The marine-derived HIF-1α inhibitor, Yardenone 2, reduces prostate cancer cell proliferation by targeting HIF-1 target genes.

BACKGROUND: Prostate cancer (PCa) ranks as the second most prevalent cancer in men, with advanced stages posing significant treatment challenges. Given its solid tumor nature, PCa is highly susceptible to hypoxia, a condition associated with resistance to radiation and chemotherapy, metastasis, and unfavorable patient outcomes. Hypoxia-inducible factors (HIFs) play a pivotal role in cancer cell adaptation to hypoxic environments, contributing to treatment resistance. Consequently, inhibitors targeting HIFs hold promise for cancer therapy. METHODS: In this study, we aimed to characterize novel HIF-1α inhibitors including Sodwanones A (1), B (2), C (3), G (4) and Yardenone 2 (5) isolated from marine sponges belonging to the Axinella genus. Our investigation evaluated the impact of these compounds on various aspects of HIF-1α regulation, including stabilization, nuclear localization, expression of HIF-1 target genes (while sparing HIF-2 target genes), cellular metabolism, as well as cell proliferation and viability in prostate cells under hypoxic conditions. RESULTS: Our findings revealed that among the compounds tested, Yardenone 2 exhibited notable effects in hypoxia: it destabilized HIF-1α at the protein level, decreased its nuclear localization, selectively altered the expression of HIF-1 target genes, and restrained cell proliferation in aggressive PC3 prostate cancer cells as well as in an MSK-PCa3 patient-derived organoid line. Moreover, it affected the morphology of these organoid. Yardenone 2 was also compared to Docetaxel, a specific microtubule inhibitor and a drug used in the treatment of prostate cancer. The comparison between the two compounds revealed notable differences, such as a lack of specificity to hypoxic cells of Docetaxel. CONCLUSION: These results mark the first demonstration that Yardenone 2 functions as a cytostatic-like inhibitor impacting microtubules, specifically targeting hypoxic cancer cells. This discovery suggests a promising avenue for novel therapeutic interventions in prostate cancer.

Improving the Quantification of Cyanotoxins Using a Mass Balance-Based Effective Concentration-Equivalent Concentration Approach.

Two commonly used methods for cyanotoxin analysis are enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Each method has its advantages and disadvantages, and discrepancies are commonly observed between the two methods due to various factors including the ELISA antibody cross-reacting to different cyanotoxin congeners. However, reliable cyanotoxin monitoring methods and accurate interpretation of results are needed for water utilities to guide recreational water planning and drinking water treatment operations. In this study, we explored an innovative "effective concentration-equivalent concentration" (EC-EQ) approach to improve the interpretation of ELISA results and the comparison to LC-MS/MS results. The precision of ELISA results was first improved by reporting the sample ECs and EQs derived from their ELISA dose curves. Concentrations of each cyanotoxin as measured by LC-MS/MS were then combined with their respective ELISA cross-reactivities to calculate their theoretical ELISA responses. Finally, instead of comparing the results from the two methods directly, the equivalent concentration based on one single reference cyanotoxin was used for reporting and comparison. This integrated mass balance-based approach provides a more reliable interpretation of results by considering the reactivity differences between toxins as well as their mixture effects. This approach has been successfully applied to microcystin (one main group of cyanotoxins) standard mixtures and cyanobacterial bloom samples to interpret and compare their ELISA and LC-MS/MS detection results. The study provides guidance to utilities on how to obtain more accurate cyanotoxin monitoring results and better understand the discrepancy between the two methods.

Comparison of mortality and complications between urgent-start peritoneal dialysis and urgent-start hemodialysis: A systematic review and meta-analysis.

The advantages of urgent-start peritoneal dialysis (PD) vis-à-vis urgent-start hemodialysis (HD) are not clear. We performed a systematic review and meta-analysis of studies comparing the two modalities. Databases of PubMed, Embase, Ovoid, and Google Scholar were searched up to November 1, 2020. The primary outcome was mortality, and secondary outcomes were dialysis-related infectious complications and mechanical complications. Risk ratios (RRs) were calculated for all outcomes. Seven studies were included. The pooled analysis revealed a statistically significant reduced risk of all-cause mortality in patients undergoing urgent-start PD as compared to urgent-start HD (RR: 0.61, 95% confidence interval [CI] [0.40, 0.94], I2  = 56.34%). A meta-analysis of dialysis-related infectious complications indicated no statistically significant difference between the two modalities (RR: 0.66, 95% CI [0.29, 1.50], I2  = 69.62%). Our analysis revealed a statistically significant reduced risk of mechanical complications in patients undergoing urgent-start PD (RR: 0.54, 95% CI [0.40, 0.73], I2  = 0%). To conclude, unadjusted data from observational studies are indicative of lower mortality and lower risk of mechanical complications with urgent-start PD versus urgent-start HD. The risk of infectious complications was not different between the two groups. Further studies with a larger sample size using propensity-matched cohorts are needed to strengthen current evidence.

