Cobalt exposure and pulmonary function reduction in chronic obstructive pulmonary disease patients: the mediating role of club cell secretory protein.

BACKGROUND: Cobalt (Co) is a metal which is widely used in the industrial production. The previous studies found the toxic effects of environmental Co exposure on multiple organs. However, the correlation of blood Co concentration with lung function was inconsistent in patients with chronic obstructive pulmonary disease (COPD). METHODS: All 771 stable COPD patients were recruited. Peripheral blood and clinical information were collected. The levels of blood Co and serum CC16 were measured. RESULTS: Cross-sectional study suggested that the level of blood Co was inversely and dose-dependently related to lung function parameters. Each 1 ppm elevation of blood Co was related to 0.598 L decline in FVC, 0.465 L decline in FEV1, 6.540% decline in FEV1/FVC%, and 14.013% decline in FEV1%, respectively. Moreover, higher age, enrolled in winter, current-smoking, higher smoking amount, and inhaled corticosteroids prominently exacerbated the negative correlation between blood Co and lung function. Besides, serum CC16 content was gradually reduced with blood Co elevation in COPD patients. Besides, serum CC16 was positively correlated with lung function, and inversely related to blood Co. Additionally, decreased CC16 substantially mediated 11.45% and 6.37% Co-triggered downregulations in FEV1 and FEV1%, respectively. CONCLUSION: Blood Co elevation is closely related to the reductions of pulmonary function and serum CC16. CC16 exerts a significantly mediating role of Co-related to pulmonary function decrease among COPD patients.

Association of blood cadmium concentration with chronic obstructive pulmonary disease progression: a prospective cohort study.

BACKGROUND: Prior studies in patients with chronic obstructive pulmonary disease (COPD) had indicated a potential correlation between cadmium (Cd) exposure and reduction in lung function. Nevertheless, the influence of Cd exposure on the progression of COPD remained unknown. Exploring the relationship between Cd exposure and the progression of COPD was the aim of this investigation. METHODS: Stable COPD patients were enrolled. Blood samples were collected and lung function was evaluated. Regular professional follow-ups were conducted through telephone communications, outpatient services, and patients' hospitalization records. RESULTS: Each additional unit of blood Cd was associated with upward trend in acute exacerbation, hospitalization, longer hospital stay, and death within 2 years. Even after adjusting for potential confounding factors, each 1 unit rise in blood Cd still correlated with a rise in the frequencies of acute exacerbation, longer hospital stay, and death. Moreover, COPD patients with less smoking amount, lower lung function and without comorbidities were more vulnerable to Cd-induced disease deterioration. CONCLUSION: Patients with COPD who have higher blood Cd concentration are susceptible to worse disease progression.

Targeted Delivery of AR-V7 siRNA with Bivalent PSMA Aptamers Effectively Suppresses the Growth of Enzalutamide-Resistant Prostate Cancer.

Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.

Design, synthesis and biological evaluation of thieno[3,2-c]pyrazol-urea derivatives as potent glycogen synthase kinase 3ß inhibitors based on the DFG-out conformation.

Glycogen synthase kinase 3ß (GSK-3ß) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3ß inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3ß inhibitor with an IC50 of 74.4 nM, while substitution on the terminal phenyl (3b-3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles.

Marcytoglobosins A and B, Cytochalasans From a Marine Sponge Associated Chaetomium globosum 162105 Fungus.

Two new cytochalasans, marcytoglobosins A (1) and B (2) were isolated from the marine sponge associated fungus Chaetomium globosum 162105, along with six known compounds (3-8). The complete structures of two new compounds were determined based on 1D/2D NMR and HR-MS spectroscopic analyses coupled with ECD calculations. All eight isolates were evaluated for their antibacterial activity. Among them, compounds 3-8 displayed antibacterial effects against Staphylococcus epidermidis, Bacillus thuringiensis, Pseudomonas syringae pv. Actinidiae, Vibrio alginolyticus, and Edwardsiella piscicida with minimum inhibitory concentration (MIC) values ranging from 10 to 25 µg/mL.

Facile synthesis and cytotoxicity of substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters of 20(S)-camptothecins.

