Synergistic ultrasound pulsed electric field extraction of litchi peel polyphenols and determination of their properties.

The effects of pulsed electric field combined with ultrasound (PEF-US) on the recovery of polyphenols from litchi peels were investigated. In addition, the optimal purification parameters for polyphenol extracts and their biological activities were also explored in this study. Single-factor and orthogonal experiments were used to optimize the extraction conditions of polyphenols. After optimization, the total phenol content (TPC) of the sample extracted by PEF-US was 2.30 times higher than that of the sample extracted by traditional hot-water extraction. The mechanism of PEF-US enhancing polyphenol recovery was also revealed by morphological analysis of the powder surface. LX-7 was the best resin by comparing the purification effect of nine macroporous resins. The optimum conditions for purification of litchi peel polyphenols by LX-7 resin were also optimized through adsorption and desorption experiments. UHPLC-MS and HPLC results revealed that gentisic acid, catechin, procyanidin A2 and procyanidin B1 are four main substances in purified samples. The results of bioactivity experiments showed that the purified polyphenol samples had strong antioxidant and antibacterial activity. Overall, PEF-US is an efficient method for recovering polyphenols from litchi peels. Our study also provides a strategy for the comprehensive utilization of fruit processing waste.

Anti-Acidification and Immune Regulation by Nano-Ceria-Loaded Mg-Al Layered Double Hydroxide for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease featuring an abnormal immune microenvironment and resultant accumulation of hydrogen ions (H+ ) produced by activated osteoclasts (OCs). Currently, clinic RA therapy can hardly achieve sustained or efficient therapeutic outcomes due to the failures in generating sufficient immune modulation and manipulating the accumulation of H+ that deteriorates bone damage. Herein, a highly effective immune modulatory nanocatalytic platform, nanoceria-loaded magnesium aluminum layered double hydroxide (LDH-CeO2 ), is proposed for enhanced immune modulation based on acid neutralization and metal ion inherent bioactivity. Specifically, the mild alkaline LDH initiates significant M2 repolarization of macrophages triggered by the elevated antioxidation effect of CeO2 via neutralizing excessive H+ in RA microenvironment, thus resulting in the efficient recruitment of regulatory T cell (Treg) and suppressions on T helper 17 cell (Th 17) and plasma cells. Moreover, the osteogenic activity is stimulated by the Mg ion released from LDH, thereby promoting the damaged bone healing. The encouraging therapeutic outcomes in adjuvant-induced RA model mice demonstrate the high feasibility of such a therapeutic concept, which provides a novel and efficient RA therapeutic modality by the immune modulatory and bone-repairing effects of inorganic nanocatalytic material.

Heterologous biosynthesis of medicarpin using engineered Saccharomyces cerevisiae.

Medicarpin is an important bioactive compound with multiple medicinal activities, including anti-tumor, anti-osteoporosis, and anti-bacterial effects. Medicarpin is associated with pterocarpans derived from medicinal plants, such as Sophora japonica, Glycyrrhiza uralensis Fisch., and Glycyrrhiza glabra L. However, these medicinal plants contain only low amounts of medicarpin. Moreover, the planting area for medicarpin-producing plants is limited; consequently, the current medicarpin supply cannot meet the high demands of medicinal markets. In this study, eight key genes involved in medicarpin biosynthesis were identified using comparative transcriptome and bioinformatic analyses. In vitro and in vivo enzymatic reaction confirmed the catalytic functions of candidate enzymes responsible for the biosynthesis of medicarpin and medicarpin intermediates. Further engineering of these genes in Saccharomyces cerevisiae achieved the heterologous biosynthesis of medicarpin using liquiritigenin as a substrate, with a final medicarpin yield of 0.82 ± 0.18 mg/L. By increasing the gene copy numbers of vestitone reductase (VR) and pterocarpan synthase (PTS), the final medicarpin yield was increased to 2.05 ± 0.72 mg/L. This study provides a solid foundation for the economic and sustainable production of medicarpin through a synthetic biology strategy.

