SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors.

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which occur in about 15% of all cancers. Here, we described a novel MAT2A inhibitor, SCR-7952 with potent and selective antitumor effects on MTAP-deleted cancers in both in vitro and in vivo. The cryo-EM data indicated the high binding affinity and the allosteric binding site of SCR-7952 on MAT2A. Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. A systematic evaluation of combination between SCR-7952 and different types of protein arginine methyltransferase 5 (PRMT5) inhibitors indicated remarkable synergistic interactions between SCR-7952 and the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative PRMT5 inhibitors, but not substrate-competitive ones. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

Long non-coding RNA Snhg15 promotes preosteoblast proliferation by interacting with and stabilizing nucleolin.

The proliferation and mineralization of preosteoblasts is crucial for bone formation and has attracted extensive attentions for decades. However, the roles of numerous long non-coding RNAs (lncRNAs) in preosteoblasts have not been fully determined. This study aimed to investigate the function of lncRNA Snhg15 in preosteoblasts as well as the potential underlying mechanism. LncRNA Snhg15 was dynamically expressed during preosteoblast proliferation and mineralization, and its transcripts were localized mainly in the cytoplasm. LncRNA Snhg15 knockdown significantly inhibited the proliferation and mineralization of preosteoblasts in both a cellular model and a murine ectopic bone formation model. RNA-seq showed that lncRNA Snhg15 knockdown downregulated multiple proliferation-related genes, and cell cycle deregulation was verified by flow cytometry. Mechanistically, we found that lncRNA Snhg15 could bind to nucleolin (NCL), thereby block NCL ubiquitination and decrease its degradation. Furthermore, the overexpression of NCL in lncRNA Snhg15-knockdown preosteoblasts ameliorated GO/G1 phase cell cycle arrest. Moreover, experiments in an in situ bone formation model confirmed the negative effects of lncRNA Snhg15 deficiency on bone formation. In conclusion, this study revealed an important regulatory role of lncRNA Snhg15/NCL complex in preosteoblast proliferation and may provide insights into the molecular mechanisms underlying bone formation.

[Zhongfeng Xingnao Decoction alleviates intracerebral haemorrhage-induced brain injury via inhibiting neuronal ferroptosis].

Zhongfeng Xingnao Decoction(ZFXN) has been utilized for treating intracerebral hemorrhage(ICH) in China, while the pharmacological mechanism of ZFXN remains unclear. Exploring the pharmacological roles of ZFXN is critical for guiding the treatment of cerebrovascular diseases. In this study, a rat model of ICH was constructed by injection of Ⅶ collagenase in the right caudate nucleus. SD rats were randomly assigned into five groups, and the neurological function of rats was evaluated based on the Bederson score. Magnetic resonance imaging(MRI) was used to assess the volume of ICH. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were employed to observe the pathological and ultrastructural changes in the brain tissue. The levels of reactive oxygen species(ROS) were measured by flow cytometry. The immunofluorescence assay was employed to detect the expression of glutathione peroxidase 4(GPX4) in neurons surrounding the hematoma. Finally, Western blot was employed to determine the expression of ferroptosis-related proteins upstream frameshift 1(UPF1), ferroportin(FPN), acyl-CoA ligase 4(ACSL4), cyclooxyge-nase-2(COX-2), GPX4, NADPH oxidase 1(NOX1), and solute carrier family 7 member 11(SLC7A11) after ICH. Compared with the model(ICH) group, ZFXN treatment for 5 days attenuated neurological dysfunction, reduced the hematoma volume, and alleviated the pathological changes induced by ICH. Meanwhile, ZFXN lowered the levels of Fe~(2+) and oxidative stress and up-regulated the expression of proteins inhibiting ferroptosis. ZFXN improved the prognosis of ICH in rats by inhibiting neuronal ferroptosis, which provided a valuable guide for the clinical application of ZFXN. ZFXN may inhibit ferroptosis by promoting the expression of SLC7A11 and FPN.

