Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer.

BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.

Intra-sample reversed pairs based on differentially ranked genes reveal biosignature for ovarian cancer.

Ovarian cancer, a major gynecological malignancy, often remains undetected until advanced stages, necessitating more effective early screening methods. Existing biomarker based on differential genes often suffers from variations in clinical practice. To overcome the limitations of absolute gene expression values including batch effects and biological heterogeneity, we introduced a pairwise biosignature leveraging intra-sample differentially ranked genes (DRGs) and machine learning for ovarian cancer detection across diverse cohorts. We analyzed ten cohorts comprising 872 samples with 796 ovarian cancer and 76 normal. Our method, DRGpair, involves three stages: intra-sample ranking differential analysis, reversed gene pair analysis, and iterative LASSO regression. We identified four DRG pairs, demonstrating superior diagnostic performance compared to current state-of-the-art biomarkers and differentially expressed genes in seven independent cohorts. This rank-based approach not only reduced computational complexity but also enhanced the specificity and effectiveness of biomarkers, revealing DRGs as promising candidates for ovarian cancer detection and offering a scalable model adaptable to varying cohort characteristics.

Isolation and Identification of Endophytic Bacteria Bacillus sp. ME9 That Exhibits Biocontrol Activity against Xanthomonas phaseoli pv. manihotis.

In recent years, the bacterial blight of cassava has caused substantial economic losses to the Chinese cassava industry. Chemical control methods have become the primary approach to control this disease; however, their widespread usage and harmful residues have raised concerns about environmental pollution. In order to avoid this, it is urgent to seek a green ecological method to prevent and control it. Biological control through the utilization of microorganisms not only effectively inhibits the disease, but also gives consideration to environmental friendliness. Therefore, investigating an endophytic biological control method for cassava bacterial blight is of great importance. In this study, cassava leaf tissues were used as test specimens in order to isolate endophytic bacteria by using dilution and separation methods. Bacillus ME9, derived from cassava endophytic bacteria, exhibits good antagonism against a diverse range of pathogens, including Xpm11. Its genome consists of a series of genes encoding antibacterial lipopeptides, which may be directly related to its antibacterial capabilities. Furthermore, inoculation resulted in a substantial change in the diversity of the endophytic bacterial community, characterized by improved diversity, and displayed an obvious inhibition of pathogenic bacterial growth, demonstrating successful colonization within plants. The results laid a foundation and provided theoretical support for the development and utilization of cassava endophytic bacterial diversity and endogenous disease control strategies.

Biomimetic Ag/ZnO@PDMS Hybrid Nanorod Array-Mediated Photo-induced Enhanced Raman Spectroscopy Sensor for Quantitative and Visualized Analysis of Microplastics.

Microplastics are persistent pollutants that accumulate in the environment and can cause serious toxicity to mammals. At present, few technologies are able to quantitatively detect chemicals and provide morphological information simultaneously. Herein, we developed a dragonfly-wing-mimicking ZnO nanorod array decorated with AgNPs on polydimethylsiloxane (PDMS) as a surface-enhanced Raman spectroscopy (SERS) and photo-induced enhanced Raman spectroscopy (PIERS) substrate for trace analysis of microplastics. The Ag/ZnO@PDMS hybrid nanorod array endows the sensor with high sensitivity and signal repeatability (RSD ∼ 5.89%), ensuring the reliable quantitative analysis of microplastics. Importantly, when the noble metal-semiconductor substrate was pre-radiated with ultraviolet light, a surprising PIERS was attained, achieving an additional enhancement of 11.3-fold higher than the normal SERS signal. By combining the PIERS technology with the "coffee ring effect", the sensor successfully discerned microplastics of polyethylene (PE) and polystyrene (PS) at a trace level of 25 µg/mL even with a portable Raman device. It was capable of identifying PS microspheres in contaminated tap water, lake water, river water, and seawater with detection limits of 25, 28, 35, and 60 µg/mL, respectively. The recovery rates of PS microspheres in four water environments ranged from 94.8 to 102.4%, with the RSD ranging from 2.40 to 6.81%. Moreover, quantitative and visualized detection of microplastics was readily realized by our sensor. This portable PIERS sensor represents a significant step toward the generalizability and practicality of quantitative and visual sensing technology.