Gene alterations in monocytes are pathogenic factors for immunoglobulin a nephropathy by bioinformatics analysis of microarray data.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulopathy worldwide. The study aimed to provide potential molecular biomarkers for IgAN management. METHODS: The public gene expression profiling GSE58539 was utilized, which contained 17 monocytes samples (8 monocytes samples isolated from IgAN patients and 9 monocytes samples isolated from healthy blood donors). Firstly, differentially expressed genes (DEGs) between the two kinds of samples were identified by limma package. Afterwards, pathway enrichment analysis was implemented. Thereafter, protein-protein interaction (PPI) network was constructed and key nodes in PPI network were predicted using four network centrality analyses. Ultimately, gene functional interaction (FI) was constructed according to expressions in each sample, and then module network was extracted from FI network. RESULTS: A total of 678 DEGs were screened out, of these, 72 DEGs were identified as crucial nodes in PPI network that could well distinguish IgAN and healthy samples. In particular, IL6, TNF, IL1B, PRKACA and CCL20 were closely related to pathways such as hematopoietic cell lineage, apoptosis and Toll-like receptor (TLR) signaling pathway. Moreover, 12 genes in the FI network belonged to the 72 identified key nodes, such as CCL20, HDAC10, FPR2 and PRKACA, which were also key genes in 4 module networks. CONCLUSIONS: Several crucial genes were identified in monocytes of IgAN patients, such as IL6, TNF, IL1B, CCL20, PRKACA, FPR2 and HDAC10. These genes might co-involve in pathways such as TLR and apoptosis signaling during IgAN progression.

Results of an interlaboratory comparison of analytical methods for contaminants of emerging concern in water.

An evaluation of existing analytical methods used to measure contaminants of emerging concern (CECs) was performed through an interlaboratory comparison involving 25 research and commercial laboratories. In total, 52 methods were used in the single-blind study to determine method accuracy and comparability for 22 target compounds, including pharmaceuticals, personal care products, and steroid hormones, all at ng/L levels in surface and drinking water. Method biases ranged from <10% to well over 100% in both matrixes, suggesting that while some methods are accurate, others can be considerably inaccurate. In addition, the number and degree of outliers identified suggest a high degree of variability may be present between methods currently in use. Three compounds, ciprofloxacin, 4-nonylphenol (NP), and 4-tert-octylphenol (OP), were especially difficult to measure accurately. While most compounds had overall false positive rates of ≤5%, bisphenol A, caffeine, NP, OP, and triclosan had false positive rates >15%. In addition, some methods reported false positives for 17ß-estradiol and 17α-ethynylestradiol in unspiked drinking water and deionized water, respectively, at levels higher than published predicted no-effect concentrations for these compounds in the environment. False negative rates were also generally <5%; however, rates were higher for the steroid hormones and some of the more challenging compounds, such as ciprofloxacin. The elevated false positive/negative rates of some analytes emphasize the susceptibility of many current methods to blank contamination, misinterpretation of background interferences, and/or inappropriate setting of detection/quantification levels for analysis at low ng/L levels. The results of both comparisons were collectively assessed to identify parameters that resulted in the best overall method performance. Liquid chromatography-tandem mass spectrometry coupled with the calibration technique of isotope dilution were able to accurately quantify most compounds with an average bias of <10% for both matrixes. These findings suggest that this method of analysis is suitable at environmentally relevant levels for most of the compounds studied. This work underscores the need for robust, standardized analytical methods for CECs to improve data quality, increase comparability between studies, and help reduce false positive and false negative rates.

Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis.

To investigate the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals in the treatment of renal fibrosis (RF). We searched articles from databases (PubMed, Embase, The Cochrane Library, CNKI, and Wanfang data) and references of included studies. The quality of literature was evaluated and data were extracted in regard to the inclusion and exclusion criteria. RevMan5.3 software was applied for all statistical analyses. Eleven eligible RCTs with a total of 898 patients were included in this meta-analysis. Compared with conventional western medicine alone, conventional western medicine with Chinese medicine for dredging collaterals in the treatment of RF has lower BUN levels and SCr levels (P < 0.05). As for fibrosis indexes, conventional western medicine with Chinese medicine for dredging collaterals has lower HA, laminin (LN), IV-Col, and PC-III levels (P < 0.05). Conventional western medicine with Chinese medicine for dredging collaterals with lower BUN, Scr, HA, LN, PC-III, and IV-Col levels, has an advantage in the treatment of RF. These lower serum levels may not be associated with the presence of RF. Ideally, kidney biopsies should be performed to confirm that these markers reduce RF. This is a major limitation of this study.

Efficacy and safety of artesunate for patients with IgA nephropathy: a study protocol for a multicenter, double-blind, randomized, placebo-controlled trial.

