Edaravone dexborneol regulates γ-aminobutyric acid transaminase in rats with acute intracerebral hemorrhage.

OBJECTIVES: Edaravone dexborneol is neuroprotective against ischemic stroke, with free radical-scavenging and anti-inflammatory effects, but its effects in hemorrhagic stroke remain unclear. We evaluated whether edaravone dexborneol has a neuroprotective effect in intracerebral hemorrhage, and its underlying mechanisms. MATERIALS AND METHODS: Bioinformatics were used to predict the pathway of action of edaravone dexborneol. An intracerebral hemorrhage model was established using type IV collagenase in edaravone dexborneol, intracerebral hemorrhage, Sham, adeno-associated virus + edaravone dexborneol, and adeno-associated virus + intracerebral hemorrhage groups. The modified Neurological Severity Score was used to evaluate neurological function in rats. Brain water content was measured using the dry-wet weight method. Tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and γ-aminobutyric acid levels were determined by enzyme-linked immunosorbent assay. The expression levels of neurofilament light chain and γ-aminobutyric acid transaminase were determined by western blot. Nissl staining was used to examine neuronal morphology. Cognitive behavior was evaluated using a small-animal treadmill. RESULTS: Edaravone dexborneol alleviated neurological defects, improved cognitive function, and reduced cerebral edema, neuronal degeneration, and necrosis in rats with cerebral hemorrhage. The expression levels of neurofilament light chain, tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and γ-aminobutyric acid were decreased, while γ-aminobutyric acid transaminase expression was up-regulated. CONCLUSIONS: Edaravone dexborneol regulates γ-aminobutyric acid content by acting on the γ-aminobutyric acid transaminase signaling pathway, thus alleviating oxidative stress, neuroinflammation, neuronal degeneration, and death caused by excitatory toxic injury of neurons after intracerebral hemorrhage.

A bibliometric analysis of cerebral microbleeds and cognitive impairment.

BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are imaging markers for small cerebral vascular diseases, which can accumulate and impact the corresponding brain networks. CMBs can affect cognitive function, including executive function, information processing speed, and visuospatial memory. Bibliometrics is a scientific and innovative method that can analyze and visualize the scientific field quantitatively. In this study, we aimed to use bibliometric analysis to demonstrate the relationship and mechanisms between CMBs and cognitive impairment. Furthermore, we reviewed the relationship between CMBs and different cognitive disorders. The use of bibliometrics can help further clarify this relationship. METHODS: We retrieved articles on CMBs and cognitive impairment from the Web of Science Core Collection. The keywords (such as stroke, dementia, and cerebral amyloid angiopathy), authors, countries, institutions and journals, in the field were visually analyzed using VOSviewer software and bibliometric websites. RESULTS: This bibliometric analysis reveals the related trends of CMBs in the field of cognitive impairment. CMBs, along with other small vascular lesions, constitute the basis of cognitive impairment, and studying CMBs is essential to understand the mechanisms underlying cognitive impairment. CONCLUSION: This bibliometric analysis reveals a strong link between CMBs and cognitive impairment-related diseases and that specific brain networks were affected by CMBs. This provides further insights into the possible mechanisms and causes of CMBs and cognitive impairment. The direct and indirect damage (such as oxidative stress and neuroinflammation) to the brain caused by CMBs, destruction of the frontal-subcortical circuits, elevated Cystatin C levels, and iron deposition are involved in the occurrence and development of cognitive impairment. CMBs may be a potential marker for detecting, quantifying, and predicting cognitive impairment.

Ketogenic diet alleviates brain iron deposition and cognitive dysfunction via Nrf2-mediated ferroptosis pathway in APP/PS1 mouse.