Epigenetic reprogramming of Runx3 reinforces CD8 + T-cell function and improves the clinical response to immunotherapy.

BACKGROUND: Checkpoint blockade immunotherapy, represented by PD-1 or PD-L1 antibody treatment, has been of tremendous success in clinical practice. However, the low clinical response rate and lack of biomarkers for prediction of the immune response limit the clinical application of anti-PD-1 immunotherapy. Our recent work showed that a combination of low-dose decitabine and PD-1-ab significantly improved the complete response (CR) rate of cHL patients from 32 to 71%, which indicates that there is a significant correlation between epigenetic regulation and the clinical response to immunotherapy. METHODS: We recruited two groups of Hodgkin lymphoma patients who were treated with anti-PD-1 and DAC+anti-PD-1. CD8+ T cells were isolated from the patients' peripheral blood, DNA methylation was analyzed by EPIC, the expression profile was analyzed by RNA-seq, and multigroup analysis was performed with IPA and GSEA functional annotations. We explored the effect of DAC on the function of CD8+ T cells in the blood, spleen, tumor and lymph nodes using a mouse model. Furthermore, we explored the function of Tils in the tumor microenvironment. Then, we constructed Runx3-knockout mice to confirm the T-cell-specific function of Runx3 in CD8+ T cells and analyzed various subtypes of T cells and cytokines using mass cytometry (CyTOF). RESULTS: Multiomics analysis identified that DNA methylation reprogramming of Runx3 was a crucial mediator of CD8+ T-cell function. Multiomics data showed that reversal of methylation of the Runx3 promoter promoted the infiltration of CD8+ TILs and mitigated the exhaustion of CD8+ T cells. Furthermore, experiments on tissue-specific Runx3-knockout mice showed that Runx3 deficiency reduced CD8+ T infiltration and the differentiation of effector T and memory T cells. Furthermore, Runx3 deficiency significantly decreased CCR3 and CCR5 levels. Immunotherapy experiments in Runx3 conditional knockout mice showed that DAC could not reverse the resistance of anti-PD-1 in the absence of Runx3. Moreover, both our clinical data and data from TISIDB showed that Runx3 could be a potential biomarker for immunotherapy to predict the clinical response rate. CONCLUSION: We demonstrate that the DNA methylation of Runx3 plays a critical role in CD8+ T-cell infiltration and differentiation during decitabine-primed PD-1-ab immunotherapy, which provides a supporting mechanism for the essential role of epiregulation in immunotherapy.

Association between air pollution exposure and outpatient visits for dermatomyositis in a humid subtropical region of China: a time-series study.

In recent years, a growing number of studies have found that air pollution plays critical roles in the onset and development of autoimmune diseases, but few studies have shown an association between air pollutants and dermatomyositis (DM). We sought to investigate the relationship between short-term exposure to air pollution and outpatient visits for DM and to quantify the burden of DM due to exposure to air pollutants in Hefei, China. Daily records of hospital outpatient visits for DM, air pollutants and meteorological factors data in Hefei from January 1, 2018 to December 31, 2021 were obtained. We used a distributed lag non-linear model (DLNM) in conjunction with a generalized linear model (GLM) to explore the association between air pollution and outpatient visits for DM, and conducted stratified analyses by gender, age and season. Moreover, we used attributable fraction (AF) and attributable number (AN) to reflect the burden of disease. A total of 4028 DM clinic visits were recorded during this period. High concentration nitrogen dioxide (NO2) exposure was associated with increased risk of DM outpatient visits (relative risk (RR) 1.063, 95% confidence interval (CI) 1.015-1.114, lag 0-5). Intriguingly, exposure to high concentration ozone (O3) was associated with reduced risk of outpatient visits for DM (RR 0.974, 95% CI 0. 0.954-0.993, lag 0-6). The results of stratified analyses showed that the cold season (vs. warm season) were more susceptible to outpatient visits for DM associated with NO2 and O3 exposure. In addition, we observed that an increased risk of DM outpatient visits was attributable to high concentration NO2 exposure, while high concentration O3 exposure was associated with a decreased risk of DM outpatient visits. This study provided a scientific basis for the etiology research and health protection of DM.

