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In China, due to the influence of geological tectonics, the phenomenon of primary structural coal and tectonic coal stratification exists in many coal seams. The existence of tectonic coal leads to a sharp increase in the risk of composite coal seam outburst, which seriously restricts the safe production of coal mines. According to the gas diffusion state in soft and hard composite coal bodies, the mechanical instability law of composite coal with unsteady diffusion was simulated and analyzed. The calculation model of adsorbed gas expansion energy by unsteady diffusion was established, and the influence of steady and unsteady diffusion on the expansion energy of adsorbed gas was discussed. The control effect of adsorbed gas expansion energy on outburst was analyzed from the perspective of energy, and the disaster-causing mechanism of composite coal outburst instability by unsteady diffusion was elucidated. The results shown that, the existence of tectonic coals in the composite coal seams could increase the plastic damage degree to the adjacent primary structural coals, and improve the gas migration rate within the plastic zone of the primary structural coals, thus increasing the risk of coal and gas outbursts. The expansion energy of adsorbed gas in primary structural coal and tectonic coal under unsteady diffusion condition was 0.50 - 0.57 times and 3.36 - 3.38 times higher than that under steady diffusion conditions, respectively. The presence of tectonic coals in composite coal seams led to a huge gas concentration difference between the fissure and matrix systems within the primary structural coal, which resulted in the rapid desorption of adsorbed gas within the primary structural coal matrix, increasing the expansion energy of adsorbed gas in the adjacent primary coals, and thus significantly increased the outburst risk of composite coal seam.

Abstract To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic‐gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL‐10)+ EVs to promote M2 polarization of macrophage, and SRY‐box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose‐of‐action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)‐sensitive self‐assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl‐hydrogel microspheres (PGE), respectively. These materials are mixed to form a “microspheres‐in‐gel” KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL‐10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor‐α and IL‐1β levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti‐inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic‐gates strategies for OA treatment.

BackgroundAlthough social capital has been linked to dietary intake particularly in disadvantaged populations, little is known about the mechanisms. This study aimed to investigate whether social support (SS) and nutrition knowledge (NK) mediate the association between social capital and healthy eating habits.MethodsA probability sample of two ethnic minority groups in Yunnan Province, Southwest China were included (n = 1,033, mean age 47.5 ± 14.7 years). Bonding and bridging social capital (BOC and BRC) were assessed with the Personal Social Capital Scale (PSCS-16). Dietary data were evaluated with the Chinese Healthy Eating Index (CHEI), a measure of diet quality which reflects adherence to the Chinese Dietary Guidelines. NK and SS were measured with a validated questionnaire and scale, respectively. Structural Equation Modeling was used to calculate the direct, indirect and total effects of social capital on CHEI scores.ResultsThe mean score of CHEI was 57.4 ± 9.8, which was significantly lower in men and older people. Low adherence to dietary guidelines were to observed in the consumption of dairy, beans, nuts, animal-source food vegetables and fruits. BOC and BRC were positively associated with CHEI score (β = 0.37 and 0.38, all p

In order to study the change characteristics of unit liquid injection volume during hydraulic fracturing of coal seams, using the engineering test method, taking the 1703 working face of Jinzhong Coal Mine in Junlian County, Yibin City, Sichuan Province as the test site. Through monitoring and analyzing the unit liquid flow of each pipeline in the process of borehole hydraulic fracturing, it is found that the fitting curves of unit liquid flow of liquid inlet pipe and liquid return pipe are “parabola” in the process of normal hydraulic fracturing, while the actual unit liquid injection volume can be divided into falling stage and fluctuating stage. Combined with the change of liquid injection pressure in the process of hydraulic fracturing, it is found that the liquid injection pressure will appear obvious “pressure relief-recovery” phenomenon when the coal body appears cracking and crack propagation, and the unit liquid injection volume will appear “ rise-recover ” phenomenon, and the two phenomenon are synchronous. In addition, the whole hydraulic fracturing process is divided into three stages according to the change characteristics of the unit liquid injection volume in the hydraulic fracturing process: filling stage, energy storage and coal cracking cycle stage and stop cracking stage.

Cigarette combustion has the potential to generate over 7000 chemicals, the majority of which are reactive free radicals that are known to trigger pro-inflammatory and carcinogenic responses. Numerous contemporary investigations have proposed that the pathophysiological and cellular mechanisms underlying the release of extracellular vesicles (EVs) in response to cigarette smoke (CS) may serve as potential pathways for CS-induced pathogenesis, while also reflecting the physiological state of the originating cells. This review provides a concise overview of the pathophysiological mechanisms linked to CS-induced EVs in various lung diseases, including chronic obstructive pulmonary disease, lung cancer, pulmonary fibrosis, and pulmonary hypertension. Additionally, it explores the potential and prospects of EVs as diagnostic biomarkers for CS-related lung diseases.

Jingzhi Guanxin Oral Liquids (JZGX), a traditional Chinese medicine formulation prepared from the decoction of five herbs, has been utilized to relieve chest pain with coronary artery disease (CAD). However, the chemical composition and therapeutic mechanisms of JZGX remain obscured. In this research, the potential targets and pathways of JZGX against CAD were anticipated through network pharmacology based on analyzing its chemical constituents using UPLC-Q-TOF-MS/MS. One hundred seven ingredients in JZGX were identified. The 39 active chemicals and 37 key targets were screened, and CAD-related signaling pathways were clustered, mainly associated with lipid metabolism. Subsequently, the atherosclerotic CAD animal model employing 24 weeks of high-fat diet (HFD) ApoE−/− mice was constructed to investigate the JZGX efficacy and underlying mechanisms validating network forecasts. The histological staining examination and cardiovascular biomarker tests confirmed that JZGX reduced plaque formation in the aorta and decreased blood lipids in vivo. It featured anti-inflammatory, anti-thrombotic, and myocardial protective effects. JZGX prevented excessive lipid deposits and inflammation within the liver and exhibited hepatoprotective properties. Serum untargeted metabolomics analysis indicated that JZGX ameliorated metabolic abnormalities in atherosclerotic CAD mice and prompted lipid metabolism, especially linoleic acid. The PPARs and attached critical targets (SREBP1, FASN, PTGS2, and CYP3A), filtered from the networks and connected with lipid metabolism, were dramatically modulated through JZGX administration, as revealed by western blotting. The molecular docking outcomes showed that all 39 active ingredients in JZGX had good binding activity with PPARα and PPARγ. These findings illustrate that JZGX alleviates atherosclerotic CAD progression by remodeling the lipid metabolism and regulating PPAR-related proteins.