Progressive cognitive decline and increased brain iron deposition with age are important features of Alzheimer's disease. Previous studies have found that the short-term ketogenic diet has neuroprotective effects in a variety of neurodegenerative diseases, but the effects of an early and long-term ketogenic diet on brain iron content and cognition of Alzheimer's disease have not been reported. In our study, 8-week-old APP/PS1 mice were given a 12-month ketogenic or standard diet, while C57BL/6 mice matched with the age and genetic background of APP/PS1 mice were used as normal controls to be given a standard diet for the same length of time. We found that 12 months of an early ketogenic diet improved the impaired learning and memory ability of APP/PS1 mice. The improvement of cognitive function may be related to the reduction of amyloid-beta deposition and neuronal ferroptosis. The mechanism was achieved by the regulation of ferroptosis-related pathways after activation of nuclear factor erythroid 2-related factor 2 by ketogenic diet-induced elevated ß-hydroxybutyrate. In addition, blood biochemical results showed that compared with the standard diet group of the disease, although the early and long-term ketogenic diet increased blood lipids to some extent, it seemed to reduce liver, renal, and myocardial damage caused by genetic differences. This will provide a piece of positive evidence for the early and long-term use of ketogenic diets in people at risk of Alzheimer's disease.

Screening of traditional Chinese medicine monomers as ribonucleotide reductase M2 inhibitors for tumor treatment.

BACKGROUND: Ribonucleotide reductase (RR) is a key enzyme in tumor proliferation, especially its subunit-RRM2. Although there are multiple therapeutics for tumors, they all have certain limitations. Given their advantages, traditional Chinese medicine (TCM) monomers have become an important source of anti-tumor drugs. Therefore, screening and analysis of TCM monomers with RRM2 inhibition can provide a reference for further anti-tumor drug development. AIM: To screen and analyze potential anti-tumor TCM monomers with a good binding capacity to RRM2. METHODS: The Gene Expression Profiling Interactive Analysis database was used to analyze the level of RRM2 gene expression in normal and tumor tissues as well as RRM2's effect on the overall survival rate of tumor patients. TCM monomers that potentially act on RRM2 were screened via literature mining. Using AutoDock software, the screened monomers were docked with the RRM2 protein. RESULTS: The expression of RRM2 mRNA in multiple tumor tissues was significantly higher than that in normal tissues, and it was negatively correlated with the overall survival rate of patients with the majority of tumor types. Through literature mining, we discovered that berberine, ursolic acid, gambogic acid, cinobufagin, quercetin, daphnetin, and osalmide have inhibitory effects on RRM2. The results of molecular docking identified that the above TCM monomers have a strong binding capacity with RRM2 protein, which mainly interacted through hydrogen bonds and hydrophobic force. The main binding sites were Arg330, Tyr323, Ser263, and Met350. CONCLUSION: RRM2 is an important tumor therapeutic target. The TCM monomers screened have a good binding capacity with the RRM2 protein.

A bibliometric analysis of the recent advances in diazepam from 2012 to 2021.

Background: Diazepam is a classic benzodiazepine drug that has been widely used for disorders such as anxiety, sleep disorders, and epilepsy, over the past 59 years. The study of diazepam has always been an important research topic. However, there are few bibliometric analyses or systematic studies in this field. This study undertook bibliometric and visual analysis to ascertain the current status of diazepam research, and to identify research hotspots and trends in the past 10 years, to better understand future developments in basic and clinical research. Methods: Articles and reviews of diazepam were retrieved from the Web of Science core collection. Using CiteSpace, VOSviewer, and Scimago Graphica software, countries, institutions, authors, journals, references, and keywords in the field were visually analyzed. Results: A total of 3,870 publications were included. Diazepam-related literature had high volumes of publications and citations. The majority of publications were from the USA and China. The highest number of publications and co-citations, among the authors, was by James M Cook. Epilepsia and the Latin American Journal of Pharmacy were the journals with the most publications on diazepam and Epilepsia was the most frequently cited journal. Through a comprehensive analysis of keywords and references, we found that current research on diazepam has focused on its mechanism of action, application in disease, pharmacokinetics, risk, assessment, and management of use, status epilepticus, gamma-aminobutyric acid receptors (GABAR), intranasal formulation, gephyrin, and that ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is the current research hotspot. Conclusion: Research on diazepam is flourishing. We identified research hotspots and trends in diazepam research using bibliometric and visual analytic methods. The clinical applications, mechanisms of action, pharmacokinetics, and assessment and management of the use of diazepam are the focus of current research and the development trend of future research.

