Associations between carotid plaque shape, biomechanical parameters, and ischemic stroke in mild carotid stenosis with a single plaque.

PURPOSE: This cross-sectional cohort-comparison observational study investigated the value of high-frame-rate vector flow (V Flow) imaging for evaluating differences in carotid plaque shape and biomechanical parameters in patients with mild stenosis according to a recent history of ipsilateral ischemic stroke. METHODS: The present study included 352 patients from February 2023 to October 2023, who were categorized as symptomatic or asymptomatic based on a history of recent ischemic stroke and ipsilateral ischemic lesions detected on head computed tomography or magnetic resonance imaging. A Mindray Resona R9 system was used for B-mode ultrasonography and V Flow imaging. The upstream and downstream surfaces of the plaques were examined at the carotid bifurcation for wall shear stress (WSS), oscillatory shear index (OSI), and turbulence index, which performed peri-plaque biomechanical condition. Multivariable logistic regression models were used to determine associations between plaque shape, V Flow parameters, and ischemic stroke. RESULTS: Symptomatic patients exhibited higher WSS values for the upstream and downstream surfaces of carotid plaque, as well as higher OSI and turbulence index values for the downstream surface. Type Ⅲ plaques and higher WSS and OSI values for the downstream surface of the plaque were significantly associated with ischemic stroke. Type Ⅲ plaques were more prevalent in symptomatic patients and demonstrated much higher WSS and OSI values for the downstream plaque surface in both groups. CONCLUSION: High-frame-rate V Flow imaging could assess peri-plaque biomechanical forces and may provide effective imaging biomarkers for early prediction of ischemic stroke in patients with mild stenosis.

Machine learning and experimental screening of chromatin regulator signatures and potential drugs in hepatitis B related hepatocellular carcinoma.

Many evidences have confirmed that chromatin regulator factors (CRs) are involved in the progression of cancer, but its potential mechanism of affecting hepatitis B related hepatocellular carcinoma still needs to be studied. Our study detected the CRs that affect hepatitis B related hepatocellular carcinoma (HBV-HCC) through machine learning analysis, conducted the analysis of immune cells, constructed the relevant risk model and immune function infiltration, and predicted the potential therapeutic drugs. We found that these CRs were significantly related to the immune cells of Macrophages, B cells, CD8+T cells, etc., and PBK, AURKA, TOP2A and AURKB were the potential risk CRs of HBV-HCC. The expression levels of these four CRs increased in HepG2.2.15 cells and the liver of HBV-HCC patients, consistent with the predicted risk model. Subsequently, ten potential drugs closely related to the risk CRs were finally obtained, experimental research on resveratrol has shown that it can inhibit the proliferation of HepG2.2.15 cells and potentially inhibit the occurrence and development of HBV-HCC. Our study provides novel insights into the function of CRs in HBV-HCC and certain ideas for more accurate targeted therapy.Communicated by Ramaswamy H. Sarma.

Associations of plaque morphology and location with Intraplaque neovascularization in the carotid artery by contrast-enhanced ultrasound imaging.

Objective: Intraplaque neovascularization (IPN) is a known indicator of plaque vulnerability, and is thus considered a predictor of stroke. The morphology and location of the carotid plaque may be correlated with plaque vulnerability. Therefore, our study aimed to examine the associations of carotid plaque morphology and location with IPN. Methods: A total of 141 patients with carotid atherosclerosis (mean age, 64.99 ± 10.96 years) who underwent carotid contrast-enhanced ultrasound (CEUS) between November 2021 and March 2022 were retrospectively analyzed. IPN was graded according to the presence and location of microbubbles within the plaque. The association of IPN grade with carotid plaque morphology and location was evaluated using ordered logistic regression. Results: Of the 171 plaques, 89 (52%) were IPN Grade 0, 21 (12.2%) were Grade 1, and 61 (35.6%) were Grade 2. IPN grade significantly associated with both plaque morphology and location, with higher grades observed among Type III morphology and common carotid artery plaques. Significant negative association was further shown between IPN grade and serum high-density lipoprotein cholesterol (HDL-C) level. Plaque morphology and location, and HDL-C remained significantly associated with IPN grade after adjusting for confounding factors. Conclusion: The location and morphology of carotid plaques were significantly associated with the IPN grade on CEUS, and therefore show potential as biomarkers for plaque vulnerability. Serum HDL-C was also identified as a protective factor against IPN, and may play a role in the management of carotid atherosclerosis. Our study provided a potential strategy for identification of vulnerable carotid plaques and elucidated the important imaging predictors of stroke.

