Unveiling the therapeutic potential of Dl-3-n-butylphthalide in NTG-induced migraine mouse: activating the Nrf2 pathway to alleviate oxidative stress and neuroinflammation.

BACKGROUND: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated. METHODS: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1ß, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C. RESULTS: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2. CONCLUSIONS: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.

Atezolizumab Plus Bevacizumab Combined with Transarterial Embolization Plus Hepatic Arterial Infusion Chemotherapy for Unresectable Hepatocellular Carcinoma with a Diameter >8 Cm: A Retrospective Study.

Purpose: Local in combination with systemic therapy might be an option for patients with advanced unresectable hepatocellular carcinoma (uHCC). This study examined the clinical benefits and adverse events (AEs) of first-line transarterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC) combined with atezolizumab (Atezo) and bevacizumab (Bev) in patients with uHCC of a diameter larger than 8 cm. Patients and methods: This retrospective study included patients with uHCC of a diameter larger than 8 cm who were treated with first-line Atezo-Bev and TAE+HAIC at the First Affiliated Hospital of Sun Yat-Sen University between September 30, 2019, and September 30, 2022. Progression-free survival (PFS), overall survival (OS), tumor response according to mRECIST, and AEs were analyzed. Multivariable Cox analyses were performed to examine the factors associated with PFS. Results: Thirty patients were included. The objective response rate (ORR) was 74.4% (95% confidence interval [CI], 59.3%-89.5%), and the disease control rate (DCR) was 93.3% (95% CI, 85.4%-98.6%). The median follow-up was 11.4 (inter-quartile range [IQR], 5.5-17.9) months. The median PFS was 6.8 (95% CI, 2.6-11.1) months. The 3-, 6-, 9-, and 12-month survival rates were 86.2%, 82.5%, 68.6%, and 60%, respectively. The median OS was not estimated. Extrahepatic metastasis was independently associated with PFS (hazard ratio [HR]=3.468, 95% CI, 1.001-12.023). The most common AEs were fever (46.7%). Grade 4 AEs occurred one time as hematemesis but no 5 AEs were observed. Conclusion: Atezo-Bev combined with TAE and HAIC might benefit patients with uHCC of a diameter larger than 8 cm, with manageable AEs.

Submersed macrophytes Vallisneria natans and Vallisneria spinulosa improve water quality and affect microbial communities in sediment and water columns.

Healthy aquatic ecosystems are essential for human beings. However, anthropogenic activities severely worsen water quality. In this study, using assembling mesocosms, we developed an efficient and easy-to-handle method to monitor the water quality by measuring the electrical conductivity (EC) of water. Our data demonstrate that the growth of two submersed macrophytes, Vallisnerianatans and Vallisneria spinulosa, improves water quality by decreasing EC. Furthermore, using high-throughput DNA sequencing, we analyzed the microbial community abundance and structure in sediment and water columns with or without plant growth. We generated 33,775 amplicon sequence variants from 69 samples of four sediment groups (BkM, CtM, VnR, and VsR) and three water column sample groups (CtW, VnW, and VsW). The results show that the relative abundance of bacteria was higher in the sediment than in the water column. Moreover, the diversity and composition of microbiomes were altered by Vallisneria spp. growth, and the α-diversity of the microbial communities decreased due to submersed macrophytes in both the sediment and water columns. The ß-diversity of the microbial communities also varied significantly with or without Vallisneria spp. growth for both the sediment and water columns.

Anlotinib combined with transarterial chemoembolization for unresectable hepatocellular carcinoma associated with hepatitis B virus: a retrospective controlled study.

Purpose: To investigate the efficacy and safety of combined treatment of anlotinib and transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (uHCC) associated with hepatitis B virus (HBV) infection. Methods: We retrospectively collected the data of 96 uHCC patients associated with HBV infection who received either TACE only (TO group; n = 64) or anlotinib combined with TACE (TA group; n = 32) from January 2017 to January 2021. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST 1.1, and adverse events (AEs). Results: The median OS and median PFS were significantly longer in the TA group compared to the TO group (17.6 months vs. 9.4 months, p = 0.018; 6.7 months vs. 3.8 months, p = 0.003, respectively). In addition, the overall objective response rate (ORR) and disease control rate (DCR) numerically increased in the TA group (mRECIST, ORR 65.6% vs. 46.9%, p = 0.064, DCR 90.6% vs. 85.9%, p = 0.382; RECIST 1.1, ORR 46.9% vs. 15.6%, p = 0.001, DCR 90.6% vs. 85.9%, p = 0.382, respectively). It was worth noting that no treatment-related mortality occurred during the study. The most common AEs included elevated transaminases (56.3%), decreased appetite (46.9%), and abdominal pain (37.5%) in the TA group. Although the incidence rate of grade 3/4 AEs was higher in the TA group, all of them were controllable. Conclusions: The combination of anlotinib and TACE has shown promising results in improving outcomes for patients with HBV-related uHCC, as compared to TACE monotherapy. In addition, this combination therapy has demonstrated a controllable safety profile. However, further validation is urgently needed through randomized controlled trials with large sample sizes.

Hydrological isolation affected the chemo-diversity of dissolved organic matter in a large river-connected lake (Poyang Lake, China).

