LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric α-synuclein through NF-κB pathway.

Parkinson's disease (PD) is characterized by the irreversible loss of dopaminergic neurons and the accumulation of α-synuclein in Lewy bodies. The oligomeric α-synuclein (O-αS) is the most toxic form of α-synuclein species, and it has been reported to be a robust inflammatory mediator. Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are also genetically linked to PD and neuroinflammation. However, how O-αS and LRRK2 interact in glial cells remains unclear. Here, we reported that LRRK2 G2019S mutation, which is one of the most frequent causes of familial PD, enhanced the effects of O-αS on astrocytes both in vivo and in vitro. Meanwhile, inhibition of LRRK2 kinase activity could relieve the inflammatory effects of both LRRK2 G2019S and O-αS. We also demonstrated that nuclear factor κB (NF-κB) pathway might be involved in the neuroinflammatory responses. These findings revealed that inhibition of LRRK2 kinase activity may be a viable strategy for suppressing neuroinflammation in PD.

[Response Characteristics of Soil Organic Carbon Pool and Its Chemical Composition During Secondary Forest Succession in the Loess Plateau].

In order to explore the characteristics of the soil organic carbon(SOC)pool and its chemical composition during the succession of secondary forests in the Loess Plateau, samples of the primary stage (Populus davidiana forest), transition stage (Populus davidiana and Quercus wutaishansea mixed forest), and top stage (Quercus wutaishansea forest) of secondary forest succession in the Huanglong Mountain forest area of the Loess Plateau in Northern Shaanxi were selected as the research object. The variation characteristics of SOC content, storage, and its chemical composition at different soil depths (0-10, 10-20, 20-30, 30-50, and 50-100 cm) were analyzed. The results showed that:① the contents and storage of SOC increased significantly with the secondary forest succession process (P<0.05). The content of SOC decreased significantly with the increase in soil depth, and the storage of SOC increased from 64.8 Mg·hm-2 in the primary stage to 129.2 Mg·hm-2 in the top stage, with an increase of 99%. ② During the succession of secondary forests, in the surface (0-30 cm) soil organic carbon, the relative content of aliphatic carbon components that have a simple structure and can be decomposed more easily decreased, and the relative content of aromatic carbon components that have a complex structure and cannot be decomposed easily increased, indicating that the chemical composition of organic carbon stability of surface-layer soil increased significantly with the process of secondary forest succession. However, the stability of the chemical composition of SOC in the deep layer (30-100 cm) first increased and then decreased, that is, the transition stage>the top stage>the primary stage. ③In the process of secondary forest succession, the stability of SOC chemical composition in the primary stage and transition stage increased significantly with the increase in soil depth. The top stage tended to be stable, and the deep soil carbon stability decreased slightly. ④ Pearson correlation analysis showed that during the secondary forest succession process, SOC storage and chemical composition stability were significantly negatively correlated with soil total phosphorus content. In general, the content and storage of SOC in the 0-100 cm soil increased significantly during the secondary forest succession, playing the role of a "carbon sink." The stability of the chemical composition of SOC in the surface layer (0-30 cm) increased significantly, but in the deep layer (30-100 cm), it increased first and then decreased.

Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice.

