Chronic dietary deoxynivalenol exposure interferes the intestinal microbial community structure and antibiotic resistome in laying hens.

Antibiotic resistance genes (ARGs) are critical emerging pollutants that have attracted considerable attention. Deoxynivalenol (DON) is one of the most prevalent mycotoxins in cereal crops worldwide, arising severe health hazards to both humans and animals. Even if numerous researches argue in favor of a notorious influence of DON on the gut, the effects of dietary DON exposure on the ARG profile in poultry intestine remain obscure. In this study, two separate feeding experiments using Jing Tint 6 laying hens exposed to 4.5 or 9.0 mg/kg DON were performed to explore the impact of dietary DON exposure on the microbial community structure and the profiles of ARGs in the intestine via 16S rDNA sequencing and metagenomics sequencing, respectively. In addition, growth performance and intestinal barrier function were also determined to assess the feasibility of using DON-contaminated feedstuffs inappropriate for pigs' consumption in laying hens. Chronic ingestion of DON at 9.0 mg/kg did not alter zootechnical parameters. However, histomorphological impairments were observed in liver and jejunum. Additionally, metagenomic sequencing revealed that dietary DON exposure at 9.0 mg/kg level dramatically changed the gut microbial structure and shifted the ARG profile. The abundance of tetracycline ARG subtype in the layer cecum was decreased, whereas the abundance of vancomycin ARG subtype was increased upon DON exposure. Co-occurrence network analysis identified that Prevotella was the major ARG host in the intestine of laying hens. In summary, our findings demonstrated that DON-contaminated feedstuffs inappropriate for pigs' consumption should be prudently used in hen production, and shed new light on the interactions between mycotoxins and ARGs in the poultry intestine.

The role of lymphocyte-C-reactive protein ratio in the prognosis of gastrointestinal cancer: a systematic review and meta-analysis.

Objective: The lymphocyte-to-C-reactive protein (LCR) ratio, an immune-inflammatory marker, shows prognostic potential in various cancers. However, its utility in gastrointestinal malignancies remains uncertain due to inconsistent findings. This systematic review and meta-analysis synthesizes recent evidence to elucidate the association between LCR and prognosis in gastrointestinal cancer patients, aiming to clarify LCR's potential role as a prognostic biomarker. Methods: We searched PubMed, Embase, Cochrane, and Web of Science databases up to May 2024 to evaluate the association between LCR and prognosis in gastrointestinal cancer patients. The main outcomes included overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS). We also analyzed secondary parameters such as geographical region, study duration, sample size, LCR threshold, and patient characteristics (age, gender, tumor location, and TNM stage). Results: This meta-analysis of 21 cohort studies (n=9,131) finds a significant association between reduced LCR levels and poor prognosis in gastrointestinal cancer. Lower LCR levels were associated with worse overall survival (HR=2.01, 95% CI=1.75-2.31, P<0.001), recurrence-free survival (HR=1.90, 95% CI=1.32-2.76, P<0.001), and disease-free survival (HR=1.76, 95% CI=1.45-2.13, P<0.001). Subgroup analyses by cancer type, timing, and LCR threshold consistently confirmed this relationship (P<0.05). Conclusion: LCR may serve as a prognostic marker in gastrointestinal cancer patients, with lower LCR levels associated with poorer prognosis. However, more high-quality studies are needed to validate these findings, considering the limitations of the current evidence. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023486858.

Identification, characterization, and expression analysis of WRKY transcription factors in Cardamine violifolia reveal the key genes involved in regulating selenium accumulation.