Genome-Wide Identification and Expression Analysis of the SHI-Related Sequence Family in Cassava.

The SHORT INTERNODES (SHI)-related sequences (SRS) are plant-specific transcription factors that have been quantitatively characterized during plant growth, regeneration, and stress responses. However, the genome-wide discovery of SRS family genes and their involvement in abiotic stress-related activities in cassava have not been documented. A genome-wide search strategy was used to identify eight family members of the SRS gene family in cassava (Manihot esculenta Crantz). Based on their evolutionary linkages, all MeSRS genes featured homologous RING-like zinc finger and IXGH domains. Genetic architecture and conserved motif analysis validated the categorization of MeSRS genes into four groups. Eight pairs of segmental duplications were detected, resulting in an increase in the number of MeSRS genes. Orthologous studies of SRS genes among cassava and three different plant species (Arabidopsis thaliana, Oryza sativa, and Populus trichocarpa) provided important insights into the probable history of the MeSRS gene family. The functionality of MeSRS genes was elucidated through the prediction of protein-protein interaction networks and cis-acting domains. RNA-seq data demonstrated tissue/organ expression selectivity and preference of the MeSRS genes. Furthermore, qRT-PCR investigation of MeSRS gene expression after exposure to salicylic acid (SA) and methyl jasmonate (MeJA) hormone treatments, as well as salt (NaCl) and osmotic (polyethylene glycol, PEG) stresses, showed their stress-responsive patterns. This genome-wide characterization and identification of the evolutionary relationships and expression profiles of the cassava MeSRS family genes will be helpful for further research into this gene family and its function in stress response. It may also assist future agricultural efforts to increase the stress tolerance of cassava.

Pathogenetic and Therapeutic Role of Gut Microbiome in Immunoglobin A Nephropathy.

Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephritis, which is mainly characterized by excessive IgA deposition in the glomerular mesangial area. Although exploring the pathogenesis of IgAN and improving the treatment strategies continuously, the exact pathogenesis of IgAN remains unclear and the disease still leads to high mortality. Recently, emerging evidence has demonstrated that dysregulated intestinal mucosal immunity and gut microbiome imbalance may play a combined role in the development and progression of IgAN. It has been suggested that reconstructing the intestinal microenvironment and maintaining the stability and metabolic balance of gut microbiome are expected to become new treatment strategies. Meanwhile, inhibiting mucosa-associated lymphoid tissue (MALT) controlled by the gut microbiome may become an alternative treatment, especially used to reduce the excessive production of IgA in IgAN. In this review, we summarized the correlation between gut microbiome and the pathogenesis of IgAN, as well as the therapeutic potential of gut microbiome in this disease.

Riemerella anatipestifer Endonuclease I displays enzymatic activity and is associated with bacterial virulence.

Riemerella anatipestifer is an important pathogen of waterfowl, causing septicemic and exudative diseases. We previously reported that the R. anatipestifer AS87_RS02625 is a secretory protein of the type IX secretion system (T9SS). In this study, R. anatipestifer T9SS protein AS87_RS02625 was determined to be a functional Endonuclease I (EndoI), which has DNase and RNase activities. Optimal temperature and pH of the recombinant R. anatipestifer EndoI (rEndoI) to cleave λDNA were determined as 55-60 °C and 7.5 respectively. The DNase activity of the rEndoI was dependent on the presence of divalent metal ions. Presence of Mg2+ at a concentration range of 7.5-15 mM in the rEndoI reaction buffer displayed the highest DNase activity. In addition, the rEndoI displayed RNase activity to cleave MS2-RNA (ssRNA), either in the absence or presence of divalent cations Mg2+, Mn2+, Ca2+, Zn2+ and Cu2+. The DNase activity of the rEndoI was significantly enhanced by Mg2+, Mn2+ and Ca2+ but not Zn2+ and Cu2+. Moreover, we indicated that R. anatipestifer EndoI functioned on the bacterial adherence, invasion, in vivo survival and inducing inflammatory cytokines. These results indicate that the R. anatipestifer T9SS protein AS87_RS02625 is a novel EndoI, displays endonuclease activity and plays an important role in bacterial virulence.

