Resveratrol regulates Thoc5 to improve maternal immune activation-induced autism-like behaviors in adult mouse offspring.

Maternal infection during pregnancy is an important cause of autism spectrum disorder (ASD) in offspring, and inflammatory infiltration caused by maternal immune activation (MIA) can cause neurodevelopmental disorders in the fetus. Medicine food homologous (MFH) refers to a traditional Chinese medicine (TCM) concept, which effectively combines food functions and medicinal effects. However, no previous study has screened, predicted, and validated the potential targets of MFH herbs for treating ASD. Therefore, in this study, we used comprehensive bioinformatics methods to screen and analyze MFH herbs and drug targets on a large scale, and identified resveratrol and Thoc5 as the best small molecular ingredient and drug target, respectively, for the treatment of MIA-induced ASD. Additionally, the results of in vitro experiments revealed that resveratrol increased the expression of Thoc5 and effectively inhibited lipopolysaccharide-induced inflammatory factor production by BV2 cells. Moreover, in vivo, resveratrol increased the expression of Thoc5 and effectively inhibited placental and fetal brain inflammation in MIA pregnancy mice, and improved ASD-like behaviors in offspring.

Yigansan ameliorates maternal immune activation-induced autism-like behaviours by regulating the IL-17A/TRAF6/MMP9 pathway: Network analysis and experimental validation.

BACKGROUND: Maternal immune activation (MIA) is a significant factor inducing to autism spectrum disorder (ASD) in offspring. The fundamental principle underlying MIA is that inflammation during pregnancy impedes fetal brain development and triggers behavioural alterations in offspring. The intricate pathogenesis of ASD renders drug treatment effects unsatisfactory. Traditional Chinese medicine has strong potential due to its multiple therapeutic targets. Yigansan, composed of seven herbs, is one of the few that has been proven to be effective in treating neuro-psychiatric disorders among numerous traditional Chinese medicine compounds, but its therapeutic effect on ASD remains unknown. HYPOTHESIS: Yigansan improves MIA-induced ASD-like behaviours in offspring by regulating the IL-17 signalling pathway. METHODS: Pregnant C57BL/6J mice were intraperitoneally injected with poly(I:C) to construct MIA models and offspring ASD models. Network analysis identified that the IL-17A/TRAF6/MMP9 pathway is a crucial pathway, and molecular docking confirmed the binding affinity between the monomer of Yigansan and target proteins. qRT-PCR and Western blot were used to detect the expression levels of inflammatory factors and pathway proteins, immunofluorescence was used to detect the distribution of IL-17A, and behavioural tests were used to evaluate the ASD-like behaviours of offspring. RESULTS: We demonstrated that Yigansan can effectively alleviate MIA-induced neuroinflammation of adult offspring by regulating the IL-17A/TRAF6/MMP9 pathway, and the expression of IL-17A was reduced in the prefrontal cortex. Importantly, ASD-like behaviours have been significantly improved. Moreover, we identified that quercetin is the effective monomer for Yigansan to exert therapeutic effects. CONCLUSION: Overall, this study was firstly to corroborate the positive therapeutic effect of Yigansan in the treatment of ASD. We elucidated the relevant molecular mechanism and regulatory pathway involved, determined the optimal therapeutic dose and effective monomer, providing new solutions for the challenges of drug therapy for ASD.

Enhanced biological phosphorus removal sustained by aeration-free filamentous microalgal-bacterial granular sludge.

