Therapeutic effects of curcumin liposomes and nanocrystals on inflammatory osteolysis: In vitro and in vivo comparative study.

Curcumin could inhibit periprosthetic osteolysis induced by wear debris and adherent endotoxin, which commonly cause prosthesis loosening and negatively influence the long-term survival of joint arthroplasty. However, its limited water solubility and poor stability pose challenges for its further clinical application. To address these issues, we developed curcumin liposomes for intraarticular injection, as liposomes possess good lubricant capacity and pharmacological synergy with curcumin. Additionally, a nanocrystal dosage form was prepared to enable comparison with the liposomes based on their ability to disperse curcumin effectively. A microfluidic method was used for its controllability, repeatability, and scalability. The Box-Behnken Design was employed to screen the formulations and flow parameters, while computational fluid dynamics was used to simulate the mixing process and predict the formation of liposomes. The optimized curcumin liposomes (Cur-LPs) had a size of 132.9 nm and an encapsulation efficiency of 97.1%, whereas the curcumin nanocrystals (Cur-NCs) had a size of 172.3 nm. Both Cur-LPs and Cur-NCs inhibited LPS-induced pro-inflammatory polarization of macrophages and reduced the expression and secretion of inflammatory factors. The mouse air pouch model further demonstrated that both dosage forms attenuated inflammatory cell infiltration and inflammatory fibrosis in subcutaneous tissues. Interestingly, the anti-inflammatory effect of Cur-LPs was more potent than that of Cur-NCs, both in vitro and in vivo, although the cellular uptake of Cur-NCs was quicker. In conclusion, the results demonstrate that Cur-LPs have great potential for the clinical treatment of inflammatory osteolysis and that the therapeutic effect is closely related to the liposomal dosage form.

The Zinc Transporter SLC39A10 Plays an Essential Role in Embryonic Hematopoiesis.

The role of zinc in hematopoiesis is currently unclear. Here, SLC39A10 (ZIP10) is identified as a key zinc transporter in hematopoiesis. The results show that in zebrafish, Slc39a10 is a key regulator of the response to zinc deficiency. Surprisingly, both slc39a10 mutant zebrafish and hematopoietic Slc39a10-deficient mice develop a more severe form of impaired hematopoiesis than animals lacking transferrin receptor 1, a well-characterized iron gatekeeper, indicating that zinc plays a larger role than iron in hematopoiesis, at least in early hematopoietic stem cells (HSCs). Furthermore, it is shown that loss of Slc39a10 causes zinc deficiency in fetal HSCs, which in turn leads to DNA damage, apoptosis, and G1 cell cycle arrest. Notably, zinc supplementation largely restores colony formation in HSCs derived from hematopoietic Slc39a10-deficient mice. In addition, inhibiting necroptosis partially restores hematopoiesis in mouse HSCs, providing mechanistic insights into the requirement for zinc in mediating hematopoiesis. Together, these findings indicate that SLC39A10 safeguards hematopoiesis by protecting against zinc deficiency-induced necroptosis, thus providing compelling evidence that SLC39A10 and zinc homeostasis promote the development of fetal HSCs. Moreover, these results suggest that SLC39A10 may serve as a novel therapeutic target for treating anemia and zinc deficiency-related disorders.

Co-biosynthesis of germacrene A, a precursor of ß-elemene, and lycopene in engineered Escherichia coli.

ß-Elemene is the major component of a traditional Chinese medicine (Rhizoma Curcumae) for cancer treatment, and plant extraction is the major methods currently. Biosynthesis of ß-elemene is a promising and attractive route due to its advantages, including environmentally friendly processes, renewable resources, and sustainable development. In this research, biosynthesis of germacrene A, direct precursor of ß-elemene, in Escherichia coli was successfully performed and 11.99 mg/L germacrene A was obtained. Thereafter, a cobiosynthesis system for germacrene A and lycopene, another kind of isoprenoid, was constructed. Furthermore, the cultivation conditions were optimized. The germacrene A production was increased to the highest level reported to date, 364.26 mg/L, threefold increase to the strain with only germacrene A production. The cobiosynthesis system was suggested to promote the metabolic flux for germacrene A production. This research enabled germacrene A production in E. coli, and it highlights the promoting mechanism of the cobiosynthesis system for two chemicals which are both belonging to isoprenoids. KEY POINTS : • Co-production of germacrene A and lycopene in E. coli. • Promoting mechanism of cobiosynthesis of two isoprenoid compounds in E. coli. • Shake-flask production of germacrene A reached to the highest 364.26 mg/L in E. coli.

