GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.

Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4-CD8- double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.

Combination of Pirfenidone and Andrographolide Ameliorates Hepatic Stellate Cell Activation and Liver Fibrosis by Mediating TGF-ß/Smad Signaling Pathway.

Background: Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays a central role in the pathogenesis of hepatic fibrosis. Our study aimed to investigate the pharmacological effect and potential mechanism of pirfenidone (PFD) and andrographolide (AGP) separately and together on liver fibrosis of BA. Materials and Methods: The bile ducts of male C57BL/6J mice were ligated or had the sham operation. The in vivo effects of PFD and/or AGP on liver fibrosis of BA were evaluated. Human hepatic stellate cells (LX-2) were also treated with PFD and/or AGP in vitro. Results: PFD and/or AGP ameliorates liver fibrosis and inflammation in the mice model of BA, as evidenced by significant downregulated in the accumulation of collagen fibers, hepatic fibrosis markers (α-SMA, collagen I, and collagen IV), and inflammatory markers (IL-1ß, IL-6, and TNF-α). Moreover, compared with monotherapy, these changes are more obvious in the combined treatment of PFD and AGP. Consistent with animal experiments, hepatic fibrosis markers (α-SMA, collagen I, and CTGF) and inflammatory markers (IL-1ß, IL-6, and TNF-α) were significantly decreased in activated LX-2 cells after PFD and/or AGP treatment. In addition, PFD and/or AGP inhibited the activation of HSCs by blocking the TGF-ß/Smad signaling pathway, and the combined treatment of PFD and AGP synergistically inhibited the phosphorylation of Smad2 and Smad3. Conclusion: The combined application of PFD and AGP exerted superior inhibitive effects on HSC activation and liver fibrosis by mediating the TGF-ß/Smad signaling pathway as compared to monotherapy. Therefore, the combination of PFD and AGP may be a promising treatment strategy for liver fibrosis in BA.

Opportunistic use of chest low-dose computed tomography (LDCT) imaging for low bone mineral density and osteoporosis screening: cutoff thresholds for the attenuation values of the lower thoracic and upper lumbar vertebrae.

Background: Osteoporosis remains substantially underdiagnosed and undertreated worldwide. Chest low-dose computed tomography (LDCT) may provide a valuable and popular opportunity for osteoporosis screening. This study sought to evaluate the feasibility of the screening of low bone mineral density (BMD) and osteoporosis with mean attenuation values of the lower thoracic compared to upper lumbar vertebrae. The cutoff thresholds of the mean attenuation values in Hounsfield units (HU) were derived to facilitate implementation of opportunistic screening using chest LDCT. Methods: The participants aged 30 years or older who underwent chest LDCT and quantitative computed tomography (QCT) examinations from August 2018 to October 2020 in our hospital were consecutively included in this retrospective study. A region of interest (ROI) was placed in the trabecular bone of each vertebral body to measure the HU values. The correlations of mean HU values of lower thoracic (T11-T12) and upper lumbar (L1-L2) vertebrae with age and lumbar BMD obtained with QCT were performed using the Pearson correlation coefficient, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was generated to determine the cutoff thresholds for distinguishing low BMD from normal and osteoporosis from non-osteoporosis. Results: A total of 1,112 participants were included in the final study cohort (743 men and 369 women, mean age 58.2±8.9 years; range, 32-88 years). The mean HU values of T11-T12 and L1-L2 were significantly different among 3 QCT-defined BMD categories of osteoporosis, osteopenia, and normal (P<0.001). The differences in HU values between T11-T12 and L1-L2 in each category of bone status were statistically significant (P<0.001). The mean HU values of T11-T12 (r=-0.453, P<0.001) and L1-L2 (r=-0.498, P<0.001) had negative correlations with age. Positive correlations were observed between the mean HU values of T11-T12 (r=0.872, P<0.001) and L1-L2 (r=0.899, P<0.001) with BMD. The optimal cutoff thresholds for distinguishing low BMD from normal were average T11-T12 ≤157 HU [AUC =0.941, 95% confidence interval (CI): 0.925-0.954, P<0.001] and L1-L2 ≤138 HU (AUC =0.950, 95% CI: 0.935-0.962, P<0.001), as well as distinguishing osteoporosis from non-osteoporosis were average T11-T12 ≤125 HU (AUC =0.960, 95% CI: 0.947-0.971, P<0.001) and L1-L2 ≤107 HU (AUC =0.961, 95% CI: 0.948-0.972, P<0.001). There was no significant difference between the AUC values of T11-T12 and L1-L2 for low BMD (P=0.07) and osteoporosis (P=0.92) screening. Conclusions: We have conducted a study on low BMD and osteoporosis screening using mean attenuation values of lower thoracic and upper lumbar vertebrae. Assessment of mean attenuation values of T11-T12 and L1-L2 can be used interchangeably for low BMD and osteoporosis screening using chest LDCT, and their cutoff thresholds were established.