BACKGROUND: IgA nephropathy is the most common glomerular disease and is a common cause of progression to end-stage renal disease in patients with kidney diseases. Proteinuria levels are critical for the prognosis of patients with IgA nephropathy, but many patients are still unable to effectively control their proteinuria levels after receiving RAAS blockers. Antimalarial drugs have shown good efficacy in the treatment of kidney disease in previous studies; however, there have been no strictly designed randomized controlled trials to confirm the clinical efficacy of artesunate for treating IgA nephropathy patients. Therefore, we designed this clinical trial to compare the effect of artesunate versus placebo in patients with IgA nephropathy. METHODS: This study is a randomized, double-blind, three-group-parallel, placebo-controlled clinical trial. One hundred and twenty eligible IgA nephropathy patients at risk of progression will be randomly divided into the artesunate 100-mg group, artesunate 50-mg group, and placebo group. Changes in proteinuria and renal function will be measured 6 months after the intervention. The levels of Gd-IgA1 and anti-Gd-IgA1 in the patient's blood will also be tested to explore the possible immune mechanisms. DISCUSSION: Clinical evidence supporting artesunate treatment of IgA nephropathy is currently lacking, and we expect that the results of this trial will provide high-quality clinical evidence for artesunate as a treatment option for IgA nephropathy in the future. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000038104 . Registered on 10 September 2020.

Modulation of the Gut Microbiota by Shen-Yan-Fang-Shuai Formula Improves Obesity Induced by High-Fat Diets.

Obesity and related metabolic disorders are associated with intestinal microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Shen-Yan-Fang-Shuai formula (SYFSF) is a traditional Chinese herbal formula composed of Astragali Radix, Radix Angelicae Sinensis, Rheum Officinale Baill, and four other herbs. In this study, we identified that SYFSF treatment prevented weight gain, low-grade inflammation and insulin resistance in high-fat diet (HFD)-fed mice. SYFSF also substantially improved gut barrier function, reduced metabolic endotoxemia, as well as systemic inflammation. Sequencing of 16S rRNA genes obtained from fecal samples demonstrated that SYFSF attenuated HFD-induced gut dysbiosis, seen an decreased Firmicutes to Bacteroidetes ratios. Microbial richness and diversity were also higher in the SYFSF-treated HFD group. Furthermore, similar therapeutic effects and changes in gut microbiota profile caused by SYFSF could be replicated by fecal microbiota transfer (FMT). Taken together, our study highlights the efficacy of SYFSF in preventing obesity and related metabolic disorders. Its therapeutic effect is associated with the modulation of gut microbiota, as a prebiotic.

Association between PAI-1 4G/5G polymorphism and diabetic nephropathy: a meta-analysis in the Chinese population.

BACKGROUNDS AND AIMS: Although a number of studies have been conducted on the association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and diabetic nephropathy (DN) in Chinese population, this association remains elusive and controversial. To further assess the effects of PAI-1 4G/5G polymorphism on the risk of DN, a meta-analysis was performed in the Chinese population. METHODS: Relevant studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine through November, 2015. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of the associations. RESULTS: This meta-analysis identified nine studies, including 777 DN cases, 413 healthy controls, and 523 DM controls. In the total analyses, a significantly elevated risk of DN was associated with variants of PAI-1 4G/5G when compared with the healthy group (4G vs. 5G, OR 2.46, 95 % CI 1.45-4.16; 4G/4G vs. 5G/5G, OR 4.32, 95 % CI 1.79-10.39; 4G/4G vs. 4G/5G +5G/5G, OR 2.96, 95 % CI 1.59-5.53; 4G/4G +4G/5G vs. 5G/5G, OR 2.78, 95 % CI 1.34-5.75) and DM group (4G vs. 5G, OR 1.93, 95 % CI 1.28-2.92; 4G/4G vs. 5G/5G, OR 2.99, 95 % CI 1.44-6.21; 4G/4G vs. 4G/5G +5G/5G, OR 2.84, 95 % CI 1.77-4.54). In the subgroup analyses stratified by ethnicity and geographic areas, it revealed the significant results in Chinese Han, in North and South China. CONCLUSIONS: This meta-analysis showed that the PAI-1 4G/4G variant, 4G allele might be risk alleles for DN susceptibility in the Chinese population, and further studies in other ethic groups are required for definite conclusions.

An electrospray ionization-tandem mass spectrometry method for identifying chlorinated drinking water disinfection byproducts.

Identification of chlorinated drinking water disinfection byproducts (DBPs) was investigated by using electrospray ionization-mass spectrometry/mass spectrometry (ESI-MS/MS). Chlorine-containing compounds were found to form chloride ion fragments by MS/MS, which can be used as a 'fingerprint' for chlorinated DBPs. Instrumental parameters that affect the formation of chloride ions by ESI-MS/MS were examined, and appropriate conditions for use in finding specific structural information were evaluated. The results show that maximizing the formation of chloride ions by MS/MS required a relatively high collision energy and collision gas pressure; also, limiting the scan range to m/z 30-40 allowed improved sensitivity for detection; but obtaining structural information required the use of lower collision energies. The conditions obtained were demonstrated to be effective in identifying chlorinated DBPs in a standard sample with relatively low concentrations of each component and in a chlorinated humic substance sample. Sample pretreatment techniques including ultrafiltration and size exclusion chromatography appeared to be helpful for identifying highly polar or high molecular weight chlorine-containing DBPs by ESI-MS/MS.