Lotus leaf mastoid inspired Ag micro/nanoarrays on PDMS film as flexible SERS sensor for in-situ analysis of pesticide residues on nonplanar surfaces.

Conventional surface-enhanced Raman scattering (SERS) molecular detection are based on hard and brittle substrate, which are not suitable for in-situ detection of analytes adsorbed on nonplanar surfaces. Here, we report a simple biomimetic synthesis method to fabricate lotus leaf mastoid structured AgNPs micro/nanoarrays as reliable SERS substrate. By ideal replicating mastoid structure of lotus leaf into a flexible and transparent PDMS film, followed by depositing plasmonic AgNPs, a powerful chemical sensor with high sensitivity and multiplex detecting capability is demonstrated. The employ of periodic mastoid structure array endows the sensor with high signal repeatability (RSD âˆ¼ 8.6 %), solving the general repeatability problem of SERS substrates. In addition, the detailed designed flexible and transparent PDMS substrate is capable of identifying trace analytes on curved surfaces with excellent durability. In the proof-of-concept experiment, a limit of detection (LOD) of (10-5 M to 10-7 M) was achieved on a portable Raman device for three common pesticides residues (thiram, fonofos and triadophos) on dendrobium leaves and stem according to the molecular fingerprint, indicating its excellent in-situ detection capability. Further, the multiplex detection ability of the Ag/PDMS film is also demonstrated by analyzing the mixture of four typical analytes. Benefiting from its high signal uniformity, this flexible Ag/PDMS substrate also showed good quantitative detection capabilities.

TNF-α and IL-1ß Promote Renal Podocyte Injury in T2DM Rats by Decreasing Glomerular VEGF/eNOS Expression Levels and Altering Hemodynamic Parameters.

Purpose: Diabetic nephropathy (DN) is a serious microvascular complication in those with type 2 diabetes mellitus (T2DM). Evidence confirms that serum tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the T2DM stage are proposed as prognostic markers for DN development, but it is unclear how they affect renal podocyte-associated nephrin and WT-1 expression. In the presence of podocyte injury, glomerular vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and hemodynamic parameters are dysregulated. The current research aimed to clarify the relationship of TNF-α and IL-1ß with podocyte injury by altering VEGF/eNOS expression and hemodynamic parameters. Methods: A high-fat diet/streptozotocin-induced DN rat model was established. Serum TNF-α and IL-1ß levels were tracked in the pre-T2DM, T2DM and DN stages. In the DN stage, the mRNA and protein expression levels of renal TNF-α, IL-1ß, VEGF, eNOS, nephrin and WT-1 were studied. Renal hemodynamic parameters, including peak systolic velocity, end-diastolic flow velocity and mean velocity were measured with a color Doppler ultrasound technique. Results: Compared to those in the normal control (CTL) group, serum TNF-α and IL-1ß levels increased significantly in the pre-T2DM stage (obesity, insulin resistance and hyperlipidemia), T2DM stage (hyperglycemia) and DN stage (abnormal renal functions) (all: P < 0.05) in the DN group. Serum TNF-α and IL-1ß levels in the T2DM stage were significantly higher than those in the pre-T2DM stage (two: P < 0.05). Compared to the CTL group, renal nephrin, WT-1, TNF-α, IL-1ß, eNOS and VEGF expression and hemodynamic parameters in the DN stage all showed significant differences separately (all: P < 0.05). Conclusion: Increased serum and renal TNF-α and IL-1ß levels played important roles in reducing renal nephrin and WT-1 expression levels, which may be related to the fact that the former affected renal VEGF/eNOS expression and blood flow parameters in the DN rats.