BACKGROUND: Cardamine violifolia is a significant Brassicaceae plant known for its high selenium (Se) accumulation capacity, serving as an essential source of Se for both humans and animals. WRKY transcription factors play crucial roles in plant responses to various biotic and abiotic stresses, including cadmium stress, iron deficiency, and Se tolerance. However, the molecular mechanism of CvWRKY in Se accumulation is not completely clear. RESULTS: In this study, 120 WRKYs with conserved domains were identified from C. violifolia and classified into three groups based on phylogenetic relationships, with Group II further subdivided into five subgroups. Gene structure analysis revealed WRKY variations and mutations within the CvWRKYs. Segmental duplication events were identified as the primary driving force behind the expansion of the CvWRKY family, with numerous stress-responsive cis-acting elements found in the promoters of CvWRKYs. Transcriptome analysis of plants treated with exogenous Se and determination of Se levels revealed a strong positive correlation between the expression levels of CvWRKY034 and the Se content. Moreover, CvWRKY021 and CvWRKY099 exhibited high homology with AtWRKY47, a gene involved in regulating Se accumulation in Arabidopsis thaliana. The WRKY domains of CvWRKY021 and AtWRKY47 were highly conserved, and transcriptome data analysis revealed that CvWRKY021 responded to Na2SeO4 induction, showing a positive correlation with the concentration of Na2SeO4 treatment. Under the induction of Na2SeO3, CvWRKY021 and CvWRKY034 were significantly upregulated in the roots but downregulated in the shoots, and the Se content in the roots increased significantly and was mainly concentrated in the roots. CvWRKY021 and CvWRKY034 may be involved in the accumulation of Se in roots. CONCLUSIONS: The results of this study elucidate the evolution of CvWRKYs in the C. violifolia genome and provide valuable resources for further understanding the functional characteristics of WRKYs related to Se hyperaccumulation in C. violifolia.

High Photocytotoxicity Iridium(III) Complex Photosensitizer for Photodynamic Therapy Induces Antitumor Effect Through GPX4-Dependent Ferroptosis.

The development of small molecule photosensitizers based on iridium complex is limited by the mismatch between therapeutic effect and systemic toxicity, as well as the incomplete understanding of the molecular mechanism underlying cell death induction. Herein, a small molecule iridium complex IrC with high photocytotoxicity is synthesized, with half maximal inhibitory concentration as low as 91 nm, demonstrating excellent anti-tumor, relief of splenomegaly, and negligible side effects. Starting from the factors of effective photosensitizers, the in-depth theoretical analysis on photon absorption efficiency, energy transfer level matching, and properties of the triplet excited state of IrC is conducted. This also elucidates the feasibility of generating the high singlet oxygen quantum yield. In addition, the death mechanism induced by IrC is focused, innovatively utilizing GPX4-overexpression and GPX4-knockout cells via CRISPR/Cas9 technique to comprehensively verify ferroptosis and its further molecular mechanism. The generation of ROS mediated by IrC, along with the direct inhibition of GPX4 and glutathione, synergistically increased cellular oxidative stress and the level of lipid peroxidation. This study provides an effective approach for small molecule complexes to induce GPX4-dependent ferroptosis at low-dose photodynamic therapy.

Association between polypharmacy and 2-year outcomes among Chinese older inpatients: a multi-center cohort study.

BACKGROUND: The escalating global prevalence of polypharmacy presents a growing challenge to public health. In light of this issue, the primary objective of our study was to investigate the status of polypharmacy and its association with clinical outcomes in a large sample of hospitalized older patients aged 65 years and over. METHODS: A two-year prospective cohort study was carried out at six tertiary-level hospitals in China. Polypharmacy was defined as the prescription of 5 or more different medications daily, including over-the-counter and non-prescription medications. Baseline polypharmacy, multimorbidity, and other variables were collected when at admission, and 2-year outcomes were recorded by telephone follow-up. We used multivariate logistic regression analysis to examine the associations between polypharmacy and 2-year outcomes. RESULTS: The overall response rate was 87.2% and 8713 participants were included in the final analysis. The mean age was 72.40 years (SD = 5.72), and women accounted for 42.2%. The prevalence of polypharmacy among older Chinese inpatients is 23.6%. After adjusting for age, sex, education, marriage status, body mass index, baseline frailty, handgrip strength, cognitive impairment, and the Charlson comorbidity index, polypharmacy is significantly associated with frailty aggravation (OR 1.432, 95% CI 1.258-1.631) and mortality (OR 1.365, 95% CI 1.174-1.592), while inversely associated with readmission (OR 0.870, 95% CI 0.764-0.989). Polypharmacy was associated with a 35.6% increase in the risk of falls (1.356, 95%CI 1.064-1.716). This association weakened after adjustment for multimorbidity to 27.3% (OR 1.273, 95%CI 0.992-1.622). CONCLUSIONS: Polypharmacy was prevalent among older inpatients and was a risk factor for 2-year frailty aggravation and mortality. These results highlight the importance of optimizing medication use in older adults to minimize the risks associated with polypharmacy. Further research and implementing strategies are warranted to enhance the quality of care and safety for older individuals exposed to polypharmacy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1800017682, registered 09/08/2018.

