HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis.

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

Evolution Law of Structural Form and Heat Transfer Performance of Thermal Insulation System.

Building thermal insulation and energy conservation have become urgent problems in the field of civil engineering because they are important for achieving the goal of carbon neutralization. Thermal conductivity is an important index for evaluating the thermal insulation of materials. To study the influence of different porosity levels on the thermal conductivity of materials, this paper established a random distribution model using MATLAB and conducted a comparative analysis using COMSOL finite element software and classical theoretical numerical calculation formulas. The thermal conductivity of composite materials was determined based on a theoretical calculation formula and COMSOL software simulations, and the theoretical calculation results and simulation results were compared with the measured thermal conductivity of the composites. Furthermore, the influence of the width of the gaps between the materials on the heat transfer process was simulated in the fabricated roof structure. The results showed the following: (1) The thermal conductivity values calculated using the Zimmerman model were quite different from those calculated using the Campbell-Allen model and those calculated using the COMSOL software; (2) The thermal conductivity values calculated using the theoretical calculation formula were lower than the measured data, and the maximum relative error was more than 29%. The COMSOL simulation results were in good agreement with the measured data, and the relative error was less than 5%; (3) When the gap width was less than 60 mm, it increased linearly with the heat transfer coefficient. The heat transfer coefficient increased slowly when the gap width was greater than 60 mm. This was mainly due to the thermal bridge effect inside the insulation system. Based on these research results, a thermal insulation system was prepared in a factory.

Linear Regression Analysis of Sleep Quality in People with Insomnia in Wuhan City during the COVID-19 Pandemic.

Objective: COVID-19 has evolved into a major global public health event. The number of people reporting insomnia is growing exponentially during the pandemic. This study aimed to explore the relationship between aggravated insomnia and COVID-19-induced psychological impact on the public, lifestyle changes, and anxiety about the future. Methods: In this cross-sectional study, we used the questionnaires from 400 subjects who were obtained from the Department of Encephalopathy of the Wuhan Hospital of Traditional Chinese Medicine between July 2020 and July 2021. The data collected for the study included demographic characteristics of the participants and psychological scales consisting of the Spiegel Sleep Questionnaire, the Fear of COVID-19 Scale (FCV-19S), the Zung Self-Rating Anxiety Scale (SAS), and the Zung Self-Rating Depression Scale (SDS). The independent sample t-test and one-way ANOVA were used to compare the results. Correlation analysis of variables affecting insomnia was performed using Pearson correlation analysis. The degree of influence of the variables on insomnia was determined using linear regression, and a regression equation was derived. Results: A total of 400 insomnia patients participated in the survey. The median age was 45.75 ± 15.04 years. The average score of the Spiegel Sleep Questionnaire was 17.29 ± 6.36, that of SAS was 52.47 ± 10.39, that of SDS was 65.89 ± 8.72, and that of FCV-19S was 16.09 ± 6.81. The scores of FCV-19S, SAS, and SDS were closely related to insomnia, and the influencing degree was in the following order: fear, depression, and anxiety (OR = 1.30, 0.709, and 0.63, respectively). Conclusion: Fear of COVID-19 can be one of the primary contributors to worsening insomnia.

Intraocular pressure fluctuation and the risk of glaucomatous damage deterioration: a Meta-analysis.

AIM: To systematically review whether the increased fluctuation of intraocular pressure (IOP) is a risk factor for open angle glaucoma (OAG) progression. METHODS: Scientific studies relevant to IOP fluctuation and glaucoma progression were retrieved from MEDLINE, EMBASE and CENTRAL databases, and were listed as references in this paper. The hazard ratio (HR) was calculated by using fixed or random-effects models according to the heterogeneity of included studies. RESULTS: Individual data for 2211 eyes of 2637 OAG patients in fourteen prospective studies were included in this Meta-analysis. All studies were longitudinal clinical studies with follow-up period ranging from 3 to 8.5y. The combined HR was 1.23 (95%CI 1.04-1.46, P=0.02) for the association between IOP fluctuation and glaucoma onset or progression with the evidence of heterogeneity (P<0.1). Subgroup analyses with different types of IOP fluctuation were also evaluated. Results indicated that the summary HR was 0.98 (95%CI 0.78-1.24) in short-term IOP fluctuation group, which showed no statistical significance with heterogeneity, whereas, the combined HR was 1.43 (95%CI 1.13-1.82, P=0.003) in long-term IOP fluctuation group without homogeneity. Sensitivity analysis further showed that the pooled HR was 1.10 (95%CI 1.03-1.18, P=0.004) for long-term IOP fluctuation and visual function progression with homogeneity among studies (P=0.3). CONCLUSION: Long-term IOP fluctuation can be a risk factor for glaucoma progression based on the presented evidence. Thus, controlling the swing of IOP is crucial for glaucoma or glaucoma suspecting patients.