The microalgal-bacterial granular sludge (MBGS) based enhanced biological phosphorus removal (EBPR) (MBGS-EBPR) was recently proposed as a sustainable wastewater treatment process. Previous work showed the possibility of obtaining an MBGS-EBPR process starting from mature MBGS and phosphate-accumulating organisms (PAOs) enriched aerobic granular sludge (AGS) and validated the effectiveness of removing carbon/nitrogen/phosphorus with mechanical aeration. The present work evaluated whether the same could be achieved starting from conventional activated sludge and operating under aeration-free conditions in an alternating dark/light photo-sequencing batch reactor (PSBR). We successfully cultivated filamentous MBGS with a high settling rate (34.5 m/h) and fast solid-liquid separation performance, which could be attributed to the proliferation of filamentous cyanobacteria and stimulation of extracellular polymeric substances (EPS) production. The process achieved near-complete steady-state removal of carbon (97.2 ± 1.9 %), nitrogen (93.9 ± 0.7 %), and phosphorus (97.7 ± 1.7 %). Moreover, improved phosphorus release/uptake driven by photosynthetic oxygenation under dark/light cycles suggests the enrichment of PAOs and the establishment of MBGS-EBPR. Batch tests showed similar phosphorus release rates in the dark but significantly lower phosphorus uptake rates in the presence of light when the filamentous granules were disrupted. This indicates that the filamentous structure of MBGS has minor limitations on substrate mass transfer while exerting protective effects on PAOs, thus playing an important role in sustaining the function of aeration-free EBPR. Microbial assays further indicated that the enrichment of filamentous cyanobacteria (Synechocystis, Leptoolybya, and Nodosilinea), putative PAOs and EPS producers (Hydrogenophaga, Thauera, Flavobacterium, and Bdellovibrio) promoted the development of filamentous MBGS and enabled the high-efficient pollutant removal. This work provides a feasible and cost-effective strategy for the startup and operation of this innovative process.

Yangyinghuoxue decoction exerts a treatment effect on hepatic fibrosis by PI3K/AKT pathway in rat model: based on the network pharmacology and molecular docking.

BACKGROUND: Yangyinghuoxue decoction (YYHXD) is a Traditional Chinese medicine (TCM) compound with satisfactory clinical efficacy in the treatment of hepatic fibrosis (HF). However, the pharmacological molecular mechanisms of YYHXD in the treatment of hepatic fibrosis have not yet been clarified. OBJECTIVE: To determine the pharmacological mechanisms of YYHXD for the treatment of hepatic fibrosis via network pharmacology analysis combined with experimental verification. METHODS: First, the bioactive ingredients and potential targets of YYHXD and HF-related targets were retrieved from the online databases and literatures. Next, the "herb-ingredient-target-disease" network and PPI network were constructed for topological analyses and key active compounds and targets screening. Enrichment analyses were performed to identify the critical biological processes and signaling pathways. Then, the molecular docking experiment was performed to initially validate the network pharmacology prediction results. Finally, the antifibrotic effect and pharmacological mechanisms of YYHXD were investigated in CCl4 induced liver fibrosis in rats. RESULTS: In total, 141 active compounds in YYHXD, 637 YYHXD-related targets and 1598 liver fibrosis-related targets were identified. Among them, 69 overlapped targets were finally obtained. Network analysis screened 5 critical bioactive components and 34 key targets. Functional enrichment analysis indicated that YYHXD obviously influenced biological processes such as oxidative stress, cellular inflammation and hepatocyte apoptosis and signaling pathways such as PI3K-Akt, Apoptosis, and JAK-STAT in the treatment of HF. The molecular docking results suggested that the YYHXD may have a direct impact on the PI3K-Akt signaling pathway. Further, in vivo experiment indicated that YYHXD treatment not only reduced liver injury and protected liver function, but also decrease the apoptosis of hepatic parenchyma cells, reducing inflammatory and attenuating oxidative stress. Moreover, YYHXD significantly attenuated the upregulation of target proteins enriched in PI3K signaling pathway, including P-PI3K, P-Akt1, HSP90, MYC, p53. CONCLUSIONS: The mechanisms of YYHXD against liver fibrosis were involved in multiple ingredients, multiple targets and multiple signaling pathways. The PI3K/Akt pathway could be the most important pharmacological mechanism of YYHXD therapy for liver fibrosis.

Magnetic Nanoparticles: A Review on Synthesis, Characterization, Functionalization, and Biomedical Applications.

Nowadays, magnetic nanoparticles (MNPs) are applied in numerous fields, especially in biomedical applications. Since biofluidic samples and biological tissues are nonmagnetic, negligible background signals can interfere with the magnetic signals from MNPs in magnetic biosensing and imaging applications. In addition, the MNPs can be remotely controlled by magnetic fields, which make it possible for magnetic separation and targeted drug delivery. Furthermore, due to the unique dynamic magnetizations of MNPs when subjected to alternating magnetic fields, MNPs are also proposed as a key tool in cancer treatment, an example is magnetic hyperthermia therapy. Due to their distinct surface chemistry, good biocompatibility, and inducible magnetic moments, the material and morphological structure design of MNPs has attracted enormous interest from a variety of scientific domains. Herein, a thorough review of the chemical synthesis strategies of MNPs, the methodologies to modify the MNPs surface for better biocompatibility, the physicochemical characterization techniques for MNPs, as well as some representative applications of MNPs in disease diagnosis and treatment are provided. Further portions of the review go into the diagnostic and therapeutic uses of composite MNPs with core/shell structures as well as a deeper analysis of MNP properties to learn about potential biomedical applications.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

The basic chemical substances of total alkaloids of Menispermi Rhizoma and their anti-inflammatory activities.