Utility of covered stents as a bypass for the treatment of central venous occlusion: a case report.

BACKGROUND: Central venous occlusion (CVO) is difficult to treat with percutaneous transluminal angioplasty because the guidewire cannot pass through the occluded segments. In this study, we devised a new method for establishing an extra-anatomic bypass between the right subclavian vein and the superior vena cava via a covered stent to treat whole-segment occlusion of the right brachiocephalic vein (BCV) with calcification. CASE PRESENTATION: We present the case of a 58-year-old female patient who complained of right arm swelling present for 1.5 years. Twelve years prior, the patient began hemodialysis because chronic glomerulonephritis had progressed to end-stage renal disease. During the first 3 years, a right internal jugular vein (IJV)-tunneled cuffed catheter was used as the dialysis access, and the catheter was replaced once. A left arteriovenous fistula (AVF) was subsequently established. Owing to occlusion of the left AVF, a new fistula was established on the right upper extremity 1.5 years prior to this visit. Angiography of the right upper extremity revealed complete occlusion of the right BCV and IJV with calcification. Because of the failure to pass the guidewire across the lesion, we established an extra-anatomic bypass between the right subclavian vein and the superior vena cava with a covered stent. Angiography confirmed the patency of whole vascular access system. After 3 months of follow-up, the patient's AVF function and the bypass patency were satisfactory. CONCLUSIONS: As a new alternative for the treatment of long, angled CVO with or without calcification, a covered stent can be used to establish an extravascular bypass between central veins.

Classification of anatomy and treatment approaches for aneurysms originating from the proximal of the A1 segment of the anterior cerebral artery in clinical settings.

Objective: To explore the spatial relationship between A1 segment proximal anterior cerebral artery aneurysms and their main trunks, classify them anatomically and develop targeted treatment strategies. Methods: This single-center retrospective analysis involved 39 patients diagnosed with aneurysms originating from the proximal of A1 segment of the anterior cerebral artery (2014-2023). Classify the patient's aneurysm into 5 types based on the location of the neck involving the carrier artery and the spatial relationship and projection direction of the aneurysm body with the carrier artery, and outcomes from treatment methods were compared. Results: Among 39 aneurysms, 18 cases underwent endovascular intervention treatment, including 6 cases of stent assisted embolization, 1 case of flow-diverter embolization, 5 cases of balloon assisted embolization, and 6 cases of simple coiling. At discharged, the mRS score of all endovascularly treated patients was 0, and the GOS score was 5 at 6 months after discharge. At discharge, the mRS score of microsurgical clipping treated patients was 0 for 15 cases, 3 for 1 case, 4 for 1 case and 5 for 2 cases. Six months after discharge, the GOS score was 5 for 16 cases, 4 for 2 cases, 3 for 2 cases, and 1 for 1 case. GOS outcomes at 6 months were better for endovascularly treated patients (p = 0.047). Conclusion: Results showed better outcomes for the endovascular treatment group compared to microsurgical clipping at 6 months after surgery. The anatomical classification of aneurysms in this region may be of help to develop effective treatment strategies.

FBXW7-Mediated Downregulation of GPX4 Aggravates Acute Kidney Injury Following Ischemia‒Reperfusion.

Acute kidney injury (AKI) is a prevalent and potentially life-threatening complication characterized by a high incidence and mortality. A large number of studies have emphasized the role of ferroptosis in AKI. Moreover, FBXW7, a ubiquitin ligase, has been implicated in acute organ injury. Analysis of the GEO database (GSE98622) revealed increased FBXW7 mRNA levels in the kidney following ischemia‒reperfusion (IR). However, the role of FBXW7 in AKI has not been elucidated. Therefore, this study aimed to investigate the role of FBXW7 in IR-AKI and its underlying mechanisms. Here, we found that IR could induce AKI and increase FBXW7 expression, while the ferroptosis inhibitor Fer-1 alleviated AKI and decreased FBXW7 expression. Furthermore, we treated HK-2 cells with hypoxia for 12 h and reoxygenation for 4 h (H12R4) to simulate IR-AKI and investigated the impact of modulating FBXW7 expression on ferroptosis by employing ferroptosis-related agonists or inhibitors. Our findings revealed that H12R4 induced HK2 ferroptosis and increased the expression of FBXW7. FBXW7 overexpression in control cells exacerbated erastin-induced ferroptosis, and FBXW7 knockdown inhibited ferroptosis in H12R4-treated cells. Mechanistically, we confirmed that FBXW7 can bind to GPX4, a key molecule that inhibits ferroptosis. The half-life of the GPX4 protein decreased after FBXW7 overexpression, GPX4 ubiquitination increased after H12R4, and GPX4 degradation decreased after FBXW7 knockdown. In conclusion, our results indicated that FBXW7 plays an important role in the development of IR-AKI by promoting ferroptosis through the downregulation of GPX4 expression. This study provides new insight into FBXW7 as a potential target for treating AKI.