Efficacy and Safety of Yangyin Shuxin Decoction-a Chinese Herbal Medicine Formula For Heart Failure with Preserved Ejection Fraction: A Randomized Controlled Trial.

Background: Heart failure with preserved ejection fraction (HFpEF) is a large subtype of heart failure (HF) characterized by exercise intolerance and reduced quality of life. Studies have shown that traditional Chinese medicine (TCM) combined with conventional Western medicine has a good effect on improving exercise tolerance and quality of life in patients with HFpEF, but the overall quality of evidence is low. This study aimed to determine the safety and efficacy of Yangyin Shuxin (YYSX) decoction in the treatment of HFpEF. Methods: A prospective, single-blind, single-center, randomized controlled clinical study was conducted. 64 patients with HFpEF were randomly assigned to receive oral YYSX decoction (150 ml, twice a day) combined with conventional Western treatment or conventional Western treatment alone at a ratio of 1 : 1. The course of treatment was 2 weeks, and the follow-up was 3 months. The primary outcome was peak oxygen uptake (peak VO2) measured by the cardiopulmonary exercise test (CPET). Furthermore, the safety of YYSX decoction was assessed. Results: 63 patients (31 in the YYSX group and 32 in the control group) were included in the full analysis set. The peak VO2 of the YYSX group was significantly higher than that of the control group (12.04 ± 3.41 vs. 11.02 ± 3.33, P = 0.013) after 2 weeks. The maximum voluntary ventilation (MVV) was significantly higher in the YYSX group compared with the control group (P < 0.05). The YYSX group had a higher EQ-visual analogue scale (EQ-VAS) score (71.13 ± 13.95 vs. 70.94 ± 13.70, P < 0.05) and a lower TCM Four-Dimensional Diagnostic Information Scale (TCMFDIS) score (49.74 ± 24.73 vs. 64.16 ± 27.15, P < 0.05) than the control group. There was no statistical difference between two groups (P = 0.160), although 51.61% of patients in the YYSX group showed a decrease in brain natriuretic peptide (BNP) levels of at least 30%, compared with 37.50% of patients in the control group. No serious adverse events were reported in either group, but systolic and diastolic blood pressure decreased and serum sodium levels increased slightly in the control group. Conclusion: The YYSX decoction combined with conventional Western treatment was superior to the conventional Western treatment alone in improving exercise tolerance, quality of life, and cardiopulmonary function of patients with HFpEF. YYSX decoction is safe and may prevent a drop in blood pressure and sodium retention. Trial Registration. Chinese Clinical Trial Registry (www.chictr.org/cn/, No. ChiCTR-IOR-17014206).

Hyperthermic intraperitoneal chemotherapy for recurrent epithelial ovarian cancer.

