Elucidating salt-reduction mechanisms of aroma-active compounds from yeast extracts through sensomics approaches and electroencephalography.

This study investigated the savory intensity of aroma-active compounds derived from yeast extract Maillard reaction models. Sensory evaluation results revealed that beef flavoring model (28.00 g) exhibited the highest savory perception intensity when the yeast extract FA34 (0.50 g) the added. Eleven aroma-active compounds associated with saltiness perception were identified via solid-phase microextraction and extraction combined with gas chromatography-mass spectrometry/olfactory. The odorant-NaCl mixture model and saltiness intensity evaluation results revealed that thiazole and 4-methylpentanoic acid could significantly (p < 0.05) enhance the saltiness perception of salt solution (5.00 g/L), 2-methylpyrazine, 2-methyl-3-furanthiol, 2,6-dimethylpyrazine, furfuryl mercaptan, and methyl 2-methyl-3-furyl disulfide could significantly (p < 0.01) enhance the saltiness perception of a salt solution (5.00 g/L). Electroencephalography revealed that the main mechanisms underlying aroma-induced saltiness perception enhancement included the strengthening of the saltiness perception signal and prolonging signal stimulation time in the frontal regions of the cerebral cortex.

Discovery of Selective Proteolysis-Targeting Chimera Degraders Targeting PTP1B as Long-Term Hypoglycemic Agents.

PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.

Effectiveness and safety of PD-1/PD-L1 inhibitors monotherapy in patients with endometrial cancer.

BACKGROUND: Studies evaluating the effectiveness of immune checkpoint inhibitors (ICI) for endometrial cancer (EC) are limited. This study aimed to assess the efficacy of PD-1/PD-L1 inhibitors as monotherapy for EC by conducting a meta-analysis. The predictive significance of MMR status, a biomarker for ICI response, also required further investigation. METHODS: A systematic literature search was conducted in English databases until September 2023. The analysis included objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and odds ratios (OR), along with their corresponding 95% confidence intervals (CI). RESULTS: There were twelve trials totaling 685 individuals. PD-1/PD-L1 inhibitor monotherapy resulted in an ORR for 34% (95% CI = 24-44%) of the pooled EC patients. Subgroup analysis revealed a significantly higher ORR in dMMR EC (45%) compared to pMMR EC (8%), with an OR of 6.36 (95% CI = 3.64-11.13). The overall DCR was 42%, with dMMR EC at 51% and pMMR EC at 30% (OR = 2.61, 95% CI = 1.69-4.05). Grade three or higher adverse events (AEs) occurred in 15% of cases (95% CI = 9-24%) of the pooled incidence of AEs, which was 68% (95% CI = 65-72%). CONCLUSIONS: This meta-analysis provides significant evidence for the effectiveness of PD-1/PD-L1 inhibitors as monotherapy for EC. Notably, dMMR EC patients demonstrated superior treatment efficacy with PD-1/PD-L1 inhibitor immunotherapy. Further research is required to explore subclassifications of EC based on dMMR molecular subtypes, enabling improved treatment strategies and outcomes for EC patients.

Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders.

Dysfunction of brain resting-state functional networks has been widely reported in psychiatric disorders. However, the causal relationships between brain resting-state functional networks and psychiatric disorders remain largely unclear. Here we perform bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causalities between 191 resting-state functional magnetic resonance imaging (rsfMRI) phenotypes (n = 34,691 individuals) and 12 psychiatric disorders (n = 14,307 to 698,672 individuals). Forward MR identified 8 rsfMRI phenotypes causally associated with the risk of psychiatric disorders. For example, the increase in the connectivity of motor, subcortical-cerebellum and limbic network was associated with lower risk of autism spectrum disorder. In adddition, increased connectivity in the default mode and central executive network was associated with lower risk of post-traumatic stress disorder and depression. Reverse MR analysis revealed significant associations between 4 psychiatric disorders and 6 rsfMRI phenotypes. For instance, the risk of attention-deficit/hyperactivity disorder increases the connectivity of the attention, salience, motor and subcortical-cerebellum network. The risk of schizophrenia mainly increases the connectivity of the default mode and central executive network and decreases the connectivity of the attention network. In summary, our findings reveal causal relationships between brain functional networks and psychiatric disorders, providing important interventional and therapeutic targets for psychiatric disorders at the brain functional network level.