Plasma cathepsin D as an early indicator of alcohol-related liver disease.

Background & Aims: People who drink alcohol excessively are at increased risk of developing metabolic dysfunction and alcohol-related liver disease (MetALD) or the more severe form alcohol-related liver disease (ALD). One of the most significant challenges concerns the early detection of MetALD/ALD. Previously, we have demonstrated that the lysosomal enzyme cathepsin D (CTSD) is an early marker for metabolic dysfunction-associated steatohepatitis (MASH). Here, we hypothesized that plasma CTSD can also serve as an early indicator of MetALD/ALD. Methods: We included 303 persistent heavy drinkers classified as having MetALD or ALD (n = 152) and abstinent patients with a history of excessive drinking (n = 151). Plasma CTSD levels of patients with MetALD/ALD without decompensation were compared with 40 healthy controls. Subsequently, the relationship between plasma CTSD levels and hepatic histological scores was established. Receiver-operating characteristic curves were generated to assess the precision of plasma CTSD levels in detecting MetALD/ALD. Lastly, plasma CTSD levels were compared between abstainers and drinkers. Results: Plasma CTSD levels were higher in patients with MetALD/ALD compared to healthy controls. While hepatic disease parameters (AST/ALT ratio, liver stiffness measurement) were higher at advanced histopathological stages (assessed by liver biopsy), plasma CTSD levels were already elevated at early histopathological stages. Furthermore, combining plasma CTSD levels with liver stiffness measurement and AST/ALT ratio yielded enhanced diagnostic precision (AUC 0.872) in detecting MetALD/ALD in contrast to the utilization of CTSD alone (AUC 0.804). Plasma CTSD levels remained elevated in abstainers. Conclusion: Elevated levels of CTSD in the circulation can serve as an early indicator of MetALD/ALD. Impact and implications: Alcohol-related liver disease is the leading cause of liver disease-related morbidity and mortality worldwide. However, the currently available non-invasive methods to diagnose MetALD/ALD are only able to detect advanced stages of MetALD/ALD. Here, we demonstrate that plasma levels of the lysosomal enzyme cathepsin D are already elevated at early stages of MetALD/ALD. Moreover, cathepsin D levels outperformed the currently available non-invasive methods to detect MetALD/ALD. Plasma levels of cathepsin D could therefore be a useful non-invasive marker for detection of MetALD/ALD.

Identification of biomarkers and potential drug targets in osteoarthritis based on bioinformatics analysis and mendelian randomization.

Background: Osteoarthritis (OA) can lead to chronic joint pain, and currently there are no methods available for complete cure. Utilizing the Gene Expression Omnibus (GEO) database for bioinformatics analysis combined with Mendelian randomization (MR) has been widely employed for drug repurposing and discovery of novel therapeutic targets. Therefore, our research focus is to identify new diagnostic markers and improved drug target sites. Methods: Gene expression data from different tissues of synovial membrane, cartilage and subchondral bone were collected through GEO data to screen out differential genes. Two-sample MR Analysis was used to estimate the causal effect of expression quantitative trait loci (eQTL) on OA. Through the intersection of the two, core genes were obtained, which were further screened by bioinformatics analysis for in vitro and in vivo molecular experimental verification. Finally, drug prediction and molecular docking further verified the medicinal value of drug targets. Results: In the joint analysis utilizing the GEO database and MR approach, five genes exhibited significance across both analytical methods. These genes were subjected to bioinformatics analysis, revealing their close association with immunological functions. Further refinement identified two core genes (ARL4C and GAPDH), whose expression levels were found to decrease in OA pathology and exhibited a protective effect in the MR analysis, thus demonstrating consistent trends. Support from in vitro and in vivo molecular experiments was also obtained, while molecular docking revealed favorable interactions between the drugs and proteins, in line with existing structural data. Conclusion: This study identified potential diagnostic biomarkers and drug targets for OA through the utilization of the GEO database and MR analysis. The findings suggest that the ARL4C and GAPDH genes may serve as therapeutic targets, offering promise for personalized treatment of OA.