Manganese-enriched photonic/catalytic nanomedicine augments synergistic anti-TNBC photothermal/nanocatalytic/immuno-therapy via activating cGAS-STING pathway.

As the clinical efficacy of immunotherapy for triple-negative breast cancer (TNBC) remains limited, exploring new immunotherapy approaches is still indispensable. Mn2+ has been proven as a cGAS-STING agonist to remarkably enhance antitumor immunity. Here, we report a combined tumor-therapeutic strategy based on Prussian blue (PB)-mediated photothermal therapy with Mn2+-augmented immunotherapy by synergistically activating the cGAS-STING pathway. Mn-enriched photonic nanomedicine (MnPB-MnOx) were constructed by integrating MnOx onto the surface of Mn-doped PB nanoparticles. All components of MnPB-MnOx are biocompatible and biodegradable, wherein sufficient Mn are endowed through rational nanostructure design, conferring easier cGAS-STING activation. Additionally, tumor hyperthermia strengthened by MnPB under near-infrared light radiation, synergistic with the generation of reactive oxygen species catalyzed by MnOx, double hits cancer cells to release abundant tumor-associated antigens for further promoting immune response stimulation. The local anti-TNBC efficacy of photothermal/immuno-therapy has been proven effective in subcutaneous 4T1-bearing mice. Especially, it has been systematically demonstrated in bilateral orthotopic 4T1-bearing mice that the as-proposed treatment could successfully activate innate and adaptive immunity, and local therapy could engender systemic responses to suppress the distant tumors. Collectively, this work represents a proof-of-concept for a non-invasive Mn-based tumor-immunotherapeutic modality, providing a paradigm for the immunotherapy of metastatic-prone tumors.

Carotid plaque score and ischemic stroke risk stratification through a combination of B-mode and contrast-enhanced ultrasound in patients with low and intermediate carotid stenosis.

Objective: The occurrence of ischemic stroke (IS) is closely related to the characteristics of carotid plaque (CP). Due to the effect of stroke risk stratification based on B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) that has not been studied in patients with low and intermediate carotid stenosis, we construct and validate a CP score and ischemic stroke risk stratification (ISRS) using a combination of B-mode and CEUS, in order to provide new convenient strategies to stratify these patients to prevent stroke. Materials and methods: This retrospective study evaluated 705 patients with low and intermediate carotid stenosis who underwent B-mode and CEUS from November 2021 to April 2023. Qualitative B-mode and CEUS features of carotid plaques were analyzed using a univariable and multivariable logistic regression to construct the CP score. Then, we combined the CP score with Essen stroke risk score (ESRS) to develop ISRS. Results: This study included a total of 705 patients with low and intermediate carotid stenosis, of which 394 were symptomatic patients (with a mean age of 71.03 ± 10.48 years) and 311 were asymptomatic patients (with a mean age of 65.13 ± 10.31 years). Plaque echogenicity, plaque morphology, carotid intima-media thickness in B-mode US and intraplaque neovascularization grading and perfusion pattern in CEUS were significantly associated with IS. The ISRS incorporating these five predictors and ESRS showed good discrimination and calibration in both primary cohort [area under the curve (AUC), 0.91; Hosmer-Lemeshow test, p = 0.903] and validation cohort (AUC, 0.84; Hosmer-Lemeshow test, p = 0.886). Conclusion: We developed an effective and practical tool to identify and stratify patients with low and intermediate carotid stenosis, based on the CP score and ISRS estimation. Our study may provide new insights into managing patients with no indication of surgery.