Preparation of Lanthanum-Modified Tea Waste Biochar and Its Adsorption Performance on Fluoride in Water.

In this study, tea waste was used as a raw material, and TBC (tea waste biochar) was prepared by pyrolysis at 700 °C. La(NO3)3·6H2O was used as the modifier to optimize one-way modification; the orthogonal experiment was undertaken to determine the optimal preparation conditions; and La-TBC (lanthanum-modified biochar) was obtained. The key factors for the adsorption of fluoride by La-TBC were investigated by means of batch adsorption experiments, and kinetics and isothermal adsorption experiments were carried out on the adsorption of fluoride in geothermal hot spring water. The adsorption mechanism of fluoride by La-TBC was analyzed via characterization methods such as SEM-EDS (Scanning Electron Microscope and Energy Dispersive Spectrometer), BET (Brunauer-Emmett-Teller), FTIR (Fourier transform infrared), XRD (X-ray diffraction), and so on. The results show that La-TBC had the best adsorption effect on fluoride at pH 7. The process of adsorption of fluoride follows the pseudo-second-order kinetics and Langmuir isothermal model, and the maximum theoretical adsorption quantity was 47.47 mg/g at 80 °C, while the removal rate of fluoride from the actual geothermal hot spring water reached more than 95%. The adsorption process was dominated by the monolayer adsorption of chemicals, and the mechanisms mainly include pore filling, ion exchange, and electrostatic interaction.

[Vertebral fractures combined with prolonged activated partial prothrombin time: A case report].

With the development of modern medical standards, autoimmune diseases and their associated successive osteoporosis have received increasing attention in recent years. Patients with autoimmune diseases, due to the characteristics of the disease and the prolonged use of glucocorticoid hormone therapy, may affect the bone formation and bone absorption of the patient, followed by severe successive osteoporosis, thereby increasing the risk of osteoporotic vertebral fractures. Vertebral compression fractures of the spine are common fracture types in patients with osteoporotic fractures. Osteoporosis is a common complication after glucocorticoid therapy in patients with autoimmune diseases. Percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) are minimally invasive operation and are commonly used surgical methods for the treatment of osteoporotic vertebral compression fractures. However, due to the operation of spinal puncture during the operation, there are serious surgical risks such as bone cement leakage, spinal epidural hemorrhage, subdural hemorrhage, and subarachnoid hemorrhage in both PVP and PKP. As a result, it is necessary to evaluate the patient' s body before surgery carefully, especially in the case of blood coagulation. This article reports a case of autoimmune disease patient admitted to Peking University People' s Hospital due to lumbar 4 vertebral compression fracture combined with Sjögren' s syndrome. The patient' s preoperative examination showed that the activated partial thromboplastin time (APTT) was significantly prolonged. After completing the APTT extended screening experiment and lupus anticoagulant factor testing, the multi-disciplinary team (MDT) of Peking University People' s Hospital jointly discussed the conclusion that the patient' s test results were caused by an abnormal self-immunity anti-copulant lupus (LAC). Based on the results of the laboratory examination, the patient was considered to be diagnosed with combined antiphospholipid syndrome (APS). For such patients, compared with the patient' s tendency to bleed, we should pay more attention to the risk of high blood clotting in the lower limbs of the patient, pulmonary clots and so on. With timely anti-coagulation treatment, the patient safely passed the peripheral period and was successfully discharged from the hospital. Therefore, for patients with autoimmune diseases with prolonged APTT in the perioperative period, doctors need to carefully identify the actual cause and carry out targeted treatment in order to minimize the risk of surgical and perioperative complications and bring satisfactory treatment results to the patients.

