Lipids as potential mediators linking body mass index to diabetes: evidence from a mediation analysis based on the NAGALA cohort.

BACKGROUND: Body mass index (BMI) and lipid disorders are both known to be strongly associated with the development of diabetes, however, the indirect effect of lipid parameters in the BMI-related diabetes risk is currently unknown. This study aimed to investigate the mediating role of lipid parameters in the association of BMI with diabetes risk. METHODS: We assessed the association of diabetes risk with BMI, as well as lipid parameters including high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-CF and LDL-CS), triglycerides(TG), total cholesterol(TC), remnant cholesterol(RC), non-HDL-C, and combined indices of lipid parameters with HDL-C (RC/HDL-C ratio, TG/HDL-C ratio, TC/HDL-C ratio, non-HDL/HDL-C ratio, LDL/HDL-C ratio) using data from 15,453 subjects in the NAGALA project. Mediation models were used to explore the mediating role of lipid parameters in the association of BMI with diabetes risk, and mediation percentages were calculated for quantifying the strength of the indirect effects. Finally, receiver operating characteristic curve (ROC) analysis was used to compare the accuracy of BMI and BMI combined with lipid parameters in predicting incident diabetes. RESULTS: Multivariate regression models, adjusted for confounding factors, demonstrated robust associations of lipid parameters, BMI, with diabetes risk, with the exception of TC, LDL-CF, LDL-CS, and non-HDL-C. Mediation analysis showed that lipid parameters except TC, LDL-CF, LDL-CS, and Non-HDL-C were involved in and mediated the association of BMI with diabetes risk, with the largest mediation percentage being the RC/HDL-C ratio, which was as high as 40%; it is worth mentioning that HDL-C and HDL-C-related lipid ratio parameters also play an important mediating role in the association between BMI and diabetes, with the mediator proportion being greater than 30%. Finally, based on the ROC results, we found that the prediction performance of all lipid parameters in the current study except TC was significantly improved when combined with BMI. CONCLUSION: Our fresh findings suggested that lipid parameters partially mediated the association of BMI with diabetes risk; this result indicated that in the context of diabetes risk screening and disease management, it is important to not only monitor BMI but also pay attention to lipid parameters, particularly HDL-C and HDL-C-related lipid ratio parameters.

Two Novel Angiotensin-Converting Enzyme (ACE) Inhibitory and ACE2 Upregulating Peptides from the Hydrolysate of Pumpkin (Cucurbita moschata) Seed Meal.

Pumpkin (Cucurbita moschata) seed meal (PSM), the major byproduct of pumpkin seed oil industry, was used to prepare angiotensin-converting enzyme (ACE) inhibitory and angiotensin-converting enzyme 2 (ACE2) upregulating peptides. These peptides were isolated and purified from the PSM hydrolysate prepared using Neutrase 5.0 BG by ultrafiltration, Sephadex G-15 column chromatography, and reversed-phase high-performance liquid chromatography. Two peptides with significant ACE inhibition activity were identified as SNHANQLDFHP and PVQVLASAYR with IC50 values of 172.07 and 90.69 µM, respectively. The C-terminal tripeptides of the two peptides contained Pro, Phe, and Tyr, respectively, and PVQVLASAYR also had Val in its N-terminal tripeptide, which was a favorable structure for ACE inhibition. Molecular docking results declared that the two peptides could interact with ACE through hydrogen bonds and hydrophobic interactions. Furthermore, the two peptides performed protective function on EA.hy926 cells by decreasing the secretion of endothelin-1, increasing the release of nitric oxide, and regulating the ACE2 activity. In vitro simulated gastrointestinal digestion showed the two peptides exhibited good stability against gastrointestinal enzyme digestion. In conclusion, PSM is a promising material for preparing antihypertensive peptides.

Analysis for Causes of Corneal Melt After the Boston Keratoprosthesis Type I: The Chinese People's Liberation Army General Hospital Experience.

