Ras-Targeting Stabilized Peptide Increases Radiation Sensitivity of Cancer Cells.

Radiation therapy is one of the most common treatments for cancer. However, enhancing tumors' radiation sensitivity and overcoming tolerance remain a challenge. Previous studies have shown that the Ras signaling pathway directly influences tumor radiation sensitivity. Herein, we designed a series of Ras-targeting stabilized peptides, with satisfactory binding affinity (KD = 0.13 µM with HRas) and good cellular uptake. Peptide H5 inhibited downstream phosphorylation of ERK and increased radio-sensitivity in HeLa cells, resulting in significantly reduced clonogenic survival. The stabilized peptides, designed with an N-terminal nucleation strategy, acted as potential radio-sensitizers and broadened the applications of this kind of molecule. This is the first report of using stabilized peptides as radio-sensitizers, broadening the applications of this kind of molecule.

Single-domain antibodies against SARS-CoV-2 RBD from a two-stage phage screening of universal and focused synthetic libraries.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an evolving global pandemic, and nanobodies, as well as other single-domain antibodies (sdAbs), have been recognized as a potential diagnostic and therapeutic tool for infectious diseases. High-throughput screening techniques such as phage display have been developed as an alternative to in vivo immunization for the discovery of antibody-like target-specific binders. METHODS: We designed and constructed a highly diverse synthetic phage library sdAb-U (single-domain Antibody - Universal library ) based on a human framework. The SARS-CoV-2 receptor-binding domain (RBD) was expressed and purified. The universal library sdAb-U was panned against the RBD protein target for two rounds, followed by monoclonal phage ELISA (enzyme-linked immunosorbent assay) to identify RBD-specific binders (the first stage). High-affinity binders were sequenced and the obtained CDR1 and CDR2 sequences were combined with fully randomized CDR3 to construct a targeted (focused) phage library sdAb-RBD, for subsequent second-stage phage panning (also two rounds) and screening. Then, sequences with high single-to-background ratios in phage ELISA were selected for expression. The binding affinities of sdAbs to RBD were measured by an ELISA-based method. In addition, we conducted competition ELISA (using ACE2 ectodomain S19-D615) and SARS-CoV-2 pseudovirus neutralization assays for the high-affinity RBD-binding sdAb39. RESULTS: Significant enrichments were observed in both the first-stage (universal library) and the second-stage (focused library) phage panning. Five RBD-specific binders were identified in the first stage with high ELISA signal-to-background ratios. In the second stage, we observed a much higher possibility of finding RBD-specific clones in phage ELISA. Among 45 selected RBD-positive sequences, we found eight sdAbs can be well expressed, and five of them show high-affinity to RBD (EC50 < 100nM). We finally found that sdAb39 (EC50 ~ 4nM) can compete with ACE2 for binding to RBD. CONCLUSION: Overall, this two-stage strategy of synthetic phage display libraries enables rapid selection of SARS-CoV-2 RBD sdAb with potential therapeutic activity, and this two-stage strategy can potentially be used for rapid discovery of sdAbs against other targets.

Trajectory model to analyze the effect of multi-metal exposures on sperm parameters and sex hormones of the MARHCS cohort in China.