Human umbilical cord-derived mesenchymal stem cells and auto-crosslinked hyaluronic acid gel complex for treatment of intrauterine adhesion.

OBJECTIVE: The purpose of this study was to explore the therapeutic characteristics of mesenchymal stem cells generated from human umbilical cord (hUC-MSCs) when utilized in conjunction with auto-crosslinked hyaluronic acid gel (HA-gel) for the management of intrauterine adhesion (IUA). The goal was to see how this novel therapy could enhance healing and improve outcomes for IUA patients. METHODS: In this study, models of intrauterine adhesion (IUA) were established in Sprague-Dawley (SD) rats, which were then organized and divided into hUC-MSCs groups. The groups involved: hUC-MSCs/HA-gel group, control group, and HA-gel group. Following treatment, the researchers examined the uterine cavities and performed detailed analyses of the endometrial tissues to determine the effectiveness of the interventions. RESULTS: The results indicated that in comparison with to the control group, both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel groups showed partial repair of IUA. However, in a more notable fashion transplantation of hUC-MSCs/HA-gel complex demonstrated significant dual repair effects. Significant outcomes were observed in the group treated with hUC-MSCs and HA-gel, they showed thicker endometrial layers, less fibrotic tissue, and a higher number of endometrial glands. This treatment strategy also resulted in a significant improvement in fertility restoration, indicating a profound therapeutic effect. CONCLUSIONS: The findings of this study suggest that both HA-gel, hUC-MSCs, and hUC-MSCs/HA-gel complexes have the potential for partial repair of IUA and fertility restoration caused by endometrium mechanical injury. Nonetheless, the transplantation of the hUC-MSCs/HA-gel complex displayed exceptional dual healing effects, combining effective anti-adhesive properties with endometrial regeneration stimuli.

Corrigendum: Lower serum insulin-like growth factor 2 level in patients with bipolar disorder is associated with the severity of manic symptoms during manic episodes.

[This corrects the article DOI: 10.3389/fpsyt.2024.1354999.].

Lower serum insulin-like growth factor 2 level in patients with bipolar disorder is associated with the severity of manic symptoms during manic episodes.

Objective: Accumulating evidence has indicated that neurodevelopmental defects may underlie the pathophysiology of bipolar disorder (BD). Insulin-like growth factors (IGFs) are a family of neurotrophic factors that are essential for the survival and development of neurons. The present study aims to investigate whether IGF-2 signaling is implicated in the pathophysiological processes of BD. Method: 50 healthy controls and 78 patients with BD, including 23 patients who diagnosed acute depressive episode and 55 patients who diagnosed acute manic episode, were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) were used to assess the severity of the depressive and manic symptoms, respectively. The serum IGF-2 level was determined by an enzyme-linked immunosorbent assay (ELISA). The Kolmogorov-Smirnov and Mann-Whitney U tests were used for between-group comparisons and spearman analysis was used to analyze correlations. Results: Patients with BD had lower serum IGF-2 levels (66.08 ± 21.22 ng/ml) when compared to healthy controls (88.72 ± 31.55 ng/ml). BD patients were divided into manic episode and depressive episode subgroups. We found that serum IGF-2 levels were reduced in both the mania and depression subgroups (mania: 67.19 ± 21.52 ng/ml, depression: 63.43 ± 20.67 ng/ml; P < 0.001), while no significant difference was observed between two groups (P > 0.05). Spearman correlation analyses revealed that the levels of serum IGF-2 were negatively correlated with the YMRS scores in BD patients (r = -0.522, P < 0.001). Furthermore, IGF-2 was found to be an independent contributor to the severity of symptoms in patients with manic episodes (B = -0.610, t = -5.299, P < 0.001). Conclusion: Lower serum IGF-2 levels were found in BD patients and correlated with the severity of the manic symptoms in these patients during manic episodes. These results suggest that reduced IGF-2 levels might be involved in the pathophysiology of BD, and serum IGF-2 could be a peripheral biomarker for the evaluation of the severity of manic symptoms in BD patients.

