Near-infrared mechanoluminescence sensor: A new method for on-site infrastructure detection.

Near-infrared mechanoluminescence is a phenomenon that produces high penetrating near-infrared light under external stimulation. Near-infrared light coincides with the biological window, lower optical loss, and the fact that the mechanoluminescence material is a medium that converts mechanical energy into light energy. The near-infrared mechanoluminescence material has potential application prospects in the fields of biological imaging, medical diagnosis, and monitoring of building materials. In this article, we report on a perovskite-type Sr3Sn2O7:Nd3+ near-infrared mechanoluminescence material, and its peaks locate in the first near-infrared window (800-1000 nm) and the second near-infrared window (1080, 1350 nm), respectively. Under the condition of pre-sintering with Li2CO3 as flux, the best sintering conditions are obtained, and the luminescence of material is in perfect agreement with the applied mechanical stress. In addition, a near-infrared mechanoluminescence sensor is proposed to solve the problem of building damage and timely maintenance.

Microstrain-Stimulated Elastico-Mechanoluminescence with Dual-Mode Stress Sensing.

Elastico-mechanoluminescence technology has shown significant application prospects in stress sensing, artificial skin, remote interaction, and other research areas. Its progress mainly lies in realizing stress visualization and 2D or even 3D stress-sensing effects using a passive sensing mode. However, the widespread promotion of mechanoluminescence (ML) technology is hindered by issues such as high stress or strain thresholds and a single sensing mode based on luminous intensity. In this study, a highly efficient green-emitting ML with dual-mode stress-sensing characteristics driven by microscale strain is developed using LiTaO3:Tb3+. In addition to single-mode sensing based on the luminous intensity, the self-defined parameter (Q) is also introduced as a dual-mode factor for sensing the stress velocity. Impressively, the fabricated LiTaO3:Tb3+ film is capable of generating discernible ML signals even when supplied with strains as low as 500 µst. This is the current minimum strain value that can drive green-emitting ML. This study offers an ideal photonic platform for exploring the potential applications of rare-earth-doped elastico-ML materials in remote interaction devices, high-precision stress sensors, and single-molecule biological imaging.

Human UDP-glucuronosyltransferase 1As catalyze aristolochic acid D O-glucuronidation to form a lesser nephrotoxic glucuronide.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochic acids (AAs) are naturally occurring nitro phenanthrene carboxylic acids primarily found in plants of the Aristolochiaceae family. Aristolochic acid D (AAD) is a major constituent in the roots and rhizomes of the Chinese herb Xixin (the roots and rhizomes of Asarum heterotropoides F. Schmidt), which is a key material for preparing a suite of marketed Chinese medicines. Structurally, AAD is nearly identical to the nephrotoxic aristolochic acid I (AAI), with an additional phenolic group at the C-6 site. Although the nephrotoxicity and metabolic pathways of AAI have been well-investigated, the metabolic pathway(s) of AAD in humans and the influence of AAD metabolism on its nephrotoxicity has not been investigated yet. AIM OF THE STUDY: To identify the major metabolites of AAD in human tissues and to characterize AAD O-glucuronidation kinetics in different enzyme sources, as well as to explore the influence of AAD O-glucuronidation on its nephrotoxicity. MATERIALS AND METHODS: The O-glucuronide of AAD was biosynthesized and its chemical structure was fully characterized by both 1H-NMR and 13C-NMR. Reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses were conducted to assess the crucial enzymes involved in AAD O-glucuronidation in humans. Docking simulations were performed to mimic the catalytic conformations of AAD in human UDP-glucuronosyltransferases (UGTs), while the predicted binding energies and distances between the deprotonated C-6 phenolic group of AAD and the glucuronyl moiety of UDPGA in each tested human UGT isoenzyme were measured. The mitochondrial membrane potentials (MMP) and reactive oxygen species (ROS) levels in HK-2 cells treated with either AAI, or AAD, or AAD O-glucuronide were tested, to elucidate the impact of O-glucuronidation on the nephrotoxicity of AAD. RESULTS: AAD could be rapidly metabolized in human liver and intestinal microsomes (HLM and HIM, respectively) to form a mono-glucuronide, which was purified and fully characterized as AAD-6-O-ß-D-glucuronide (AADG) by NMR. UGT1A1 was the predominant enzyme responsible for AAD-6-O-glucuronidation, while UGT1A9 contributed to a lesser extent. AAD-6-O-glucuronidation in HLM, HIM, UGT1A1 and UGT1A9 followed Michaelis-Menten kinetics, with the Km values of 4.27 µM, 9.05 µM, 3.87 µM, and 7.00 µM, respectively. Docking simulations suggested that AAD was accessible to the catalytic cavity of UGT1A1 or UGT1A9 and formed catalytic conformations. Further investigations showed that both AAI and AAD could trigger the elevated intracellular ROS levels and induce mitochondrial dysfunction and in HK-2 cells, but AADG was hardly to trigger ROS accumulation and mitochondrial dysfunction. CONCLUSION: Collectively, UGT1A-catalyzed AAD 6-O-glucuronidation represents a crucial detoxification pathway of this naturally occurring AAI analogs in humans, which is very different from that of AAI.