BACKGROUND: At present, several cross-sectional studies have found that exposure to metal/metalloid elements is closely associated with male reproduction. However, the long-term effects of metal exposure on male reproduction have not been explored. METHODS: In 2013, 796 volunteers were recruited, followed by first and second follow-ups in 2014 and 2015. Urine, semen, and blood samples were collected at each stage to examine urinary metal/metalloid levels, sperm parameters, and sex hormones. Initially, the latent class trajectory model (LCTM) was utilized to analyze the trajectories of urinary metals. Subsequently, the effects of urinary metal trajectories on semen parameters and sex hormones were examined using the linear mixed model. Finally, the impact of urinary metal trajectories on the classification of semen quality (normal or abnormal) was evaluated using the generalized linear mixed model. RESULTS: Among the 18 metals/metalloids studied, trajectories were formed by 6 of them (Li, Al, Fe, Zn, As, Rb). Further analysis using the linear mixed model and the generalized linear mixed model revealed that Li was negatively correlated with semen volume, and sperm motility (P < 0.05). The maximum-decreasing trajectory group had a detrimental effect on semen quality (OR = 1.75, 95%CI: 1.22, 2.53) compared to the minimum-stable trajectory group. Al showed negative associations with sperm concentration, total sperm count, and normal morphology (P < 0.05). Rb was positively associated with progressive motility (P < 0.05). The high-stable trajectory group exhibited a protective effect on semen quality (OR = 0.66, 95%CI: 0.49, 0.90) compared to the low-stable trajectory group. Additionally, Fe was observed to have a negative relationship with follicle-stimulating hormone (FSH) (P < 0.05), and Rb exhibited a negative correlation with progesterone (P) (P < 0.05). CONCLUSION: Our three-year cohort study provides new evidence that Li and Al have a negative impact on semen quality, whereas Rb is associated with beneficial effects. Additionally, Rb and Fe are endocrine disruptors of sex hormones.

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism.

It is particularly challenging to develop a truly effective pharmacotherapy for cocaine use disorder (CUD) treatment. Accelerating cocaine metabolism via hydrolysis at cocaine benzoyl ester using an efficient cocaine hydrolase (CocH) is known as a promising pharmacotherapeutic approach to CUD treatment. Preclinical and clinical studies on our first CocH (CocH1), in its human serum albumin-fused form known as TV-1380, have demonstrated the promise of a general concept of CocH-based pharmacotherapy for CUD treatment. However, the biological half-life of TV-1380 (t1/2 = 8 h in rats, associated with t1/2 = 43-77 h in humans) is not long enough for practical treatment of cocaine dependence, which requires enzyme injection for no more than once weekly. Through protein fusion of a human butyrylcholinesterase mutant (denoted as CocH5) with a mutant (denoted as Fc(M6)) of Fc from human IgG1, we have designed, prepared, and tested a new fusion protein (denoted as CocH5-Fc(M6)) for its pharmacokinetic profile and in vivo catalytic activity against (-)-cocaine. CocH5-Fc(M6) represents the currently most efficient long-acting cocaine hydrolase with both the highest catalytic activity against (-)-cocaine and the longest elimination half-life (t1/2 = 229 ± 5 h) in rats. As a result, even at a single modest dose of 3 mg/kg, CocH5-Fc(M6) can significantly and effectively accelerate the metabolism of cocaine in rats for at least 60 days. In addition, ∼70 nM CocH5-Fc(M6) in plasma was able to completely block the toxicity and physiological effects induced by intraperitoneal injection of a lethal dose of cocaine (60 mg/kg).

Mitochondrial pyruvate carrier 1: a novel prognostic biomarker that predicts favourable patient survival in cancer.

Mitochondrial pyruvate carrier 1 (MPC1) is a key metabolic protein that regulates the transport of pyruvate into the mitochondrial inner membrane. MPC1 deficiency may cause metabolic reprogramming. However, whether and how MPC1 controls mitochondrial oxidative capacity in cancer are still relatively unknown. MPC1 deficiency was recently found to be strongly associated with various diseases and cancer hallmarks. We utilized online databases and uncovered that MPC1 expression is lower in many cancer tissues than in adjacent normal tissues. In addition, MPC1 expression was found to be substantially altered in five cancer types: breast-invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and prostate adenocarcinoma (PRAD). However, in KIRC, LUAD, PAAD, and PRAD, high MPC1 expression is closely associated with favourable prognosis. Low MPC1 expression in BRCA is significantly associated with shorter overall survival time. MPC1 expression shows strong positive and negative correlations with immune cell infiltration in thymoma (THYM) and thyroid carcinoma (THCA). Furthermore, we have comprehensively summarized the current literature regarding the metabolic reprogramming effects of MPC1 in various cancers. As shown in the literature, MPC1 expression is significantly decreased in cancer tissue and associated with poor prognosis. We discuss the potential metabolism-altering effects of MPC1 in cancer, including decreased pyruvate transport ability; impaired pyruvate-driven oxidative phosphorylation (OXPHOS); and increased lactate production, glucose consumption, and glycolytic capacity, and the underlying mechanisms. These activities facilitate tumour progression, migration, and invasion. MPC1 is a novel cancer biomarker and potentially powerful therapeutic target for cancer diagnosis and treatment. Further studies aimed at slowing cancer progression are in progress.