The impact of ACTH levels on neurotransmitters and antioxidants in patients with major depressive disorder: A novel investigation.

BACKGROUND: The relationship between neurotransmitters and oxidative stress in Major Depressive Disorder (MDD) patients, considering HPA axis activity and psychological and cognitive states, is unclear. This study examines changes in neurotransmitters (GABA, Glx) and antioxidants (GSH) in the dorsal anterior cingulate cortex (dACC) of MDD patients under varying levels of ACTH, and their relationship with psychological and cognitive conditions. METHODS: Forty-five MDD patients were divided into high-ACTH (>65 pg/mL; n = 16) and normal-ACTH (7-65 pg/mL; n = 29) groups based on blood ACTH levels, along with 12 healthy controls (HC). All participants underwent HAM-D, HAM-A assessments, and most completed MMSE and MoCA tests. GABA+, Glx, and GSH levels in the dACC were measured using the MEGA-PRESS sequence. Intergroup differences and correlations between clinical factors, HPA axis activity, and metabolites were analyzed. RESULTS: Compared to HC, the normal ACTH group showed higher Glx and lower GSH levels. Glx and GSH were negatively correlated with MDD severity. In the high-ACTH MDD group, Glx positively correlated with delayed memory, and GSH positively correlated with abstraction. Factors influencing GABA included ACTH levels, depression duration, and negative events. Predictive factors for HAM-D scores were GSH and GABA. LIMITATIONS: The sample size is small. CONCLUSION: MDD patients exhibit neurochemical differences in the brain related to HPA axis levels, MDD severity, and cognitive function. Clinical factors, neurotransmitters, and neuroendocrine levels significantly influence depression severity.

Epimedium-Curculigo herb pair enhances bone repair with infected bone defects and regulates osteoblasts through LncRNA MALAT1/miR-34a-5p/SMAD2 axis.

Infected bone defects (IBDs) are the common condition in the clinical practice of orthopaedics. Although surgery and anti-infective medicine are the firstly chosen treatments, in many cases, patients experience a prolonged bone union process after anti-infective treatment. Epimedium-Curculigo herb pair (ECP) has been proved to be effective for bone repair. However, the mechanisms of ECP in IBDs are insufficiency. In this study, Effect of ECP in IBDs was verified by micro-CT and histological examination. Qualitative and quantitative analysis of the main components in ECP containing medicated serum (ECP-CS) were performed. The network pharmacological approaches were then applied to predict potential pathways for ECP associated with bone repair. In addition, the mechanism of ECP regulating LncRNA MALAT1/miRNA-34a-5p/SMAD2 signalling axis was evaluated by molecular biology experiments. In vivo experiments indicated that ECP could significantly promote bone repair. The results of the chemical components analysis and the pathway identification revealed that TGF-ß signalling pathway was related to ECP. The results of in vitro experiments indicated that ECP-CS could reverse the damage caused by LPS through inhibiting the expressions of LncRNA MALAT1 and SMAD2, and improving the expressions of miR-34a-5p, ALP, RUNX2 and Collagen type І in osteoblasts significantly. This research showed that ECP could regulate the TGF-ß/SMADs signalling pathway to promote bone repair. Meanwhile, ECP could alleviate LPS-induced bone loss by modulating the signalling axis of LncRNA MALAT1/miRNA-34a-5p/ SMAD2 in IBDs.

Confinement Synthesis of Atomic Copper-Anchored Polymeric Carbon Nitride in Crystalline UiO-66-NH2 for High-Performance CO2-to-CH3OH Photocatalysis.