Menispermi Rhizoma is the dried rhizome of Menispermum dauricum DC. (Menispermaceae), which commonly used to treat sore throat, enteritis, and dysentery in traditional Chinese medicine. To clarify the chemical basis of the total alkaloids of M. Rhizoma, HPLC was used to analyze total alkaloids, and then representative chemical constituents were separated by tracking. Nineteen compounds, including two new alkaloids (1R-methymenidaurine A-α-N-oxide (1) and 1R-7'-hydroxymethyl-menidaurine A (2)), thirteen known alkaloids, and four known flavonoids were isolated and identified using spectroscopic methods. Meanwhile, seven characteristic peaks were identified from the total alkaloids using HPLC analysis. Furthermore, compounds 1-18 were screened in vitro for their inhibitory effect against nitric oxide production in BV-2 microglia cells stimulated by lipopolysaccharide. Among them, six compounds showed weak inhibition, and the IC50 values of compounds 1 and 2 were 56.87 ± 1.61 and 53.67 ± 1.52 mM, respectively.

Student standardized patients versus occupational standardized patients for improving clinical competency among TCM medical students: a 3-year prospective randomized study.

BACKGROUND: Standardized patient (SP) simulations are well-recognized patterns for practicing clinical skills and interactions. Our previous study showed that a simulation program using occupational SP for Traditional Chinese Medicine (OSP-TCMs) was efficient, however, a high cost and time-intensive nature have limited its use. TCM postgraduates trained as student SPs (SSP-TCMs) present a potentially cost-effective alternative. The purpose of this study was to examine and determine whether SSP simulation offered more benefits over didactic training alone for improving clinical competency among TCM medical students, and conduct a multifaceted analysis comparing SSP-TCMs and OSP-TCMs. METHODS: This was a prospective, single-blinded, randomized controlled trial. Fourth-year TCM undergraduates were recruited as trainees from the Clinical Medical School, Chengdu University of TCM. Data were collected from September 2018 to December 2020. Trainees were randomly divided into the three following groups: traditional method training group, OSP-TCM training group, and SSP-TCM training group (1:1:1). At the end of a 10-week curriculum, trainees received a two-station examination comprising a systematic online knowledge test and an offline clinical performance examination. Post-training and post-exam questionnaires were administered to collect feedback from these trainees. RESULTS: Students assigned to the SSP-TCM training and OSP-TCM training groups received favorable marks for the "systematic knowledge test" and "TCM clinical skills" (2018, Pa=0.018, Pb=0.042; 2019, Pa=0.01, Pb=0.033; 2020, Pa=0.035, Pb=0.039) compared to the TM trainees. Additionally, trainees in the intervention groups demonstrated a positive post-training edge in scores of "medical records" (2018, Pa=0.042, Pb=0.034; 2019, Pa=0.032, Pb=0.042; 2020, Pa=0.026, Pb=0.03) and "TCM syndrome differentiation and therapeutic regimen" (2018, Pb=0.032; 2019, Pa=0.037, Pb=0.024; 2020, Pa=0.036, Pb=0.043). For the simulation encounter assessment given by SP-TCMs, OSP-TCM trainees and SSP-TCM trainees scored higher than TM trainees (2018, Pa=0.038, Pb=0.037; 2019, Pa=0.024, Pb=0.022; 2020, Pa=0.019, Pb=0.021). For the feedback questionnaires, the students in TM group provided less positive feedback for training efficacy and test performance compared to those in the SSP-TCM and OSP-TCM groups. The trainees responded that the training effect of clinical simulations was similar between the SSP-TCM and OSP-TCM groups. SSP-TCMs were more responsive to unexpected emergencies (Pa=0.022, Pb>0.05) and more likely to encourage questioning (Pa=0.029, Pb>0.05) but tended to provide implied hints (Pc=0.015) and utilize medical jargon (Pc=0.007) as compared to OSP-TCMs. CONCLUSION: Simulation training for SSP-TCMs and OSP-TCMs showed great benefits for enhancing clinical competency. SSP-TCM simulation was feasible, practical, and cost-effective, and may serve as an alternative method to OSP-TCM simulation.