Association of serum microcystin levels with neurobehavior of school-age children in rural area of Southwest China: A cross-sectional study.

To investigate whether microcystin-LR (MC-LR) influences children's cognitive function and memory ability, we measured serum MC-LR and whole blood lead levels in 697 primary students, and collected their academic and neurobehavioral test scores. The median of serum MC-LR levels was 0.80 µg/L (the value below the limit of detection to 1.67 µg/L). The shapes of the associations of serum MC-LR levels (cut-point: 0.95 µg/L) with scores on academic achievements, digit symbol substitution test and long-term memory test were parabolic curves. Logistic regression analysis showed that MC-LR at concentrations of 0.80-0.95 µg/L was associated with the increased probability of higher achievements on academic achievements [odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.28-3.79], and also with scores on digit symbol substitution test (OR = 1.73, 95% CI: 1.05-2.86), overall memory quotient (OR = 2.27, 95% CI: 1.21-4.26), long-term memory (OR = 1.85, 95% CI: 1.01-3.38) and short-term memory (OR = 2.13, 95% CI: 1.14-3.98) after adjustment for confounding factors. Antagonism of MC-LR and lead on long-term memory was observed (synergism index = 0.15, 95% CI: 0.03-0.74). In conclusion, serum MC-LR at concentrations of 0.80-0.95 µg/L was positively associated with higher scores on cognitive and neurobehavioral tests, and antagonism between MC-LR at concentrations of 0.80-1.67 µg/L and lead exposure was obviously observed on long-term memory in children. Concerning that MC-LR is a neurotoxin at high doses, our observation is interesting and need further investigation.

Peptide-Aptamer Coassembly Nanocarrier for Cancer Therapy.

We reported methionine bis-alkylated nonapeptide Wpc as an efficient siRNA vehicle previously. Herein, we report an aptamer could also spontaneously coassemble with Wpc to form uniformed nanoparticles for efficient delivery. This unique peptide-based aptamer nanocarrier showed significantly improved cell penetration and antiproliferation effect with high biocompatibility toward various cancer cell lines.

Mitochondrial functionality modifies human sperm acrosin activity, acrosome reaction capability and chromatin integrity.

STUDY QUESTION: In addition to sperm motility, which major biological characteristics of sperm fertility potential are associated with mitochondrial functionality? SUMMARY ANSWER: Sperm fertilization capacities, including acrosin activity, acrosome reaction (AR) capability and chromatin integrity, are related to the mitochondria functionality as evaluated by the mitochondrial membrane potential (MMP). WHAT IS KNOWN ALREADY: Correlative studies suggest a potential role of sperm MMP in predicting sperm fertilization ability and ensuring sperm motility. However, researches characterizing other determinants of sperm fertility potential according to MMP are lacking. STUDY DESIGN, SIZE, DURATION: The sperm MMP was examined in 627 young college students in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Among these participants, acrosin activity and chromatin integrity were measured in 378 and 604 subjects, respectively. These two determinants of sperm fertility potential were first compared among high-, moderate- and low-MMP groups in the college population. The effects of MMP collapse caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on acrosin activity, AR, DNA fragmentation, reactive oxygen species (ROS) production, and ATP content in human spermatozoa were evaluated in vitro. PARTICIPANTS/MATERIALS, SETTING, METHODS: The sperm MMP was evaluated by using JC-1 staining, acrosin activity was measured using a N-α-benzoyl-dl-arginine-para-nitroanilide HCl (BAPNA) substrate method, the integrity of chromatin represented by DNA fragmentation index (DFI) was measured by sperm chromatin structure assay (SCSA), AR was evaluated with chlortetracycline staining, and intracellular ROS production was evaluated with dihydroethidium. ATP concentration was determined with luciferase. Measurements were performed by spectrophotometry or flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: Nonparametric analysis revealed significantly higher acrosin activity and a lower DFI in subjects with moderate or high MMP compared to those with low MMP. After adjustment for potential confounders, increases of 7.9 and 44.4% in sperm acrosin activity and deceases of 12.0 and 25.2% in the sperm DFI were found in the moderate- and high-MMP groups, respectively. The MMP dissipation induced by CCCP caused significant declines in acrosin activity and AR capacity and increased DFI in human spermatozoa. Moreover, sperm MMP dissipation induced ROS overproduction and decreased ATP content. LIMITATIONS, REASONS FOR CAUTION: We cannot exclude a contribution of leukocytes to ROS production and no size gating was used to exclude these cells from the FACS measurements. No simultaneous live-dead staining was done and a contribution of dead sperm to the MMP and acrosome assays cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Mitochondrial functionality might be necessary to maintain sperm acrosin activity, AR and chromatin integrity. Tests of mitochondrial functionality should be developed and used independently of or in addition to conventional semen parameters in infertility diagnosis or risk-assessment processes. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Key Program of the National Natural Science Foundation of China (No. 81630087) and the National Natural Science Foundation of China (No. 81703254). None of the authors have any competing interests to declare.