Photocatalytic CO2 reduction to value-added fuels displays an attractive scenario to enhance energy supply and reduce global warming. We report herein the confinement synthesis of polymeric carbon nitride (PCN) incorporating with Cu single atoms (CuSAs) inside the crystalline UiO-66-NH2, which combines the merits of heterojunction photocatalysis and single-atom catalysis (SAC) to achieve high-performance CO2-to-CH3OH conversion. A series of spectral studies displays the formation of CuSAs@PCN inside the crystalline UiO-66-NH2. Remarkably, the ternary composite shows an excellent photocatalytic turnover frequency of 4.15 mmol·h-1·g-1 for CO2-to-CH3OH conversion. Theoretical and experimental studies demonstrate the doping of CuSAs, as well as the formation of type-II heterojunction, are causal factors to achieve CH3OH generation. The study provides new insights designing high-performance photocatalyst for CO2 conversion to fuels at atomic scale.

Seven-year long-term inoculation with Funneliformis mosseae increases maize yield and soil carbon storage evidenced by in situ 13C-labeling in a dryland.

Arbuscular mycorrhizal fungi (AMF) establish symbiotic relationships with roots of most plants, contributing to plant water uptake and soil carbon (C) sequestration. However, the interactive contribution and of long-term field AMF inoculation and water conservation on maize yield and soil organic carbon (SOC) sequestration in drylands remain largely unknown. After 7-year long-term field inoculation with AMF Funneliformis mosseae, AMF suppression by fungicide benomyl, and no-AMF/no-benomyl control, and two water conservation practices of half-film and full-film mulching (∼50 % and ∼100 crop planted area covered with plastic film), this study thus applied in situ 13CO2-C labeling and high-throughput sequencing to quantify newly photosynthetically assimilated C into different soil C pools including soil aggregates and respiration, and their effects on maize growth and productivity. Results showed that 7-year long-term AMF inoculation significantly increased the relative abundance of F. mosseae in rhizosphere soil and root AMF colonization, indicating that F. mosseae successfully dominated in AMF communities. Compared to no-AMF/no-benomyl control, AMF colonization significantly increased shoot biomass and maize yield by 17.9 % and 20.3 % while mitigated the less water conservation effects of half-film mulching on maize performance. The SOC content under field AMF inoculation SOC was increased from 7.9 to 8.4 g kg-1 and also the mean weight diameter of aggregates (1.21 to 1.35), e.g. aggregate stability. After 1 and/or 40 days 13C labeling, the enhanced 13C translocations into macro-aggregates with decreased 13C emissions from microbial decomposition under field AMF inoculation had contributed to SOC conservation in bulk soil. These results suggest that AMF inoculation in dryland crops is promising to increase crop yield while promoting more atmospheric CO2 fixation in soil aggregates. A long-term field AMF inoculation will enhance our understanding of applying beneficial mycorrhizal fungi to enhance soil C sequestration and also crop yield via plant-fixed atmospheric CO2 in semi-arid and arid farmlands.

miRNA-seq analysis of high glucose induced osteoblasts provides insight into the mechanism underlying diabetic osteoporosis.

The present study aims to explore the etiology of Diabetic osteoporosis (DOP), a chronic complication associated with diabetes mellitus. Specifically, the research seeks to identify potential miRNA biomarkers of DOP and investigated role in regulating osteoblasts. To achieve this, an animal model of DOP was established through the administration of a high-sugar and high-fat diet, and then injection of streptozotocin. Bone microarchitecture and histopathology analysis were analyzed. Rat calvarial osteoblasts (ROBs) were stimulated with high glucose (HG). MiRNA profiles of the stimulated osteoblasts were compared to control osteoblasts using sequencing. Proliferation and mineralization abilities were assessed using MTT assay, alkaline phosphatase, and alizarin red staining. Expression levels of OGN, Runx2, and ALP were determined through qRT-PCR and Western blot. MiRNA-sequencing results revealed increased miRNA-702-5p levels. Luciferase reporter gene was utilized to study the correlation between miR-702-5p and OGN. High glucose impaired cell proliferation and mineralization in vitro by inhibiting OGN, Runx2, and ALP expressions. Interference with miR-702-5p decreased OGN, Runx2, and ALP levels, which were restored by OGN overexpression. Additionally, downregulation of OGN and Runx2 in DOP rat femurs was confirmed. Therefore, the miRNA-702-5p/OGN/Runx2 signaling axis may play a role in DOP, and could be diagnostic biomarker and therapeutic target for not only DOP but also other forms of osteoporosis.

