Structural Brain Connectivity guided Optimal Contact Selection for STN-DBS.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy in ameliorating the motor symptoms of Parkinson's disease (PD). However, postoperative optimal contact selection is crucial for achieving the best outcome of STN-DBS surgery, but the process is currently a trial-and-error and time-consuming procedure that relies heavily on surgeons' clinical experience. METHODS: In this study, we propose a structural brain connectivity guided optimal contact selection method for STN-DBS. Firstly, we reconstruct the DBS electrode location and estimate the stimulation range using volumes of tissue activated (VTA) from each DBS contact. Then, we extract the structural connectivity features by concatenating fractional anisotropy (FA) and the number of streamlines (NOS) features of activated regions and the whole brain regions. Finally, we use a convolutional neural network (CNN) with convolutional block attention module (CBAM) to identify the structural connectivity features for the optimal contact selection. RESULTS: We review the data of 800 contacts from 100 patients with Parkinson disease for the experiment. The proposed method achieves promising results, with the average accuracy of 97.63%, average precision of 94.50%, average recall of 94.46% and average specificity of 98.18%, respectively. Our method can provide the suggestion for optimal contact selection. CONCLUSIONS: Our proposed method can improve the efficiency and accuracy of DBS optimal contact selection, reduce the dependence on surgeons' experience, and has the potential to facilitate the development of advanced DBS technology.

Multimodal MRI segmentation of key structures for microvascular decompression via knowledge-driven mutual distillation and topological constraints.

PURPOSE: Microvascular decompression (MVD) is a widely used neurosurgical intervention for the treatment of cranial nerves compression. Segmentation of MVD-related structures, including the brainstem, nerves, arteries, and veins, is critical for preoperative planning and intraoperative decision-making. Automatically segmenting structures related to MVD is still challenging for current methods due to the limited information from a single modality and the complex topology of vessels and nerves. METHODS: Considering that it is hard to distinguish MVD-related structures, especially for nerve and vessels with similar topology, we design a multimodal segmentation network with a shared encoder-dual decoder structure and propose a clinical knowledge-driven distillation scheme, allowing reliable knowledge transferred from each decoder to the other. Besides, we introduce a class-wise contrastive module to learn the discriminative representations by maximizing the distance among classes across modalities. Then, a projected topological loss based on persistent homology is proposed to constrain topological continuity. RESULTS: We evaluate the performance of our method on in-house dataset consisting of 100 paired HR-T2WI and 3D TOF-MRA volumes. Experiments indicate that our model outperforms the SOTA in DSC by 1.9% for artery, 3.3% for vein and 0.5% for nerve. Visualization results show our method attains improved continuity and less breakage, which is also consistent with intraoperative images. CONCLUSION: Our method can comprehensively extract the distinct features from multimodal data to segment the MVD-related key structures and preserve the topological continuity, allowing surgeons precisely perceiving the patient-specific target anatomy and substantially reducing the workload of surgeons in the preoperative planning stage. Our resources will be publicly available at https://github.com/JaronTu/Multimodal_MVD_Seg .

Electrochemical annulation of 1,2,3-benzotriazinones with alkynes to access isoquinolin-1(2H)-ones.

An eco-friendly approach for electrochemical radical cascade annulation of 1,2,3-benzotriazinones with alkynes is described. Under catalyst-free and external reductant-free electrolysis conditions, a range of isoquinolin-1(2H)-ones were obtained in moderate to good yields. Cyclic voltammetry and control studies suggest that the reaction proceeds via a radical pathway. Furthermore, this approach could be easily scaled up.