Pediatric Cardio-Oncology: Screening, Risk Stratification, and Prevention of Cardiotoxicity Associated with Anthracyclines.

Anthracyclines have significantly improved the survival of children with malignant tumors, but the associated cardiotoxicity, an effect now under the purview of pediatric cardio-oncology, due to its cumulative and irreversible effects on the heart, limits their clinical application. A systematic screening and risk stratification approach provides the opportunity for early identification and intervention to mitigate, reverse, or prevent myocardial injury, remodeling, and dysfunction associated with anthracyclines. This review summarizes the risk factors, surveillance indexes, and preventive strategies of anthracycline-related cardiotoxicity to improve the safety and efficacy of anthracyclines.

Prognostic and clinicopathological significance of tertiary lymphoid structure in non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the primary reason for cancer-related deaths globally. Tertiary lymphoid structure (TLS) is an organized collection of immune cells acquired in non-physiological, non-lymphoid tissues. High expression of TLS in tumor tissues is generally associated with better prognosis. This research aimed to investigate the prognostic and clinicopathological significance of TLS in patients with NSCLC. METHODS: A comprehensive literature search was conducted based on Pubmed, EMBASE, and Cochrane Library databases to identify eligible studies published up to December 8, 2023. The prognostic significance and clinicopathological value of TLS in NSCLC were evaluated by calculating the combined hazard ratios (HRs) and odds ratios (ORs) and their 95% confidence intervals (CIs). Following that, additional analyses, including subgroup analysis and sensitivity analysis, were conducted. RESULTS: This meta-analysis evaluated the prognostic and clinicopathological significance of TLS in 10 studies involving 1,451 patients with NSCLC. The results revealed that the high levels of TLS were strongly associated with better overall survival (OS) (HR = 0.48, 95% CI: 0.35-0.66, p < 0.001), disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.37, 95% CI: 0.24-0.54, p < 0.001), and disease-specific survival (DSS) (HR = 0.45, 95% CI: 0.30-0.68, p < 0.001) in NSCLC patients. In addition, the increased expression of TLS was closely related to the Tumor Node Metastasis (TNM) stage of tumors (OR = 0.71, 95% CI: 0.51-1.00, p < 0.05) and neutrophil-lymphocyte ratio (NLR) (OR = 0.33, 95% CI: 0.17-0.62, p < 0.001). CONCLUSIONS: The results revealed that highly expressed TLS is closely associated with a better prognosis in NSCLC patients. TLS may serve as a novel biomarker to predict the prognosis of NSCLC patients and guide the clinical treatment decisions.

NIR Light and GSH Dual-Responsive Upconversion Nanoparticles Loaded with Multifunctional Platinum(IV) Prodrug and RGD Peptide for Precise Cancer Therapy.

Platinum(II) drugs as a first-line anticancer reagent are limited by side effects and drug resistance. Stimuli-responsive nanosystems hold promise for precise spatiotemporal manipulation of drug delivery, with the aim to promote bioavailability and minimize side effects. Herein, a multitargeting octahedral platinum(IV) prodrug with octadecyl aliphatic chain and histone deacetylase inhibitor (phenylbutyric acid, PHB) at axial positions to improve the therapeutic effect of cisplatin was loaded on the upconversion nanoparticles (UCNPs) through hydrophobic interaction. Followed attachment of DSPE-PEG2000 and arginine-glycine-aspartic (RGD) peptide endowed the nanovehicles with high biocompatibility and tumor specificity. The fabricated nanoparticles (UCNP/Pt(IV)-RGD) can be triggered by upconversion luminescence (UCL) irradiation and glutathione (GSH) reduction to controllably release Pt(II) species and PHB, inducing profound cytotoxicity. Both in vitro and in vivo experiments demonstrated that UCNP/Pt(IV)-RGD exhibited remarkable antitumor efficiency, high tumor-targeting specificity, and real-time UCL imaging capacity, presenting an intelligent platinum(IV) prodrug-loaded nanovehicle for UCL-guided dual-stimuli-responsive combination therapy.

