Peroxymonosulfate activation by Fe-Mn Co-doped biochar for carbamazepine degradation.

Antibiotics in aquatic environments present a serious threat to the ecological environment and human health. Activation of carbon-catalyzed persulfate is a prospective approach for oxidizing antibiotics. There is a pressing need for inexpensive carbon catalysts of high quality. In this study, biochar (BC) modified by Fe, Mn and Fe@Mn was employed to activate peroxymonosulfate (PMS) to degrade carbamazepine (CBZ) in water. The surface of Fe@Mn BC had a dense, stalactite-like morphology comprising a square chassis that was elliptical. The catalyst Fe@Mn-BC possessed the optimal degradation effect (99%) on CBZ at 100 min. Electron paramagnetic resonance spectroscopy and the quenching spectrum suggested that ˙O2- and 1O2 contributed to CBZ degradation.

Corrigendum: Systems pharmacology approach to investigate the mechanism of Kai-Xin-San in Alzheimer's disease.

[This corrects the article DOI: 10.3389/fphar.2020.00381.].

Network Pharmacology Approach to Investigate the Mechanism of Danggui-Shaoyao-San against Diabetic Kidney Disease.

Background: Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine formula that has been widely used to treat a variety of disorders, including renal diseases. Despite being well-established in clinical practice, the mechanisms behind the therapeutic effects of DSS on diabetic nephropathy (DN) remain elusive. Methods: To explore the therapeutic mechanism, we explored the action mechanism of DSS on DN using network pharmacology strategies. All ingredients were selected from the relevant databases, and active ingredients were chosen on the basis of their oral bioavailability prediction and drug-likeness evaluation. The putative proteins of DSS were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, whereas the potential genes of DN were obtained from the GeneCards and OMIM databases. Enrichment analysis using gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) was performed to discover possible hub targets and gene-related pathways. Afterwards, the underlying molecular mechanisms of DSS against DN were validated experimentally in vivo against db/db mice. Results: We identified 91 phytochemicals using the comprehensive network pharmacology technique, 51 of which were chosen as bioactive components. There were 40 proteins and 20 pathways in the target-pathway network. The experimental validation results demonstrated that DSS may reduce the expression of TNF-α, IL-6, and ICAM-1, as well as extracellular matrix deposition, by blocking the JNK pathway activation, which protects against kidney injury. Conclusion: This study discovered the putative molecular mechanisms of action of DSS against diabetic kidney damage through a network pharmacology approach and experimental validation.

Hsa_circ_0008301 as a potential biomarker of disease activity for primary Sjogren's syndrome: Increased expression in peripheral blood of patients with primary Sjogren's syndrome.

