Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron.

The SARS-CoV-2 Omicron variant with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the spike (S) from Omicron reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of the viral fusion step. Alterations in local conformation, charge, and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Structure of the Omicron S bound with human ACE2, together with the analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members, as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies, sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

Multi-sequence MRI-based radiomics model to preoperatively predict the WHO/ISUP grade of clear Cell Renal Cell Carcinoma: a two-center study.

OBJECTIVES: To develop radiomics models based on multi-sequence MRI from two centers for the preoperative prediction of the WHO/ISUP grade of Clear Cell Renal Cell Carcinoma (ccRCC). METHODS: This retrospective study included 334 ccRCC patients from two centers. Significant clinical factors were identified through univariate and multivariate analyses. MRI sequences included Dynamic contrast-enhanced MRI, axial fat-suppressed T2-weighted imaging, diffusion-weighted imaging, and in-phase/out-of-phase images. Feature selection methods and logistic regression (LR) were used to construct clinical and radiomics models, and a combined model was developed using the Rad-score and significant clinical factors. Additionally, seven classifiers were used to construct the combined model and different folds LR was used to construct the combined model to evaluate its performance. Models were evaluated using receiver operating characteristic (ROC) curves, area under the curve (AUC), and decision curve analysis (DCA). The Delong test compared ROC performance, with p < 0.050 considered significant. RESULTS: Multivariate analysis identified intra-tumoral vessels as an independent predictor of high-grade ccRCC. In the external validation set, the radiomics model (AUC = 0.834) outperformed the clinical model (AUC = 0.762), with the combined model achieving the highest AUC (0.855) and significantly outperforming the clinical model (p = 0.003). DCA showed that the combined model had a higher net benefit within the 0.04-0.54 risk threshold range than clinical model. Additionally, the combined model constructed using logistic regression has a higher priority compared to other classifiers. Additionally, 10-fold cross-validation with LR for the combined model showed consistent AUC values (0.849-0.856) across different folds. CONCLUSION: The radiomics models based on multi-sequence MRI might be a noninvasive and effective tool, demonstrating good efficacy in preoperatively predicting the WHO/ISUP grade of ccRCC.

Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipid alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer.

Atomic Structures of Coxsackievirus B5 Provide Key Information on Viral Evolution and Survival.

Coxsackie virus B5 (CVB5), a main serotype in human Enterovirus B (EVB), can cause severe viral encephalitis and aseptic meningitis among infants and children. Currently, there is no approved vaccine or antiviral therapy available against CVB5 infection. Here, we determined the atomic structures of CVB5 in three forms: mature full (F) particle (2.73 Å), intermediate altered (A) particle (2.81 Å), and procapsid empty (E) particle (2.95 Å). Structural analysis of F particle of CVB5 unveiled similar structures of "canyon," "puff," and "knob" as those other EV-Bs. We observed structural rearrangements that are alike during the transition from F to A particle, indicative of similar antigenicity, cell entry, and uncoating mechanisms shared by all EV-Bs. Further comparison of structures and sequences among all structure-known EV-Bs revealed that while the residues targeted by neutralizing MAbs are diversified and drive the evolution of EV-Bs, the relative conserved residues recognized by uncoating receptors could serve as the basis for the development of antiviral vaccines and therapeutics. IMPORTANCE As one of the main serotypes in Enterovirus B, CVB5 has been commonly reported in recent years. The atomic structures of CVB5 shown here revealed classical features found in EV-Bs and the structural rearrangement occurring during particle expansion and uncoating. Also, structure- and sequence-based comparison between CVB5 and other structure-known EV-Bs screened out key domains important for viral evolution and survival. All these provide insights into the development of vaccine and therapeutics for EV-Bs.

CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the main malignant tumors with high mortality and short survival time. Immunotherapy has become the standard treatment for advanced NSCLC, but it has the problems of drug resistance and low response rate. Therefore, obtaining effective biomarkers to predict and enhance immune checkpoint inhibitors (ICIs) efficacy in NSCLC is important. Sphingolipid metabolism is recently found to be closely involved in tumor immunotherapy. CERS4, an important sphingolipid metabolizing enzyme, is positively correlated with the efficacy of anti-PD-1 therapy for NSCLC. Upregulation of CERS4 expression could improve the efficacy of anti-PD-1 therapy for NSCLC. High expression of CERS4 could downregulate the expression of Rhob in tumor. Significantly, the ratio of CD4+/CD8+ T cell increased and the ratio of Tim-3+/CD8+ T cell decreased in spleen and peripheral blood cells. When Rhob was knocked out, the efficacy of PD-1 mAb treatment increased, and the frequency of Tim-3+ CD8+ T cell decreased. This finding further confirmed the role of sphingolipid metabolites in regulating the immunotherapeutic function of NSCLC. These metabolites may improve the efficacy of PD-1 mAb in NSCLC by regulating the CERS4/Rhob/Tim-3 axis. Overall, this study provided a potential and effective target for predicting and improving the efficacy of ICIs for NSCLC. It also provided a new perspective for the study on the mechanisms of ICIs resistance for NSCLC.