Dietary patterns interfere with gut microbiota to combat obesity.

Obesity and obesity-related metabolic disorders are global epidemics that occur when there is chronic energy intake exceeding energy expenditure. Growing evidence suggests that healthy dietary patterns not only decrease the risk of obesity but also influence the composition and function of the gut microbiota. Numerous studies manifest that the development of obesity is associated with gut microbiota. One promising supplementation strategy is modulating gut microbiota composition by dietary patterns to combat obesity. In this review, we discuss the changes of gut microbiota in obesity and obesity-related metabolic disorders, with a particular emphasis on the impact of dietary components on gut microbiota and how common food patterns can intervene in gut microbiota to prevent obesity. While there is promise in intervening with the gut microbiota to combat obesity through the regulation of dietary patterns, numerous key questions remain unanswered. In this review, we critically review the associations between dietary patterns, gut microbes, and obesity, aiming to contribute to the further development and application of dietary patterns against obesity in humans.

Secure computation protocol of Chebyshev distance under the malicious model.

Secure multi-party computation of Chebyshev distance represents a crucial method for confidential distance measurement, holding significant theoretical and practical implications. Especially within electronic archival management systems, secure computation of Chebyshev distance is employed for similarity measurement, classification, and clustering of sensitive archival information, thereby enhancing the security of sensitive archival queries and sharing. This paper proposes a secure protocol for computing Chebyshev distance under a semi-honest model, leveraging the additive homomorphic properties of the NTRU cryptosystem and a vector encoding method. This protocol transforms the confidential computation of Chebyshev distance into the inner product of confidential computation vectors, as demonstrated through the model paradigm validating its security under the semi-honest model. Addressing potential malicious participant scenarios, a secure protocol for computing Chebyshev distance under a malicious model is introduced, utilizing cryptographic tools such as digital commitments and mutual decryption methods. The security of this protocol under the malicious model is affirmed using the real/ideal model paradigm. Theoretical analysis and experimental simulations demonstrate the efficiency and practical applicability of the proposed schemes.

Developmental 6:2 FTCA exposure impairs renal development in chicken embryos via IGF signaling.

6:2 fluorotelomer carboxylic acid (6:2 FTCA) is a perfluorooctanoic acid (PFOA) substitute, which is supposedly less accumulative and toxic than PFOA. However, 6:2 FTCA is structurally similar to PFOA, and there had already been reports about its toxicities comparable to PFOA. The aim of the current study is to assess potential effects of developmental exposure to 6:2 FTCA on the development of kidney in chicken embryo and to investigate underlying mechanism. Fertile chicken eggs were exposed to 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg doses of 6:2 FTCA, or 2 mg/kg PFOA, then incubated to hatch. Serum and kidney of hatchling chickens were collected. Blood urea nitrogen (BUN) and creatinine (Cre) levels were measured with commercially available kits. Morphology of kidney was assessed with histopathology. To further reveal molecular mechanism of observed endpoints, IGF signaling molecules were assessed in the kidney samples with qRT-PCR, results indicated that IGFBP3 is a potentially crucial molecule. Lentiviruses overexpressing or silencing IGFBP3 were designed and applied to enhance/suppress the expression of IGFBP3 in developing chicken embryo for further verification of its role in the observed effects. Disrupted nephron formation, in the manifestation of decreased glomeruli number/area and increased serum BUN/Cre levels, was observed in the animals developmentally exposed to 6:2 FTCA. Correspondingly, IGF signaling molecules (IGF1, IGF1R and IGFBP3) were affected by 6:2 FTCA exposure. Meanwhile, overexpression of IGFBP3 effectively alleviated such changes, while silencing of IGFBP3 mimicked observed effects. In conclusion, developmental exposure to 6:2 FTCA is associated with disrupted chicken embryo renal development, in which IGFBP3 seems to be a remarkable contributor, suggesting potential health risks for human and other species. Further risk assessments and mechanistic works are necessary.

Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy.