Automatic Localization of Key Structures for Subthalamic Nucleus-Deep Brain Stimulation Surgery via Prior-Enhanced Multi-Object Magnetic Resonance Imaging Segmentation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established and effective neurosurgical treatment for relieving motor symptoms in Parkinson disease. The localization of key brain structures is critical to the success of DBS surgery. However, in clinical practice, this process is heavily dependent on the radiologist's experience. METHODS: In this study, we propose an automatic localization method of key structures for STN-DBS surgery via prior-enhanced multi-object magnetic resonance imaging segmentation. We use the U-Net architecture for the multi-object segmentation, including STN, red nucleus, brain sulci, gyri, and ventricles. To address the challenge that only half of the brain sulci and gyri locate in the upper area, potentially causing interference in the lower area, we perform region of interest detection and ensemble joint processing to enhance the segmentation performance of brain sulci and gyri. RESULTS: We evaluate the segmentation accuracy by comparing our method with other state-of-the-art machine learning segmentation methods. The experimental results show that our approach outperforms state-of-the-art methods in terms of segmentation performance. Moreover, our method provides effective visualization of key brain structures from a clinical application perspective and can reduce the segmentation time compared with manual delineation. CONCLUSIONS: Our proposed method uses deep learning to achieve accurate segmentation of the key structures more quickly than and with comparable accuracy to human manual segmentation. Our method has the potential to improve the efficiency of surgical planning for STN-DBS.

Atractylenolide III suppresses senescence-associated secretome via inhibiting cGAS/NF-κB pathway in hepatic stellate cells.

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Induction of aHSCs senescence by inhibiting SASP may be a potential therapeutic model against hepatic fibrosis. To evaluate the role of atractylenolide III (ATR III) in the development of chemotherapeutic drug-induced SASPs in hepatic stellate cells. Etoposide-induced senescent HSC-LX2 model was established and treated with ATR III at different concentrations (20, 30 and 40 µM). We found that ATR III dose-dependently enhanced senescence in etoposide-induced LX2 cells. ATR III dose-dependently decreased the release and expression of SASP factors (interleukin [IL]-1α, IL-1ß, IL6 and IL-8) in senescent cells. ATR III regulated cyclic GMP-AMP synthase (cGAS)/nuclear factor κ (NF-κB) signalling to affect SASP expression in senescent cells. The addition of 2'3' cGAMP counteracted the effect of ATR III. The release of SASP factors in the conditioned medium from senescent cells could affect cell migration, proliferation and contraction through paracrine manner. Our results indicated ATR III could still enter senescence and prevent the production of SASP and its paracrine effects in senescent cells, an effect that may be related to the possible inhibition of cGAS/NF-κB signalling by ATR III. Our study proves that ATR III may be an effective potential drug against liver fibrosis by promoting aHSC senescence, which can provide a new choice for the future clinical treatment of liver fibrosis.

Network Pharmacology Analysis and Experimental Verification on Antiangiogenesis Mechanism of Hedyotis diffusa Willd in Liver Cancer.

Purpose: Hedyotis diffusa Willd (HDW) is one of the most well-known herbs used in the therapy of cancer. However, the potential mechanisms of its antiangiogenic effects have not been fully explored. Here, we applied a network pharmacology approach to explore the potential mechanisms of HDW against liver cancer angiogenesis (LCA) and used a mouse orthotopic liver cancer model for experimental verification accordingly. Methods: The effective components, primary active compounds, and possible targets in the therapy of LCA were predicted using network pharmacology and bioinformatics. In vivo testing of the pharmacodynamic foundation of HDW in the treatment of LCA was performed. Hepa1-6 cells were implanted in C57BL/6 mice to establish an orthotopic liver cancer model to evaluate the antitumor and antiangiogenesis effects of the drug. Furthermore, protein levels were evaluated by western blotting, immunofluorescence, and immunohistochemistry. Results: We firstly confirmed the therapeutic effect of HDW on LCA and subsequently screened 7 active compounds from HDW according to their pharmacokinetic properties. Network analysis and enrichment analysis indicated that these compounds exhibit antiangiogenic effect by acting on multiple targets and thereby regulating multiple pathways mainly involved in Akt1, IL-6, IL-1ß, IL-17, hypoxia inducible factor-1α (HIF-1α), and tumor necrosis factor-α (TNF-α). Importantly, we preliminarily verified the results of the network pharmacology analysis in vivo. Conclusion: Collectively, our work initially explored the therapeutic mechanism of HDW on tumor angiogenesis, which lays an experimental reference for further exploring its pharmacological action and its clinical application.

