Sintilimab combined with bevacizumab in relapsed or persistent ovarian clear cell carcinoma (INOVA): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Ovarian clear cell carcinoma rarely responds to second-line chemotherapy, the recommended treatment for relapsed epithelial ovarian cancer. Here, we report the activity and safety of sintilimab in combination with bevacizumab in patients with relapsed or persistent ovarian clear cell carcinoma. METHODS: In the prospective, multicentre, single-arm, phase 2 INOVA trial, patients aged 18-75 years with histologically confirmed relapsed or persistent ovarian clear cell carcinoma were enrolled from eight tertiary hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0-2 and previous exposure to at least one cycle of platinum-containing chemotherapy. Enrolled patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks until disease progression. The primary endpoint was objective response rate assessed by independent central review based on Response Evaluation Criteria in Solid Tumours version 1.1. Eligible enrolled patients who received at least one cycle of treatment and had at least one tumour response assessment following the baseline assessment per protocol were included in the activity analysis. Patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04735861) and is ongoing. FINDINGS: Between April 8, 2021, and July 3, 2023, 51 patients were screened and 41 patients received at least one dose of sintilimab in combination with bevacizumab. Response evaluation was completed in 37 patients. Objective responses were observed in 15 patients (objective response rate 40·5%; 95% CI 24·8-57·9), of which five (14%) were complete responses and ten (27%) were partial responses. At data cutoff (Jan 29, 2024), the median follow-up was 16·9 months (IQR 7·5-23·4). Three (7%) patients developed grade 3 treatment-related adverse events including one patient with proteinuria, one patient with myocarditis, and one patient with rash. No treatment-related adverse events of worse than grade 3 severity were recorded. Treatment-related serious adverse events occurred in two (5%) patients including one patient with immune-related myocarditis and another with hypertension and renal dysfunction. No treatment-related deaths occurred. INTERPRETATION: Sintilimab in combination with bevacizumab showed promising anti-tumour activity and manageable safety in patients with relapsed or persistent ovarian clear cell carcinoma. Larger, randomised trials are warranted to compare this low-toxicity, chemotherapy-free combinatorial regimen with standard chemotherapy. FUNDING: National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Curcumin alleviates osteoarthritis in mice by suppressing osteoclastogenesis in subchondral bone via inhibiting NF-κB/JNK signaling pathway.

This study explored the mechanism of curcumin (CUR) suppressing osteoclastogenesis and evaluated its effects on osteoarthritis (OA) mouse. Bone marrow-derived macrophages were isolated as osteoclast precursors. In the presence or absence of CUR, cell proliferation was detected by CCK-8, osteoclastogenesis was detected by tartrate-resistant acid phosphatase (TRAP) staining, F-actin rings formation was detected by immunofluorescence, bone resorption was detected by bone slices, IκBα, nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were detected using western blot, osteoclastogenesis-related gens were measured using quantitative polymerase chain reaction. A knee OA mouse model was designed by destabilizing the medial meniscus (DMM). Thirty-six male mice were divided into sham+vehicle, OA+vehicle, and OA+CUR groups. Mice were administered with or without CUR at 25 mg/kg/d from the first post-operative day until sacrifice. After 4 and 8 weeks of OA induction, micro-computed tomography was performed to analyze microstructure changes in subchondral bone, hematoxylin and eosin staining was performed to calculate the thickness of the calcified and hyaline cartilage layers, toluidine blue O staining was performed to assess the degenerated cartilage, TRAP-stained osteoclasts were counted, and NF-κB, phosphorylated Jun N-terminal Kinases (p-JNK), and receptor activator of nuclear factor κB ligand (RANKL) were detected using immunohistochemistry. CUR suppressed osteoclastogenesis and bone resorption without cytotoxicity. CUR restrained RANKL-induced activation of NF-κB, p-JNK and up-regulation of osteoclastogenesis-related genes. CUR delayed cartilage degeneration by suppressing osteoclastogenesis and bone resorption in early OA. The mechanism of CUR inhibiting osteoclastogenesis might be associated with NF-κB/JNK signaling pathway, indicating a novel strategy for OA treatment.

Mechanism of exogenous methyl jasmonate in regulating the quality of fresh-cut Chinese water chestnuts.