Mitochondrial DNA copy number mediated the associations between perfluoroalkyl substances and breast cancer incidence: A prospective case-cohort study.

Epidemiologic studies have reported the relationships between perfluoroalkyl substances (PFASs) and breast cancer incidence, yet the underlying mechanisms are not well understood. This study aimed to elucidate the mediation role of mitochondrial DNA copy number (mtDNAcn) in the relationships between PFASs exposure and breast cancer risk. We conducted a case-cohort study within the Dongfeng-Tongji cohort, involving 226 incident breast cancer cases and a random sub-cohort (n = 990). Their plasma concentrations of six PFASs [including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], and peripheral blood levels of mtDNAcn, were detected at baseline by using ultraperformance liquid chromatography-tandem mass spectrometry and quantitative real-time PCR, respectively. Linear regression and Barlow-weighted Cox models were employed separately to assess the relationships of mtDNAcn with PFASs and breast cancer risk. Mediation analysis was further conducted to quantify the mediating effects of mtDNAcn on PFAS-breast cancer relationships. We observed increased blood mtDNAcn levels among participants with the highest PFNA and PFHpA exposure [Q4 vs. Q1, ß(95%CI) = 0.092(0.022, 0.162) and 0.091(0.022, 0.160), respectively], while no significant associations were observed of PFOA, PFDA, PFOS, or PFHxS with mtDNAcn. Compared to participants within the lowest quartile subgroup of mtDNAcn, those with the highest mtDNAcn levels exhibited a significantly increased risk of breast cancer and postmenopausal breast cancer [Q4 vs. Q1, HR(95%CI) = 3.34(1.80, 6.20) and 3.71(1.89, 7.31)]. Furthermore, mtDNAcn could mediate 14.6 % of the PFHpA-breast cancer relationship [Indirect effect, HR(95%CI) = 1.02(1.00, 1.05)]. Our study unveiled the relationships of PFNA and the short-chain PFHpA with mtDNAcn and the mediation role of mtDNAcn in the PFHpA-breast cancer association. These findings provided insights into the potential biological mechanisms linking PFASs to breast cancer risk.

Inhibiting the activation of enteric glial cells alleviates intestinal inflammation and comorbid anxiety- and depressive-like behaviors in the ulcerative colitis mice.

Ulcerative colitis (UC) is a common inflammatory bowel disease with a complex origin in clinical settings. It is frequently accompanied by negative emotional responses, including anxiety and depression. Enteric glial cells (EGCs) are important components of the gut-brain axis and are involved in the development of the enteric nervous system (ENS), intestinal neuroimmune, and regulation of intestinal motor functions. Since there is limited research encompassing the regulatory function of EGCs in anxiety- and depression-like behaviors induced by UC, this study aims to reveal their regulatory role in such behaviors and associated intestinal inflammation. This study applied morphological, molecular biological, and behavioral methods to observe the morphological and functional changes of EGCs in UC mice. The results indicated a significant activation of EGCs in the ENS of dextran sodium sulfate -induced UC mice. This activation was evidenced by morphological alterations, such as elongation or terminal swelling of processes. Besides EGCs activation, UC mice exhibited significantly elevated expression levels of pro-inflammatory cytokines in the peripheral blood, accompanied by anxiety- and depression-like behaviors. The inhibition of EGCs activity within the ENS can ameliorate the anxiety- and depression-like behaviors caused by UC. Our data suggest that UC and its resulting behaviors may be related to the activation of EGCs within the ENS. Moreover, the modulation of intestinal inflammation through inhibition of EGCs activation emerges as a promising clinical approach for alleviating UC-induced anxiety- and depression-like behaviors.

Targeting a mTOR/autophagy axis: a double-edged sword of rapamycin in spontaneous miscarriage.

