Safranal alleviates pentetrazole-induced epileptic seizures in mice by inhibiting the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3ß inactivation.

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron, a traditional Chinese medicine, is derived from Crocus sativus L. stigmas and has been reported to possess neuroprotective properties and potentially contribute to the inhibition of apoptosis and inflammation. Safranal, a potent monothyral aldehyde, is a main component of saffron that has been reported to have antiepileptic activity. However, the specific mechanism by which safranal suppresses epileptic seizures via its antiapoptotic and anti-inflammatory properties is unclear. AIM: To evaluate the effect of safranal on seizure severity, inflammation, and postictal neuronal apoptosis in a mouse model of pentetrazole (PTZ)-induced seizures and explore the underlying mechanism involved. MATERIALS AND METHODS: The seizure stage and latency of stage 2 and 4 were quantified to assess the efficacy of safranal in mitigating PTZ-induced epileptic seizures in mice. Electroencephalography (EEG) was employed to monitor epileptiform afterdischarges in each experimental group. The cognitive abilities and motor functions of the mice were evaluated using the novel object recognition test and the open field test, respectively. Neurons were quantified using hematoxylin and eosin staining. Additionally, bioinformatics tools were utilized to predict the interactions between safranal and specific target proteins. Glycogen synthase kinase-3ß (GSK-3ß), mitochondrial apoptosis-related proteins, and inflammatory factor levels were analyzed through western blotting. Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) concentrations in brain tissue were assessed by ELISA. RESULTS: Safranal decreased the average seizure stage and increased the lantency of stage 2 and 4 seizures in PTZ-induced epileptic mice. Additionally, safranal exhibited neuroprotective effects on hippocampal CA1 and CA3 neurons and reduced hyperactivity caused by postictal hyperexcitability. Bioinformatics analysis revealed that safranal can bind to five specific proteins, including GSK-3ß. By promoting Ser9 phosphorylation and inhibiting GSK-3ß activity, safranal effectively suppressed the NF-κB signaling pathway. Moreover, the findings indicate that safranal treatment can decrease TNF-α and IL-1ß levels in the cerebral tissues of epileptic mice and downregulate mitochondrial apoptosis-related proteins, including Bcl-2, Bax, Bak, Caspase 9, and Caspase 3. CONCLUSION: Safranal can suppress the NF-κB signaling pathway and mitochondrial-dependent apoptosis through GSK-3ß inactivation, suggesting that it is a promising therapeutic agent for epilepsy treatment.

Effects of riparian pioneer plants on soil aggregate stability: Roles of root traits and rhizosphere microorganisms.

Pioneer plants are vital in stabilizing soil structure while restoring reservoir drawdown areas. However, uncertainties persist regarding the mechanism of pioneer plants to soil stability in these delicate ecosystems. This study aims to unravel the plant-soil feedback mechanisms from the roles of root traits and rhizosphere microorganisms. We conducted a mesocosm experiment focusing on four common pioneer plants from the drawdown area of Three Gorges Reservoir, China. Using the wet sieving methodology, trait-based approach and high-throughput sequencing technology, we explored soil aggregate stability parameters, plant root traits and rhizosphere microbial communities in experimental plant groups. The interacting effect of pioneer plant species richness, root traits, and rhizosphere microbial communities on soil aggregate stability was quantified by statistical models. Our results demonstrate that diverse pioneer plant communities significantly enhance soil aggregate stability. Notably, specific species, such as Cynodon dactylon (L.) Pers and Xanthium strumarium L, exert a remarkably strong influence on soil stability due to their distinctive root traits. Root length density (RLD) and root specific surface area (RSA) were identified as crucial root traits mediating the impact of plant diversity on soil aggregate stability. Additionally, our study highlights the link between increased rhizosphere fungal richness, accompanied by plant species richness, and enhanced soil aggregate stability, likely attributable to elevated RLD and RSA. These insights deepen our understanding of the role of pioneer vegetation in soil structure and stability, providing valuable implications for ecological restoration and management practices in reservoir drawdown areas.

Corrigendum: Investigating the dynamic responses of Aegilops tauschii Coss. to salinity, drought, and nitrogen stress: a comprehensive study of competitive growth and biochemical and molecular pathways.

[This corrects the article DOI: 10.3389/fpls.2023.1238704.].

Targeting lipid reprogramming in the tumor microenvironment by traditional Chinese medicines as a potential cancer treatment.