Modulating Smart Mechanoluminescent Phosphors for Multistimuli Responsive Optical Wood.

Mechanoluminescence is a smart light-emitting phenomenon in which applied mechanical energy is directly converted into photon emissions. In particular, mechanoluminescent materials have shown considerable potential for applications in the fields of energy and sensing. This study thoroughly investigates the mechanoluminescence and long afterglow properties of singly doped and codoped Sr2 MgSi2 O7 (SMSO) with varying concentrations of Eu2+ and Dy3+ ions. Subsequently, a comprehensive analysis of its multimode luminescence properties, including photoluminescence, mechanoluminescence, long afterglow, and X-ray-induced luminescence, is conducted. In addition, the density of states mapping is acquired through first-principles calculations, confirming that the enhanced mechanoluminescence properties of SMSO primarily stem from the deep trap introduced by Dy3+ . In contrast to traditional mixing with Polydimethylsiloxane, in this study, the powders are incorporated into optically transparent wood to produce a multiresponse with mechanoluminescence, long afterglow, and X-ray-excited luminescence. This structure is achieved by pretreating natural wood, eliminating lignin, and subsequently modifying the wood to overall modification using various smart phosphors and epoxy resin composites. After natural drying, a multifunctional composite wood structure with diverse luminescence properties is obtained. Owing to its environmental friendliness, sustainability, self-power, and cost-effectiveness, this smart mechanoluminescence wood is anticipated to find extensive applications in construction materials and energy-efficient displays.

Complicated Bosworth fracture-dislocation: A case report and review of the literature.

Bosworth fracture and dislocation is relatively rare, accounting for about 1% of ankle fractures. It is characterized by the proximal fibula fracture embedded in the posterolateral distal tibia. Due to an insufficient understanding of this fracture, it is easy to cause missed diagnosis and misdiagnosis in clinical practice. Due to the insertion of the fracture, it is challenging to perform closed reduction, and improper treatment is easy to cause complications. Surgical treatment is recommended for this type of fracture. In order to improve the understanding of orthopedic surgeons about Bosworth fracture and dislocation, this paper reports the diagnosis and treatment of 2 cases of Bosworth fracture and dislocation, and reviews the literature on Bosworth fracture's mechanism, diagnosis, classification, complications, and treatment options in recent years.

The diagnostic significance of the ZNF gene family in pancreatic cancer: a bioinformatics and experimental study.