OBJECTIVES: To explore the expression level, association with disease activity and clinical significance of hsa_circ_0008301 in the peripheral blood of patients with primary Sjögren's syndrome (pSS). METHODS: We selected 70 pSS patients hospitalized under the Rheumatology service line at the General Hospital of Ningxia Medical University from September 2018 to June 2021 as the disease group, in which general data and clinical indicators were collected. Fifty-three patients with healthy physical examinations for the same period were selected as the healthy control group, and 32 patients with non-pSS rheumatic diseases were selected as the disease control group. We collected peripheral blood samples and used fluorescence quantitative PCR to detect the expression level of hsa_circ_0008301. In addition, we analyzed the association of the expression level of hsa_circ_0008301 with the clinical characteristics and disease activity of pSS patients. A receiver operating characteristic curve was used to evaluate the diagnosis and the disease activity value of hsa_circ_0008301 in patients with pSS. Meanwhile, we analyzed the differential expression of hsa_circ_0008301 in 24 pSS patients selected from the disease group before and after treatment. RESULTS: The relative expression of hsa_circ_0008301 in the peripheral blood of pSS patients was significantly higher than that in the control groups including healthy control group and disease control group. The expression level of hsa_circ_0008301 was high in pSS patients with a course of disease ≥ 10 years, fatigue symptoms, platelets < 100*10^9/L, erythrocyte sedimentation rate ≥ 50 mm/h, immunoglobulin IgG > 16 g/L, complement C3 < 0.9 g/L, ESSDAI score ≥ 5 and positively correlated with the above groups. Furthermore, ROC analysis showed that hsa_circ_0008301 was statistically significant between pSS patients and healthy controls. We selected patients from the disease group before and after treatment and showed that the expression level of hsa_circ_0008301 decreased significantly after treatment, compared with before. The area under the curve (AUC) was 0.825 (95% CI: 0.754 âˆ¼ 0.897; P < 0.0001). The AUC of hsa_circ_0008301 in pSS patients and the disease control group was 0.673 (95% CI: 0.563 âˆ¼ 0.782; P = 0.005), the sensitivity was 40.00%, the specificity was 93.70%, the optimal truncation value was > 0.0420, and the maximum Youden index was 0.337. In addition, ROC analysis revealed that hsa_circ_0008301 was statistically significant between disease-active patients and stable patients. The AUC value was 0.681 (95% CI: 0.553 âˆ¼ 0.809; P = 0.010), the sensitivity was 65.90%, the specificity was 72.40%, the optimal truncation value was > 0.0285, and the maximum Youden index was 0.383. ROC analysis indicated that hsa_circ_0008301 has some value in the diagnosis and disease activity of patients with pSS. Comparison of 24 pSS patients selected from the disease group before and after treatment showed that the expression level of hsa_circ_0008301 decreased significantly after treatment compared with before treatment (Z =  - 4.257, P < 0.0001). ROC analysis indicated that hsa_circ_0008301 has some value in the diagnosis and disease activity of patients with pSS. CONCLUSIONS: Hsa_circ_0008301 is expressed in higher levels in the peripheral blood of patients with pSS, which is related to the disease activity. It may be involved in the occurrence and development of pSS and may have a potential biomarker for the disease.

Angong Niuhuang Wan reduces hemorrhagic transformation and mortality in ischemic stroke rats with delayed thrombolysis: involvement of peroxynitrite-mediated MMP-9 activation.

BACKGROUND: Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood-brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation. METHODS: We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague-Dawley rats were subjected to 5 h of middle cerebral artery occlusion (MCAO) followed by 19 h of reperfusion plus t-PA infusion (10 mg/kg) at 5 h of cerebral ischemia. AGNHW (257 mg/kg) was given orally at 2 h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood-brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5 h of oxygen and glucose deprivation (OGD) plus 5 h of reoxygenation with t-PA treatment (20 µg/ml). RESULTS: AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains. CONCLUSION: AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation.

Danggui-Shaoyao-San (DSS) Ameliorates Cerebral Ischemia-Reperfusion Injury via Activating SIRT1 Signaling and Inhibiting NADPH Oxidases.

Danggui-Shayao-San (DSS) is a famous Traditional Chinese Medicine formula that used for treating pain disorders and maintaining neurological health. Recent studies indicate that DSS has neuroprotective effects against ischemic brain damage but its underlining mechanisms remain unclear. Herein, we investigated the neuroprotective mechanisms of DSS for treating ischemic stroke. Adult male Sprague-Dawley (S.D.) rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 22 h of reperfusion. Both ethanol extract and aqueous extract of DSS (12 g/kg) were orally administrated into the rats at 30 min prior to MCAO ischemic onset. We found that 1) ethanol extract of DSS, instead of aqueous extract, reduced infarct sizes and improved neurological deficit scores in the post-ischemic stroke rats; 2) Ethanol extract of DSS down-regulated the expression of the cleaved-caspase 3 and Bax, up-regulated bcl-2 and attenuated apoptotic cell death in the ischemic brains; 3) Ethanol extract of DSS decreased the production of superoxide and peroxynitrite; 4) Ethanol extract of DSS significantly down-regulated the expression of p67phox but has no effect on p47phox and iNOS statistically. 5) Ethanol extract of DSS significantly up-regulated the expression of SIRT1 in the cortex and striatum of the post-ischemic brains; 6) Co-treatment of EX527, a SIRT1 inhibitor, abolished the DSS's neuroprotective effects. Taken together, DSS could attenuate oxidative/nitrosative stress and inhibit neuronal apoptosis against cerebral ischemic-reperfusion injury via SIRT1-dependent manner.