A systematic review of pharmacokinetic studies on herbal drug Fuzi: Implications for Fuzi as personalized medicine.

BACKGROUND: Fuzi, which is the processed lateral roots of Aconitum carmichaeli Debx. (Ranunculaceae), is a traditional herbal medicine that is well known for its excellent pharmacological effects and acute toxicity. Aconitum alkaloids are responsible for its pharmacological activity and toxicity. Although a large number of studies on Fuzi have been reported, no comprehensive review on its pharmacokinetics has yet been published. PURPOSE: This paper seeks to present a comprehensive review regarding the phytochemistry, pharmacokinetic features and toxicity of Fuzi. The regulation of drug-metabolizing enzymes (DMEs) and efflux transporters (ETs) by Fuzi is also concluded. Additionally, the use of Fuzi as a personalized medicine based on the bioavailability barrier (BB), which mainly comprises DMEs and ETs, is discussed. METHODS: All available information on Fuzi was collected by searching for key words in PubMed, ScienceDirect, CNKI, Google Scholar, Baidu Scholar, and Web of Science. RESULTS: Aconitum alkaloids, which mainly include diester-diterpene alkaloids (DDAs), monoester-diterpene alkaloids (MDAs) and unesterified-diterpene alkaloids (UDAs), could be detected after Fuzi ingestion in vivo. The Aconitum alkaloids are rapidly absorbed in the intestine and extensively distributed in the body. DMEs, especially CYP3A4/5, are responsible for various types of metabolic reactions of the Aconitum alkaloids. ETs, including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), are involved in the efflux of the DDAs and MDAs. The kidney is the most important organ involved in the excretion of the Aconitum alkaloids. DDAs are the main toxic compounds present in Fuzi, and their acute toxicity is mainly due to their effects on the voltage-dependent sodium channels. Furthermore, Fuzi can substantially regulate DMEs and ETs. CONCLUSIONS: The toxicity of DDAs is acute. However, further investigations are necessary to determine the exact toxicological mechanisms. The significant impact of Fuzi on DMEs and ETs suggests that the co-administration of Fuzi with drugs that are substrates of DMEs and/or ETs may cause herb-drug interactions (HDIs). The BB network controlled exposure to the Aconitum alkaloids in vivo. Polymorphisms of DMEs and ETs in different individuals contribute to the differences in the efficacy and toxicity of Fuzi ingestion. In the future, the use of Fuzi as personalized medicine based on the BB network is necessary and practical to achieve ideal therapeutic efficacy with minimal toxicity.

Aconitum alkaloids, the major components of Aconitum species, affect expression of multidrug resistance-associated protein 2 and breast cancer resistance protein by activating the Nrf2-mediated signalling pathway.

BACKGROUND: Aconitum alkaloids from Aconitum species are often used to treat arthritis and rheumatic diseases but have the drawback of high toxicity. Identifying their pharmacokinetic behaviour is important for the safe clinical application of Aconitum species. Efflux transporters (ETs), including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), have important functions in regulating the pharmacokinetic behaviours of drugs and in herb-herb or herb-drug interactions (HDIs). The Aconitum alkaloids regulate P-gp expression and function, but their effects on MRP2 and BCRP expression remain unknown. PURPOSE: To determine the effects of three Aconitum alkaloids, aconitine (AC), benzoylaconine (BAC), and aconine, on MRP2 and BCRP. METHODS: The levels of the protein and mRNA expression of MRP2 and BCRP in vivo and in vitro were measured via Western blotting and real-time PCR, respectively. Fluorescence signals of MRP2 and BCRP were detected via confocal fluorescence microscopy. A reporter assay using HepG2-C8 cells, which were generated by transfecting plasmids containing the antioxidant response element (ARE)-luciferin gene into HepG2 cells, was used to examine the ARE-luciferin activity. The transport activities of MRP2 and BCRP were tested via flow cytometry using substrate probes. RESULTS: The Aconitum alkaloids significantly up-regulated MRP2 and BCRP expression, accompanied by a marked increase in nuclear factor E2-related factor-2 (Nrf2) expression in the jejunum, ileum, and colon of FVB mice, in the order AC < BAC < aconine. In the in vitro model, the Aconitum alkaloids increased MRP2 and BCRP expression in Caco-2 and LS174T cells, in the order AC < BAC < aconine. Additionally, these alkaloids promoted the translocation of Nrf2 from the cytoplasm to the nucleus and significantly increased ARE-luciferin activity in HepG2-C8 cells. Luteolin, a potent inhibitor of Nrf2, markedly prevented MRP2 and BCRP expression from being induced by the three Aconitum alkaloids. The efflux activity of MRP2 was also significantly increased in cells receiving the same treatment. CONCLUSIONS: The tested Aconitum alkaloids significantly increased the expression of MRP2 and BCRP by activating the Nrf2-mediated signalling pathway and enhanced the efflux activity of MRP2. The potential for herb-herb interactions or HDIs exists when Aconitum species are co-administered with substrate drugs that are transported via MRP2 and BCRP. Therefore, the Aconitum alkaloids may be used as quality indicators for the herbs of Aconitum species.