Background: Pancreatic adenocarcinoma (PAAD) is among the most devastating of all cancers with a poor survival rate. Therefore, we established a zinc finger (ZNF) protein-based prognostic prediction model for PAAD patients. Methods: The RNA-seq data for PAAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Differentially expressed ZNF protein genes (DE-ZNFs) in PAAD and normal control tissues were screened using the "lemma" package in R. An optimal risk model and an independent prognostic value were established by univariate and multivariate Cox regression analyses. Survival analyses were performed to assess the prognostic ability of the model. Results: We constructed a ZNF family genes-related risk score model that is based on the 10 DE-ZNFs (ZNF185, PRKCI, RTP4, SERTAD2, DEF8, ZMAT1, SP110, U2AF1L4, CXXC1, and RMND5B). The risk score was found to be a significant independent prognostic factor for PAAD patients. Seven significantly differentially expressed immune cells were identified between the high- and low-risk patients. Then, based on the prognostic genes, we constructed a ceRNA regulatory network that includes 5 prognostic genes, 7 miRNAs and 35 lncRNAs. Expression analysis showed ZNF185, PRKCI and RTP4 were significantly upregulated, while ZMAT1 and CXXC1 were significantly downregulated in the PAAD samples in all TCGA - PAAD, GSE28735 and GSE15471 datasets. Moreover, the upregulation of RTP4, SERTAD2, and SP110 were verified by the cell experiments. Conclusion: We established and validated a novel, Zinc finger protein family - related prognostic risk model for patients with PAAD, that has the potential to inform patient management.

Novel cementitious materials with mechanoluminescence for the application of visible stress monitoring and recording.

The development of real-time and accurate visual stress detection is crucial for the field of building engineering. Herein, a new strategy is explored for the development of novel cementitious materials by hierarchical aggregation smart luminescent material and resin-based material. The cementitious material with such layered structure is inherently capable of visualization of stress monitoring and recording by converting the stress to visible light. The specimen fabricated by the novel cementitious material could repetitively emit green visible light under excitation of a mechanical pulse for 10 cycles, suggesting that the cementitious material shows highly reproducible performance. Moreover, the numerical simulations and analysis for the models of stress indicate that the luminescent time is synchronous with the stress and the emission intensity is proportional to the value of stress. To the best of our knowledge, this is the first study that the cementitious material realizes visible stress monitoring and recording, which supplies new insights for exploring modern multi-functional building materials.

Subtypes of the Completely Reversed Flow Waveform in Vertebral Artery Can Help to Differentiate Subclavian Artery Occlusion from Severe Stenosis.

OBJECTIVES: To investigate the value of subtypes of completely reversed flow (CRF) waveform in vertebral artery (VA) on Doppler ultrasound in differentiation occlusion from severe stenosis of the ipsilateral proximal subclavian artery (SA). METHODS: A total of 357 patients with CRF in the VA on Doppler US were reviewed retrospectively. Among them, 49 patients (mean age, 68.2 ± 7.8 years) confirmed by digital subtraction angiography (DSA) were included. According to the status of diastolic flow, the CRF was divided into continuous CRF (CCRF, n = 27) and intermittent CRF (ICRF, n = 22). The correlation of subtypes of CRF waveform and VA parameters with the severity of SA stenosis was evaluated. The severity of SA stenosis was determined by DSA. RESULTS: Of those 49 patients, SA occlusion was observed in 33 patients (67%, occlusion group) and severe stenosis in 16 patients (33%, stenosis group). The subtypes of CRF waveforms showed a significant between-group difference (p = 0.005). CCRF exhibited an accuracy of 85.2% (23/27) in diagnosing SA occlusion. The diameter of the target VA with ICRF showed a significant between-group difference (p = 0.041). The target VA diameter ≥ 3.8 mm in ICRF achieved an accuracy of 81.8% (18/22), and its combination with CCRF achieved an accuracy of 83.7% (41/49) in the differentiation of SA occlusion from severe stenosis. CONCLUSIONS: Subtypes of CRF in VA can help to differentiate SA occlusion from severe stenosis. CCRF has higher accuracy in diagnosing SA occlusion. The CCRF waveform plus VA diameter in ICRF is more accurate for differentiating SA occlusion from severe stenosis.

Smart Mechanoluminescent Phosphors: A Review of Strontium-Aluminate-Based Materials, Properties, and Their Advanced Application Technologies.