Introduction: Paclitaxel is a chemotherapy drug that is commonly used to treat cancer, but it can cause paclitaxel-induced neuropathic pain (PINP) as a side effect. Resolvin D1 (RvD1) has been shown to be effective in promoting the resolution of inflammation and chronic pain. In this study, we evaluated the effects of RvD1 on PINP and its underlying mechanisms in mice. Methods: Behavioral analysis was used to assess the establishment of the PINP mouse model and to test the effects of RvD1 or other formulations on mouse pain behavior. Quantitative real-time polymerase chain reaction analysis was employed to detect the impact of RvD1 on 12/15 Lox, FPR2, and neuroinflammation in PTX-induced DRG neurons. Western blot analysis was used to examine the effects of RvD1 on FPR2, Nrf2, and HO-1 expression in DRG induced by PTX. TUNEL staining was used to detect the apoptosis of DRG neurons induced by BMDM conditioned medium. H2DCF-DA staining was used to detect the reactive oxygen species level of DRG neurons in the presence of PTX or RvD1+PTX treated BMDMs CM. Results: Expression of 12/15-Lox was decreased in the sciatic nerve and DRG of mice with PINP, suggesting a potential involvement of RvD1 in the resolution of PINP. Intraperitoneal injection of RvD1 promoted pain resolution of PINP in mice. Intrathecal injection of PTX-treated BMDMs induced mechanical pain hypersensitivity in naïve mice, while pretreatment of RvD1 in BMDMs prevented it. Macrophage infiltration increased in the DRGs of PINP mice, but it was not affected by RvD1 treatment. RvD1 increased IL-10 expression in the DRGs and macrophages, while IL-10 neutralizing antibody abolished the analgesic effect of RvD1 on PINP. The effects of RvD1 in promoting IL-10 production were also inhibited by N-formyl peptide receptor 2 (FPR2) antagonist. The primary cultured DRG neurons apoptosis increased after stimulation with condition medium of PTX-treated BMDMs, but decreased after pretreatment with RvD1 in BMDMs. Finally, Nrf2-HO1 signaling was additionally activated in DRG neurons after stimulation with condition medium of RvD1+PTX-treated BMDMs, but these effects were abolished by FPR2 blocker or IL-10 neutralizing antibody. Discussion: In conclusion, this study provides evidence that RvD1 may be a potential therapeutic strategy for the clinical treatment of PINP. RvD1/FPR2 upregulates IL-10 in macrophages under PINP condition, and then IL-10 activates the Nrf2- HO1 pathway in DRG neurons, relieve neuronal damage and PINP.

Cf/SiC Ceramic Matrix Composites with Extraordinary Thermomechanical Properties up to 2000 °C.

The thermomechanical properties of carbon fiber reinforced silicon carbide ceramic matrix composites (Cf/SiC CMCs) were studied up to 2000 °C using high-temperature in situ flexural testing in argon. The CMC specimens were fabricated using an ultrahigh concentration (66 vol%) aqueous slurry containing nano-sized silicon carbide powder. The SiC powder compacts were obtained by drying the slurry and were densified using the precursor impregnation and pyrolysis (PIP) method with field assisted sintering technology/spark plasma sintering (FAST/SPS). The high relative density of the SiC green body (77.6%) enabled densification within 2.5 days using four PIP cycles. In contrast, conventional PIP processes take over 7 days. The in situ flexural strength of the Cf/SiC CMC was 434 MPa at 1750 °C, which was 84% higher than the room temperature value. The value further increased to 542 MPa at 2000 °C. Possible mechanisms to explain the excellent strength of the CMC at elevated temperatures are discussed.

Entropy Landscaping of High-Entropy Carbides.

The entropy landscape of high-entropy carbides can be used to understand and predict their structure, properties, and stability. Using first principles calculations, the individual and temperature-dependent contributions of vibrational, electronic, and configurational entropies are analyzed, and compare them qualitatively to the enthalpies of mixing. As an experimental complement, high-entropy carbide thin films are synthesized with high power impulse magnetron sputtering to assess structure and properties. All compositions can be stabilized in the single-phase state despite finite positive, and in some cases substantial, enthalpies of mixing. Density functional theory calculations reveal that configurational entropy dominates the free energy landscape and compensates for the enthalpic penalty, whereas the vibrational and electronic entropies offer negligible contributions. The calculations predict that in many compositions, the single-phase state becomes stable at extremely high temperatures (>3000 K). Consequently, rapid quenching rates are needed to preserve solubility at room temperature and facilitate physical characterization. Physical vapor deposition provides this experimental validation opportunity. The computation/experimental data set generated in this work identifies "valence electron concentration" as an effective descriptor to predict structural and thermodynamic properties of multicomponent carbides and educate new formulation selections.

Thioredoxin-Interacting Protein (TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson's Disease and Diabetes.

Patients with diabetes mellitus have a higher risk of developing Parkinson's disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.

X-ray induces mechanical and heat allodynia in mouse via TRPA1 and TRPV1 activation.