The management of rock mass deformation in high-stress roadways is a pivotal aspect of deep geotechnical engineering. Given the fruitful outcomes of research in rock mechanics regarding traditional confining pressure control methods, scholars have increasingly turned their attention to exploring pressure-relieving techniques, including borehole pressure relief and blasting pressure relief. However, there is limited research on pressure relief methods for deep-buried hard rock tunnels. This article commences with an overview of pressure relief in the roadway and conducts a detailed study on the parameters and methods of pressure relief in the roadway. To address safety and mining efficiency challenges, such as severe deformation leading to support failures, this study conducted a parameter analysis using the Sanshandao Gold Mine as a case study. Based on existing support methods, a strategy for arranging pressure relief roadways at varying distances from the main roadway is proposed, significantly enhancing the stress environment there. Numerical simulation software was employed to model two scenarios: (1) excavating the pressure relief roadway, main roadway, and maintenance roadway simultaneously and (2) first excavating the pressure relief roadway, followed by the main roadway and the maintenance roadway simultaneously. Simulation results indicated that the first pressure relief approach outperforms the second. The optimal position for both pressure relief roadways is 15 m from the main roadway, resulting in maximum deformation of the main roadway within 100 mm. These findings align with on-site stress monitoring data and satisfy safety production criteria. The research offers a theoretical foundation for similar pressure relief techniques in deeply buried, high-stress roadways.

Gas diffusion ability directly affects gas exploitation, outburst risk, emission and content determination. In order to study the influence of stress, gas pressure and temperature on gas diffusion coefficient in coal, the gas diffusion coefficient in columnar coal sample was measured with stable concentration difference, which avoided the model dependence that caused by deducing diffusion coefficient through desorption curve. The experimental results shown that the diffusion coefficient was approximately negative linear related to the effective stress for both the adsorbed methane and the non-adsorbed helium, but it was less affected than the permeability. The methane diffusion coefficient decreased as a power function with increasing inlet pressure (concentration gradient), and the relationship with temperature satisfied the Arrhenius formula. The diffusion coefficient measured by the steady-state method was compared with those obtained by the classical model and the time-varying model. It was found that the obtained diffusion coefficients were of the same order of magnitude, the sizes can be several times different, and the variation trend of diffusion coefficient was different with increasing gas pressure. Based on the law of diffusion coefficient affected by pressure (concentration) and temperature, a variable diffusion coefficient model was established. The gas desorption for granular coal at constant and variable temperature was predicted utilizing measured diffusion coefficient for columnar coal, and the prediction results were validated by desorption test. It indicated that the model can well reflect the gas diffusion process in the coal matrix under both constant and variable temperature condition.

Atherosclerosis is the main pathological basis of cardiovascular diseases (CVDs). Fufang Danshen Tablet (FDT) is a traditional Chinese medicine that has been clinically used to treat CVDs for more than 40 years. Nevertheless, owing to the complexity of the ingredients, the pharmacological mechanism of FDT in the treatment of CVDs has not been fully elucidated. In this study, an integrated strategy of UFLC-Q-TOF-MS/MS, network pharmacology, molecular biology, and transcriptomics was used to elucidate the mechanisms of action of FDT in the treatment of atherosclerosis. In total, 22 absorbed constituents were identified in rat serum after oral administration of FDT. In silico, network pharmacology studies have shown that FDT regulates four key biological functional modules for the treatment of atherosclerosis: oxidative stress, cell apoptosis, energy metabolism, and immune/inflammation. In animal experiments, FDT exerted protective effects against atherosclerosis by reducing the plaque area and lipid levels in ApoE−/− mice. Furthermore, we found that FDT inhibited inflammatory macrophage accumulation by regulating the expression of Selp and Ccl2, which are both involved in monocyte adhesion and migration. The inhibition of monocyte recruitment by FDT is a new perspective to elucidate the anti-atherosclerotic mechanism of FDT, which has not been adopted in previous studies on FDT. Our results may help to elucidate the therapeutic mechanism of FDT against CVDs and provide potential therapeutic targets.

Xiaochaihu granules (XCHG) are extensively used to treat fever. Nevertheless, the underlying mechanism remains elusive. This study aimed to explore the potential of XCHG in mitigating yeast-induced fever and the underlying metabolic pathways. The chemical composition of XCHG was ascertained using ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS), followed by integrated network analysis to predict potential targets. We then conducted experimental validation using pharmacological assays and metabolomics analysis in a yeast-induced mouse fever model. The study identified 133 compounds in XCHG, resulting in the development of a comprehensive network of herb–compound–biological functional modules. Subsequently, molecular dynamic (MD) simulations confirmed the stability of the complexes, including γ-aminobutyric acid B receptor 2 (GABBR2)–saikosaponin C, prostaglandin endoperoxide synthases (PTGS2)–lobetyolin, and NF-κB inhibitor IκBα (NFKBIA)–glycyrrhizic acid. Animal experiments demonstrated that XCHG reduced yeast-induced elevation in NFKBIA’s downstream regulators [interleukin (IL)-1β and IL-8], inhibited PTGS2 activity, and consequently decreased prostaglandin E2 (PGE2) levels. XCHG also downregulated the levels of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), corticotropin releasing hormone (CRH), and adrenocorticotrophin (ACTH). These corroborated the network analysis results indicating XCHG’s effectiveness against fever in targeting NFKBIA, PTGS2, and GABBR2. The hypothalamus metabolomics analysis identified 14 distinct metabolites as potential antipyretic biomarkers of XCHG. In conclusion, our findings suggest that XCHG alleviates yeast-induced fever by regulating inflammation/immune responses, neuromodulation, and metabolism modules, providing a scientific basis for the anti-inflammatory and antipyretic properties of XCHG.

Abstract Background Cold-dampness Syndrome (RA-Cold) and Hot-dampness Syndrome (RA-Hot) are two distinct groups of rheumatoid arthritis (RA) patients with different clinical symptoms based on traditional Chinese medicine (TCM) theories and clinical empirical knowledge. However, the biological basis of the two syndromes has not been fully elucidated, which may restrict the development of personalized medicine and drug discovery for RA diagnosis and therapy. Methods An integrative strategy combining clinical transcriptomics, phenomics, and metabolomics data based on clinical cohorts and adjuvant-induced arthritis rat models was performed to identify novel candidate biomarkers and to investigate the biological basis of RA-Cold and RA-Hot. Results The main clinical symptoms of RA-Cold patients are joint swelling, pain, and contracture, which may be associated with the dysregulation of T cell-mediated immunity, osteoblast differentiation, and subsequent disorders of steroid biosynthesis and phenylalanine metabolism. In contrast, the main clinical symptoms of RA-Hot patients are fever, irritability, and vertigo, which may be associated with various signals regulating angiogenesis, adrenocorticotropic hormone release, and NLRP3 inflammasome activation, leading to disorders of steroid biosynthesis, nicotinamide, and sphingolipid metabolism. IL17F, 5-HT, and IL4I1 were identified as candidate biomarkers of RA-Cold, while S1P and GLNS were identified as candidate biomarkers of RA-Hot. Conclusions The current study presents the most comprehensive metabonomic and transcriptomic profiling of serum, urine, synovial fluid, and synovial tissue samples obtained from RA-Cold and RA-Hot patients and experimental animal models to date. Through the integration of multi-omics data and clinical independent validation, a list of novel candidate biomarkers of RA-Cold and RA-Hot syndromes were identified, that may be useful in improving RA diagnosis and therapy.

