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Top electrodes of organic photovoltaics (OPVs) are usually thermally evaporated in the vacuum, which is non-continuous and time-consuming and has been the bottleneck for the OPV fabrication process. Printable top electrodes that are free of vacuum, high temperature, and solvents will make OPVs more attractive. Low-melting-point alloys (LMPAs) are promising candidates for printable OPV electrodes thanks to the merits of matching work functions, high electron conductivity, high environment stability, and no need for post-treatment. Here, LMPA electrodes are directly deposited on OPVs by simply falling a single LMPA droplet onto the substrate. The LMPA droplet spreads to form a thin film with a smooth interface intimately contacting the substrate. The electrode area can be tailored by adjusting the droplet diameter or the Weber number, which is the ratio of inertia to surface tension. The interface morphology is mainly affected by the contact temperature. The degree of oxidation and charges on the droplet can also influence the electrode area and interface morphology. OPVs with droplet-impacted LMPA electrodes exhibit power conversion efficiencies of up to 16.17%. This work demonstrates the potential of single-droplet impact deposition as a simple method for printing OPV electrodes for scalable manufacturing.
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Bright dipolar excitons, which contain electrical dipoles and have high oscillator strength, are an ideal platform for studying correlated quantum phenomena. They usually rely on carrier tunneling between two quantum wells or two layers to hybridize with nondipolar excitons to gain oscillator strength. In this work, we uncovered a new type of bright infrared dipolar exciton by stacking 90°-twisted black phosphorus (BP) structures. These excitons, inherent to the reconstructed band structure, exhibit high oscillator strength. Most importantly, they inherit the linear polarization from BP, which allows light polarization to be used to select the dipole direction. Moreover, the dipole moment and resonance energy can be widely tuned by the thickness of the BP. Our results demonstrate a useful platform for exploring tunable correlated dipolar excitons.
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Polygala tenuifolia Willd., a famous traditional Chinese medicine, has been widely applied to treat central nervous system diseases. In this study, P. tenuifolia root extract exhibited a moderate anti-ischemic effect on in-vitro oxygen-glucose deprivation/reperfusion (OGD/R) model. In transient middle cerebral artery occlusion (tMCAO) rats, P. tenuifolia root extract significantly attenuated brain infarction and neurological deficits in a dose-dependent manner. Compared with the sham group, the release of damage-associated molecular patterns (DAMPs)-HMGB1 in the ischemic brain was significantly higher, which was inhibited by P. tenuifolia root extract. To further explore such neuroprotective effects whether associated with aseptic inflammation, HMGB1-activated BV2 microglial cells model was established. The extract of P. tenuifolia was found to inhibit the downstream inflammatory response driven by HMGB1, with an IC50 value of 49.46 µg/mL. In addition, the extract was also found to be able to directly interact with HMGB1 in the surface plasmon resonance (SPR) experiment. Phytochemical studies showed that the extract of P. tenuifolia root contains a large number of terpenoids, oligosaccharides and phenolic compounds, which likely contribute to the above observed biological activities. Our results not only provide some data support for the clinical application of P. tenuifolia against cerebral ischemia, but also clarify the potential target of P tenuifolia's anti-inflammatory properties.
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The interlayer electronic coupling is responsible for the electronic structure evolution from monolayer graphene to graphite and for the moiré potential in twisted bilayer graphene. Here we demonstrate that the interlayer transfer integral (hopping parameter) increases nearly 40% with a quite moderate pressure of â¼3.5 GPa, manifested by the resonance peak shift in the infrared spectra of all 2-10 L graphene. A simple model based on the Morse potential enabled us to establish the relationship between the transfer integral and pressure. Our work provides fundamental insights into the dependence of the electronic coupling on the interlayer distance.
