Si-Ni-San alleviates intestinal and liver damage in ulcerative colitis mice by regulating cholesterol metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS), a traditional Chinese medicinal formula derived from Treatise on Febrile Diseases, is considered effective in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice. However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation. AIM OF THE STUDY: This study aimed to evaluate the effect, explore the bioactive ingredients and the underlying mechanisms of SNS in ameliorating ulcerative colitis (UC) and associated liver injury in dextran sodium sulphate (DSS)-induced mouse colitis models. MATERIALS AND METHODS: The effect of SNS (1.5, 3, 6 g/kg) on 3% DSS-induced acute murine colitis was evaluated by disease activity index (DAI), colon length, inflammatory cytokines, hematoxylin-eosin (H&E) staining, tight junction proteins expression, ALT, AST, and oxidative stress indicators. HPLC-ESI-IT/TOF MS was used to analyze the chemical components of SNS and the main xenobiotics in the colon of UC mice after oral administration of SNS. Network pharmacological study was then conducted based on the main xenobiotics. Flow cytometry and immunohistochemistry techniques were used to demonstrate the inhibitory effect of SNS on Th17 cells differentiation and the amelioration of Th17/Treg cell imbalance. LC-MS/MS, Real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting techniques were performed to investigate the oxysterol-Liver X receptor (LXRs) signaling activity in colon. Targeted bile acids metabolomics was conducted to reveal the change of the two major pathways of bile acid synthesis in the liver, and the expression of key metabolic enzymes of bile acids synthesis was characterized by RT-qPCR and western blotting techniques. RESULTS: SNS (1.5, 3, 6 g/kg) decreased the DAI scores, protected intestinal mucosa barrier, suppressed the production of pro-inflammatory cytokines, improved hepatic and splenic enlargement and alleviated liver injury in a dose-dependent manner. A total of 22 components were identified in the colon of SNS (6 g/kg) treated colitis mice, and the top 10 components ranked by relative content were regarded as the potential effective chemical components of SNS, and used to conduct network pharmacology research. The efficacy of SNS was mediated by a reduction of Th17 cell differentiation, restoration of Th17/Treg cell homeostasis in the colon and spleen, and the experimental results were consistent with our hypothesis and the biological mechanism predicted by network pharmacology. Mechanistically, SNS regulated the concentration of 25-OHC and 27-OHC by up-regulated CH25H, CYP27A1 protein expression in colon, thus affected the expression and activity of LXR, ultimately impacted Th17 differentiation and Th17/Treg balance. It was also found that SNS repressed the increase of hepatic cholesterol and reversed the shift of BA synthesis to the acidic pathway in UC mice, which decreased the proportion of non-12-OH BAs in total bile acids (TBAs) and further ameliorated colitis and concomitant liver injury. CONCLUSIONS: This study set the stage for considering SNS as a multi-organ benefited anti-colitis prescription based on the significant effect of ameliorating intestinal and liver damage, and revealed that derivatives of cholesterol, namely oxysterols and bile acids, were closely involved in the mechanism of SNS anti-colitis effect.

Associations between peripheral whole blood cell counts derived indexes and cancer prognosis: An umbrella review of meta-analyses of cohort studies.

Meta-analyses have reported conflicting data on the whole blood cell count (WBCC) derived indexes (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and lymphocyte-to-monocyte ratio [LMR]) and cancer prognosis. However, the strength and quality of this evidence has not been quantified in aggregate. To grade the evidence from published meta-analyses of cohort studies that investigated the associations between NLR, PLR, and LMR and cancer prognosis. A total of 694 associations from 224 articles were included. And 219 (97.8%) articles rated as moderate-to-high quality according to AMSTAR. There were four associations supported by convincing evidence. Meanwhile, 165 and 164 associations were supported by highly suggestive and suggestive evidence, respectively. In this umbrella review, we summarized the existing evidence on the WBCC-derived indexes and cancer prognosis. Due to the direction of effect sizes is not completely consistent between studies, further research is needed to assess causality and provide firm evidence.

Application of PROTACs in Target Identification and Target Validation.