Mechanoluminescence, a smart luminescence phenomenon in which light energy is directly produced by a mechanical force, has recently received significant attention because of its important applications in fields such as visible strain sensing and structural health monitoring. Up to present, hundreds of inorganic and organic mechanoluminescent smart materials have been discovered and studied. Among them, strontium-aluminate-based materials are an important class of inorganic mechanoluminescent materials for fundamental research and practical applications attributed to their extremely low force/pressure threshold of mechanoluminescence, efficient photoluminescence, persistent afterglow, and a relatively low synthesis cost. This paper presents a systematic and comprehensive review of strontium-aluminate-based luminescent materials' mechanoluminescence phenomena, mechanisms, material synthesis techniques, and related applications. Besides of summarizing the early and the latest research on this material system, an outlook is provided on its environmental, energy issue and future applications in smart wearable devices, advanced energy-saving lighting and displays.

[Progress on knee cartilage repair by knee joint distraction].

Knee joint distraction is a new technology for the treatment of knee osteoarthritis in recent years. It could reduce knee pain and improve knee function, which is inseparable from the role of cartilage repair. The mechanism and influencing factors of knee joint distraction in repairing cartilage are the focus of current research. In this paper, the author reviewed literature and found that knee joint distraction could reduce knee joint load and provide a appropriate mechanical environment for cartilage repair, and it is resulting hydrostatic pressure fluctuation in the knee joint not only helps cartilage to absorb nutrients, but also promotes cartilage formation genes and inhibits cartilage matrix degrading enzyme gene expression. In addition, knee joint distraction creates conditions for synovial mesenchymal stem cells to be collected to cartilage injury, and improves ability of synovial mesenchymal stem cells to proliferate and differentiate into a chondrogenic lineage. Knee joint distraction could reduce inflammatory reaction and cartilage injury of knee joint by reducing content of inflammatory factors and inhibiting expression of inflammatory genes. At present, it is known that the factors affect repair of cartilage by knee joint distraction include, increasing weight-bearing activity and height and time of distraction is helpful for cartilage repair, male patients and patients with higher severity of knee osteoarthritis have better cartilage repair effect after knee joint distraction.The better efficacy of cartilage repair on the first year after knee joint distraction predicts a higher long-term survival rate of knee joint distraction with knee preservation. However, the research on the above hot spots is only at the initial stage and further exploration is still needed, in order to better guide clinical application of knee joint distraction.

Mechanoluminescence from an Ion-Irradiated Single Crystal of Lithium Niobium Oxide.

Mechanoluminescence (ML) is a well-known phenomenon that has a wide range of applications in security monitoring, biomechanical sensing, and displays. Although several mechanisms relating to ML have been proposed, significant ambiguity persists due to the coexistence of crystal boundaries, luminescence centers, and defects within the samples, making them hard to disentangle. Here we preclude such ambiguity by using a Kr+-irradiated single crystal of lithium niobium oxide (LiNbO3) as the ML materials so that oxygen vacancies are retained to modulate the ML properties. We explore the ion concentration- and species-dependent ML properties along with the band calculations to explicitly reveal that it is the trapped electrons at the oxygen vacancies that are transferred to the conduction band under the piezopotentials of LiNbO3, which combine with holes in the valence band and emit photons. This in-depth understanding not only clarifies the long-standing obscurity of the ML mechanism but also paves a rational and scalable way for the design of advanced ML materials with superior performances.

Twenty Years Development of Tibial Cortex Transverse Transport Surgery in PR China.