Effects of dietary chito-oligosaccharide and ß-glucan on the water quality and gut microbiota, intestinal morphology, immune response, and meat quality of Chinese soft-shell turtle (Pelodiscus sinensis).

Chito-oligosaccharides (COS) and ß-glucan are gradually being applied in aquaculture as antioxidants and immunomodulators. However, this study examined the effects of dietary supplementation of COS and ß-glucan on the water quality, gut microbiota, intestinal morphology, non-specific immunity, and meat quality of Chinese soft-shell turtle. To investigate the possible mechanisms, 3-year-old turtles were fed basal diet (CK group) and 0.1%, 0.5%, and 1% COS or ß-glucan supplemented diet for 4 weeks. Colon, liver, blood and muscle tissues, colon contents, water and sediment of paddy field samples were collected and analyzed after feeding 2 and 4 weeks. The results indicated that COS and ß-glucan altered microbial community composition and diversity in Chinese soft-shell turtles. The relative abundance of Cellulosilyticum, Helicobacter and Solibacillus were increased after feeding COS, while Romboutsia, Akkermansia and Paraclostridium were increased after feeding ß-glucan, whereas Cetobacterium, Vibrio and Edwardsiella were enriched in the control group. Furthermore, colon morphology analysis revealed that COS and ß-glucan improved the length and number of intestinal villi, and the effect of 0.5% ß-glucan was more obvious. Both ß-glucan and COS significantly improved liver and serum lysozyme activity and antibacterial capacity. COS significantly increased the total antioxidant capacity in the liver. Further, 0.1% ß-glucan significantly increased the activity of hepatic alkaline phosphatase, which closely related to the bacteria involved in lipid metabolism. Moreover, dietary supplementation with 1% COS and 1% ß-glucan significantly enhanced the content of total amino acids, especially umami amino acids, in muscle tissue, with ß-glucan exerting a stronger effect than COS. Additionally, these two prebiotics promoted the quality of culture water in paddy fields and reshaped the bacterial community composition of aquaculture environment. All these phenotypic changes were closely associated with the gut microbes regulated by these two prebiotics. In summary, the findings suggest that dietary supplementation with COS and ß-glucan in Pelodiscus sinensis could modulate the gut microbiota, improve intestinal morphology, enhance non-specific immunity and antioxidant capacity of liver and serum, increase meat quality, and improve the culture water environment. This study provides new insights and a comprehensive understanding of the positive effects of COS and ß-glucan on Pelodiscus sinensis.

QbD-Guided Traditional Chinese Medicine Manufacturing Process: Development and Optimization of Fluid-Bed Granulation and Drying Processes for Xiaochaihu Capsules.

Traditional methods of producing Xiaochaihu (XCH) capsules, a traditional Chinese medicine, are time-consuming, costly, and labor-intensive, which is not conductive to modernizing TCM. To address the challenges, new fluid-bed granulation and drying processes with water as the binder were developed and optimized guided by the principles of Quality by Design (QbD) in this study. Ishikawa diagram was applied to conduct a preliminary risk assessment, followed by 6-factor definitive screening design (DSD) serving as a QbD statistical tool to develop and optimize the new processes. Multiple potential factors and interactions were studied with a small number of experiments using the DSD. This study identified critical process parameters (CPPs), established quadratic regression models to reveal CPP-critical quality attributes (CQAs) connections within the DSD framework, and defined a dependable design space. Processes conducted by parameter combinations in the design space produced qualified granules with production yield and raw material utilization higher than 90% and moisture content lower than 4%. Furthermore, quantitative analysis of baicalin of all the granules ensured qualified contents of active pharmaceutical ingredient. The newly developed processes for XCH capsules, with advantages of shorter time, environmental friendliness, and decreased cost, exemplify the effective application of QbD and design of experiments (DoE) methodologies in the modernization of TCM manufacturing processes.

Clinical, biological and genome-wide comparison of carbapenem-resistant Klebsiella pneumoniae with susceptibility transformation to polymyxin B during therapy.