A Review: Meridianins and Meridianins Derivatives.

Meridianins are a family of indole alkaloids derived from Antarctic tunicates with extensive pharmacological activities. A series of meridianin derivatives had been synthesized by drug researchers. This article reviews the extraction and purification methods, biological activities and pharmacological applications, pharmacokinetic characters and chemical synthesis of meridianins and their derivatives. And prospects on discovering new bioactivities of meridianins and optimizing their structure for the improvement of the ADMET properties are provided.

Polygonatum sibiricum Polysaccharides Attenuate Lipopoly-Saccharide-Induced Septic Liver Injury by Suppression of Pyroptosis via NLRP3/GSDMD Signals.

Sepsis is a systemic inflammatory response syndrome with high mortality. Acute liver injury is an independent predictor for poor prognosis in septic patients. Polygonatum sibiricum polysaccharides (PSP) have been reported to possess anti-inflammatory and hepatoprotective activities. To evaluate the effects of PSP on septic liver injury and demonstrate the potential molecular mechanisms, the septic acute liver injury (SALI) model was established in BALB/c mice via intraperitoneal injection of lipopolysaccharide (LPS). We found that PSP treatment could remarkably reduce the 48 h mortality rate of septic mice; alleviate liver histopathologic damage; lower the activity of neutrophil infiltration marker MPO in liver tissue; and decrease the levels of liver function indexes AST, ALT, ALP, and TBIL, inflammatory cytokines TNFα and IL-6, and pyroptosis-related inflammatory cytokines IL-18 and IL-1ß in serum. TUNEL staining and detecting GSDMD-NT protein expression level in liver tissue revealed that PSP could restrain excessive pyroptosis. In addition, PSP treatment reversed the upregulations of mRNA expression levels of the NLRP3/GSDMD signals in the liver. Our results indicated the potential protective role of PSP against SALI by inhibiting pyroptosis via NLRP3/GSDMD signals.

Metabolite Profiling of Meridianin C In Vivo of Rat by UHPLC/Q-TOF MS.

Meridianin C (MC), as a marine alkaloid, is a potent protein kinase inhibitor which exhibits good anticancer activity. However, the in vivo metabolism of MC has not been described to date. In this study, an ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method is employed to investigate the in vivo metabolites of MC in rats. Plasma, bile, urine, and feces are collected after a single oral dose of MC. Protein precipitation, solid phase extraction (SPE), and ultrasonic extraction methods are used to prepare samples. Based on the mass spectral fragmentation patterns, elution order, and retrieving literatures, a total of 13 metabolites of MC were detected and tentatively identified, utilizing MetaboLynx software. The metabolic pathways of MC in rats include N- or O-glucuronidation, O-sulfation, N-hydroxylation, dihydroxylation, and trihydroxylation. The relative content of the metabolites in each kinds of biological samples is also evaluated. This study will help to understand the in vivo properties of MC for the future usage.

Automatic identification of sweet spots from MERs for electrodes implantation in STN-DBS.

