The biomedical knowledge graph of symptom phenotype in coronary artery plaque: machine learning-based analysis of real-world clinical data.

A knowledge graph can effectively showcase the essential characteristics of data and is increasingly emerging as a significant means of integrating information in the field of artificial intelligence. Coronary artery plaque represents a significant etiology of cardiovascular events, posing a diagnostic challenge for clinicians who are confronted with a multitude of nonspecific symptoms. To visualize the hierarchical relationship network graph of the molecular mechanisms underlying plaque properties and symptom phenotypes, patient symptomatology was extracted from electronic health record data from real-world clinical settings. Phenotypic networks were constructed utilizing clinical data and protein‒protein interaction networks. Machine learning techniques, including convolutional neural networks, Dijkstra's algorithm, and gene ontology semantic similarity, were employed to quantify clinical and biological features within the network. The resulting features were then utilized to train a K-nearest neighbor model, yielding 23 symptoms, 41 association rules, and 61 hub genes across the three types of plaques studied, achieving an area under the curve of 92.5%. Weighted correlation network analysis and pathway enrichment were subsequently utilized to identify lipid status-related genes and inflammation-associated pathways that could help explain the differences in plaque properties. To confirm the validity of the network graph model, we conducted coexpression analysis of the hub genes to evaluate their potential diagnostic value. Additionally, we investigated immune cell infiltration, examined the correlations between hub genes and immune cells, and validated the reliability of the identified biological pathways. By integrating clinical data and molecular network information, this biomedical knowledge graph model effectively elucidated the potential molecular mechanisms that collude symptoms, diseases, and molecules.

Study on material basis and anti-hypertensive metabolomics of Zhengan-Xifeng-Tang(ZXT): A comparison between ZXT decoction and granules.

High blood pressure is a serious human health problem and one of the leading risk factors for fatal complications in cardiovascular disease. The ZXT granules were prepared based on the Zhengan-Xifeng-Tang (ZXT) decoction. However, the therapeutic effects of ZXT granules on spontaneous hypertension and the metabolic pathways in which they may intervene are unclear. The aim of this study was to investigate the antihypertensive effect of ZXT granules on spontaneously hypertensive rats (SHR) and to analyze the metabolic pathway of intervention through chemical composition characterization, pharmacodynamics, and serum metabolomics analysis. After eight weeks of administration, serum and aortic arch samples were collected for biochemical, histopathology and serum metabolomics analysis to assess the effect of ZXT granules on SHR. The results showed that ZXT granules reduced aortic arch injury and blood pressure in SHR rats. Serum data from rats in each group was collected using LC-MS and 74 potential biomarkers were identified that showed significant differences between the model and control groups. Of these, 18 potential biomarkers were found to be deregulated after intervention with ZXT granules. These 18 potential differential metabolic markers are primarily involved in bile acid biosynthesis, arachidonic acid metabolism pathway, and fatty acid degradation. The results demonstrated that ZXT granules significantly affected blood lipids, aortic arch, and metabolic disorders in SHR rats. ZXT granules offer a new possibility for effective and convenient treatment of hypertensive patients.

Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study.