PURPOSE: The purpose of this study was to evaluate the long-term incidence, risk factors, and the management of corneal melt following Boston type I keratoprosthesis (B-KPro I) implantation. METHODS: This is a retrospective observational case series. Data were collected regarding demographics, preoperative characteristics, incidence, and outcomes of corneal melt in 102 patients who underwent B-KPro I in the Chinese PLA General Hospital between 2011 and 2018, with a follow-up period ranging from 4 to 11 years. RESULTS: Chemical burn was the most common indication for B-KPro I (n = 56; 53.8%), followed by ocular trauma (n = 26; 25.0%). During the follow-up period (107 ± 25.7 months), corneal melt occurred in 60 cases among 37 eyes (35.6%), with an incidence of 20.2% at 1 year after surgery. Fourteen cases presented with recurrent corneal melt. Patients with multiple corneal allograft failures had a higher risk of corneal melt. Thermal burns, compared with alkali burns, significantly elevated the odds ratio (OR) of corneal melt (OR, 5.11; 95% confidence interval, 1.05-24.86; P = 0.043). CONCLUSIONS: Corneal melt significantly reduced the retention time of KPro (P < 0.01), and its coexistence with other complications further shortened the retention time. A specific pattern of corneal melt occurrence was identified, with a peak incidence at 1 year postoperatively. Our findings suggest variations in the risk of corneal melt among different indications, with thermal burns carrying the highest OR. Moreover, each previous failed keratoplasty doubled the risk of corneal melt after B-KPro I.

Enhanced efficacy of brucine dissolving-microneedles as a targeted delivery system in rheumatoid arthritis treatment: a comprehensive pharmacokinetic-pharmacodynamic analysis.

Our previous studies have shown the therapeutic efficacy of brucine dissolving-microneedles (Bru-DMNs) in treating rheumatoid arthritis (RA). Bru delivered via the DMNs can bypass some of the issues related to oral and systemic delivery, including extensive enzymatic activity, liver metabolism and in the case of systemic delivery via hypodermic needles, pain resulting from injections and needle stick injury. However, the underlying mechanism of Bru-DMNs against RA has not been investigated in depth at the pharmacokinetic-pharmacodynamic (PK-PD) level. In this study, a microdialysis-based method combined with ultra-performance liquid chromatography-tandem mass spectrometry was developed for the simultaneous and continuous sampling and quantitative analysis of blood and joint cavities in fully awake RA rats. The acquired data were analyzed by the PK-PD analysis method. Bru delivered via microneedles showed enhanced distribution and prolonged retention in the joint cavity compared to its administration in blood. The correlation between the effect of Bru and its concentration at the action site was indirect. In this study, we explored the mechanism of Bru-DMNs against RA and established a visualization method to express the PK-PD relationship of Bru-DMNs against RA. This study provides insights into the mechanism of action of drugs with potential side effects administered transdermally for RA treatment.

Perioperative Outcomes and Survival of Modified Subxiphoid VATS Thymectomy for T2-3 Thymic Malignancies: A Retrospective Comparison Study.

OBJECTIVE: Our previous study demonstrated that modified subxiphoid VATS thymectomy (mSVT) with an auxiliary sternal retractor is feasible for locally invasive thymic malignancies. This study aimed to compare perioperative and oncological outcomes of mSVT versus median sternotomy thymectomy (MST) for locally advanced thymic malignancies. METHODS: In total, 221 patients of T2-3 thymic malignancies who underwent mSVT or MST between 2015 and 2020 were enrolled in our prospectively maintained database. A 1:1 propensity score-matching analysis was performed to balance the bias. Surgical difficulty was evaluated by a modified resection index. Perioperative and oncological results were compared between mSVT and MST groups. RESULTS: There were 72 patients in each group in the final analysis. Our results showed that the mSVT group had a shorter operative duration (98 vs. 129 min, P<0.001), less blood loss (40 vs.100 mL, P<0.001), shorter drainage duration (3 vs. 5 days, P<0.001), shorter length of hospital stay (5 vs. 6 days, P<0.001) and fewer postoperative complications (5.6% vs. 23.6%; P=0.005). No significant difference was detected in complete resection (98.6% vs. 98.6%, P =0.001) between the two groups. Conversion occurred in 5/106 (4.7%). Survival analyses indicated similar recurrence-free survival (HR=0.94; 95% CI: 0.40-2.20; p=0.883) and overall survival (HR=0.52; 95% CI: 0.05-5.02; p=0.590) between the two groups. CONCLUSION: The mSVT was safe and effective for T2-3 thymic malignancies and could be an alternative for selected patients with locally advanced thymic diseases. Further prospective studies are needed to evaluate the long-term survival of modified subxiphoid approach thoracoscopic thymectomy.

3D printing processes in precise drug delivery for personalized medicine.