(1) Background: Immune-related adverse events (irAEs) are a series of unique organ-specific inflammatory toxicities observed in patients with hepatocellular carcinoma (HCC) undergoing PD-1 inhibition combination therapy. The specific underlying mechanisms remain unclear. (2) Methods: We recruited 71 patients with HCC undergoing PD-1 inhibition combination therapy. These patients were then divided into two groups based on irAE occurrence: 34 had irAEs and 37 did not. Using Olink proteomics, we analyzed the aberrant inflammation-related proteins (IRPs) in these patient groups. For single-cell RNA sequencing (scRNA-seq) analysis, we collected peripheral blood mononuclear cells (PBMCs) from two representative patients at the pretreatment, irAE occurrence, and resolution stages. (3) Results: Our study revealed distinct plasma protein signatures in HCC patients experiencing irAEs after PD-1 inhibition combination therapy. We clarified the relationship between monocyte activation and irAEs, identified a strongly associated CD14-MC-CCL3 monocyte subset, and explored the role of the IFN-γ signaling pathway in monocyte activation during irAEs. (4) Conclusions: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.

Jujubae Fructus extract prolongs lifespan and improves stress tolerance in Caenorhabditis elegans dependent on DAF-16/SOD-3.

Jujubae Fructus, the fruit of Ziziphus jujuba Mill has been used as one of the medicine food homology species for thousands of years in China. Studies have shown that the active ingredients of Jujubae Fructus have a variety of biological effects, but its role in the aging process still lacks knowledge. Here, we investigated the effect of Jujubae Fructus extract (JE) on Caenorhabditis elegans lifespan and its potential mechanism. The lifespan of C. elegans treated with JE was signifificantly increased in a dose-dependent manner. In addition, JE treatment prolonged the reproductive period and increased normal activity during aging in C. elegans. Similarly, JE supplementation also enhanced the resistance to heat and oxidative stress in C. elegans. Furthermore, the mutant worms' lifespan assays demonstrated that JE requires daf-16 to prolong lifespan. DAF-16::GFP analysis of TJ356 showed that JE treatment translocates DAF-16::GFP to nucleus in transgenic worms. By analyzing the downstream of daf-16, we identify that JE may regulate sod3 downstream of daf-16. Mutant worms' lifespan and transgenic reporter gene expression assays revealed that increasing SOD-3 expression was critical for extending longevity in C. elegans with JE therapy. Collectively, these data indicate that JE may have an important role in C. elegans longevity that is dependent on DAF-16 and SOD-3.

Deactivation of the Unfolded Protein Response Aggravated Renal AA Amyloidosis in HSF1 Deficiency Mice.

Systemic amyloid A (AA) amyloidosis, which is considered the second most common form of systemic amyloidosis usually takes place several years prior to the occurrence of chronic inflammation, generally involving the kidney. Activated HSF1, which alleviated unfolded protein response (UPR) or enhanced HSR, is the potential therapeutic target of many diseases. However, the effect of HSF1 on AA amyloidosis remains unclear. This study focused on evaluating effect of HSF1 on AA amyloidosis based on HSF1 knockout mice. As a result, aggravated amyloid deposits and renal dysfunction have been found in HSF1 knockout mice. In progressive AA amyloidosis, HSF1 deficiency enhances serum amyloid A production might to lead to severe AA amyloid deposition in mice, which may be related to deactivated unfolded protein response as well as enhanced inflammation. Thus, HSF1 plays a significant role on UPR related pathway impacting AA amyloid deposition, which can mitigate amyloidogenic proteins from aggregation pathologically and is the possible way for intervening with the pathology of systemic amyloid disorder. In conclusion, HSF1 could not only serve as a new target for AA amyloidosis treatment in the future, but HSF1 knockout mice also can be considered as a valuable novel animal model for renal AA amyloidosis.

Changing Trends in the Global Disease Burden of Pancreatic Cancer from 1990 to 2030.