BACKGROUND: This study focused on circulating plasma protein profiles to identify mediators of hypertension-driven myocardial remodeling and heart failure. METHODS: A Mendelian randomization design was used to investigate the causal impact of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure on 82 cardiac magnetic resonance traits and heart failure risk. Mediation analyses were also conducted to identify potential plasma proteins mediating these effects. RESULTS: Genetically proxied higher SBP, DBP, and pulse pressure were causally associated with increased left ventricular myocardial mass and alterations in global myocardial wall thickness at end diastole. Elevated SBP and DBP were linked to increased regional myocardial radial strain of the left ventricle (basal anterior, mid, and apical walls), while higher SBP was associated with reduced circumferential strain in specific left ventricular segments (apical, mid-anteroseptal, mid-inferoseptal, and mid-inferolateral walls). Specific plasma proteins mediated the impact of blood pressure on cardiac remodeling, with FGF5 (fibroblast growth factor 5) contributing 2.96% (P=0.024) and 4.15% (P=0.046) to the total effect of SBP and DBP on myocardial wall thickness at end diastole in the apical anterior segment and leptin explaining 15.21% (P=0.042) and 23.24% (P=0.022) of the total effect of SBP and DBP on radial strain in the mid-anteroseptal segment. Additionally, FGF5 was the only mediator, explaining 4.19% (P=0.013) and 4.54% (P=0.032) of the total effect of SBP and DBP on heart failure susceptibility. CONCLUSIONS: This mediation Mendelian randomization study provides evidence supporting specific circulating plasma proteins as mediators of hypertension-driven cardiac remodeling and heart failure.

Zwitterionic Conductive Hydrogel-Based Nerve Guidance Conduit Promotes Peripheral Nerve Regeneration in Rats.

In recent years, conductive biomaterials have been widely used to enhance peripheral nerve regeneration. However, most biomaterials use electronic conductors to increase the conductivity of materials. As information carriers, electronic conductors always transmit discontinuous electrical signals, while biological systems essentially transmit continuous signals through ions. Herein, an ion-based conductive hydrogel was fabricated by simple copolymerization of the zwitterionic monomer sulfobetin methacrylate and hydroxyethyl methacrylate. Benefiting from the excellent mechanical stability, suitable electrical conductivity, and good cytocompatibility of the zwitterionic hydrogel, the Schwann cells cultured on the hydrogel could grow and proliferate better, and dorsal root ganglian had an increased neurite length. The zwitterionic hydrogel-based nerve guidance conduits were then implanted into a 10 mm sciatic nerve defect model in rats. Morphological analysis and electrophysiological data showed that the grafts achieved a regeneration effect close to that of the autologous nerve. Overall, our developed zwitterionic hydrogel facilitates efficient and efficacious peripheral nerve regeneration by mimicking the electrical and mechanical properties of the extracellular matrix and creating a suitable regeneration microenvironment, providing a new material reserve for the repair of peripheral nerve injury.

Protocatechuic aldehyde increases pericyte coverage and mitigates pericyte damage to enhance the atherosclerotic plaque stability.

Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural polyphenol, exerts anti-atherosclerotic effects. However, the effects and mechanisms of this polyphenol on pericyte recruitment, coverage, and pericyte function remain unknown. We here treated apolipoprotein E-deficient mice having high-fat diet-induced atherosclerosis with PCAD. PCAD achieved therapeutic effects similar to rosuvastatin in lowering lipid levels and thus preventing atherosclerosis progression. With PCAD administration, plaque phenotype exhibited higher stability with markedly reduced lesion vulnerability, which is characterized by reduced lipid content and macrophage accumulation, and a consequent increase in collagen deposition. PCAD therapy increased pericyte coverage in the plaques, reduced VEGF-A production, and inhibited intraplaque neovascularization. PCAD promoted pericyte proliferation, adhesion, and migration to mitigate ox-LDL-induced pericyte dysfunction, which thus maintained the capillary network structure and stability. Furthermore, TGFBR1 silencing partially reversed the protective effect exerted by PCAD on human microvascular pericytes. PCAD increased pericyte coverage and impeded ox-LDL-induced damages through TGF-ß1/TGFBR1/Smad2/3 signaling. All these novel findings indicated that PCAD increases pericyte coverage and alleviates pericyte damage to improve the stability of atherosclerotic plaques, which is accomplished by regulating TGF-ß1/TGFBR1/Smad2/3 signaling in pericytes.

Association of estimated carotid-femoral pulse wave velocity with frailty in middle-aged and older adults with cardiometabolic disease.