Development of a Multibiomarker Panel of Healthy Eating Index in United States Adults: A Machine Learning Approach.

BACKGROUND: Dietary and nutritional biomarkers are objective dietary assessment tools that will enable a more accurate and precise determination of diet-disease relations. However, the lack of established biomarker panels for dietary patterns is concerning, as dietary patterns continue to be the focus of dietary guidelines. OBJECTIVES: We aimed to develop and validate a panel of objective biomarkers that reflects the Healthy Eating Index (HEI) by applying machine learning approaches to the National Health and Nutrition Examination Survey data. METHODS: Cross-sectional population-based data (eligible criteria: age ≥20 y, not pregnant, no reported supplement use of dedicated vitamin A, D, E, or fish oils; n = 3481) from the 2003 to 2004 cycle of the NHANES were used to develop 2 multibiomarker panels of the HEI, 1 with (primary panel) and 1 without (secondary panel) plasma FAs. Up to 46 blood-based dietary and nutritional biomarkers (24 FAs, 11 carotenoids, and 11 vitamins) were included for variable selection using the least absolute shrinkage and selection operator controlling for age, sex, ethnicity, and education. The explanatory impact of selected biomarker panels was assessed by comparing the regression models with and without the selected biomarkers. In addition, 5 comparative machine learning models were constructed to validate the biomarker selection. RESULTS: The primary multibiomarker panel (8 FAs, 5 carotenoids, and 5 vitamins) significantly improved the explained variability of the HEI (adjusted R2 increased from 0.056 to 0.245). The secondary multibiomarker panel (8 vitamins and 10 carotenoids) had lesser predictive capabilities (adjusted R2 increased from 0.048 to 0.189). CONCLUSIONS: Two multibiomarker panels were developed and validated to reflect a healthy dietary pattern consistent with the HEI. Future research should seek to test these multibiomarker panels in randomly assigned trials and identify whether they have broad application in healthy dietary pattern assessment.

Effect of ß-glucosidase on the aroma of liquid-fermented black tea juice as an ingredient for tea-based beverages.

The effects of ß-glucosidase on the volatile profiles and aroma stability of black tea juice were evaluated using gas-chromatography-mass spectrometry coupled with sensory analysis. During liquid fermentation of tea leaves, the addition of ß-glucosidase increased the concentration of aldehydes, strengthening the undesirable "green grassy" odour. However, the "green grassy" odour was counteracted by adding green tea extract during fermentation. At the same time, "flowery" flavour notes were enhanced, improving the overall aroma quality and strengthening the characteristic "sweet" aroma of black tea. Increased addition of ß-glucosidase released more free aroma alcohols from their glucosides. Two "fruity" and "floral" aroma components, benzyl alcohol and phenylethyl alcohol, were not significantly affected by heat treatment (95 °C water bath) and the overall aroma stability was not significantly affected by ß-glucosidase treatment. ß-Glucosidase treatment improved the aroma, colour and overall suitability of fermented black tea juice as an ingredient for tea-based beverages.

Effects of Compound Chinese Herbal Medicine Additive on Growth Performance and Gut Microbiota Diversity of Zi Goose.

This study investigated the effects of CCHMA on growth performance, slaughter performance, serum biochemical indicators, intestinal morphology and microbiota of Zi goose. Initially, it was determined the optimal addition concentration of CCHMA to be 3 g/kg by the first feeding experiment. Then, 78 Zi geese were divided into control and CCHMA supplemented groups. The results showed that the body weight (BW) and average daily gain (ADG) of the CCHMA supplemented group was significantly increased (p < 0.05), and the feed/gain (F/G) of the CCHMA supplemented group was significantly decreased (p < 0.05) compared with the control group. The dressed yield percentage in the CCHMA supplemented group significantly increased by 0.78% (p < 0.05). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly lower in the CCHMA fed birds than in the control group (p < 0.05). Further, 16S rDNA gene sequencing conducted for cecal flora composition found that 3 g/kg CCHMA significantly increased the abundance of beneficial bacteria (CHKCI001, Colidextribacter and Subdoligranulum) (p < 0.05; p < 0.01) and suppressing harmful bacteria (Bacteroidetes and Methanobrevibacter) (p < 0.05) in the cecum of Zi goose. In conclusion, adding 3 g/kg of CCHMA in the diet can improve the growth performance, slaughter performance of Zi goose, and optimize the cecum microflora.