Dickkopf-1 as a promising therapeutic target for autoimmune diseases.

Dickkopf-1 (DKK-1) is mostly known as a mature inhibitor of classic Wnt signaling pathways, which plays a critically role in regulating bone formation and bone metastasis. In recent years, the roles of DKK-1 played in bone resorption, bone formation, immune homeostasis and inflammation have been investigated. The role of DKK-1 in the pathogenesis and treatment of autoimmune diseases (ADs), including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), etc, has attracted widespread attention. Various studies have found that DKK-1 may be used as a biomarker for the occurrence and development of ADs, and as a potential target for the treatment of ADs. In this review, we have briefly summed up the intricate immunological functions and regulatory mechanisms of DKK-1 in ADs, aiming to further learning more about the role of DKK-1 involved in the pathogenesis of ADs and provide an outlook for the potential future researches.

Riemerella anatipestifer AS87_RS02955 Acts as a Virulence Factor and Displays Endonuclease Activity.

Riemerella anatipestifer is an important bacterial pathogen in the global duck industry and causes heavy economic losses. In our previous study, we demonstrated that R. anatipestifer type IX secretion system components GldK and GldM, and the secretion protein metallophosphoesterase, acted as virulence factors. In this study, R. anatipestifer AS87_RS02955 was investigated for virulence and enzymatic activity properties. We constructed AS87_RS02955 mutation and complementation strains to assess bacterial virulence. In vivo bacterial loads showed a significantly reduced bacterial loads in the blood of ducks infected with mutant strain Yb2Δ02955, which was recovered in the blood of ducks infected with the complementation strain cYb2Δ02955, demonstrating that AS87_RS02955 was associated with virulence. Further studies showed AS87_RS02955 was a novel nonspecific endonuclease with no functionally conserved domain, but enzymatic activity toward DNA and RNA was indicated. DNase activity was activated by Zn2+, Cu2+, Mg2+, Ca2+, and Mn2+ ions but inhibited by ethylenediaminetetraacetic acid. RNase activity was independent of metal cations, but stimulated by Mg2+, Ca2+, and Mn2+. RAS87_RS02955 enzymatic activity was active across a broad pH and temperature range. Moreover, we identified four sites in rAS87_RS02955, F39, F92, I134, and F145, which were critical for enzymatic activity. In summary, we showed that R. anatipestifer AS87_RS02955 encoded a novel endonuclease with important roles in bacterial virulence. IMPORTANCE R. anatipestifer AS87_RS02955 was identified as a novel T9SS effector and displayed a nonspecific endonuclease activity in this study. The protein did not contain a conserved His-Asn-His motif structure, which is similar to the endonuclease from Prevotella sp. Its mutant strain Yb2Δ02955 demonstrated significantly attenuated virulence, suggesting AS87_RS02955 is an important virulence factor. Moreover, AS87_RS02955 displayed nonspecific endonuclease activity to cleave λ DNA and MS2 RNA, while four protein sites were critical for endonuclease activity. In conclusion, R. anatipestifer AS87_RS02955 plays important roles in bacterial virulence.

The effect of air pollution exposure on risk of outpatient visits for Sjogren's syndrome: A time-series study.