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BACKGROUND: Breast cancer is the most common cancer among women. Second primary malignancies (SPMs) related to radiotherapy are significant complications. This study aims to investigate the correlation between radiotherapy and the occurrence of SPMs in breast cancer patients with different estrogen receptor statuses. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) database, selecting estrogen receptor(+) and estrogen receptor(-) breast cancer patients from 1990 to 2015, with SPMs as the outcome measure. Fine-Gray competing risks regression and Poisson regression were employed to analyze the relationship between radiotherapy and the risk of SPMs in different estrogen receptor status groups. RESULTS: Radiotherapy was associated with an increased risk of lung cancer, melanoma, non-Hodgkin lymphoma, and leukemia in estrogen receptor(+) patients. In estrogen receptor(-) patients, radiotherapy was linked to an increased risk of brain cancer and leukemia. The cumulative incidence, standardized incidence ratio, and subgroup analyses showed consistent results. In the dynamic assessment of radiotherapy-related risks, estrogen receptor(+) patients aged 50-70 exhibited a higher risk of leukemia and melanoma. Lung cancer risk was highest during a latency period of 20-30 years, while melanoma, non-Hodgkin lymphoma, and leukemia risks peaked within the first 10 years. For estrogen receptor(-) patients, brain cancer risk was higher between ages 50 and 70, and leukemia risk was elevated between ages 20 and 50. CONCLUSION: Postoperative radiotherapy for breast cancer is associated with an increased risk of SPMs, with risks varying by estrogen receptor status and SPM type. Further research into the prevention of radiotherapy-related SPMs in different estrogen receptor status groups is crucial.
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HMGB1 interacts with TLR4 to activate the inflammatory cascade response, contributing to the pathogenesis of endogenous tissue damage and infection. The immense importance of HMGB1-TLR4 interaction in the immune system has made its binding interface an area of significant interest. To map the binding interface of HMGB1 occupied by TLR4, triterpenoids that disrupt the HMGB1-TLR4 interaction and interfere with HMGB1-induced inflammation were developed. Using the unique triterpenoid PT-22 as a probe along with photoaffinity labeling and site-directed mutagenesis, we found that the binding interface of HMGB1 was responsible for the recognition of TLR4 located on the "L" shaped B-box with K114 as a crucial hot-spot residue. Amazingly, this highly conserved interaction surface overlapped with the antigen-recognition epitope of an anti-HMGB1 antibody. Our findings propose a novel strategy for better understanding the druggable interface of HMGB1 that interacts with TLR4 and provide insights for the rational design of HMGB1-TLR4 PPI inhibitors to fine tune immune responses.
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Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (P=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (P<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(P<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.
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Metilação de DNA , Fatores de Transcrição Box Pareados , Fatores de Transcrição SOXB1 , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Humanos , Feminino , Fatores de Transcrição Box Pareados/genética , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia , Fatores de Transcrição SOXB1/genética , Adulto , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto JovemRESUMO
Automatic assessment of impairment and disease severity is a key challenge in data-driven medicine. We propose a framework to address this challenge, which leverages AI models trained exclusively on healthy individuals. The COnfidence-Based chaRacterization of Anomalies (COBRA) score exploits the decrease in confidence of these models when presented with impaired or diseased patients to quantify their deviation from the healthy population. We applied the COBRA score to address a key limitation of current clinical evaluation of upper-body impairment in stroke patients. The gold-standard Fugl-Meyer Assessment (FMA) requires in-person administration by a trained assessor for 30-45 minutes, which restricts monitoring frequency and precludes physicians from adapting rehabilitation protocols to the progress of each patient. The COBRA score, computed automatically in under one minute, is shown to be strongly correlated with the FMA on an independent test cohort for two different data modalities: wearable sensors (ρ = 0.814, 95% CI [0.700,0.888]) and video (ρ = 0.736, 95% C.I [0.584, 0.838]). To demonstrate the generalizability of the approach to other conditions, the COBRA score was also applied to quantify severity of knee osteoarthritis from magnetic-resonance imaging scans, again achieving significant correlation with an independent clinical assessment (ρ = 0.644, 95% C.I [0.585,0.696]).