With the advent of personalized medicine, the drug delivery system will be changed significantly. The development of personalized medicine needs the support of many technologies, among which three-dimensional printing (3DP) technology is a novel formulation-preparing process that creates 3D objects by depositing printing materials layer-by-layer based on the computer-aided design method. Compared with traditional pharmaceutical processes, 3DP produces complex drug combinations, personalized dosage, and flexible shape and structure of dosage forms (DFs) on demand. In the future, personalized 3DP drugs may supplement and even replace their traditional counterpart. We systematically introduce the applications of 3DP technologies in the pharmaceutical industry and summarize the virtues and shortcomings of each technique. The release behaviors and control mechanisms of the pharmaceutical DFs with desired structures are also analyzed. Finally, the benefits, challenges, and prospects of 3DP technology to the pharmaceutical industry are discussed.

Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Differential expression and analysis of extrachromosomal circular DNAs as serum biomarkers in pulmonary arterial hypertension.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) have been reported to play a key role in the occurrence and development of various diseases. However, the characterization and role of eccDNAs in pulmonary arterial hypertension (PAH) remain unclear. METHODS: In the discovery cohort, we first explored eccDNA expression profiles by Circle-sequencing analysis. The candidate eccDNAs were validated by routine polymerase chain reaction (PCR), TOPO-TA cloning and Sanger sequencing. In the validation cohort, 30 patients with PAH and 10 healthy controls were recruited for qPCR amplification to detect the candidate eccDNAs. Datas at the baseline were collected, including clinical background, biochemical variables, echocardiography and hemodynamic factors. Receiver operating characteristic curve was used to investigate the diagnostic effect of the eccDNA. RESULTS: We identified a total of 21,741 eccDNAs in plasma samples of 3 IPAH patients and 3 individuals in good health, and the expression frequency, GC content, length distribution, and genome distribution of the eccDNAs were thoroughly characterized and analyzed. In the validation cohort, 687 eccDNAs were differentially expressed in patients with IPAH compared with healthy controls (screening threshold: |FC|≥2 and P < 0.05). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the specific eccDNAs in IPAH were significantly enriched in calcium channel activity, the mitogen-activated protein kinase pathway, and the wnt signaling pathway. Verification queue found that the expression of eccDNA-chr2:131208878-131,424,362 in PAH was considerably higher than that in healthy controls and exhibited a high level of accuracy in predicting PAH with a sensitivity of 86.67% and a specificity of 90%. Furthermore, correlation analysis disclosed a significant association between serum eccDNA-chr2:131208878-131,424,362 and mean pulmonary artery pressure (mPAP) (r = 0.396, P = 0.03), 6 min walking distance (6MWD) (r = -0.399, P = 0.029), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (r = 0.685, P < 0.001) and cardiac index (CI) (r = - 0.419, P = 0.021). CONCLUSIONS: This is the first study to identify and characterize eccDNAs in patients with PAH. We revealed that serum eccDNA-chr2:131208878-131,424,362 is significantly overexpressed and can be used in the diagnosis of PAH, indicating its potential as a novel non-invasive biomarker.

Process for Producing Lithium Iodide Cleanly through Electrodialysis Metathesis.

Lithium iodide is commonly used in the production of batteries and drugs. Currently, the neutralization method is the primary means of producing lithium iodide. This method involves using hydriodic acid as a raw material, adding lithium carbonate or lithium hydroxide, and obtaining lithium iodide through evaporation and concentration. However, hydriodic acid is chemically unstable. Its preparation can lead to explosive accidents and encountering high temperatures generates toxic iodine vapors. These limitations restrict its industrial production. The study evaluates the impact of membrane stack configuration, operating voltage, and initial concentrations and volume ratios of reactants on the production process. Electrodialysis metathesis, characterized by a simpler process flow, lower energy consumption, and environmental benefits, emerges as an effective technique for electrically driven membrane separation in lithium salt production and purification. Under the specific conditions of a C-C-A-C-A-C membrane stack configuration, operating voltage at 25 V, initial potassium iodide concentration at 0.4 mol/L, initial lithium sulfate concentration at 0.2 mol/L, and a 1:1 volume ratio of product liquid to raw material liquid, the method achieves a lithium iodide purity of 98.9% with a production cost of approximately 0.502 $/kg LiI.

Prognostic Impact of Left Atrial Appendage Patency After Device Closure.

BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Uncommon pathogen misidentification of Herbaspirillum huttiense as Burkholderia cepacia in bacteremia: a case report.