In Silico Observation of the Conformational Opening of the Glutathione-Binding Site of Microsomal Prostaglandin E2 Synthase-1.

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is known as an ideal target for next-generation anti-inflammatory drugs to effectively and safely treat a variety of inflammation-related diseases. High-resolution X-ray crystal structures are available for human mPGES-1, but all in a closed conformation for a glutathione (GSH)-binding site. Here, we report an in silico observation of the desirable open conformation of mPGES-1 using a simple computational strategy with fully relaxed molecular dynamics simulations starting a high-resolution X-ray crystal structure in the closed conformation. The open conformation mainly exists in the apo-form. Once GSH enters the binding site, the binding site is closed and, thus, mPGES-1 becomes the closed conformation. According to the determined free energy profile, both the open and closed conformations can co-exist in solution with a thermodynamic equilibrium, and the conformational distribution is dependent on the GSH concentration. In addition, the cap domain responsible for the conformational transition is located right on the crystal packing interface, showing that only closed conformation is suitable for the crystal packing. All of the computational insights are consistent with reported experimental observations. The computationally simulated open conformation of mPGES-1 may serve as a new target state for the rational design of novel inhibitors of mPGES-1. We anticipate that a computational strategy similar to the one used in this study may also be used to explore open conformation starting from a crystal structure of the corresponding closed conformation with a ligand bound for other proteins.

Solvent-Controlled Synthesis of Highly Luminescent Carbon Dots with a Wide Color Gamut and Narrowed Emission Peak Widths.

Carbon dots (CDs) have tremendous potential applications in bioimaging, biomedicine, and optoelectronics. By far, it is still difficult to produce photoluminescence (PL) tunable CDs with high quantum yield (QY) across the entire visible spectrum and narrow the emission peak widths of CDs close to those of typical quantum dots. In this work, a series of CDs with tunable emission from 443 to 745 nm, quantum yield within 13-54%, and narrowed full width at half maximum (FWHM) from 108 to 55 nm, are obtained by only adjusting the reaction solvents in a one-pot solvothermal route. The distinct optical features of these CDs are based on their differences in the particle size, and the content of graphitic nitrogen and oxygen-containing functional groups, which can be modulated by controlling the dehydration and carbonization processes during solvothermal reactions. Blue, green, yellow, red, and even pure white light emitting films (Commission Internationale de L'Eclairage (CIE)= 0.33, 0.33, QY = 39%) are prepared by dispersing one or three kinds of CDs into polyvinyl alcohol with appropriate ratios. The near-infrared emissive CDs are excellent fluorescent probes for both in vitro and in vivo bioimaging because of their high QY in water, long-term stability, and low cytotoxicity.

Lignocellulosic biomass to biofuels and biochemicals: A comprehensive review with a focus on ethanol organosolv pretreatment technology.