BACKGROUND: Emerging evidence showed that air pollutants are associated with development and recurrence of autoimmune disorders, but there is scarce evidence regarding the relationship between air pollutants and Sjogren's syndrome (SS). We sought to investigate whether air pollutants affect the risk of outpatient visits for SS and to quantify the burden of SS visits attributable to air pollution exposure in Hefei, China. METHODS: Daily data on outpatient visits for SS, air pollutants and meteorological data in Hefei, China, from January 1, 2015 to December 31, 2020 were obtained. A distributed lag non-linear model in conjunction with a generalized linear model were employed to assess the relationship between air pollution and SS outpatient visits. Stratified analyses were further performed by gender, age and season. Attributable fraction (AF) and attributable number (AN) were used to reflect disease burden. RESULTS: There were 4501 records of outpatient visits for SS. Exposure to PM2.5 was associated with increased risk of SS outpatient visits (relative risk (RR) = 1.218, 95% confidence interval (CI): 1.017-1.458, lag 0-14 day). An increase of 24 µg/m3 (interquartile range) in NO2 concentration was associated with 26.3% increase in the risk of SS outpatient visits (RR = 1.263, 95%CI: 1.105-1.445, lag 0-10 day). In contrast, exposure to O3 was associated with decreased risk of SS outpatient visits (RR = 0.692, 95%CI: 0.510-0.939, per 63 µg/m3 in O3 exposure, lag 0-27 day). Stratified analyses showed that females (vs. males) was more vulnerable to SS outpatient visits associated with NO2 and O3 exposure. SS patients aged ≥65 years (vs. aged <65 years) were susceptible to PM2.5 exposure. Exposure to PM2.5 or NO2 in the cold season was associated with higher risk of SS outpatient visits than that in the warm season. In addition, the AN (232, 95%CI: 119, 324) and AF (5.16%, 95%CI: 2.55%, 7.21%) of NO2 exposure were higher than those of PM2.5 exposure. CONCLUSION: PM2.5 and NO2 exposure are associated with increased risk of SS outpatient visits, while O3 exposure appears to be associated with decreased risk of SS outpatient visits. The effect of air pollutants exposure on risk of SS outpatients can be modified by age, gender and season. The burden of SS outpatient visits attributable to NO2 exposure is higher than those attributable to PM2.5 exposure.

Protective effects of budesonide on LPS-induced podocyte injury by modulating macrophage M1/M2 polarization: Evidence from in vitro and in silico studies.

Budesonide (Bud), one of the most widely used lung medicines, is currently used as a repurposing medicine for immunoglobulin A nephropathy (IgAN) treatment. The progression of IgAN is related to inflammation involving macrophages and podocytes. The present study aimed to explore the effects of Bud on classically activated (M1)/alternatively activated (M2) macrophage polarization and podocyte injury under lipopolysaccharide (LPS)-induced inflammatory stress in vitro. Anti-inflammatory bioinformation of Bud was identified based on the Gene Expression Omnibus database. RAW264.7 cells were treated with normal medium, LPS, curcumin (Cur, positive control), or Bud 5, 10, or 20 µM. The expression levels of inducible nitric oxide synthase (iNOS), TNF-α, mannose receptor (CD206) and arginase (Arg)-1 were quantified by western blotting. The collected supernatants from macrophages were termed (Nor)MS, (LPS)MS, (Cur)MS and (Bud)MS. The TNF-α, IL-1ß and nitric oxide (NO) levels in the supernatants were evaluated by ELISA and Griess assay. The podocytes were cultured in different supernatants and their survival rates were assessed by bromodeoxyuridine assay. TNF signaling is an important pathway by which Bud exerts anti-inflammatory activities. Compared with the LPS group, 5, 10 and 20 µM Bud significantly increased Arg-1 and decreased iNOS expression (Six: P<0.05) and 20 µM Bud significantly increased Arg-1 and CD206 and decreased iNOS and TNF-α expression (Four: P<0.05). Cur significantly decreased iNOS and TNF-α expression (Two: P<0.05). Compared with LPS, 5, 10 and 20 µM Bud and Cur significantly decreased TNF-α, IL-1ß and NO levels (All: P<0.05). The podocyte survival rates of (Bud)MS and (Cur)MS were significantly higher than those of (LPS)MS (Four: P<0.05). The protective effect of Bud on podocyte injury is related to its modulation of M1/M2 polarization.

A plasmonic AgNP decorated heterostructure substrate for synergetic surface-enhanced Raman scattering identification and quantification of pesticide residues in real samples.