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ETHNOPHARMACOLOGICAL RELEVANCE: Dioscoreae Rhizoma, a kind of Chinese yam, is a medicinal and edible plant used in China for strengthening the spleen and stomach. However, there is a lack of modern pharmacology studies regarding its anti-gastric injury activity. AIM OF THE STUDY: This study aimed to investigate the phytochemical composition of Chinese yam aqueous extract (CYW) and evaluate its gastroprotective effects against ethanol-induced gastric injury in vitro and in vivo. MATERIALS AND METHODS: The active components of CYW were identified using HPLC-QTOF-MS/MS in combination with the GNPS molecular networking and network pharmacology. In vitro studies were performed in the RAW264.7/GES-1 cell coculture system. In vivo study, mice were treated with CYW (0.31, 0.63, and 3.14 g/kg BW, orally) for 14 days, followed by a single oral dose of ethanol (10 mL/kg BW) to induce gastric injury. The biochemical, inflammation and oxidative stress markers were analyzed using commercial kits. Histopathology was used to assess the degree of gastric injury. Gene and protein expressions were studied using RT-qPCR and western blotting, respectively. RESULTS: CYW significantly restored the levels of SOD, GPx and CAT, and reduced the MDA content. Further analyses showed that CYW significantly alleviated the gastric oxidative stress by inhibiting the inflammation via decreasing p-NF-κB and p-IκB-α expression levels and inhibiting the generation of IL-6, TNF-α, and IL-1ß. At the same time, the fraction remarkably upregulated Bcl-2, downregulated Bax and increased growth factor secretion, thereby prevented gastric mucous cell. Besides, The combination of HPLC-QTOF-MS/MS, GNPS molecular networking analysis, and network pharmacology demonstrated that linoleic acid, 3-acetyl-11-keto-beta-boswellic acid, adenosine, aminocaproic acid, tyramine, DL-tryptophan, cycloleucine, lactulose, melibiose, alpha-beta-trehalose, and sucrose would be the main active compounds of CYW against ethanol-induced gastric injury. CONCLUSION: This study showed that CYW is potentially rich source of anti-oxidant and anti-inflammatory bioactive compounds. It showed efficacy against ethanol-induced gastric injury by inhibiting inflammation, oxidative stress, and apoptosis in the stomach. The results of the current work indicate that Dioscoreae Rhizoma could be utilized as a type of natural resource for production of new medicine and functional foods to prevent and/or ameliorate ethanol-induced gastric injury.
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Dioscorea , Etanol , Extratos Vegetais , Rizoma , Animais , Etanol/química , Dioscorea/química , Camundongos , Masculino , Rizoma/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/análise , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificaçãoRESUMO
In the development of ultra-deep wells, extremely high temperatures can lead to inefficiency of additives in drilling fluids. Hence, there is a need to prepare additives with a simple preparation process and good effects at ultra-high temperatures to ensure stable drilling fluid performance. In this study, a high temperature resistant filtration loss polymer (LY-2) was prepared using γ-methacryloyloxypropyltrimethoxysilane (KH570), N,N-dimethylallyl ammonium chloride (DMDAAC), sodium p-styrenesulfonate (SSS), and ß-cyclodextrin (ß-CD). The impact of the different monomer ratios on particle size, rheology, and filtration performance was systematically investigated. Infrared spectroscopy afforded the structural features. Thermogravimetric Analysis detected the temperature stability, and scanning electron microscopy characterized the polymer micromorphology. LY-2 was completely decomposed at a temperature above 600 °C. Experiments showed FLAPI of the drilling fluid containing 3% LY-2 aged at 260 °C/16 h was only 5.1 mL, which is 85.4% lower compared to the base fluid. This is attributed to the synergistic effect of the polymer adsorption through chemical action at high temperatures and the blocking effect of carbon nanoparticles on the filter cake released by cyclodextrin carbonization at high temperatures. Comparing LY-2 with commercial filter loss reducers shows that LY-2 has excellent temperature resistance, which exhibited five times higher filtration performance and relatively low cost, making it possible to be applied to ultra-high temperature drilling operations in an industrial scale-up.