Mutant p53R211* ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammation disease characterized by imbalance of immune homeostasis. p53 mutants are commonly described as the guardian of cancer cells by conferring them drug-resistance and immune evasion. Importantly, p53 mutations have also been identified in RA patients, and this prompts the investigation of its role in RA pathogenesis. METHODS: The cytotoxicity of disease-modifying anti-rheumatic drugs (DMARDs) against p53 wild-type (WT)/mutant-transfected RA fibroblast-like synoviocytes (RAFLSs) was evaluated by MTT assay. Adeno-associated virus (AAV) was employed to establish p53 WT/R211* adjuvant-induced arthritis (AIA) rat model. The arthritic condition of rats was assessed by various parameters such as micro-CT analysis. Knee joint samples were isolated for total RNA sequencing analysis. The expressions of cytokines and immune-related genes were examined by qPCR, ELISA assay and immunofluorescence. The mechanistic pathway was determined by immunoprecipitation and Western blotting in vitro and in vivo. RESULTS: Among p53 mutants, p53R213* exhibited remarkable DMARD-resistance in RAFLSs. However, AAV-induced p53R211* overexpression ameliorated inflammatory arthritis in AIA rats without Methotrexate (MTX)-resistance, and our results discovered the immunomodulatory effect of p53R211* via suppression of T-cell activation and T helper 17 cell (Th17) infiltration in rat joint, and finally downregulated expressions of pro-inflammatory cytokines. Total RNA sequencing analysis identified the correlation of p53R211* with immune-related pathways. Further mechanistic studies revealed that p53R213*/R211* instead of wild-type p53 interacted with TANK-binding kinase 1 (TBK1) and suppressed the innate immune TBK1-Interferon regulatory factor 3 (IRF3)-Stimulator of interferon genes (STING) cascade. CONCLUSIONS: This study unravels the role of p53R213* mutant in RA pathogenesis, and identifies TBK1 as a potential anti-inflammatory target.

Isolation and identification of 1,3,6,8-tetrabromocarbazole - degrading bacteria.

Halogenated carbazoles are a new class of persistent organic pollutants with dioxin-like toxicity, and this study focused on the microbial degradation of 1,3,6,8-tetrabromocarbazole. In this study, a novel 1,3,6,8-tetrabromocarbazole (1,3,6,8-TBCZ) degrading strain TB-1 was isolated from contaminated soil and identified as Achromobacter sp. based on its 16S rRNA gene sequence analysis, morphological, physiological, and biochemical characteristics. The soil sample was collected from a pharmaceutical factory in Suzhou, China. The strain was able to effectively degrade 1 mg L-1 1,3,6,8-TBCZ in 7 d at pH 7.0 and 30 °C with 80% degradation rate. During the process, the intermediate metabolites were identified as Tribromocarbazole, dibromocarbazole and bromocarbazole via gas chromatography mass spectrometry (GC-MS). The results indicated that strain TB-1 may contribute to the bioremediation of polyhalogenated carbazoles (PHCs) in contaminated environment.

Isolation and identification of acetaminophen degrading strain Shinella sp. HZA2.

Acetaminophen (APP), frequently used as analgesic and antipyretic drug in our life, is potentially toxic to both animals and humans. A novel acetaminophen degrading strain HZA2, was isolated from the activated sludge, and identified as Shinella sp. based on its 16S rRNA gene sequence analysis, morphological, physiological, and biochemical characterizations. This strain could degrade 100 mg L-1 acetaminophen completely within 12 h, and it was also a very effective strain for the degradation of high concentration of acetaminophen below 3000 mg L-1 under the optimal condition. The optimal degrading conditions of acetaminophen by HZA2 were pH 7.5 and 32.7 °C by the analysis of response surface methodology. Exogenous carbon source could enhance the biodegradation of acetaminophen. During the process, the intermediate metabolites were identified as 4-aminophenol and hydroquinone via gas chromatography-mass spectrometry analysis. The results indicated that strain HZA2 may be a promising bacterium for the bioremediation of acetaminophen pollutions.

Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular docking-based virtual screening with bio-layer interferometry.

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 µM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.

Isolation and molecular characterization of bovine herpesvirus 4 from cattle in mainland China.

Bovine herpesvirus 4 (BoHV-4) is one of the most important of the known viral respiratory and reproductive pathogens of both young and adult cattle. However, BoHV-4 has not been isolated or detected in mainland China prior to this study. In 2019, BoHV-4 strain 512 was isolated from cattle in Heilongjiang Province, China, using MDBK cells, and characterized by PCR, nucleotide sequence analysis, and transmission electron microscopy. Two other unknown herpesvirus strains, BL6010 and J4034, which were isolated from cattle in 2009 in China and stored at -70℃, were also propagated in MDBK cells and identified as BoHV-4 by PCR. Phylogenetic analysis based on partial nucleotide sequences of the thymidine kinase (TK) gene and glycoprotein B (gB) gene for the three isolates indicated that these three Chinese strains belong to BoHV-4 genotype 1. A preliminary virus neutralization test revealed that 64% of the 70 bovine sera (45/70) collected from Inner Mongolia Autonomous Region, China, had anti-BoHV-4 antibodies and that natural BoHV-4 infection occurred in cattle in China. Here, we report for the first time the isolation and molecular characterization of BoHV-4 from cattle in mainland China.

Zinc oxide nanoparticles induce human tenon fibroblast apoptosis through reactive oxygen species and caspase signaling pathway.

Glaucoma is the leading cause of irreversible blindness in the world and trabeculectomy remains still the most commonly performed filtration surgery. Failure of trabeculectomy is due to the formation of scarring, which is associated with the increased fibroblast proliferation, activation, and collagen deposition at the site of the drainage channel with subconjunctival fibrosis. Our previous study has revealed that zinc oxide (ZnO) nanoparticles could efficiently decrease the expressions of TGF-ß1 and inhibit fibroblast-mediated collagen lattice contraction. However, the mechanism underlying ZnO nanoparticle-induced fibroblast apoptosis is still unclear. In the present study, we investigated the effect of ZnO nanoparticles on the reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) in human Tenon fibroblasts (HTFs). Moreover, we also explored the influence of ZnO nanoparticles on the expression of Caspase-3, Caspase-9, apoptotic protease-activating factor-1 (Apaf-1), fibroblast-specific protein-1 (FSP-1), collagen III, and E-cadherin. The results indicated that ZnO nanoparticles markedly inhibit HTFs viability and decrease the Δψm in a concentration-dependent pattern. Exposure of HTFs to ZnO nanoparticles could also induce the elevated Caspase-3, Caspase-9, and Apaf-1 expression, decrease the levels of FSP-1, collagen III, and E-cadherin expression, leading to HTFs apoptosis. Our results suggested that elevated ROS and activated Caspase signaling play a fundamental role in ZnO nanoparticle-induced HTFs apoptosis.

Computed tomography colonography versus colonoscopy for detection of colorectal cancer: a diagnostic performance study.

BACKGROUND: Colonoscopy is the reference standard for the detection of colorectal cancer but it is an invasive technique and has the risk of bowel perforation and bleeding. Unlike colonoscopy, sedation is not required in computed tomography colonography and requires additional reassurance endoscopy. The objectives of the study were to compare the diagnostic performance of computed tomography colonography against colonoscopy for a diagnosis of colorectal cancer. METHODS: Data regarding any polyp ≥10 mm diameter (ø) and < 10 mm ø but suspicious polyps of computed tomography colonography (n = 318), colonoscopy (n = 318), and surgical pathology (n = 77) for symptomatic colorectal cancer patients were collected and analyzed. Lesion ulceration, extramural invasion, and/ or lesion shouldering was considered as a suspicious polyp. Beneficial scores for decision making of curative surgeries were evaluated for each modality. The cost of diagnosis of colorectal cancer was also evaluated. RESULTS: Either of diagnosis showed polyps ≥10 mm ø in 27 patients and polyps of 50 patients were < 10 mm ø but suspicious. Therefore, a total of 77 patients were subjected to surgery. With respect to surgical pathology, sensitivities for computed tomographic colonography and colonoscopy were 0.961 and 0.831. For detection of ≥10 mm ø polyp, benefit score for computed tomographic colonography and colonoscopy were 0-0.906 diagnostic confidence and 0.035-0.5 diagnostic confidence. For polyps, ≥ 10 mm ø but not too many large polyps, colonoscopy had the risk of underdiagnosis. For < 10 mm ø but suspicious polyps, < 0.6 mm ø and < 2.2 mm ⌀ polyps could not be detected by computed tomographic colonography and colonoscopy, respectively. The computed tomographic colonography had less cost than colonoscopy (1345 ± 135 ¥/ patient vs. 1715 ± 241 ¥/ patient, p < 0.0001) for diagnosis of colorectal cancer. CONCLUSION: Computed tomographic colonography would be a non-inferior alternative than colonoscopy for a diagnosis of colorectal cancer. LEVEL OF EVIDENCE: III.