Coronavirus disease 2019 (COVID-19) caused a severe epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Recent studies have found that patients do not completely recover from acute infections, but instead, suffer from a variety of post-acute sequelae of SARS-CoV-2 infection, known as long COVID. The effects of long COVID can be far-reaching, with a duration of up to six months and a range of symptoms such as cognitive dysfunction, immune dysregulation, microbiota dysbiosis, myalgic encephalomyelitis/chronic fatigue syndrome, myocarditis, pulmonary fibrosis, cough, diabetes, pain, reproductive dysfunction, and thrombus formation. However, recent studies have shown that naringenin and naringin have palliative effects on various COVID-19 sequelae. Flavonoids such as naringin and naringenin, commonly found in fruits and vegetables, have various positive effects, including reducing inflammation, preventing viral infections, and providing antioxidants. This article discusses the molecular mechanisms and clinical effects of naringin and naringenin on treating the above diseases. It proposes them as potential drugs for the treatment of long COVID, and it can be inferred that naringin and naringenin exhibit potential as extended long COVID medications, in the future likely serving as nutraceuticals or clinical supplements for the comprehensive alleviation of the various manifestations of COVID-19 complications.

Summary: Articular cartilage tissue engineering is being considered an alternative treatment strategy for promoting cartilage damage repair. Herein, we proposed a modular hydrogel-based bioink containing microsphere-embedded chondrocytes for 3D printing multiscale scaffolds integrating the micro and macro environment of the native articular cartilage. Gelatin methacryloyl (GelMA)/alginate microsphere was prepared by a microfluidic approach, and the chondrocytes embedded in the microspheres remained viable after being frozen and resuscitated. The modular hydrogel bioink could be printed via the gel-in-gel 3D bioprinting strategy for fabricating the multiscale hydrogel-based scaffolds. Meanwhile, the cells cultured in the scaffolds showed good proliferation and differentiation. Furthermore, we also found that the composite hydrogel was biocompatible in vivo. These results indicated that the modular hydrogel-based bioinks containing microsphere-embedded chondrocytes for 3D printing multiscale scaffolds could provide a 3D multiscale environment for enhancing cartilage repairing, which would be encouraging considering the numerous alternative applications in articular cartilage tissue engineering.

Porcine epidemic diarrhea virus (PEDV) infection causes lethal watery diarrhea and high mortality in neonatal piglets, leading to huge economic losses in the global swine industry. Currently, the existing commercial vaccines cannot fully control PEDV, so it is urgent to develop effective antiviral agents to complement vaccine therapy. In the present study, we investigated the antiviral effect of Hypericum japonicum extract (HJ) against PEDV in vivo and in vitro. In in vitro assays, HJ could directly inactivate PEDV strains; moreover, it inhibited the proliferation of PEDV strains in Vero or IPI-FX cells at its non-cytotoxic concentrations. Time of addition assays revealed that HJ mainly inhibited PEDV at the later stages of the viral life cycle. In in vivo, compared with the model group, HJ could reduce the viral titers in the intestines of infected piglets, and improve their intestinal pathological, indicating that HJ could protect the newborn piglets from highly pathogenic PEDV variant infection. Furthermore, this effect may be related to the fact that HJ can not only directly inhibit viruses, but also regulate the structure of intestinal microbiota. In conclusion, our results indicate that Hypericum japonicum could inhibit PEDV replication in vitro and in vivo and might possess the potential to develop as the anti-PEDV drug.

The gas extraction radius is affected by coal seam gas pressure, borehole diameter, extraction time, extraction negative pressure and other factors. Under the coupling of different factors, the gas extraction radius of borehole is also different. For complex under the condition of the shortage of the radius of the gas extraction method, combining with TianAn comes up out of no. 3 coal mine coal seam gas occurrence and mining conditions, puts forward the method of pressure drop and gas flow method, combination method of determining the radius of the gas extraction, analysis of the 1∼3 m, 4 m and 5∼6 m extraction under the condition of radius of influence range, ultimately determine the radius of extraction for 3 m, It can not only meet the gas extraction rate of working face, but also ensure the safety of production and efficient utilization of gas.

Incorporating polypropylene fiber as an additive material into the mixture can effectively improve the mechanical properties of concrete. In this paper, in order to investigate the mechanical properties of fully recycled coarse aggregate (FRCA) concrete with PP fiber, four groups of specimens with different volume ratio of PP fiber were designed and manufactured to conduct experiments of uniaxial compression and bending respectively. Based on the test results, the influence of volume ratio of PP fiber on the compressive and flexural mechanical properties of FRCA concrete were analyzed. The results showed that the integrity of compression specimens with PP fiber was better after failure and the flexural failure of the specimens without fiber or with PP fiber was brittle after the peak value. Moreover, with the increase of volume ratio of PP fiber, the slump of specimens presented a downward trend, the cube compressive strength increased continuously, and the cylinder compressive strength first decreased and then increased. Besides, with the increase of volume ratio of PP fiber, the static pressure elastic modulus increased as a whole, and the flexural strength increased.

We address the properties of nonlinear localized gap modes supported by the width-modulated Fibonacci lattices, including their existence and stability. Linear system with the width-modulated Fibonacci lattices has multiple gaps. We find the existence of different families of nonlinear localized modes in two relatively large gaps. One of the nonlinear localized gap modes originates from the upper band-edge linear mode. Such gap modes are mostly stable in their entire existence domain, except for a small region in the middle of their existence. The other two families of nonlinear modes localized in the relatively large gap are pure nonlinear modes, and they have a narrow stable region near their upper cutoff. The results of the linear stability analysis are in good agreement with that of the propagation simulations.

Hierarchical anisotropy structure directing 3D cellular orientation plays a crucial role in designing tendon tissue engineering scaffolds. Despite recent development of fabrication technologies for controlling cellular organization and design of scaffolds that mimic the anisotropic structure of native tendon tissue, improvement of tenogenic differentiation remains challenging. Herein, we present 3D aligned poly (ε-caprolactone) nanofiber yarns (NFYs) of varying diameter, fabricated using a dry-wet electrospinning approach, that integrate with nano- and micro-scale structure to mimic the hierarchical structure of collagen fascicles and fibers in native tendon tissue. These aligned NFYs exhibited good in vitro biocompatibility, and their ability to induce 3D cellular alignment and elongation of tendon stem/progenitor cells was demonstrated. Significantly, the aligned NFYs with a diameter of 50 μm were able to promote the tenogenic differentiation of tendon stem/progenitor cells due to the integration of aligned nanofibrous structure and suitable yarn diameter. Rat tendon repair results further showed that bundled NFYs encouraged tendon repair in vivo by inducing neo-collagen organization and orientation. These data suggest that electrospun bundled NFYs formed by aligned nanofibers can mimic the aligned hierarchical structure of native tendon tissue, highlighting their potential as a biomimetic multi-scale scaffold for tendon tissue regeneration.