Immune dysfunction is a primary culprit behind spontaneous miscarriage (SM). To address this, immunosuppressive agents have emerged as a novel class of tocolytic drugs, modulating the maternal immune system's tolerance towards the embryo. Rapamycin (PubChem CID:5284616), a dual-purpose compound, functions as an immunosuppressive agent and triggers autophagy by targeting the mTOR pathway. Its efficacy in treating SM has garnered significant research interest in recent times. Autophagy, the cellular process of self-degradation and recycling, plays a pivotal role in numerous health conditions. Research indicates that autophagy is integral to endometrial decidualization, trophoblast invasion, and the proper functioning of decidual immune cells during a healthy pregnancy. Yet, in cases of SM, there is a dysregulation of the mTOR/autophagy axis in decidual stromal cells or immune cells at the maternal-fetal interface. Both in vitro and in vivo studies have highlighted the potential benefits of low-dose rapamycin in managing SM. However, given mTOR's critical role in energy metabolism, inhibiting it could potentially harm the pregnancy. Moreover, while low-dose rapamycin has been deemed safe for treating recurrent implant failure, its potential teratogenic effects remain uncertain due to insufficient data. In summary, rapamycin represents a double-edged sword in the treatment of SM, balancing its impact on autophagy and immune regulation. Further investigation is warranted to fully understand its implications.

Lycorine relieves the CCl4-induced liver fibrosis mainly via the JAK2/STAT3 and PI3K/AKT signaling pathways.

Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.

Optimizing enzyme properties to enhance dihydroxyacetone production via methylglyoxal biosensor development.

BACKGROUND: Dihydroxyacetone (DHA) stands as a crucial chemical material extensively utilized in the cosmetics industry. DHA production through the dephosphorylation of dihydroxyacetone phosphate, an intermediate product of the glycolysis pathway in Escherichia coli, presents a prospective alternative for industrial production. However, insights into the pivotal enzyme, dihydroxyacetone phosphate dephosphorylase (HdpA), remain limited for informed engineering. Consequently, the development of an efficient tool for high-throughput screening of HdpA hypermutants becomes imperative. RESULTS: This study introduces a methylglyoxal biosensor, based on the formaldehyde-responding regulator FrmR, for the selection of HdpA. Initial modifications involved the insertion of the FrmR binding site upstream of the -35 region and into the spacer region between the -10 and -35 regions of the constitutive promoter J23110. Although the hybrid promoter retained constitutive expression, expression of FrmR led to complete repression. The addition of 350 µM methylglyoxal promptly alleviated FrmR inhibition, enhancing promoter activity by more than 40-fold. The methylglyoxal biosensor system exhibited a gradual increase in fluorescence intensity with methylglyoxal concentrations ranging from 10 to 500 µM. Notably, the biosensor system responded to methylglyoxal spontaneously converted from added DHA, facilitating the separation of DHA producing and non-producing strains through flow cytometry sorting. Subsequently, the methylglyoxal biosensor was successfully applied to screen a library of HdpA mutants, identifying two strains harboring specific mutants 267G > T and D110G/G151C that showed improved DHA production by 68% and 114%, respectively. Expressing of these two HdpA mutants directly in a DHA-producing strain also increased DHA production from 1.45 to 1.92 and 2.29 g/L, respectively, demonstrating the enhanced enzyme properties of the HdpA mutants. CONCLUSIONS: The methylglyoxal biosensor offers a novel strategy for constructing genetically encoded biosensors and serves as a robust platform for indirectly determining DHA levels by responding to methylglyoxal. This property enables efficiently screening of HdpA hypermutants to enhance DHA production.

Synergistic promotion of angiogenesis after intracerebral hemorrhage by ginsenoside Rh2 and chrysophanol in rats.

