issue among university students. However, existing empirical studies have revealed mixed evidence with little attention to the heterogeneity across the design and, therefore, the potential therapeutic effects across different landscapes. METHOD: This research examined how 13 landscape sites on a university campus might be differentially related to student well-being. These sites were identified from a variety of sources (campus design documents, photos used in the university's social media posts, and interviews with a small group of students) to represent a comprehensive list of places that students might visit. The data was collected in a large online survey of a Chinese university (n = 2,528). We asked about students' use of individual landscape sites and the associated motivations for visits, and measured well-being using a perceived stress scale and overall evaluation of the happiness level. Bivariate analysis was used to explore the zero-order associations between landscape use and well-being. OLS (for stress) and logistic regressions (for happiness) were conducted to further evaluate the associations after controlling the student background variables and potential correlations of uses across different landscapes. RESULTS: Among 13 landscape sites, four sites had significant positive associations with either or both measures of well-being after controlling for the student characteristics and use of the other landscape sites. There was also an additive benefit of visiting more landscapes. Compared to those who did not frequently visit any of the sites, well-being had a significant stepwise increase among those who frequently visited one or two and more sites. One site that was significantly related to both measures of well-being only offered distant views of landscapes, but it was right next to the study areas. CONCLUSIONS: This study demonstrates the heterogeneity of restorative effects across different landscapes on campus. The findings suggest that effective landscape design that aims to promote student well-being should be placed close to stressors (i.e., where they study), and between where they study and live to offer students opportunities to break from the common routines and to relax. The findings hold greater relevance for universities in China and institutions with similar student campus lifestyles, occupancies, and behavior patterns worldwide.

Multiple machine-learning tools identifying prognostic biomarkers for acute Myeloid Leukemia.

BACKGROUND: Acute Myeloid Leukemia (AML) generally has a relatively low survival rate after treatment. There is an urgent need to find new biomarkers that may improve the survival prognosis of patients. Machine-learning tools are more and more widely used in the screening of biomarkers. METHODS: Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), Random Forest (RF), eXtreme Gradient Boosting (XGBoost), lrFuncs, IdaProfile, caretFuncs, and nbFuncs models were used to screen key genes closely associated with AML. Then, based on the Cancer Genome Atlas (TCGA), pan-cancer analysis was performed to determine the correlation between important genes and AML or other cancers. Finally, the diagnostic value of important genes for AML was verified in different data sets. RESULTS: The survival analysis results of the training set showed 26 genes with survival differences. After the intersection of the results of each machine learning method, DNM1, MEIS1, and SUSD3 were selected as key genes for subsequent analysis. The results of the pan-cancer analysis showed that MEIS1 and DNM1 were significantly highly expressed in AML; MEIS1 and SUSD3 are potential risk factors for the prognosis of AML, and DNM1 is a potential protective factor. Three key genes were significantly associated with AML immune subtypes and multiple immune checkpoints in AML. The results of the verification analysis show that DNM1, MEIS1, and SUSD3 have potential diagnostic value for AML. CONCLUSION: Multiple machine learning methods identified DNM1, MEIS1, and SUSD3 can be regarded as prognostic biomarkers for AML.

Influence of myoglobin on the antibacterial activity of carvacrol and the binding mechanism between the two compounds.

BACKGROUND: Myoglobin (MB), a pigmentation protein, can adversely affect the antibacterial activity of carvacrol (CAR) and weaken its bacteriostasis effect. This study aimed to clarify the influence of MB on the antibacterial activity of CAR and ascertain the mechanism involved in the observed influence, especially the interaction between the two compounds. RESULTS: Microbiological analysis indicated that the presence of MB significantly suppressed the antibacterial activity of CAR against Listeria monocytogenes. Ultraviolet-visible spectrometry and fluorescence spectroscopic analysis confirmed the interaction between CAR and MB. The stoichiometric number was determined as ~0.7 via double logarithmic Stern-Volmer equation analysis, while thermodynamic analysis showed that the conjugation of the two compounds occurred as an exothermal reaction (ΔH° = -32.3 ± 11.4 kJ mol-1 and ΔS° = -75 J mol-1 K-1 ). Circular dichroism, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy showed hydrogen bonding in the carvacrol-myoglobin complex (CAR-MB). Molecular docking analysis confirmed that amino acid residues, including GLY80 and HIS82, were most likely to form hydrogen bonds with CAR, while hydrogen bonds represented the main driving force for CAR-MB formation. CONCLUSION: CAR antibacterial activity was significantly inhibited by the presence of MB in the environment due to the notable reduction in the effective concentration of CAR caused by CAR-MB formation. © 2023 Society of Chemical Industry.