Extracellular vesicles (EVs)-mediated epithelium-macrophage crosstalk has been proved to maintain lung homeostasis in cigarette smoke-induced lung diseases such as chronic obstructive pulmonary disease (COPD). In our previous study, we found that EVs derived from cigarette smoke extract (CSE) treated BEAS-2B promoted M1 macrophage polarization, which probably accelerated the development of inflammatory responses. Naringenin has been proved to suppress M1 macrophage polarization, but whether naringenin regulates macrophage polarization mediated by EVs has not been reported. In this study, we firstly found that EVs derived from naringenin and CSE co-treated BEAS-2B significantly inhibited the expression of CD86 and CD80 and the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS), and IL-12 in macrophage induced by EVs derived from CSE-treated BEAS-2B. Further research revealed that naringenin downregulated BEAS-2B-derived EVs miR-21-3p which targeted phosphatase and tensin homolog deleted on chromosome ten/protein kinase B (PTEN/AKT) cascade in macrophages and then suppressed M1 macrophage polarization. Subsequent proteomics suggested that naringenin decreased BEAS-2B-derived EVs poly ADP-ribose polymerase (PARP)1 expression thereby suppressing M1 macrophage polarization probably. Our study provides novel pharmacological references for the mechanism of naringenin in the treatment of cigarette smoke-induced lung inflammatory diseases.

Growing evidence shows that Baihu-Guizhi decoction (BHGZD), a traditional Chinese medicine (TCM)-originated disease-modifying anti-rheumatic prescription, may exert a satisfying clinical efficacy for rheumatoid arthritis (RA) therapy. In our previous studies, we verified its immunomodulatory and anti-inflammatory activities. However, bioactive compounds (BACs) of BHGZD and the underlying mechanisms remain unclear. Herein, an integrative research strategy combining UFLC-Q-TOF-MS/MS, gene expression profiling, network calculation, pharmacokinetic profiling, surface plasmon resonance, microscale thermophoresis, and pharmacological experiments was carried out to identify the putative targets of BHGZD and underlying BACs. After that, both in vitro and in vivo experiments were performed to determine the drug effects and pharmacological mechanisms. As a result, the calculation and functional modularization based on the interaction network of the “RA-related gene–BHGZD effective gene” screened the TLR4/PI3K/AKT/NFκB/NLRP3 signaling-mediated pyroptosis to be one of the candidate effective targets of BHGZD for reversing the imbalance network of “immune-inflammation” during RA progression. In addition, both mangiferin (MG) and cinnamic acid (CA) were identified as representative BACs acting on that target, for the strong binding affinities between compounds and target proteins, good pharmacokinetic features, and similar pharmacological effects to BHGZD. Notably, both BHGZD and the two-BAC combination of MG and CA effectively alleviated the disease severity of the adjuvant-induced arthritis-modified rat model, including elevating pain thresholds, relieving joint inflammation and bone erosion via inhibiting NF-κB via TLR4/PI3K/AKT signaling to suppress the activation of the NLRP3 inflammasome, leading to the downregulation of downstream caspase-1, the reduced release of IL-1β and IL-18, and the modulation of GSDMD-mediated pyroptosis. Consistent data were obtained based on the in vitro pyroptosis cellular models of RAW264.7 and MH7A cells induced by LPS/ATP. In conclusion, these findings offer an evidence that the MG and CA combination identified from BHGZD may interact with TLR4/PI3K/AKT/NFκB signaling to inhibit NLRP3 inflammasome activation and modulate pyroptosis, which provides the novel representative BACs and pharmacological mechanisms of BHGZD against active RA. Our data may shed new light on the mechanisms of the TCM formulas and promote the modernization development of TCM and drug discovery.

AbstractThe sediment bedding direction and loading-unloading have significant effect on permeability of coal sample. The coal samples taken from Zhangcun Coal Mine in Shanxi were used to measure coal permeability with different sediment beddings under the effect of loading and unloading by the triaxial coal-rock seepage experimental apparatus. The influence of gas pressure, loading-unloading, and sediment bedding direction on the permeability of coal samples was analyzed, and the functional relationship among these parameters was recovered by fitting. The results show that the permeability of all vertical, dip, and horizontal bedding coal samples decreases exponentially with the increase of effective stress during stress loading, while the permeability of three kinds of bedding coal samples increases exponentially with the decrease of effective stress during stress unloading. Under the same gas pressure, the fracture space of coal samples with vertical and dip bedding is more likely to be compressed and closed at the initial stage of loading, resulting in great decrease of the permeability. In the initial stage of unloading, the microcracks and natural beddings in coals gradually expand and connect. Due to the well development of fractures, the permeability of vertical bedding coal samples increases greatly, while the permeability of dip and horizontal bedding coal samples increases slightly. In the loading process, the permeability of coal sample is vertical bedding > dip bedding > horizontal bedding in order. For the tested samples, the permeability of vertical bedding coal samples is 1.3 to 2.8 times that of dip or horizontal bedding coal samples. In the unloading process, the permeability of the vertical bedding coal samples was 2.8 to 3.3 times that of the dip or horizontal bedding coal samples.

Sleep disorders were associated with oral health. Inflammation has especially been thought to be a key factor in linking oral diseases and sleep deficiency. However, how chronic sleep deprivation (CSD) affects oral homeostasis, particularly oral inflammation and oral microbiota, is still unknown. This study aimed to uncover the systematic relationship between oral homeostasis and CSD in rats. The metabolomics in serum, proteomics in the tongue tissues, and microbiome analysis in the oral cavity in CSD rats were performed. Multi-omics data integration analysis was performed to uncover the systematic relationship between oral homeostasis and CSD through the weighted correlation network analysis. We found that CSD could lead to oral inflammation in rats. CSD significantly increased systemic inflammation by enhancing the serum levels of IL-1β, IL-6 and inhibiting the serum level of IL-10. Serum levels of adrenocorticotropin hormone, corticosterone, and triiodothyronine were increased in CSD rats, and the steroid hormone biosynthesis pathway was also found to be involved in the perturbation resulting from CSD, together suggesting the activation of the hypothalamic-pituitary-adrenocortical and hypothalamic‐pituitary‐thyroid axis. CSD led to changes of oral microbiota composition, and g_Acinetobacter, Candidatus Chryseobacterium massiliae, and g_Moraxella were significantly correlated with multiple proteins in bacterial invasion of epithelial cells pathway, which may partially responsible for oral inflammation resulting from CSD. The changes of proteomic profiling expression caused by CSD in tongue tissues were mainly enriched in neurodegenerative diseases pathways and immune/inflammation-related pathways. Multi-omics analysis indicated that the inflammatory response-related modules were significantly correlated with the neurodegenerative disease-related module suggesting a possible link between neurodegenerative diseases and oral inflammation. Together, CSD induced oral inflammation and subtle changes on oral microbiota. Our study is helpful to further understand the role that oral homeostasis plays in the process by which CSD affects human health and disease.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). However, there are still no specific treatments. Recently, traditional Chinese medicine (TCM) was proposed as a potential therapeutic strategy for the prevention and treatment of COVID-19. The present study aims to explore the potential of Hypericum japonicum Thunb. ex Murray against COVID-19 based on network pharmacology and molecular docking methods. Potential targets of H. japonicum were collected from available databases for protein–protein interaction analysis. Further GO and KEGG pathway analysis were performed to reveal the corresponding mechanism. Molecular docking was employed to evaluate the binding energy between the components in H. japonicum and three target proteins (ACE2, Mpro and PLP). Finally, a total of 45 core targets were screened. GO and KEGG pathway analysis revealed that several key pathways were involved in the potential beneficial effects of H. japonicum against COVID-19. Molecular docking results showed that most components in H. japonicum have a binding affinity to ACE2, Mpro and PLP molecules less than −5 kcal/mol, indicating good binding capacity to these target proteins. Vincetoxicoside B, bijaponicaxanthone and quercetin possess the top binding activity to ACE2, Mpro and PLP, respectively. The molecular docking results and the traditionally known possible functions of H. japonicum, including stabilizing blood oxygen environment, preventing inflammatory storms, regulating immune response and inhibiting viral infections, hereby indicate the potential of H. japonicum against COVID-19.