In vivo Fate of Targeted Drug Delivery Carriers.

This review aimed to systematically investigate the intracellular and subcellular fate of various types of targeting carriers. Upon entering the body via intravenous injection or other routes, a targeting carrier that can deliver therapeutic agents initiates their journey. If administered intravenously, the carrier initially faces challenges presented by the blood circulation before reaching specific tissues and interacting with cells within the tissue. At the subcellular level, the car2rier undergoes processes, such as drug release, degradation, and metabolism, through specific pathways. While studies on the fate of 13 types of carriers have been relatively conclusive, these studies are incomplete and lack a comprehensive analysis. Furthermore, there are still carriers whose fate remains unclear, underscoring the need for continuous research. This study highlights the importance of comprehending the in vivo and intracellular fate of targeting carriers and provides valuable insights into the operational mechanisms of different carriers within the body. By doing so, researchers can effectively select appropriate carriers and enhance the successful clinical translation of new formulations.

Nowadays, scientists are actively researching nanocarrier drugs. After administration via injection or other methods, these drugs experience in the body and reach the target treatment site to relieve or cure symptoms. As research progresses, scientists are gaining more insights into the behavior of nanocarrier drugs in the body, which is useful in developing safer and more effective drugs. Historically, research has focused primarily on the drug itself. However, it is important to understand that the carrier that delivers and protects the drug (often described as the drug sitting in a "car" or under an "umbrella") plays an essential role in the drug's therapeutic effect. This paper aims to highlight the importance of the carrier's role, which is vital for developing new drugs and advancing basic research.

Intraparticle Electron Transfer for Long-Lasting Tumor Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a novel tumor treatment method by using hydroxyl radicals (•OH) to kill cancer cells. However, its therapeutic effects are strictly confined by the short lifespan of •OH and reduced •OH generation speed. Herein, an effective CDT is achieved by both improving •OH lifetime and long-lasting generating •OH through intraparticle electron transfer within heterogeneous nanoparticles (NPs). These heterogeneous NPs are composed of evenly distributed Cu and Fe3O4 (CFO NPs) with large interaction interfaces, and electrons tend to transfer from Cu to Fe3O4 for the appearance of ≡Cu2+ and increase in ≡Fe2+. The generated ≡Cu2+ can interact with GSH, which prolongs the lifespan of •OH, produces ≡Cu+ for higher speed •OH generation with H2O2, and induces cell ferroptosis for tumor therapy. The improved ≡Fe2+ can also improve the •OH release under H2O2 until Cu is depleted. As a result, a sustainable •OH generation is achieved to promote cell apoptosis for effective tumor therapy. Since H2O2 and GSH are only overexpressed at tumor, and CFO NPs can degrade in the tumor microenvironment, these NPs are with high biosafety and can be metabolized by urine. This work provides a novel biomaterial for effective cancer CDT through intraparticle electron transfer.

Green Fluorescent Carbon Dots with Critically Controlled Surface States: Make Silk Shine via Feeding Silkworms.