PURPOSE: Microelectrode recordings (MERs) are a significant clinical indicator for sweet spots identification of implanted electrodes during deep brain stimulation of the subthalamic nucleus (STN) surgery. As 1D MERs signals have the unboundedness, large-range, large-amount and time-dependent characteristics, the purpose of this study is to propose an automatic and precise identification method of sweet spots from MERs, reducing the time-consuming and labor-intensive human annotations. METHODS: We propose an automatic identification method of sweet spots from MERs for electrodes implantation in STN-DBS. To better imitate the surgeons' observation and obtain more intuitive contextual information, we first employ the 2D Gramian angular summation field (GASF) images generated from MERs data to perform the sweet spots determination for electrodes implantation. Then, we introduce the convolutional block attention module into convolutional neural network (CNN) to identify the 2D GASF images of sweet spots for electrodes implantation. RESULTS: Experimental results illustrate that the identification result of our method is consistent with the result of doctor's decision, while our method can achieve the accuracy and precision of 96.72% and 98.97%, respectively, which outperforms state-of-the-art for intraoperative sweet spots determination. CONCLUSIONS: The proposed method is the first time to automatically and accurately identify sweet spots from MERs for electrodes implantation by the combination an advanced time series-to-image encoding way with CBAM-enhanced networks model. Our method can assist neurosurgeons in automatically detecting the most likely locations of sweet spots for electrodes implantation, which can provide an important indicator for target selection while it reduces the localization error of the target during STN-DBS surgery.

Liver injury in septic mice were suppressed by a camptothecin-bile acid conjugate via inhibiting NF-κB signaling pathway.

BACKGROUND AND OBJECTIVES: Sepsis is a life-threatening organ dysfunction syndrome arising from uncontrolled inflammatory responses. Liver injury is a crucial factor for the prognosis of sepsis. Camptothecins (CPTs) have been reported to suppress the inflammatory response induced by sepsis. G2, a CPT-bile acid conjugate, has been demonstrated the property of liver targeting in our previous research. This study aimed to research the effects of G2 on liver injury induced by cecal ligation and puncture (CLP). METHODS: C57BL/6 mice were subjected to CLP surgery, and effects of G2 on liver damage and survival rates of CLP-induced mice were evaluated. To detect the related markers of hepatic injury or neutrophil infiltration, inflammatory cytokines and protein levels, hematoxylin-eosin staining assay, corresponding Detection Kits assay, ELISA and Western blot analysis were performed. RESULTS: Intraperitoneal administration of G2 reduced liver injury and enhanced the survival rates in mice with sepsis. Treatment with G2 decreased the levels of hepatic injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice induced by CLP. The hepatic level of neutrophil infiltration marker myeloperoxidase (MPO) was reduced in G2 administration group. And the levels of serum inflammatory cytokines, including Tumor Necrosis Factor-α (TNFα), Interleukin-6 (IL-6) and IL-1ß, were decreased by G2. Furthermore, the results of Western blot analysis indicated that G2 suppressed the up-regulation of NF-κB p-P65 and p-IκBα. It suggested that G2 suppressed the activation of NF-κB signaling pathway. CONCLUSION: G2 alleviated sepsis-induced liver injury via inhibiting the NF-κB signaling pathway.

Regio- and stereoselective thiocyanatothiolation of alkynes and alkenes by using NH4SCN and N-thiosuccinimides.

A highly regioselective thiocyanatothiolation of alkynes and alkenes assisted by hydrogen bonding under simple and mild conditions is developed. Our thiocyanatothiolation reagents are readily available ammonium thiocyanate and N-thiosuccinimides. This metal-free system offers good chemical yields for a wide range of alkyne and alkene substrates with good functional group tolerance.

Mechanism of a Novel Camptothecin-Deoxycholic Acid Derivate Induced Apoptosis against Human Liver Cancer HepG2 Cells and Human Colon Cancer HCT116 Cells.