OBJECTIVES: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major clinical concern, and polymyxin B (PMB) is a 'last resort' antibiotic for its treatment. Understanding the effects of drug susceptibility transformation in CRKP-infected patients undergoing PMB treatment would be beneficial to optimize PMB treatment strategies. METHODS: We retrospectively collected data from patients infected with CRKP and treated with PMB from January 2018 to December 2020. CRKPs were collected before and after PMB therapy, and patients were classified into the 'transformation' group (TG) and 'non-transformation' group (NTG) by the shift of susceptibility to PMB. We compared clinical characteristics between these groups, and further analysed the phenotypic and genome variation of CRKP after PMB susceptibility transformation. RESULTS: A total of 160 patients (37 in the TG and 123 in the NTG) were included in this study. The duration of PMB treatment before PMB-resistant K. pneumoniae (PRKP) appearance in TG was even longer than the whole duration of PMB treatment in NTG (8 [8] vs. 7 [6] days; p 0.0496). Compared with isogenic PMB-susceptible K. pneumoniae (PSKP), most PRKP strains had missense mutations in mgrB (12 isolates), yciC (10 isolates) and pmrB (7 isolates). The competition index of 82.4% (28/34) of PRKP/PSKP pairs was <67.6% (23/34), and 73.5% (25/34) of PRKP strains showed a higher 7-day lethality in Galleria mellonella and a greater ability to resist complement-dependent killing than their corresponding PSKP, respectively. CONCLUSION: Low dose with longer PMB treatment durations may be associated with the emergence of polymyxin resistance. The evolution of PRKP is predominantly mediated by an accumulation of mutations, including those in mgrB, yciC, and pmrB. Lastly, PRKP exhibited reduced growth and increased virulence compared with parental PSKP.

[Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond].

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Thermoresponsive Hydrogel-Enabled Thermostatic Photothermal Therapy for Enhanced Healing of Bacteria-Infected Wounds.

Photothermal therapy (PTT) has emerged as an attractive technique for the treatment of bacterial infections. However, the uncontrolled heat generation in conventional PTT inevitably causes thermal damages to healthy tissues and/or organs. It is thus essential to develop a smart and universal strategy to regulate the photothermal equilibrium temperature to a preset safe threshold. Herein, a thermoresponsive hydrogel-enabled thermostatic PTT system for enhanced healing of bacteria-infected wounds is reported. In this system, the near-infrared (NIR)-triggered heat generation by photothermal nanomaterials is spontaneously transferred to a thermoresponsive hydrogel with a lower critical solution temperature (LCST), leading to its rapid phase transition by forming considerable light-scattering centers to block NIR penetration. Such a dynamic and reversible process automatically regulates the photothermal equilibrium temperature to the phase-transition point of the LCST-type hydrogel. In contrast to temperature-uncontrolled conventional PTT with severe thermal damages, the thermoresponsive hydrogel-enabled thermostatic PTT provides effective protection on healthy tissues and/or organs, which remarkably accelerates wound healing by efficient bacterial eradication. This study establishes a smart, simple and universal PTT platform, holding great promise in the safe and efficient treatment of bacterial skin infections.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond / 中国中药杂志

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Qu-Du-San-Jie decoction induces growth inhibition and vascular normalization in NF2-associated vestibular schwannoma.

Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.

A Smart Photothermal Nanosystem with an Intrinsic Temperature-Control Mechanism for Thermostatic Treatment of Bacterial Infections.

Photothermal therapy (PTT) has attracted extensive attention in disease treatments. However, conventional photothermal systems do not possess a temperature-control mechanism, which poses a serious risk to healthy tissues and/or organs due to inevitable thermal damage. Herein, a smart photothermal nanosystem with an intrinsic temperature-control mechanism for thermostatic treatment of bacterial infections is reported. The smart photothermal nanosystem is constructed by loading a thermochromic material into a hollow-structured silica nanocarrier, in which the thermochromic material is composed of naturally occurring phase-change materials (PCMs), a proton-responsive spirolactone, and a proton source. The resulting nanosystem shows strong near-infrared (NIR) absorption and efficient photothermal conversion in solid PCMs but becomes NIR-transparent when PCMs are melted upon NIR irradiation. Such an attractive feature can precisely regulate the photothermal equilibrium temperature to the melting point of PCMs, regardless of the variation in external experimental parameters. In contrast to conventional PTT with severe thermal damage, the reported smart photothermal nanosystem provides an internal protection mechanism on healthy tissues and/or organs, which remarkably accelerates the recovery of bacteria-infected wounds. The smart photothermal nanosystem is a versatile PTT platform, holding great promise in the safe and efficient treatment of bacterial infections and multimodality synergistic therapy.