Structural optimization has always been the main solution for increasing the stability of flexible screens. The bending method used to test a flexible display screen is an important factor in assessing the functionality and practicability of the electronic device. The bending mode of the display screen impacts the screen service life. In this study, 2D simulation models with different bending radii, bending directions, and bending times were constructed in ABAQUS and compared to determine the effects on the flexible screen from changing the stress value, the location of the stress concentration area and the deformation state of the screen under U- and water-drop-shaped bending. The simulation results show that U-shaped bending severely strains the junction between the bent and unbent areas of a model, whereas water-drop-shaped bending can avoid such problems. In addition, the results of multiple bending experiments were used to determine an appropriate reserved length of r=2.1~2.4 mm for a model under water-drop-shaped bending.

Abstract Background Naoshuantong capsule (NSTC) is an oral Chinese medicine formula composed of Typhae Pollen, Radix Paeoniae Rubra, Curcumae Radix, Gastrodiae Rhizoma and Radix Rhapontici. It has been widely used at the acute and recovery stage of ischemic stroke since 2001. Comparing with its wide clinical application, there are only few studies emphasize on investigating its pharmacological effects. Methods To more generally elucidate the underlying mechanisms in this study, we identified active ingredients in NSTC by a network pharmacology approach based on transcriptomics analysis and pharmacological experiments. Modified neurological severity scores and morphometric analysis using Nissl staining were employed to evaluate the neuroprotective effects of NSTC on ischemia stroke in mice. Results The results showed that NSTC had preventive and protective effects on ischemia stroke, featuring repair of brain tissue during the sub-acute stage of stroke. This may attribute to the underlying mechanisms including anti-inflammatory, antioxidant, and anti-apoptotic activities, as well as an attenuation of excitatory amino acids (EAAs) toxicity of the active ingredients, especially the most active apigenin, from NSTC. Specifically, naringenin, calycosin, gastrodin, caffeic acid, paeoniflorin, and β-elemene seem to be also pharmacological active substances responsible for the anti-inflammatory effects. Meanwhile, 13-hydroxygemone, gastrodin, and p-hydroxybenzyl alcohol contributed to the attenuation of EAAs toxicity Furthermore, apigenin, naringenin, calycosin, gastrodin, and β-elemene accelerated the repair of brain ischemic tissue by up-regulating the expression of TGF-β1 levels. Conclusions The present study identifies the active ingredients of NSTC and illustrates the underlying mechanism using a combination of network pharmacology, transcriptomics analysis, and pharmacological experiments.

Two non-ionic reagents, polyethylene glycol 4000 and Tween-80, two anionic reagents, sodium dodecyl benzenesulfonate and sodium lauryl sulfate, and a mixture of these non-ionic and anionic reagents were used as penetrants. The processes of replacement desorption and relief-pressure desorption of gas-containing coal were studied, the influence of the penetrant on the amount of gas replacement desorption and relief-pressure desorption was explored, and the change rule of the amounts of gas replacement desorption and relief-pressure desorption was analysed. The results show that the increase rate of the replacement desorption amount of the mixed penetrant is 11.81%-34.75%, and the decrease rate of the relief-pressure desorption amount is 51.68%-72.69%, which are higher values than those with a single penetrant. As the mass fraction of penetrant increases within the range of 0.5%~2%, the capacity of gas replacement desorption and hindering gas relief-pressure desorption will increase. At the same mass fraction, the effect of the mixed penetrant is better than that of the anionic penetrant, which in turn is better than that of the non-ionic penetrant.

With the vigorous development of blockchain technology, researches on various “blockchain+” scenarios continue to bring forth new ideas. As some of the characteristics of the blockchain technology itself deeply meet the demands of the development of chain enterprises, it can better control the related risks of enterprises. Therefore, it is necessary to combine the characteristics of blockchain technology with the characteristics of chain enterprise risks and the interaction mechanism for research. This article aims to study how to strengthen risk management for chain enterprises in the digital economy. For this reason, this article proposes a method to empower the digital economy through the blockchain and calculates and analyzes the risk measurement so that it can effectively estimate the risk. This article also designs an experimental analysis to explore its effect. The experimental results of this paper show that after the improvement, the risk of chain enterprises is reduced by 35%, and the risk is effectively controlled.

The interlayer stress (IS) analysis of the flexible active-matrix organic light-emitting diode (AMOLED) panel is critical for decreasing the stress concentration and reducing the risk of overall screen failure. This article relies on the linear elastic models of ABAQUS to simulate finite element analysis of foldable panels. This article discussed three sensitive locations of the flexible AMOLED panel caused by two different bending methods including U bends and water droplet bends. The finite element method for simulating the layer analysis was constructed to analyze the effect of optically clear adhesive (OCA) film thickness on the distribution of stress and strain. The module can be optimized by changing the thickness and shear modulus of OCA. With the decrease of OCA thickness and the increase of stiffness, the maximum stress of the organic light-emitting diode (OLED) layer is decreased by 20% which is 55 Mpa; meanwhile, the IS of the entire module is reduced by about 30%.

Abstract Background Oral ulcer diseases are complex inflammatory diseases caused by multi-factors, which severely impact patient quality of life. Kouyanqing Granule (KYQG) has been used to treat inflammatory diseases of the mouth and throat, including recurrent aphthous stomatitis (RAS), traumatic ulcers, oral leukoplakia and so on. However, the underlying molecular mechanisms of KYQG in treating these diseases are still unclear. We aimed to explore the possible mechanisms in KYQG for the treatment of oral ulcers. Methods An innovative network pharmacology method was established by incorporating targets searching and fishing, network analysis, and silico validation to discover the pharmacological mechanisms of action of KYQG for the treatment of oral ulcers. Then, we verified the reliability of this method by an animal experiment. Results Our data indicated that a total of 47 key targets were screened, which mainly involved in three function modules including the inhibition of inflammation, the regulation of immunological response, and the suppression of oxidative stress. The implementation of these functions relies on the complex multi-pathways network, especially TNF signaling pathway and HIF-1 signaling pathway. The results of the experimental verification indicated that KYQG significantly inhibited the serum levels of cyclooxygenase-2 (COX2), matrix metalloproteinase 9 (MMP9) and tumor necrosis factor-alpha (TNF-α) in rats with oral ulcer. Conclusion KYQG exhibited the therapeutic effects on oral ulcers probably by inhibiting inflammation, regulating immunological response, and suppressing oxidative stress through a complex multi-pathways network. Particularly, TNF signaling pathway and HIF-1 signaling pathway may play crucial roles in the protection of KYQG against oral ulcers. This work not only offers a method for understanding the functional mechanisms of KYQG for treating oral ulcer diseases from a multi-scale perspective but also may provide an efficient way for research and development of complex composition formula.