BACKGROUND: To investigate outcomes and morbidity of patients undergoing secondary cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent ovarian cancer. MATERIALS AND METHODS: Between April 2014 and January 2019, a total of 51 recurrent ovarian cancer patients receiving secondary CRS and HIPEC were retrospectively reviewed. RESULTS: Among the 51 patients, median peritoneal cancer index score was 13 (range 3-34), and completeness of cytoreduction (CC) score of 0/1 was achieved in 41 patients (78.8%). Regimen of HIPEC included cisplatin and paclitaxel in 39 (75%) cases. The median follow-up duration of survivors was 20.2 months. Sixteen (30.8%) patients remained free of recurrence after HIPEC. The median progression-free survival (PFS) and overall survival (OS) were 11.8 months and 34.5 months respectively. Multivariate analysis showed previous chemotherapy <2 lines (HR 0.24, 0.11-0.52; p = 0.001), chemotherapy-free interval ≥6 months (HR 0.19, 0.09-0.37; p < 0.001) and CA125 < 35 U/mL before HIPEC (HR 0.133, 0.021-0.0832; p = 0.031) were good prognostic factors for PFS. CC0/1 was not significant in multivariate analysis. The most common grade 3/4 toxicity was anemia (17.3%), pleural effusion (11.5%) and renal insufficiency (5.7%). Patients with age ≥50, peritoneal carcinomatosis index (PCI) ≥ 11, operation time ≥10 h and diaphragm surgery had significantly higher incidence of pleural effusion. CONCLUSIONS: The current study showed adding HIPEC to secondary CRS might prolong PFS especially in patients with previous chemotherapy <2 lines, chemotherapy-free interval ≥6 months and CA125 < 35 U/mL before HIPEC.

Quantitative Determination of Quercitrin Levels in Rat Plasma Using UHPLC-MS/MS and its Application in a Pharmacokinetic Study after the Oral Administration of Polygoni cuspidati Folium Capsules.

BACKGROUND: Quercitrin is widely found in herbal medicines, and it is particularly important in the design of new therapeutic agents. Because of its wide range of biological activities, methods for detecting quercitrin and its pharmacokinetics in biological samples must be investigated. OBJECTIVES: To develop and validate a sensitive and reliable ultra-high-performance liquid chromatography- tandem mass spectrometry (UHPLC-MS/MS) method for the quantitative determination of quercitrin levels in rat plasma, and test its application in a pharmacokinetic investigation after the oral administration of Polygoni cuspidati folium capsules (HC). METHODS: First, a rapid analytical method implementing UHPLC-MS/MS for the quantification of quercitrin levels in rat plasma was developed and validated. The analyte and internal standard (IS) tinidazole were extracted from rat plasma via protein precipitation with 800 µL of methanol and 50 µL of 1% formic acid solution. Chromatographic separation was performed using an Agilent ZORBAX C18 column within 4 min. Mass spectrometry was performed for quantification using a triple-quadrupole mass spectrometer employing electrospray ionization in the negative ion mode. The MRM transitions for quercitrin and IS were m/z 447.2→229.9 and m/z 246.0→125.8, respectively. The UHPLC-MS/MS method for the quantitative determination of quercitrin levels in rat plasma was then applied to investigate its pharmacokinetics after the oral administration of HC in rats. RESULTS: The developed UHPLC-MS/MS method for detecting quercitrin in rat plasma was linear over the range of 0.1-160 ng/mL. The linear regression equation was Y = (0.7373 ± 0.0023)X - (0.0087 ± 0.0021) (r2 = 0.9978). The intra- and interday precision values were within 7.8%, and the recoveries of quercitrin and IS exceeding 67.3%. The UHPLC-MS/MS method was successfully applied to characterize the pharmacokinetic profile of quercitrin in eight rats after the oral administration of HC. The experimentally obtained values were fit to a one-compartment, first-order pharmacokinetic model, and they appeared to fit the concentration-time curve. CONCLUSION: Quercitrin was proven to be stable during sample storage, preparation, and the analytical procedures. The pharmacokinetic parameters suggested that quercitrin may be present in the peripheral tissues of rats.

Efficacy and potential mechanisms of Chinese herbal compounds in coronavirus disease 2019: advances of laboratory and clinical studies.

The Coronavirus disease 2019 (COVID-19) pandemic is still spread and has made a severe public health threat around the world. To improve disease progression, emerging Chinese herbal compounds were used in clinical practice and some agents have proven beneficial in treating COVID-19. Here, the relevant literature from basic researches to clinical application were identified and comprehensively assessed. A variety of Chinese herbal compounds have been reported to be effective in improving symptoms and outcomes in patients with COVID-19, particularly together with routine treatment strategy. The pharmacological activities were mainly attributed to the relief of clinical symptoms, inhibition of cytokine storm, and improvement of organ function. Besides, the development of novel antiviral drugs from medicinal herbs were further discussed. The updated laboratory and clinical studies provided the evidence of Chinese herbal compounds such as Lianhua Qingwen prescription, Shufeng Jiedu prescription, and Qingfei Paidu Tang for the relief of COVID-19. However, both of the randomized controlled trials and real world researches need to be done for supporting the evidence including the efficacy and safety in fighting COVID-19.