Feeding silkworms with functional materials as additives to produce naturally modified silk is a facile, diverse, controllable, and environmentally friendly method with a low cost of time and investment. Among various additives, carbon dots (CDs) show unique advantages due to their excellent biocompatibility and fluorescence stability. Here, a new type of green fluorescent carbon dots (G-CDs) is synthesized with a high oil-water partition ratio of 147, a low isoelectric point of 5.16, an absolute quantum yield of 71%, and critically controlled surface states. After feeding with G-CDs, the silkworms weave light yellow cocoons whose green fluorescence is visible to the naked eye under UV light. The luminous silk is sewn onto the cloth to create striking patterns with beautiful fluorescence. Such G-CDs have no adverse effect on the survival rate and the life cycle of silkworms and enable their whole bodies to glow under UV light. Based on the strong fluorescence, chemical stability, and biological safety, G-CDs are found in the digestive tracts, silk glands, feces, cocoons, and even moth bodies. G-CDs accumulate in the posterior silk glands where fibroin protein is secreted, indicating its stronger combination with fibroin than sericin, which meets the requirements for practical applications.

Metal-Organic Framework-Derived Au-Doped In2O3 Nanotubes for Monitoring CO at the ppb Level.

Achieving selective detection of ppb-level CO is important for air quality testing at industrial sites to ensure personal safety. Noble metal doping enhances charge transfer, which in turn reduces the detection limit of metal oxide gas sensors. In this work, metal-organic framework-derived Au-doped In2O3 nanotubes with high electrical conductivity are synthesized by pyrolysis of the Au-doped metal-organic framework (In-MIL-68) as a template. Gas-sensing experiments reveal that the detection limit of 0.2% Au-doped In2O3 nanotubes (0.2% Au, mass fraction) is as low as 750 ppb. Meanwhile, the sensing material shows a response value of 18.2 to 50 ppm of CO at 240 °C, which is about 2.8 times higher than that of pure In2O3. Meanwhile, the response and recovery times are short (37 s/86 s). The gas-sensing mechanism of CO is uncovered by in situ DRIFTS through the reaction intermediates. In addition, first-principles calculations suggest that Au doping of In2O3 significantly enhances its adsorption energy for CO and improves the electron transfer properties. This study reveals a novel synthesis pathway for Au-doped In2O3 nanotubular structures and their potential application in low concentration CO detection.

A life-threatening, massive subcutaneous hematoma caused by trauma in a patient with neurofibromatosis type 1: a case report and literature review.

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that can give rise to the formation of vascular lesions in affected individuals. These lesions, whether occurring spontaneously or as a result of trauma, have the potential to cause severe and even fatal hemorrhage. Case description: We presented a case demonstrating the most extensive hematoma ever documented in a patient with NF1, resulting from a minor trauma. He experienced hemodynamic instability due to severe anemia. Arteriography revealed a rupture in the intercostal artery, which was successfully treated through interventional embolization to stop the hemorrhage. Additionally, we implemented a refined surgical approach, beginning with suturing, followed by the meticulous resection of necrotic and aberrant tissues, thereby markedly diminishing bleeding. Conclusion: Minor trauma may cause severe bleeding in patients with NF1, which can be life-threatening. Timely diagnosis of NF1 and effective hemostatic techniques are key to successful treatment.

Prognostic significance of the aspartate aminotransferase to lymphocyte ratio index in patients with acute myocardial infarction.