Mechanisms Underlying the Protective Effect of Maternal Zinc (ZnSO4 or Zn-Gly) against Heat Stress-Induced Oxidative Stress in Chicken Embryo.

Environmental factors such as high temperature can cause oxidative stress and negatively affect the physiological status and meat quality of broiler chickens. The study was conducted to evaluate the effects of dietary maternal Zn-Gly or ZnSO4 supplementation on embryo mortality, hepatocellular mitochondrial morphology, liver antioxidant capacity and the expression of related genes involved in liver oxidative mechanisms in heat-stressed broilers. A total of 300 36-week-old Lingnan Yellow broiler breeders were randomly divided into three treatments: (1) control (basal diet, 24 mg zinc/kg); (2) inorganic ZnSO4 group (basal diet +80 mg ZnSO4/kg); (3) organic Zn-Gly group (basal diet +80 mg Zn-Gly/kg). The results show that maternal zinc alleviated heat stress-induced chicken embryo hepatocytes' oxidative stress by decreasing the content of ROS, MDA, PC, 8-OHdG, and levels of HSP70, while enhancing T-SOD, T-AOC, CuZn-SOD, GSH-Px, CTA activities and the content of MT. Maternal zinc alleviated oxidative stress-induced mitochondrial damage in chick embryo hepatocytes by increasing mitochondrial membrane potential and UCP gene expression; and Caspase-3-mediated apoptosis was alleviated by increasing CuZn-SOD and MT gene expression and decreasing Bax gene expression and reducing the activity of caspase 3. Furthermore, maternal zinc treatment significantly increased Nrf2 gene expression. The results above suggest that maternal zinc can activate the Nrf2 signaling pathway in developing chick embryos, enhance its antioxidant function and reduce the apoptosis-effecting enzyme caspase-3 activities, thereby slowing oxidative stress injury and tissue cell apoptosis.

Rhodotorula benthica culture as an alternative to antibiotics improves growth performance by improving nutrients digestibility and intestinal morphology, and modulating gut microbiota of weaned piglets.

The effects of Rhodotorula benthica culture (RBC) and antibiotics (AB) on the growth performance, nutrients digestibility, morphological indicators, and colonic microbiota of weaning piglets were explored. Ninety-six (Duroc × Landrace × Large) weaned piglets (21-day-old) weighing 7.7 ± 0.83 kg, were randomly allocated to 4 dietary treatments. They were fed with basal diet (CON), basal diet + 25 mg/kg bacitracin zinc + 5 mg/kg colistin sulfate (AB), 5 g/kg reduction in soybean meal of basal diet + 5 g/kg RBC (RBC1), or 10 g/kg reduction in soybean meal of basal diet + 10 g/kg RBC (RBC2). The results showed that dietary RBC1 improved the body gain/feed intake (G/F) of weaned piglets than the CON diet, and the RBC2 diet improved the average daily gain and G/F than CON and AB diets from days 15 to 28 (P < 0.05). Supplementation of RBC2 improved the apparent total tract digestibility of dry matter, nitrogen, and gross energy in weaned piglets compared to controls from days 15 to 28 (P < 0.05). Dietary AB, RBC1, and RBC2 enhanced the ileal villus height (VH) and VH/crypt depth (CD), and these two indicators were greater in the RBC2-treated piglets than in the AB- and RBC1-treated piglets (P < 0.05). The activity of serum superoxide dismutase (SOD) was enhanced by dietary AB, RBC1, and RBC2 (P < 0.05). Serum glutathione (GSH) concentration was elevated by dietary RBC1 and RBC2 (P < 0.05). According to 16S rRNA sequence analysis, AB- and RBC2-treated piglets had a higher relative abundance of Firmicutes and Lachnospiraceae in the colon digesta, and more abundant Lactobacillus was found in RBC1-treated piglets, as compared to the CON group. Additionally, RBC2 supplementation increased the α diversity [Chao1, PD-whole-tree, and observed operational taxonomic units (OTUs)] compared to the CON group. Taken together, the dietary RBC improved the growth performance of weaned piglets. In addition, 10 g/kg of RBC2 in the diet achieved better effects on higher ADG, ileal villi morphology, and stronger antioxidant capacity than dietary AB and RBC1 in weaning piglets.