PROTAC, as a novel therapeutic drug model, has received widespread attention from the academic and pharmaceutical industries. At the same time, PROTAC technology has led many researchers to focus on developing chemical biology tool properties due to its unique operating mechanism and protein dynamic regulatory properties. In recent years, the rapid development of PROTAC technology has gradually made it an essential tool for target identification and target validation. To further promote the application of PROTAC tools in drug discovery and basic medical sciences research, this review distinguished between target identification and target validation concepts. It summarized the research progress of PROTAC technology in these aspects.

In Situ Built ZnS/MXene Heterostructure by a Mild Method for Inhibiting Polysulfide Shuttle in Li-S Batteries.

With high specific surface area, excellent polysulfide conversion activity, and fast electron/ion transfer at the interface, MXene-derived heterostructures can be employed as catalysts for lithium-sulfur (Li-S) batteries to accelerate sulfur redox kinetics and suppress shuttle effect. However, the preparation of MXene-derived heterostructures often requires high-temperature reactions, which can easily lead to the oxidation of MXene and sacrifice the electrical conductivity. Herein, a catalytic two-dimensional heterostructure (ZnS/MXene) was successfully synthesized via a mild method. The MXene skeleton retains the original nanosheet structure without oxidation. The in situ-grown ZnS nanospheres prevent the restacking of MXene nanosheets, which not only increases the active sites, but also guarantees channels for the fast passage of lithium ions. The interfacial built-in electric field further promotes electron/ion migration, thereby expediting the polysulfide conversion and suppressing the shuttle effect. Consequently, the batteries using ZnS/MXene modified separators exhibit a high initial discharge capacity of 1230 mAh g-1 at 0.1 C and a low decaying rate of 0.082% per cycle after 500 cycles at 0.5 C. This work offers a reference for the fabrication of MXene-based heterostructure in Li-S batteries.

Engineering lipase TLL to improve its acid tolerance and its biosynthesis in Trichoderma reesei for biodiesel production from acidified oil.

Lipases catalyze the synthesis of biodiesel, which is an important renewable alternative energy source. Cost-efficient conversion of waste acidified oil to biodiesel entails acid-tolerant lipases which have not been extensively studied. This study showed that the commonly used Thermomyces lanuginosus lipase TLL displayed a weak acid tolerance and an unsatisfactory performance in biodiesel production from acidified oil. Directed evolution of TLL identified one TLL-T3 variant with three residue substitutions (A69S/V150P/N222G). TLL-T3 displayed significantly enhanced acid tolerance, and its application in acidified oil treatment led to a biodiesel yield up to 90 % (w/w). A scaled-up production of TLL-T3 in Trichoderma reesei was further achieved and the highest extracellular lipase activity reached 16,123 U/mL after fermentation optimization. These results provide new insights into structural adaptation to acid tolerance by lipases and show that TLL-T3 holds great potential in commercial biodiesel production from waste acidified oil.

Chronic constipation and gut microbiota: current research insights and therapeutic implications.

Chronic constipation is a prevalent clinical condition. Its etiology and pathogenesis have not yet been fully understood. In recent years, mounting evidence suggests a close association between chronic constipation and intestinal dysbiosis, including alterations in the colony structure and metabolites, as well as the modulation of bowel movements via the brain-gut-microbiota axis. With the deepening of related research, probiotic-related therapies are expected to become a potential first-line treatment for chronic constipation in the future. In this review, we summarize the current research insights into the intricate relationships between chronic constipation and the gut microbiota and briefly discuss several different approaches for treating chronic constipation. The findings from this review may advance our understanding of the pathological mechanisms underlying chronic constipation and, ultimately, translate them into improvements in patient care.

Structural damage and organelle destruction: Mechanisms of pseudolaric acid B against S. parasitica.