Nao Tan Qing ameliorates Alzheimer's disease-like pathology by regulating glycolipid metabolism and neuroinflammation: A network pharmacology analysis and biological validation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and currently there are no available treatments. Alongside the conventional Aß and tau hypotheses, neuroinflammation and metabolism disruption have also been regarded as crucial hallmarks of AD. In this study, a novel Chinese formula Nao Tan Qing (NTQ) was developed and shown to improve AD. In vivo experiments showed that NTQ significantly mitigated cognitive impairment, Aß burden and neuroinflammation in a transgenic AD mouse model (5×FAD). Network pharmacology results revealed that the active components of NTQ could target inflammatory and metabolic pathways. In addition, hippocampal transcriptomics suggested that NTQ regulated signaling pathways related to inflammation and lipid metabolism. Consistently, serum metabolomics further indicated that NTQ could modulate glycolipid metabolism. In summary, a combination of systems pharmacology analysis and biological validation study demonstrates that NTQ could alleviate behavioral abnormality and pathological alterations of AD by targeting glycolipid metabolism and neuroinflammation, and is accordingly a potential therapeutic agent for AD.

Exploration of the Potential Mechanism of Qi Yin San Liang San Decoction in the Treatment of EGFRI-Related Adverse Skin Reactions Using Network Pharmacology and In Vitro Experiments.

Background: Adverse skin reactions are the most common side effects of epidermal growth factor receptor inhibitors (EGFRIs) in the treatment of cancer, significantly affecting the survival rate and quality of life of patients. Qi Yin San Liang San Decoction (QYSLS) comes from folk prescription and is currently used in the clinical treatment of adverse skin reactions caused by EGFRIs. However, its therapeutic mechanism remains unclear. Objectives: To explore the potential mechanism of QYSLS in the treatment of adverse skin reactions caused by EGFR inhibition using network pharmacology and experimental research. Methods: First, we verified the effectiveness of QYSLS in vivo using model mice. Second, the related targets of adverse skin reactions associated with EGFR inhibition were predicted by the Gene Expression Omnibus (GEO) database, and effective components and predictive targets of QYSLS were analyzed by Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Batman-TCM databases. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed via the Bioconductor (R) V3.8 bioinformatics software. Molecular docking studies verified the selected key ingredients and targets. Finally, the results of network pharmacology were verified by in vitro experiments. Results: In the in vivo mouse model, QYSLS effectively reduced the occurrence of skin side effects. Network pharmacological results showed that the active ingredient luteolin, quercetin, licochalcone a, and kaempferol and the effective targets prostaglandin-endoperoxide synthase 2 (PTGS2), matrix metallopeptidase 9 (MMP9), and C-C motif chemokine ligand 2 (CCL2) were related to the interleukin-17 (IL-17) and tumor necrosis factor (TNF) pathway. Subsequently, the related active compounds and targets were verified using HaCaT cells as an in vitro adverse reaction model. The results showed that luteolin and quercetin increased the expression of PTGS2 and MMP9 and reduced the expression of CCL2 in HaCaT cells treated with gefitinib. Conclusions: The results revealed that QYSLS effectively treats EGFRI-related adverse skin reactions through multi-target and multi-pathway mechanisms. Luteolin and quercetin may be the core active ingredients of QYSLS in the treatment of EGFRI-related adverse skin reactions, and their therapeutic effects are potentially mediated through PTGS2, CCL2, and MMP9 in the IL-17 and TNF signaling pathway.

Spatiotemporal Dynamics and Mechanisms of Actin Cytoskeletal Re-modeling in Cells Perforated by Ultrasound-Driven Microbubbles.