Mn oxides enhanced pyrene removal with both rhizosphere and non-rhizosphere microorganisms in subsurface flow constructed wetlands.

The polycyclic aromatic hydrocarbons (PAHs) are substantial wastewater pollutants emitted mostly by petroleum refineries and petrochemical industries, and their environmental fate has been of increasing concern among the public. Consequently, subsurface flow constructed wetlands (SFCWs) filled with Mn oxides (W-CW) or without Mn oxides (K-CW) were established to investigate the performance and mechanisms of pyrene (PYR) removal. The average removal rates of PYR in W-CW and K-CW were 96.00% and 92.33%, respectively. The PYR removal via other pathways (microbial degradation, photolysis, volatilisation, etc.) occupied a sizeable proportion, while the total PYR content in K-CW plant roots was significantly higher than that of W-CW. The microorganisms on the root surface and rhizosphere played an important role in PYR degradation in W-CW and K-CW and were higher in W-CW than that in K-CW in all matrix zones. The microorganisms between the 10-16 cm zone from the bottom of W-CW filled with Mn oxides (W-16) were positively correlated with PYR-degrading microorganisms, aerobic bacteria and facultative anaerobes, whereas K-16 without birnessite-coated sand was negatively correlated with these microorganisms.

Rhodojaponin III-Loaded Chitosan Derivatives-Modified Solid Lipid Nanoparticles for Multimodal Antinociceptive Effects in vivo.

Background: Rhodojaponin III (RJ-III) is a bioactive diterpenoid, which is mainly found in Rhododendron molle G. Don (Ericaceae), a potent analgesia in traditional Chinese medicine with several years of clinical applications in the country. However, its clinical use is limited by its acute toxicity and poor pharmacokinetic profiles. To reduce such limitations, the current study incorporated RJ-III into the colloidal drug delivery system of hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) to improve its sustained release and antinociceptive effects in vivo for oral delivery. Results: The optimized RJ-III@HACC-SLNs were close to spherical, approximately 134 nm in size, and with a positive zeta potential. In vitro experiments showed that RJ-III@HACC-SLNs were stable in the simulated gastric fluid and had a prolonged release in PBS (pH = 6.8). Pharmacokinetic results showed that after intragastric administration in mice, the relative bioavailability of RJ-III@HACC-SLNs was 87.9%. Further, it was evident that the peak time, half-time, and mean retention time of RJ-III@HACC-SLNs were improved than RJ-III after the administration. In addition, pharmacodynamic studies revealed that RJ-III@HACC-SLNs markedly reduced the acetic acid, hot, and formalin-induced nociceptive responses in mice (P < 0.001), and notably increased the analgesic time (P < 0.01). Moreover, RJ-III@HACC-SLNs not only showed good biocompatibility with Caco-2 cells in vitro but its LD50 value was also increased by 1.8-fold as compared with that of RJ-III in vivo. Conclusion: These results demonstrated that RJ-III@HACC-SLNs improved the pharmacokinetic characteristics of the RJ-III, thereby exhibiting toxicity-attenuating potential and antinociceptive enhancing properties. Consequently, HACC-SLNs loaded with RJ-III could become a promising oral formulation for pain management that deserves further investigation in the future.

Deciphering the pharmacological mechanisms of Scutellaria baicalensis Georgi on oral leukoplakia by combining network pharmacology, molecular docking and experimental evaluations.