Systems Pharmacology Approach to Investigate the Mechanism of Kai-Xin-San in Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by cognitive dysfunction. Kai-Xin-San (KXS) is a traditional Chinese medicine (TCM) formula that has been used to treat AD patients for over a thousand years in China. However, the therapeutic mechanisms of KXS for treating AD have not been fully explored. Herein, we used a comprehensive network pharmacology approach to investigate the mechanism of action of KXS in the treatment of AD. This approach consists of construction of multiple networks and Gene Ontology enrichment and pathway analyses. Furthermore, animal experiments were performed to validate the predicted molecular mechanisms obtained from the systems pharmacology-based analysis. As a result, 50 chemicals in KXS and 39 AD-associated proteins were identified as major active compounds and targets, respectively. The therapeutic mechanisms of KXS in treating AD were primarily related to the regulation of four pathology modules, including amyloid beta metabolism, tau protein hyperphosphorylation process, cholinergic dysfunction, and inflammation. In scopolamine-induced cognitive dysfunction mice, we validated the anti-inflammatory effects of KXS on AD by determining the levels of inflammation cytokines including interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. We also found cholinergic system dysfunction amelioration of KXS is correlated with upregulation of the cholinergic receptor CHRNB2. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the underlying therapeutic mechanism of KXS for the treatment of AD.

Non-fragile dissipative filtering of cyber-physical systems with random sensor delays.

This paper considers the problem of non-fragile state estimation under dissipative constraint for a class of nonlinear cyber-physical systems (CPSs) with sensor delays. The dynamics of the considered CPSs is characterized by the well-known T-S fuzzy model and system measurements are valued by wireless sensors. The communication link between the filter and the plant is described by a relatively practical model and sensor delays occurred in signal transmissions are taken into consideration. A stochastic variable which yields the standard Bernoulli distribution is exploited to model sensor delays encountered by the sensor measurements. With the help of a basis-dependent Lyapunov function and predefined performance constraint, sufficient conditions are then developed to establish the stochastic stability as well as strict dissipativity for the resultant filtering error system. The existence of the corresponding filter is guaranteed and the expression of desired filter parameters are shown explicitly. In the end, the established theoretical results are validated by a tunnel diode circuit example and corresponding simulations are also provided.

In silico Identification and Mechanism Exploration of Hepatotoxic Ingredients in Traditional Chinese Medicine.

BACKGROUNDS AND AIMS: Recently, a growing number of hepatotoxicity cases aroused by Traditional Chinese Medicine (TCM) have been reported, causing increasing concern. To date, the reported predictive models for drug induced liver injury show low prediction accuracy and there are still no related reports for hepatotoxicity evaluation of TCM systematically. Additionally, the mechanism of herb induced liver injury (HILI) still remains unknown. The aim of the study was to identify potential hepatotoxic ingredients in TCM and explore the molecular mechanism of TCM against HILI. MATERIALS AND METHODS: In this study, we developed consensus models for HILI prediction by integrating the best single classifiers. The consensus model with best performance was applied to identify the potential hepatotoxic ingredients from the Traditional Chinese Medicine Systems Pharmacology database (TCMSP). Systems pharmacology analyses, including multiple network construction and KEGG pathway enrichment, were performed to further explore the hepatotoxicity mechanism of TCM. RESULTS: 16 single classifiers were built by combining four machine learning methods with four different sets of fingerprints. After systematic evaluation, the best four single classifiers were selected, which achieved a Matthews correlation coefficient (MCC) value of 0.702, 0.691, 0.659, and 0.717, respectively. To improve the predictive capacity of single models, consensus prediction method was used to integrate the best four single classifiers. Results showed that the consensus model C-3 (MCC = 0.78) outperformed the four single classifiers and other consensus models. Subsequently, 5,666 potential hepatotoxic compounds were identified by C-3 model. We integrated the top 10 hepatotoxic herbs and discussed the hepatotoxicity mechanism of TCM via systems pharmacology approach. Finally, Chaihu was selected as the case study for exploring the molecular mechanism of hepatotoxicity. CONCLUSION: Overall, this study provides a high accurate approach to predict HILI and an in silico perspective into understanding the hepatotoxicity mechanism of TCM, which might facilitate the discovery and development of new drugs.