Long-term clinical outcomes of lipiodol marking using standard gastroscopy for image-guided radiotherapy of upper gastrointestinal cancers.

BACKGROUND: Image-guided radiotherapy (IGRT) has significantly improved the precision in which radiotherapy is delivered in cancer treatment. Typically, IGRT uses bony landmarks and key anatomical structures to locate the tumor. Recent studies have demonstrated the feasibility of peri-tumor fiducials in enabling even more accurate delineation of target and normal tissue. The use of gold coils as fiducials in gastrointestinal tumors has been extensively studied. However, placement requires expertise and specialized endoscopic ultrasound equipment. This article reports the long-term outcomes of using a standard gastroscopy to inject liquid fiducials for the treatment of oesophageal and gastric tumors with IGRT. AIM: To assess the long-term outcomes of liquid fiducial-guided IGRT in a cohort of oesophageal and gastric cancer patients. METHODS: A retrospective cohort study of consecutive adults with Oesophagogastric cancers referred for liquid fiducial placement before definitive/neo-adjuvant or palliative IGRT between 2013 and 2021 at a tertiary hospital in Melbourne, Australia was conducted. Up to four liquid fiducials were inserted per patient, each injection consisting of 0.2-0.5mL of a 1:1 mixture of iodized oil (Lipiodol; Aspen Pharmacare) and n-butyl 2-cyanoacrylate (Histoacryl®; B. Braun). A 23-gauge injector (Cook Medical) was used for the injection. All procedures were performed by or under the supervision of a gastroenterologist. Liquid fiducial-based IGRT (LF-IGRT) consisted of computer-assisted direct matching of the fiducial region on cone-beam computerised tomography at the time of radiotherapy. Patients received standard-IGRT (S-IGRT) if fiducial visibility was insufficient, consisting of bone match as a surrogate for tumor position. Radiotherapy was delivered to 54Gy in 30 fractions for curative patients and up to 45Gy in 15 fractions for palliative treatments. RESULTS: 52 patients were referred for liquid fiducial placement within the study period. A total of 51 patients underwent liquid fiducial implantation. Of these a total of 31 patients received radiotherapy. Among these, the median age was 77.4 years with a range between 57.5 and 88.8, and 64.5% were male. Twenty-seven out of the 31 patients were able to have LF-IGRT while four had S-IGRT. There were no complications after endoscopic implantation of liquid fiducials in our cohort. The cohort overall survival (OS) post-radiotherapy was 19 mo (range 0 to 87 mo). Whilst the progression-free survival (PFS) post-radiotherapy was 13 mo (range 0 to 74 mo). For those treated with curative intent, the median OS was 22.0 mo (range 0 to 87 mo) with a PFS median of 14.0 mo (range 0 to 74 mo). Grade 3 complication rate post-radiotherapy was 29%. CONCLUSION: LF-IGRT is feasible in 87.1% of patients undergoing liquid fiducial placement through standard gastroscopy injection technique. Our cohort has an overall survival of 19 mo and PFS of 13 mo. Further studies are warranted to determine the long-term outcomes of liquid-fiducial based IGRT.

Macrophage-biomimetic porous Se@SiO2 nanocomposites for dual modal immunotherapy against inflammatory osteolysis.