Lightweight tea bud recognition network integrating GhostNet and YOLOv5.

Aiming at the problems of low detection accuracy and slow speed caused by the complex background of tea sprouts and the small target size, this paper proposes a tea bud detection algorithm integrating GhostNet and YOLOv5. To reduce parameters, the GhostNet module is specially introduced to shorten the detection speed. A coordinated attention mechanism is then added to the backbone layer to enhance the feature extraction ability of the model. A bi-directional feature pyramid network (BiFPN) is used in the neck layer of feature fusion to increase the fusion between shallow and deep networks to improve the detection accuracy of small objects. Efficient intersection over union (EIOU) is used as a localization loss to improve the detection accuracy in the end. The experimental results show that the precision of GhostNet-YOLOv5 is 76.31%, which is 1.31, 4.83, and 3.59% higher than that of Faster RCNN, YOLOv5 and YOLOv5-Lite respectively. By comparing the actual detection effects of GhostNet-YOLOv5 and YOLOv5 algorithm on buds in different quantities, different shooting angles, and different illumination angles, and taking F1 score as the evaluation value, the results show that GhostNet-YOLOv5 is 7.84, 2.88, and 3.81% higher than YOLOv5 algorithm in these three different environments.

In Situ Synthesis of Natural Antioxidase Mimics for Catalytic Anti-Inflammatory Treatments: Rheumatoid Arthritis as an Example.

Mimicking the coordination geometry of the active metal sites of natural enzymes is an efficient strategy in designing therapeutic chemicals with enzymelike in vivo reaction thermodynamics and kinetics. In this study, this chemical concept has been applied for the in situ synthesis of natural antioxidase mimics for catalytic anti-inflammatory treatment by using rheumatoid arthritis, a common and hardly curable immune-mediated diseases, as an example. Briefly, a composite nanomedicine has been first constructed by loading cationic porphyrin ligands into a manganese-engineered mesoporous silica nanocarrier, which can respond to a mildly acidic environment to concurrently release manganous ions and porphyrin ligands, enabling their subsequent coordination and synthesis of manganese porphyrin with a coordination environment of an active Mn site similar to those of the metal sites in natural superoxide dismutase (SOD) and catalase. Due to the strong metal-ligand exchange coupling enabled by the N-ethylpyridinium-2-yl groups tetrasubstituted in the meso positions of N4-macroheterocycles, such a manganese porphyrin presents the SOD-like activity of disproportionating superoxide anions via outer-sphere proton-coupled one-electron transfer (diaquamanganese(III)/monoaquamanganese(II) cycling), as well as the catalase-like activity of disproportionating hydrogen peroxide via inner-sphere proton-coupled two-electron transfer (diaquamanganese(III)/dioxomanganese(V) cycling). Cellular experiments demonstrated the high antioxidative efficacy of the composite nanomedicine in M1 macrophages by promoting their polarization shift to the anti-inflammatory M2 phenotype. Equally importantly, the silicon-containing oligomers released from the manganese silicate nanocarrier can act as heterogeneous nucleation centers of hydroxyapatite for facilitating biomineralization by bone mesenchymal stem cells. Finally, an in vivo adjuvant-induced arthritis animal model further reveals the high efficacy of the nanomedicine in treating rheumatoid arthritis.

GDF-15 Suppresses Atherosclerosis by Inhibiting oxLDL-Induced Lipid Accumulation and Inflammation in Macrophages.