TAWAWA1, a regulator of rice inflorescence architecture, functions through the suppression of meristem phase transition.

Inflorescence structures result from the activities of meristems, which coordinate both the renewal of stem cells in the center and organ formation at the periphery. The fate of a meristem is specified at its initiation and changes as the plant develops. During rice inflorescence development, newly formed meristems acquire a branch meristem (BM) identity, and can generate further meristems or terminate as spikelets. Thus, the form of rice inflorescence is determined by a reiterative pattern of decisions made at the meristems. In the dominant gain-of-function mutant tawawa1-D, the activity of the inflorescence meristem (IM) is extended and spikelet specification is delayed, resulting in prolonged branch formation and increased numbers of spikelets. In contrast, reductions in TAWAWA1 (TAW1) activity cause precocious IM abortion and spikelet formation, resulting in the generation of small inflorescences. TAW1 encodes a nuclear protein of unknown function and shows high levels of expression in the shoot apical meristem, the IM, and the BMs. TAW1 expression disappears from incipient spikelet meristems (SMs). We also demonstrate that members of the SHORT VEGETATIVE PHASE subfamily of MADS-box genes function downstream of TAW1. We thus propose that TAW1 is a unique regulator of meristem activity in rice and regulates inflorescence development through the promotion of IM activity and suppression of the phase change to SM identity.

[Effect of bazedoxifene on endometriosis in a rat model].

OBJECTIVE: To investigate the therapeutic mechanism of bazedoxifene, the third-generation selective ER modulator (SERM), on endometriosis lesions in a rat model. METHODS: Endometriosis was induced by transplanting pieces of endometrium from other syngeneic rats that were as donors onto the subcutaneous of other unmated female rats. The rats with successful ectopic implants were divided into two groups: control group (n=10) and bazedoxifene group (n=10). The macroscopic morphology, volume, histopathology of ectopic implant and rats uterine wet weight were determined before and after the treatment. Expression of proliferation cell nuclear antigen (PCNA), ER and PR in the eutopic endometrium and endometriosis lesions detected by immunohistochemistry in the two groups. RESULTS: (1) The gross morphology and histological changes of endometriosis lesions in rats after treatment: compared with the control group, it was obviously depauperated and had more less glands and blood vessels in the stroma. (2) The change of rats' weight, the volume of endometriosis lesion before and after treatment and rats uterine wet weigh after treatment respectively in the control group and the bazedoxifene group: rats' weight were respectively before treatment: (201±17) g, (202±18) g, that were respectively after treatment: (266±16) g, (261±16) g, which showed no significant difference between two groups before and after treatment (P>0.05). The volume of ectopic implant before treatment were respectively (85±17) mm3, (85±12) mm3, and showed no significant difference between two groups; that were respectively (48±11) mm3, (24±9) mm3 afte rtreatment, which was significantly decreased compared with the control group (P<0.05). Rats uterine wet weight after treatment were respectively: (0.77±0.16) g, (0.45±0.18) g, and was significantly reduced compared with the control group (P<0.05). (3) The protein expression levels of PCNA, ER and PR in the endometriosis lesions after treatment were respectively 0.282±0.044, 0.51±0.06, 0.49±0.05 in the control group, 0.191±0.020, 0.23±0.03, 0.48±0.06 in the bazedoxifene group; that in eutopic endometrium were respectively 0.369±0.081, 0.56±0.08, 0.56±0.10 in the control group, 0.211±0.037, 0.27±0.05, 0.54±0.08 in the bazedoxifene group; the protein expression levels of PCNA and ER in endometriosis lesions and the eutopic endometrium were significantly decreased in the bazedoxifene group compared with the control group (P<0.05), but the protein levels of PR in endometriosis lesionsand and the eutopic endometrium were not significantly altered by treatment (P>0.05). CONCLUSION: Bazedoxifene could obviously reduce the size of endometriosis lesions, the mechanism may be related with suppressing estrogen-induced proliferation, the expression of ER and direct ER antagonism by this SERM.