To develop new strategies for improving the efficacy and biosafety of sonoporation-based macromolecule delivery, it is essential to understand the mechanisms underlying plasma membrane re-sealing and function recovery of the cells perforated by ultrasound-driven microbubbles. However, we lack a clear understanding of the spatiotemporal dynamics of the disrupted actin cytoskeleton and its role in the re-sealing of sonoporated cells. Here we used a customized experimental setup for single-pulse ultrasound (133.33-µs duration and 0.70-MPa peak negative pressure) exposure to microbubbles and for real-time recording of single-cell (human umbilical vein endothelial cell) responses by laser confocal microscopic imaging. We found that in reversibly sonoporated cells, the locally disrupted actin cytoskeleton, which was spatially correlated with the perforated plasma membrane, underwent three successive phases (expansion; contraction and re-sealing; and recovery) to re-model and that each phase of the disrupted actin cytoskeleton was approximately synchronized with that of the perforated plasma membrane. Moreover, compared with the closing time of the perforated plasma membrane, the same time was used for the re-sealing of the actin cytoskeleton in mildly sonoporated cells and a longer time was required in moderately sonoporated cells. Further, the generation, directional migration, accumulation and re-polymerization of globular actin polymers during the three phases drove the re-modeling of the actin cytoskeleton. However, in irreversibly sonoporated cells, the actin cytoskeleton, which underwent expansion and no contraction, was progressively de-polymerized and could not be re-sealed. Finally, we found that intracellular calcium transients were essential for the recruitment of globular actin and the re-modeling of the actin cytoskeleton. These results provide new insight into the role of actin cytoskeleton dynamics in the re-sealing of sonoporated cells and serve to guide the design of new strategies for sonoporation-based delivery.

Machine learning enables discovery of Gentianine targeting TLR4/NF-κB pathway to repair ischemic stroke injury.

Inflammatory response is believed to accelerate the development of stroke injury. Gentianine, an alkaloid isolated from Gentiana Scabra Bunge, shows effectiveness in anti-inflammation. In this study, the effect of Gentianine on transient middle cerebral artery occlusion (tMCAO) induced mouse model in vivo and further related mechanism in LPS-injuried microglia BV-2 cells in vitro were explored. Effect of Gentianine on tMCAO mouse demonstrated that Gentianine significantly ameliorated tMCAO induced ischemic injury by decreasing brain infarct volume and increasing the neurological score and upper limb muscle strength. Meanwhile, Gentianine significantly decreased the release of serum inflammatory cytokines. Machine learning enables that Gentianine might had anti-ischemic stroke effect through the TLR4/NF-κB signaling pathway. This was verified in vivo and in vitro. Gentianine significantly decrease the TLR4 and Iba-1 expression in vivo. These results also verified in BV-2 cells. Gentianine significantly decreased TLR4, MyD88 and NF-κB expression, as well as NO production and inflammatory cytokines release. Gentianine co-treatment with TLR4 inhibitor, further decreased TLR4, MyD88 and NF-κB expression, NO production, as well as the inflammatory cytokines. Taken together, Gentianine could be used as a potential anti-ischemic stroke agent by suppressing inflammatory responses via TLR4/NF-κB signaling pathway. This study is expected to provide an integrated traditional Chinese and western medicine solution to find potential anti-ischemic stroke compounds based on machine learning.

Plasma Membrane Blebbing Dynamics Involved in the Reversibly Perforated Cell by Ultrasound-Driven Microbubbles.

The perforation of plasma membrane by ultrasound-driven microbubbles (i.e., sonoporation) provides a temporary window for transporting macromolecules into the cytoplasm that is promising with respect to drug delivery and gene therapy. To improve the efficacy of delivery while ensuring biosafety, membrane resealing and cell recovery are required to help sonoporated cells defy membrane injury and regain their normal function. Blebs are found to accompany the recovery of sonoporated cells. However, the spatiotemporal characteristics of blebs and the underlying mechanisms remain unclear. With a customized platform for ultrasound exposure and 2-D/3-D live single-cell imaging, localized membrane perforation was induced with ultrasound-driven microbubbles, and the cellular responses were monitored using multiple fluorescent probes. The results indicated that localized blebs undergoing four phases (nucleation, expansion, pausing and retraction) on a time scale of tens of seconds to minutes were specifically involved in the reversibly sonoporated cells. The blebs spatially correlated with the membrane perforation site and temporally lagged (about tens of seconds to minutes) the resealing of perforated membrane. Their diameter (about several microns) and lifetime (about tens of seconds to minutes) positively correlated with the degree of sonoporation. Further studies revealed that intracellular calcium transients might be an upstream signal for triggering blebbing nucleation; exocytotic lysosomes not only contributed to resealing of the perforated membrane, but also to the increasing bleb volume during expansion; and actin components accumulation facilitated bleb retraction. These results provide new insight into the short-term strategies that the sonoporated cell employs to recover on membrane perforation and to remodel membrane structure and a biophysical foundation for sonoporation-based therapy.