Tibial cortex transverse transport (TTT) surgery is an extension of the Ilizarov technique. Based on the law of tension-stress, its primary function is to rebuild microcirculation which can relieve ischemic symptoms and promote wound healing. It has received more and more scholars' attention and has experienced a series of changes for 20 years since it entered PR China. The mechanisms involved have gradually become clear, such as the reconstruction of the polarization balance of macrophages, the promotion of vascular tissue regeneration, and the mobilization and regulation of bone marrow-derived stem cells. TTT technique is mainly used in the treatment of chronic ischemic diseases of the lower extremities. It has recently been successfully used in the treatment of primary lymphedema of the lower extremities. A series of improvements have been made in the external fixator's style, the size of skin incision and osteotomy, and distraction method. For example, the annular external fixator has been redesigned as a unilateral external fixator, and accordion technology has been introduced. For distraction methods after surgery, there was no uniform standard in the past. The technique can also be used in combination with other treatments to achieve better effects, such as interventional therapy, negative pressure sealed drainage, 3D printing technology, traditional Chinese medicine. Nevertheless, the surgery may bring some complications, such as secondary fracture, nail infection, skin necrosis at the surgical site, etc. Reports of complications and doubts about the technique have made the TTT technique controversial. In 2020, the relevant expert consensus was published with treatment and management principles, which might guide the better application and development of this technique.

Clinical significance of breast cancer susceptibility gene 1 expression in resected non-small cell lung cancer: A meta-analysis.

BACKGROUND: The clinical significance of breast cancer susceptibility gene 1 (BRCA1) in non-small cell lung cancer (NSCLC) patients undergoing surgery remains unclear up to now. AIM: To explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC. METHODS: EMBASE, PubMed, Web of Science, and The Cochrane Library databases were searched to identify the relevant articles. To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients, the combined relative risks or hazard ratios (HRs) with their corresponding 95% confidence intervals [CIs] were estimated. RESULTS: Totally, 11 articles involving 1041 patients were included in the meta-analysis. The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC. Positive BRCA1 expression signified a shorter overall survival (HR = 1.60, 95%CI: 1.25-2.05; P < 0.001) and disease-free survival (HR = 1.78, 95%CI: 1.42-2.23; P < 0.001). However, no significant association of BRCA1 expression with any clinicopathological parameters was observed. CONCLUSION: BRCA1 expression indicates a poor prognosis in resected NSCLC patients. BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.

Effective Repeatable Mechanoluminescence in Heterostructured Li1- x Nax NbO3 : Pr3.

Mechanoluminescence (ML) is a striking optical phenomenon that is achieved through mechanical to optical energy conversion. Here, a series of Li1 -x Nax NbO3 : Pr3+ (x = 0, 0.2, 0.5, 0.8, 1.0) ML materials have been developed. In particular, due to the formation of heterostructure, the synthesized Li0.5 Na0.5 NbO3 : Pr3+ effectively couples the trap structures and piezoelectric property to realize the highly repeatable ML performance without traditional preirradiation process. Furthermore, the ML performances measured under sunlight irradiation and preheating confirm that the ML properties of Li0.5 Na0.5 NbO3 : Pr3+ can be ascribed to the dual modes of luminescence mechanism, including both trap-controllable and self-recoverable modes. In addition, DFT calculations further confirm that the doping of Na+ ions in LiNbO3 leads to electronic modulations by the formation of the heterostructures, which optimizes the trap distributions and concentrations. These modulations improve the electron transfer efficiency to promote ML performances. This work has supplied significant references for future design and synthesis of efficient ML materials for broad applications.

Methylophiopogonanone A is a naturally occurring broad-spectrum inhibitor against human UDP-glucuronosyltransferases: Inhibition behaviours and implication in herb-drug interactions.

Methylophiopogonanone A (MOA) is an abundant homoisoflavonoid in the Chinese herb Ophiopogonis Radix. Recent investigations revealed that MOA inhibited several human cytochrome P450 enzymes (CYPs) and stimulated OATP1B1. However, the inhibitory effects of MOA on phase II drug-metabolizing enzymes, such as human UDP-glucuronosyltransferases (hUGTs), have not been well investigated. Herein, the inhibition potentials of MOA on hUGTs were assessed. The results clearly demonstrated that MOA dose-dependently inhibited all tested hUGTs including UGT1A1 (IC50 = 1.23 µM), one of the most important detoxification enzymes in humans. Further investigations showed that MOA strongly inhibited UGT1A1-catalysed NHPH-O-glucuronidation in a range of biological settings including hUGT1A1, human liver microsomes (HLM) and HeLa cells overexpressing UGT1A1. Inhibition kinetic analyses demonstrated that MOA competitively inhibited UGT1A1-catalysed NHPH-O-glucuronidation in both hUGT1A1 and HLM, with Ki values of 0.52 and 1.22 µM, respectively. Collectively, our findings expanded knowledge of the interactions between MOA and human drug-metabolizing enzymes, which would be very helpful for guiding the use of MOA-related herbal products in clinical settings.