Roles of red mud-based biochar carriers in the recovery of anammox activity: characteristics and mechanisms.

Anaerobic ammonium oxidation (anammox) sludge is easily deactivated in the process of treating ammonia-laden wastewater. To investigate an effective recovery method, red mud-based biochar carriers (RMBC) were prepared and added to a deactivated anammox reactor; the operation of this reactor had been interrupted for 6 months with starvation and low temperature. The deactivated sludge with added RMBC was recovered rapidly after 31 days, with the specific anammox activity rapidly increasing to 0.84 g N/(g VSS∙day), and the recovery efficiency of nitrogen removal rate increased by four times compared to the unadded control. The granulation degree and extracellular polymeric substances secretion of the anammox sludge with the added RMBC were significantly higher than that of the control group. In addition, a large number of spherical anammox bacteria were observed moored at the porous channels of RMBC, and the copy numbers of functional genes of anammox bacteria were approximately twice that of the control group. Hence, RMBC is a potential sludge activator, and it can provide a "house" to protect anammox bacteria, enhance the metabolic activity and the agglomerative growth of anammox bacteria, and synergistically achieve rapid recovery of deactivated anammox sludge.

Haplotype-resolved T2T reference genomes for wild and domesticated accessions shed new insights into the domestication of jujube.

Chinese jujube (Ziziphus jujuba Mill.) is one of the most important deciduous tree fruits in China, with substantial economic and nutritional value. Jujube was domesticated from its wild progenitor, wild jujube (Z. jujuba var. spinosa), and both have high medicinal value. Here we report the 767.81- and 759.24-Mb haplotype-resolved assemblies of a dry-eating 'Junzao' jujube (JZ) and a wild jujube accession (SZ), using a combination of multiple sequencing strategies. Each assembly yielded two complete haplotype-resolved genomes at the telomere-to-telomere (T2T) level, and ~81.60 and 69.07 Mb of structural variations were found between the two haplotypes within JZ and SZ, respectively. Comparative genomic analysis revealed a large inversion on each of chromosomes 3 and 4 between JZ and SZ, and numerous genes were affected by structural variations, some of which were associated with starch and sucrose metabolism. A large-scale population analysis of 672 accessions revealed that wild jujube originated from the lower reaches of the Yellow River and was initially domesticated at local sites. It spread widely and was then independently domesticated at the Shanxi-Shaanxi Gorge of the middle Yellow River. In addition, we identified some new selection signals regions on genomes, which are involved in the tissue development, pollination, and other aspects of jujube tree morphology and fertilization domestication. In conclusion, our study provides high-quality reference genomes of jujube and wild jujube and new insights into the domestication history of jujube.

LincRNA-p21/AIF-1/CMPK2/NLRP3 pathway promoted inflammation, autophagy and apoptosis of human tubular epithelial cell induced by urate via exosomes.

Urate nephropathy, a common complication of hyperuricemia, has garnered increasing attention worldwide. However, the exact pathogenesis of this condition remains unclear. Currently, inflammation is widely accepted as the key factor in urate nephropathy. Therefore, the aim of this study was to elucidate the interaction of lincRNA-p21/AIF-1/CMPK2/NLRP3 via exosomes in urate nephropathy. This study evaluated the effect of lincRNA-p21/AIF-1/CMPK2/NLRP3 using clinical data collected from patients with urate nephropathy and human renal tubular epithelial cells (HK2) cultured with different concentrations of urate. In clinical research section, the level of lincRNA-p21/AIF-1 in exosomes of urine in patients with hyperuricemia or urate nephropathy was found to be increased, particularly in patients with urate nephropathy. In vitro study section, the level of exosomes, inflammation, autophagy, and apoptosis was increased in HK2 cells induced by urate. Additionally, the expression of lincRNA-p21, AIF-1, CMPK2, and NLRP3 was upregulated in exosomes and HK2 cells. Furthermore, manipulating the activity of lincRNA-p21, AIF-1, CMPK2, and NLRP3 through overexpression or interference vectors regulated the level of inflammation, autophagy, and apoptosis in HK2 cells. In conclusion, the pathway of lincRNA-p21/AIF-1/CMPK2/NLRP3 contributed to inflammation, autophagy, and apoptosis of human renal tubular epithelial cell induced by urate via exosomes. Additionally, the specific exosomes in urine might serve as novel biomarkers for urate nephropathy.