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Cardiovascular disease has become a common ailment that endangers human health, having garnered widespread attention due to its high prevalence, recurrence rate, and sudden death risk. Ginseng possesses functions such as invigorating vital energy, enhancing vein recovery, promoting body fluid and blood nourishment, calming the nerves, and improving cognitive function. It is widely utilized in the treatment of various heart conditions, including palpitations, chest pain, heart failure, and other ailments. Although numerous research reports have investigated the cardiovascular activity of single ginsenoside, there remains a lack of systematic research on the specific components group that predominantly contribute to cardiovascular efficacy in ginseng medicinal materials. In this research, the spectrum-effect relationship, target cell extraction, and BP neural network classification were used to establish a rapid screening system for potential active substances. The results show that red ginseng extract (RGE) can improve the decrease in cell viability and ATP content and inhibit the increase in ROS production and LDH release in OGD-induced H9c2 cells. A total of 70 ginsenosides were identified in RGE using HPLC-Q-TOF-MS/MS analysis. Chromatographic fingerprints were established for 12 batches of RGE by high-performance liquid chromatography (HPLC). A total of 36 common ingredients were found in 12 batches of RGE. The cell viability, ATP, ROS, and LDH of 12 batches RGE were tested to establish gray relationship analysis (GRA) and partial least squares discrimination analysis (PLS-DA). BP neural network classification and target cell extraction were used to narrow down the scope of Spectral efficiency analysis and screen the potential active components. According to the cell experiments, RGE can improve the cell viability and ATP content and reduce the oxidative damage. Then, seven active ingredients, namely, Ginsenoside Rg1, Rg2, Rg3, Rb1, Rd, Re, and Ro, were screened out, and their cardiovascular activity was confirmed in the OGD model. The seven ginsenosides were the main active substances of red ginseng in treating myocardial injury. This study offers a reference for quality control in red ginseng and preparations containing red ginseng for the management of cardiovascular diseases. It also provides ideas for screening active ingredients of the same type of multi-pharmacologically active traditional Chinese medicines.
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Sobrevivência Celular , Ginsenosídeos , Redes Neurais de Computação , Panax , Extratos Vegetais , Panax/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Ginsenosídeos/farmacologia , Ginsenosídeos/química , Ginsenosídeos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Ratos , Animais , Linhagem Celular , Espécies Reativas de Oxigênio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Cromatografia Líquida de Alta Pressão , Humanos , Espectrometria de Massas em TandemRESUMO
Ephedra herb (EH), an important medicine prescribed in herbal formulas by Traditional Chinese Medicine practitioners, has been widely used in the treatment of viral pneumonia in China. However, the molecular basis of EH in viral pneumonia remains unclear. In this study, a ternary correlation multi-symptom network strategy was established based on in vivo chemical profile identification and metabolomics to explore the molecular basis of EH against viral pneumonia. Results showed that 143 compounds of EH and 70 prototype components were identified in vivo. EH could reduce alveolar-capillary barrier disruption in rats with viral pneumonia and significantly downregulate the expression of inflammatory factors and bronchoalveolar lavage fluid. Plasma metabolomics revealed that EH may be involved in the regulation of arachidonic acid, tryptophan, tyrosine, nicotinate, and nicotinamide metabolism. The multi-symptom network showed that 12 compounds have an integral function in the treatment of viral pneumonia by intervening in many pathways related to viruses, immunity and inflammation, and lung injury. Further verification demonstrated that sinapic acid and frambinone can regulate the expression of related genes. It has been shown to be a promising representative of the pharmacological constituents of ephedra.
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Medicamentos de Ervas Chinesas , Ephedra , Metabolômica , Ratos Sprague-Dawley , Animais , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Ephedra/química , Masculino , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologiaRESUMO
Low-maintenance membrane cleaning is essential for the stable operation of membrane bioreactors. This work proposes an in-situ electrical-cleaning method using an electro-MBR. When the applied bias was transiently increased, the membrane flux recovered rapidly because of the scouring effect from gas evolution reactions. The exfoliation of the cake layer induced by gas scouring played a major role in mitigating membrane fouling, recovering the transmembrane pressure (TMP) by 88.6 % under optimal conditions. Membrane modules did not require replacement during the operation period due to the efficacy of electrical cleaning, with the TMP varying between 37.5 % and 62.5 % of the ultimate pressure requiring change of the membrane modules. Despite the increase in power consumption of 0.66 Wh·m-3 due to the additional applied bias, there was no need for chemical additives or manual maintenance. Therefore, the electrical cleaning method enhanced the service life and reduced the maintenance costs of the electro-MBR.
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Reatores Biológicos , Eletrodos , Membranas Artificiais , Gases , Incrustação Biológica/prevenção & controle , PressãoRESUMO
Selecting thresholds to convert continuous predictions of species distribution models proves critical for many real-world applications and model assessments. Prevalent threshold selection methods for presence-only data require unproven pseudo-absence data or subjective researchers' decisions. This study proposes a new method, Boyce-Threshold Quantile Regression (BTQR), to determine thresholds objectively without pseudo-absence data. We summarize that the mutation point is a typical shape feature of the predicted-to-expected (P/E) curve after reviewing relevant articles. Analysis based on source-sink theory suggests that this mutation point may represent a transition in habitat types and serve as an appropriate threshold. Threshold regression is introduced to accurately locate the mutation point. To validate the effectiveness of BTQR, we used four virtual species of varying prevalence and a real species with reliable distribution data. Six different species distribution models were employed to generate continuous suitability predictions. BTQR and nine other traditional methods transformed these continuous outputs into binary results. Comparative experiments show that BTQR has advantages in terms of accuracy, applicability, and consistency over the existing methods.