BACKGROUND: This study aimed to investigate the clinical value and prognostic significance of the alanine aspartate aminotransferase-to-lymphocyte ratio index (ALRI) in patients diagnosed with acute myocardial infarction (AMI). METHODS: Clinical indices of patients with AMI were collected from the Medical Information Mark for Intensive Care (MIMIC) III database and Wuhan Sixth Hospital. Cox regression analysis was used to explore whether ALRI was a risk factor for a worse prognosis in patients with AMI, and a nomogram including ALRI was created to estimate its predictive performance for 28-day mortality. RESULTS: Based on clinical data from the MIMIC-III database, we found that a high ALRI was closely associated with a variety of clinical parameters. It was an important risk factor for 28-day survival in patients with AMI (HR = 5.816). ALRI had a high predictive power for worse 28-day survival in patients with AMI (area under the curve [AUC] = 0.754). Additionally, we used clinical data from the Wuhan Sixth Hospital to verify the predictive power of ALRI in patients with AMI, and a high level of ALRI remained an independent risk factor for worse survival in patients with AMI (HR = 4.969). The AMI nomogram, including ALRI, displayed a good predictive performance for 28-day mortality in both the MIMIC-III (AUC = 0.826) and Wuhan Sixth Hospital cohorts (AUC = 0.795). CONCLUSION: The ALRI is closely related to the survival outcomes of patients with newly diagnosed AMI, indicating that it could serve as a novel biomarker for risk stratification such patients.

One-step electrodeposition of MWCNTs-Cu MOF films for the ratiometric electrochemical analysis of glyphosate.

Sensitive and accurate determination of glyphosate (GLYP) is vital for food safety and environmental protection. Herein, a novel electrochemical ratiometric biosensor was designed for the accurate quantification of GLYP through one-step electrodeposition of MWCNTs-Cu MOF films. MWCNTs-Cu MOF nanostructures were directly electro-synthesized in situ on the electrode from the precursor solution. The combination of Cu MOFs with MWCNTs not merely improved the conductivity of MOFs, but also enhanced the sensitivity of the biosensor. Furthermore, Cu sites within Cu MOFs were turned into CuCl to further amplify the current signal and enable the specific recognition of GLYP through competing reactions with the transformation of CuCl into non-electroactive Cu-GLYP. Meanwhile, internal reference molecules of methylene blue (MB) were incorporated to improve the measurement accuracy of GLYP for reducing unpredictable measurement errors aroused by environmental deviations. The ratiometric electrochemical sensor exhibited a high linearity with the logarithmic value of GLYP concentration from 0.5 nM to 400 nM. The detection limit was estimated to be as low as 0.014 nM. Finally, the present sensor with ratiometric signal export was applied for GLYP analysis in real samples with high sensitivity and accuracy. The simplicity and reliability of the ratiometric sensor make it a worthy and powerful tool for food and environmental monitoring. This design strategy also provides an avenue for the development of simple and efficient biosensors for other substances.

Temporal dynamics of spatial attentional biases toward weight-related words among females with weight dissatisfaction.

Attentional bias toward weight-related stimuli plays a crucial role in the development and maintenance of body image disturbances. However, the temporal dynamics of attentional biases responsible for the previously reported behavioral effects caused by the task-irrelevant but spatial-relevant weight-related stimuli presented in the peripheral visual field among females with high weight dissatisfaction (HWD) remain unclear. The present study combined the modified dot-probe task and event-related potentials to explore the temporal dynamics of spatial attentional biases toward weight-related words among females with HWD. The results showed significantly larger N2pc amplitudes were elicited by fat-related and thin-related words than neutral words only in the HWD group. Moreover, only fat-related words elicited a significant PD for the HWD group, and the PD amplitudes were larger in the HWD group than in the control group. These findings revealed that weight-related words initially captured spatial allocation among females with HWD, and then fat-related words were actively suppressed after the initial capturing.