Abstract Background Pheretima is a minister drug in Naoxintong capsule (NXTC), a well-known traditional Chinese medicine (TCM) formula for the treatment of cardiovascular and cerebrovascular diseases. Owing to the loss of morphological and microscopic characteristics and the lack of recognized chemical marker, it is difficult to identify Pheretima in NXTC. This study aims to evaluate the feasibility of using DNA techniques to authenticate Pheretima, especially when it is processed into NXTC. Methods DNA was extracted from crude drugs of the genuine and adulterant species, as well as nine batches of NXTCs. Based on mitochondrial cytochrome c oxidase subunit I (COI) gene, specific primers were designed for two genera of genuine species, Metaphire and Amynthas, respectively. PCR amplification was performed with the designed primers on crude drugs of Pheretima and NXTCs. The purified PCR products were sequenced and the obtained sequences were identified to species level with top hit of similarity with BLAST against GenBank nucleotide database. Results Primers MF2R2 and AF3R1 could amplify specific DNA fragments with sizes around 230–250 bp, both in crude drugs and NXTC. With sequencing and the BLAST search, identities of the tested samples were found. Conclusion This study indicated that the molecular approach is effective for identifying Pheretima in NXTC. Therefore, DNA identification may contribute to the quality control and assurance of NXTC.

Naringin is a dietary flavonoid glycoside with broad bioactivities, and it has been found to undergo extensive microbial metabolism in human gut. Microbial metabolites are believed to play an important role in the overall bioactivity of naringin. However, knowledge is scarce about its microbial metabolism in laboratory rats, which are the most commonly used animal model for naringin-related biomedical studies. Herein, we profiled the microbial metabolism of naringin in rat by an in vitro anaerobic fermentation combined with LC-MS/MS methods. A total of 35 microbial metabolites were identified, and corresponding metabolic pathways were proposed. Naringin and its metabolites were further quantified in fermentation samples. Rhoifolin, neoeriocitrin, neohesperidin, naringenin, methylated naringin, and hydroxylated naringin were detected as the primary microbial metabolites. Moreover, antioxidant capacity assays suggested that fermentation-associated microbial metabolites exhibited higher antioxidant activity than original naringin. Obtained results contribute to a more comprehensive understanding of the microbial metabolism and antioxidant capacity of naringin.

Naoxintong Capsule (NXTC), a standardized herbal medicine, has been widely applied in treating cardiovascular and cerebrovascular diseases with remarkable efficacy. However, the efficacy contributing components of NXTC are unclear, and the in vivo absorption and metabolism processes of NXTC remain largely obscured. In this study, using beagle dog as model species, we have identified and tentatively characterized 25 prototype and 15 catabolites of NXTC in beagle dog plasma by ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS). We have proposed the in vivo bio-transformation pathways of these absorbed constituents. In addition, for six crucial components, we have developed a quantitative method and conducted plasma pharmacokinetic study of these six components by rapid resolution liquid chromatography tandem triple quadrupole mass spectrometry (RRLC-QQQ-MS/MS). In conclude, our study provided comprehensive insights into the understanding of the plasma absorbed components profiling of NXTC as well as their in vivo transformation behaviors, which would be of great value for identifying efficacy contributing critical components as well as mechanism related investigations of NXTC in the future.

Citri Reticulatae Pericarpium (CRP), dried peels of Citrus reticulata Blanco and its cultivars, is an important traditional Chinese medicine for the treatment of spleen deficiency-related diseases. To date, the mechanism of CRP alleviating spleen deficiency has not been well investigated. This study aimed to explore corresponding mechanisms with integrating pharmacology and gut microbiota analysis. Firstly, the therapeutic effects of CRP against spleen deficiency were evaluated in reserpine-treated rats. CRP was found to effectively relieve the typical symptoms of spleen deficiency, including poor digestion and absorption capacity, and disorder in gastrointestinal hormones, immune cytokines and oxidative stress. Secondly, high throughput 16S rRNA gene sequencing revealed that CRP could not only up-regulate some short-chain fatty acids producing and anti-inflammatory bacteria but also down-regulate certain spleen deficiency aggravated related bacteria, eventually led to the rebalance of gut microbiota in spleen deficiency rats. In addition, a total of 49 compounds derived from CRP were identified in rat urine using ultra-high performance liquid chromatography-quadrupole- time of flight tandem mass spectrometry. Network pharmacology analysis showed that apigenin, luteolin, naringenin, hesperidin, hesperetin, homoeriodictyol, dihydroxy-tetramethoxyflavone, and monohydroxy-tetramethoxyflavone were the core bioactive components for CRP against spleen deficiency. Further Gene Ontology analysis and pathway enrichment suggested that therapeutic effects of CRP against spleen deficiency involved multiple pathways such as tumor necrosis factor signaling, hypoxia-inducible factor-1 signaling and Toll-like receptor signaling pathway. These results would help to understand the mechanism of CRP alleviating spleen deficiency and provide a reference for further studies.

Naringin is a dietary flavonoid glycoside with multiple bioactivities. It has been involved in numerous metabolism and excretion studies, and its metabolic properties are clear. However, information concerning the excretion profile of its original metabolites are still scarce, and few methods for simultaneous determination of multiple original metabolites of naringin in biological samples have been reported so far. In this study, a rapid and sensitive method for simultaneous determination of ten flavonoid metabolites of naringin in rat urine was developed with an UHPLC-Q-Trap-MS/MS system. One-step protein precipitation method with acetonitrile was used to extract analytes. A rapid chromatographic separation within 11 min was performed on an ACQUITY UPLC® BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using gradient elution with a mobile phase of water and methanol, both with 0.1% formic acid (v/v). MS/MS detection was conducted in negative ion mode and multiple reactions monitoring scanning mode. The analytical method was fully validated and successfully applied to monitor the excretion profiles of naringin in rat urine. Quantitative results revealed the visible individual difference and low urinary recovery of flavonoid metabolites in the excretion of naringin, which may be helpful for further study to understand the in vivo behavior and action mechanism of naringin.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neuronal loss, cognitive impairment, and aphasia. Aggregation of β-amyloid (Aβ) peptide in the brain is considered a key mechanism in the development of AD. In the past 20 years, many compounds have been developed to inhibit Aβ aggregation and accelerate its degradation. Platycladus orientalis seed is a traditional Chinese medicine used to enhance intelligence and slow aging. We previously found that Platycladus orientalis seed extract (EPOS) inhibited Aβ-peptide aggregation in the hippocampus and reduced cognitive deficits in 5×FAD mice. However, the mechanisms of these effects have not been characterized. To characterize the protective mechanisms of EPOS, we used a transgenic Caenorhabditis elegans CL4176 model to perform Bioactivity-guided identification of active compounds. Four active compounds, comprising communic acid, isocupressic acid, imbricatolic acid, and pinusolide, were identified using 13C-and 1H-NMR spectroscopy. Furthermore, we showed that isocupressic acid inhibited Aβ generation by modulating BACE1 activity via the GSK3β/NF-κB pathway in HEK293-APPsw cells. These findings showed that EPOS reduced cognitive deficits in an AD model via modulation of the Aβ peptide aggregation pathway.