BACKGROUND: Camptothecin (CPT) is known as an anticancer drug in traditional Chinese medicine. However, due to the lack of targeting, low solubility, and instability of CPT, its therapeutic applications are hampered. Therefore, we synthesized a series of CPT-bile acid analogues that obtained a national patent to improve their tumour-targeting chemotherapeutic effects on liver or colon cancers. Among these analogues, the compound G2 shows high antitumor activity with enhanced liver targeting and improved oral absorption. It is significant to further investigate the possible anticancer mechanism of G2 for its further clinical research and application. OBJECTIVE: We aimed to unearth the anticancer mechanism of G2 in HepG2 and HCT116 cells. METHODS: Cell viability was measured using MTT assay; cell cycle, Mitochondrial Membrane Potential (MMP), and cell apoptosis were detected by flow cytometer; ROS was measured by Fluorescent Microplate Reader; the mRNA and protein levels of cell cycle-related and apoptosis-associated proteins were examined by RT-PCR and western blot, respectively. RESULTS: We found that G2 inhibited cells proliferation of HepG2 and HCT116 remarkably in a dosedependent manner. Moreover, G2-treatment led to S and G2/M phase arrest in both cells, which could be elucidated by the change of mRNA levels of p21, p27 and Cyclin E and the increased protein level of p21. G2 also induced dramatically ROS accumulated and MMP decreased, which contributed to the apoptosis through activation of both the extrinsic and intrinsic pathways via changing the genes and proteins expression involved in apoptosis pathway in both of HepG2 and HCT116 cells. CONCLUSION: These findings suggested that the apoptosis in both cell lines induced by G2 was related to the extrinsic and intrinsic pathways.

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption.

Camptothecin (CPT), a natural alkaloid, possesses potent anticancer activity. However, its application was terminated due to its low bioavailability and high toxicity. This work evaluated the potential of deoxycholic acid-CPT conjugate (G2) to improve the oral absorption of CPT. Deoxycholic acid significantly reduced cytotoxicity and inhibited the uptake of G2, in vitro. And G2 showed sodium-dependent uptake. In addition, in vivo study in rats indicated that the oral bioavailability of G2 was 2.06-fold higher than that of CPT. The present study suggested that using bile acid as the conjugated moiety is a hopeful strategy to improve the oral bioavailability of CPT.

Curcumin analogues attenuate Aß25-35-induced oxidative stress in PC12 cells via Keap1/Nrf2/HO-1 signaling pathways.

Beta-amyloid (Aß) has pivotal functions in the pathogenesis of Alzheimer's Disease (AD). In the present study, we adopted an vitro model that involved Aß25-35-induced oxidative damage in PC12 cells. Aß25-35 (10 µΜ) treatment for 24 h induced significant cell death and oxidative stress in PC12 cells, as evidenced by cell viability reduction, LDH release, ROS accumulation and increased production MDA. (1E,4E)-1, 5-bis(4-hydroxy-3-methoxyphenyl) penta-1, 4-dien-3-one (CB) and (1E, 4E)-1-(3, 4-dimethoxyphenyl)-5-(4-hydroxy-3, 5-dime-thoxyphenyl) Penta-1, 4-dien-3-one (FE), two Curcumin (Cur) analogues displayed neuroprotective effects against Aß25-35-induced oxidative damage and cellular apoptosis in PC12 cells. Here, we investigated three different treatment ways of CB and FE. It was interesting that post-treatment of CB and FE (restoring way) showed similar effect to the preventive way, while attenuating way did not show any protective effect. We found that low dose CB and FE increased transcriptional factor NF-E2-related factor 2 (Nrf2)/hemo oxygenase 1 (HO-1) protein expression and decreased Kelch-like ECH-associated protein 1 (Keap1) in PC 12 cells. In addition, CB and FE promoted the translation of Nrf2 into nuclear and enhanced the activity of superoxide dismutase (SOD)/catalase, which confirmed cytoprotection against Aß25-35-induced oxidative damage. Moreover, CB and FE could increase Bcl-2 expression level, decrease the level of Bax and Cyt-c in Aß25-35-treated PC12 cells. Ultimately, the neuroprotective effect of CB and FE provides a pharmacological basis for its clinical use in prevention and treatment of AD.

Enhanced Liver Targeting of Camptothecin via Conjugation with Deoxycholic Acid.