A machine learning-driven study indicates emodin improves cardiac hypertrophy by modulation of mitochondrial SIRT3 signaling.

Cardiac hypertrophy (CH) is an enormous risk factor in the process of heart failure development, however, there is still lack of effective treatment for CH. Mitochondrial protection is an effective way against CH. Rheum palmatum L. (rhubarb) has been used to treat chronic heart diseases such as heart failure, especially to inhibit cardiac compensatory enlargement. The aim of this study was to explore the pharmacodynamic component of rhubarb and reveal its pharmacological effects and targets in the treatment of CH. Based on network pharmacology and machine learning approach, ingredients of rhubarb and targets for CH were extracted and surflex docking was conducted for obtaining the optimal ingredient-target combination(s) and emodin-SIRT3 was identified for further functional analysis. Transverse aortic constriction or isoproterenol induced CH mice and phenylephrine injured cardiomyocytes were used to verify the mitochondria protection effect and CH improvement of emodin in vivo and in vitro by modulation of mitochondrial SIRT3 signaling. The results showed that emodin could block agonist-induced and pressure overload-mediated CH. Emodin prevented mitochondrial dysfunction and its underlying mechanism was attributed to the activation of SIRT3, but the effect was not obvious with the presence of SIRT3 inhibitors (3-TYP)/SIRT3 siRNA. Furthermore, PGC-1ɑ was involved in the process of emodin regulating SIRT3 signaling pathway as an upstream target. Our findings clarified the main material basis and mechanism of rhubarb in the treatment of CH. Emodin, as the major ingredient of rhubarb, has therapeutic potential for CH through mitochondrial protection due to the modulation of SIRT3 signaling.

Metabolomic Profiling of the Synergistic Effects of Ginsenoside Rg1 in Combination with Neural Stem Cell Transplantation in Ischemic Stroke Rats.

As the greatest medical and socioeconomic problem in developing countries, stroke is the second or third leading cause of death in China and worldwide. In adult organisms suffering from stroke, transplanted stem cells have the ability to repair damaged tissues by regenerating autologous cells, while ginsenoside Rg1 could promote proliferation and differentiation of stem cells. Although obvious antistroke effects of ginsenoside Rg1 and transplanted stem cells have been verified in publications, the mechanism exploration remains challenging. Our study was carried out to investigate the synergistic effects of ginsenoside Rg1 and neural stem cell (NSC) transplantation on MCAO rats with a 1H NMR-based nontargeted metabolomics method to identify potential biomarkers and protein targets and discover the potential mechanism. NSCs transplantation after MCAO combined with ginsenoside Rg1 administration could significantly improve the cerebral infarct and neurological deficits. The treatment significantly intervened the levels of ten metabolites, and perturbed energy metabolism, amino acids metabolism, and lipids metabolism. And 11 enzymes were identified and verified as the targets of NSCs transplantation and ginsenoside Rg1 administration on MCAO rats. Our findings helped to improve the antistroke mechanism of NSCs transplantation and ginsenoside Rg1 and supply a theory basis for the combined research of stem cells and Chinese medicine in the future.

Artificial intelligence based discovery of the association between depression and chronic fatigue syndrome.

BACKGROUND: Both of the modern medicine and the traditional Chinese medicine classify depressive disorder (DD) and chronic fatigue syndrome (CFS) to one type of disease. Unveiling the association between depressive and the fatigue diseases provides a great opportunity to bridge the modern medicine with the traditional Chinese medicine. METHODS: In this work, 295 general participants were recruited to complete Zung Self-Rating Depression Scales and Chalder Fatigue Scales, and meanwhile, to donate plasma and urine samples for 1H NMR-metabolic profiling. Artificial intelligence methods was used to analysis the underlying association between DD and CFS. Principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to analyze the metabolic profiles with respect to gender and age. Variable importance in projection and t-test were employed in conjunction with the PLS-DA models to identify the metabolite biomarkers. Considering the asymmetry and complexity of the data, convolutional neural networks (CNN) model, an artificial intelligence method, was built to analyze the data characteristics between each groups. RESULTS: The results showed the gender- and age-related differences for the candidate biomarkers of the DD and the CFS diseases, and indicated the same and different biomarkers of the two diseases. PCA analysis for the data characteristics reflected that DD and CFS was separated completely in plasma metabolite. However, DD and CFS was merged into one group. LIMITATION: Lack of transcriptomic analysis limits the understanding of the association of the DD and the CFS diseases on gene level. CONCLUSION: The unmasked candidate biomarkers provide reliable evidence to explore the commonality and differences of the depressive and the fatigue diseases, and thereby, bridge over the traditional Chinese medicine with the modern medicine.