ipRGCs: possible causation accounts for the higher prevalence of sleep disorders in glaucoma patients.

Sleep accounts for a third of one's lifetime, partial or complete deprivation of sleep could elicit sever disorders of body function. Previous studies have reported the higher prevalence of sleep disorders in glaucoma patients, but the definite mechanism for this phenomenon is unknown. On the other hand, it is well known by us that the intrinsically photosensitive retinal ganglion cells (ipRGCs) serve additional ocular functions, called non-image-forming (NIF) functions, in the regulation of circadian rhythm, melatonin secretion, sleep, mood and others. Specifically, ipRGCs can directly or indirectly innervate the central areas such as suprachiasmatic nucleus (SCN), downstream pineal gland (the origin of melatonin), sleep and wake-inducing centers and mood regulation areas, making NIF functions of ipRGCs relate to sleep. The more interesting thing is that previous research showed glaucoma not only affected visual functions such as the degeneration of classical retinal ganglion cells (RGCs), but also affected ipRGCs. Therefore, we hypothesize that higher prevalence of sleep disorders in glaucoma patients maybe result from the underlying glaucomatous injuries of ipRGCs leading to the abnormalities of diverse NIF functions corresponding to sleep.

Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication.

Cholesterol 25-hydroxylase (CH25H) catalyses the production of 25-hydroxycholesterol (25HC) from cholesterol by adding a second hydroxyl group at position 25. The aim of this study was to examine the antiviral effect of CH25H on pseudorabies virus (PRV), a swine pathogen that can cause devastating disease and economic losses worldwide. The results showed that porcine ch25h was induced by either interferon or PRV infection. PRV infection of porcine alveolar macrophages (3D4/21 cells) was attenuated by CH25H overexpression and enhanced by silencing of CH25H. Furthermore, treatment of 3D4/21 cells with 25HC inhibited the growth of PRV in vitro, suggesting that CH25H may restrict PRV replication by 25HC production. We further identified that the anti-PRV role of CH25H and 25HC was subject to their inhibitory effect on PRV attachment and entry. Collectively, these findings demonstrate that CH25H is an intrinsic host restriction factor in PRV infection of porcine alveolar macrophages.

SP600125 Attenuates Nicotine-Related Aortic Aneurysm Formation by Inhibiting Matrix Metalloproteinase Production and CC Chemokine-Mediated Macrophage Migration.

Nicotine, a major chemical component of cigarettes, plays a pivotal role in the development of abdominal aortic aneurysm (AAA). c-Jun N-terminal kinase (JNK) has been demonstrated to participate in elastase-induced AAA. This study aimed to elucidate whether the JNK inhibitor SP600125 can attenuate nicotine plus angiotensin II- (AngII-) induced AAA formation and to assess the underlying molecular mechanisms. SP600125 significantly attenuated nicotine plus AngII-induced AAA formation. The expression of matrix metalloproteinase- (MMP-) 2, MMP-9, monocyte chemoattractant protein- (MCP-) 1, and regulated-on-activation, normal T-cells expressed and secreted (RANTES) was significantly upregulated in aortic aneurysm lesions but inhibited by SP600125. In vitro, nicotine induced the expression of MCP-1 and RANTES in both RAW264.7 (mouse macrophage) and MOVAS (mouse vascular smooth muscle) cells in a dose-dependent manner; expression was upregulated by 0.5 ng/mL nicotine but strongly downregulated by 500 ng/mL nicotine. SP600125 attenuated the upregulation of MCP-1 and RANTES expression and subsequent macrophage migration. In conclusion, SP600125 attenuates nicotine plus AngII-induced AAA formation likely by inhibiting MMP-2, MMP-9, MCP-1, and RANTES. The expression of chemokines in MOVAS cells induced by nicotine has an effect on RAW264.7 migration, which is likely to contribute to the development of nicotine-related AAA.