Development of a nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis.

In this study, we aimed to investigate the risk factors associated with in-hospital mortality in patients with cirrhosis and sepsis, establish and validate the nomogram. This retrospective study included patients diagnosed with liver cirrhosis and sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV). Models were compared by the area under the curve (AUC), integrated discriminant improvement (IDI), net reclassification index (NRI) and decision curve analysis (DCA). A total of 1,696 patients with cirrhosis and sepsis were included in the final cohort. Our final model included the following 9 variables: age, heartrate, total bilirubin (TBIL), glucose, sodium, anion gap (AG), fungal infections, mechanical ventilation, and vasopressin. The nomogram were constructed based on these variables. The AUC values of the nomograms were 0.805 (95% CI 0.776-0.833), which provided significantly higher discrimination compared to that of SOFA score [0.684 (95% CI 0.647-0.720)], MELD-Na [0.672 (95% CI 0.636-0.709)] and ABIC [0.674(95% CI 0.638-0.710)]. We established the first nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis based on these factors. This nomogram can performs well and facilitates clinicians to identify people at high risk of in-hospital mortality.

Synthesis and Neuroprotective Evaluation of Substituted Indanone/Benzofuranone and Piperidine Hybrids.

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

Nanomaterials in crossroad of autophagy control in human cancers: Amplification of cell death mechanisms.

Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.

The Causal Relationship between Angina Pectoris and Gout Based on Two Sample Mendelian Randomization.

Purpose: Two-sample Mendelian randomization (MR) was conducted to assess the causal relationship between angina pectoris and gout. Material and Methods. Based on genome-wide association studies, single nucleotide polymorphisms (SNPs) that were closely associated with gout were selected from the UK Biobank-Neale Lab (ukb-a-107) as genetic instrumental variables. Considering that gout is characterized by elevated blood uric acid levels, SNPs related to blood uric acid levels were screened from BioBank Japan (bbj-a-57) as auxiliary gene instrumental variables. SNPs closely associated with angina pectoris onset were screened from the FINN dataset (finn-b-I9_ANGINA) as outcome variables. Two-sample MR was conducted, with inverse variance weighting (IVW) of the random effects model as the primary result, along with the weighted median method (WME) and the MR-Egger regression method. To further confirm the causal relationship between angina and gout incidence, a meta-analysis was conducted on the IVW results of the ukb-a-107 and bbj-a-57. Results: The odds ratios and 95% confidence intervals of the IVW, WME, and MR-Egger results of ukb-a-107 were (OR = 33.72; 95% CI: 2.07∼550.38), (OR = 57.94; 95% CI: 2.75∼1219.82), and (OR = 96.38; 95% CI: 0.6∼15556.93), respectively. The P values of IVW and WME were 0.014 and 0.014 (both <0.05), respectively, indicating that the development of angina pectoris was significantly associated with the incidence of gout. The odds ratios and 95% confidence intervals of the IVW, WME, and MR-Egger about bbj-a-57 were (OR = 1.20; 95% CI: 1.07∼1.34), (OR = 1.19; 95% CI: 1.02∼1.38), and (OR = 1.30; 95% CI; 1.06∼1.60), respectively. The P values of IVW, WME and MR-Egger were 0.001, 0.027 and 0.017 (all <0.05), respectively, indicating a significant correlation between angina and blood uric acid levels. Scatter plots of ukb-a-107 and bbj-a-57 showed that the causal association estimates of the IVW, MR-Egger, and weighted median methods were similar and that the MR results were accurate. Funnel plots and the MR-Egger intercept of ukb-a-107 and bbj-a-57 showed the absence of horizontal pleiotropy. The leave-out sensitivity analysis results of ukb-a-107 and bbj-a-57 are stable. The meta-analysis of IVW results for ukb-a-107 and bbj-a-57 showed (OR = 1.20; 95% CI: 1.07-1.34, P=0.02), confirming that gout characterized by high blood uric acid levels significantly increases the risk of angina attacks. Conclusions: This MR study found a clear causal relationship between angina pectoris and gout, which increases the risk of angina pectoris.

mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice.