Fresh-cut Chinese water chestnuts (CWCs) are susceptible to yellowing and browning during storage due to mechanical damage and the loss of protective outer skin, adversely affecting their marketability and shelf life. Methyl jasmonate (MeJA) is currently extensively used for food preservation, but it has not been used in Chinese water chestnuts. This study investigated the effect of MeJA treatment on the quality of fresh-cut CWCs. Fresh-cut CWCs immersed in 20 µM MeJA solution for 10 min and stored at 10°C for 5 d effectively delayed the yellowing process, reduced the respiration rate, and minimized the weight and soluble solids loss during storage. In addition, MeJA treatment induced the activities of superoxide dismutase (SOD) and catalase (CAT), which improved the antioxidant capacity of fresh-cut CWCs and inhibited the generation of reactive oxygen species (ROS). Meanwhile, MeJA treatment inhibited the activities of phenylalanine aminotransferase (PAL), polyphenol oxidase (PPO) and peroxidase (POD). The results of quantitative real-time PCR (qRT-PCR) showed that MeJA down-regulated the expression of CwCHS1, CwCHS2, CwCHS3 and CwCHI2 in freshly cut CWCs and inhibited the accumulation of flavonoids, thus delaying the surface discoloration of freshly cut CWCs.

Comprehensive structural analysis of anthocyanins in blue honeysuckle (Lonicera caerulea L.), bilberry (Vaccinium uliginosum L.), cranberry (Vaccinium macrocarpon Ait.), and antioxidant capacity comparison.

The objectives of this research were to analyze anthocyanins in blue honeysuckle (Lonicera caerulea L.), bilberry (Vaccinium vitis-idaea L), and cranberry (Vaccinium macrocarpon Ait.), using HPLC-ESI-QTOF-MS2, Fourteen, fifteen, and eight anthocyanins were identified in blue honeysuckle, bilberry, and cranberry, respectively. Cyanidin-3-glucoside (C3G) and peonidin-3-glucoside were detected in all three types of berries, with blue honeysuckle showing the highest C3G content at 5686.28 mg/100 g DW. Total phenolic content (TPC) and total flavonoid content (TFC), along with ABTS, DPPH, and FRAP assays, were measured. Blue honeysuckle exhibited the highest levels of TPC and TFC. The SOD, POD, and CAT activities in blue honeysuckle were 1761.17 U/g, 45,525.65 U/g, and 1043.24 U/g, respectively, which were significantly superior to those in bilberry and cranberry. The antioxidant mechanisms of these enzymes were investigated by molecular docking, C3G showed a higher affinity for POD, confirming the effectiveness of C3G as an antioxidant.

Network pharmacology screening, in vitro and in vivo evaluation of antianxiety and antidepressant drug-food analogue.

BACKGROUND: Depression and anxiety disorders are prevalent psychiatric conditions, and currently utilized chemical drugs typically come with significant adverse effects. China boasts a wealth of medicinal and food herbs known for their safe and effective properties. PURPOSE: This study aimed to develop novel formulations with improved antidepressant and anxiolytic effects derived from medicinal and food herbs. STUDY DESIGN: Screening combinations with antidepressant and anxiolytic effects using techniques such as network pharmacology and validating their effects in vitro and in vivo experiments. METHODS: Utilizing network pharmacology and molecular docking, we identified the top ten medicinal herbs with anxiolytic and antidepressant potential. Herbs with cytoprotective effects and non-toxic characteristics were further screened to formulate the herbal blends. Subsequently, we established a PC12 cell injury model and a chronic unpredictable mild stress (CUMS) model in mice to assess the effects of our formulations. RESULTS: Ten medicinal herbs were initially screened, and six of them were deemed suitable for formulating the blend, namely Gancao, Dazao, Gouqizi, Sangye, Huangqi, and Jinyinhua (GDGSHJ). The GDGSHJ formulation reduced Lactate Dehydrogenase (LDH) leakage, decreased apoptosis, and demonstrated a favorable antidepressant and antianxiety effect in the CUMS mouse model. Besides, GDGSHJ led to the upregulation of serum 5-Hydroxytryptamine (5-HT) content and brain tissue 5-HT, Gamma-aminobutyric acid (GABA), and Dopamine (DA) levels. It also downregulated the expression of SLC6A4 and SLC6A3 genes in the mouse hippocampus while upregulating HTR1A, DRD1, DRD2, and GABRA1 genes. CONCLUSION: Our formulation exhibited robust antidepressant and antianxiety effects without inducing substantial toxicity. This efficacy appears to be mediated by the expression of relevant genes within the hippocampus of mice. The formulation achieved this effect by balancing 5-HT levels in the serum and DA, GABA, and 5-HT levels within brain tissue.