Rapid and on-site Raman spectroscopic identification and quantification of pesticide residues have been restricted to the low instrumental sensitivity of a portable Raman instrument, and no ideal platforms have been reported for analyzing pesticides on real sample surfaces. An efficient method to improve the detection sensitivity is to fabricate a highly sensitive surface-enhanced Raman scattering (SERS) substrate. Here, we present a MOF-derived ZnO@TiO2 heterostructure combined with plasmonic AgNPs as a SERS sensor to achieve synergetic EM and CM enhancement, exhibiting high sensitivity, excellent signal reproducibility (RSD < 5.9%) and superior stability for analysis of model molecules. The SERS sensor achieved a low detection concentration of 10-8 M for both CV and R6G molecular solutions on a portable Raman device. As a proof of concept, we modelled a pesticide residue on real samples of dendrobium leaves. Thiram, triazophos and fonofos solutions were selected as analytes for mimicking the function of on-site analysis. The SERS analytical platform showed not only high sensitivity for single- and multi-component identification, but also quantitative detection of pesticide residues on dendrobium leaves. These preliminary investigations indicate that this SERS analytical platform will allow the development and potential applications in rapid and on-site pesticide analysis.

Early Humoral Responses of Hemodialysis Patients After Inactivated SARS-CoV-2 Vaccination.

Purpose: To detect antibody responses to inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis and to investigate vaccine-related adverse events. Patients and Methods: A total of 120 hemodialysis (HD) patients and 24 healthy controls (HCs) who had not been previously infected with SARS-CoV-2 and had received their first dose of the inactivated vaccine (CoronaVac; Sinovac Biotech Ltd) were recruited for this study. All participants were scheduled to receive a second dose of inactivated SARS-CoV-2 vaccine. Serum-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against the SARS-CoV-2 were detected at least 14 days after the second dose of vaccine using a commercial kit. Positive and negative results were defined as a sample/cutoff (S/CO) ratio≥1.00 and <1.00, respectively. Vaccination-related adverse events were assessed using a standardized questionnaire. Results: There were no significant differences regarding the seroprevalences of IgG and IgM antibodies against SARS-CoV-2 and the self-reported vaccination-related adverse events between HD patients and HCs. The analysis results for HD patients suggest that 82 (68.3%) and 27 (22.5%) tested positive for IgG and IgM, respectively. The levels of IgG were higher than IgM levels (P<0.0001). In addition, the IgG-positive group had significantly higher serum albumin levels than the IgG-negative group (P<0.05). Only mild vaccine-related adverse events were observed in two patients (1.66%) and in one healthy individual (4.2%). Conclusion: The seroprevalences of IgG and IgM antibodies against SARS-CoV-2 and vaccination-related adverse effects are similar between HD and HCs. The inactivated SARS-CoV-2 vaccine is effective and safe in inducing near-term immunity in hemodialysis patients.

Environmental factors and risk of gout.

Gout is a chronic disease with inflammatory arthritis caused by monosodium urate (MSU) crystals deposition, an elevated serum urate level (hyperuricaemia) is the critical factor leading to MSU crystals deposition and promoting the progression of gout. The onset and development of gout is generally the result of multiple factors, such as diet, heredity and environmental factors. Although genetics and diet are thought to play as major factors, a growing body of research evidence has highlighted that environmental factors also play a significant role in the onset and exacerbation of gout. Recent studies have shown that air pollutants such as particulate matter, sulfur dioxide (SO2) and carbon monoxide (CO) may increase the risk of hospitalizations for gout, and that the changes in temperature and humidity may affect uric acid (UA) levels. There is also seasonal trend in gout. It has been demonstrated that environmental factors may induce or accelerate the production and release of pro-inflammatory mediators, causing an unbalance oxidative stress and systemic inflammation, and then participating in the overall process or a certain link of gout. Moreover, several environmental factors have shown the ability to induce the production urate and regulate the innate immune pathways, involving in the pathogenesis of gout. Nevertheless, the role of environmental factors in the etiology of gout remains unclear. In this review, we summarized the recent literatures and aimed to discuss the relationship between environmental factors (such as microclimate, season, ambient/indoor air pollution and extreme weather) and gout. We further discussed the inflammatory mechanisms of environmental factors and gout and the comprehensive effects of environmental factors on gout. We also made a prospect of the management and treatment of gout, with special consideration to environmental factors associated with gout.