The activation of NLRP3 inflammasome in microglia is critical for neuroinflammation during postoperative cognitive dysfunction (POCD) induced by sevoflurane. However, the molecular mechanism by which sevoflurane activates the NLRP3 inflammasome in microglia remains unclear. The cGAS-STING pathway is an evolutionarily conserved inflammatory defense mechanism. The role of the cGAS-STING pathway in sevoflurane-induced NLRP3 inflammasome-dependent neuroinflammation and the underlying mechanisms require further investigation. We found that prolonged anesthesia with sevoflurane induced cognitive dysfunction and triggered the neuroinflammation characterized by the activation of NLRP3 inflammasome in vivo. Interestingly, the cGAS-STING pathway was activated in the hippocampus of mice receiving sevoflurane. While the blockade of cGAS with RU.521 attenuated cognitive dysfunction and NLRP3 inflammasome activation in mice. In vitro, we found that sevoflurane treatment significantly activated the cGAS-STING pathway in microglia, while RU.521 pre-treatment robustly inhibited sevoflurane-induced NLRP3 inflammasome activation. Mechanistically, sevoflurane-induced mitochondrial fission in microglia and released mitochondrial DNA (mtDNA) into the cytoplasm, which could be abolished with Mdivi-1. Blocking the mtDNA release via the mPTP-VDAC channel inhibitor attenuated sevoflurane-induced mtDNA cytosolic escape and reduced cGAS-STING pathway activation in microglia, finally inhibiting the NLRP3 inflammasome activation. Therefore, regulating neuroinflammation by targeting the cGAS-STING pathway may provide a novel therapeutic target for POCD.

Prevalence, outcomes and associated factors of SARS-CoV-2 infection in psoriasis patients of Southwest China: a cross-sectional survey.

In this study we aimed to investigate the prevalence of SARS-CoV-2 infection in psoriasis patients, and outcomes of SARS-CoV-2 infection and associated risk factors. A cross-sectional survey was conducted from February 2023 to March 2023. Information was obtained with online questionnaire about psoriasis patients on demographic characteristics, clinical characteristics, SARS-CoV-2 infection and outcomes, vaccination, and routine protection against COVID-19. Logistic regression analysis was used to explore risk factors with SARS-CoV-2 infection and exacerbation of psoriasis. A total of 613 participants were recruited. 516 (84.2%) were infected, and associated factors were sex, working status, routine protection against COVID-19, COVID-19 vaccination, impaired nail, infection exacerbate psoriasis, and severity of psoriasis. Among the patients infected with SARS-CoV-2, 30 (5.8%) required hospitalization, 122 (23.6%) had psoriasis exacerbation due to SARS-CoV-2 infection, and associated factors were subtype of psoriasis, discontinuation of psoriasis treatment during SARS-CoV-2 infection, response following COVID-19 vaccination, and severity of psoriasis. Booster dose vaccination contributed a low probability of COVID-19 sequelae. COVID-19 vaccine's effectiveness was unsatisfactory, while booster dose vaccination reduced the occurrence of COVID-19 sequelae in psoriasis patients of Southwest China. Patients treated with psoriasis shown to be safe, without a higher incidence of SARS-CoV-2 infection or COVID-19hospitalization compared to untreated patients. Stopping treatment during SARS-CoV-2 infection led to psoriasis exacerbation, so psoriasis treatment could be continued except severe adverse reaction.

Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease.

Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease.

FGF17 protects cerebral ischemia reperfusion-induced blood-brain barrier disruption via FGF receptor 3-mediated PI3K/AKT signaling pathway.