BACKGROUND: Oral leukoplakia (OLK), an uncharacterized pathological condition that occurs as a white patch in the oral mucosa, is the most common precancerous condition. Scutellaria baicalensis Georgi (SBG) is a medicinal plant with a wide range of pharmacological effects. Increased evidence shows that SBG has potential therapeutic effects on OLK. However, the therapeutic mechanisms of SBG against OLK have not yet been completely elucidated. PURPOSE: This study aimed to clarify the active components and multi-target mechanisms of SBG against OLK via network pharmacology, molecular docking and experimental evaluations. STUDY DESIGN AND METHODS: The active components and related targets of SBG were screened by the TCMSP database and Swiss Target Prediction database. Potential therapeutic targets of OLK were collected using the GeneCards and OMIM databases. Then, we established protein-protein interaction (PPI), compound-target-disease (C-T-D), and compound-target-pathway (C-T-P) networks by Cytoscape to identify the main components, core targets, and pharmacological pathways of SBG against OLK via applying data mining techniques and topological parameters. Metascape database was utilized for GO and KEGG pathway analysis. Molecular docking techniques were used to estimate the binding force between the components and the hub genes. Subsequently, a series of in vitro experiments, specifically CCK-8 assay, clone formation assay, wound healing assay, flow cytometry, RT-qPCR and western blotting were conducted for further verification. RESULTS: There were 25 active components and 31 related target genes in SBG against OLK. PPI analysis showed that Akt1, VEGFA, EGFR, HIF1A and PTGS2 shared the highest centrality among all target genes. KEGG pathway analysis found that PI3K-Akt signaling pathway may occupy core status in the anti-OLK system. Molecular docking results showed that the main active components of SBG had a strong binding affinity to the hub genes. In vitro experiments showed that the leading component baicalein may inhibit proliferation, block cells in the S phase, induce DOK cell apoptosis, and downregulate the mRNA expression of 5 hub genes by inhibiting PI3K/Akt signaling pathway activation. CONCLUSION: The most predominant component of SBG against OLK was baicalein and the key pathway was PI3K/Akt. The main components and hub genes had robust binding abilities. In vitro experiments showed that baicalein could inhibit the proliferation of DOK cells, induce apoptosis, block the cell cycle, and inhibit the mRNA expression level of the hub genes by inhibiting the PI3K/Akt pathway.

Artificial Assembled Macrophage Co-Deliver Black Phosphorus Quantum Dot and CDK4/6 Inhibitor for Colorectal Cancer Triple-Therapy.

In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.

Assessment of clinical competency among TCM medical students using standardized patients of traditional Chinese medicine: A 5-year prospective randomized study.

BACKGROUND: Some Western medicine schools in China established standardized patient (SP) programs for medical education. However, SP programs are rarely applied to the education of traditional Chinese medicine (TCM). In this study, we evaluated the effectiveness of using standardized patient traditional Chinese medicine (SP-TCM) to improve clinical competency among TCM medical students. METHODS: This study was a prospective, 2-group, parallel-training randomized trial over the course of 5 years. Data were collected from September 2016 to December 2020. Participants in each year were randomly allocated into the traditional-method training group or the SP-TCM training group (1:1) for a 3-month curriculum. Measurement of clinical competency among all trainees was based on a standardized examination composed of scores of medical record documentation, scores of TCM syndrome differentiation and therapeutic regimen, and checklist assessment from both SP-TCMs and TCM professionals. Feedback was collected using semi-constructive questionnaires from both groups. RESULTS: Compared with those assigned to traditional-method training, those assigned to SP-TCM training demonstrated significantly greater post-training improvement in medical record documentation and TCM syndrome differentiation and therapeutic regimen. Moreover, SP-TCM trainees outscored those assigned to traditional training in the assessment for encounter performance given by independent SP-TCMs and TCM professionals. The SP-TCM method gained higher satisfaction of training efficacy and test performance than the traditional method. CONCLUSION: This SP-TCM program demonstrated great benefits for improving clinical competency among TCM medical students.

The basic chemical substances of three medicinal parts from Rhododendron molle G. Don.

Rhododendron Molle G. Don belongs to Ericaceae family. As a toxic traditional Chinese medicine, its roots, flowers, and fruit are often mixed and substituted arbitrarily to treat rheumatoid arthritis in clinic. To clarify the main chemical basis of each medicinal part, and provide sufficient scientific basis for clinical application, analysis using HPLC-ELSD of the roots, flowers, and fruit from R. molle was established, and characteristic chemical constituents of them were separated by tracking. The structures were determined by NMR methods. Finally, 16, 21, and 18 compounds were obtained from the roots, flowers, and fruit, respectively. Overall, 49 compounds were obtained, of which 25 were identified for the first time in R. molle. Meanwhile, among the obtained compounds, 12, 11, and 6 characteristic peaks were identified from the roots, flowers, and fruit, respectively. Thus, the basic chemical substances of the medicinal parts of R. molle were determined initially.

Carbapenem-resistant K. pneumoniae exhibiting clinically undetected amikacin and meropenem heteroresistance leads to treatment failure in a murine model of infection.

Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic. In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail. Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.