Development of V2O3 Nanostructures for Alkali Metal Ion Batteries: A Novel Approach through Mild Metal Vapor Reduction and Interface Engineering.

V2O3 has been extensively researched as a battery electrode material due to its ample reserves and high theoretical capacity. However, the synthesis of valence-sensitive V2O3 presents technical challenges as it requires a strict combination of high-temperature treatment and a narrow range of oxygen partial pressures. This study proposes a gentle Li vapor-assisted thermal reduction method to synthesize pure-phase V2O3 at a relatively low temperature of 480 °C without any hazardous gases. It has been discovered that reducing the temperature also improves the specific surface area of the nanoto-mesoscale hierarchical structures and enhances the reactive sites between their secondary grains. These advantages enable the V2O3 micronano particles to store higher levels of Li+, Na+, and K+, increase ionic transport, and tolerate volume expansion. It demonstrates a significant capacity of 767 mA h g-1 in lithium-ion batteries, 393 mA h g-1 in sodium-ion batteries, and 209 mA h g-1 in potassium-ion batteries. It has also been discovered that the crystal structure of V2O3 is easily adjustable by varying the synthesis temperature, which significantly affects the electrochemical storage mechanism. The V2O3 synthesized at 480 °C with low crystallinity exhibits a notable intercalation reaction, facilitating the electrochemical kinetics of reversible insertion/extraction of Li+, Na+, and K+. In contrast, the highly crystalline sample synthesized at 580 °C displays pseudocapacitance behavior instead of an intercalation reaction. The highly crystalline sample synthesized at 680 °C exhibits a thorough pseudocapacitance reaction possessing the capacitive functionality for the electrochemical storage of Na+ or K+ with larger ion radii. This study describes a new synthesis strategy and rational modification of vanadium-based electrodes for alkali metal ion batteries, leading to the development of reasonably priced rechargeable battery systems with applications extending beyond lithium-ion batteries.

Comparison of Nutritional Quality and Functional Active Substances in Different Parts of Eight Lotus Seed Cultivars.

In this study, "Honghu White Lotus", "Red Lotus (HH)", "Hunan Cunshan Lotus (CS)", "Wuyi Xuanlian", "Space Lotus 36", "Fujian Jianning White Lotus (JB)", "Jiangsu Yangzhou Lotus (JY)", and "Suzhou Dongshan Lotus" were selected as experimental subjects. The lotus seed flesh and lotus plumule of each cultivar were selected for nutritional quality and functional active substance analyses. Comparing different cultivars of lotus seeds, the protein and crude fat contents of JY flesh were the highest at 65.59 mg/g and 13%, respectively. The VC content of JB flesh and lotus plumule is the highest at 41.56 mg/g and 204.29 mg/g, respectively. JB flesh has the lowest soluble sugar content, at 17.87 mg/g, while HB's lotus plumule and flesh have the highest content, at 33.67 mg/g and 29.62 mg/g, respectively. There was no significant difference in the crude fat content of the flesh and lotus plumule among the eight cultivars. TK flesh and lotus plumule have the highest amylose content, at 23.67 mg/g and 76.81 mg/g, respectively. Among them, the total starch content of JB (476.17 mg/g) was relatively high, whereas its amylose content was only 26.09 mg/g. Lower amylose content makes it less prone to aging. The total phenolic and flavonoid contents of the JY lotus plumule were the highest, at 18.64 and 21.04 mg/g, respectively. The alkaloid content of CS, HH, and JY was relatively high at 20.01, 19.29, and 18.68 mg/g, respectively. These can provide a consultation for the estimation and processing of the nutritional quality of different lotus seeds.

Artificial Intelligence-Generated Patient Education Materials for Helicobacter pylori Infection: A Comparative Analysis.