Identification of host gene-microbiome associations in colorectal cancer patients using mendelian randomization.

BACKGROUND: There are many studies indicating that alterations in the abundance of certain gut microbiota are associated with colorectal cancer (CRC). However, a causal relationship has not been identified due to confounding factors such as lifestyle, environmental, and possible reverse causal associations between the two. Furthermore, certain host gene mutations can also contribute to the development of CRC. However, the association between genes and gut microbes in patients with CRC has not been extensively studied. METHODS: We conducted a two-sample Mendelian randomization (MR) study to reveal the causal relationship between gut microbiota and CRC. We obtained SNPs associated with gut microbiome abundance as instrumental variables (IVs) from a large-scale, multi-ethnic GWAS study, and extracted CRC-related datasets from an East Asian Population genetic consortia GWAS (AGWAS) study and FinnGen consortium, respectively. We analyzed a total of 166 bacterial features at four taxonomic levels, including order, family, genus, and species. The inverse-variance-weighted (IVW), weighted median, MR-Egger, and simple median methods were applied to the MR analysis, and the robustness of the results were tested using a series of sensitivity analyses. We extracted IVs of gut microbiota with direct causal association with CRC for SNP annotation to identify the genes in which these genetic variants were located to reveal the possible host gene-microbiome associations in CRC patients. RESULTS: The findings from our MR analysis based on CRC-associated GWAS datasets from AGWAS revealed causal relationships between 6 bacterial taxa and CRC at a locus-wide significance level (P < 1 × 10-5). The IVW method found that family Porphyromonadaceae, genera Anaerotruncus, Intestinibacter, Slackia, and Ruminococcaceae UCG004, and species Eubacterium coprostanoligenes group were positively associated with CRC risk, which was generally consistent with the results of other complementary analyses. The results of a meta-analysis of the MR estimates from the AGWAS and the FinnGen datasets showed that family Porphyromonadaceae and genera Slackia, Anaerotruncus, and Intestinibacter replicated the same causal association. Sensitivity analysis of all causal associations did not indicate significant heterogeneity, horizontal pleiotropy, or reverse causal associations. We annotated the SNPs at a locus-wide significance level of the above intestinal flora and identified 24 host genes that may be related to pathogenic intestinal microflora in CRC patients. CONCLUSION: This study supported the causal relationship of gut microbiota on CRC and revealed a possible correlation between genes and pathogenic microbiota in CRC. These findings suggested that the study of the gut microbiome and its further multi-omics analysis was important for the prevention and treatment of CRC.

GIPC1 CGG Repeat Expansion Is Associated with Movement Disorders.

OBJECTIVE: CGG/GGC repeat expansion in FMR1 and NOTCH2NLC is reportedly associated with movement disorders; therefore, we hypothesized that the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1, which was previously identified in myopathy, might also be associated with movement-disorder phenotypes. Here, we investigated whether CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 presents in a cohort of patients with movement disorders. METHODS: We screened for the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 in 1,346 movement-disorder patients and 1,451 matched healthy controls. RESULTS: No patients or controls harbored expanded CGG repeats in LRP12 or NUTM2B-AS1, whereas 16 patients harbored >40 CGG repeats in GIPC1, with 11 of these patients harboring >60 CGG repeats. One control individual harbored an expanded GIPC1 allele (83 CGG units), suggesting that approximately 1% of patients affected by movement disorders in our population might harbor GIPC1 CGG repeat expansion, with this likely extremely rare in healthy controls (<0.001). The clinical phenotypes of the GIPC1 CGG repeat-positive patients strongly resembled those in patients displaying NOTCH2NLC GGC repeat-positive movement disorders. Additionally, the GIPC1 CGG repeat-positive patients presented white-matter hyperintensities but without typical NOTCH2NLC-related high-intensity signals in the corticomedullary junction. Furthermore, 44% of the GIPC1 CGG repeat-positive patients showed a cognitive deficit, and skin biopsies in 2 patients revealed deposition of intranuclear inclusions. INTERPRETATION: The CGG repeat expansion in GIPC1 might be associated with movement-disorder phenotypes and lead to diseases related to intranuclear inclusions. ANN NEUROL 2022;91:704-715.