Systems pharmacology-based investigation of Sanwei Ganjiang Prescription: related mechanisms in liver injury.

Liver injury remains a significant global health problem and has a variety of causes, including oxidative stress (OS), inflammation, and apoptosis of liver cells. There is currently no curative therapy for this disorder. Sanwei Ganjiang Prescription (SWGJP), derived from traditional Chinese medicine (TCM), has shown its effectiveness in long-term liver damage therapy, although the underlying molecular mechanisms are still not fully understood. To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view, in the present study, a systems pharmacology approach was developed, which involved drug target identification and multilevel data integration analysis. Using a comprehensive systems approach, we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets. We further deciphered the mechanisms of SWGJP in treating liver injury, including compound-target network analysis, target-function network analysis, and integrated pathways analysis. We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway, such as Nrf2-dependent anti-oxidative stress module. Notably, systems pharmacology provides an alternative way to investigate the complex action mode of TCM.

The Mechanisms of Bushen-Yizhi Formula as a Therapeutic Agent against Alzheimer's Disease.

Bushen-Yizhi prescription (BSYZ) has been an effective traditional Chinese medicine (TCM) prescription in treating Alzheimer's disease (AD) for hundreds of years. However, the underlying mechanisms have not been fully elucidated yet. In this work, a systems pharmacology approach was developed to reveal the underlying molecular mechanisms of BSYZ in treating AD. First, we obtained 329 candidate compounds of BSYZ by in silico ADME/T filter analysis and 138 AD-related targets were predicted by our in-house WEGA algorithm via mapping predicted targets into AD-related proteins. In addition, we elucidated the mechanisms of BSYZ action on AD through multiple network analysis, including compound-target network analysis and target-function network analysis. Furthermore, several modules regulated by BSYZ were incorporated into AD-related pathways to uncover the therapeutic mechanisms of this prescription in AD treatment. Finally, further verification experiments also demonstrated the therapeutic effects of BSYZ on cognitive dysfunction in APP/PS1 mice, which was possibly via regulating amyloid-ß metabolism and suppressing neuronal apoptosis. In conclusion, we provide an integrative systems pharmacology approach to illustrate the underlying therapeutic mechanisms of BSYZ formula action on AD.

In silico prediction of ROCK II inhibitors by different classification approaches.

ROCK II is an important pharmacological target linked to central nervous system disorders such as Alzheimer's disease. The purpose of this research is to generate ROCK II inhibitor prediction models by machine learning approaches. Firstly, four sets of descriptors were calculated with MOE 2010 and PaDEL-Descriptor, and optimized by F-score and linear forward selection methods. In addition, four classification algorithms were used to initially build 16 classifiers with k-nearest neighbors [Formula: see text], naïve Bayes, Random forest, and support vector machine. Furthermore, three sets of structural fingerprint descriptors were introduced to enhance the predictive capacity of classifiers, which were assessed with fivefold cross-validation, test set validation and external test set validation. The best two models, MFK + MACCS and MLR + SubFP, have both MCC values of 0.925 for external test set. After that, a privileged substructure analysis was performed to reveal common chemical features of ROCK II inhibitors. Finally, binding modes were analyzed to identify relationships between molecular descriptors and activity, while main interactions were revealed by comparing the docking interaction of the most potent and the weakest ROCK II inhibitors. To the best of our knowledge, this is the first report on ROCK II inhibitors utilizing machine learning approaches that provides a new method for discovering novel ROCK II inhibitors.