BACKGROUND: Patient education contributes to improve public awareness of Helicobacter pylori. Large language models (LLMs) offer opportunities to revolutionize patient education transformatively. This study aimed to assess the quality of patient educational materials (PEMs) generated by LLMs and compared with physician sourced. MATERIALS AND METHODS: Unified instruction about composing a PEM about H. pylori at a sixth-grade reading level in both English and Chinese were given to physician and five LLMs (Bing Copilot, Claude 3 Opus, Gemini Pro, ChatGPT-4, and ERNIE Bot 4.0). The assessments of the completeness and comprehensibility of the Chinese PEMs were conducted by five gastroenterologists and 50 patients according to three-point Likert scale. Gastroenterologists were asked to evaluate both English and Chinese PEMs and determine the accuracy and safety. The accuracy was assessed by six-point Likert scale. The minimum acceptable scores were 4, 2, and 2 for accuracy, completeness, and comprehensibility, respectively. The Flesch-Kincaid and Simple Measure of Gobbledygook scoring systems were employed as readability assessment tools. RESULTS: Accuracy and comprehensibility were acceptable for English PEMs of all sources, while completence was not satisfactory. Physician-sourced PEM had the highest accuracy mean score of 5.60 and LLM-generated English PEMs ranged from 4.00 to 5.40. The completeness score was comparable between physician-sourced PEM and LLM-generated PEMs in English. Chinese PEMs from LLMs proned to have lower score in accuracy and completeness assessment than English PEMs. The mean score for completeness of five LLM-generated Chinese PEMs was 1.82-2.70 in patients' perspective, which was higher than gastroenterologists' assessment. Comprehensibility was satisfactory for all PEMs. No PEM met the recommended sixth-grade reading level. CONCLUSION: LLMs have potential in assisting patient education. The accuracy and comprehensibility of LLM-generated PEMs were acceptable, but further optimization on improving completeness and accounting for a variety of linguistic contexts are essential for enhancing the feasibility.

Exploration of undergraduate nursing students' perspectives on conducting specialized nursing education during internship: A phenomenological research study.

AIM: To comprehend the perspectives of undergraduate nursing students on conducting specialized nursing education during the internship phase, providing a basis for colleges to formulate plans for specialized nursing education. BACKGROUND: Nursing specialty in China was included in the national controlled specialty in 2024, which means signifying an effort to decrease the enrollment of junior college degree nurses, thereby increasing the number of high-quality undergraduate nurses. While the higher the education level of nursing students, the higher their expectations for themselves. However, after entering clinical practice, their social status and job nature are significantly different from those of doctors, which creates a psychological imbalance. In addition, employers lack a reasonable employment mechanism and undergraduate nursing students are used equally with vocational and technical nursing students, making them feel that their self-worth is difficult to realize. Therefore, their professional attitude becomes more negative (Meng Wei, 2018). In the process of forming professional identity among undergraduate nursing students, the professional role models and clinical experience of specialized nurses can serve as important promoting factors. By increasing interaction with specialized nurses and learning specialized nursing, undergraduate nursing students can better understand the professional role and values of nurses and form positive professional ethics and attitudes (Huang et al., 2023). To better adapt to the national health needs and assist undergraduates in transitioning to clinical practice, deepening the understanding of the profession and career, the integration of professional education during the internship phase can enable students to recognize their strengths, cultivate an awareness of suitable professions and facilitate a targeted adaptation from academic studies to clinical practice. DESIGN: The researcher initially drafted the interview outline through a literature review and intra-group discussions. To ensure the research content's richness, a semi-structured interview method was adopted. The Colaizzi seven-step analysis method was applied in the analysis. METHODS: Employing phenomenological study and purposive sampling, with data saturation as the guiding principle, 24 undergraduate nursing students undergoing internship at a tertiary hospital in China were selected for focus group interviews. RESULTS: Four main themes were extracted from the perspectives of undergraduate nursing students. These themes encompass awareness of specialized nursing and specialized nurses, recognition of specialized nursing education during the internship phase, demands for specialized nursing education during the internship phase and career expectations. CONCLUSION: Nursing administrators in hospitals and educational managers in colleges should prioritize align education with clinical needs, address the requirements of nursing students, strengthen collaboration between institutions，and advance the further development of specialized nursing.

Evaluation of Pre-Harvest Nutrient Composition and Functional Active Substances in Various Lotus Roots.