Oral ulcers are the most prevalent oral mucosal diseases globally, and no specific treatment schemes are currently available due to the complexity of oral ulcer diseases. Sleep deprivation increases the risk of a deterioration in oral health. Kouyanqing Granule (KYQG) has been used for decades in China to treat inflammatory diseases of the mouth and throat associated with the hyperactivity of fire due to yin deficiency syndrome. However, the mechanisms underlying the effects of KYQG in the treatment of oral ulcers are still unclear. The aims of this study were to investigate whether KYQG treatment could attenuate the symptoms of oral ulcers worsened by sleep deprivation and identify the involved metabolic pathways. First, we conducted chemical profiling of KYQG via UPLC–MS analysis. We then combined pharmacological and metabolomics approaches in a phenol-induced rat model of oral ulcers worsened by sleep deprivation. A total of 79 compounds were initially identified. Our observations showed that KYQG treatment induced a significantly higher healing rate in oral ulcers worsened by sleep deprivation. KYQG significantly reduced the levels of 5-HT and GABA in serum, and only decreased the 5-HT level in brain tissue after phenol injury followed by sleep deprivation. Moreover, KYQG administration significantly suppressed systemic inflammation by inhibiting TNF-α, IL-1β, IL-6, IL-18, and MCP-1. Immunohistochemical analysis further revealed that KYQG inhibited IL-6 expression in buccal mucosa tissues. KYQG treatment also significantly decreased the serum levels of ACTH, CORT, IgM, and 8-OHdG. Serum metabolomics analysis showed that a total of 30 metabolites showed significant differential abundances under KYQG intervention, while metabolic pathway analysis suggested that the altered metabolites were associated with the dysregulation of eight metabolic pathways. Taken together, our results indicated that KYQG attenuates the symptoms of oral ulcers worsened by sleep deprivation probably through the regulation of the neuroimmunoendocrine system, oxidative stress levels, and tryptophan metabolism. This study also provides a novel approach for addressing the increased health risks resulting from sleep deficiency using an herbal medicine formula.

Abstract Excess electrons play important roles for the construction of superficial active sites on nanocatalysts. However, providing excess electrons to nanocatalysts in vivo is still a challenge, which limits the applications of nanocatalysts in biomedicine. Herein, auger electrons (AEs) emitted from radionuclide 125 (125I) are used in situ to construct active sites in a nanocatalyst (TiO2) and the application of this method is further extended to cancer catalytic internal radiotherapy (CIRT). The obtained 125I‐TiO2 nanoparticles first construct superficial Ti3+ active sites via the reaction between Ti4+ and AEs. Then Ti3+ stretches and weakens the OH bond of the absorbed H2O, thus enhancing the radiolysis of H2O molecules and generating hydroxyl radicals (•OH). All in vitro and in vivo results demonstrate a good CIRT performance. These findings will broaden the application of radionuclides and introduce new perspectives to nanomedicine.

Hyperglycemia induces vascular endothelial dysfunction, which contributes to the development of vascular complication of diabetes. A classic prescription of traditional medicine, HuangqiGuizhiWuwu Decoction (HGWWD) has been used for the treatment of various cardiovascular and cerebrovascular diseases, which all are related with vascular pathology. The present study investigated the effect of HGWWD treatment in streptozocin (STZ)-induced vascular dysfunction in mouse models. In vivo studies were performed using wild type mice as well as arginase 1 knockout specific in endothelial cells (EC-A1–/–) of control mice, diabetes mice and diabetes mice treated with HGWWD (60 g crude drugs/kg/d) for 2 weeks. For in vitro studies, aortic tissues were treated with mice serum containing HGWWD with or without adenoviral arginase 1 (Ad-A1) transduction in high glucose (HG) medium. We found that HGWWD treatment restored STZ-induced impaired mean velocity and pulsatility index of mouse left femoral arteries, aortic pulse wave velocity and vascular endothelial relaxation accompanied by elevated NO production in the aorta and plasma, as well as reduced endothelial arginase activity and aortic arginase 1 expression. The protective effect of HGWWD is reversed by an inhibitor of nitric oxide synthesis. Meanwhile, the preventive effect of serum containing HGWWD in endothelial vascular dysfunction is completely blocked by Ad-A1 transduction in HG incubated aortas. HGWWD treatment further improved endothelial vascular dysfunction in STZ induced EC-A1–/– mice. This study demonstrates that HGWWD improved STZ-induced vascular dysfunction through arginase 1 – NO signaling, specifically targeting endothelial arginase 1.

BackgroundPharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development.MethodsSeparate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry.ResultsThe pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin.ConclusionThe results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development.Clinical Trial Registrationhttp://www.chinadrugtrials.org.cn/eap/main, identifiers CTR20130704 and CTR20190127.

Microctis Folium is the dried leaves of a plant (Microcos paniculata L.) used to improve the digestive system, alleviate diarrhoea, and relieve fever, but information regarding its chemical composition has rarely been reported. The traditional research approach of determining chemical composition has included isolating, purifying, and identifying compounds with high-cost and time-consuming processes. In this study, molecular networking (MN) and fingerprint analysis were integrated as a comprehensive approach to study the chemical composition of Microctis Folium by an ultra fast liquid chromatography-photo diode array detector-triple-time of flight-tandem mass spectrometry (UFLC-DAD-Triple TOF-MS/MS). Large numbers of mass spectrometric data were processed to identify constituents, and the identified compounds and their unknown analogues were comprehensively depicted as visualized figures comprising distinct families by MN. A validated fingerprint methodology was established to quantitatively determine compounds in Microctis Folium. Ultimately, 165 constituents were identified in Microctis Folium for the first time and the identified compounds and approximately five hundred unknown analogues were applied to create visualized figures by MN, indicating compound groups and their chemical structure analogues in Microctis Folium. The validated fingerprint methodology was indicated to be specific, repeatable, precise, and stable and was used to determine 15 batches of samples during three seasons in three districts. Furthermore, seasonal or geographic environmental influences on the chemical profile were estimated by principal coordinate analysis. The results can be used to control the quality of Microctis Folium, observe seasonal or geographic environmental influences on the chemical profiles, and provide a reference for further exploitation of potential active unknown analogues in the future.

The fluorescent gel with good flexibility and biocompatibility has attracted more and more attention due to its excellent optical properties. In this paper, the research progresses in preparation methods and applications of fluorescent gels are reviewed. In addition, the preparation methods of self-assembly and polymerization of fluorescent gel are also introduced. In this paper, it should be noted that some outstanding research about the fluorescent gels used in sensors, bio-imaging probes, drug delivery, and other application fields is summarized. This work provides useful reference information for further exploration and study of fluorescent hydrogels.