Ocular delivery of cyanidin-3-glycoside in liposomes and its prevention of selenite-induced oxidative stress.

CONTEXT: Cataracts have become the leading cause of blindness around the world, which is mainly mediated by oxidative stress. OBJECTIVE: N-trimethyl chitosan (TMC)-coated liposomes of cyanidin-3-glycoside (C3G) (C3G-TCL) were prepared to attenuate oxidative stress induced by selenite sodium in rats. MATERIALS AND METHODS: C3G-TCL were prepared by reverse-phase evaporation method and then coated with self-synthesized TMC. The physicochemical properties were determined. A gamma-scintigraphy study was employed to evaluate the precorneal elimination of the radioactive preparations. The transcorneal visualization for fluorescence-labeled samples was determined by confocal laser scanning microscopy (CLSM). The in vivo anti-oxidative study using C3G-TCL was carried out in rats with selenite-induced cataracts by topical administration. RESULTS: The sphere-like morphological characterization of the vesicles was confirmed by TEM, with a size of 158.3 ± 2.8 nm and a zeta potential of 31.7 mV. The encapsulation efficiency was (53.7 ± 0.2) % as measured by ultrafiltration. C3G-TCL showed a 3.3-fold increment in precorneal residence time when compared with that of the (99m)Tc-solution. A TMC coating enhanced the transepithelial transport of liposomes to a depth of 40-µm in the cornea. Moreover, C3G-TCL could significantly elevate the activity of superoxide dismutase and catalase in lens and also show a considerable reversal of reduced glutathione activity. The lipid peroxidation in lens was strongly prevented when compared with that of groups treated with uncoated C3G-loaded liposomes. DISCUSSION AND CONCLUSION: The coating material TMC for liposomes helps improve the anti-oxidative effect of C3G in vivo through prolonged residence time on the cornea and improved permeability in the corneal epithelium.

A systems pharmacology approach to decipher the mechanism of danggui-shaoyao-san decoction for the treatment of neurodegenerative diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Neurodegenerative diseases (NDs) is a time-dependent course for a sequence of conditions that primarily impact the neurons in the human brain, ultimately, resulting in persistence and progressive degeneration and / or death of nerve cells and reduction of cognition and memory function. Currently, there are no therapeutic approaches to cure neurodegeneration, except certain medicines that temporarily alleviate symptoms, facilitating the improvement of a patients' quality of life. Danggui-shaoyao-san (DSS), as a famous Chinese herbal formula, has been widely used in the treatment of various illnesses, including neurodegenerative diseases. Although well-practiced in clinical medicine, the mechanisms involved in DSS for the treatment of neurodegenerative diseases remain elusive. MATERIALS AND METHODS: In the present study, a novel systems pharmacology approach was developed to decipher the potential mechanism between DSS and neurodegenerative disorders, implicated in oral bioavailability screening, drug-likeness assessment, target identification and network analysis. RESULTS: Based on a comprehensive systems approach, active compounds of DSS, relevant potential targets and targets associated with diseases were predicted. Active compounds, targets and diseases were used to construct biological networks, such as, compound-target interactions and target-disease networks, to decipher the mechanisms of DSS to address NDs. CONCLUSIONS: Overall, a well-understood picture of DSS, hallmarked by multiple herbs-compounds-targets-pathway-cooperation networks for the treatment of NDs, was revealed. Notably, this systems pharmacology approach provided a novel in silico approach for the development paradigm of traditional Chinese medicine (TCM) and the generation of new strategies for the management of NDs.