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Renal fibrosis poses a significant threat to individuals suffering from chronic progressive kidney disease. Given the absence of effective medications for treating renal fibrosis, it becomes crucial to assess the extent of fibrosis in real time and explore the development of novel drugs with substantial therapeutic benefits. Due to the accumulation of renal tissue damage and the uncontrolled deposition of fibrotic matrix during the course of the disease, there is an increase in viscosity both intracellularly and extracellularly. Therefore, a viscosity-sensitive near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging probe, BDP-KY, was developed to detect aberrant changes in viscosity during fibrosis. Furthermore, BDP-KY has been applied to screen the effective components of herbal medicine, rhubarb, resulting in the identification of potential antirenal fibrotic compounds such as emodin-8-glucoside and chrysophanol 8-O-glucoside. Ultrasound, PA, and NIRF imaging of a unilateral uretera obstruction mice model show that different concentrations of emodin-8-glucoside and chrysophanol 8-O-glucoside effectively reduce viscosity levels during the renal fibrosis process. The histological results showed a significant decrease in fibrosis factors α-smooth muscle actin and collagen deposition. Combining these findings with their pharmacokinetic characteristics, these compounds have the potential to fill the current market gap for effective antirenal fibrosis drugs. This study demonstrates the potential of BDP-KY in the evaluation of renal fibrosis, and the two identified active components from rhubarb hold great promise for the treatment of renal fibrosis.
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Gardenia is both a food and medicine plant. It is widely used for cardiovascular protection, and its main bioactive ingredient is crocetin. This study aims to observe the therapeutic effects of crocetin on chronic heart failure in rats induced by various etiologies. It further compares the efficacy differences between preventative and treatment administration, varying dosages, and treatment durations, to provide improved guidance for medication in heart failure rats and determine which categories of chronic heart failure rats might benefit most from crocetin. Chronic heart failure models induced by abdominal aorta constriction, renal hypertension, and coronary artery ligation were constructed. By examining cardiac function, blood biochemistry, and histopathology, the study assessed the preventive and therapeutic effects of crocetin on load-induced and myocardial ischemia-induced heart failure. The results showed that in all three models, both treatment and preventative administration of crocetin significantly improved chronic heart failure in rats, especially in preventative administration. The results indicate crocetin may be beneficial for improving symptoms and functional capacity in rats with heart failure. Furthermore, long-term administration was more effective than short-term administration across all three rat models, with therapeutic onset observed over 6 weeks.
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Organic single crystals (OSCs) with uniform morphologies and highly ordered molecular aggregations are promising for high-performance optoelectronic devices, such as organic solid-state lasers (OSSLs), organic light-emitting transistors (OLETs), and organic light-emitting diodes (OLEDs). However, manipulating OSC morphologies and aggregation is challenging. In this study, we synthesized two-dimensional (2D) OSCs of 4,4'-bis[(N-carbazole)styryl]biphenyl (BSBCz) in hexagonal and parallelogram microplate (H-MP and P-MP) forms. Both types exhibit H-aggregation in the 2D plate plane but with different molecular transition dipole moment (TDM) orientations. This leads to different photon coupling modes with H-MP and P-MP microcavities. H-MPs enable isotropic 2D-waveguiding, forming whispering gallery mode (WGM) resonators, while P-MPs create unidirectional waveguiding, forming Fabry-Pérot mode (FP) resonators. These resonators can generate low-threshold laser emissions at 467 and 473 nm, respectively, and exhibit superior lasing stability with a half-life exceeding 2 h. Our BSBCz microplate OSCs are attractive candidates to combine controlled organic microcavities with photon transporting for realizing future integrated optoelectronic devices.