Correction: The potential role of borophene as a radiosensitizer in boron neutron capture therapy (BNCT) and particle therapy (PT).

Correction for 'The potential role of borophene as a radiosensitizer in boron neutron capture therapy (BNCT) and particle therapy (PT)' by Pengyuan Qi et al., Biomater. Sci., 2020, 8, 2778-2785, DOI: .

Three-dimensional printing combined with open reduction and internal fixation versus open reduction and internal fixation in the treatment of acetabular fractures: A systematic review and meta-analysis.

PURPOSE: This meta-analysis compared the clinical outcome of three-dimensional (3D) printing combined with open reduction and internal fixation (ORIF) to traditional ORIF in the treatment of acetabular fractures. METHODS: We searched the Cochrane Library, PubMed, Embase, VIP database, CNKI, and Wanfang database with keywords "acetabular fracture", "3D printing", "three-dimensional printing", "open reduction and internal fixation", "Acetabulum", "Acetabula" from January 2000 to March 2020. Two reviewers independently selected articles, extracted data, assessed the quality evidence and risk bias of included trials using the Cochrane Collaboration' s tools and/or Newcastle-Ottawa scale. When the two analysts had different opinions, they would ask the third analyst for opinion. Randomized controlled trials or retrospective comparative studies of 3D printing combined with ORIF (3D printing group) versus traditional ORIF (conventional group) in the treatment of acetabular fractures were selected. The data of operation time, intraoperative blood loss, intraoperative fluoroscopy times, incidence of complications, excellent and good rate of Matta score for reduction, and excellent and good rate of hip function score were extracted. Stata14.0 statistical software was used for data analysis. RESULTS: Altogether 9 articles were selected, including 5 randomized controlled trials and 4 retrospective studies. A total of 467 patients were analyzed, 250 in the conventional group, and 217 in the 3D printing group. The operation time in the 3D printing group was less than that in the conventional group and the difference was statistically significant (standardized mean difference (SMD) = -1.19, 95% CI: -1.55 to -0.82, p < 0.05). The intraoperative bleeding volume of the 3D printing group was significantly lower than that of the conventional group (SMD = -1.08, 95% CI: -1.65 to -0.51, p < 0.05). The fluoroscopy times were less in the 3D printing group than in the conventional group and the difference was statistically significant (SMD = -1.64, 95% CI: -2.35 to -0.93, p < 0.05). The total incidence of complications in the 3D printing group was significantly lower than that in the conventional group (OR = 0.43, 95% CI: 0.24-0.79, p < 0.05). There was no significant difference in the excellent and good rate of Matta score for reduction between the two groups (OR = 0.60, 95% CI: 0.34-1.06, p > 0.05). There was no significant difference in the excellent and good rate of hip function score at the end of postoperative follow-up between the two groups (OR = 0.84, 95% CI: 0.46-1.56, p > 0.05), but the follow-up time varies from 6 months to 40 months. CONCLUSION: Compared with traditional ORIF, 3D printing combined with ORIF has certain advantages in terms that 3D printing not only helps surgeons to understand acetabular fractures more intuitively, but also effectively reduces operation time, intraoperative blood loss, intraoperative fluoroscopy times, and postoperative complications. However, there were no significant differences in the excellent and good rate of Matta score for reduction and the excellent and good rate of hip function score at the end of follow-up.

A broad-spectrum substrate for the human UDP-glucuronosyltransferases and its use for investigating glucuronidation inhibitors.