The White Matter Integrity and Functional Connection Differences of Fornix (Cres)/Stria Terminalis in Individuals with Mild Cognitive Impairment Induced by Occupational Aluminum Exposure.

Long-term aluminum (Al) exposure increases the risk of mild cognitive impairment (MCI). The aim of the present study was to investigate the neural mechanisms of Al-induced MCI. In our study, a total of 52 individuals with occupational Al exposure >10 years were enrolled and divided into two groups: MCI (Al-MCI) and healthy controls (Al-HC). Plasma Al concentrations and Montreal Cognitive Assessment (MoCA) score were collected for all participants. And diffusion tensor imaging and resting-state functional magnetic resonance imaging were used to examine changes of white matter (WM) and functional connectivity (FC). There was a negative correlation between MoCA score and plasma Al concentration. Compared with the Al-HC, fractional anisotropy value for the right fornix (cres)/stria terminalis (FX/ST) was higher in the Al-MCI. Furthermore, there was a difference in FC between participants with and without MCI under Al exposure. We defined the regions with differing FC as a "pathway," specifically the connectivity from the right temporal pole to the right FX/ST, then to the right sagittal stratum, and further to the right anterior cingulate and paracingulate gyri and right inferior frontal gyrus, orbital part. In summary, we believe that the observed differences in WM integrity and FC in the right FX/ST between participants with and without MCI under long-term Al exposure may represent the neural mechanisms underlying MCI induced by Al exposure.

Natural small-molecules reverse Xeroderma Pigmentosum Complementation Group C (XPC) deficient-mediated drug-resistance in renal cell carcinoma.

BACKGROUND: Renal cancer is insensitive to radiotherapy or most chemotherapies. While the loss of the XPC gene was correlated with drug resistance in colon cancer, the expression of XPC and its role in the drug resistance of renal cancer have not yet been elucidated. With the fact that natural small-molecules have been adopted in combinational therapy with classical chemotherapeutic agents to increase the drug sensitivity and reduce adverse effects, the use of herbal compounds to tackle drug-resistance in renal cancer is advocated. PURPOSE: To correlate the role of XPC gene deficiency to drug-resistance in renal cancer, and to identify natural small-molecules that can reverse drug-resistance in renal cancer via up-regulation of XPC. METHODS: IHC was adopted to analyze the XPC expression in human tumor and adjacent tissues. Clinical data extracted from The Cancer Genome Atlas (TCGA) database were further analysed to determine the relationship between XPC gene expression and tumor staging of renal cancer. Two types of XPC-KD renal cancer cell models were established to investigate the drug-resistant phenotype and screen XPC gene enhancers from 134 natural small-molecules derived from herbal plants. Furthermore, the identified XPC enhancers were verified in single or in combination with FDA-approved chemotherapy drugs for reversing drug-resistance in renal cancer using MTT cytotoxicity assay. Drug resistance gene profiling, ROS detection assay, immunocytochemistry and cell live-dead imaging assay were adopted to characterize the XPC-related drug resistant mechanism. RESULTS: XPC gene expression was significantly reduced in renal cancer tissue compared with its adjacent tissue. Clinical analysis of TCGA database also identified the downregulated level of XPC gene in renal tumor tissue of stage IV patients with cancer metastasis, which was also correlated with their lower survival rate. 6 natural small-molecules derived from herbal plants including tectorigenin, pinostilbene, d-pinitol, polygalasaponin F, atractylenolide III and astragaloside II significantly enhanced XPC expression in two renal cancer cell types. Combinational treatment of the identified natural compound with the treatment of FDA-approved drug, further confirmed the up-regulation of XPC gene expression can sensitize the two types of XPC-KD drug-resistant renal cancer cells towards the FDA-approved drugs. Mechanistic study confirmed that GSTP1/ROS axis was activated in drug resistant XPC-KD renal cancer cells. CONCLUSION: XPC gene deficiency was identified in patient renal tumor samples, and knockdown of the XPC gene was correlated with a drug-resistant phenotype in renal cancer cells via activation of the GSTP1/ROS axis. The 6 identified natural small molecules were confirmed to have drug sensitizing effects via upregulation of the XPC gene. Therefore, the identified active natural small molecules may work as an adjuvant therapy for circumventing the drug-resistant phenotype in renal cancer via enhancement of XPC expression.