Exploring the Mechanism of Danshensu in the Treatment of Doxorubicin-Induced Cardiotoxicity Based on Network Pharmacology and Experimental Evaluation.

Background: Doxorubicin (DOX) is one of the most effective chemotherapeutic agents available; however, its use is limited by the risk of serious cardiotoxicity. Danshensu (DSS), an active ingredient in Salvia miltiorrhiza, has multiple cardioprotective effects, but the effect of DSS on DOX-induced cardiotoxicity has not been reported. Objectives: Predicting the targets of DOX-induced cardiotoxicity and validating the protective effects and mechanisms of DSS. Methods: (1) Using methods based on network pharmacology, DOX-induced cardiotoxicity was analyzed by data analysis, target prediction, PPI network construction and GO analysis. (2) The cardiotoxicity model was established by continuous intraperitoneal injection of 15 mg/kg of DOX into mice for 4 days and the protective effects and mechanism were evaluated by treatment with DSS. Results: The network pharmacology results indicate that CAT, SOD, GPX1, IL-6, TNF, BAX, BCL-2, and CASP3 play an important role in this process, and Keap1 is the main target of DOX-induced cardiac oxidative stress. Then, based on the relationship between Keap1 and Nrf2, the Keap1-Nrf2/NQO1 pathway was confirmed by animal experiments. In the animal experiments, by testing the above indicators, we found that DSS effectively reduced oxidative stress, inflammation, and apoptosis in the damaged heart, and significantly alleviated the prolonged QTc interval caused by DOX. Moreover, compared with the DOX group, DSS elevated Keap1 content and inhibited Nrf2, HO-1, and NQO1. Conclusion: The results of network pharmacology studies indicated that Keap1-Nrf2/NQO1 is an important pathway leading to DOX-induced cardiotoxicity, and the results of animal experiments showed that DSS could effectively exert anti-oxidative stress, anti-inflammatory and anti-apoptotic therapeutic effects on DOX-induced cardiotoxicity by regulating the expression of Keap1-Nrf2/NQO1.

Atomistic Simulations on Metal Rod Penetrating Thin Target at Nanoscale Caused by High-Speed Collision.

The penetration process has attracted increasing attention due to its engineering and scientific value. In this work, we investigate the deformation and damage mechanism about the nanoscale penetration of single-crystal aluminum nanorod with atomistic simulations, where distinct draw ratio (∅) and different incident velocities (up) are considered. The micro deformation processes of no penetration state (within 2 km/s) and complete penetration (above 3 km/s) are both revealed. The high-speed bullet can cause high pressure and temperature at the impacted region, promoting the localized plastic deformation and even solid-liquid phase transformation. It is found that the normalized velocity of nanorod reduces approximately exponentially during penetration (up < 3 km/s), but its residual velocity linearly increased with initial incident velocity. Moreover, the impact crater is also calculated and the corresponding radius is manifested in the linear increase trend with up while inversely proportional to the ∅. Interestingly, the uniform fragmentation is observed instead of the intact spallation, attributed to the relatively thin thickness of the target. It is additionally demonstrated that the number of fragments increases with increasing up and its size distribution shows power law damping nearly. Our findings are expected to provide the atomic insight into the micro penetration phenomena and be helpful to further understand hypervelocity impact related domains.

Distribution of bacteria infected by metagenomic sequencing technology in maxillofacial space.

OBJECTIVES: This study aimed to compare and analyze the consistency and difference between metageno-mic next-generation sequencing (mNGS) and conventional bacterial culture in the detection of pathogenic microorganisms in maxillofacial space infection, as well as to provide a new detection method for the early clinical identification of pathogenic bacteria in maxillofacial space infection. METHODS: The clinical data of 16 patients with oral and maxillofacial space infections in the First Affiliated Hospital of Zhengzhou University from March 2020 to June 2020 were collected. mNGS and conventional bacterial culture methods were used to detect pus. We then analyzed and compared the test results of the two methods, including the test cycle, positive detection rate, anaerobic bacteria, facultative anaerobes and aerobic bacteria detection rates, distribution of pathogenic bacteria, relative species abundance, and resistance genes. RESULTS: The average inspection period of mNGS was (18.81±3.73) h, and the average inspection period of bacterial culture was (83.25±11.64) h, the former was shorter than the latter (P<0.05). The positive detection rate of mNGS was 100% (16/16), and the positive detection rate of conventional bacterial culture was 31.25% (5/16), the former was higher than the latter (P<0.05). The detection rate of mNGS anaerobic bacteria was 93.75% (15/16), the detection rate of bacterial culture anaerobes was 0 (0/16), the former was higher than the latter (P<0.05). Using mNGS, the detection rate of facultative anaerobes in bacterial culture was 75.00% (12/16), and the detection rate of facultative anaerobes in bacterial culture was 25.00% (4/16), the former was higher than the latter (P<0.05). The detection rate of aerobic bacteria in bacterial culture was 12.50% (1/16), the former was higher than the latter (P>0.05). mNGS detected 15 kinds of pathogenic bacteria, among which 3 were Gram positive, 12 were Gram negative, 49 were non-pathogenic, 16 were Gram positive, and 32 were Gram negative, 1 was fungus. CONCLUSIONS: Compared with conventional bacterial culture, mNGS has the characteristics of short test time, high sensitivity, and high accuracy. Thus, it is a new detection method for the early identification of pathogenic bacteria in maxillofacial space infection and is beneficial to the early clinical diagnosis and treatment of the disease.