PURPOSE: The prevalence of frailty in individuals with cardiometabolic disease (CMD) has become a growing concern in public health. The purpose of this study was to investigate the association between estimated pulse wave velocity (ePWV) and frailty in middle-aged and older adults with CMD. METHODS: We analyzed data from 23,313 non-institutionalized adults with CMD from the National Health and Nutrition Examination Survey 2003-2018. Frailty status was determined using the frailty index, and logistic regression models were used to assess the association of ePWV with frailty risk. Multivariable logistic regression and propensity-score matching (PSM) were used to adjust for potential confounders. The restricted cubic spline regression model was used to evaluate the non-linear association between ePWV and frailty risk. RESULTS: After adjusting for potential confounding factors, we found that each one m/s increase in ePWV was associated with a 15% higher risk of frailty (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.12 to 1.18, P < 0.001). After PSM, the association remained significant (OR = 1.05, 95% CI 1.03 to 1.08, P < 0.001). The logistic models with restricted cubic splines showed a non-linear dose-response association, with the risk of frailty increasing more rapidly when ePWV exceeded 9.5 m/s. CONCLUSIONS: The findings of this study suggest that a higher level of ePWV is associated with an increased risk of frailty in middle-aged and older adults with CMD, and may serve as a viable alternative to directly measured cfPWV.

Isorhynchophylline improves lipid metabolism disorder by mediating a circadian rhythm gene Bmal1 in spontaneously hypertensive rat.

Hypertension is a progressive metabolic disease characterized by circadian regulation of lipid metabolism disorder. Identifying specific lipid components and maintaining circadian homeostasis of lipid metabolism might be a promising therapeutic strategy for hypertension. Isorhynchophylline (IRP) can regulate lipid metabolism; however, the underlying mechanism of IRP in improving lipid metabolism rhythm disorder is still unclear. The lipid circadian biomarkers and abnormal metabolic pathways intervened by IRP were investigated using diurnal lipidomic research methods. The 24-h circadian changes in mRNA and protein expression levels of circadian genes, including Bmal1, Clock, Cry1, Cry2, Per1, and Per2, and lipid metabolism-related factors (PPARα and LPL) were determined using RT-PCR and western blot analyses, respectively. The underlying mechanisms were intensively investigated by inhibiting Bmal1. Molecular docking and drug affinity responsive target stability analyses were performed to assess the binding affinity of IRP and Bmal1. IRP treatment could effectively improve 24-h blood pressure, ameliorate the lipid metabolic rhythm disorder, reverse the expression levels of circadian rhythm genes, and regulate lipid metabolism-related genes (PPARα and LPL) by mediating Bmal1. This study highlighted the potential effects of IRP in maintaining the circadian homeostasis of lipid metabolism and the treatment of hypertension.

Association of remnant cholesterol with frailty: findings from observational and Mendelian randomization analyses.

BACKGROUND: Recent insights suggest that remnant cholesterol (RC) plays a role in cellular senescence, yet its specific contribution to frailty remains indeterminate. Through the integration of observational and mendelian randomization (MR) studies, this research explores the impact of elevated serum RC levels on frailty susceptibility. METHODS: A dual-method approach, combining an observational study with an MR study, was employed to investigate the connection between RC and frailty. The observational study included 11,838 participants from the National Health and Nutrition Examination Survey. Multivariable logistic regression and propensity score matching were employed to control for potential confounders. The non-linear relationship was assessed using restricted cubic splines. To circumvent observational study limitations, a two-sample MR analysis was conducted using the inverse-variance weighted method, leveraging genome-wide association studies (GWAS) data. RESULTS: After adjusting for potential confounding variables, the observational study identified a significant association between high serum RC levels and frailty in middle-aged and older adults (odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.20 to 2.33, P = 0.003), exhibiting a non-linear dose-response correlation (non-linear P = 0.011). This association persisted after propensity score matching (OR = 1.53, 95% CI = 1.14 to 2.06, P = 0.005). The MR study echoed these results, demonstrating a causal association of RC with the frailty index (ß = 0.059, 95% CI = 0.033 to 0.085, P = 1.05E-05), consistent with the observational findings (ß = 0.017, 95% CI = 0.008 to 0.026, P = 4.51E-04). CONCLUSION: This study provides evidence that higher RC levels amplify frailty risk in middle-aged and older adults, implying that the reduction of RC levels may present a promising strategy for frailty prevention and management.