BACKGROUND: Inflammatory osteolysis, a major complication of total joint replacement surgery, can cause prosthesis failure and necessitate revision surgery. Macrophages are key effector immune cells in inflammatory responses, but excessive M1-polarization of dysfunctional macrophages leads to the secretion of proinflammatory cytokines and severe loss of bone tissue. Here, we report the development of macrophage-biomimetic porous SiO2-coated ultrasmall Se particles (porous Se@SiO2 nanospheres) to manage inflammatory osteolysis. RESULTS: Macrophage membrane-coated porous Se@SiO2 nanospheres(M-Se@SiO2) attenuated lipopolysaccharide (LPS)-induced inflammatory osteolysis via a dual-immunomodulatory effect. As macrophage membrane decoys, these nanoparticles reduced endotoxin levels and neutralized proinflammatory cytokines. Moreover, the release of Se could induce macrophage polarization toward the anti-inflammatory M2-phenotype. These effects were mediated via the inhibition of p65, p38, and extracellular signal-regulated kinase (ERK) signaling. Additionally, the immune environment created by M-Se@SiO2 reduced the inhibition of osteogenic differentiation caused by proinflammation cytokines, as confirmed through in vitro and in vivo experiments. CONCLUSION: Our findings suggest that M-Se@SiO2 have an immunomodulatory role in LPS-induced inflammation and bone remodeling, which demonstrates that M-Se@SiO2 are a promising engineered nanoplatform for the treatment of osteolysis occurring after arthroplasty.

Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2.

Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases.

Effectiveness and safety of Liuhedan for treating cellulitis: A protocol for systematic review and meta-analysis.

BACKGROUND: Liuhedan is a famous traditional Chinese Medicine formula used to treat cellulitis in China. However, there are no systematic reviews for the evidence and the therapeutic effectiveness and safety of Liuhedan for treating cellulitis. The aim of this study is to summarize previous evidence, assessing the efficacy and safety of Liuhedan treating cellulitis. METHODS: We will search the EMBASE, WANFANG DATA, Web of Knowledge, CNKI, PubMed, ClinicalTrials.gov, and Cochrane Library from inception to June 30, 2021 to retrieve relevant studies using the search strategy: ("Liuhedan" OR "Liuhe Pill" OR "Liu-He-Dan") AND ("cellulitis" OR "phlegmon" OR "skin and soft tissue infection" OR "skin tissue infection" OR "soft tissue infection"). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic. RESULTS: This study assessed the efficiency and safety of Liuhedan for treating cellulitis. CONCLUSIONS: This study will provide reliable evidence-based evidence for the clinical application of Liuhedan for treating cellulitis. ETHICS AND DISSEMINATION: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.

Effectiveness and safety of Liuhedan for treating acute pancreatitis: A protocol for systematic review and meta analysis.

BACKGROUND: Liuhedan is a famous traditional Chinese medicine (TCM) formula used to treat acute pancreatitis (AP) in China. However, there is no systematic reviews for the evidence and the therapeutic effectiveness and safety of Liuhedan for treating AP. The aim of this study is to summarize previous evidence, assessing the efficacy and safety of Liuhedan in the treatment of AP. METHODS: We will search the EMBASE, WANFANG DATA, Web of Knowledge, CNKI, PubMed, ClinicalTrials.gov and Cochrane Library from inception to June 30, 2021 to retrieve relevant studies using the search strategy: ("Liuhedan" OR "Liuhe Pill" OR "Liu-He-Dan") AND ("pancreatitis" OR "pancreatitides"). Two authors independently judged study eligibility and extracted data. Heterogeneity will be examined by computing the Q statistic and I2 statistic. RESULTS: This study assessed the efficiency and safety of Liuhedan for treating acute pancreatitis. CONCLUSIONS: This study will provide reliable evidence-based evidence for the clinical application of Liuhedan for treating AP. ETHICS AND DISSEMINATION: Ethical approval is unnecessary as this protocol is only for systematic review and does not involve privacy data. The findings of this study will be disseminated electronically through a peer-review publication or presented at a relevant conference.

Honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) Suppress SARS-CoV-2 Entry and COVID-19 Related Cytokine Storm in Vitro.