Dasatinib in combination with BMS-754807 induce synergistic cytotoxicity in lung cancer cells through inhibiting lung cancer cell growth, and inducing autophagy as well as cell cycle arrest at the G1 phase.

Lung cancer is the leading cause of cancer-related deaths worldwide. Combination of drugs targeting independent signaling pathways would effectively block the proliferation of cancer cells with lower concentrations and stronger synergy effects. Dasatinib, a multi-targeted protein tyrosine kinase inhibitor targeting BCR-ABL and kinases of SRC family, has been successfully applied in the treatment of chronic myeloid leukemia (CML). BMS-754807, an inhibitor targeting the insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor (IR) family kinases, has been in phase I development for the treatment of a variety of human cancers. Herein, we demonstrated that dasatinib in combination with BMS-754807 inhibited lung cancer cell growth, while induced autophagy as well as cell cycle arrest at the G1 phase. Dasatinib in combination with BMS-754807 suppressed the expression of cell cycle marker proteins, Rb, p-Rb, CDK4, CDK6 and Cyclin D1, and the PI3K/Akt/mTOR signaling pathway. Dasatinib in combination with BMS-754807 induced autophagy in lung cancer cells, evidenced by the upregulation of LC3B II and beclin-1, the downregulation of LC3B I and SQSTM1/p62, and the autophagic flux observed with a confocal fluorescence microscopy. Furthermore, dasatinib (18 mg/kg) in combination with BMS-754807 (18 mg/kg) inhibited the growth of tumors in NCI-H3255 xenografts without changing the bodyweight. Overall, our results suggest that dasatinib in combination with BMS-754807 inhibits the lung cancer cell proliferation in vitro and tumor growth in vitro, which indicates promising evidence for the application of the drug combination in lung cancer therapy.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Inactivation of horseradish peroxidase with crotonic acid for reprobing of western blotting.

Inactivation of horseradish peroxidase (HRP) treatment is a conventional preference to stripping for sequential detections of different proteins of chemiluminescent western blotting (WB). However, little evidence exists on whether other chemical substances treatment can affects the biological activity of HRP during stripping and re-probing of WB blots. Here, we successfully develop 20% crotonic acid (CA) as an alternative to stripping to inhibit HRP used for sequential chemiluminescent WB on polyvinylidene difluoride (PVDF) and Nitrocellulose (NC) membrane. Moreover, NC blots incubation in CA (40 °C, 30min) allow us to perform three round HRP inhibition in sequential detections without losing transferred proteins and damaging membrane. Hence, the method will help us save time and valuable samples without the need to rerun gels.

Parasedimentitalea psychrophila sp. nov., a psychrophilic bacterium isolated from deep-sea sediment.

A novel bacterium, strain QS115T, was isolated from deep-sea sediment collected from the South China Sea at a depth of 1151 m. Phylogenetic analyses based on 16S rRNA gene sequences indicated that QS115T was most closely related to Parasedimentitalea marina W43T, with similarity of 98.21 %. Strain QS115T shared 82.39 % average nucleotide identity, 26.3 % digital DNA-DNA hybridization and 85.32 % average amino acid identity with P. marina W43T. Cells of strain QS115T were Gram-stain-negative, rod-shaped and grew optimally at 10 °C, pH 7.5 and 2 % (w/v) NaCl. The principal fatty acids were summed feature 8 (C18 : 1 ω7c/ω6c), the major respiratory quinone was ubiquinone-10 and predominant polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, glycophospholipid, phosphatidylglycerol and phosphatidylcholine. Polyphasic analyses of physiological and phenotypic characteristics and genomic studies suggested that strain QS115T represents a novel species of the genus Parasedimentitalea, for which the name Parasedimentitalea psychrophila sp. nov. is proposed (type strain QS115T=MCCC 1K04395T=JCM 34219T).