Novel Near-Infrared Fluorescence Probe for Bioimaging and Evaluating Superoxide Anion Fluctuations in Ferroptosis-Mediated Epilepsy.

Ferroptosis is an iron-regulated, caspase-mediated pathway of cell death that is associated with the excessive aggregation of lipid-reactive oxygen species and is extensively involved in the evolution of many diseases, including epilepsy. The superoxide anion (O2•-), as the primary precursor of ROS, is closely related to ferroptosis-mediated epilepsy. Therefore, it is crucial to establish a highly effective and convenient method for the real-time dynamic monitoring of O2•- during the ferroptosis process in epilepsy for the diagnosis and therapy of ferroptosis-mediated epilepsy. Nevertheless, no probes for detecting O2•- in ferroptosis-mediated epilepsy have been reported. Herein, we systematically conceptualized and developed a novel near-infrared (NIR) fluorescence probe, NIR-FP, for accurately tracking the fluctuation of O2•- in ferroptosis-mediated epilepsy. The probe showed exceptional sensitivity and outstanding selectivity toward O2•-. In addition, the probe has been utilized effectively to bioimage and evaluate endogenous O2•- variations in three types of ferroptosis-mediated epilepsy models (the kainic acid-induced chronic epilepsy model, the pentylenetetrazole-induced acute epilepsy model, and the pilocarpine-induced status epilepticus model). The above applications illustrated that NIR-FP could serve as a reliable and suitable tool for guiding the accurate diagnosis and therapy of ferroptosis-mediated epilepsy.

Recent advances in regulating lipid metabolism to prevent coronary heart disease.

The pathogenesis of coronary heart disease is a highly complex process, with lipid metabolism disorders being closely linked to its development. Therefore, this paper analyzes the various factors that influence lipid metabolism, including obesity, genes, intestinal microflora, and ferroptosis, through a comprehensive review of basic and clinical studies. Additionally, this paper delves deeply into the pathways and patterns of coronary heart disease. Based on these findings, it proposes various intervention pathways and therapeutic methods, such as the regulation of lipoprotein enzymes, lipid metabolites, and lipoprotein regulatory factors, as well as the modulation of intestinal microflora and the inhibition of ferroptosis. Ultimately, this paper aims to offer new ideas for the prevention and treatment of coronary heart disease.

Atractylenolide-III alleviates osteoarthritis and chondrocyte senescence by targeting NF-κB signaling.

Atractylenolide-III (AT-III) is well known as its role in antioxidant and anti-inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT-III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT-III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT-III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro-CT) and chondrocyte senescence (indexed by levels of SA-ß-gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT-III might play role through NF-κB pathway. Further experiments revealed that AT-III reduced phosphorylation of IKKα/ß, IκBα and P65 in NF-κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT-III's effects on osteoarthritis and anti-senescence were reversed by an NF-κB agonist. AT-III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF-κB pathway, which indicated that AT-III is a prospective drug for osteoarthritis treatment.