COVID-19 is threatening human health worldwide but no effective treatment currently exists for this disease. Current therapeutic strategies focus on the inhibition of viral replication or using anti-inflammatory/immunomodulatory compounds to improve host immunity, but not both. Traditional Chinese medicine (TCM) compounds could be promising candidates due to their safety and minimal toxicity. In this study, we have developed a novel in silico bioinformatics workflow that integrates multiple databases to predict the use of honeysuckle (Lonicera japonica) and Huangqi (Astragalus membranaceus) as potential anti-SARS-CoV-2 agents. Using extracts from honeysuckle and Huangqi, these two herbs upregulated a group of microRNAs including let-7a, miR-148b, and miR-146a, which are critical to reduce the pathogenesis of SARS-CoV-2. Moreover, these herbs suppressed pro-inflammatory cytokines including IL-6 or TNF-α, which were both identified in the cytokine storm of acute respiratory distress syndrome, a major cause of COVID-19 death. Furthermore, both herbs partially inhibited the fusion of SARS-CoV-2 spike protein-transfected BHK-21 cells with the human lung cancer cell line Calu-3 that was expressing ACE2 receptors. These herbs inhibited SARS-CoV-2 Mpro activity, thereby alleviating viral entry as well as replication. In conclusion, our findings demonstrate that honeysuckle and Huangqi have the potential to be used as an inhibitor of SARS-CoV-2 virus entry that warrants further in vivo analysis and functional assessment of miRNAs to confirm their clinical importance. This fast-screening platform can also be applied to other drug discovery studies for other infectious diseases.

Unraveling the Action Mechanism of Buyang Huanwu Tang (BYHWT) for Cerebral Ischemia by Systematic Pharmacological Methodology.

BACKGROUND: Buyang Huanwu Tang (BYHWT) and relevant Traditional Chinese medicine (TCM) has its unique advantages in the treatment of cerebral ischemia. However, its pharmacological mechanism has not been fully explained. OBJECTIVE: Base on the multi-component, also the entire disease network targets, the present study sets out to identify major bioactive ingredients, key disease targets, and pathways of BYHWT against cerebral ischemia disease by systematic pharmacological methodology. METHODS: Both the bioactive compounds from the BYHWT and the positive drugs against cerebral ischemia were fully investigated. The binding targets of the positive drugs were then obtained. A virtual screening protocol was then used to highlight the compound-target interaction and network was constructed to visualize the compound-target binding effect after docking analysis. Moreover, the targets enrichment analysis for biological processes and pathways were performed to further explore the function of bio-targets protein gene and its role in the signal pathway. RESULTS: A total of 382 active ingredients of the BYHWT and 23 candidate disease targets were identified. Virtual screening results indicated that multiple bioactive compounds targeted multiple proteins. Each compound acts on one or more targets. The mechanisms were linked to 20 signaling pathways, and the key mechanism was related to serotonergic synapse, calcium signaling pathway and camp signaling pathways. CONCLUSION: The present study explored the bioactive ingredients and mechanisms of BYHWT against cerebral ischemia by systematic pharmacological methodology. The novel methodology would provide a reference for the lead discovery of precursors, disease mechanism and material base for TCM.

Weighted Gene Coexpression Network Analysis in Mouse Livers following Ischemia-Reperfusion and Extensive Hepatectomy.

In mouse models, the recovery of liver volume is mainly mediated by the proliferation of hepatocytes after partial hepatectomy that is commonly accompanied with ischemia-reperfusion. The identification of differently expressed genes in liver following partial hepatectomy benefits the better understanding of the molecular mechanisms during liver regeneration (LR) with appliable clinical significance. Briefly, studying different gene expression patterns in liver tissues collected from the mice group that survived through extensive hepatectomy will be of huge critical importance in LR than those collected from the mice group that survived through appropriate hepatectomy. In this study, we performed the weighted gene coexpression network analysis (WGCNA) to address the central candidate genes and to construct the free-scale gene coexpression networks using the identified dynamic different expressive genes in liver specimens from the mice with 85% hepatectomy (20% for seven-day survial rate) and 50% hepatectomy (100% for seven-day survial rate under ischemia-reperfusion condition compared with the sham group control mice). The WGCNA combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses pinpointed out the apparent distinguished importance of three gene expression modules: the blue module for apoptotic process, the turquoise module for lipid metabolism, and the green module for fatty acid metabolic process in LR following extensive hepatectomy. WGCNA analysis and protein-protein interaction (PPI) network construction highlighted FAM175B, OGT, and PDE3B were the potential three hub genes in the previously mentioned three modules. This work may help to provide new clues to the future fundamental study and treatment strategy for LR following liver injury and hepatectomy.