The transportation processes during aquatic systems regulate the ultimate chemistry of dissolved organic matter (DOM), and in recent years, climate changes and human activities have altered the hydrological patterns of many rivers and lakes, which generated some severe issues, such as hydrological isolation. However, how hydrological isolation affects variations of DOM chemistry in large lake systems is still poorly understood. Here, optical properties and molecular compositions of DOM samples derived from a large river-connected lake (Poyang Lake, China) and its nearby seasonal sub-lakes (formed by hydrological isolation) were characterized using Fourier transform ion cyclotron resonance mass spectrometry (FT ICR MS) and ultraviolet-visible (UV-Vis) spectroscopy. The results revealed more abundance of organic matter in sub-lakes than that in the main lake according to high dissolved organic carbon (DOC) concentrations and absorption coefficients (a254 and a280). Large proportions of CHOS formulas were identified by FT ICR MS in sub-lakes DOM, which were produced through Kraft reactions (sulfide/bisulfide + lignin CHO → CHOS) in the interface of sediment/water, and greatly contributed to aliphatic compounds. In addition, obvious variations of compounds (such as polyphenols, highly unsaturated and aliphatic compounds) and lability of DOM were observed between sub-lakes and main lakes, which were mainly caused by the different degradation pathways of DOM (photodegradation in sub-lakes while biodegradation in the main lake). Our results demonstrated that hydrological isolation has significant impacts on DOM chemistry, and provides an improved understanding of the DOM biogeochemistry process in Poyang Lake and supports the management of the large lake systems.

Short-term responses of soil nutrients, heavy metals and microbial community to partial substitution of chemical fertilizer with spent mushroom substrates (SMS).

Currently, many spent mushroom substrates (SMS) are produced each year, which have the great potential to replace partial chemical fertilizer in agricultural production due to the high content of organic matter in SMS. However, how the replacement of chemical fertilizer by different SMS affected soil nutrients and contamination was less reported. Therefore, this study applied Enoki mushroom substrates (EMR), Agaricus bisporus substrates (ABR), or Auricularia auricula substrates (AAR) to replace 25 % chemical fertilizers (based on N fertilizer) with understanding the role of SMS replacement in affecting soil nutrients, heavy metals, and microbial community via the short-term field study, respectively. Compared to chemical fertilizer (CF), the contents of organic matter (OM), total P (TP), and K (TK) in SMS replaced soils were significantly increased by 1.96-4.22, 0.08-0.12, and 0.03-0.53 g kg-1, respectively. Among three SMS replacements, AAR demonstrated the highest increment of soil nutrients. On the other hand, EMR and ABR replacements reduced the contents of total and acid-soluble Cd, Pb, and As by 7.94-30.32 % and 0-31.61 % in soils relative to CF, respectively. Unlike EMR and ABR, AAR reduced 11.08-16.04 % of total Cd, Pb, and As but increased 62.58 % acid-soluble As in soils. Furthermore, it was found that all SMS replacements increased the relative abundance of Proteobacteria, while ABR also increased the relative abundance of Actinobacteria in soils compared to CF. Besides, EMR and ABR replacements increased the relative abundance of Mortierellomycota relative to CF. Finally, it can be known that partial replacement of chemical fertilizer by SMS could elevate soil nutrients (especially AAR) and reduce heavy metals (especially EMR), which further improved microbial diversity and community composition. This study provides information on applying SMS to replace partial chemical fertilizer to elevate nutrients and reduce heavy metals contamination.

Establishing an in vitro model of MR-T1ρ imaging technology to quantify nucleus pulposus tissue proteoglycans: a preliminary study.

BACKGROUND: The aim of the present study was to construct an in vitro model of degenerated nucleus pulposus with different combinations of biochemical components, and to find an in vitro model for the early degeneration of nucleus pulposus suitable for the detection of magnetic resonance T1rho (MR-T1ρ) sequence for the early diagnosis of degeneration of lumbar intervertebral disc. METHODS: The proteoglycan concentration gradient in the first experimental group was 5%, with a concentration range of 7 samples in vitro models from 5% to 35%. The second experimental group had 15 samples with a 1% concentration gradient of proteoglycan (range, 10-24%), with a higher water content compared with the first group. The third experimental group contained 20 samples with a concentration gradient of 1% proteoglycan (range, 10-29%), with 75% water content. All of the in vitro models were scanned using a 3.0T GE MR. To analyze the correlation between the proteoglycan content of the in vitro model and the T1ρ value, we investigated the feasibility and stability of modeling. RESULTS: There was no correlation between the in vitro model proteoglycan concentration and T1ρ value in the first experimental group; however, there was a significant negative correlation between the proteoglycan concentration and T1ρ value in the second experimental group (Y=-3.02X+131.8, R2=0.852, P<0.05). In the third experimental group, the proteoglycan concentration was significantly positively correlated with T1ρ value (Y=3.05X+11.99, R2=0.834, P<0.05). The comparison of the T1ρ values in the third experimental group before and 3 months after yielded an intraclass correlation coefficient value of 0.980, indicating that the biochemical components in the third experimental group were still stable after 3 months of storage. The slope of the regression equation between the Pfirrmann grading and T1ρ value in the third experimental group was not statistically different from the volunteer group (F=0.54, P=0.814), suggesting that the lumbar disc nucleus pulposus tissue of in vitro model samples fitted well with the volunteer group. CONCLUSIONS: In this experiment, we successfully constructed an in vitro model of nucleus pulposus tissue proteoglycan that can be used for the quantitative evaluation of the MR-T1ρ imaging.