The walnut transcription factor JrGRAS2 contributes to high temperature stress tolerance involving in Dof transcriptional regulation and HSP protein expression.

BACKGROUND: GRAS transcription factor (TF) family is unique and numerous in higher plants with diverse functions that involving in plant growth and development processes, such as gibberellin (GA) signal transduction, root development, root nodule formation, and mycorrhiza formation. Walnut tree is exposed to various environmental stimulus that causing concern about its resistance mechanism. In order to understand the molecular mechanism of walnut to adversity response, a GRAS TF (JrGRAS2) was cloned and characterized from Juglans regia in this study. RESULTS: A 1500 bp promoter fragment of JrGRAS2 was identified from the genome of J. regia, in which the cis-elements were screened. This JrGRAS2 promoter displayed expression activity that was enhanced significantly by high temperature (HT) stress. Yeast one-hybrid assay, transient expression and chromatin immunoprecipitation (Chip)-PCR analysis revealed that JrDof3 could specifically bind to the DOFCOREZM motif and share similar expression patterns with JrGRAS2 under HT stress. The transcription of JrGRAS2 was induced by HT stress and up-regulated to 6.73-~11.96-fold in the leaf and 2.53-~4.50-fold in the root to control, respectively. JrGRAS2 was overexpressed in Arabidopsis, three lines with much high expression level of JrGRAS2 (S3, S7, and S8) were selected for HT stress tolerance analysis. Compared to the wild type (WT) Arabidopsis, S3, S7, and S8 exhibited enhanced seed germination rate, fresh weight accumulation, and activities of catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and glutathione-S-transferase (GST) under HT stress. In contrast, the Evans blue staining, electrolyte leakage (EL) rates, hydrogen dioxide (H2O2) and malondialdehyde (MDA) content of transgenic seedlings were all lower than those of WT exposed to HT stress. Furthermore, the expression of heat shock proteins (HSPs) in S3, S7, and S8 was significant higher than those in WT plants. The similar results were obtained in JrGRAS2 transient overexpression walnut lines under normal and HT stress conditions. CONCLUSIONS: Our results suggested that JrDof3 TF contributes to improve the HT stress response of JrGRAS2, which could effectively control the expression of HSPs to enhance HT stress tolerance. JrGRAS2 is an useful candidate gene for heat response in plant molecular breeding.

The Effect of Chinese Herbal Medicine on Quality of Life and Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Chinese herbal medicine (CHM) has a good effect of alleviating symptoms and improving quality of life and exercise tolerance in patients with heart failure with preserved ejection fraction (HFpEF), but it wasn't sufficiently valued and promoted because of the lack of evidence-based medical evidence. Aim: To systematically review the effect of CHM on quality of life and exercise tolerance in patients with HFpEF. Methods: We conducted a systematic literature search for Chinese and English studies in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, China Knowledge Resource Integrated Database, Wanfang Data, and China Science and Technology Journal Database. Databases were searched using terms relating to or describing CHM, HFpEF and randomized controlled trials, without any exclusion criteria for other types of diseases or disorders. Literature retrieval, data extraction, and risk of bias assessments were performed independently by two investigators. Differences were resolved by consensus. RevMan 5.3.0 was used for data analysis. Quantitative synthesis was used when the included studies were sufficiently homogeneous and subgroup analyses were performed for studies with different sample sizes and blind methods. GRADEpro was used to grade the available evidence to minimize bias in our findings. Results: Seventeen studies with 2,724 patients were enrolled in this review. ROB assessments showed a relatively high selection and performance bias. Meta-analyses showed that compared with conventional western medicine, combined CHM and conventional western medicine could significantly improve 6-min walk distance (MD = 52.13, 95% CI [46.91, 57.34], P < 0.00001), and it seemed to be more effective as compared with combined placebo and conventional western medicine. Similar results were observed for quality of life and the results were better in a larger sample. The GRADEpro showed a very low to moderate level of the available evidence. Conclusion: Combined CHM and conventional western medicine might be effective to improve exercise tolerance and quality of life in HFpEF patients, but new well-designed studies with larger sample size, strict randomization, and clear description about detection and reporting processes are needed to further strengthen this evidence.