Strong inhibition of the human UDP-glucuronosyltransferase enzymes (UGTs) may lead to undesirable effects, including hyperbilirubinaemia and drug/herb-drug interactions. Currently, there is no good way to examine the inhibitory effects and specificities of compounds toward all the important human UGTs, side-by-side and under identical conditions. Herein, we report a new, broad-spectrum substrate for human UGTs and its uses in screening and characterizing of UGT inhibitors. Following screening a variety of phenolic compound(s), we have found that methylophiopogonanone A (MOA) can be readily O-glucuronidated by all tested human UGTs, including the typical N-glucuronidating enzymes UGT1A4 and UGT2B10. MOA-O-glucuronidation yielded a single mono-O-glucuronide that was biosynthesized and purified for structural characterization and for constructing an LC-UV based MOA-O-glucuronidation activity assay, which was then used for investigating MOA-O-glucuronidation kinetics in recombinant human UGTs. The derived Km values were crucial for selecting the most suitable assay conditions for assessing inhibitory potentials and specificity of test compound(s). Furthermore, the inhibitory effects and specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate for all tested UGTs. Collectively, MOA is a broad-spectrum substrate for the human UGTs, which offers a new and practical tool for assessing inhibitory effects and specificities of UGT inhibitors.

Inhibition of drug-metabolizing enzymes by Qingfei Paidu decoction: Implication of herb-drug interactions in COVID-19 pharmacotherapy.

Corona Virus Disease 2019 (COVID-19) has spread all over the world and brings significantly negative effects on human health. To fight against COVID-19 in a more efficient way, drug-drug or drug-herb combinations are frequently used in clinical settings. The concomitant use of multiple medications may trigger clinically relevant drug/herb-drug interactions. This study aims to assay the inhibitory potentials of Qingfei Paidu decoction (QPD, a Chinese medicine compound formula recommended for combating COVID-19 in China) against human drug-metabolizing enzymes and to assess the pharmacokinetic interactions in vivo. The results demonstrated that QPD dose-dependently inhibited CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 but inhibited CYP3A in a time- and NADPH-dependent manner. In vivo test showed that QPD prolonged the half-life of lopinavir (a CYP3A substrate-drug) by 1.40-fold and increased the AUC of lopinavir by 2.04-fold, when QPD (6 g/kg) was co-administrated with lopinavir (160 mg/kg) to rats. Further investigation revealed that Fructus Aurantii Immaturus (Zhishi) in QPD caused significant loss of CYP3A activity in NADPH-generating system. Collectively, our findings revealed that QPD potently inactivated CYP3A and significantly modulated the pharmacokinetics of CYP3A substrate-drugs, which would be very helpful for the patients and clinicians to avoid potential drug-interaction risks in COVID-19 treatment.

Design, synthesis and biological evaluation of novel chalcone-like compounds as potent and reversible pancreatic lipase inhibitors.

Pancreatic lipase (PL), a crucial enzyme responsible for hydrolysis of dietary lipids, has been validated as a key therapeutic target to prevent and treat obesity-associated metabolic disorders. Herein, we report the design, synthesis and biological evaluation of a series of chalcone-like compounds as potent and reversible PL inhibitors. Following two rounds of structural modifications at both A and B rings of a chalcone-like skeleton, structure-PL inhibition relationships of the chalcone-like compounds were studied, while the key substituents that would be beneficial for PL inhibition were revealed. Among all tested chalcone-like compounds, compound B13 (a novel chalcone-like compound bearing two long carbon chains) displayed the most potent PL inhibition activity, with an IC50 value of 0.33 µM. Inhibition kinetic analyses demonstrated that B13 could potently inhibit PL-mediated 4-MUO hydrolysis in a mixed inhibition manner, with the Ki value of 0.12 µM. Molecular docking simulations suggested that B13 could tightly bind on PL at both the catalytic site and a non-catalytic site that was located on the surface of PL, which was consistent with the mixed inhibition mode of this agent. In addition, B13 displayed excellent stability in artificial gastrointestinal fluids and good metabolic stability in human liver preparations. Collectively, our findings suggested that chalcone-like compounds were good choices for design and development of orally administrated PL inhibitors, while B13 could be served as a promising lead compound to develop novel anti-obesity agents via targeting on PL.