Radiotherapy-related pain is a common adverse reaction with a high incidence among cancer patients undergoing radiotherapy and remarkably reduces the quality of life. However, the mechanisms of ionizing radiation-induced pain are largely unknown. In this study, mice were treated with 20 Gy X-ray to establish ionizing radiation-induced pain model. X-ray evoked a prolonged mechanical, heat, and cold allodynia in mice. Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 were significantly upregulated in lumbar dorsal root ganglion. The mechanical and heat allodynia could be transiently reverted by intrathecal injection of transient receptor potential vanilloid 1 antagonist capsazepine and transient receptor potential ankyrin 1 antagonist HC-030031. Additionally, the phosphorylated extracellular regulated protein kinases (ERK) and Jun NH2-terminal Kinase (JNK) in pain neural pathway were induced by X-ray treatment. Our findings indicated that activation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 is essential for the development of X-ray-induced allodynia. Furthermore, our findings suggest that targeting on transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 may be promising prevention strategies for X-ray-induced allodynia in clinical practice.

[Effect of Acupuncture Combined with Rehabilitation on Immune and Neural Functions in Elderly Patients with Stroke].

OBJECTIVE: To investigate the therapeutic effect of acupuncture combined with rehabilitation and neuro-immune functional activities in elderly patients with stroke. METHODS: A total of 196 elderly stroke patients were randomly divided into control (rehabilitation exercise) and observation(acupuncture＋ rehabilitation exercise)groups (n＝98 in each). Patients of the control group were treated by general healing treatment including good limb placement, timely conversion of body position, joint-motor exercise, sitting balance exercise, sitting-standing-walking, walking up and down stairs, daily life ability exercise, etc. and those of the observation group were treated by using the same methods mentioned in the control group and manual acupuncture stimulation of Sishencong (EX-HN 1), Xuanli (GB 6), the midpoint of EX-HN 1 and GB 6, Baihui (GV 20), Qubin (GB 7), and the midpoint between GV 20 and GB 7 on the affected side (once a day for three 10-day courses). Serum interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitive C-reactive protein (hs-CRP) contents were assayed using ELISA, and serum CD 3＋， CD 4＋ and CD 8＋ contents assayed using flow cytometry. The disability severity was assessed by using National Institutes of Health Stroke Scale (NIHSS, for dysneuria), modified Rankin Scale，(mRS, stroke severity), and Barthel Index (BI, performance in activities of daily living), separately. The therapeutic effect was determined according to NIHSS score, clinical symptoms and daily activity ability. RESULTS: On day 30 after the treatment, serum IL-2, IL-6, TNF-α and hs-CRP contents were significantly decreased in the observation group in comparison with its own pre-treatment and day 10 after the treatment, and on day 10 and 30 after the treatment, the above were lower than the control group (P<0.05). On day 30 after the treatment, serum CD 3＋， CD 4＋ and CD 4＋/CD 8＋ levels were significantly increased in both control and observation groups in comparison with their own pre-treatment and 10 days' treatment (P<0.05), while CD 8＋ levels obviously decreased in both groups relevant to their own pre-treatment and 10 days' treatment (P<0.05), and the increased CD 3＋， CD 4＋ and CD 4＋/CD 8＋ levels were significant higher in the observation group than in the control group (P<0.05), and the CD 8＋ level was obviously lower in the control group than in the observation group (P<0.05). On day 30 after the treatment, the NIHSS and mRS scores were significantly decreased in both groups (P<0.05), and significantly lower in the observation group than in the control group (P<0.05); the BI scores were evidently increased in both groups relevant to their own pre-treatment (P<0.05), and the BI level was considerably higher in the observation group than in the control group (P<0.05). The total effective rate was 72.4% (71/98) and 93.9% (92/98) respectively in the control and observation groups, being obviously higher in the latter group than in the former (P<0.05). CONCLUSION: Acupuncture combined with rehabilitation therapy is effective in promoting the recovery of neurological function and in regulating T lymphocyte subsets and the expression of inflammatory factors in elderly patients with stroke.

[Steroidal Glycoside Constituents from Solanum cumingii].

OBJECTIVE: To investigate the steroidal glycoside constituents of Solanum cumingii. METHODS: The compounds were isolated by silica gel, Sephadex LH-20, RP-C18 column and Pre-HPLC chromatography. Their structures were identified by ESI-MS and NMR. RESULTS: Six known compounds including torvoside K (1), torvoside J (2), torvoside L (3), khasianine (4), aculeatiside A (5) and solamargine (6) were isolated from Solanum cumingii. CONCLUSION: All compounds are isolated from Solanum cumingii for the first time.

High hydrostatic pressure inactivation of total aerobic bacteria, lactic acid bacteria, yeasts in sour Chinese cabbage.