A series of novel substituted uracil-1'(N)-acetic acid esters (5-9) and 4-pyridone-1'(N)-acetic acid esters (10-11) of 20(S)-camptothecins (CPTs) have been synthesized by the acylation method. All of these new esters were assayed for in vitro cytotoxicity against five human cancer cell lines A549, Bel7402, BGC-823, HCT-8 and A2780. The in vitro bioassay results showed that all the synthesized compounds 5-11 had cytotoxities that were higher than TPT and comparable to CPT on these five tumor cell lines, some of them even showed comparable or superior cytotoxic activity to CPT. The in vitro data exhibited the cytotoxicity of the ester depended on that of its parent compound. The ester 5, 6, 8, 10, 11 even possessed the cytotoxity activity comparable to or even a little better than CPT on A549, HCT-8 and A2780. The compound 11 had the same level of cytoxity on Bel7402 as that of CPT. Here the synthesis and the in vitro antitumor evaluation of a series of novel 20-O-linked substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters derivatives of CPTs are reported.

Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives.

An organocatalytic enantioselective [3+2] cycloaddition reaction involving 2-arylidene-1,3-indandiones and N-2,2-difluoroethylbenzothiophenone imines was developed. This approach efficiently afforded dispiro[benzothiophenone-indandione-pyrrolidine]s, featuring three stereocenters, in 84-98% yields with 3-93% ee and 9:1->20:1 dr. Notably, the method maintained its yield and enantioselectivity integrity even in a gram-scale amplification experiment. For example, the product with substituents on aromatics were obtained in 90% yield with 91% ee and >20:1 dr. Its absolute configuration was established through X-ray single-crystal diffraction analysis, and a plausible reaction mechanism was proposed.

Recent advances in the influences of drying technologies on physicochemical properties and biological activities of plant polysaccharides.

Plant polysaccharides, as significant functional macromolecules with diverse biological properties, are currently receiving increasing attention. Drying technologies play a pivotal role in the research, development, and application of various foods and plant polysaccharides. The chemical composition, structure, and function of extracted polysaccharides are significantly influenced by different drying technologies (e.g., microwave, infrared, and radio frequency) and conditions (e.g., temperature). This study discusses and compares the principles, advantages, disadvantages, and effects of different drying processes on the chemical composition as well as structural and biological properties of plant polysaccharides. In most plant-based raw materials, molecular degradation, molecular aggregation phenomena along with intermolecular interactions occurring within cell wall components and cell contents during drying represent primary mechanisms leading to variations in chemical composition and structures of polysaccharides. These differences further impact their biological properties. The biological properties of polysaccharides are determined by a combination of multiple relevant factors rather than a single factor alone. This review not only provides insights into selecting appropriate drying processes to obtaining highly bioactive plant polysaccharides but also offers a fundamental theoretical basis for the structure-function relationship of these compounds.

Wheat authentication：An overview on different techniques and chemometric methods.

Wheat (Triticum aestivum L.) is one of the most important cereal crops and is consumed as a staple food around the globe. Wheat authentication has become a crucial issue over the last decades. Recently, many techniques have been applied in wheat authentication including the authentication of wheat geographical origin, wheat variety, organic wheat, and wheat flour from other cereals. This paper collected related literature in the last ten years, and attempted to highlight the recent studies on the discrimination and authentication of wheat using different determination techniques and chemometric methods. The stable isotope analysis and elemental profile of wheat are promising tools to obtain information regarding the origin, and variety, and to differentiate organic from conventional farming of wheat. Image analysis, genetic parameters, and omics analysis can provide solutions for wheat variety, organic wheat, and wheat adulteration. Vibrational spectroscopy analyses, such as NIR, FTIR, and HIS, in combination with multivariate data analysis methods, such as PCA, LDA, and PLS-DA, show great potential in wheat authenticity and offer many advantages such as user-friendly, cost-effective, time-saving, and environment friendly. In conclusion, analytical techniques combining with appropriate multivariate analysis are very effective to discriminate geographical origin, cultivar classification, and adulterant detection of wheat.

Synthesis of (E)-2-(1-(methoxyimino)ethyl)-2-phenylbenzofuran-3(2H)-ones from (E)-1-(benzofuran-2-yl)ethan-1-one O-methyl oximes and iodobenzenes via a palladium-catalyzed dearomative arylation/oxidation reaction.

A new method has been successfully developed that offers a facile and reliable approach for synthesizing (E)-2-(1-(methoxyimino)ethyl)-2-phenylbenzofuran-3(2H)-one, providing 28 compounds. This optimized process enables efficient preparation of a wide range of compounds using readily available (E)-1-(benzofuran-2-yl)ethan-1-one O-methyl oxime and iodobenzene, and provides alternative ideas for the structural modification of benzofuran ketones.