Isorhynchophylline inhibits inflammatory responses in endothelial cells and macrophages through the NF-κB/NLRP3 signaling pathway.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease of arterial wall, which is closely related to inflammatory reaction. In this study, the anti-inflammatory effect of isorhynchophylline was studied by NF- κB / NLRP3 pathway. METHODS: (1) ApoE-/- mice were fed with high-fat diet to establish atherosclerotic model, while C57 with the same genetic background was fed with common diet as control group. Body weight was recorded and blood lipids were detected. The expression of NLRP3, NF-κB, IL-18 and Caspase-1 in aorta was detected by Western-Blot and PCR, and plaque formation was detected by HE and oil red O staining. (2) Lipopolysaccharide interfered with Human Umbilical Vein Endothelial Cells (HUVECs) and RAW264.7 to form inflammatory model, and was treated with isorhynchophylline. The expression of NLRP3, NF-κB, IL-18 and Caspase-1 in aorta was detected by Western-Blot and PCR, and the ability of cell migration was detected by Transwell and scratch test. RESULTS: (1) the expression of NLRP3, NF- κB, IL-18 and Caspase-1 in aorta of model group was higher than that of control group, and plaque formation was obvious. (2) the expressions of NLRP3, NF- κB, IL-18 and Caspase-1 in HUVECs and RAW264.7 model groups were higher than those in control group, while isorhynchophylline decreased their expression and enhanced cell migration ability. CONCLUSION: Isorhynchophylline can reduce the inflammatory reaction induced by lipopolysaccharide and promote the ability of cell migration.

Integrating network pharmacology and experimental validation to decipher the mechanism of action of Jingfang Granule in the treatment of viral myocarditis.

This study investigated the mechanisms of Jingfang Granule (JFG) in viral myocarditis (VMC) treatment via network pharmacology-based approach combined with molecular docking and validated the results through in vitro and in vivo experiments. The chemical composition of JFG and its therapeutic targets was queried in Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The targets related to VMC were retrieved from the disease database, and the overlapping targets were screened. Based on the STRING database, a protein-protein interaction network was constructed. Cytoscape software was used to construct the "component-target-disease" interaction network for visualization. GO and KEGG pathway enrichment analyses were performed using Metascape data. Molecular docking was performed using PyMoL2.3.0 and AutoDock Vina software programs. The target genes were further verified in vitro and in vivo. JFG contains 88 active components. The main biological targets of JFG in VMC include quercetin, luteolin, and kaempferol. The molecular docking results showed that the three key targets showed strong binding properties with both the height components of the molecular docking interaction energies. The results of experimental verification results showed that JFG may be used to treat VMC mainly by down-regulating inflammatory factors TNF-α and NF-κB and inhibiting myocardial apoptosis. The results support the network pharmacological data. JFG reduces myocardial inflammation and myocardial cell apoptosis in VMC and protects myocardial tissue.

Decompression Mechanism of Radish Seed in Prehypertension Rats through Integration of Transcriptomics and Metabolomics Methods.

Radish seed (RS), the dried ripe seed of Raphanus sativus L., is widely used in traditional Chinese medicine (TCM) to reduce blood pressure. However, the molecular and pharmacological mechanisms underlying its therapeutic effects are still unclear. In this study, we analyzed the effects of RS in a rat model of prehypertension and assessed the mechanistic basis by integrating transcriptomics and metabolomics. RS administration significantly reduced blood pressure in prehypertensive male Wistar rats, negatively regulated endothelin-1, increased nitric oxide levels, and reduced the exfoliation of endothelium cells. In vitro vascular ring experiments further confirmed the effects of RS on vascular endothelial cells. Furthermore, we identified 65 differentially expressed genes (DEGs; P adj < 0.05 and fold change (FC) > 2) and 52 metabolites (VIP > 1, P < 0.05 and FC ≥ 2 or ≤0.5) in the RS intervention group using RNA-seq and UPLC-MS/MS, respectively. A network of the DEGs and the metabolites was constructed,q which indicated that RS regulates purine metabolism, linoleic acid metabolism, arachidonic acid metabolism, circadian rhythm, and phosphatidylinositol signaling pathway, and its target genes are Pik3c2a, Hspa8, Dnaja1, Arntl, Ugt1a1, Dbp, Rasd1, and Aldh1a3. Thus, the antihypertensive effects of RS can be attributed to its ability to improve vascular endothelial dysfunction by targeting multiple genes and pathways. Our findings provide new insights into the pathological mechanisms underlying prehypertension, along with novel targets for the prevention and treatment of hypertension.