Herbaspirillum huttiense is an opportunistic pathogen associated with rare cases of bacteremia. In this case report, H huttiense was isolated from blood samples collected from an intravenous catheter (incubated for 20.8 hours) and a peripheral vein (incubated for 14.16 hours) of a lung adenocarcinoma patient. Positive blood culture bottles were subjected to smear preparation, and Gram staining and microscopic examination revealed the presence of gram-negative rods in both aerobic bottles. We used the VITEK MS automatic microbial mass spectrometry system, VITEK 2 Compact automatic microbial analysis system, and high-throughput nucleic acid sequencing for accurate identification of the isolate. It is noteworthy that although the VITEK 2 Compact identified the isolate as Burkholderia cepacia, confirmation through VITEK MS mass spectrometry and 16S ribosomal DNA (rDNA) sequencing identified it as H huttiense. Subsequently, antimicrobial susceptibility testing was performed using the broth microdilution method, following the guidelines for nonfermenting gram-negative bacilli provided by the Clinical and Laboratory Standards Institute. This case highlights the possibility of misidentification of H huttiense as B cepacia by VITEK 2 Compact in certain situations, emphasizing the importance of considering uncommon pathogens, such as H huttiense, in the context of bacteremia in cancer patients.

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch.

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.

Hydrothermal route upcycling surgical masks into dual-emitting carbon dots as ratiometric fluorescent probe for Cr (VI) and corrosion inhibitor in saline solution.

Exploration effective route to convert plastic waste into valuable carbon dots with bifunction of metal fluorescence monitoring and corrosion protection in seawater is promising. Herein, using "white-pollution" polypropylene surgical masks as a single precursor, dual-emitting carbon dots (CDs) with excellent ratiometric fluorescent sensitivity and corrosion inhibitor efficiency were fabricated with high yield (∼100 %) by a one-pot in situ acid oxidation hydrothermal strategy without post-treatment and organic solvents. Chemical, structural, morphological, optical properties and the Cr (VI) detection and Cu inhibition mechanism of the synthesized CDs had been systematically studied. Furthermore, a dual-response-OFF proportional fluorescent probe had been developed for the detection of the analyte Cr (VI) with a low detection limit of 24 nM. Additionally, the corrosion inhibition efficiency of the prepared CDs reached approximately 94.01 % for Cu substrate in 3.5 wt% NaCl electrolyte under a CDs concentration of 200 mg/L, which is higher than that of most previous reports.

Establishment of a novel microfluidic co-culture system for simultaneous analysis of multiple indicators of gefitinib sensitivity in colorectal cancer cells.

The therapeutic effect of gefitinib on colorectal cancer (CRC) is unclear, but it has been reported that stromal cells in the tumor microenvironment may have an impact on drug sensitivity. Herein, we established a microfluidic co-culture system and explored the sensitivity of CRC cells co-cultured with cancer-associated fibroblasts (CAFs) to gefitinib. The system consisted of a multichannel chip and a Petri dish. The chambers in the chip and dish were designed to continuously supply nutrients for long-term cell survival and create chemokine gradients for driving cell invasion without any external equipment. Using this system, the proliferation and invasiveness of cells were simultaneously evaluated by quantifying the area of cells and the migration distance of cells. In addition, the system combined with live cell workstation could evaluate the dynamic drug response of co-cultured cells and track individual cell trajectories in real-time. When CRC cells were co-cultured with CAFs, CAFs promoted CRC cell proliferation and invasion and reduced the sensitivity of cells to gefitinib through the exosomes secreted by CAFs. Furthermore, the cells that migrated out of the chip were collected, and EMT-related markers were determined by immunofluorescent and western blot assays. The results demonstrated that CAFs affected the response of CRC cells to gefitinib by inducing EMT, providing new ideas for further research on the resistance mechanism of gefitinib. This suggests that targeting CAFs or exosomes might be a new approach to enhance CRC sensitivity to gefitinib, and our system could be a novel platform for investigating the crosstalk between tumor cells and CAFs and understanding multiple biological changes of the tumor cells in the tumor microenvironment.

Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer.

Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H2O2-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H2O2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.

D-arabinose acts as antidepressant by activating the ACSS2-PPARγ/TFEB axis and CRTC1 transcription.