Lignocellulosic biomass is one of the potential feedstocks to produce second-generation cellulosic ethanol and biochemicals. To enhance the enzymatic digestibility of lignocellulosic biomass for efficient enzymatic saccharification, a variety of pretreatment methods have been studied. Among these, organosolv pretreatment using ethanol is a promising pretreatment method owing to its inherent advantages, such as low solvent cost, lack of toxicity, the ability to retain most cellulose fraction in substrates for enzymatic hydrolysis, coproduction of high-purity lignin and hemicellulosic sugars, easy solvent recovery, and reuse. In this review, the research progress regarding different types of ethanol organosolv pretreatment processes has been summarized in terms of methods, substrate properties, reaction mechanisms, delignification kinetic as well as the impact of pretreatment methods on the enzymatic digestibility. Attempts are also made to provide insights into the complete utilization of lignocellulosic biomass to achieve high potential revenues. Though some ethanol organosolv processes have been studied or are being developed towards commercialization, ethanol organosolv pretreatment is still facing some challenges. Finally, the direction for future work is given to develop a proper ethanol organosolv pretreatment for commercialization.

Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1.

Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

Exposures to Atmospheric PM10 and PM10-2.5 Affect Male Semen Quality: Results of MARHCS Study.

Studies have shown that the effects of ambient particulate matter (PM) may be related to particle's size. However, results on the relationships between different PM and reproductive health are controversial. To explore the impacts of various PM fractions on male reproductive health, a total of 796 eligible subjects recruited in 2013 baseline investigation. In addition, there were 656 (82.4%) and 568 (71.3%) subjects participated follow-up surveys in 2014 and 2015, respectively. We used multivariable regression analysis and mixed-effect model to investigate the associations between air pollutants PM10, PM10-2.5, and PM2.5 exposures and semen quality, sperm DNA fragmentation and serum reproductive hormones of subjects. In the preliminary regression analysis, PM10, PM10-2.5, and PM2.5 exposure all associated with sperm concentration, morphology, sperm high DNA stainability (HDS), serum estradiol and testosterone levels. However, in mixed models, we only found that PM10 exposure were negatively associated with sperm normal morphology (95% CI: -14.13, -24.47) but positively associated with sperm progressive motility (95% CI: 23.00, 8.49), and PM10-2.5 exposure was inversely associated with sperm concentration (95% CI: -9.06, -27.31) after multiplicity adjustment. Our results provide the evidence that air PM10 and PM10-2.5 exposures, not PM2.5, are risk factors of semen quality.

Selective inhibitors of human mPGES-1 from structure-based computational screening.

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors of mPGES-1 provide some interesting clues for rational design of modified structures of the inhibitors to more favorably bind with mPGES-1.

Mccrearamycins A-D, Geldanamycin-Derived Cyclopentenone Macrolactams from an Eastern Kentucky Abandoned Coal Mine Microbe.

Four cyclopentenone-containing ansamycin polyketides (mccrearamycins A-D), and six new geldanamycins (Gdms B-G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD-23-14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19-hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.

Anogenital distance is associated with serum reproductive hormones, but not with semen quality in young men.