In the last ten years, there has been a notable rise in the study of metabolic abnormalities in cancer cells. However, compared to glucose or glutamine metabolism, less attention has been paid to the importance of lipid metabolism in tumorigenesis. Recent developments in lipidomics technologies have allowed for detailed analysis of lipid profiles within cancer cells and other cellular players present within the tumor microenvironment (TME). Traditional Chinese medicine (TCM) and its bioactive components have a long history of use in cancer treatments and are also being studied for their potential role in regulating metabolic reprogramming within TME. This review focuses on four core abnormalities altered by lipid reprogramming in cancer cells: de novo synthesis and exogenous uptake of fatty acids (FAs), upregulated fatty acid oxidation (FAO), cholesterol accumulation, which offer benefits for tumor growth and metastasis. The review also discusses how altered lipid metabolism impacts infiltrating immune cell function and phenotype as these interactions between cancer-stromal become more pronounced during tumor progression. Finally, recent literature is highlighted regarding how cancer cells can be metabolically reprogrammed by specific Chinese herbal components with potential therapeutic benefits related to lipid metabolic and signaling pathways.

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.

Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.

Preparation and Performance Evaluation of a Zinc Oxide-Graphene Oxideloaded Chitosan-Based Thermosensitive Gel.

This study aimed to develop and assess a chitosan biomedical antibacterial gel ZincOxideGrapheneOxide/Chitosan/ß-Glycerophosphate (ZnO-GO/CS/ß-GP) loaded with nano-zinc oxide (ZnO) and graphene oxide (GO), known for its potent antibacterial properties, biocompatibility, and sustained drug release. ZnO nanoparticles (ZnO-NPs) were modified and integrated with GO sheets to create 1% and 3% ZnO-GO/CS/ß-GP thermo-sensitive hydrogels based on ZnO-GO to Chitosan (CS) mass ratio. Gelation time, pH, structural changes, and microscopic morphology were evaluated. The hydrogel's antibacterial efficacy against Porphyromonas gingivalis, biofilm biomass, and metabolic activity was examined alongside its impact (MC3T3-e1). The findings of this study revealed that both hydrogel formulations exhibited temperature sensitivity, maintaining a neutral pH. The ZnO-GO/CS/ß-GP formulation effectively inhibited P. gingivalis bacterial activity and biofilm formation, with a 3% ZnO-GO/CS/ß-GP antibacterial rate approaching 100%. MC3T3-e1 cells displayed good biocompatibility when cultured in the hydrogel extract.The ZnO-GO/CS/ß-GP thermo-sensitive hydrogel demonstrates favorable physical and chemical properties, effectively preventing P. gingivalis biofilm formation. It exhibits promising biocompatibility, suggesting its potential as an adjuvant therapy for managing and preventing peri-implantitis, subject to further clinical investigations.

Effect of osmotic pressure and simultaneous heat-moisture phosphorylation treatments on the physicochemical properties of mung bean, water caltrop, and corn starches.

This study aimed to investigate the physicochemical properties of modified starch prepared through the simultaneous heat-moisture and phosphorylation treatment (HMPT) and osmotic pressure treatment (OPT) for water caltrop starch (WCS), mung bean starch (MBS), and amylose-rich corn starch (CS) for different time periods. Furthermore, variations in starch content [amylose and resistant starch (RS)], swelling powder (SP), water solubility index (WSI), crystallinity, thermal properties, gelatinization enthalpy (ΔH), and glycemic index (GI) were examined. This study demonstrates that neither HMPT nor OPT resulted in a significant increase in the resistant starch (RS) content, whereas all samples succeeded in heat-treating at 105 °C for another 10 min exhibited a significant increase in RS content compared to their native counterparts. Moreover, the gelatinization temperatures of the three starches increased (To, Tp, and Tc), whereas their gelatinization enthalpy (ΔH) and pasting viscosity decreased. In particular, the GI of all three modified starches subjected to HMPT or OPT showed a decreasing trend with modification time, with OPT exhibiting the best effect. Therefore, appropriate modification through HMPT or OPT is a viable approach to develop MBS, WCS, and CS as processed foods with low GI requirements, which exceptionally may be suitable for canned foods, noodles, and bakery products.

Berberine inhibits the malignant cell phenotype by inactivating PI3K/AKT/mTOR signaling in laryngeal squamous cell carcinoma.