Isorhynchophylline Regulates the Circadian Rhythm of the Hypothalamus in Spontaneously Hypertensive Rats to Treat Hypertension.

BACKGROUND: The neurotransmitter metabolism in spontaneously hypertensive rats (SHR) is disordered, and these disturbances in neurotransmitter levels can further exacerbate the development of hypertension. Neurotransmitters can affect the expression of circadian clock genes. OBJECTIVE: To clarify the time-dependent internal mechanism of the imbalance of the target neurotransmitter metabolic rhythm of spontaneously hypertensive rats, the circadian research was carried out by the method of targeted metabolomics and molecular biology technology. METHODS: We have explored the mechanism of isorhynchophylline regulating the circadian rhythm through the ERK signaling pathway and thus treating hypertension by detecting the changes of central hypothalamic biological clock rhythm genes after isorhynchophylline intervention, from hypothalamic neurotransmitter rhythmicity. RESULTS: The expression of rhythm genes in normal rats showed a certain rhythm at 6 time points, while the expression of rhythm genes in model rats decreased, and the gene rhythm returned to normal after isorhynchophylline treatment. Cosine analysis of 12 neurotransmitters in hypothalamus showed that there were 6 rhythmic neurotransmitters in the normal group, while in the model group, 4 of the 6 neurotransmitters lost their rhythmicity, and the rhythmicity returned to normal after isorhynchophylline intervention. Compared with the normal group, the expression of ERK protein in the model group increased significantly and decreased after isorhynchophylline treatment. CONCLUSION: The mechanism of isorhynchophylline treating hypertension is not only the regulation of serum neurotransmitters rhythm, but also acting on rhythm genes in the feedback loop of the central biological clock.

Effect of dietary inflammatory potential on the aging acceleration for cardiometabolic disease: A population-based study.

Background/Aim: Optimized dietary patterns have been considered an important determinant of delaying aging in cardiometabolic disease (CMD). Dietary pattern with high-level dietary inflammatory potential is a key risk factor for cardiometabolic disease, and has drawn increasing attention. The aim of this study was to investigate whether dietary pattern with high dietary inflammatory potential was associated with aging acceleration in cardiometabolic disease. Materials and methods: We analyzed the cross-sectional data from six survey cycles (1999-2000, 2001-2002, 2003-2004, 2005-2006, 2007-2008, and 2009-2010) of the National Health and Nutritional Examination Surveys (NHANES). A total of 16,681 non-institutionalized adults and non-pregnant females with CMD were included in this study. Dietary inflammatory index (DII) was used to assess the dietary inflammatory potential. The two age acceleration biomarkers were calculated by the residuals from regressing chronologic age on Klemera-Doubal method biological age (KDM BioAge) or Phenotypic Age (PhenoAge), termed "KDMAccel" and "PhenoAgeAccel." A multivariable linear regression accounting for multistage survey design and sampling weights was used in different models to investigate the association between DII and aging acceleration. Four sensitivity analyses were used to ensure the robustness of our results. Besides, we also analyzed the anti-aging effects of DASH-type dietary pattern and "Life's Simple 7". Results: For 16,681 participants with CMD, compared with the first tertile of DII after adjusting for all potential confounders, the patients with second tertile of DII showed a 1.02-years increase in KDMAccel and 0.63-years increase in PhenoAgeAccel (KDMAccel, ß = 1.02, 95% CI = 0.64 to 1.41, P < 0.001; PhenoAgeAccel, ß = 0.63, 95% CI = 0.44 to 0.82, P < 0.001), while the patients with the third tertile of DII showed a 1.48-years increase in KDMAccel and 1.22-years increase in PhenoAgeAccel (KDMAccel, ß = 1.48, 95% CI = 1.02 to 1.94, P < 0.001; PhenoAgeAccel, ß = 1.22, 95% CI = 1.01 to 1.43, P < 0.001). In addition, DASH-type dietary pattern was associated with a 0.57-years reduction in KDMAccel (ß = -0.57, 95% CI = -1.08 to -0.06, P = 0.031) and a 0.54-years reduction in PhenoAgeAccel (ß = -0.54, 95% CI = -0.80 to -0.28, P < 0.001). The each one-unit increase in CVH score was associated with a 1.58-years decrease in KDMAccel (ß = -1.58, 95% CI = -1.68 to -1.49, P < 0.001) and a 0.36-years in PhenoAgeAccel (ß = -0.36, 95% CI = -0.41 to -0.31, P < 0.001). Conclusion: Among CMD, the dietary pattern with high dietary inflammatory potential was association with aging acceleration, and the anti-aging potential of DASH-type dietary pattern and "Life's Simple 7" should also be given attention, but these observations require future prospective validation.