Exploring the role of blood pressure in the black-white disparity in cardiovascular disease mortality: a causal mediation analysis.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death in the USA, and high blood pressure is a major risk factor for CVD. Despite the overall declining rates of CVD mortality in the USA in recent years, marked disparities between racial and ethnic groups persist, with black adults having a higher mortality rate than white adults. We investigated the extent to which blood pressure mediated the black-white disparity in CVD mortality. METHODS: Data came from the Multi-Ethnic Study of Atherosclerosis, a diverse longitudinal cohort. We included 1325 black and 2256 white community-based adults aged 45-80 years free of clinical CVD at baseline and followed for 14 years. We used causal mediation analysis to estimate the effect of race on CVD mortality that was mediated through blood pressure. RESULTS: Black participants had a higher hazard of dying from CVD compared with white participants (adjusted hazard ratio (HR): 1.28 (95% CI 0.88, 1.88)), though estimates were imprecise. Systolic blood pressure mediated 27% (HR: 1.02, 95% CI 1.00, 1.06) and diastolic blood pressure mediated 55% (HR: 1.07, 95% CI 1.01, 1.10) of the racial disparities in CVD mortality between white and black participants. Mediation effects were present in men but not in women. CONCLUSIONS: We found that black-white differences in blood pressure partially explain the observed black-white disparity in CVD mortality, particularly among men. Our findings suggest that public health interventions targeting high blood pressure prevention and management could be important strategies for reducing racial disparities in CVD mortality.

Influence of helicobacter pylori on composition and function of gastric microbiota in patients with chronic non-atrophic gastritis.

Objective: Helicobacter pylori (H. pylori) plays a major role in causing and advancing gastrointestinal illnesses. Our aim is to analyze the unique makeup and functional changes in the gastric microbiota of patients with chronic non-atrophic gastritis (CNAG), regardless of the presence of H. pylori, and to determine the potential signaling pathways. Methods: We performed metagenomic sequencing on gastric mucosa samples collected from 17 individuals with non-atrophic gastritis, comprising 6 cases were infected with H. pylori (H. pylori-infected case group) and 11 cases without (control group). The species composition was evaluated with DIAMOND software, and functional enrichment was assessed utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We analyzed antibiotic resistance patterns using the Comprehensive Antibiotic Resistance Database as a reference (CARD). Results: The presence of H. pylori colonization in CNAG patients was associated with increased diversity in the gastric microbiota. The Phylum Firmicutes was found to be less prevalent, while the Phylum Proteobacteria showed an increase. Functionally, pathways associated with metabolic pathways, including vitamins, auxiliaries, amino acid residue, carbon hydrate, and metabolic energy pathways, were enriched in CNAG patients with H. pylori infection. Additionally, antibiotic resistance genes correlated with antibiotic efflux pump were enriched. Conclusions: From a holistic genomic perspective, our findings offer fresh perspectives into the gastric microbiome among CNAG patients carrying H. pylori, which is valuable for future research on CNAG.

The road to evolution of ProTx2: how to be a subtype-specific inhibition of human Nav1.7.

The human voltage-gated sodium channel Nav1.7 is a widely proven target for analgesic drug studies. ProTx2, a 30-residue polypeptide from Peruvian green tarantula venom, shows high specificity to activity against human Nav1.7, suggesting its potential to become a non-addictive analgesic. However, its high sensitivity to human Nav1.4 raises concerns about muscle side effects. Here, we engineered three mutants (R13A, R13D, and K27Y) of ProTx2 to evaluate their pharmacological activities toward Nav1.7 and Nav1.4. It is demonstrated that the mutant R13D maintained the analgesic effect in mice while dramatically reducing its muscle toxicity compared with ProTx2. The main reason is the formation of a strong electrostatic interaction between R13D and the negatively charged amino acid residues in DII/S3-S4 of Nav1.7, which is absent in Nav1.4. This study advances our understanding and insights on peptide toxins, paving the way for safer, effective non-addictive analgesic development.

In vitro digestion mimicking conditions in adults and elderly reveals digestive characteristics of pork from different cooking ways.

