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- ArticleSu YK, Bamodu OA, Tzeng YM, Hsiao M, Yeh CT, Lin CM.Phytomedicine. 2019 Aug;61:152840.BACKGROUND: Ovatodiolide (Ova), a major bioactive diterpenoid isolate of Anisomeles indica has drawn considerable attention lately as an effective anticancer agent with several published works demonstrating its tumor-inhibitory activity in various cancer types.
PURPOSE: In this study, we examined the modulatory effect of Ova on the oncogenicity, proliferation, and cancer stem cell-like traits of glioblastoma (GBM) cells, as well as investigated the underlying molecular mechanism for the anticancer activity of Ova in GBM cell lines, U-87MG and GBM8401.
METHODS: The antiproliferative, apoptotic, and stemness-attenuating effects of Ova were evaluated using the sulforhodamine B (SRB) colorimetric assay, western blot and fluorescent immunocytochemistry. Cell apoptosis was analyzed based on variation in the expression levels of Bcl-2 family of regulator proteins Bax, Bak, Bcl-2 and Bcl-xL.
RESULTS: Ova induced the apoptosis of the U-87MG and GBM8401 cells, as well as effectively inhibited the proliferation and motility of the GBM cell lines in a dose- and time-dependent manner. Ova-induced apoptosis correlated with increased Bax/Bcl-2 ratio, while inhibition of tumor cell migration and colony formation was associated with reduced Slug, Vimentin, NCadherin and β-catenin protein expression and increased E-Cadherin. In addition, exposure to Ova inhibited tumorsphere formation, elicited downregulation of CD44, CD133, Sox2, and Oct4, as well as correlated with dysregulation of the JAK2-STAT3 signaling pathway. Furthermore, we showed for the first time to the best of our knowledge that Ova potentiate the chemotherapeutic effect of Temozolomide.
CONCLUSION: Taken together, our findings demonstrate the anticancer potential of Ova in GBM and its efficacy in the treatment of GBM as monotherapy and in combination with Temozolomide. - ArticleRicotti V, Spinty S, Roper H, Hughes I, Tejura B, Robinson N, Layton G, Davies K, Muntoni F, Tinsley J.PLoS One. 2016;11(4):e0152840.PURPOSE: SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage.
METHODS: This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A-C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study.
RESULTS: Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing.
CONCLUSIONS: SMT C1100 was well tolerated in pediatric DMD patients.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02383511. - ArticleShi JH, Liu H, Pham TC, Hu XJ, Liu L, Wang C, Foba CN, Wang SB, Wang MQ.Sci Total Environ. 2022 Apr 01;815:152840.Plant root-leaf communication signals are critical for plant defense. Numerous studies show that belowground organisms can alter systemically resistance traits in aboveground parts against herbivores. However, there are limited studies on root-knot nematode-aphid interaction. Moreover, the impact of nematode's initial density and infection time on plant defense is poorly understood. Here we aim to examine the induced defense responses by root-knot nematode Meloidogyne incognita against aboveground feeding aphid Sitobion avenae in wheat. Further, we investigated the influence of the nematode infection density as well as the length of infection in these interactions. We tested the direct and indirect defense responses triggered by M. incognita against S. avenae as well as how the responses affect the preference of Harmonia axyridis. Plant volatiles and hormones were determined to explore plant defense mechanisms that mediate aboveground-belowground defense. The photosynthetic rate was tested to examine plant tolerance strategy. We found that, both low and high densities M. incognita root infection at 7 days post inoculation (dpi) reduced the feeding of the aphid S. avenae. Behavioral assay showed that H. axyridis preferred plants co-damaged by both M. incognita and S. avenae at 7 dpi. M. incognita infection induced the changes of jasmonic acid, salicylic acid and volatile content, which mediated plant response to S. avenae. Furthermore, photosynthetic rate in wheat increased at 5 dpi under 300 M. incognita or 1000 M. incognita infection. These results suggest that plant roots induced multiple defense strategies against foliar herbivores as damages increased. Our study provides evidence of a complex dynamic response of wheat aboveground defense against aphids in response to belowground nematode damage on a temporal scale.