Camptothecin (CPT) shows potent anticancer activity through inhibition of topoisomerase I. However, its water insolubility and severe toxicity limit its clinical application. Coupling with bile acid moieties is a promising method for liver-targeted drug delivery, which takes advantage of the bile acid receptors on hepatocytes. In this study, we evaluated the potential liver targeting and stability of a deoxycholic acid-CPT conjugate (G2). The competitive inhibition of antitumor activity experiment based on bile acid transporters was performed using the MTT method. The effects of deoxycholic acid on uptake of G2 and CPT were assessed in 2D and 3D HepG2 cell models. The stability of G2 and CPT was evaluated in vitro (in simulated gastric fluid, simulated intestinal fluid, and fresh rat plasma). Finally, biodistribution of G2 and CPT was investigated in Kunming mice following oral administration. The results showed that deoxycholic acid pretreatment could significantly reduce the antitumor activity and cellular uptake of G2 in HepG2 cells, but had no distinct effects on CPT. Meanwhile, G2 exhibited better stability compared with CPT. More importantly, biodistribution study in mice demonstrated that the liver targeting index of G2 increased 1.67-fold than that of CPT. Overall, the study suggests that conjugation with deoxycholic acid is a feasible method to achieve liver targeting delivery of CPT.

Microwave-Assisted Degradation of Polysaccharide from Polygonatum sibiricum and Antioxidant Activity.

Four polysaccharide fractions (P-1: 71.40%, P-2: 1.95%, P-3: 1.14%, P-4: 1.64%) were isolated from crude Polygonatum sibiricum polysaccharide (PSP), processed by water extraction, ethanol precipitation, and further separated with diethylaminoethyl cellulose-52 anion-exchange chromatography. Their molecular weights and monosaccharide compositions were characterized by high performance gel chromatography with evaporative light scattering detector and ultraviolet-visible detector. The antioxidant activity of four polysaccharides fractions were assessed by the electron transfer menchanism (DPPH, ferric reducing power, and ABST assays) and chelation of transition metals (Fe2+ and Cu2+ chelation ability). The highest content fraction P-1 exhibited the lowest antioxidant activity, and the ranking of antioxidant capacity was P-4 > P-3 > P-2 > PSP > P-1. After processed by microwave-assisted degradation, the molecular weight of P-1 was decreased from 2.99 × 105 to 2.33 × 103 Da, while the antioxidant activity of degraded P-1 was about eightfold higher than natural P-1. These results indicated that the proposed microwave-assisted degradation approach was an efficacious methodology to improve their bioactivity by lower the molecular weight of polysaccharides. PRACTICAL APPLICATION: This study provided an environmentally friendly, convenient and efficient microwave-assisted degradation technology to process the neutral polysaccharides from Polygonatum sibiricum. The results could be used for the development and utilization of various plant polysaccharides as a kind of food supplement in our daily life.

Study on the degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chloro-phenoxyacetic sodium (MCPA sodium) in natural agriculture-soils of Fuzhou, China using capillary electrophoresis.

A new method of analyzing trace 2,4-Dichlorophenoxyacetic acid (2,4-D) and 2-methy-4-chloro-lphenoxyacetic sodium (MCPA sodium) in soils by capillary electrophoresis (CE) has been developed in this study. The optimum analytical conditions including chemical component and concentration of buffer solution, pH, separation voltage and sample injection time were studied in detail. Under the optimum conditions, 2,4-D and MCPA sodium in soils can be speedy separated and determined within 20 min with detection limits of 0.15 microg/g (2,4-D) and 0.25 microg/g (MCPA sodium) , a RSD (n=6)<5% and a recovery>89%. With the help of analytical method developed in this study, the degradations of 2,4-D and MCPA sodium in natural agriculture-soils of Fuzhou were studied. The experimental results indicated that the degradations of 2,4-D and MCPA sodium follow first-order kinetics with degradation constants of 0.1509 day(-1) (2,4-D) and 0.2722 day(-1) (MCPA sodium) respectively. The degradation half-life were calculated to be 4.6 days (2,4-D) and 2.6 days (MCPA sodium) at 27 degrees C, implied that 2,4-D and MCPA sodium can be speedy degraded in natural agriculture-soils of Fuzhou, China.