Modulating the Fluorescence of Silver Nanoclusters Wrapped in DNA Hairpin Loops via Confined Strand Displacement and Transient Concatenate Ligation for Amplifiable Biosensing.

It is intriguing to modulate the fluorescence emission of DNA-scaffolded silver nanoclusters (AgNCs) via confined strand displacement and transient concatenate ligation for amplifiable biosensing of a DNA segment related to SARS-CoV-2 (s2DNA). Herein, three stem-loop structural hairpins for signaling, recognizing, and assisting are designed to assemble a variant three-way DNA device (3WDD) with the aid of two linkers, in which orange-emitting AgNC (oAgNC) is stably clustered and populated in the closed loop of a hairpin reporter. The presence of s2DNA initiates the toehold-mediated strand displacement that is confined in this 3WDD for repeatable recycling amplification, outputting numerous hybrid DNA-duplex conformers that are implemented for a transient "head-tail-head" tandem ligation one by one. As a result, the oAgNC-hosted hairpin loops are quickly opened in loose coil motifs, bringing a significant fluorescence decay of multiple clusters dependent on s2DNA. Demonstrations and understanding of the tunable spectral performance of a hairpin loop-wrapped AgNC via switching 3WDD conformation would be highly beneficial to open a new avenue for applicable biosensing, bioanalysis, or clinical diagnostics.

Sweet tea (Lithocarpus polystachyus rehd.) as a new natural source of bioactive dihydrochalcones with multiple health benefits.

Sweet tea (Lithocarpus polystachyus Rehd.) has been consumed as herbal tea to prevent and manage diabetes for a long time. Recent studies indicate that sweet tea is rich in a variety of bioactive compounds, especially a class of nonclassical flavonoids, dihydrochalcones. In order to provide a better understanding of sweet tea and its main dihydrochalcones on human health, this review mainly summarizes related literature in the recent ten years, with the potential molecular mechanisms emphatically discussed. Phlorizin, phloretin, and trilobatin, three natural sweeteners, are the main dihydrochalcones in sweet tea. In addition, sweet tea and its dihydrochalcones exhibit plenty of health benefits, such as antioxidant, anti-inflammatory, antimicrobial, cardioprotective, hepatoprotective, antidiabetic, and anticancer effects, which are associated with the regulation of different molecular targets and signaling pathways. Therefore, sweet tea, as a rare natural source of dihydrochalcones, can be processed and developed into nutraceuticals or functional foods, with the potential application in the prevention and management of certain chronic diseases.

Adzuki bean (Vigna angularis): Chemical compositions, physicochemical properties, health benefits, and food applications.

Adzuki bean (Vigna angularis), also called red bean, is a legume of Fabaceae (Leguminosae) family. This crop is native to East Asia and is also commercially available in other parts of the world. It is becoming a research focus owing to its distinct nutritional properties (e.g., abundant in polyphenols). The diverse health benefits and multiple utilization of this pulse are associated with its unique composition. However, there is a paucity of reviews focusing on the nutritional properties and potent applications of adzuki beans. This review summarizes the chemical compositions, physicochemical properties, health benefits, processing, and applications of adzuki beans. Suggestions on how to better utilize the adzuki bean are also provided to facilitate its development as a functional grain. Adzuki bean and its components can be further developed into value-added and nutritionally enhanced products.

The associations of serum S100A9 with the severity and prognosis in patients with community-acquired pneumonia: a prospective cohort study.

BACKGROUND: Previous studies found that S100A9 may involve in the pathophysiology of community-acquired pneumonia (CAP). However, the role of S100A9 was unclear in the CAP. The goal was to explore the correlations of serum S100A9 with the severity and prognosis of CAP patients based on a prospective cohort study. METHODS: A total of 220 CAP patients and 110 control subjects were recruited. Demographic and clinical data were collected. Serum S100A9 and inflammatory cytokines were measured. RESULTS: Serum S100A9 was elevated in CAP patients on admission. Serum S100A9 was gradually elevated parallelly with CAP severity scores. Additionally, inflammatory cytokines were increased and blood routine parameters were changed in CAP patients compared with control subjects. Correlation analysis found that serum S100A9 was positively associated with CAP severity scores, blood routine parameters (WBC, NLR and MON) and inflammatory cytokines. Further, logistic regression analysis demonstrated that there were positive associations between serum S100A9 and CAP severity scores. Besides, the prognosis of CAP was tracked. Serum higher S100A9 on the early stage elevated the death of risk and hospital stay among CAP patients. CONCLUSION: Serum S100A9 is positively correlated with the severity of CAP. On admission, serum higher S100A9 elevates the risk of death and hospital stay in CAP patients, suggesting that S100A9 may exert a certain role in the pathophysiology of CAP and regard as a serum diagnostic and managing biomarker for CAP.