Generation of Reactive Oxygen Species in Heterogeneously Sonoporated Cells by Microbubbles with Single-Pulse Ultrasound.

To develop and realize sonoporation-based macromolecule delivery, it is important to understand the underlying cellular bioeffects involved. It is known that an appropriate level of reactive oxygen species (ROS) is necessary to maintain normal physiologic function, but excessive ROS triggers adverse downstream bioeffects. However, it is still unclear whether a relationship exists between intracellular ROS levels and sonoporation. Using a customized platform for 1.5-MHz ultrasound exposure (13.33 µs duration and 0.70 MPa peak negative pressure) and imaging the dynamics of sonoporation and intracellular ROS at the single-cell level, we quantified the exogenous molecular uptake and the concentration of intracellular ROS indicator to evaluate the extent of sonoporation and ROS change, respectively. Our results revealed that the intracellular ROS level was correlated with the degree of the sonoporation. (i) Within ~120 s of the onset of ultrasound, during which membrane perforation and complete membrane resealing occurred, intracellular ROS rapidly decreased because of extracellular diffusion of dichlorofluorescein through the perforated membrane and positively correlated with the degree of the sonoporation. (ii) In the following 270 s (120-390 s post-exposure), ROS generation in reversibly sonoporated cells gradually increased and was positively correlated with the degree of the sonoporation. (iii) The ROS level in irreversibly sonoporated cells reduced to depletion during this time interval. It is possible that ROS generation in reversibly sonoporated cells can impact their long-term fate. These results thus provide new insight into the biological response to sonoporation.

Effects of Qijian mixture on type 2 diabetes assessed by metabonomics, gut microbiota and network pharmacology.

Qijian mixture, a new traditional Chinese medicine (TCM) formula comprising of Astragalus membranaceus, Ramulus euonymi, Coptis chinensis and Pueraria lobata, was designed to ameliorate the type 2 diabetes (T2D), and its safety and efficacy were evaluated in the research by metabonomics, gut microbiota and system pharmacology. To study the hypoglycemic effect of Qijian mixture, male KKay mice (28-30 g, 8-9 week) and C57/BL6 mice (18-19 g, 8-9 week) were used. Thirty KKay diabetic mice were randomly distributed into 5 groups, abbreviated as Model group (Model), Low Qijian Mixture group (QJM(L)), High Qijian Mixture group (QJM(H)), Chinese Medicine (Gegen Qinlian Decoction) Positive group (GGQL), and Western Medicine (Metformin hydrochloride) Positive group (Metformin). C57/BL6 was considered as the healthy control group (Control). Moreover, a system pharmacology approach was utilized to assess the physiological targets involved in the action of Qijian mixture. There was no adverse drug reaction of Qijian mixture in the acute toxicity study and HE result, and, compared with Model group, Qijian mixture could modulate blood glycemic level safely and effectively. Qijian Mixture was lesser effective than metformin hydrochloride; however, both showed similar hypoglycemic trend. Based on 1H NMR based metabonomics study, the profoundly altered metabolites in Qijian mixture treatment group were identified. Qijian mixture-related 55 proteins and 4 signaling pathways, including galactose metabolism, valine, leucine and isoleucine degradation metabolism, aminoacyl-tRNA biosynthesis metabolism and alanine, aspartate and glutamate metabolism pathways, were explored. The PCoA analysis of gut microbiota revealed that Qijian mixture treatment profoundly enriched bacteroidetes. In addition, the system pharmacology paradigm revealed that Qijian mixture acted through TP53, AKT1 and PPARA proteins. It was concluded that Qijian mixture effectively alleviated T2D, and this effect was linked with the altered features of the metabolite profiles and the gut microbiota.