Natural drugs targeting inflammation pathways can be used to treat atherosclerosis.

Atherosclerosis (AS) is the chronic gradual degradation of arteries in combination with inflammation. Currently, the main research focus has been on interactions between inflammatory cells, inflammatory mediators, and immune mechanisms, while some studies have reported natural drugs were exerting a critical role against AS, whereas the usage of natural drugs was always limited by various factors such as poor penetration across biological barriers, low bioavailability, and unclear mechanisms. Herein, we reviewed the potential targets for inflammation against AS, discussed the underlying mechanisms of natural drugs for AS, particularly highlighted the dilemma of current research, and finally, offered perspectives in this field.

Precise Monitoring and Assessing Treatment Response of Sepsis-Induced Acute Lung Hypoxia with a Nitroreductase-Activated Golgi-Targetable Fluorescent Probe.

Sepsis-induced acute lung injury (ALI) is mostly attributed to an outbreak of reactive oxygen species (ROS), which makes leukocytes infiltrate into the lung and results in lung hypoxia. Nitroreductase (NTR) is significantly upregulated under hypoxia, which is commonly regarded as a potential biomarker for assessing sepsis-induced acute lung hypoxia. Increasing evidence shows that NTR in the Golgi apparatus could be induced in sepsis-induced ALI. Meanwhile, the prolyl hydroxylase (PHD) inhibitor (dimethyloxalylglycine, DMOG) attenuated sepsis-induced ALI through further increasing the level of Golgi NTR by improving hypoxia inducible factor-1α (HIF-1α) activity, but as yet, no Golgi-targetable probe has been developed for monitoring and assessing treatment response of sepsis-induced ALI. Herein, we report a Golgi-targetable probe, Gol-NTR, for monitoring and assessing treatment response of sepsis-induced ALI through mapping the generation of NTR. The probe displayed high sensitivity with a low detection limit of 54.8 ng/mL and good selectivity to NTR. In addition, due to the excellent characteristics of Golgi-targetable, Gol-NTR was successfully applied in mapping the change of Golgi NTR in cells and zebrafish caused by various stimuli. Most importantly, the production of Golgi NTR in the sepsis-induced ALI and the PHD inhibitor (DMOG) against sepsis-induced ALI were visualized and precisely assessed for the first time with the assistance of Gol-NTR. The results demonstrated the practicability of Gol-NTR for the precise monitoring and assessing of the personalized treatment response of sepsis-induced ALI.

Analyzing the pathogenesis of systemic lupus erythematosus complicated by atherosclerosis using transcriptome data.