The drug preparations from dried flower of Carthamus tinctorius L. (CTL) are widely used as an adjuvant medication in cardiovascular diseases in China. In this research, Safflower yellow extract (SYE), a CTL drug in market, was studied through components analysis and two animal experiments with different dosages to assess its pharmacodynamic effects. The whole constituents of SYE were characterized through ultra-fast liquid chromatography–diode array detector–quadrupole time-of-flight tandem mass spectrometry. Cerebral arteriole thrombus was induced in C57BL/6J mouse by laser irradiation in vivo using two-photon laser-scanning microscopy. The time of thrombus formation and vessel diameter were calculated to evaluate the antithrombotic effect. In the model of blood stasis syndrome, rats were injected with adrenaline injection before and after ice-bath to induce hemorheology disorders. The results identified 29 constituents in SYE and hydroxysafflor yellow A was the main component (19.8%). In the mouse model, SYE inhibited thrombus formation in a dose-dependent manner and postponed the occlusion time in brain arteriole at dosages of 26.0 and 52.0 mg/kg. In the rat model of blood stasis syndrome, SYE significantly decreased the whole blood viscosity, suppressed red blood cell aggregation and platelet aggregation in high-dose (p < 0.01). The activated partial thromboplast in time was prolonged at a dosage of 7.0 mg/kg (p < 0.05) as well. In conclusion, SYE administration could inhibit the thrombus formation and beneficially influence the blood rheologyin blood stasis syndromes at relevant low dosages.

Aging is an inevitable biological process characterized by the loss of functional capacity and associated with changes in all phases of pharmacokinetic processes. Naringin, a dietary flavanone glycoside, has been proved to be beneficial for the treatment of multiple age-associated chronic diseases. To date, the pharmacokinetic processes of naringin in aged individuals are still unknown. Thus, a rapid resolution liquid chromatography tandem triple quadrupole mass spectrometry (RRLC-QQQ-MS/MS) method was established for the determination of naringin and its metabolite naringenin in rat plasma, urine, feces, and tissue homogenate. The pharmacokinetic parameters were calculated and a higher exposure of naringin and naringenin were observed in aged rats. Naringin and naringenin were mostly distributed in gastrointestinal tract, liver, kidney, lung, and trachea. Furthermore, a total of 39 flavonoid metabolites (mainly glucuronides and sulfates) and 46 microbial-derived phenolic catabolites were screened with ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS). Naringenin, hippuric acid, and 3-(4’-hydroxyphenyl)propionic acid were predominated metabolites. This study systemically investigated the pharmacokinetics, tissue distribution, metabolism, and excretion of naringin in aged rats, revealing age- and gender-related changes in the in vivo behavior of naringin. These results would be helpful for the interpretation of pharmacokinetics and pharmacodynamics of naringin in aged population.

Naringenin, a natural flavonoid widely found in citrus fruits, has been reported to possess anti-oxidant, anti-inflammatory, and hepatoprotective properties as a natural dietary supplement. However, the regulatory mechanism of naringenin in human liver remains unclear. In the present study, messenger RNA sequencing (mRNA-seq), microRNA sequencing (miRNA-seq), and real-time qPCR were used to distinguish the expression differences between control and naringenin-treated HepaRG cells. We obtained 1037 differentially expressed mRNAs and 234 miRNAs. According to the target prediction and integration analysis in silico, we found 20 potential miRNA-mRNA pairs involved in liver metabolism. This study is the first to provide a perspective of miRNA–mRNA interactions in the regulation of naringenin via an integrated analysis of mRNA-seq and miRNA-seq in HepaRG cells, which further characterizes the nutraceutical value of naringenin as a food additive.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by incompletely reversible airflow limitation and seriously threatens the health of humans due to its high morbidity and mortality. Naringenin, as a natural flavanone, has shown various potential pharmacological activities against multiple pathological stages of COPD, but available studies are scattered and unsystematic. Thus, we combined literature review with network pharmacology analysis to evaluate the potential therapeutic effects of naringenin on COPD and predict its underlying mechanisms, expecting to provide a promising tactic for clinical treatment of COPD.

Naringenin is found mainly in citrus fruits, and is thought to be beneficial in the prevention and control of lung diseases. This study aims to investigate the mechanisms of naringenin against the damage in the lung caused by cigarette smoke. A system bioinformatic approach was proposed to predict the mechanisms of naringenin for protecting lung health. Then, we validated this prediction in BEAS-2B cells treated with cigarette smoke extract (CSE). System bioinformatic analysis indicated that naringenin exhibits protective effects on lung through the inhibition of inflammation and suppression of oxidative stress based on a multi-pathways network, mainly including oxidative stress pathway, Nrf2 pathway, Lung fibrosis pathway, IL-3 signaling pathway, and Aryl hydrocarbon receptor pathway. The in vitro results showed that naringenin significantly attenuated CSE-induced up-regulation of IL-8 and TNF-α. CSE stimulation increased the mRNA expressions of Nrf2, HO-1, and NQO1; the levels of total protein and nuclear protein of Nrf2; and the activity of SOD on days 2 and 4; but decreased these indexes on day 6. Naringenin can balance the antioxidant system by regulating Nrf2 and its downstream genes, preliminarily validating that Nrf2 pathway is involved in the protection offered by naringenin against cigarette smoke-induced damage to the lung. It suggests that dietary naringenin shows possible potential use in the management of lung health.

Ganpu tea is an emerging tea drink produced from Pu-erh tea and the pericarp of Citrus reticulate Chachi (GCP). Recently, it has been increasingly favored by consumers due to the potential health effects and special taste. However, information concerning its chemical profile and biological activities is scarce. In this work, a total of 92 constituents were identified in hot-water extracts of Ganpu tea with ultra-high performance liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS). Moreover, the antioxidative and gut microbiota modulatory properties of Ganpu tea were investigated in rats after long-term dietary consumption. Ganpu tea and GCP could significantly enhance the activities of superoxide dismutase (SOD) by 13.4% (p < 0.05) and 15.1% (p < 0.01), as well as the activities of glutathione peroxidase (GSH-Px) by 16.3% (p < 0.01) and 20.5% (p < 0.01), respectively. Both showed better antioxidant capacities than Pu-erh tea. Ganpu tea increased the abundance of Bifidobacterium, Lactobacillus, and Lactococcus, suggesting the potential of Ganpu tea in modulating the gut microbiota to benefit human health. The obtained results provide essential information for further investigation of Ganpu tea.

Naringenin, a flavonoid compound which exists abundantly in Citrus fruits, is proven to possess excellent antitussive and expectorant effects. However, the clinical applications of naringenin are restricted by its poor solubility and low local concentration by oral administration. The aim of the present study is to prepare a naringenin-hydroxypropyl-β-cyclodextrin (naringenin-HPβCD) inclusion as an inhalation solution for pulmonary delivery. The naringenin-HPβCD inclusion was characterized by phase solubility study, XRD, differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1HNMR), and two-dimensional rotating frame Overhauser effect spectroscopy (2D ROESY). The in vitro permeability of the inclusion was evaluated on Calu-3 cells and the pharmacokinetic profile of pulmonary delivery was investigated in Sprague-Dawley (SD) rats. Based on the linear model of phase solubility study, the relationship between naringenin and HPβCD was identified as AL type with a 1:1 stoichiometry. XRD, DSC, and NMR studies indicated that the entire naringenin molecule is encapsulated into the cavity of HPβCD. HPβCD could increase the concentration of naringenin in the epithelium-lining fluid (ELF) of Calu-3 cells and act as a sustained release system for naringenin. The pharmacokinetic profile of naringenin-HPβCD inclusion showed rapid response and higher local concentration by pulmonary delivery. In conclusion, pulmonary delivery of naringenin-HPβCD inclusion is a promising formulation strategy, which could provide a new possibility for the clinical application of naringenin.