BACKGROUND: Berberine is an active compound found in different herbs used in Chinese medicine and is well-known for its potential anticancer properties. The study aimed to figure out the role of berberine in regulating the malignant behavior of laryngeal squamous cell carcinoma (LSCC) cells. METHODS: LSCC cell lines (SNU-899 and AMC-HN-8) were treated with different concentrations of berberine (0-200 µM) to determine its cytotoxicity. The migration, invasion, and apoptosis of LSCC cells were measured by wound healing assays, Transwell assays, and flow cytometry. Western blot was performed for the quantification of proteins involved in PI3K/AKT/mTOR signaling. RESULTS: The viability of LSCC cells was dose-dependently reduced by berberine. Berberine dampened LSCC cell migration and invasion while augmenting cell apoptosis, as evidenced by a reduced wound closure rate, a decrease in invaded cell number, and a surge in cell apoptosis in the context of berberine stimulation. Importantly, the effects of berberine on the cancer cell process were enhanced by LY294002 (an inhibitor for PI3K) treatment. Moreover, the protein levels of phosphorylated PI3K, AKT, and mTOR were markedly reduced in response to berberine treatment. CONCLUSION: Berberine inhibits cell viability, migration, and invasion but augments cell apoptosis by inactivating PI3K/AKT/mTOR signaling in LSCC.

Magnetic leakage behavior assessment in pipeline stress-concentrated areas using improved force-magnetic coupling model.

Magnetic flux leakage (MFL) technology is remarkable for its capability to detect pipeline geometric deformation and general corrosion defects. However, it cannot characterize the MFL behavior in stress-concentrated areas, thereby greatly challenging the subsequent pipeline maintenance. This study suggests that the MFL characteristics of pipeline in stress-concentrated areas are caused by the combined effect of the face magnetic charge on the deformed end-face and the body magnetic charge of the dislocation stack. In addition, an improved force-magnetic coupling model of the pipeline in stress-concentrated areas is established based on the magnetic dipole model and Jiles-Atherton (J-A) theory. In the verification experiment, the Q235 steel plate is magnetized along the extension direction (axis of the pipeline) through the solenoid coil to obtain the distribution law of the MFL signal in the stress-concentrated area under different excitation intensities. The results show that with the increase in excitation intensity, the deformation of the MFL field signal caused by the end-face of the stress-concentrated area gradually increases to a stable state. Moreover, the internal stress of the MFL field signal generated by the pipe dislocation rapidly increases to a peak value and then decays exponentially to a certain base value. The overall change trend is in good agreement with the calculation results of the established force-magnetic coupling model. Meanwhile, the differentiation research between deformation and internal stress MFL field signals under different magnetic field intensities can provide a reliable theoretical basis for the subsequent accurate identification and quantification of pipeline stress-concentrated areas.

Low preoperative serum uric acid is associated with early acute kidney injury after living donor liver transplantation.

BACKGROUND: Liver transplantation is treatment option for patients with end stage liver disease and hepatocellular carcinoma. Renal function deterioration significantly impacts the survival rates of liver recipients, and serum uric acid (SUA) is associated with both acute and chronic renal function disorders. Thus, our study aimed to assess the relationship and predictive value of preoperative SUA level and postoperative acute kidney injury (AKI) in living donor liver transplantation (LDLT). METHODS: We conducted a prospective observational study on 87 patients undergoing LDLT. Blood samples were collected immediately prior to LDLT, and renal function status was followed up for 3 consecutive days postoperatively. RESULTS: Low SUA levels (cutoff value 4.15 mg/dL) were associated with a high risk of early post-transplantation AKI. The area under the curve was 0.73 (sensitivity, 79.2%; specificity, 59.4%). Although not statistically significant, there were no deaths in the non-AKI group but two in the early AKI group secondary to liver graft dysfunction in addition to early AKI within the first month after LDLT. CONCLUSION: AKI after liver transplantation may lead to a deterioration of patient status and increased mortality rates. We determined low preoperative SUA levels as a possible risk factor for early postoperative AK.

NEK2 promotes TP53 ubiquitination to enhance the proliferation and migration of TP53 wild-type glioblastoma cells.