Age-related Changes in the Global DNA Methylation Profile of Oligodendrocyte Progenitor Cells Derived from Rat Spinal Cords.

Demyelination of axons plays an important role in the pathology of many spinal cord diseases and injuries. Remyelination in demyelinated lesions is primarily performed by oligodendrocyte progenitor cells (OPCs), which generate oligodendrocytes in the developing and mature central nervous system. The efficiency of remyelination decreases with age. Many reports suggest that this decline in remyelination results from impaired OPC recruitment and differentiation during aging. Of the various molecular mechanisms involved in aging, changes in epigenetic modifications have received particular attention. Global DNA methylation is a major epigenetic modification that plays important roles in cellular senescence and organismal aging. Thus, we aimed to evaluate the dynamic changes in the global DNA methylation profiles of OPCs derived from rat spinal cords during the aging process. We separated and cultured OPCs from the spinal cords of neonatal, 4-month-old, and 16-month-old rats and investigated the age-related alterations of genomic DNA methylation levels by using quantitative colorimetric analysis. To determine the potential cause of dynamic changes in global DNA methylation, we further analyzed the activity of DNA methyltransferases (DNMTs) and the expression of DNMT1, DNMT3a, DNMT3b, TET1, TET2, TET3, MBD2, and MeCP2 in the OPCs from each group. Our results showed the genomic DNA methylation level and the activity of DNMTs from OPCs derived from rat spinal cords decreased gradually during aging, and OPCs from 16-month-old rats were characterized by global hypomethylation. During OPC aging, the mRNA and protein expression levels of DNMT3a, DNMT3b, and MeCP2 were significantly elevated; those of DNMT1 were significantly down-regulated; and no significant changes were observed in those for TET1, TET2, TET3, or MBD2. Our results indicated that global DNA hypomethylation in aged OPCs is correlated with DNMT1 downregulation. Together, these data provide important evidence for partly elucidating the mechanism of age-related impaired OPC recruitment and differentiation and assist in the development of new treatments for promoting efficient remyelination.

[Anterior radical debridement and bone grafting with one-stage instrumentation anteriorly or posteriorly for the treatment of thoracic and lumbar spinal tuberculosis].

OBJECTIVE: To evaluate the clinical outcomes of anterior radical debridement and autologous ilium or titanium cage interbody autografting with one-stage instrumentation anteriorly or posteriorly for the treatment of thoracic and lumbar tuberculosis. METHODS: Sixty-eight cases of thoracic and lumbar tuberculosis were surgically treated with anterior radical debridement and autologous ilium or titanium cage interbody autografting with one-stage instrumentation anteriorly or posteriorly from Jan 2001 to Feb 2006. Thirty-nine were male and 29 were female age ranged from 28 to 76 years, (average 36.8 years. The course of illness was from 3 months to 1.5 years average 8 months). Fifty-five of them underwent anterior instrumentations, and the remaining underwent posterior instrumentations. All patients were followed up to determine the stages of intervertebral bony fusion and the corrections of spinal kyphosis and the restoration of neurological deficit RESULTS: The follow-up period ranged from 1.5 years to 5 years (mean 36 months). Sinus formation occurred in 3 cases and healed after continuous dressing changes. The ESR of these patients decreased to normal levels after an average of 3.2 months postoperatively. The functions of feeling, motion and sphincter in 27 cases among all 28 paraplegia cases gradually recovered 24 h to 3 months postoperatively and ASIA grades increased at least one grade at the final follow-up. Only 1 case did not recover at all and ASIA grade did not increase at the final follow-up. Intervertebral bony fusions were all achieved for a mean of 4.8 months (ranged from 3 to 15 months) postoperatively. No internal fixation devices were loose, extracted or broken. Average Cobb angle of kyphotic deformities was 41.2 degree preoperatively and decreased to 13.6 degree at 1 week postoperatively. The average correction was 27.6 degree. The average Cobb angle was 15.8 degree at the final follow-up and the average loss of correction was only 2.2 degree. There were no recurrences in all cases. CONCLUSION: The method of anterior radical debridement and interbody grafting with one-stage instrumentation anteriorly or posteriorly was effective for the treatment of thoracic and lumbar spinal tuberculosis.