STUDY QUESTION: Is anogenital distance associated with semen parameters and serum reproductive hormone levels in males? SUMMARY ANSWER: Anogenital distance is associated with serum reproductive hormones, but not with semen quality. WHAT IS KNOWN ALREADY: Epidemiological studies have suggested that anogenital distance (AGD) may be associated with testicular dysfunction in adult men. However, the role of AGD in estimating male reproductive function remains unclear. STUDY DESIGN, SIZE, DURATION: We examined the associations between AGD and semen parameters and reproductive hormones levels in 656 young college students in a Male Reproductive Health in Chongqing College Students (MARHCSs) cohort study in June of 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, two variants of AGD (AGDAP and AGDAS) were measured in 656 university students. Serum levels of testosterone (T), estradiol (E2), progesterone (P), prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG) and inhibin-B; and semen quality outcomes, including semen volume, sperm concentration, total sperm number, sperm progressive motility, total motility and morphology, were assessed. The associations between AGD and semen parameters/reproductive hormones levels were analyzed using multiple regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Both AGDAS and AGDAP were not associated with any semen parameters. In the non-parametric correlation analysis, AGDAP were correlated with sperm progressive motility and reproductive hormones of E2, testosterone, SHBG and the testosterone/LH ratio. However, body mass index (BMI) also significantly correlated with serum testosterone ( ITALIC! r = -0.216, ITALIC! P = <0.0001) and SHBG ( ITALIC! r = -0.229, ITALIC! P = <0.001). In the multiple regression models, AGDAP was negatively associated with the serum E2 level (95% CI, -0.198 to -0.043; ITALIC! P = 0.002) and positively associated with the ratio of T/E2 (95% CI, 0.004-0.011; ITALIC! P = 0.001) after an adjustment for BMI and other confounders. LIMITATIONS, REASONS FOR CAUTION: Using only a single semen sample to predict male reproductive function over a longer period is a potential limitation of the present study. The other limitation is the cross-sectional nature of the study design. Longitudinal data from an extended follow-up on a large cohort would be more definitive. WIDER IMPLICATIONS OF THE FINDINGS: Our results do not support previous studies where AGD is associated with male semen quality. The utility of AGD in predicting reproductive outcomes in adult males should thus be considered prudently. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Key Program of Natural Science Funding of China (no. 81130051), Young Scientist Program of NSFC (no. 81502788) and the National Scientific and Technological Support Program of China (no. 2013BAI12B02). None of authors had any competing interests to declare.

Determination of Environmental Exposure to Microcystin and Aflatoxin as a Risk for Renal Function Based on 5493 Rural People in Southwest China.

Although the nephrotoxicity of microcystin and aflatoxin has been observed in animal and clinical cases, few population data are available. We conducted a cross-sectional study in Southwest China to investigate the association of renal function indicators (RFIs, including BUN, SCr, and eGFR) with exposure to microcystin and aflatoxin in 5493 members of the general population. Microcystin-LR levels in water and aquatic products and aflatoxin B1 levels in daily foods were measured by ELISA, and individual estimated daily intake (EDI) was assessed on the basis of the measurement and questionnaire. We found that participants with abnormal RFIs had a much higher mean level of microcystin-LR EDI than those with normal RFIs and that there was a significant increasing trend for abnormal rates and odds ratios of RFIs with increasing microcystin-LR EDI quartiles (p for trend = 0.000). Compared with the lowest quartile of microcystin-LR exposure, those in the highest quartile had significantly higher risks of abnormal BUN (OR = 1.80, 95% CI = 1.34-2.42), SCr (OR = 4.58, 95% CI = 2.92-7.21), and eGFR (OR = 4.41, 95% CI = 2.55-7.63), respectively, but no higher risk was found in subjects with higher AFB1 exposure. After adjustment for confounding factors, risk associations with microcystin-LR persisted. Consequently, our results suggest that microcystin, rather than aflatoxin, might be one important risk of renal-function impairment.

Associations between variants on ADIPOQ and ADIPOR1 with colorectal cancer risk: a Chinese case-control study and updated meta-analysis.

BACKGROUND: Epidemiological studies have suggested that variants on adiponectin (ADIPOQ) and its receptor ADIPOR1 (adiponectin receptor 1) are associated with colorectal cancer (CRC) risk; however, the results were inconclusive. The aim of the study was to evaluate the associations between the variants on ADIPOQ and ADIPOR1 and the CRC risk with a hospital-based case-control study in the Chinese population along with meta-analysis of available epidemiological studies. METHODS: With a hospital-based case-control study of 341 cases and 727 controls, the associations between the common variants on ADIPOQ (rs266729, rs822395, rs2241766 and rs1501299) and ADIPOR1 (rs1342387 and rs12733285) and CRC susceptibility were evaluated. Meta-analysis of the published epidemiological studies was performed to investigate the associations between the variants and CRC risk. RESULTS: For the population study, we found that variant rs1342387 of ADIPOR1 was associated with a reduced risk for CRC [adjusted odds ratio (OR) = 0.74, 95% confidential intervals (95% CI) = 0.57-0.97; CT/TT vs. CC]. The meta-analysis also suggested a significant association for rs1342387 and CRC risk; the pooled OR was 0.79 (95% CI = 0.66-0.95) for the CT/TT carriers compared to CC homozygotes under the random-effects model (Q = 8.06, df = 4, P = 0.089; I(2) = 50.4%). The case-control study found no significant association for variants rs266729, rs822395, rs2241766, and rs1501299 on ADIPOQ or variant rs12733285 on ADIPOR1 and CRC susceptibility, which were consistent with results from the meta-analysis studies. CONCLUSIONS: These data suggested that variant rs1342387 on ADIPOR1 may be a novel CRC susceptibility factor.