The growth differentiation factor-15 (GDF-15) may be involved in atherosclerosis. However, the role of GDF-15 in atherosclerosis remains unclear. The main goal of this study was to verify the role and mechanism of GDF-15 in atherogenesis. We first compared the serum GDF-15 level between patients with coronary atherosclerosis and healthy people. And then one ApoE-/- mouse model of atherosclerosis was used to explore the effects of GDF-15 on oxidized low-density lipoprotein (oxLDL) accumulation, atherosclerosis-related gene expression, and lipid accumulation-related protein expression in mouse macrophages. As a result, the level of serum GDF-15 in patients with coronary atherosclerosis was significantly higher than that in healthy people. In the mouse model, GDF-15 expression was elevated in the core of plaque, and it was secreted mainly by the macrophages. In addition, GDF-15 decreased oxLDL-induced lipid accumulation and inflammation activation in macrophages. GDF-15 decreased the mRNA expressions of CD36, LOX1, and TLR4 that are associated with lipoprotein accumulation in macrophages. Further study showed that GDF-15 might suppress oxLDL-induced lipoprotein accumulation via inhibiting CD36 and LOX1 and decrease inflammation in macrophages by inhibiting TLR4. Thus, GDF-15 may suppress atherosclerosis and plaque formation by inhibiting lipoprotein accumulation and inflammation activation.

Correlation and Diagnostic Value of Serum Cys-C, RBP4, and NGAL with the Condition of Patients with Traumatic Acute Kidney Injury.

There is a lack of targeted biomarkers that can diagnose Acute Kidney Injury (AKI) early and accurately, which leads to deterioration of renal function and even death in patients who do not receive timely and effective treatment. In recent years, an increasing number of studies have shown that AKI-related markers such as cystatin C (Cys-C) and retinol-binding protein (RBP) can be used for early diagnosis of AKI to a certain extent. A total of 262 subjects were included in this study, of which 132 patients with traumatic AKI were enrolled in one group and named as the AKI group; 130 healthy subjects were enrolled in another group and named as the healthy group. AKI patients with different conditions were classified into AKI phase I, II, and III according to the KDIGO AKI diagnostic criteria, with 45, 59, and 28 in each group. In this study, we examined and compared serum Cys-C, RBP4, and neutrophil gelatinase-associated lipid transport protein (NGAL) levels between the AKI and healthy groups and between patients with AKI of different conditions, and the correlation and diagnostic value of three serum markers with the condition of traumatic AKI patients were also analyzed. The results showed that serum Cys-C, RBP4, and NGAL were significantly higher in the AKI group compared with the healthy group (P < 0.05), and the mean concentrations of the three serum markers increased as the severity of the disease increased, while correlation analysis showed that all three serum markers were positively correlated with serum Scr levels (P < 0.001). Further ROC curve analysis was performed, and the diagnostic values of serum Cys C, RBP4, and NGAL alone and in combination for traumatic AKI were 0.769, 0.741, 0.771, and 0.905, respectively. In short, serum Cys C, RBP4, NGAL have important value for the assessment and diagnosis of traumatic AKI patients.

In-line monitoring and endpoint determination of percolation process of herbal medicine using ultraviolet spectroscopy combined with convolutional neural network.

OBJECTIVES: As a common step in the herbal medicine production process, percolation usually lacks effective process monitoring methods and is often conducted with fixed process parameters. In this study, an in-line ultraviolet (UV) spectroscopy was used for monitoring the Caulis Sinomenii percolation process. METHODS: The spectra and concentration data of 156 percolation samples from five batches were collected. Convolutional neural networks (CNNs) were used to develop quantitative calibration models. The mean squared error (MSE), mean absolute percentage error (MAPE) and mean absolute error (MAE) were compared to select the proper loss function for developing the CNN models. Meanwhile, partial least square regression (PLSR) was also used to develop calibration models for performance comparison. KEY FINDINGS: The CNN models with MAPE or MAE as the loss function could provide accurate predictions for all samples. However, CNN models adopting MSE as the loss function tended not to predict low-concentration samples accurately. The CNN models mostly achieved satisfactory results without any preprocessing techniques and surpassed PLSR models in all the performance metrics. CONCLUSIONS: An in-line UV spectroscopy system combining the CNN algorithm was implemented to monitor the percolation process of Caulis Sinomenii. The system can accurately determine the endpoint of the percolation process.