CREB-regulated transcription coactivator 1 (CRTC1), a pivotal synaptonuclear messenger, regulates synaptic plasticity and transmission to prevent depression. Despite exhaustive investigations into CRTC1 mRNA reductions in the depressed mice, the regulatory mechanisms governing its transcription remain elusive. Consequently, exploring rapid but non-toxic CRTC1 inducers at the transcriptional level is important for resisting depression. Here, we demonstrate the potential of D-arabinose, a unique monosaccharide prevalent in edible-medicinal plants, to rapidly enter the brain and induce CRTC1 expression, thereby eliciting rapid-acting and persistent antidepressant responses in chronic restrain stress (CRS)-induced depressed mice. Mechanistically, D-arabinose induces the expressions of peroxisome proliferator-activated receptor gamma (PPARγ) and transcription factor EB (TFEB), thereby activating CRTC1 transcription. Notably, we elucidate the pivotal role of the acetyl-CoA synthetase short-chain family member 2 (ACSS2) as an obligatory mediator for PPARγ and TFEB to potentiate CRTC1 transcription. Furthermore, D-arabinose augments ACSS2-dependent CRTC1 transcription by activating AMPK through lysosomal AXIN-LKB1 pathway. Correspondingly, the hippocampal down-regulations of ACSS2, PPARγ or TFEB alone failed to reverse CRTC1 reductions in CRS-exposure mice, ultimately abolishing the anti-depressant efficacy of D-arabinose. In summary, our study unveils a previously unexplored role of D-arabinose in activating the ACSS2-PPARγ/TFEB-CRTC1 axis, presenting it as a promising avenue for the prevention and treatment of depression.

Omega-3 fatty acids and their influence on hypertension and coronary atherosclerosis: Insights from a Mendelian randomization approach.

It has been suggested that Omega-3 fatty acids may improve endothelial thickness and thereby reduce the onset of cardiovascular diseases such as coronary atherosclerosis and hypertension. However, published observational epidemiological studies on the relationship between cardiovascular disease (CVD) and Omega-3 fatty acids remain inconclusive. Here, we performed a two-sample Mendelian randomisation analysis using publicly available GWAS pooled statistics to study a GWAS dataset of 16 380 466 SNPs in 23 363 cases and 195 429 controls (also of European ancestry) to determine genetic susceptibility to hypertension. We performed random-effects Inverse Variance Weighted (IVW) Mendelian Randomization (MR) analyses supplemented by a series of sensitivity assessments to measure the robustness of the findings and to detect any violations of the MR assumptions. During the course of the study, we used IVW, MR-Egger, and weighted median regression to infer that Omega-3 intake has a potentially adverse effect against atherosclerosis, although the trend was not significant (OR = 1.1198; 95%; CI: 0.9641-1.3006, p = .130). Meanwhile, our analyses showed a statistically significant negative association between Omega-3 fatty acid levels and risk of hypertension (OR = 0.9006; 95% CI: 0.8179-0.9917, p = .033). In addition, we explored the causal relationship between atherosclerosis and hypertension and found a significant correlation (OR = 1.3036; 95% CI: 1.0672-1.5923, p = .009). In conclusion, our extensive data investigated by MR suggest that elevated levels of Omega-3 fatty acids may be associated with an decreased risk of hypertension. Although there is no direct link between hypertension and atherosclerosis, the possibility of a subtle association cannot be categorically excluded.

Unveiling the biointerfaces characteristics and removal pathways of Cr(â ¥) in Bacillus cereus FNXJ1-2-3 for the Cr(â ¥)-to-Cr(0) conversion.

Although less toxic than hexavalent chromium, Cr (Ⅲ) species still pose a threat to human health. The Cr (Ⅵ) should be converted to Cr (0) instead of Cr (Ⅲ), which is still involved in biological detoxification filed. Herein, for the first time, it was found that Cr(Ⅵ) can be reduced into Cr(0) by Bacillus cereus FNXJ1-2-3, a way to completely harmless treatment of Cr(Ⅵ). The bacterial strain exhibited excellent performance in the reduction, sorption, and accumulation of Cr(Ⅵ) and Cr (Ⅲ). XPS etching characterization inferred that the transformation of Cr(Ⅵ) into Cr(0) followed a reduction pathway of Cr(Ⅵ)→Cr (Ⅲ)→metallic Cr(0), in which at least two secretory chromium reductases (ECrⅥ→Ⅲ and ECrⅢ→0) worked. Under the optimum condition, the yield ratio of Cr(0)/Cr (Ⅲ) reached 33.90%. In addition, the interfacial interactions, ion channels, chromium reductases, and external electron donors also contributed to the Cr(Ⅵ)/Cr(0) transformation. Findings of this study indicate that Bacillus cereus FNXJ1-2-3 is a promising bioremediation agent for Cr(Ⅵ) pollution control.