- ArticleSawoo R, Bishayi B.Immunobiology. 2024 09;229(5):152840.Due to the urgent need to create appropriate treatment techniques, which are currently unavailable, LPS-induced sepsis has become a serious concern on a global scale. The primary active component in the pathophysiology of inflammatory diseases such as sepsis is the Gram-negative bacterial lipopolysaccharide (LPS). LPS interacts with cell surface TLR4 in macrophages, causing the formation of reactive oxygen species (ROS), TNF-α, IL-1β and oxidative stress. It also significantly activates the MAPKs and NF-κB pathway. Excessive production of pro-inflammatory cytokines is one of the primary characteristic features in the onset and progression of inflammation. Cytokines mainly signal through the JAK/STAT pathway. We hypothesize that blocking of TLR4 along with TNFR1 might be beneficial in suppressing the effects of STAT1/STAT3 due to the stimulation of SOCS3 proteins. Prior to the LPS challenge, the macrophages were treated with antibodies against TLR4 and TNFR1 either individually or in combination. On analysis of the macrophage populations by flowcytometry, it was seen that receptor blockade facilitated the phenotypic shift of the M1 macrophages towards M2 resulting in lowered oxidative stress. Blocking of TLR4/TNFR1 upregulated the SOCS3 and mTOR expressions that enabled the transition of inflammatory M1 macrophages towards the anti-inflammatory M2 phenotype, which might be crucial in curbing the inflammatory responses. Also the reduction in the production of inflammatory cytokines such as IL-6, IL-1β due to the reduction in the activation of the STAT1 and STAT3 molecules was observed in our combination treatment group. All these results indicated that neutralization of both TLR4 and TNFR1 might provide new insights in establishing an alternative therapeutic strategy for LPS-sepsis.
- ArticleEzhilarasan D.Toxicology. 2021 06 30;458:152840.Methotrexate (MTX) is one of the most effective and widely used drugs in the management of autoimmune and dermatological diseases. Rheumatoid arthritis and psoriasis patients who are under long term MTX-therapy are at high risk of developing a liver injury. Accumulation of intracellular MTX-polyglutamate (MTX-PG), a metabolite of MTX triggers oxidative stress, inflammation, steatosis, fibrosis, and apoptosis in hepatocytes. MTX-PG causes oxidative stress in the liver by inducing lipid peroxidation thereby releasing reactive oxygen species and suppressing antioxidant response elements. MTX-PG induces several pro-inflammatory signaling pathways and cytokines such as tumor necrosis factor-α, nuclear factor kappa B and interleukin 6 (IL-6), IL- β1, IL-12. MTX-PG depletes hepatic folate level and decreases RNA and DNA synthesis leading to hepatocyte death. MTX-PG inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase enzyme and thereby causes accumulation of intracellular adenosine, which causes activation of hepatic stellate cells, extracellular matrix accumulation and hepatic fibrosis. MTX-PG induces hepatocytes apoptosis by activation of caspase 3 via the intrinsic pathway. Clinically, aggravation of underlying fatty liver to non-alcoholic steatohepatitis with fibrosis seems to be an important mechanism of liver injury in MTX-treated RA patients. Therefore, there is a need for monitoring liver injury in RA, psoriatic and cancer patients with NAFLD and fibrosis risk factors during MTX treatment. This review summarizes the possible molecular mechanism of MTX-induced hepatotoxicity. It may pave the way for early detection of liver injury and develop novel strategies for treating MTX mediated hepatotoxicity.
- BookSummary: "Clinical Capsules: Multisystem Processes and Disorders is a collection of clinical learning modules covering diseases and disorders that affect multiple body systems created for students to reference during rotations and preparation for taking Shelf and USMLE exams. Originally derived from Thieme's authoritative German-language medical textbook content and digital learning platform, Via Medici, the modules have been translated and carefully adapted by 4th-year medical students and residents in the U.S. to fit the standards of practice in the U.S. health care system. Modules are templated and include Epidemiology, Pathogenesis, Signs and Symptoms, Diagnosis, and Treatment for multisystem diseases and disorders commonly tested on Shelf and USMLE exams. The modules are also useful for exam preparation, with concise overviews, learning and exam tips, and high-yield facts, and clinical rotation support, with links to key treatment guidelines and other information for each disease and disorder. Additionally, volumes are organized by organ system and specialty with regularly updated information supplemented by illustrations, diagrams, radiographic images, and tables." -- Provided by the publisher.Digital Access Thieme MedOne Education [2024]