Integrated strategy of LC-MS and network pharmacology for predicting active constituents and pharmacological mechanisms of Ranunculus japonicus Thunb. for treating rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ranunculus japonicus Thunb. (short for R. japonicus) is a topically applied herb with the activities of removing jaundice, nebula and edema, preventing malaria, stopping asthma, promoting diuresis and relieving pain. It was firstly recorded in Zhouhou Beiji Fang and has been used for the treatment of malaria, ulcers, carbuncle, jaundice, migraine, stomachache, toothache and arthritis for over 1800 years. AIM OF THE STUDY: This study aimed to uncover the potentially effective components of R. japonicus and the pharmacological mechanisms against rheumatoid arthritis (RA) by combing LC-MS and network pharmacology. MATERIALS AND METHODS: Firstly, the chemical constituents of R. japonicus were qualitatively identified by UPLC-ESI-LTQ-Orbitrap MS. Then we performed target prediction by PharmMapper, protein-protein interaction (PPI) analysis via String, GO and KEGG pathway enrichment analysis by DAVID and constructed the compound-target-pathway network using Cytoscape. Thirdly, crucial compounds in the network were quantitatively analyzed to achieve quality control of R. japonicus. Finally, the pharmacological activities of R. japonicus and two potentially bioactive ingredients were validated in RA-FLSs (Rheumatoid Arthritis Fibroblast-like Synoviocytes) in vitro. RESULTS: Overall fifty-four ingredients of R. japonicus were identified and forty-five components were firstly discovered in R. japonicus. Among them, twenty-seven validated compounds were predicted to act on twenty-five RA-related targets and they might exhibit therapeutic effects against RA via positive regulation of cell migration, etc. Nine potentially bioactive components of R. japonicus which played important roles in the compound-target-pathway network were simultaneously quantified by an optimized UPLC-ESI-Triple Quad method. In vitro, compared to control group, R. japonicus extract, berberine and yangonin significantly inhibited the migration capacity of RA-FLSs after 24 h treatment. CONCLUSION: This study clarified that R. japonicus and the bioactive ingredients berberine and yangonin might exert therapeutic actions for RA via suppressing the aggressive phenotypes of RA-FLSs through combined LC-MS technology and network pharmacology tools for the first time. The present research provided deeper understanding into the chemical profiling, pharmacological activities and quality control of R. japonicus and offered reference for further scientific research and clinical use of R. japonicus in treating RA.

Unexplained Hyperthyroglobulinemia in Differentiated Thyroid Cancer Patients as an Indication for Radioiodine Adjuvant Therapy: A Prospective Multicenter Study.

The management for totally thyroidectomized differentiated thyroid cancer (TT-DTC) patients with unexplained hyperthyroglobulinemia remains indeterminate because of evidence scarcity. This multicenter study aimed at prospectively evaluating the response to radioiodine (131I) adjuvant therapy (RAT) and its potential role in risk stratification and causal clarification. Methods: TT-DTC patients with stimulated serum thyroglobulin levels greater than 10 ng/mL but no structurally evident disease were consecutively enrolled in 5 tertiary-care institutions. After the administration of 5.55 GBq of 131I, the risk of persistent, recurrent, or metastatic differentiated thyroid cancer (prmDTC) was compared with that before RAT. The causes of hyperthyroglobulinemia were explored-and the response to RAT assessed-6-12 mo after RAT. The change in suppressed thyroglobulin level was reported. Results: A cohort of 254 subjects with a median stimulated thyroglobulin level of 27.1 ng/mL was enrolled for the analyses. Immediately after RAT, low, intermediate, and high risk were identified in 5.9%, 88.6%, and 5.5% patients, respectively, with no significant difference in risk stratification compared with that before RAT (P = 0.952). During the follow-up (median, 10.6 mo), hyperthyroglobulinemia was ultimately attributed to a thyroid remnant, biochemical disease, and structural or functional disease in 17.3%, 54.3%, and 28.4% of subjects, respectively. In addition, responses that were excellent, indeterminate, biochemically incomplete, and structurally or functionally incomplete were achieved in 18.1%, 27.2%, 36.2%, and 18.5% of patients, respectively. Notably, the distribution for either cause of hyperthyroglobulinemia or response to RAT was comparable among the 3 postoperative risk groups. Suppressed thyroglobulin levels in patients who merely received RAT declined significantly over time. Conclusion: Our study demonstrated that over 90% of TT-DTC patients with unexplained hyperthyroglobulinemia are stratified as being at intermediate to high risk, and RAT using 5.55 GBq of 131I reveals biochemical, functional, or structural disease and yields a non-structurally or -functionally incomplete response in more than 80% patients, suggesting that TT-DTC patients with unexplained hyperthyroglobulinemia are explicit candidates for RAT.