This study investigated the impact of variety and harvest time on the visual appearance, nutritional quality, and functional active substances of six lotus root cultivars: "Xinsanwu", "Wuzhi No. 2", "Baiyuzhan", "Huaqilian", "Elian No. 6", and "Elian No. 5". Samples were collected monthly from December 2023 to April 2024. A nutrient analysis revealed a decrease in the water content with a delayed harvest. The total soluble solids and soluble sugar content peaked towards the end and middle-to-late harvest periods, respectively. Starch levels initially increased before declining, while the soluble protein exhibited a triphasic trend with an initial rise, a dip, and a final increase. The vitamin C (Vc) content varied across cultivars. Functional active substances displayed dynamic changes. The total phenolics initially decreased, then increased, before ultimately declining again. The total flavonoid content varied by both cultivar and harvest time. The phenolic acid and flavonoid content mirrored the trends observed for total phenolics and total flavonoids. Gastrodin was the most abundant non-flavonoid compound across all varieties. "Wuzhi No. 2" and "Baiyuzhan" displayed higher levels of functional active substances and starch, while the Elian series and "Xinsanwu" cultivar exhibited a greater content of Vc, soluble sugar, and soluble protein. Specific harvest periods yielded optimal results: "Wuzhi No. 2" (H1 and H5), "Huaqilian" (H2), and "Baiyuzhan" (H3 and H4) demonstrated a high nutrient and functional active substance content. Overall, the lotus roots harvested in period H4 achieved the highest score. Overall, this study provides the foothold for the rapid identification of superior lotus root cultivars and the valorization of lotus root by-products via advanced processing methods. Additionally, it offers valuable insights for market participants and consumers to select optimal varieties and harvest times based on their specific needs.

Prevalence and risk factors of deep venous thrombosis of hospitalizations in plateau: a cross-section analysis.

BACKGROUND: Deep venous thrombosis (DVT) is a serious public health issue that threatens human health and economic development. Presently, differences in the prevalence of DVT among individuals from different nationalities, residents of high-altitude areas, and those consuming any special diet are unknown. Therefore, we aimed to elucidate the prevalence of and the associated risk factors for DVT in hospitalized patients in the plateau areas. METHODS: The subjects were hospitalized patients in three grade III-a hospitals in the Qinghai Province, China, during January-October 2020. The demographic, clinical, and laboratory data were collected at admission, and ultrasonography of the bilateral lower extremities was performed. The hospital stay-duration was recorded at the time of discharge. RESULTS: A total of 3432 patients were enrolled, of which 159 (4.60%) were diagnosed with DVT. The age of > 50 years (OR = 2.434, 95% CI: 1.521-3.894252, P < 0.001), residence altitude of ≥ 3000 m (OR = 2.346, 95% CI: 1.239-4.440, P = 0.009), D-dimer level of ≥ 0.5 mg/L (OR = 2.211, 95% CI: 1.547-3.161, P < 0.001), presence of comorbidities (OR = 1.904, 95% CI: 1.386-2.705, P < 0.001), a history of varicose veins (OR = 1.990, 95% CI: 0.959-4.128, P = 0.045), and current medications (OR = 2.484, 95% CI: 1.778-3.471, P < 0.001) were identified as risk factors for DVT in these plateau areas. CONCLUSION: The prevalence of DVT in the hospitalized patients of the studied plateau areas was 4.60%. We recommend considering individualized risk stratification (age > 50 years, residence altitude ≥ 3000 m, a history of varicose veins, D-dimer level ≥ 0.5 mg/L, current medications, and comorbidities) for patients at the time of admission.

Pharmacokinetic study of Q808 in rhesus monkey using liquid chromatography-tandem mass spectrometry.