This study investigated the inactivation of total aerobic bacteria (TAB), lactic acid bacteria (LAB), yeasts in sour Chinese cabbage (SCC) treated by high hydrostatic pressure (HHP). The pressure level ranged from 200 to 600 MPa and the treatment time were 10-30 min. All samples were stored at 4, 27 and 37 degrees C for 90 days. The pressure level of 200 MPa had no significant impact on these microorganisms. The counts of TAB were significantly reduced by 2.7-4.0 log(10)CFU/g at 400 MPa and 4.2-4.5 log(10)CFU/g at 600 MPa from 6.2 log(10)CFU/g; the counts of LAB were also reduced by 2.4-4.3 log(10)CFU/g at 400 MPa from 7.0 log(10)CFU/g and LAB was completely inactivated at 600 MPa; the counts of yeasts were reduced by 1.5-2.0 log(10)CFU/g at 400 and 600 MPa from 4.2 log(10)CFU/g. Storage temperatures significantly influenced the microbial proliferation in HHP-treated SCC depending on the pressure levels. The surviving TAB and LAB at 400 MPa equaled initial counts after 15-day storage at 27 and 37 degrees C, whereas they were inhibited at 4 degrees C up to 60 days. The surviving TAB at 600 MPa did not grow. Yeasts at 400 and 600 MPa decreased below detectable level after 2 days at all the three storage temperatures. From the microbial safety point of view, the result indicated that HHP at 600 MPa could be used as an alternative preservation method for SCC.

Simultaneous quantitation of three major triterpenoid glycosides in Centella asiatica extracts by high performance liquid chromatography with evaporative light scattering detection.

A high-performance liquid chromatography method with evaporative light scattering detection was established for simultaneous determination of three major triterpenoid glycosides, i.e. asiaticoside, madecassoside and asiaticoside-B, in Centella asiatica extracts. The optimal chromatographic conditions were achieved on a COSMOSIL 5C(18)-MS-II column by constant elution with water (0.01% trifluoroacetic acid, v/v) and acetonitrile (1.0% methyl tert-butyl ether, 0.01% trifluoroacetic acid, v/v) (78:22) as mobile phase at a flow rate of 1.0 mL/min; the column temperature was 30 degrees C. The evaporative light scattering detector was set at an evaporating temperature of 40 degrees C and nitrogen gas pressure of 3.5 bar. The validation of the method included tests of linearity, sensitivity, precision, repeatability, stability and accuracy. All calibration curves showed good linear regression (r(2) > 0.9993) within test ranges. The established method showed good precision and accuracy with overall intra-day and inter-day variations of 1.73-3.06 and 3.89%-4.92%, respectively, and overall recoveries of 97.63-99.39% for the three compounds analyzed. The method developed was successfully applied to quantify the main triterpenoid glycosides in Centella asiatica extracts from different companies.

[In vitro experiment of inhibiting cell proliferation on human esophageal squamous cell cancer T. Tn cell line by proliferating cell nuclear antigen antisense oligodeoxynucleotide].

BACKGROUND & OBJECTIVES: The high expression of proliferation cell nuclear antigen were found in the patients with esophageal carcinoma in poor prognosis. The aim of this study was to investigate the effect in vitro of antisense oligodeoxynucleotide (ASODN) of PCNA on its gene expression and cell proliferation in human esophageal squamous cell cancer T. Tn cell line. METHODS: Phosphorothioate PCNA ASODN and sense oligodeoxynucleotide (SODN) were synthesized and transfected to T. Tn cells mediated by dosper liposomal. Their effects on cell proliferation were examined by MTT method, 3H-TdR method, immunohistochemical study, and flow cytometer (FCM). RESULTS: PCNA ASODN could significantly inhibit the growth of T. Tn cell lines. The SODN and control lipsome showed no such effect. The inhibition peaked at 24 hour after transfection, the inhibition rate reached 63.3% at 0.2 mumol/L by MTT method, the inhibition effect was dose-dependent. ASODN could downregulate the expression levels of PCNA protein. And PCNA ASODN transfection could inhibit the transition period of G0/G1 phase to S phase. CONCLUSIONS: The data suggested that ASODN could specific inhibit the expression of PCNA protein and regulate cell cycle and cell proliferation in T. Tn cells and antisense therapy could be an useful method to improve prognosis in ESCC.