This study aimed to investigate the potential of Chinese herbs in treating aquatic diseases. More particularly, the antibacterial properties and mechanisms of Chinese herbs and their monomers against Saprolegnia parasitica were investigated. In vitro antibacterial testing revealed that Cortex pseudolaricis exhibited significant antibacterial activity, with a minimum inhibitory concentration (MIC) of 0.98 mg/mL. The primary monomer responsible for this antibacterial effect was identified as pseudolaric acid B (PAB), with an MIC of 0.03 mg/mL. SEM and TEM analyses demonstrated that treatment with PAB resulted in structural damage to the cell wall and cell membrane of hyphae, leading to lysis of the cell wall and membrane of spores, organelle destruction, and vacuole formation within the cells. Analysis of the transcriptome and metabolome revealed that PAB disrupts amino acid, lipid, and nucleic acid metabolism in S. parasitica. This disruption impacts the biosynthesis and metabolism of various amino acids, including arginine, proline, glycine, serine, cysteine, methionine, glutamate, lysine, histidine, phenylalanine, tyrosine, and tryptophan. PAB also results in increased energy consumption and hindered energy generation in S. parasitica, as well as interference with the synthesis of membrane components such as DAG and phytosphingosine. Furthermore, PAB disrupts RNA, DNA, and ATP production in S. parasitica. Consequently, protein synthesis, energy supply, immune function and barrier structure in S. parasitica are weakened, and potentially leading to death. This study identifies potential antibacterial agents for environmentally friendly solutions for controlling fish saprolegniasis.

Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K.

A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.

Insight into the charge transfer behavior of an electrochemiluminescence sensor based on porphyrin-coumarin derivatives with a donor-acceptor configuration.

The excellent photophysical and electrochemical properties of porphyrins have inspired widespread interest in the realm of electrochemiluminescence (ECL). The aggregation-caused deficiency of ECL emission in aqueous solution, however, still severely impedes further applications. Herein, a molecule with a donor-acceptor (D-A) configuration, ATPP-Cou, consisting of monoaminoporphyrin as an electron donor and coumarin as an electron acceptor, was designed as an ECL luminophore to address the susceptibility of the porphyrin to aggregation-caused quenching (ACQ) in aqueous solution. ATPP-Cou demonstrated a three-fold enhanced ECL signal compared to pristine ATPP. Despite the acknowledged significance of intramolecular charge transfer (ICT) in generating excited states in ECL, there is a lack of quantitative descriptions. Herein, intensity-modulated photocurrent spectroscopy (IMPS) and scanning photoelectrochemical microscopy (SPECM) were utilized to validate the influence of ICT on the enhancement performance of D-A type ECL molecules. Additionally, ATPP-Cou was also developed as a probe for the successful detection of Cu2+ in aqueous solution. The present study not only enriches the repertoire of efficient porphyrin-based ECL luminophores applicable in aqueous environments but also exemplifies the successful integration of novel measurement techniques to provide more comprehensive insights into the underlying mechanisms responsible for improved ECL performance.

Status quo and factors influencing dyadic disease appraisal in chronic heart failure based on latent profile analysis in Northern Sichuan Province, China.

PURPOSE: This study explored potential categories of dyadic disease appraisal differences among patients hospitalized with chronic heart failure (CHF) in China and analyzed the main factors influencing these categories. METHODS: A survey was conducted using various tools and scales, including the Chinese version of the Memorial Heart Failure Symptom Appraisal Scale, Heart failure self-care index scale, Social Support Rating Scale, Zarit burden interview, and Self-rating anxiety scale. The data was collected from patients who were hospitalized with CHF in the cardiology department of one of two tertiary hospitals in Nanchong City, China. The dyadic disease appraisal categories were identified using latent profile analysis (LPA). Multiple logistic regression analysis was also employed to analyze the factors influencing the formation of potential categories of differences in dyadic disease appraisal in CHF patients. RESULTS: A total of 262 pairs of hospitalized CHF patients and their caregivers participated in this study. The dyadic disease appraisal of CHF patients was potentially categorized as the "negative difference group" (28 individuals, 10.7%) and the "positive or convergence group" (234 persons, 89.3%). The results showed that the factors influencing the categorization of dyadic disease appraisal differences included the patient's social support, disease progression, and Caregivers anxiety level, burden, gender, educational attainment, and age (p < 0.05). CONCLUSION: The study findings demonstrated heterogeneity between the two groups of CHF patients in the dyadic disease appraisal. Therefore, it is necessary to focus on patients who have a brief duration of illness and limited social support. Specifically, it is important to prioritize support for female caregivers who are 65 years or older, have lower levels of educational attainment, and experience a significant burden and anxiety. Regular implementation of support person-bilateral co-management strategies can effectively reduce differences in how the disease is perceived and enhance the overall well-being of both caregivers and patients.