Research reviews and prospects of gut microbiota in liver cirrhosis: a bibliometric analysis (2001-2023).

Introduction: The gut-liver axis has emerged as a focal point in chronic liver disorders, prompting more research into the role of the gut microbiota in liver cirrhosis. In individuals with liver cirrhosis, changes in the structure and function of the gut microbiota are closely tied to clinical prognosis. However, there is a scarcity of bibliometric evaluations conducted in this particular field. Methods: This study is aiming to conduct a complete analysis of the knowledge structure and centers pertaining to gut microbiota in liver cirrhosis using bibliometric methods. Publications on gut microbiota and liver cirrhosis from 2001 to 2023 are sourced from the Web of Science Core Collection. For the bibliometric analysis, we employ VOSviewer, CiteSpace, and the R package "bibliometrix". Results: Our study encompasses a comprehensive collection of 3109 articles originating from 96 countries, with notable contributions from leading nations such as the United States and China. The quantity of publications concerning the gut microbiota of liver cirrhosis rises annually. The University of California San Diego, Virginia Commonwealth University, Zhejiang University are the primary research institutions. World Journal of Gastroenterology publishes the most papers in this field, while hepatology is the most frequently co-cited journal. These publications come from a total of 15,965 authors, and the most prolific authors are Bajaj Jasmohan S., Schnabl Bernd and Gillevet Patrick M., while the most co-cited authors are Bajaj Jasmohan S., Younossi Zobair M., and Reiner Wiest. In addition, "dysbiosis", "gut microbiota", "intestinal barrier", "fecal microbiota transplantation", and "complement-system" are the primary keywords of research trends in recent years. Discussion: This study offering a comprehensive insight into the research dynamics surrounding gut microbiota in patients with liver cirrhosis. It delineates the current research frontiers and hotspots, serving as a valuable guide for scholars.

Identification of RAS-like oncoprotein B (RALB) as a potential prognostic and therapeutic target in head and neck squamous cell carcinoma.

BACKGROUND/PURPOSE: The RAS superfamily oncogenes play significant roles in various types of malignant tumors. However, little is known about the role of RAS-like oncoprotein B (RALB) in head and neck squamous cell carcinoma (HNSCC). This study evaluated whether RALB can be a prognostic and therapeutic target for HNSCC. MATERIALS AND METHODS: A total of 504 HNSCC samples from The Cancer Genome Atlas database were segregated into two groups: RALB-high and RALB-low. The clinical significance of RALB expression in HNSCC patients was investigated. Cell proliferation, migration, and invasion assays were performed in HN-1 and HN-5 cells by silencing RALB using siRNA. Gene enrichment and immune infiltration analyses were also performed. RESULTS: RALB expression was elevated in HNSCC tissues compared with normal tissues and was an independent risk factor associated with poor prognosis. A nomogram including the RALB expression level was established to predict the prognosis of HNSCC patients and showed highest sensitivity and benefit in predicting the three-year survival. The inhibition of RALB expression effectively impeded the proliferation, invasion, and migration of HNSCC cells. Importantly, RALB levels were significantly correlated with T cell-mediated immune responses, especially in human papillomavirus-positive HNSCC samples. CONCLUSION: This study identified RALB as a potential prognostic and therapeutic target for HNSCC, and provided insight into the relationship between RALB and revealed an innovative strategy for HNSCC immunotherapy.