Identifying causal genes for migraine by integrating the proteome and transcriptome.

BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.

Effects of mokF gene deletion and overexpression on the Monacolin K metabolism yields of Monascus purpureus.

Monascus purpureus is a fungus known for producing various physiologically active secondary metabolites. Of these, Monacolin K, a compound with hypocholesterolemic effects, is controlled by the biosynthetic gene mokF. Here, mokF deletion and overexpression strains (F2 and C3, respectively) were constructed using genetic engineering and compared with the M. purpureus wild strain (M1). The results showed that Monacolin K production was reduced by 50.86% in F2 and increased by 74.19% in C3. Of the three strains, C3 showed the highest production of Monacolin K and the most abnormal morphology. In addition, mokF influenced the expression level of mokA-mokI and might play an important role in regulating the biosynthesis of secondary metabolites in M. purpureus. Overall, our study verified the function of mokF in M. purpureus using gene deletion and overexpression technology. KEY POINTS: • The deletion and overexpression strains of mokF gene were successfully constructed. • The deletion or overexpression of mokF gene directly affected Monacolin K production. •The mokF gene had little effect on Monascus pigments and cell biomass.

Association of CYP19A1 rs28757157 polymorphism with lung cancer risk in the Chinese Han population.

BACKGROUND: Lung cancer is the leading cause of cancer death globally. Recent studies have revealed that CYP19A1 gene plays a crucial role in cancer initiation and development. The aim of this study was to assess the association of CYP19A1 genetic polymorphisms with the risk of lung cancer in the Chinese Han population. METHODS: This study randomly recruited 489 lung cancer patients and 467 healthy controls. The genotypes of four single nucleotide polymorphisms (SNPs) of the CYP19A1 gene were identified by the Agena MassARRY technique. Genetic model analysis was used to assess the association between genetic variations and lung cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the effect of four selected SNPs on lung cancer risk. RESULTS: CYP19A1 rs28757157 might contribute to an increased risk of lung cancer (p = 0.025, OR = 1.30, 95% CI 1.03-1.64). In stratified analysis, rs28757157 was associated with an increased cancer risk in the population aged under 60 years, females, smokers, and drinkers. Besides, rs3751592 and rs59429575 were also identified as risk biomarkers in the population under 60 years and drinkers. Meanwhile, a relationship between an enhanced risk of squamous cell carcinoma and rs28757157 was found, while the rs3751592 CC genotype was identified as a risk factor for lung adenocarcinoma development. CONCLUSIONS: This study has identified revealed that the three SNPs (rs28757157, rs3751592, and rs59429575) of CYP19A1 are associated with lung cancer in the Chinese Han population. These findings will provide theoretical support for further functional studies of CYP19A1 in lung cancer.

Targeting HDL in tumor microenvironment: New hope for cancer therapy.

Epidemiological studies have shown that plasma HDL-C levels are closely related to the risk of prostate cancer, breast cancer, and other malignancies. As one of the key carriers of cholesterol regulation, high-density lipoprotein (HDL) plays an important role in tumorigenesis and cancer development through anti-inflammation, antioxidation, immune-modulation, and mediating cholesterol transportation in cancer cells and noncancer cells. In addition, the occurrence and progression of cancer are closely related to the alteration of the tumor microenvironment (TME). Cancer cells synthesize and secrete a variety of cytokines and other factors to promote the reprogramming of surrounding cells and shape the microenvironment suitable for cancer survival. By analyzing the effect of HDL on the infiltrating immune cells in the TME, as well as the relationship between HDL and tumor-associated angiogenesis, it is suggested that a moderate increase in the level of HDL in vivo with consequent improvement of the function of HDL in the TME and induction of intracellular cholesterol efflux may be a promising strategy for cancer therapy.