The most common primary malignant tumor in the adult brain is glioblastoma multiforme (GBM); however, its underlying pathogenic mechanism remains elusive. The never in mitosis (NIMA)-related kinase 2 (NEK2) has been closely associated with the prognosis of various malignancies. Nevertheless, the complete elucidation of NEK2's potential clinical value, particularly in glioma prognosis and development, remains lacking. U87MG and A172 glioblastoma cells were infected with sh-NEK2 lentivirus or oe-NEK2 plasmid to investigate the effect of NEK2 on cell proliferation, migration, and invasion. Cell viability was measured using CCK-8 and colony formation assays, while Transwell assay was utilized to assess cell migration and invasion. Protein expression levels were determined through western blot analysis. Additionally, CGGA and TCGA databases were used for bioinformatics analysis in order to examine the NEK2 expression. Through comprehensive bioinformatics analysis, we identified elevated mRNA expression levels of NEK2 in gliomas compared to normal tissues, which correlated with poor prognosis among glioma patients. Moreover, functional experiments revealed that silencing NEK2 suppressed glioma cell proliferation while overexpression of NEK2 promoted migration and invasion capabilities. Finally, our study uncovered that NEK2 regulates the malignant progression of TP53 wild-type glioblastoma by facilitating TP53 ubiquitination.

Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.

Immune checkpoint inhibitors as the second-line treatment for advanced esophageal squamous cell carcinoma: a cost-effectiveness analysis based on network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated superior clinical efficacy in prolonging overall survival (OS) as the second-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), and were recommended by the guidelines. However, it remains uncertain which ICI is the most cost-effective. This study assessed the cost-effectiveness of ICIs as the second-line treatment for ESCC based on the perspective of the Chinese healthcare system. METHODS: A network meta-analysis (NMA) was performed to obtain the Hazard ratios (HRs) for indirect comparisons. A three-state Markov model with a 10-year time horizon was conducted to assess the cost-effectiveness. The state transition probabilities were calculated with Kaplan-Meier (KM) curves data from clinical trial and HRs from the NMA. Utilities and costs were derived from local charges or previously published studies. Univariate and probabilistic sensitivity analyses (PSA) were performed to examine model robustness. The results were assessed based on the total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Five clinical trials (ATTRACTION-3, ESCORT, KEYNOTE-181, ORIENT-2, RATIONALE-302) with a total of 1797 patients were included in the NMA. The NMA showed that both camrelizumab and tislelizumab received relatively high rankings for progression-free survival (PFS) and OS. Compared with sintilimab, treatment with tislelizumab and camrelizumab gained 0.018 and 0.034 additional QALYs, resulting in incremental ICERs of $75,472.65/QALY and $175,681.9/QALY, respectively. Nivolumab and pembrolizumab produced lower QALYs and greater costs, suggesting that both were dominated in comparison to sintilimab. HRs and health state utilities were the most influential parameters in most univariate sensitivity analyses of paired comparisons. PSA results suggested that sintilimab had an 84.4% chance of being the most cost-effective treatment regimen at the WTP threshold of $38,223.34/QALY. In the scenario analysis, sintilimab would no longer be cost-effective, if the price of camrelizumab was assumed to decrease by 64.6% or the price of tislelizumab was assumed to decrease by 16.9%. CONCLUSIONS AND RELEVANCE: Among the five potential competing ICIs, sintilimab was likely to be the most cost-effective regimen as the second-line treatment for locally advanced or metastatic ESCC in China.

Dabrafenib alleviates hepatotoxicity caused by lenvatinib via inhibiting the death receptor signaling pathway.

Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.

Corrigendum: Investigating the dynamic responses of Aegilops tauschii Coss. to salinity, drought, and nitrogen stress: a comprehensive study of competitive growth and biochemical and molecular pathways.

[This corrects the article DOI: 10.3389/fpls.2023.1238704.].

Artificial neural network optimisation of natural deep eutectic solvent extraction process of Danshen-Gegen and cytotoxicity study.

Natural deep eutectic solvents (NaDESs) are environmentally friendly and efficient for the componential extraction of traditional Chinese medicine compared to conventional organic solvents. In this study, NaDES was screened and employed to extract Danshen-Gegen (DG), and the extraction process was optimised by response surface methodology (RSM) and artificial neural networks (ANN) model. Besides, the in vitro security of extracts of DG were evaluated in PC12 cells. As a result, Betaine-Urea (Bet-Ur) was screened as extraction solvent and ANN model was more accurate than RSM model in optimising the extraction parameter. The extraction process optimised by ANN was as follows: 70% NaDES concentration, 80 mg/mL solid to liquid ratio, 67 °C ultrasonic temperature, and 33 min of ultrasonic time. The comprehensive value of extraction yield was 0.7251 ± 0.84%. IC50 of Bet-Ur, NaDES DG extract and aqueous DG extract were 0.15%, 0.3% and 10% (v/v).