Establishment of a Rapid Detection Method for Cadmium Ions via a Specific Cadmium Chelator N-(2-Acetamido)-Iminodiacetic Acid Screened by a Novel Biological Method.

Heavy metal ions such as cadmium, mercury, lead, and arsenic in the soil cannot be degraded naturally and are absorbed by crops, leading to accumulation in agricultural products, which poses a serious threat to human health. Therefore, establishing a rapid and efficient method for detecting heavy metal ions in agricultural products is of great significance to ensuring the health and safety. In this study, a novel optimized spectrometric method was developed for the rapid and specific colorimetric detection of cadmium ions based on N-(2-Acetamido)-iminodiacetic acid (ADA) and Victoria blue B (VBB) as the chromogenic unit. The safety evaluation of ADA showed extremely low biological toxicity in cultured cells and live animals. The standard curve is y = 0.0212x + 0.1723, R2 = 0.9978, and LOD = 0.08 µM (0.018 mg/kg). The liner concentrations detection range of cadmium is 0.1-10 µM. An inexpensive paper strip detection method was developed with a detection limit of 0.2 µM to the naked eye and a detection time of less than 1 min. The method was successfully used to assess the cadmium content of rice, soybean, milk, grape, peach, and cabbage, and the results correlated well with those determined by inductively coupled plasma-mass spectrometry (ICP-MS). Thus, our study demonstrated a novel rapid, safe, and economical method for onsite, real-time detection of cadmium ions in agricultural products.

Lathyrane and ent-isopimarane diterpenoids from Euphorbia wallichii and target prediction of active ingredient.

Fourteen undescribed diterpenoids, including eleven lathyrane diterpenoids wallathyanes A-K (1-11) and three ent-isopimarane diterpenoids wallisopiranes A-C (12-14), together with fourteen known analogues 15-28, were obtained from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallography. Bioactivity screening indicated that compound 2 exhibited an inhibitory effect on NO generation in LPS-stimulated RAW264.7 macrophage cells with an IC50 value of 4.76 ± 1.08 µM. The network pharmacology and molecular docking studies also revealed that compound 2 can bind with the potential targets GRB, AKT1, MAPK1, MAPK14, HSP90AA1, PIK3R1, PIK3CB, PRKACA, SRC, CASP3, RXRA, PTPNA11, ZAP70, and PRKC of inflammation.

Social support mediates social frailty with anxiety and depression.

BACKGROUND: Anxiety and depression are prevalent comorbidities in patients with chronic obstructive pulmonary disease (COPD). However, existing research has yielded conflicting findings regarding the effects of social frailty on anxiety and depression. The primary aim of this study is to validate the relationship between social frailty and social support with anxiety and depression in patients with acute exacerbations of COPD (AECOPD) and to investigate whether social support could explain the variations in prior study outcomes for patients with AECOPD. METHODS: Of the 315 patients hospitalized with AECOPD at the respiratory intensive care unit of a large tertiary care institution in Sichuan Province of China, between August 2022 and June 2023 who were surveyed, 306 were included in the analysis after excluding missing data. We conducted a logistic regression analysis to examine the associations of social frailty and social support with anxiety and depression and performed mediation analyses to examine whether social support mediates the relationship of social frailty with anxiety and depression. RESULTS: The logistic regression analysis revealed that social frailty did not associate anxiety or depression in patients with AECOPD. The mediation analysis supported this idea and indicated that while social frailty does not directly influence anxiety or depression, it can through social support. CONCLUSIONS: The findings suggest that while social frailty may not directly impact anxiety or depression in patients with AECOPD, social support plays a crucial mediating role. Enhancing social support can indirectly alleviate anxiety and depression among these patients. Enhancing social support networks should thus be prioritized by healthcare providers and family members to improve mental health outcomes in this patient population.

Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice.

Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer's disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis identified the bacterial acetyl-CoA pathway as the main butyrate synthesis pathway impacted. Concomitantly, there was an age-associated decline in the transcriptionally permissive acetylation of histone 3 at lysines 9 and 14 (H3K9/K14-Ac) in hippocampal neurons. Importantly, these microbiome-gut-brain changes preceded AD-related neuropathology, including oxidative stress, tau hyperphosphorylation, memory deficits, and neuromuscular dysfunction, which manifest by 17-18 months. Initiation of oral administration of tributyrin, a butyrate prodrug, at 6 months of age mitigated the age-related decline in butyrate-producing bacteria, protected the H3K9/K14-Ac status, and attenuated the development of neuropathological and cognitive changes associated with AD pathogenesis. These data causally implicate age-associated decline in butyrate-producing bacteria as a key pathogenic feature of the microbiome-gut-brain axis affecting the onset and progression of AD. Importantly, the regulation of butyrate-producing bacteria and consequent butyrate synthesis could be a significant therapeutic strategy in the prevention and treatment of AD.

Development of Leptolyngbya sp. BL0902 into a model organism for synthetic biological research in filamentous cyanobacteria.

Cyanobacteria have great potential in CO2-based bio-manufacturing and synthetic biological studies. The filamentous cyanobacterium, Leptolyngbya sp. strain BL0902, is comparable to Arthrospira (Spirulina) platensis in commercial-scale cultivation while proving to be more genetically tractable. Here, we report the analyses of the whole genome sequence, gene inactivation/overexpression in the chromosome and deletion of non-essential chromosomal regions in this strain. The genetic manipulations were performed via homologous double recombination using either an antibiotic resistance marker or the CRISPR/Cpf1 editing system for positive selection. A desD-overexpressing strain produced γ-linolenic acid in an open raceway photobioreactor with the productivity of 0.36 g·m-2·d-1. Deletion mutants of predicted patX and hetR, two genes with opposite effects on cell differentiation in heterocyst-forming species, were used to demonstrate an analysis of the relationship between regulatory genes in the non-heterocystous species. Furthermore, a 50.8-kb chromosomal region was successfully deleted in BL0902 with the Cpf1 system. These results supported that BL0902 can be developed into a stable photosynthetic cell factory for synthesizing high value-added products, or used as a model strain for investigating the functions of genes that are unique to filamentous cyanobacteria, and could be systematically modified into a genome-streamlined chassis for synthetic biological purposes.

Antioxidant, Antimicrobial, and Anti-Inflammatory Effects of Liriodendron chinense Leaves.

Liriodendron chinense has been widely utilized in traditional Chinese medicine to treat dispelling wind and dampness and used for alleviating cough and diminishing inflammation. However, the antioxidant, antimicrobial, and anti-inflammatory effects of L. chinense leaves and the key active constituents remained elusive. So, we conducted some experiments to support the application of L. chinense in traditional Chinese medicine by investigating the antioxidant, antibacterial, and anti-inflammatory abilities, and to identify the potential key constituents responsible for the activities. The ethanol extract of L. chinense leaves (LCLE) was isolated and extracted, and assays measuring ferric reducing antioxidant power, total reducing power, DPPH•, ABTS•+, and •OH were used to assess its in vitro antioxidant capacities. Antimicrobial activities of LCLE were investigated by minimal inhibitory levels, minimum antibacterial concentrations, disc diffusion test, and scanning electron microscope examination. Further, in vivo experiments including macro indicators examination, histopathological examination, and biochemical parameters measurement were conducted to investigate the effects of LCLE on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LCLE was further isolated and purified through column chromatography, and LPS-induced RAW264.7 cells were constructed to assess the diminished inflammation potential of the identified chemical composites. ABTS•+ and •OH radicals were extensively neutralized by the LCLE treatment. LCLE administration also presented broad-spectrum antimicrobial properties, especially against Staphylococcus epidermidis by disrupting cell walls. LPS-induced ALI in mice was significantly ameliorated by LCLE intervention, as evidenced by the histological changes in the lung and liver tissues as well as the reductions of nitric oxide (NO), TNF-α, and IL-6 production. Furthermore, three novel compounds including fragransin B2, liriodendritol, and rhamnocitrin were isolated, purified, and identified from LCLE. These three compounds exhibited differential regulation on NO accumulation and IL-10, IL-1ß, IL-6, TNF-α, COX-2, and iNOS mRNA expression in RAW264.7 cells induced by LPS. Fragransin B2 was more effective in inhibiting TNF-α mRNA expression, while rhamnocitrin was more powerful in inhibiting IL-6 mRNA expression. LCLE had significant antioxidant, antimicrobial, and anti-inflammatory effects. Fragransin B2, liriodendritol, and rhamnocitrin were probably key active constituents of LCLE, which might act synergistically to treat inflammatory-related disorders. This study provided a valuable view of the healing potential of L. chinense leaves in curing inflammatory diseases.