[Exposure of acute severe air pollution promotes inflammatory cell infiltration and increases the levels of proinflammatory cytokines and chemokines in lung tissues of rats].

Objective To observe the effect of acute severe air pollution exposure on cytokines and chemokines in lung tissues of rats and explore its significance. Methods During the period of severe air pollution in Beijing from December 17 to 22, 2016, rats were exposed to air pollution for 6 days, and then sacrificed on the 7th day. Lung tissues were taken and their histological changes were observed by HE staining. The levels of 22 cytokines/chemokines in the lung tissue homogenate supernatant were detected by liquid chip method. Results Compared with the control group, the lung tissues of the rats in the air pollution exposure group were characterized by widened alveolar septum, inflammatory cell infiltration and vascular bleeding. Chemokines eotaxin, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), regulated on activation, normal T cell expressed and secreted factor (RANTES), and proinflammatory cytokines interleukin 1ß (IL-1ß), IL-17, IL-18, tumor necrosis factor α (TNF-α) in the supernatant of lung homogenate of rats in the air pollution exposure group significantly increased. But anti-inflammatory IL-10 significantly decreased. Th1 cytokines IL-2 and interferon-γ (IFN-γ) did not change, and Th2 cytokines IL-5 increased by 1.65 times and IL-10 decreased by 0.82 times. Conclusion Acute severe air pollution exposure can lead to inflammatory response in lung tissues of rats. The secretion of chemokines eotaxin, MCP-1, MIP-2, RANTES and proinflammatory cytokines IL-1ß, IL-17, IL-18, TNF-α are promoted in this process. The infiltrated T cells in lung tissues are dominated by Th2 cells.

[Collagen Peptides Improve Lymphocyte Distribution in Peripheral Blood and T Lymphocyte Proliferation in Spleen of Mice under the Condition of Simulated Weightlessness].

OBJECTIVE: To investigate whether collagen peptides can improve the immune functions of mice under the condition of simulated weightlessness. METHODS: Mouse tail-suspension model was used to simulate the effects of weightlessness. Tail-suspended mice were intraperitoneally injected with 600 mg collagen peptides per kilogram body weight once a day for 10 days. Then, the mice were killed, and white blood cells were counted and classified. Lymphocyte subsets and T lymphocyte proliferations in spleens were analyzed. RESULTS: Compared with normal control group, total and differential count of leukocytes, lymphocytes, T cells，CD4+ and CD8+ T cells, B cells and NK cells, and splenic T lymphocyte proliferation all decreased in the weightlessness simulated mice (P＜0.05). Except for NK cells, the above-mentioned parameters were increased after administration of collagen peptides, and some of the parameters were recovered to the levels of normal control mice (P＜0.05). CONCLUSION: Collagen peptides can effectively improve peripheral blood lymphocyte distributions and T lymphocyte proliferations of mice under the condition of simulated weightlessness. This study nay provid the experimental basis for improvement of immune functions of astronauts.

Recombinant adenovirus of SEA and CD80 genes driven by MMRE and mouse TERT promoter induce effective antitumor immune responses against different types of tumor cells in vitro and in vivo.

Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant and can stimulate T cells bearing certain T-cell receptor ß-chain variable regions when bound to major histocompatibility complex II molecules. SEA is widely used in research of antitumor therapy. The low affinity T-cell receptor (TCR) interaction with SEA in the absence of MHC class II antigens is sufficient for the induction of cytotoxicity but requires additional CD28/B7 signaling to result in proliferation of resting T cells. In this study, we constructed recombinant adenovirus (named as Ad-MMRE-mTERT-BIS) carrying membrane-expressing SEA (named as SEAtm) and CD80 driven by Myc-Max response elements (MMRE) and mouse telomerase reverse transcriptase (mTERT) promoter to reduce toxicity and to improve safety and efficiency. We demonstrated that Ad-MMRE-mTERT-BIS could make SEAtm and CD80 to co-express highly on the surface of Hepa1-6 and B16 cells, at low level on the surface of CT26 cells, but not in NIH3T3. Hepa1-6 and B16 cells infected by the recombinant adenovirus induced proliferation of CD4+ and CD8+ T cells and increased cytokine [interleukin (IL)-2, tumor necrosis factor (TNF)-α, interferon (IFN)-γ] production in vitro. Intratumoral injection of Ad-MMRE-mTERT-BIS in hepatoma and melanoma mouse models induced tumor-specific cytotoxic T cells in the spleen. Moreover, hepatoma and melanoma xenografts were suppressed by treatment with Ad-MMRE-mTERT-BIS and the survival time of treated mice was prolonged. These findings suggest that recombinant adenovirus of SEA and CD80 genes driven by mTERT promoter could induce effective antitumor immune responses against different kinds of tumor cells in vitro and in vivo.

The effect of different molecular weight collagen peptides on MC3T3-E1 cells differentiation.

Our study aimed at investigating the effect of different molecular weight bovine collagen peptides, namely CH878, CH1370, CH2900, and CH7747 on the differentiation of MC3T3-E1 cells. Osteogenic differentiation of MC3T3-E1 cells was assessed by a series of specific assays, after culturing of cells in the presence of collagen peptides. Alkaline phosphatase activity (ALP) was evaluated by NBT/BCIP staining. Osteocalcin expression was determined by a radioimmunology method. Mineralization was quantified by Alizarin Red staining. ALP staining results demonstrated that the ALP staining of cells after culture in the presence of collagen peptides were significantly higher than the control group (P<0.05), indicating the promotion of ALP activity in MC3T3-E1 cells by these peptides. Radioimmunology results demonstrated that collagen peptides groups were all significantly higher than the control group (P<0.01). Alizarin Red staining results demonstrated that CH1370, CH2900, and CH7747 significantly promoted the formation of mineralized bone matrix. We therefore conclude that CH1370, CH2900, and CH7747 play an active role in the differentiation of MC3T3-E1 cells. Based on the above results, we provide molecular basis for further development of collagens with different molecular weight for the prevention and treatment of osteoporosis.

Combined oral administration of bovine collagen peptides with calcium citrate inhibits bone loss in ovariectomized rats.

PURPOSE: Collagen peptides (CPs) and calcium citrate are commonly used as bone health supplements for treating osteoporosis. However, it remains unknown whether the combination of oral bovine CPs with calcium citrate is more effective than administration of either agent alone. METHODS: Forty 12-week-old Sprague-Dawley rats were randomly divided into five groups (n = 8) for once-daily intragastric administration of different treatments for 3 months at 3 months after ovariectomy (OVX) as follows: sham + vehicle; OVX + vehicle; OVX + 750 mg/kg CP; OVX + CP-calcium citrate (75 mg/kg); OVX + calcium citrate (75 mg/kg). After euthanasia, the femurs were removed and analyzed by dual energy X-ray absorptiometry and micro-computed tomography, and serum samples were analyzed for bone metabolic markers. RESULTS: OVX rats supplemented with CPs or CP-calcium citrate showed osteoprotective effects, with reductions in the OVX-induced decreases in their femoral bone mineral density. Moreover, CP-calcium citrate prevented trabecular bone loss, improved the microarchitecture of the distal femur, and significantly inhibited bone loss with increased bone volume, connectivity density, and trabecular number compared with OVX control rats. CP or CP-calcium citrate administration significantly increased serum procollagen type I N-terminal propeptide levels and reduced serum bone-specific alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen levels. CONCLUSIONS: Our data indicate that combined oral administration of bovine CPs with calcium citrate inhibits bone loss in OVX rats. The present findings suggest that combined oral administration of bovine CPs with calcium citrate is a promising alternative for reducing bone loss in osteopenic postmenopausal women.