Compound Dan Zhi tablet attenuates experimental ischemic stroke via inhibiting platelet activation and thrombus formation.

BACKGROUND: Compound Dan Zhi tablet (DZT) is a commonly used traditional Chinese medicine formula. It has been used for the treatment of ischemic stroke for many years in clinical. However, its pharmacological mechanism is unclear. PURPOSE: The aim of the current study was to understand the protective effects and underlying mechanisms of DZT on ischemic stroke. METHODS: Fifteen representative chemical markers in DZT were determined by ultra-performance liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). The protective effect of DZT against ischemic stroke was studied in a rat model of middle cerebral artery occlusion (MCAO), and the mechanism was further explored through a combination of network pharmacology and experimental verification. RESULTS: Quantitative analysis showed that the contents of phenolic acids, furan sulfonic acids, tanshinones, flavonoids, saponins and phthalides in DZT were calculated as 7.47, 0.788, 0.627, 0.531 and 0.256 mg/g, respectively. Phenolic acids were the most abundant constituents. Orally administered DZT (1.701 g kg-1) significantly alleviated the infarct size and neurological scores in MCAO rats. The network analysis predicted that 53 absorbed active compounds in DZT-treated plasma targeted 189 proteins and 47 pathways. Ten pathways were associated with anti-platelet activity. In further experiments, DZT (0.4 and 0.8 mg mL-1) markedly inhibited in vitro prostaglandin G/H synthase 1 (PTGS1) activity. DZT (0.4 and 0.8 mg mL-1) significantly inhibited in vitro platelet aggregation in response to ADP or AA. DZT (113 and 226 mg kg-1, p.o.) also produced a marked inhibition of ADP- or AA-induced ex vivo platelet aggregation with a short duration of action. DZT decreased the level of thromboxane A2 (TXA2) in MCAO rats. In the carrageenan-induced tail thrombosis model and ADP-induced acute pulmonary thromboembolism mice model, DZT (113 and 226 mg kg-1, p.o.) prevented thrombus formation. Importantly, DZT (113 and 226 mg kg-1, p.o.) exhibited a low bleeding liability. CONCLUSION: DZT protected against cerebral ischemic injury. The inhibition of TXA2 level, platelet aggregation and thrombosis formation might involve in the protective mechanism.

Research based on the core pathogenesis in the treatment according to traditional Chinese medicine syndrome differentiation for heart failure with normal ejection fraction.

BACKGROUND: The incidence of heart failure with normal ejection fraction (HFNEF) is increasing yearly, accounting for approximately half of all heart failure cases. Even after standardized treatment, the patient's prognosis is not good. Therefore, it is necessary to explore new treatment methods for HFNEF. Yangyin Shuxin Decoction, a traditional Chinese medicine prescription from our clinical experience in the treatment of HFNEF, has a potential cardioprotective effect. Preliminary clinical trials have shown that this prescription can improve the quality of life of HFNEF. This prompted us to use more objective indicators to further evaluate whether Yangyin Shuxin Decoction can improve the exercise capacity in HENEF patients. METHODS: This is a single-center parallel randomized controlled trial. The 64 patients who met the inclusion criteria were from the Cardiovascular Clinic. They will be randomly assigned to the treatment group (Yangying Shuxin Decoction combined with standard treatment) or the control group (standard treatment) according to the ratio of 1:1. The course of treatment will be 2 weeks. Both groups were interviewed at the following time points: of at enrollment (V1), and week 2 (V2), week 4 (V3), week 8 (V4), and week 12 (V5) after enrollment. The primary indicator is the peak oxygen consumption (Peak VO2) of the cardiopulmonary exercise test (CPET). Secondary indicators include CPET indicators such as anaerobic threshold oxygen consumption, carbon dioxide ventilation equivalent slope, echocardiographic indicators such as the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity(E/e'), left atrial volume index (LAVI), left ventricular mass index (LVMI), the peak velocity of tricuspid regurgitation (TR), B-type natriuretic peptide (BNP), New York Heart Association (NYHA) cardiac function grading, and so on. These indicators will be used to evaluate the effect of Yangyin Shuxin Decoction on exercise capacity in patients with HFNEF. DISCUSSION: At present, it is unclear whether the exercise capacity can be maintained after long-term use of Yangyin Shuxin Decoction. In this study, we will evaluate whether Yangyin Shuxin Decoction can improve the exercise capacity and quality of life of patients with HFNEF. This will provide an objective basis for the therapeutic effect of traditional Chinese medicine on HFNEF. TRIAL REGISTRATION: This study protocol has been listed in the Chinese Clinical Trial Registry (registration number: ChiCTR-IOR-17014206, http://www.chictr.org.cn/showproj.aspx?proj=24304) on December 28, 2017.