Background: Q808 is a novel antiepileptic agent currently in development. In this study, we established and validated a LC-MS/MS method for the quantification of Q808 in Rhesus monkey plasma. Furthermore, we applied this method to investigate the pharmacokinetics of Q808 in Rhesus monkeys. Methods: Samples containing diazepam as an internal standard (IS) were subjected to liquid-liquid extraction (LLE) and separated using a Zorbax Extend C18 column. The detection of Q808 and IS was performed using multiple reaction monitoring mode (MRM), specifically monitoring precursor-to-product ion transitions at m/z 297.9 to 213.9 and m/z 285.2 to 193.1 for Q808 and IS, respectively. For the pharmacokinetic study of Q808, a total of 30 healthy Rhesus monkeys (half male and half female) were administered single oral doses, single IV doses, or multiple oral doses of Q808. Blood samples were collected at predetermined time points for subsequent pharmacokinetic analysis. Results: The developed LC-MS/MS method exhibited linearity within the concentration range of 1.5-750 ng/mL with intra-day precision ≤8.3% and inter-day precision ≤14.6%. Additionally, accuracy was found to be ≤ 3.4%. In the pharmacokinetic study involving single oral doses of Q808 in Rhesus monkeys, Q808 was absorbed with a median time to peak plasma concentration ranging from 4.50-6.00 h and was eliminated with a terminal elimination half-life (t1/2) between 9.34-11.31 h. No definitive conclusion regarding linear pharmacokinetic characteristics could be drawn. The absolute bioavailability was determined as 20.95%, indicating limited systemic exposure after oral administration. Multiple dosing did not result in significant accumulation based on an accumulation factor Rac value of 1.31. Conclusion: We have successfully developed and validated a rapid yet sensitive LC-MS/MS method for quantifying levels of Q808 in rhesus monkey plasma for the first time. The determination method and pharmacokinetic characteristics of Q808 in rhesus monkey support the next steps in drug development.

Identification and characterization of a potential strain for the production of polyhydroxyalkanoate from glycerol.

While poly (3-hydroxybutyrate) (PHB) holds promise as a bioplastic, its commercial utilization has been hampered by the high cost of raw materials. However, glycerol emerges as a viable feedstock for PHB production, offering a sustainable production approach and substantial cost reduction potential. Glycerol stands out as a promising feedstock for PHB production, offering a pathway toward sustainable manufacturing and considerable cost savings. The identification and characterization of strains capable of converting glycerol into PHB represent a pivotal strategy in advancing PHB production research. In this study, we isolated a strain, Ralstonia sp. RRA (RRA). The strain exhibits remarkable proficiency in synthesizing PHB from glycerol. With glycerol as the carbon source, RRA achieved a specific growth rate of 0.19 h-1, attaining a PHB content of approximately 50% within 30 h. Through third-generation genome and transcriptome sequencing, we elucidated the genome composition and identified a total of eight genes (glpR, glpD, glpS, glpT, glpP, glpQ, glpV, and glpK) involved in the glycerol metabolism pathway. Leveraging these findings, the strain RRA demonstrates significant promise in producing PHB from low-cost renewable carbon sources.

An end-to-end infant brain parcellation pipeline.

Objective: Accurate infant brain parcellation is crucial for understanding early brain development; however, it is challenging due to the inherent low tissue contrast, high noise, and severe partial volume effects in infant magnetic resonance images (MRIs). The aim of this study was to develop an end-to-end pipeline that enabled accurate parcellation of infant brain MRIs. Methods: We proposed an end-to-end pipeline that employs a two-stage global-to-local approach for accurate parcellation of infant brain MRIs. Specifically, in the global regions of interest (ROIs) localization stage, a combination of transformer and convolution operations was employed to capture both global spatial features and fine texture features, enabling an approximate localization of the ROIs across the whole brain. In the local ROIs refinement stage, leveraging the position priors from the first stage along with the raw MRIs, the boundaries o the ROIs are refined for a more accurate parcellation. Results: We utilized the Dice ratio to evaluate the accuracy of parcellation results. Results on 263 subjects from National Database for Autism Research (NDAR), Baby Connectome Project (BCP) and Cross-site datasets demonstrated the better accuracy and robustness of our method than other competing methods. Conclusion: Our end-to-end pipeline may be capable of accurately parcellating 6-month-old infant brain MRIs.

The mechanism of interaction between tri-para-cresyl phosphate and human serum protein: A multispectroscopic and in-silico study.