Dysiscalarones A-E, scalarane sesterterpenoids with nitric oxide production inhibitory activity from marine sponge Dysidea granulosa.

Dysiscalarones A-E (1-5), five new scalarane-type bishomoscalarane sesterterpenoids, were isolated from marine sponge Dysidea granulosa collected from the South China Sea, together with two known ones, honulactone A (6) and phyllofolactone I (7). The new structures were determined by extensive spectroscopic analysis including HR-ESI-MS and 1D and 2D NMR data, and their absolute configurations were assigned by single crystal X-ray diffraction analyses. The inhibitory activity of all the seven isolates on the production of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages was evaluated. Of these metabolites, dysiscalarones A-B (1-2), honulactone A (6), and phyllofolactone I (7) showed inhibitory activities with respective IC50 values of 16.4, 18.5, 2.6, and 3.7 µM, which suggested that the γ-methylated α,ß-unsaturated γ-lactone might be the functional group. In addition, all the seven metabolites showed no significant cytotoxicity against lung cancer PC9 cell line at the concentration of 20 µM.

[Association between the inter-aural latency difference of brainstem auditory evoked potential wave V and neonatal hyperbilirubinemia].

OBJECTIVE: To study brainstem auditory evoked potential (BAEP) in neonates with hyperbilirubinemia using short auditory stimuli (60 dBnHL), and to investigate the differences in the inter-aural latency difference (ILD) of wave V between neonates with different total serum bilirubin (TSB) levels. METHODS: A prospective study was conducted in neonates with hyperbilirubinemia who were admitted to the Department of Neonatology, Yuhuan People's Hospital of Zhejiang Province, from May 2019 to October 2020. The neonates were divided into a severe group (n=50) and a mild group (n=50) according to their TSB levels. The mild group was divided into two subgroups: 7-10 days (n=20) and 11-14 days (n=20) according to their age. ILD was compared between the neonates with different TSB levels, and its diagnostic value was analyzed. RESULTS: Compared with the mild group, the severe group had significantly higher proportions of neonates with abnormal hearing threshold and abnormal ILD (P < 0.05) and a significantly larger ILD of wave V (P < 0.05). The latency of wave V (left ear) in the 7-10 days subgroup was significantly longer than that in the 11-14 days subgroup (P < 0.05), but there was no significant difference in the ILD of wave V between the two groups (P > 0.05). The receiver operating characteristic (ROC) analysis showed that ILD had predictive value for hearing impairment caused by neonatal hyperbilirubinemia (P < 0.05), with an area under the ROC curve of 0.727 as well as a sensitivity of 52.4% and a specificity of 90.9% at the optimal cut-off value of 0.365 ms. CONCLUSIONS: Serum bilirubin in neonates affects the ILD of BAEP wave V, especially in those with severe hyperbilirubinemia. ILD at the optimal cut-off value of ≥0.4 ms shows potential value in the diagnosis of hearing impairment caused by neonatal hyperbilirubinemia.

MRI-based Bosniak Classification of Cystic Renal Masses, Version 2019: Interobserver Agreement, Impact of Readers' Experience, and Diagnostic Performance.

Background The 2019 Bosniak classification (version 2019) of cystic renal masses (CRMs) provides a systematic update to the currently used 2005 Bosniak classification (version 2005). Further validation is required before widespread application. Purpose To evaluate the interobserver agreement of MRI criteria, the impact of readers' experience, and the diagnostic performance between version 2019 and version 2005. Materials and Methods From January 2009 to December 2018, consecutive patients with CRM who had undergone renal MRI and surgical-pathologic examination were included in this retrospective study. On the basis of version 2019 and version 2005, all CRMs were independently classified by eight radiologists with different levels of experience. By using multirater κ statistics, interobserver agreement was evaluated with comparisons between classifications and between senior and junior radiologists. Diagnostic performance between classifications by dichotomizing classes I-IV into lower (I-IIF) and higher (III-IV) classes was compared by using the McNemar test. P < .05 was considered to indicate a statistically significant difference. Results A total of 207 patients (mean age ± standard deviation, 49 years ± 12; 139 male and 68 female patients) with CRMs were included. Overall, interobserver agreement was higher with version 2019 than version 2005 (weighted κ = 0.64 vs 0.50, respectively; P < .001). Interobserver agreement between senior and junior radiologists did not differ between version 2019 (weighted κ = 0.65 vs 0.64, respectively; P = .71) and version 2005 (weighted κ = 0.54 vs 0.46; P < .001). Diagnostic specificity for malignancy was higher with version 2019 than with version 2005 (83% [92 of 111] vs 68% [75 of 111], respectively; P < .001), without any difference in sensitivity (89% [85 of 96] vs 84% [81 of 96]; P = .34). Conclusion In the updated Bosniak classification, interobserver agreement improved and was unaffected by observers' experience. The diagnostic performance with version 2019 was superior to that with version 2005, with higher specificity. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Choyke in this issue.