Associations of Pap test utilisation with comorbidity and functional impairment among middle-aged non-Hispanic black women in the USA: a cross-sectional analysis of the 2018 BRFSS data.

OBJECTIVES: Limited evidence exists on the association of Pap test utilisation with comorbidity and functional impairment among middle-aged non-Hispanic black (NHB) women in the USA. We aimed to assess whether middle-aged NHB women with a higher burden of comorbidity and functional impairment have a lower rate of Pap test utilisation. DESIGN: Nationwide cross-sectional survey in the USA. SETTING: 2018 Behavioral Risk Factor Surveillance System. PARTICIPANTS: 6359 middle-aged NHB women. EXPOSURES AND OUTCOME: The primary exposures were comorbidity and functional impairment. The outcome of interest was whether a woman reported having a Pap test in the last 3 years. DATA ANALYSIS: We fit unadjusted and multivariable logistic regression models to calculate ORs and 95% CI for comorbidity and functional impairment. Sensitivity analysis was restricted to women without a history of hysterectomy or cancer. We added interaction terms between exposures and age, as well as lifestyle indicators. RESULTS: Of the 6359 women, 4141 (65.1%) had comorbidity and 2429 (38.2%) had functional impairment. Middle-aged NHB women with comorbidity (≥2 vs 0, aOR=0.72, 95% CI=0.61 to 0.85, p trend<0.01) or functional impairment (≥2 vs 0, aOR=0.69, 95% CI=0.57 to 0.83, p trend<0.01) had a lower rate of Pap test utilisation compared with healthier counterparts, regardless of histories of hysterectomy and prior cancer. The analyses for age and lifestyle indicators subgroup difference indicated no statistically significant effect (p interaction>0.05). However, the magnitude of these associations was stronger among women with adverse lifestyle factors (eg, comorbidity ≥2 v.s. 0, aOR=0.53, 95% CI=0.40, to 0.71; functional impairment ≥2 v.s. 0, aOR=0.35, 95% CI=0.16, to 0.72 among binge drinkers). CONCLUSION: Comorbidity or functional impairment could be a potential barrier to Pap test utilisation among middle-aged NHB women in the USA. Our study highlights the importance of implementing targeted intervention programmes and prioritised health resource allocation to promote Pap test utilisation. Cohort studies with clear temporality and indicators reflecting disease severity will be essential for further understanding this association.

Preparation of antioxidant peptides from yak skin gelatin and their protective effect on myocardial ischemia reperfusion injury.