BACKGROUND: Intracerebral hemorrhage (ICH) is a debilitating condition characterized by the rupture of cerebral blood vessels, resulting in profound neurological deficits. A significant challenge in the treatment of ICH lies in the brain's limited capacity to regenerate damaged blood vessels. This study explores the potential synergistic effects of Ginsenoside Rh2 and Chrysophanol in promoting angiogenesis following ICH in a rat model. METHODS: Network pharmacology was employed to predict the potential targets and pathways of Ginsenoside Rh2 and Chrysophanol for ICH treatment. Molecular docking was utilized to assess the binding affinity between these compounds and their respective targets. Experimental ICH was induced in male Sprague-Dawley rats through stereotactic injection of type VII collagenase into the right caudate putamen (CPu). The study encompassed various methodologies, including administration protocols, assessments of neurological function, magnetic resonance imaging, histological examination, observation of brain tissue ultrastructure, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunofluorescence staining, Western blot analysis, and statistical analyses. RESULTS: Network pharmacology analysis indicated that Ginsenoside Rh2 and Chrysophanol may exert their therapeutic effects in ICH by promoting angiogenesis. Results from animal experiments revealed that rats treated with Ginsenoside Rh2 and Chrysophanol exhibited significantly improved neurological function, reduced hematoma volume, and diminished pathological injury compared to the Model group. Immunofluorescence analysis demonstrated enhanced expression of vascular endothelial growth factor receptor 2 (VEGFR2) and CD31, signifying augmented angiogenesis in the peri-hematomal region following combination therapy. Importantly, the addition of a VEGFR2 inhibitor reversed the increased expression of VEGFR2 and CD31. Furthermore, Western blot analysis revealed upregulated expression of angiogenesis-related factors, including VEGFR2, SRC, AKT1, MAPK1, and MAPK14, in the combination therapy group, but this effect was abrogated upon VEGFR2 inhibitor administration. CONCLUSION: The synergistic effect of Ginsenoside Rh2 and Chrysophanol demonstrated a notable protective impact on ICH injury in rats, specifically attributed to their facilitation of angiogenesis. Consequently, this research offers a foundation for the utilization of Ginsenosides Rh2 and Chrysophanol in medical settings and offers direction for the advancement of novel pharmaceuticals for the clinical management of ICH.

Discovering two general characteristic times of transient responses in solid oxide cells.

A comprehensive understanding of the transient characteristics in solid oxide cells (SOCs) is crucial for advancing SOC technology in renewable energy storage and conversion. However, general formulas describing the relationship between SOC transients and multiple parameters remain elusive. Through comprehensive numerical analysis, we find that the thermal and gaseous response times of SOCs upon rapid electrical variations are on the order of two characteristic times (τh and τm), respectively. The gaseous response time is approximately 1τm, and the thermal response time aligns with roughly 2τh. These characteristic times represent the overall heat and mass transfer rates within the cell, and their mathematical relationships with various SOC design and operating parameters are revealed. Validation of τh and τm is achieved through comparison with an in-house experiment and existing literature data, achieving the same order of magnitude for a wide range of electrochemical cells, showcasing their potential use for characterizing transient behaviors in a wide range of electrochemical cells. Moreover, two examples are presented to demonstrate how these characteristic times can streamline SOC design and control without the need for complex numerical simulations, thus offering valuable insights and tools for enhancing the efficiency and durability of electrochemical cells.

3D bioprinting of DPSCs with GelMA hydrogel of various concentrations for bone regeneration.