Nicotine-induced upregulation of VCAM-1, MMP-2, and MMP-9 through the α7-nAChR-JNK pathway in RAW264.7 and MOVAS cells.

The ability of nicotine to induce aortic aneurysms has been shown in animal models; however, its underlying mechanisms remain elusive. In the present experiment, both the RAW264.7 and MOVAS cell lines were employed to examine the nicotine-induced modulation of VCAM-1, MMP-2, and MMP-9 expressions in macrophages and vascular smooth muscle cells. Our results showed that nicotine concentrations of both 0.5 and 5 ng/ml induced VCAM-1, MMP-2, and MMP-9 upregulation, while a concentration of 50 ng/ml had a slight inhibitory effect and a concentration of 500 ng/ml showed a significant inhibitory effect. When cells were pretreated with either SP600125 (JNK inhibitor) or PNU-282987 (α7-nAChR agonist) prior to nicotine exposure, the nicotine-induced upregulation of VCAM-1, MMP-2, MMP-9, and p-JNK was suppressed, with a joint treatment producing a more significant inhibitory effect. Moreover, PNU-282987 had a comparable inhibitory effect on VCAM-1, MMP-2, and MMP-9 expressions and JNK activation via phosphorylation as did SP600125. In conclusion, nicotine-induced VCAM-1, MMP-2, and MMP-9 expressions occur in a dose-dependent fashion in both of the cell lines tested. Furthermore, the nicotine exposure equivalent to plasma levels found in regular smokers can augment VCAM-1, MMP-2, and MMP-9 expressions through the α7-nAChR-JNK pathway.

The crosstalk between gut inflammation and gastrointestinal disorders during acute pancreatitis.

The intestinal inflammation caused by intestinal ischemia reperfusion during acute pancreatitis (AP) often leads to multiple organ dysfunction and aggravation of acute pancreatitis. This review concerns up-date progress of the pathophysiology and molecular mechanism of the excessive production of gut-derived cytokines. The regulation effects of immuno-neuro-endocrine network for pancreatic necrosis are the basis for pharmacological therapeutic in AP. The translation from basic research to clinical trials for the prevention or treatment of severe acute pancreatitis (SAP) is of great value. Early enteral nutrition is necessary for the restitution, proliferation, and differentiation of the intestinal epithelial cells adjacent to the wounded area. Clearance of the excess intestinal bacteria and supplement of probiotics may be helpful to prevent bacterial translocation and infection of pancreas.

[Comparative study on different anti-adhesion agents in preventing tubal obstruction after interventional recanalization.].

OBJECTIVE: To study the efficacy of different anti-adhesion agents used in preventing tubal obstruction after recanalization. METHODS: Five hundred and eight patients with tubal obstruction were divided into 245 cases in control group, 108 cases in chitosan group; 113 cases in sodium hyaluronate group and 42 cases in lipiodol group. The patients in control group were injected with anti-inflammation agents after recanalization, while other groups were injected with chitosan, sodium hyaluronate or lipiodol at dose of 2 - 3 ml in every therapeutic group. The rate of location of tubal obstruction and tubal recanalization were recorded during operation. Then patients in every group were followed up on tubal patency after 3 months, and pregnancy rate after 12 months. RESULTS: Among 1016 fallopian tubes in 508 patients, there were 330 tubes occlusion at isthmus portion and 563 tubes occlusion at interstitial portion of fallopian tube. Thirty-seven fallopian tubes were ablated because of ectopic pregnancy, 86 fallopian tubes were unobstructed. (1) The recanalization rate were 95.7% (179/187) in chitosan group, 97.9% (191/195) in sodium hyaluronate group, 98.7% (75/76) in lipiodol group and 97.7% (425/435) in control group, which did not show statistical difference (P > 0.05). (2) The rates of tubal patency after 3 months of 91.7% (99/108) in chitosan group and 88.5% (100/113) in sodium hyaluronate group were significantly higher than 71.4% (30/42) in lipiodol group and 74.3% (182/245) in control group (P < 0.05). (3) The rates of intrauterine pregnancy after 12 months were 48.1% (52/108) in chitosan group and 41.6% (47/113) in sodium hyaluronate group, which were significantly higher than 23.8% (10/42) in lipiodol group and 24.1% (59/245) in control group (P < 0.05). CONCLUSION: Chitosan and sodium hyaluronate could be effective to prevent tubal obstruction after interventional recanalization and increase pregnancy rate.