In Vitro Immunomodulatory Effects of Inonotus obliquus Extracts on Resting M0 Macrophages and LPS-Induced M1 Macrophages.

Background: Inonotus obliquus (Chaga) is a parasitic fungus that is distributed mainly in northeast China. Our literature research showed chaga polysaccharides have bilateral effects on tumor necrosis factor (TNF)-α and interleukin (IL)-1ß levels when they exert antitumor and antidiabetic activities. The current research tried to explore the influence of chaga extracts on inflammatory factors via macrophage polarization which has bilateral immune-regulation not only on healthy tissue homeostasis but also on pathologies. Methods: Chaga was extracted with 100°C water and precipitated with 80% ethanol. The extracts were studied on RAW264.7 macrophage at resting condition (M0) and lipopolysaccharide (LPS)-activated subtype (classic activated macrophage, M1). The IL-1ß, TNF-α, nitric oxide (NO) level, and the protein expressions of M1 and alternative activated macrophage (M2) markers including IL-1ß, inducible NO synthase (iNOS), mannose receptor (CD206), and arginase (Arg)-1 were compared. Results: The 100 g extracts contained 13.7 g polysaccharides and 1.9 g polyphenols. Compared with M0, the 50 µg/mL extracts increased NO level (P < 0.05) and decreased CD206 and Arg-1 expression significantly (P < 0.05). The extracts at 100-200 µg/mL increased NO and TNF-α level (P < 0.05), but increased iNOS and IL-1ß expression significantly (P < 0.05). Compared with M1, the extracts decreased NO level at 25, 50, 100, and 200 µg/mL and decreased IL-1ß and TNF-α level at 100-200 µg/mL significantly (P < 0.05). At 25-200 µg/mL, the extracts significantly increased CD206 and Arg-1 expression and decreased IL-1ß and iNOS expression separately (P < 0.05). Conclusions: Our research suggested that the bilateral effects of the chaga extracts on iNOS, IL-1ß, and NO level on M0/M1 macrophages might be related with chaga polysaccharides and chaga polyphenols. Some in vivo anticancer and antidiabetic research of purified chaga polysaccharides related to macrophage differentiation should be conducted further.

Antiosteoporosis Studies of 20 Medicine Food Homology Plants Containing Quercetin, Rutin, and Kaempferol: TCM Characteristics, In Vivo and In Vitro Activities, Potential Mechanisms, and Food Functions.

Dietary nutraceutical compounds have been evidenced as backbone for bone health in recent years. It is reported that medicine food homology (MFH) plants have multiple nutraceutical compounds. Based on our literature research, 20 MFH plants caught our attention because they contain three popular antiosteoporosis compounds simultaneously: quercetin, rutin, and kaempferol. According to traditional Chinese medicine (TCM), their characteristics including natures, flavors, attributive to meridian tropism, and efficacies were listed. The relationships between TCM efficacies, such as "heat clearing," "tonic," and "the interior warming," and antiosteoporosis pharmacological actions such as antioxidant and immune regulation were discussed. The in vivo antiosteoporosis effects of the 20 MFH plants were summarized. The in vitro antiosteoporosis activities and related mechanisms of the 20 plants and quercetin, rutin, kaempferol were detailed. The TGF-ß-Smad signaling, fibroblast growth factor, and Wnt/ß-catenin signaling on bone formation and the RANKL signaling, NF-κB signaling, and macrophage-colony-stimulating factor on bone resorption were identified. From food point, these 20 MFH plants could be classified as condiment, vegetable, fruit, tea and related products, beverage, etc. Based on the above discussion, these 20 MFH plants could be used as daily food supplements for the prevention and treatment against osteoporosis.