Celastrol induces lipophagy via the LXRα/ABCA1 pathway in clear cell renal cell carcinoma.

Celastrol is a triterpene derived from the traditional Chinese medicine Tripterygium wilfordii Hook f, which displays potential anticancer activity. In the present study, we investigated the anticancer effects of celastrol against clear cell renal cell carcinoma (ccRCC) and the underlying mechanisms. Using Cancer Genome Atlas (TCGA) database and genotype-tissue expression (GTEx) database we conducted a bioinformatics analysis, which showed that the mRNA levels of liver-X receptors α (LXRα) and ATP-binding cassette transporter A1 (ABCA1) in ccRCC tissues were significantly lower than those in adjacent normal tissues. This result was confirmed by immunoblotting analysis of 4 ccRCC clinical specimens, which showed that the protein expression of LXRα and ABCA1 was downregulated. Similar results were obtained in a panel of ccRCC cell lines (786-O, A498, SN12C, and OS-RC-2). In 786-O and SN12C cells, treatment with celastrol (0.25-2.0 µM) concentration-dependently inhibited the cell proliferation, migration, and invasion as well as the epithelial-mesenchymal transition (EMT) process. Furthermore, we demonstrated that celastrol inhibited the invasion of 786-O cells through reducing lipid accumulation; celastrol concentration-dependently promoted autophagy to reduce lipid storage. Moreover, we revealed that celastrol dramatically activated LXRα signaling, and degraded lipid droplets by inducing lipophagy in 786-O cells. Finally, celastrol promoted cholesterol efflux from 786-O cells via ABCA1. In high-fat diet-promoted ccRCC cell line 786-O xenograft model, administration of celastrol (0.25, 0.5, 1.0 mg·kg-1·d-1, for 4 weeks, i.p.) dose-dependently inhibited the tumor growth with upregulated LXRα and ABCA1 protein in tumor tissue. In conclusion, this study reveals that celastrol triggers lipophagy in ccRCC by activating LXRα, promotes ABCA1-mediated cholesterol efflux, suppresses EMT progress, and ultimately inhibits cell proliferation, migration, and invasion as well as tumor growth. Thus, our study provides evidence that celastrol can be used as a lipid metabolism-based anticancer therapeutic approach.

Gut microbiota alterations associated with antibody-mediated rejection after kidney transplantation.

Antibody-mediated rejection (AMR) has become the major challenge for kidney transplantation, and the efficacy of existing therapies was limited to prevent AMR. Increasing evidences have demonstrated the link between gut microbiota alterations and allograft outcome. However, there has been no comprehensive analysis to profile the gut microbiota associated with AMR after kidney transplantation. We performed this study to characterize the gut microbiota possibly associated with AMR. Fecal specimens were collected from 24 kidney transplantation recipients with AMR and 29 controls. DNA extracted from the specimens was processed for 16S rRNA gene sequencing using Illumina MiSeq. Gut microbial community of recipients with AMR was significantly different from that of controls based on unweighted (P = 0.001) and weighted (P = 0.02) UniFrac distances, and the bacterial richness (observed species: P = 0.0448; Chao1 index: P = 0.0450; ACE index: P = 0.0331) significantly decreased in the AMR group. LEfSe showed that 1 phylum, 5 classes, 7 families, and 10 genera were increased, whereas 1 class, 2 order, 3 families, and 4 genera were decreased in the AMR group. Specific taxa such as Clostridiales could be potentially used as biomarkers to distinguish the recipients with AMR from the controls (AUC = 0.77). PICRUSt analysis illustrated that 16 functional pathways were with significantly different abundances in the AMR and control groups. Our findings provide a foundation for further investigation on the role of gut microbiota in AMR after kidney transplantation, and potentially support novel diagnostic biomarkers and therapeutic options for AMR. KEY POINTS: • Gut microbial community of kidney recipients with AMR was different from that of controls. • Clostridiales is a potential marker to distinguish recipients with AMR from controls.