We herein report a study on the antioxidant peptides that show potential in alleviating myocardial ischemia reperfusion injury (MI/RI). Yak skin gelatin fraction Ac (YSG-Ac), obtained through ultrafiltration and gel filtration with Sephadex G-15, exhibits a favorable nutrient composition, high foaming capacity and stability, and resistance against gastrointestinal digestion. LC-MS/MS analysis reveals that YSG-Ac contains 26 peptide segments with sequence lengths of 8 to 12 amino acids. Online screening suggests that the antioxidant capacity of YSG-Ac is mainly attributed to the presence of hydrophobic and antioxidant amino acids. In vitro, our results demonstrate the MI/RI protective effects of YSG-Ac by effectively repairing H2O2-induced oxidative damage in H9c2 cells, which is achieved by inhibiting malondialdehyde (MDA) levels, and increasing glutathione peroxidase (GSH-pX) and superoxide dismutase (SOD) activity. In vivo, our results further confirm the effectiveness of YSG-Ac in narrowing the area of myocardial infarction, decreasing MDA levels, increasing SOD activity, and reducing the content of lactate dehydrogenase (LDH) in a mouse MI/RI model. Molecular docking analysis indicates that PGADGQPGAK with xanthine dehydrogenase (XDH) and GAAGPTGPIGS with tumor necrosis factor-alpha (TNF-α) exhibit strong bonding capability, and other related targets also show certain binding ability toward YSG-Ac. This suggests that YSG-Ac can regulate MI/RI through multiple targets and pathways. Overall, our findings highlight the potential of YSG-Ac as a functional food ingredient with antioxidant and MI/RI protective characteristics.

A Comparative Study of the Stability, Transport, and Structure-Activity Relationship of Round Scad Derived Peptides with Antineuroinflammatory Ability.

Our previous study identified round scad neuroprotective peptides with different characteristics. However, the intrinsic relationship between their structure and bioactivity, as well as their bioavailability, remains unclear. The aim of this study is to elucidate the bioavailability of these peptides and their structure-activity relationship against neuroinflammation. Results showed that the SR and WCP peptides were resistant to gastrointestinal digestion. Additionally, peptides SR, WCP, and WCPF could transport Caco-2 monolayers as intact peptides. The permeability coefficients (Papp) of SR, WCP, and WCPF in Caco-2 monolayer were (1.53 ± 0.01) × 10-5, (2.12 ± 0.01) × 10-5, and (8.86 ± 0.03) × 10-7 cm/s, respectively. Peptides SR, WCP, and WCPF, as promising inhibitors of JAK2 and STAT3, could attenuate the levels of pro-inflammatory cytokines and regulate the NFκB and JAK2/STAT3 signaling pathway in LPS-treated BV-2 cells. WCPF exerted the highest anti-inflammatory activity. Moreover, bioinformatics, molecular docking, and quantum chemistry studies indicated that the bioactivity of SR was attributed to Arg, whereas those of WCP and WCPF were attributed to Trp. This study supports the application of round-scad peptides and deepens the understanding of the structure-activity relationship of neuroprotective peptides.

A Single-Arm Phase II Clinical Trial of Fulvestrant Combined with Neoadjuvant Chemotherapy of ER+/HER2- Locally Advanced Breast Cancer: Integrated Analysis of 18F-FES PET-CT and Metabolites with Treatment Response.

Purpose: This Phase II trial was objected to evaluate the efficacy and safety of adding fulvestrant to NCT in patients with ER+/HER2- locally advanced breast cancer (LABC). Additionally, the study aimed to investigate the association of 18F-FES PET-CT and metabolites with efficacy. Materials and Methods: Fulvestrant and EC-T regimen were given to ER+/HER2- LABC patients before surgery. At baseline, patients received 18F-FES PET-CT scan, and plasma samples were taken for LC-MS analysis. The primary endpoint was ORR. Secondary endpoints included tpCR and safety. Results: Among the 36 patients enrolled, the ORR was 86.1%, the tpCR rate was 8.3%. The incidence of grade ≥3 TEAEs was 22%. The decrease in ER value in sensitive patients was larger than that in non-sensitive patients, as was Ki-67 (p<0.05). The SUVmax, SUVmean, TL-ER of 18F-FES PET-CT in sensitive patients were significantly higher than those in non-sensitive patients (p<0.05). Moreover, these parameters were significantly correlated with MP grade and the change in ER expression before and after treatment (p<0.05). Thirteen differential expressed metabolites were identified, which were markedly enriched in 19 metabolic pathways. Conclusion: This regimen demonstrated acceptable toxicity and encouraging antitumor efficacy. 18F-FES PET-CT might serve as a tool to predict the effectiveness of this therapy. Altered metabolites or metabolic pathways might be associated with treatment response.