84 research outputs found
Abstract 4795: Nrf2 protects against chemotherapy-induced steatohepatitis and peripheral neurotoxicity
No full textAbstract
The indiscriminating protection of either normal or cancerous cells against electrophilic stresses by nuclear factor E2-related factor 2 (Nrf2) has evoked continuous controversy over its Janus face in cancer. However, both normal and cancerous cells co-exist in cancer patients, and the outcome of therapy is determined by responses of both. Here we systemically analyzed the correlation between Nrf2 expression in normal cells and chemotherapy-associated myelosuppression, steatohepatitis and peripheral neurotoxicity, and explored the possibility to predict and prevent these adverse effects by targeting Nrf2 signaling. Firstly, the toxicities of 22 clinically-used chemotherapeutic drugs were tested in bone marrow cells, liver cells and embryonic fibroblasts derived from either Nrf2 (-/-) or wild type mice, and the toxicities of drugs with IC50 in wild type cells > 2 folds higher than their Nrf2(-/-) counterparts are considered as significantly dependent on Nrf2. The dependency of taxol-induced myelosuppression on Nrf2 was confirmed in vivo, and the mRNA level of Nrf2 in peripheral blood mononuclear cells from cancer patients was reversely correlated to taxol-associated myelosuppression. Then steatohepatitis induced by irinotecan (CPT-11) and peripheral neurotoxicity induced by oxaliplatin were further investigated. CPT-11 induced intestinal toxicity in wild type mice but no significant steatohepatitis/liver toxicity was observed; however, CPT-11 treatment in Nrf2 (-/-) mice caused severer intestinal toxicity and pronounced steatohepatitis, associated with dramatically elevated serum biomarkers, accumulation of fat in liver cells, and altered liver histology. Similar results were observed for oxaliplatin-induced hepatotoxicity. Furthermore, Nrf2 deficiency significantly exaggerated oxaliplatin-induced peripheral neurotoxicity, as indicated by Von Frey test and cold plate assay. Interestingly, CDDO-Me was found to activate Nrf2 signaling in both normal tissues and xenograft tumors, while sulforaphane selectively activated Nrf2 in liver, bone marrow and peripheral nerves but not in tumors. As expected, sulforaphane significantly alleviated CPT-11-induced intestinal toxicity and oxaliplatin-induced peripheral neurotoxicity, while did not impact the therapeutic efficacy of drugs. Taken together, our results demonstrate that the toxicities of some of chemotherapeutic drugs currently in clinic usage are significantly affected by Nrf2, therefore it is possible to personalize therapeutic regimens according to Nrf2 expression in tumors and normal tissues. Specifically, CPT-11-induced steatohepatitis and intestinal toxicity and oxaliplatin-induced peripheral neurotoxicity are significantly determined by Nrf2, and Nrf2 could be selectively targeted to prevent or treat chemotherapy-induced toxicities. The present works were supported by the NSFC (No. 81272468, 91429305 and 81372266).
Note: This abstract was not presented at the meeting.
Citation Format: Liu He, Linling Que, Wenchen Yin, Baoshan Cao, Siwang Yu. Nrf2 protects against chemotherapy-induced steatohepatitis and peripheral neurotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4795. doi:10.1158/1538-7445.AM2017-4795</jats:p
Neutralizing antibodies induced by first-generation gp41-stabilized HIV-1 envelope trimers and nanoparticles
No full textThe immunogenicity of gp41-stabilized HIV-1 BG505 envelope (Env) trimers and nanoparticles (NPs) was recently assessed in mice and rabbits. Here, we combined Env-specific B-cell sorting and repertoire sequencing to identify neutralizing antibodies (NAbs) from immunized animals. A panel of mouse NAbs was isolated from mice immunized with a 60-meric I3-01 NP presenting 20 stabilized trimers. Three mouse NAbs potently neutralized BG505.T332N by recognizing a glycan epitope centered in the C3/V4 region on BG505 Env, as revealed by electron microscopy (EM), X-ray crystallography, and epitope mapping. A set of rabbit NAbs was isolated from rabbits immunized with a soluble trimer and a 24-meric ferritin NP presenting 8 trimers. Neutralization assays against BG505.T332N variants confirmed that potent rabbit NAbs targeted previously described glycan holes on BG505 Env and accounted for a significant portion of the autologous NAb response in both the trimer and ferritin NP groups. Last, we examined NAb responses that were induced by non-BG505 Env immunogens. We determined a 3.4-Å-resolution crystal structure for the clade C transmitted/founder (T/F) Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend in gp41. This clade C Env, in a soluble trimer form and in a multivalent form with 8 trimers attached to ferritin NP, and the gp41-stabilized clade A Q482-d12 Env trimer elicited distinct NAb responses in rabbits, with notable differences in neutralization breadth. Although eliciting a broad NAb response remains a major challenge, our study provides valuable information on an HIV-1 vaccine design strategy that combines gp41 stabilization and NP display. IMPORTANCE Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env. This study validates the gp41 stabilization strategy for HIV-1 Env vaccine design and highlights the challenge in eliciting a broad NAb response.</p
Data Mining Technology in Teaching Evaluation of Colleges and Universities
No full textData Mining refers to the large amount of data from the database through algorithmic search reveals implicit, previously unknown and potentially valuable process information[1]. Currently, many areas during the application of data mining. Data mining association rules is one of the most important and most mature technology research methods, association rule mining can find the hidden link between the transaction and meaningful rules. The purpose of this study is to evaluate data mining techniques combined with teaching, to extract useful information from a large number of evaluation data hiding, thereby providing a basis for decision support educational administration department, improve teaching quality
Rational design of DNA-expressed stabilized native-like HIV-1 envelope trimers