Combining convolutional neural networks and on-line Raman spectroscopy for monitoring the Cornu Caprae Hircus hydrolysis process.

Cornu Caprae Hircus (goat horn, GH) is one of the frequently used medicinal animal horns in traditional Chinese medicine (TCM). Hydrolysis is one of the key steps for GH pretreatment in pharmaceutical manufacturing. However, the physicochemical complexity of the hydrolysis samples imposes a challenge for hydrolysis process analysis and monitoring. In this study, convolutional neural networks (CNNs), one of the most popular deep learning methods, were used to develop quantitative calibration models based on on-line Raman spectroscopy for monitoring the GH hydrolysis process. Partial least squares (PLS) calibration models were also developed for model performance comparison. For CNN modeling, raw Raman spectra were used as inputs and hyperparameters in the CNN structure were optimized. Results show for four of the seven analytes, the optimized CNN models using raw spectra as inputs outperform the optimized PLS models developed with preprocessed spectra. Therefore, compared with the commonly used PLS algorithm, CNN modeling is also a practicable regression method and can be employed for the analytical purpose of this study. Models with better performance are expected to be obtained by improving the CNN model structure and using more effective hyperparameter optimization approaches in further studies. To the best of our knowledge, this is the first reported case study of combining CNNs and on-line Raman spectroscopy for a regression task.

Real-World Adherence to Guideline-Recommended Treatment for Small Cell Lung Cancer.

OBJECTIVES: The authors sought to quantify the treatment patterns and outcomes for limited-stage (LS) and extensive-stage (ES) small cell lung cancer (SCLC) in a real-world setting. METHODS: A review was conducted using the Glans-Look Research Database of patients with SCLC managed at a tertiary cancer center in Canada from 2010 to 2016. Adherence was defined as the commencement of planned SCLC treatment. Rate of compliance with the Alberta Health Services, American Society of Clinical Oncology, and National Comprehensive Cancer Network SCLC treatment guidelines was evaluated. Outcomes were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: A total of 404 patients met our inclusion criteria, 31% were LS. The median age at first treatment receipt was 67 years. LS treatment consisted mostly of chemoradiation (62%). Chemoradiation and surgery±adjuvant predicted better survival (median, 32 and 40 mo, respectively) compared with no treatment. ES treatment consisted mostly of chemotherapy (90%). Chemotherapy and thoracic radiotherapy correlated with longer overall survival (13 vs. 9 mo, respectively) compared with chemotherapy alone. Prophylactic cranial irradiation receipt in LS (50%) and ES (20%) predicted favorable survivals than none (LS: hazard ratio, 0.48; 95% CI, 0.29-0.79; ES: hazard ratio, 0.48; 95% CI, 0.33-0.70). Approximately a quarter of relapsed LS and ES had second-line chemotherapy; improved survival with second line was observed only in ES (P<0.01). CONCLUSIONS: This study highlights high rates of guideline-recommended first treatment among the real-world LS and ES patients but it also revealed important outcome differences in relapsed LS and ES patients treated with second-line chemotherapy.