Background: Accumulating evidence supports the predisposition of systemic lupus erythematosus (SLE) to atherosclerosis (AS). However, the common pathogenesis of these two diseases remains unclear. This study aimed to explore the mechanisms of SLE complicated by AS. Methods: Gene expression profiles of SLE (GSE50772) and AS (GSE100927) were downloaded from the Gene Expression Omnibus. We analyzed differentially expressed genes (DEGs) of SLE and AS and performed enrichment analyses separately. After analyzing the common DEGs (CDEGs), we performed functional enrichment analysis, protein-protein interaction (PPI) network analysis, and hub genes (HGs) identification of CDEGs. Then, we performed a co-expression analysis of HGs and verified their expression and diagnostic value. We further explored immune cell infiltration and analyzed the correlation between HGs and infiltrating immune cells (IICs). Finally, we verified the reliability of the screening pathway. Results: We obtained 530 DEGs from the GSE50772 dataset and 448 DEGs from the GSE100927 dataset. The results of the enrichment analysis showed that there were many similar immune- and inflammation-related processes between the two diseases. We analyzed 26 CDEGs (two downregulated genes and 24 upregulated genes) and enrichment analysis highlighted the important role of the IL-17 signaling pathway. We identified five HGs (CCR1, CD163, IL1RN, MMP9, and SIGLEC1) using the CytoHubba plugin and HGs validation showed that the five HGs screened were reliable. Co-expression networks showed that five HGs can affect mononuclear cell migration. Immune cell infiltration analysis indicated monocytes in SLE and M0 macrophages in AS accounted for a high proportion of all IICs, and the difference in infiltration was obvious. We also found a significant positive correlation between CCR1, CD163, IL1RN, and MMP9 and monocytes in SLE, and a significant positive correlation between CCR1, IL1RN, MMP9, and SIGLEC1 and M0 macrophages in AS. Pathway validation also demonstrated that the IL-17 signaling pathway was a key pathway for the differentiation of monocytes into macrophages. Conclusions: The five HGs may promote the differentiation of monocytes into macrophages by influencing the IL-17 signaling pathway, leading to SLE complicated by AS. Our study provides insights into the mechanisms of SLE complicated by AS.

Effect of astragaloside IV and salvianolic acid B on antioxidant stress and vascular endothelial protection in the treatment of atherosclerosis based on metabonomics.

Vascular endothelial cells and oxidation reduction system play an important role in the pathogenesis of atherosclerosis (AS). If these conditions are disordered, it will inevitably lead to plaque formation and even rupture. Astragaloside IV (AsIV) and salvianolic acid B (Sal B) are the main active ingredients of Astragalus membranaceus and Salvia miltiorrhiza, respectively, and found to ameliorate vascular endothelial dysfunction and protect against oxidative stress in recent studies. However, it is still unknown if the combination of AsIV and Sal B (AsIV + Sal B) can inhibit the development of plaque through amplifying the protective effect of vascular endothelial cells and anti-oxidative stress effect. To clarify the role of AsIV + Sal B in AS, we observed the efficacy of each group (Control, Model, AsIV, Sal B, and AsIV + Sal B) by biomolecular assays, such as observing the pathological morphology of the aorta by oil red O staining, evaluating the level of oxidative stress and endothelial cells in the serum by the Elisa test, and analyzing the changes of all small molecule metabolites in liver tissue by UPLC-QTOF-MS. Results showed that AsIV, Sal B and AsIV + Sal B decreased the deposition of lipid in the arterial wall, so as to exert the effect of anti-oxidant stress and vascular endothelial protection, where the inhibitory effect of AsIV + Sal B was the most obvious. Metabonomics analysis showed that Sal B regulated the metabolic pathways of arginine and proline. AsIV regulated glycerol metabolism and saturated fatty acid biosynthesis metabolism. AsIV + Sal B is mainly related to the regulation of the citrate cycle (TCA cycle), alanine, aspartic acid, and glutamate metabolism, cysteine, and methionine metabolism. Succinic acid and methionine are synergistic metabolites that exert an enhancing effect when AsIV and Sal B were used in combination. In conclusion, we demonstrated that AsIV acompanied with Sal B can be successfully used for anti-oxidative stress and vascular endothelial protection of AS, and succinic acid and methionine are the synergistic metabolites.