No full textThe HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies
Activation of Nrf2-ARE signaling mitigates cyclophosphamide-induced myelosuppression
No full textMyelosuppression is the most common dose-limiting adverse effect of chemotherapies. In the present study, we investigated the involvement of nuclear erythroid 2-related factor 2 (Nrf2) in cyclophosphamide-induced myelosuppression in mice, and evaluated the potential of activating Nrf2 signaling as a preventive strategy. The whole blood from Nrf2(-/-) mice exhibited decreased antioxidant capacities, while the bone marrow cells, peripheral blood mononuclear cells and granulocytes from Nrf2(-/-) mice were more susceptible to acrolein-induced cytotoxicity than those from wild type mice. Single dosage of cyclophosphamide induced significantly severer acute myelosuppression in Nrf2(-/-) mice than in wild type mice. Furthermore, Nrf2(-/-) mice exhibited greater loss of peripheral blood nucleated cells and recovered slower from myelosuppression nadir upon multiple consecutive dosages of cyclophosphamide than wild type mice did. This was accompanied with decreased antioxidant and detoxifying gene expressions and impaired colony formation ability of Nrf2(-/-) bone marrow cells. More importantly, activation of Nrf2 signaling by CDDO-Me significantly alleviated cyclophosphamide-induced myelosuppression, while this alleviation was diminished in Nrf2(-/-) mice. In conclusion, the present study shows that Nrf2 plays a protective role in cyclophosphamide-induced myelosuppression and activation of Nrf2 is a promising strategy to prevent or treat chemotherapy-induced myelosuppression. (C) 2016 Elsevier Ireland Ltd. All rights reserved.National Natural Science Foundation of China [81272468, 21001011]; WU JIEPING Medical foundation [320.6750.12196]SCI(E)[email protected]; [email protected]
Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates
No full textAbstract Uncleaved prefusion-optimized (UFO) design can stabilize diverse HIV-1 envelope glycoproteins (Envs). Single-component, self-assembling protein nanoparticles (1c-SApNP) can display 8 or 20 native-like Env trimers as vaccine candidates. We characterize the biophysical, structural, and antigenic properties of 1c-SApNPs that present the BG505 UFO trimer with wildtype and modified glycans. For 1c-SApNPs, glycan trimming improves recognition of the CD4 binding site without affecting broadly neutralizing antibodies (bNAbs) to major glycan epitopes. In mice, rabbits, and nonhuman primates, glycan trimming increases the frequency of vaccine responders (FVR) and steers antibody responses away from immunodominant glycan holes and glycan patches. The mechanism of vaccine-induced immunity is examined in mice. Compared with the UFO trimer, the multilayered E2p and I3-01v9 1c-SApNPs show 420 times longer retention in lymph node follicles, 20-32 times greater presentation on follicular dendritic cell dendrites, and up-to-4 times stronger germinal center reactions. These findings can inform future HIV-1 vaccine development
Research on Voltage Sag Loss Assessment Based on a Two-Stage Taguchi Quality Perspective Method
No full textVoltage sags resulting from symmetrical or asymmetrical faults pose a significant threat to power quality. In response to this challenge, a voltage sag loss assessment method based on a two-stage Taguchi quality perspective approach is proposed to address the quantitative analysis of voltage sag economic losses. Initially, using the Taguchi quality perspective method, single-index quality loss functions are separately established for voltage sag magnitude and fault duration. Subsequently, by introducing a comprehensive load tolerance curve, sensitivity parameters within the quality loss function are accurately calculated. This yields a deterministic model for voltage sag assessment. Building upon this, the relative impact of the two indices on voltage sag loss is evaluated using the quality loss function. Consequently, a comprehensive loss model under the influence of multiple indices is formed by integrating two single-index evaluation models. The simulation results indicate that this method can effectively assess the economic losses of voltage sags under the combined influence of multiple factors. Compared to the original economic loss assessment method, it improves quantitative accuracy by approximately 3.72%. Moreover, the method reduces the computational complexity of loss assessment through the consolidation of intervals with similar sensitivity parameters
The efficacy and safety of acupuncture-related therapy in the treatment of rheumatoid arthritis: A protocol for systematic review and network meta-analysis
No full textAbstract：
Background: Rheumatoid arthritis (RA) has seriously affected the quality of life of patients with its refractory, recurrent and disabled characteristics, and has become a major public health problem. Previous studies have confirmed that acupuncture and moxibustion has a reliable effect on RA, but there are many forms of acupuncture and moxibustion, and the efficacy of each form is different. This study is to evaluate the clinical efficacy of different acupuncture-related therapies in the treatment of RA by means of network meta-analysis.
Methods: According to the retrieval strategy, we retrieved the randomized controlled studies on acupuncture-related therapy for RA from CNKI, Wanfang, VIP, China Biomedicine, PubMed, Embase, Web of Science, and The Cochrane Library databases from the establishment of the database to July 2021. We assessed the quality of the studies using the Cochrane Risk Bias Assessment Tool and assessed the strength of the evidence using the GRADE methodology. All data analyses were performed by Revman5.3, Gemtc 0.14.3 and Stata 14.0.
Results: This study is to evaluate the efficacy of different acupuncture-related therapies in the treatment of RA by evaluating the total effective rate, pain scores, joint function scores, quality of life scores, laboratory indicators, adverse reactions, etc.
Conclusion: This study will provide a reliable evidence-based basis for the selection of the best acupuncture form for the treatment of RA
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