AIM: To explore the global burden of pancreatic cancer (PC) from 1990 to 2019, evaluate independent effects of age, period, and cohort on the incidence of PC, and predict the incidence of PC in the next decade. METHODS: Data were obtained from the Global Burden of Disease Study 2019. We calculated the age-standardized disability-adjusted life years (DALY) rate, age-standardized mortality rate (ASMR), age-standardized incidence rate (ASIR), and age-standardized prevalence rate (ASPR) of PC. Joinpoint Poisson regression analysis was performed to identify the temporal trends in the incidence of PC. Then, a two-factor model was constructed using the Poisson log-linear model, and a three-factor model was constructed using the intrinsic estimator (IE) method to estimate the independent effects of age, period, and cohort on the incidence of PC. Finally, the Bayesian age-period-cohort (BAPC) model was also used to predict the age-standardized global incidence rate of PC and age-standardized new PC cases from 2020 to 2030. RESULTS: Overall, the DALY rate, ASMR, ASIR, and ASPR all increased from 1990 to 2019. The ASIR in males increased from 6 per 100,000 in 1990 to 7.5 per 100,000 in 2019 and was predicted to rise to 8.2 per 100,000 by 2030. Meanwhile, the ASIR in females rose from 4.5 per 100,000 in 1990 to 5.7 per 100,000 in 2019 and was predicted to rise to 6.3 per 100,000 by 2030. The age effect on the incidence of PC showed sharp increasing trends from 40 to 79 years. The period effect continuously increased with advancing periods, but the cohort effect showed substantial decreasing trends. CONCLUSIONS: The age and period effect on the incidence of PC presented increasing trends, while the cohort effect showed decreasing trends. All indicators of the global burden of PC are increasing in both males and females, and the ASIR is predicted to rise at an alarming rate by 2030. Thus, timely screening and intervention are recommended, especially for earlier birth cohorts at high risk.

Determination of six volatile fatty acids in human serum, urine and faeces by low temperature derivatisation combined with HPLC-MS/MS.

A stable isotope dilution-liquid chromatography tandem mass spectrometry method based on a low-temperature derivatization strategy with 3-nitrophenylhydrazine (3-NPH) was developed for the determination of six volatile fatty acids (VFAs) in serum, urine, and feces. Ice acetonitrile was used to precipitate proteins and extract the target analytes. The extract was derivatized with 3-NPH methanol solution at 4 °C. BEH C8 (1.7 µm, 2.1 × 100 mm) column was used for chromatographic separation, and acetonitrile-water (both containing 0.01 % formic acid) were used as the mobile phase with a gradient elution of 10 min. Electrospray ionization source (ESI) in negative ion multiple reaction monitoring (MRM) mode were used for analyte detection. The regression coefficients R2 of the calibration curves for the six VFAs were in the range of 0.9963-0.9994, and the LOQs were in the range of 0.02-0.5 µg mL-1, with the recoveries in the range of 85.3-104.3 %, and the intra- and inter-day precision in the range of 1.8-9.1 %. The method is simple, accurate and reliable, and has been applied in the sensitive determination of VFAs in complex biological samples.

Multi-omics explores the potential regulatory role of acetylation modification in flavonoid biosynthesis of Ginkgo biloba.

Flavonoids are crucial medicinal active ingredients in Ginkgo biloba L. However, the effect of protein post-translational modifications on flavonoid biosynthesis remains poorly explored. Lysine acetylation, a reversible post-translational modification, plays a crucial role in metabolic regulation. This study aims to investigate the potential role of acetylation in G. biloba flavonoid biosynthesis. Through comprehensive analysis of transcriptomes, metabolomes, proteomes and acetylated proteins in different tissues, a total of 11,788 lysine acetylation sites were identified on 4324 acetylated proteins, including 89 acetylation sites on 23 proteins. Additionally, 128 types of differentially accumulated flavonoids were identified among tissues, and a dataset of differentially expressed genes related to the flavonoid biosynthesis pathway was constructed. Twelve (CHI, C3H1, ANR, DFR, CCoAOMT1, F3H1, F3H2, CCoAOMT2, C3H2, HCT, F3'5'H and FG2) acetylated proteins that might be involved in flavonoid biosynthesis were identified. Specifically, we found that the modification levels of CCoAOMT1 and F3'5'H sites correlated with the catalytic production of homoeriodictyol and dihydromyricetin, respectively. Inhibitors of lysine deacetylase (trichostatin A) impacted total flavonoid content in different tissues and increased flavonoid levels in G. biloba roots. Treatment with trichostatin A revealed that expression levels of GbF3'5'H and GbCCoAOMT1 in stems and leaves aligned with total flavonoid content variations, while in roots, expression levels of GbC3H2 and GbFG2 corresponded to total flavonoid content changes. Collectively, these findings reveal for the first time the important role of acetylation in flavonoid biosynthesis.