Bioprinting technology promotes innovation of fabricating tissue engineered constructs. Dental pulp stem cells (DPSCs) have significant advantages over classical bone mesenchymal stem cells (BMSCs) and are a promising seed cell candidate for bone engineering bioprinting. However, current reports about bioprinted DPSCs for bone regeneration are incomprehensive. The objective of this study was to investigate the osteogenic potential of DPSCs in methacrylate gelatin (GelMA) hydrogels bioprinted scaffolds in vitro and in vivo. Firstly, we successfully bioprinted GelMA with different concentrations embedded with or without DPSCs. Printability, physical features and biological properties of the bioprinted constructs were evaluated. Then, osteogenic differentiation levels of DPSCs in bioprinted constructs with various concentrated GelMA were compared. Finally, effects of bioprinted constructs on cranial bone regeneration were evaluated in vivo. The results of our study demonstrated that 10% GelMA had higher compression modulus, smaller pores, lower swelling and degradation rate than 3% GelMA. Twenty-eight days after printing, DPSCs in three groups of bioprinted structures still maintained high cell activities (>90%). Moreover, DPSCs in 10% GelMA showed an upregulated expression of osteogenic markers and a highly activated ephrinB2/EphB4 signaling, a signaling involved in bone homeostasis. In vivo experiments showed that DPSCs survived at a higher rate in 10% GelMA, and more new bones were observed in DPSC-laden 10% GelMA group, compared with GelMA of other concentrations. In conclusion, bioprinted DPSC-laden 10% GelMA might be more appropriate for bone regeneration application, in contrast to GelMA with other concentrations.

Characteristics of Different Obesity Metabolic Indexes and their Correlation with Insulin Resistance in Patients with Polycystic Ovary Syndrome.

This study is aimed to investigate the characteristics of different obesity metabolic indexes [body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), cardiometabolic index (CMI), body roundness index (BRI), visceral adiposity index (VAI), and lipid aggregation products (LAP)] and their correlation with insulin resistance (IR) in patients with polycystic ovary syndrome (PCOS). The study was conducted on 140 subjects with PCOS and 133 control subjects aged 18-44 years. According to insulin resistance index (HOMA-IR) ≥ 2.69 and HOMA-IR < 2.69, PCOS group members were divided into insulin resistance group and non-insulin resistance group. Anthropometric and serological characteristics of the population with PCOS focused on calculating different obesity metabolic indexes and HOMA-IR. BMI, WC, WHR, WHtR, CMI, BRI, VAI, and LAP were significantly higher in PCOS patients than in the control group, and the differences were all statistically significant (P < 0.05); In the insulin resistance group of PCOS patients, BMI, WC, WHR, WHtR, CMI, BRI, VAI, and LAP were significantly higher than in the non-insulin resistance group (P < 0.05). In PCOS patients, BMI (r = 0.658, P < 0.001), WC (r = 0.0.662, P < 0.001), WHR (r = 0.377, P < 0.001), WHtR (r = 0.660, P < 0.001), CMI (r = 0.698, P < 0.001), BRI (r = 0.757, P < 0.001), VAI (r = 0.640, P < 0.001), and LAP (r = 0.767, P < 0.001) were positively correlated with IR. Obesity metabolic indexes associated with PCOS were elevated in the PCOS group compared to the control group, and in the PCOS insulin-resistant group compared to the non-insulin resistant group. Novel obesity metabolic indexes, especially CMI, BRI and LAP, might be more appropriate for evaluating the risk of concurrent IR in PCOS.

Validation of mitochondrial biomarkers and immune dynamics in polycystic ovary syndrome.

PROBLEM: Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, presents considerable therapeutic challenges due to its complex and elusive pathophysiology. METHOD OF STUDY: We employed three machine learning algorithms to identify potential biomarkers within a training dataset, comprising GSE138518, GSE155489, and GSE193123. The diagnostic accuracy of these biomarkers was rigorously evaluated using a validation dataset using area under the curve (AUC) metrics. Further validation in clinical samples was conducted using PCR and immunofluorescence techniques. Additionally, we investigate the complex interplay among immune cells in PCOS using CIBERSORT to uncover the relationships between the identified biomarkers and various immune cell types. RESULTS: Our analysis identified ACSS2, LPIN1, and NR4A1 as key mitochondria-related biomarkers associated with PCOS. A notable difference was observed in the immune microenvironment between PCOS patients and healthy controls. In particular, LPIN1 exhibited a positive correlation with resting mast cells, whereas NR4A1 demonstrated a negative correlation with monocytes in PCOS patients. CONCLUSION: ACSS2, LPIN1, and NR4A1 emerge as PCOS-related diagnostic biomarkers and potential intervention targets, opening new avenues for the diagnosis and management of PCOS.