Inhibition of flowering by gibberellins in the woody plant Jatropha curcas is restored by overexpression of JcFT.

Jatropha curcas (J. curcas) is a perennial oil-seed plant with vigorous vegetative growth but relatively poor reproductive growth and low seed yield. Gibberellins (GAs) promotes flowering in most annual plants but inhibits flowering in many woody plants, including J. curcas. However, the underlying mechanisms of GA inhibits flowering in perennial woody plants remain unclear. Here, we found that overexpression of the GA biosynthesis gene JcGA20ox1 inhibits flowering in J. curcas and in J. curcas × J. integerrima hybrids. Consistent with this finding, overexpression of the GA catabolic gene JcGA2ox6 promotes flowering in J. curcas. qRTPCR revealed that inhibits floral transition by overexpressing JcGA20ox1 resulted from a decrease in the expression of JcFT and other flowering-related genes, which was restored by overexpressing JcFT in J. curcas. Overexpression of JcGA20ox1 or JcGA2ox6 reduced seed yield, but overexpression of JcFT significantly increased seed yield. Furthermore, hybridization experiments showed that the reduction in seed yield caused by overexpression of JcGA20ox1 or JcGA2ox6 was partially restored by the overexpression of JcFT. In addition, JcGA20ox1, JcGA2ox6 and JcFT were also found to be involved in the regulation of seed oil content and endosperm development. In conclusion, our study revealed that the inhibitory effect of GA on flowering is mediated through JcFT and demonstrated the effects of JcGA20ox1, JcGA2ox6 and JcFT on agronomic traits in J. curcas. This study also indicates the potential value of GA metabolism genes and JcFT in the breeding of new varieties of woody oil-seed plants.

The association in diabetic retinopathy and stroke finding from NHANES evidence.

PURPOSE: Diabetic retinopathy and stroke are both vascular pathologies, and this study intends to investigate the relationship between diabetic retinopathy and stroke. METHODS: The NHANES database was used to find the relationship between diabetic retinopathy and stroke with 1948 individuals aged 40 years or older. The sensitivity of the data was verified by multiple interpolation, further analysis was done by subgroup analyses, and possible links were investigated with mediation studies. RESULTS: Diabetes retinopathy was found to be closely associated with stroke, with the PDR group having a higher stroke incidence than the NPDR group. After controlling for covariates, there were still substantial differences in the risk of stroke among patients with NPDR and PDR. Overall, subgroup analysis revealed DR group showed an important distinction, compared to the non-DR (OR = 1.76, 95% CI 1.15-2.64). The results of the mediation research indicated that the connection between DR and stroke was mediated by the frailty index and hypertension. CONCLUSION: This study demonstrated a statistically significant correlation between DR and stroke, which persisted even after DR staging and was more prevalent in PDR patients than in NPDR patients. Stroke prevention may benefit from DR health management.

Peptide Transporter 1-Mediated Dipeptide Transport Promotes Hepatocellular Carcinoma Metastasis by Activating MAP4K4/G3BP2 Signaling Axis.

Cancer metastasis is the leading cause of mortality in patients with hepatocellular carcinoma (HCC). To meet the rapid malignant growth and transformation, tumor cells dramatically increase the consumption of nutrients, such as amino acids. Peptide transporter 1 (PEPT1), a key transporter for small peptides, has been found to be an effective and energy-saving intracellular source of amino acids that are required for the growth of tumor cells. Here, the role of PEPT1 in HCC metastasis and its underlying mechanisms is explored. PEPT1 is upregulated in HCC cells and tissues, and high PEPT1 expression is associated with poor prognosis in patients with HCC. PEPT1 overexpression dramatically promoted HCC cell migration, invasion, and lung metastasis, whereas its knockdown abolished these effects both in vitro and in vivo. Mechanistic analysis revealed that high PEPT1 expression increased cellular dipeptides in HCC cells that are responsible for activating the MAP4K4/G3BP2 signaling pathway, ultimately facilitating the phosphorylation of G3BP2 at Thr227 and enhancing HCC metastasis. Taken together, these findings suggest that PEPT1 acts as an oncogene in promoting HCC metastasis through dipeptide-induced MAP4K4/G3BP2 signaling and that the PEPT1/MAP4K4/G3BP2 axis can serve as a promising therapeutic target for metastatic HCC.