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INTRODUCTION: HMGB1 is a non-histone chromatin protein released or secreted in response to tissue damage or infection. Extracellular HMGB1, as a crucial immunomodulatory factor, binds with several different receptors to innate inflammatory responses that aggravate acute and chronic liver diseases. The increased levels of HMGB1 have been reported in various liver diseases, highlighting that it represents a potential biomarker and druggable target for therapeutic development. AREAS COVERED: This review summarizes the current knowledge on the structure, function, and interacting receptors of HMGB1 and its significance in multiple liver diseases. The latest patented and preclinical studies of HMGB1 inhibitors (antibodies, peptides, and small molecules) for liver diseases are summarized by using the keywords 'HMGB1,' 'HMGB1 antagonist, HMGB1-inhibitor,' 'liver disease' in Web of Science, Google Scholar, Google Patents, and PubMed databases in the year from 2017 to 2023. EXPERT OPINIONS: In recent years, extensive research on HMGB1-dependent inflammatory signaling has discovered potent inhibitors of HMGB1 to reduce the severity of liver injury. Despite significant progress in the development of HMGB1 antagonists, few of them are approved for clinical treatment of liver-related diseases. Developing safe and effective specific inhibitors for different HMGB1 isoforms and their interaction with receptors is the focus of future research.
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Desenvolvimento de Medicamentos , Proteína HMGB1 , Hepatopatias , Patentes como Assunto , Humanos , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/metabolismo , Hepatopatias/tratamento farmacológico , Hepatopatias/fisiopatologia , Animais , Biomarcadores/metabolismo , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Índice de Gravidade de DoençaRESUMO
14-3-3ζ protein, the key target in the regulation and control of integrin ß3 outside-in signaling, is an attractive new strategy to inhibit thrombosis without affecting hemostasis. In this study, 4'-O-methylbavachalconeB (4-O-MB) in Psoraleae Fructus was identified as a 14-3-3ζ ligand with antithrombosis activity by target fishing combined with ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) analysis. The competitive inhibition analysis showed that 4-O-MB targeted 14-3-3ζ and blocked the 14-3-3ζ/integrin ß3 interaction with inhibition constant (Ki) values of 9.98 ± 0.22 µM. Molecular docking and amino acid mutation experiments confirmed that 4-O-MB specifically bound to 14-3-3ζ through LSY9 and SER28 to regulate the 14-3-3ζ/integrin ß3 interaction. Besides, 4-O-MB affected the integrin ß3 early outside-in signal by inhibiting AKT and c-Src phosphorylation. Meanwhile, 4-O-MB could inhibit ADP-, collagen-, or thrombin-induced platelet aggregation function but had no effect on platelet adhesion to collagen-coated surfaces in vivo. Administration of 4-O-MB could significantly inhibit thrombosis formation without disturbing hemostasis in mice. These findings provide new prospects for the antithrombotic effects of Psoraleae Fructus and the potential application of 4-O-MB as lead compounds in the therapy of thrombosis by targeting 14-3-3ζ.
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Agregação Plaquetária , Trombose , Camundongos , Animais , Integrina beta3/genética , Integrina beta3/química , Integrina beta3/metabolismo , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/farmacologia , Simulação de Acoplamento Molecular , Trombose/tratamento farmacológico , Trombose/genética , Trombose/metabolismo , Colágeno/metabolismo , Plaquetas/metabolismoRESUMO
In the current study, tea saponin, identified as the primary bioactive constituent in seed pomace of Camellia oleifera Abel., was meticulously extracted and hydrolyzed to yield five known sapogenins: 16-O-tiglogycamelliagnin B (a), camelliagnin A (b), 16-O-angeloybarringtogenol C (c), theasapogenol E (d), theasapogenol F (e). Subsequent biotransformation of compound a facilitated the isolation of six novel metabolites (a1-a6). The anti-inflammatory potential of these compounds was assessed using pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns molecules (DAMPs)-mediated cellular inflammation models. Notably, compounds b and a2 demonstrated significant inhibitory effects on both lipopolysaccharide (LPS) and high-mobility group box 1 (HMGB1)-induced inflammation, surpassing the efficacy of the standard anti-inflammatory agent, carbenoxolone. Conversely, compounds d, a3, and a6 selectivity targeted endogenous HMGB1-induced inflammation, showcasing a pronounced specificity. These results underscore the therapeutic promise of C. oleifera seed pomace-derived compounds as potent agents for the management of inflammatory diseases triggered by infections and tissue damage.