Mechanism of Chinese Medicine Herbs Effects on Chronic Heart Failure Based on Metabolic Profiling.

Chronic heart failure (CHF) is a major public health problem in huge population worldwide. The detailed understanding of CHF mechanism is still limited. Zheng (syndrome) is the criterion of diagnosis and therapeutic in Traditional Chinese Medicine (TCM). Syndrome prediction may be a better approach for understanding of CHF mechanism basis and its treatment. The authors studied disturbed metabolic biomarkers to construct a predicting mode to assess the diagnostic value of different syndrome of CHF and explore the Chinese herbal medicine (CHM) efficacy on CHF patients. A cohort of 110 patients from 11 independent centers was studied and all patients were divided into 3 groups according to TCM syndrome differentiation: group of Qi deficiency syndrome, group of Qi deficiency and Blood stasis syndrome, and group of Qi deficiency and Blood stasis and Water retention syndrome. Plasma metabolomic profiles were determined by UPLC-TOF/MS and analyzed by multivariate statistics. About 6 representative metabolites were highly possible to be associated with CHF, 4, 7, and 5 metabolites with Qi deficiency syndrome, Qi deficiency and Blood stasis syndrome, and Qi deficiency and Blood stasis and Water retention syndrome (VIP > 1, p < 0.05). The diagnostic model was further constructed based on the metabolites to diagnose other CHF patients with satisfying sensitivity and specificity (sensitivity and specificity are 97.1 and 80.6% for CHF group vs. NH group; 97.1 and 80.0% for QD group vs. NH group; 97.1 and 79.5% for QB group vs. NH group; 97.1 and 88.9% for QBW group vs. NH group), validating the robustness of plasma metabolic profiling to diagnostic strategy. By comparison of the metabolic profiles, 9 biomarkers, 2-arachidonoylglycerophosphocholine, LysoPE 16:0, PS 21:0, LysoPE 20:4, LysoPE 18:0, linoleic acid, LysoPE 18:2, 4-hydroxybenzenesulfonic acid, and LysoPE 22:6, may be especially for the effect of CHM granules. A predicting model was attempted to construct and predict patient based on the related symptoms of CHF and the potential biomarkers regulated by CHM were explored. This trial was registered with NCT01939236 (https://clinicaltrials.gov/).

Significance of Resveratrol in Clinical Management of Chronic Diseases.

Resveratrol could be beneficial to health and provides protection against a wide array of pathologies and age-associated problems, as evident from preclinical studies. However, a comparison of animal and human studies reveals that this dietary polyphenol cannot protect against metabolic diseases and their associated complications. The clinical outcomes are affected by many factors such as sample size. This article not only presents a comprehensive review of the current advances concerning the dose, the extent of absorption, interaction and toxicity of resveratrol in human studies, but also describes its therapeutic effects against several chronic diseases such as diabetes mellitus, obesity, cardiovascular diseases, cancer and aging and the related diseases.

The Synthesis and Evaluation of Arctigenin Amino Acid Ester Derivatives.

The use of arctigenin (ARG), a traditional medicine with many pharmacological activities, has been restricted due to its poor solubility in water. Five amino acid derivatives of ARG have been synthesized using glycine, o-alanine, valine, leucine, and isoleucine, which have t-butyloxy carbonyl (BOC) as a protective group. In this study, we examined the effects of removing these protective groups. The results showed that the amino acid derivatives have better solubility and nitrite-clearing ability than ARG. Among the compounds tested, the amino acid derivatives without protective group were the best. Based on these results, ARG and its two amino acid derivatives without protective group (ARG8, ARG10) were selected to evaluate their anti-tumor activity in vivo at a dosage of 40 mg/kg. The results indicated that ARG8 and ARG10 both exhibit more anti-tumor activity than ARG in H22 tumor-bearing mice. The tumor inhibition rates of ARG8 and ARG10 were 69.27 and 43.58%, which was much higher than ARG. Furthermore, the mice treated with these compounds exhibited less damage to the liver, kidney and immune organs compared with the positive group. Furthermore, ARG8 and ARG10 improved the serum cytokine levels significantly compared to ARG. In brief, this study provides a method to improve the water solubility of drugs, and we also provide a reference basis for new drug development.