Organophosphate flame retardants (OPFRs) pose the significant risks to the environment and human health and have become a serious public health issue. Tricresyl phosphates (TCPs), a group of aryl OPFRs, exhibit neurotoxicity and endocrine disrupting toxicity. However, the binding mechanisms between TCPs and human serum albumin (HSA) remain unknown. In this study, through fluorescence and ultraviolet-visible (UV-vis) absorption spectroscopy, molecular docking and molecular dynamics (MD), tri-para-cresyl phosphate (TpCP) was selected to explore potential interactions between HSA and TCPs. The results of the fluorescence spectroscopy demonstrated that a decrease in the fluorescence intensity of HSA and a blue shift were observed with the increasing concentrations of TpCP. The binding constant (Ka) was 2.575 × 104 L/mol, 4.701 × 104 L/mol, 5.684 × 104 L/mol and 9.482 × 104 L/mol at 293 K, 298 K, 303 K, and 310 K, respectively. The fluorescence process between HSA and TpCP involved a mix of static and dynamic quenching mechanism. The gibbs free energy (ΔG0) of HSA-TpCP system was -24.452 kJ/mol, -25.907 kJ/mol, -27.363 kJ/mol, and - 29.401 kJ/mol at 293 K, 298 K, 303 K, and 310 K, respectively, suggesting that the HSA-TpCP reaction was spontaneous. The enthalpy change (ΔH0) and thermodynamic entropy change (ΔS0) of the HSA-TpCP system were 60.83 kJ/mol and 291.08 J/(mol·>k), respectively, indicating that hydrophobic force was the major driving force in the HSA-TpCP complex. Furthermore, multispectral analysis also revealed that TpCP could alter the microenvironment of tryptophan residue and the secondary structure of HSA and bind with the active site I of HSA. Molecular docking and MD simulations confirmed that TpCP could spontaneously form a stable complex with HSA, which was consistent with the fluorescence experimental results. This study provides novel insights into the mechanisms of underlying the transportation and distribution of OPFRs in humans.

HPGD: An Intermediate Player in Microglial Polarization and Multiple Sclerosis Regulated by Nr4a1.

HPGD encodes 15-Hydroxyprostaglandin dehydrogenase catalyzing the decomposition of prostaglandin E2 and has not been reported in multiple sclerosis (MS). We previously found that Nr4a1 regulated microglia polarization and inhibited the progression of experimental autoimmune encephalomyelitis (EAE). Bioinformatics analysis suggested that HPGD might be regulated by Nr4a1. Therefore, this study aimed to explore the role of HPGD in microglia polarization and determine whether HPGD mediates the inhibition of EAE by Nr4a1. C57BL/6 mice were treated with MOG35-55 peptide to induce EAE. BV-2 cells were treated with LPS/IL-4 to induce M1/M2 polarization. We then analyzed the pathological changes of spinal cord tissue, detected the expression levels of M1/M2 genes in tissues and cells, and explored the effect of HPGD on PPARγ activation to clarify the role of HPGD in EAE. The interaction between HPGD and Nr4a1 was verified by ChIP and pull-down assay. HPGD was downregulated in the spinal cord of EAE mice and HPGD overexpression alleviated the progression of EAE. Experiments in vitro and in vivo revealed that HPGD inhibited M1 polarization, promoted M2 polarization and increased PPARγ-DNA complex level. Nr4a1 could bind to the promoter of HPGD and its overexpression increased HPGD level. HPGD overexpression (or knockdown) reversed the effect of Nr4a1 knockdown (or overexpression) on M1/2 polarization. HPGD is regulated by Nr4a1 and inhibits the progression of EAE through shifting the M1/M2 polarization and promoting the activation of PPARγ signaling pathway. This study provides potential targets and basis for the development of MS therapeutic drugs.

Intestinal T-cell lymphomas NOS presenting as a polypoidal lesion: A case report.

RATIONALE: Intestinal T-cell lymphomas are exceedingly rare diseases. Intestinal T-cell lymphoma NOS, as a "wastebasket" category, is difficult to diagnosis. Endoscopy can identify abnormal mucosa in most patients at a reasonably early stage. Therefore, it is crucial to increase the understanding of endoscopists in terms of the endoscopic characteristics of ITCL. PATIENT CONCERNS: A 74-year-old male alone with wasting as the major complaint, had multiple polypoid lesions in the large intestine. The patient then had endoscopic care. DIAGNOSES: Only 1 polypoid lesion on white-light endoscopy in the sigmoid colon was pathologically diagnosed as intestinal T-cell lymphomas, not otherwise specified (ITCL-NOS). INTERVENTIONS: The patient underwent intensity-reduced CHOP therapy. OUTCOMES: The patient is still with controlled disease but developed chemotherapy-related side effects. LESSONS: In the individual with unexplained anemia and waste, endoscopy should not be delayed. For each of polypoid lesion on white-light endoscopy, the endoscopist need to remain cautious, because every lesion in the same patient can exhibit the independence of histopathological features. Meanwhile, we suggest that endoscopists should routinely observe the terminal ileum, even take biopsy samples if necessary.