This study aimed to investigate the impact of three cooking ways (sous vide (SV), frying (FR) and roasting (RO)) on pork protein digestion characteristics under conditions simulating healthy adult (control, C) and elderly individuals with achlorhydria (EA). Changes in degree of hydrolysis (DH), SDS-PAGE profiles, zeta potential, particle size and secondary structure during digestion were evaluated. Our results revealed the EA condition markedly affected the protein digestion process of pork with different cooking ways. The DH values of SV (25.62%), FR (21.38%) and RO (19.40%) under the EA condition were significantly lower than those of under the control condition (38.32%, 33.00% and 30.86%, respectively). Moreover, differences were also observed among three cooking ways under the EA condition. For a given cooking way, the differences between control and EA conditions gradually diminished from the gastric to the intestinal phase. Under a certain digestion condition, SV maintained the highest degree of digestion throughout the process, particularly under the EA condition. Therefore, we conclude that pork cooked by sous vide is more recommendable for the elderly considering protein digestibility.

Hygroscopic cooling (h-cool) fabric with highly efficient sweat evaporation and heat dissipation for personal thermo-moisture management.

Moisture evaporation plays a crucial role in thermal management of human body, particularly in perspiration process. However, current fabrics aim for sweat removal and takes little account of basic thermo-regulation of sweat, resulted in their limited evaporation capacity and heat dissipation at moderate/intense scenarios. In this study, a hygroscopic cooling (h-cool) fabric based on multi-functional design, for personal perspiration management, was described. By using economic and effective weaving technology, directional moisture transport routes and heat conductive pathways were incorporated in the construct. The resultant fabric showed 10 times greater one-way transport index higher than cotton, Dri-FIT and Coolswitch fabrics, which contributed to highly enhanced evaporation ability (∼4.5 times than cotton), not merely liquid diffusion. As a result, h-cool fabric performed 2.1-4.2 °C cooling efficacy with significantly reduced sweat consuming than cotton, Dri-FIT and Coolswitch fabrics in the artificial sweating skin. Finally, the practical applications by actually wearing h-cool fabric showed great evaporative-cooling efficacy during different physical activities. Owing to the excellent thermo-moisture management ability, we expect the novel concept and construct of h-cool fabric can provide promising strategy for developing functional textiles with great "cool" and comfortable "dry" tactile sensation at various daily scenarios.

Homotherapy-for-heteropathy of Bupleurum Chinense DC.-Scutellaria baicalensis Georgi in treating depression and colorectal cancer: A network pharmacology and animal model approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Bupleurum chinense DC.-Scutellaria baicalensis Georgi (BS) is a classic drug pair that has good clinical effects on depression and many tumors. However, the concurrent targeting mechanism of how the aforementioned drug pair is valid in the two distinct diseases, has not been clarified yet. AIM OF THE STUDY: The components of BS were detected by LC-MS, combined with network pharmacology to explore the active ingredients and common targeting mechanism of its multi-pathway regulation of BS in treating depression and CRC, and to validate the dual effects of BS using the CUMS mice model and orthotopic transplantation tumor mice model of CRC. RESULTS: Twenty-nine components were screened, 84 common gene targets were obteined, and the top 5 key targets including STAT3, PIK3R1, PIK3CA, AKT1, IL-6 were identified by PPI network. GO and KEGG analyses revealed that PI3K/AKT and JAK/STAT signaling pathways might play a crucial role of BS in regulating depression and CRC. BS significantly modulated CUMS-induced depressive-like behavior, attenuated neuronal damage, and reduced serum EPI and NE levels in CUMS model mice. BS improved the pathological histological changes of solid tumors and liver tissues and inhibited solid tumors and liver metastases in tumor-bearing mice. BS significantly decreased the proteins' expression of IL-6, p-JAK2, p-STAT3, p-PI3K, p-AKT1 in hippocampal tissues and solid tumors, and regulated the levels of IL-2, IL-6 and IL-10 in serum of two models of mice. CONCLUSION: BS can exert dual antidepressant and anti-CRC effects by inhibiting the expression of IL-6/JAK2/STAT3 and PI3K/AKT pathway proteins and regulating the release of inflammatory cytokines.

ZEB2 alleviates Hirschsprung's-associated enterocolitis by promoting the proliferation and differentiation of enteric neural precursor cells via the Notch-1/Jagged-2 pathway.