Maintaining blood-brain barrier (BBB) integrity is critical components of therapeutic approach for ischemic stroke. Fibroblast growth factor 17 (FGF17), a member of FGF8 superfamily, exhibits the strongest expression throughout the wall of all major arteries during development. However, its molecular action and potential protective role on brain endothelial cells after stroke remains unclear. Here, we observed reduced levels of FGF17 in the serum of patients with ischemic stroke, as well as in the brains of mice subjected to middle cerebral artery occlusion (MCAO) injury and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (bEnd.3) cells. Moreover, treatment with exogenous recombinant human FGF17 (rhFGF17) decreased infarct volume, improved neurological deficits, reduced Evans Blue leakage and upregulated the expression of tight junctions in MCAO-injured mice. Meanwhile, rhFGF17 increased cell viability, enhanced trans-endothelial electrical resistance, reduced sodium fluorescein leakage, and alleviated reactive oxygen species (ROS) generation in OGD/R-induced bEnd.3 cells. Mechanistically, the treatment with rhFGF17 resulted in nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and upregulation of heme oxygenase-1 (HO-1) expression. Additionally, based on in-vivo and in-vitro research, rhFGF17 exerted protective effects against ischemia/reperfusion (I/R) -induced BBB disruption and endothelial cell apoptosis through the activation of the FGF receptor 3/PI3K/AKT signaling pathway. Overall, our findings indicated that FGF17 may hold promise as a novel therapeutic strategy for ischemic stroke patients.

Histone modification-linked prognostic model for ovarian cancer reveals LBX2 as a novel growth promoter.

Ovarian cancer (OC) is a deadly disease with limited treatment options and poor overall survival rates. This study aimed to investigate the role of histone modification-related genes in predicting the prognosis of OC patients. Transcriptome data from multiple cohorts, including bulk RNA-Seq data and single-cell scRNA-Seq data, were collected. Gene set enrichment analysis was used to identify enriched gene sets in the histone modification pathway. Differentially expressed genes (DEGs) between histone modification-high and histone modification-low groups were identified using Lasso regression. A prognostic model was constructed using five selected prognostic genes from the DEGs in the TCGA-OV cohort. The study found enrichment of gene sets in the histone modification pathway and identified five prognostic genes associated with OC prognosis. The constructed risk score model based on histone modification-related genes was correlated with immune infiltration of T cells and M1 macrophages. Mutations are more prevalent in the high-risk group compared to the low-risk group. Several drugs were screened against the model genes. Through in vitro experiments, we confirmed the expression patterns of the model genes. LBX2 facilitates the proliferation of OC. Histone modification-related genes have the potential to serve as biomarkers for predicting OC prognosis. Targeting these genes may lead to the development of more effective therapies for OC. Additionally, LBX2 represents a novel cell proliferation promoter in OC carcinogenesis.

METTL3/MALAT1/ELAVL1 Axis Promotes Tumor Growth in Ovarian Cancer.

Background: Studies increasingly recognize the role of N6-methyladenosine (m6A) modification in cancer occurrence and development. METTL3 is a core catalytic subunit of m6A-modified methyltransferases complex, but its regulatory mechanism in ovarian cancer (OC) is not clear. Methods: In this study, GEPIA 2.0 database was applied for expression analysis, survival analysis and correlation analysis for OC. Additionally, in vitro and in vivo assays were conducted to explore regulatory mechanisms of METTL3 in OC. Results: We found that METTL3 and MALAT1 were significantly overexpressed in OC tissues and cells compared to normal ovarian tissues and cells. The proliferation rate of OC cells was reduced significantly after knocking down the expression of METTL3 or MALAT1. Subsequently, MALAT1 as oncogene was found to interact with METTL3 and was upregulated in OC tissues and cells. Silencing MALAT1 inhibited OC cell proliferation. Further studies indicated that METTL3 enhanced the stability of MALAT1 by promoting the m6A modification of MALAT1 and that ELAVL1 as a downstream binding protein significantly up-regulated MALAT1 expression. Conclusion: In conclusion, METTL3 was a carcinogenic molecule that promoted the occurrence of OC. The potential mechanism of the carcinogenic effect of METTL3 was realized by enhancing the m6A modification of MALAT1 mRNA through RNA binding protein ELAVL1.