Investigation of the chemical compounds in Pheretima aspergillum (E. Perrier) using a combination of mass spectral molecular networking and unsupervised substructure annotation topic modeling together with in silico fragmentation prediction.

Untargeted mass spectrometry analysis is one of the most challenging and meaningful steps in the rapid structural elucidation of the highly complex and diverse constituents of traditional Chinese medicine. Specifically, it is a laborious and time-consuming way to identify unknown compounds. Herein, a workflow was proposed to expedite the annotations of the chemical structures in Pheretima aspergillum (E. Perrier) (Di-Long, DL). First, ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS) was performed to obtain the untargeted mass spectral data. Then, the spectral data were uploaded to the Global Natural Products Social Molecular Networking (GNPS) platform to create a network and extract the Mass2Motifs (co-occurring fragments and neutral losses) using unsupervised substructure annotation topic modeling (MS2LDA). Finally, a structural analysis was performed using the proposed workflow of MS2LDA in combination with mass spectral molecular networking and in silico fragmentation prediction. As a result, a total of 124 compounds from DL were effectively characterized, of which 89 (7 furan sulfonic acids, 57 phospholipids and 25 carboxamides) were identified as potentially new compounds from DL. The results presented in this article significantly improve the understanding of the chemical composition of DL and provide a solid scientific basis for the future study of the quality control, underlying pharmacology and mechanism of DL. Moreover, the proposed workflow was used for the first time to accelerate the annotations of unknown molecules from TCM. Furthermore, this workflow will increase the efficiency of characterizing the 'unknown knowns' and elucidation of the 'unknown unknowns' from TCM, which are crucial steps of discovering the natural product drugs in TCM.

Graphene oxide-facilitated uranium transport and release in saturated medium: Effect of ionic strength and medium structure.

Natural subsurface environment is a complex heterogeneous system. To investigate the effect of ionic strength (IS) and heterogeneity on the transport and remobilization of graphene oxide (GO)-facilitated uranium (U(VI)) in saturated porous media, column experiments were performed by the injection of U(VI) alone and U(VI)+GO mixtures into homogeneous and heterogeneous porous media under low and high ionic strength (1 and 50 mM) conditions, and then the columns were successively flushed with background solution and DI water. Results showed that when U(VI) only was introduced into the columns, IS had little effect on the migration of U(VI) alone in both media and the presence of preferential flow in heterogeneous media slightly enhanced the mobility of U(VI). As U(VI)+GO mixtures were injected into the columns, GO showed strong mobility at low IS and high released peak at high IS. The appearance of GO significantly enhanced U(VI) transport in both media. Under low IS condition, the mobility of U(VI) was significantly enhanced at the injection phase, and the medium heterogeneity further promoted the amount of GO-sorbed U(VI) transport. At high IS, less GO-sorbed U(VI) was observed during injection phase, and a large amount of retained GO-sorbed U(VI) were released with GO remobilization during water flushing phase, and the release showed the longer-tailing phenomenon and the release amount was more pronounced in heterogeneous media. The findings in this study showed that the coupled effect of solution chemistry and media heterogeneity played important roles on GO-facilitated U(VI) transport and release in soil and groundwater system.