BACKGROUND: Hirschsprung's-associated enterocolitis (HAEC) is a prevalent complication of Hirschsprung's disease (HSCR). Zinc finger E-box binding homeobox 2 (ZEB2) and Notch-1/Jagged-2 are dysregulated in HSCR, but their role in HAEC progression remains poorly understood. We aimed to explore the role and underlying mechanism of enteric neural precursor cells (ENPCs) and the ZEB2/Notch-1/Jagged-2 pathway in HAEC development. METHODS: Colon tissues were collected from HSCR and HAEC patients. ENPCs were isolated from the HAEC group and stimulated by lipopolysaccharide (LPS). The expressions of ZEB2/Notch-1/Jagged-2 were measured using RT-qPCR and Western blot. Immunofluorescence and cell counting kit-8 assays were performed to assess the differentiation and proliferation of ENPCs. Inflammatory factors were measured by ELISA kits. Co-immunoprecipitation and bioinformatic analysis were used to explore the interaction between ZEB2 and Notch-1. Small interfering RNA and overexpression vectors were used to investigate the role and mechanism of ZEB2 and Notch-1 in regulating ENPCs' proliferation and differentiation during HAEC progression. RESULTS: We observed increased LPS in the colon tissues of HAEC, with downregulated ZEB2 expression and upregulated Notch-1/Jagged-2 expression. ZEB2 interacts with Notch-1. LPS treatment downregulated ZEB2 expression, upregulated Notch-1/Jagged-2 expression, and induced proliferation and differentiation disorders in ENPCs, which were reversed by the knockdown of Notch-1. Furthermore, overexpression of ZEB2 inhibited Notch-1/Jagged-2 signaling and ameliorated inflammation and dysfunction in LPS-induced ENPCs. Notch-1 overexpression enhanced LPS-induced dysfunction, but this effect was antagonized by the overexpression of ZEB2. CONCLUSION: Overexpression of ZEB2 ameliorates LPS-induced ENPCs' dysfunction via the Notch-1/Jagged-2 pathway, thus playing a role in HAEC.

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling.

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 µM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

ALKBH5 facilitates the progression of infantile hemangioma by increasing FOXF1 expression in a m6A-YTHDF2 dependent manner to activate HK-2 signaling.

Alkylation repair homolog protein 5 (ALKBH5) is reported to participate in infantile hemangioma (IH) progression. However, the underlying mechanism of ALKBH5 in IH remains unclear. Using qRT-PCR and Western blotting, ALKBH5, forkhead box F1 (FOXF1) and hexokinase 2 (HK-2) expressions in IH tissues and IH-derived endothelial cells XPTS-1 were assessed. The Me-RIP assay was used to analyze FOXF1 m6A level. CCK8, colony formation, flow cytometry and transwell assays were employed to determine IH cell viability, proliferation, apoptosis, migration and invasion. The interactions between YTH (YT521-B homology) domain 2 (YTHDF2), FOXF1 and HK-2 were analyzed by RIP, dual luciferase reporter gene assay and/or ChIP assay. The in vivo IH growth was evaluated in immunocompromised mice. FOXF1 was overexpressed in IH tissues, and its silencing inhibited IH cell proliferation, migration and invasion whereas promoting cell apoptosis in vitro. ALKBH5 upregulation facilitated FOXF1 mRNA stability and expression in IH cells in a m6A-YTHDF2-dependent manner. FOXF1 downregulation reversed the impact of ALKBH5 upregulation on IH cellular phenotypes. It also turned out that FOXF1 positively regulated HK-2 expression in IH cells through interacting with the HK-2 promoter. HK-2 upregulation abolished FOXF1 knockdown's inhibition on IH cell aggressive behaviors. ALKBH5 or FOXF1 silencing suppressed IH tumor development via HK-2 signaling in immunocompromised mice. ALKBH5 promoted FOXF1 expression m6A-YTHDF2 dependently, which in turn elevated HK-2 expression, thereby accelerating IH development.