Characterization of a Cu2+, SDS, alcohol and glucose tolerant GH1 ß-glucosidase from Bacillus sp. CGMCC 1.16541.

A ß-glucosidase gene (bsbgl1a) from Bacillus sp. CGMCC 1.16541 was expressed in Escherichia coli BL21 and subsequently characterized. The amino acid sequence shared 83.64% identity with ß-glucosidase (WP_066390903.1) from Fictibacillus phosphorivorans. The recombinant ß-glucosidase (BsBgl1A) had a molecular weight of 52.2 kDa and could hydrolyze cellobiose, cellotriose, cellotetrose, p-nitrophenyl-ß-D-glucopyranoside (pNPG), and p-nitrophenyl-ß-D-xylopyranoside (pNPX). Optimal activity for BsBgl1A was recorded at 45 °C with a pH between 5.6 and 7.6, and 100% of its activity was maintained after a 24 h incubation between pH 4 and 9. Kinetic characterization revealed an enzymatic turnover (Kcat) of 616 ± 2 s-1 (with cellobiose) and 3.5 ± 0.1 s-1 (with p-nitrophenyl-ß-D-glucopyranoside). Interestingly, the recombinant enzyme showed cupric ion (Cu2+), sodium dodecyl sulfate (SDS) and alcohol tolerance at 10 mM for Cu2+ and 10% for both SDS and alcohol. Additionally, BsBgl1A had high tolerance for glucose (Ki = 2095 mM), which is an extremely desirable feature for industrial applications. Following the addition of BsBgl1A (0.05 mg/ml) to a commercial cellulase reaction system, glucose yields from sugarcane bagasse increased 100% after 1 day at 45 °C. This work identifies a Cu2+, SDS, alcohol, and glucose tolerant GH1 ß-glucosidase with potential applications in the hydrolysis of cellulose for the bioenergy industry.

Trichodermaloids A-C, Cadinane Sesquiterpenes from a Marine Sponge Symbiotic Trichoderma sp. SM16 Fungus.

Three new cadinane sesquiterpenes, trichodermaloids A (1), B (2), and C (5) were isolated from a symbiotic fungus Trichoderma sp. SM16 derived from the marine sponge Dysidea sp., together with three known ones, aspergilloid G (3), rhinomilisin E (4), and rhinomilisin G (6). The complete structures of three new compounds were determined by HR-MS and NMR spectroscopic analyses coupled with ECD calculations. The absolute configurations of two known compounds (4 and 6) were determined for the first time. The six isolates were inactive as antibacterial agents. However, trichodermaloids A and B have shown cytotoxicity on human NCIH-460 lung, NCIC-H929 myeloma, and SW620 colorectal cancer cell lines with IC50 values at the range of 6.8-12.7 µm.

Attentional bias toward emotional stimuli in type 2 diabetic Chinese patients with different self-management levels.

Extensive evidence has been obtained that supports an association between an attentional bias (AB) toward negative stimuli and vulnerability to mental and behavioral problems; however, diabetes self-management (DSM) behavior in type 2 diabetic patients has not specifically been assessed. The current study investigated whether type 2 diabetic Chinese patients who had different levels of self-management behaviors showed different patterns of AB toward either positive or negative stimuli. A sample of 195 patients completed questionnaires measuring DSM and a modified dot-probe task measuring AB. Patients with low levels of DSM had an avoidance bias for positive stimuli, the regression showed that negative orienting index significantly predicted lower DSM; patients with medium levels of DSM had difficulty in disengaging attention from negative stimuli, the regression showed that negative disengaging index significantly predicted lower DSM; while patients with high levels of DSM had an avoidance bias for negative stimuli and difficulty in disengaging from positive stimuli. An implication of this finding is that the understanding of information processing bias affects DSM and therefore suggests a novel target for prevention and treatment interventions.