scholarly journals In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78

2010 ◽  
Vol 54 (11) ◽  
pp. 4596-4604 ◽  
Author(s):  
Urs Duthaler ◽  
Thomas A. Smith ◽  
Jennifer Keiser
Keyword(s):  
Negative Binomial ◽  
Fasciola Hepatica ◽  
Single Agent ◽  
Treatment Strategies ◽  
Drug Combinations ◽  
Antagonistic Effects ◽  
Experimental Drugs ◽  
New Treatment

ABSTRACT Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P = 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.

scholarly journals “Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

2021 ◽  
Vol 22 (4) ◽  
pp. 1824
Author(s):  
Matthias Mietsch ◽  
Rabea Hinkel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Treatment Strategies ◽  
Cardiac Cells ◽  
Aging Effects ◽  
Beneficial Effects ◽  
Micro Rnas ◽  
New Treatment

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

scholarly journals BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000387 ◽  
Author(s):  
Chiara Tarantelli ◽  
Elena Bernasconi ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Valentina Restelli ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Antitumour Activity ◽  
Single Agent ◽  
Treatment Strategies ◽  
Bet Inhibitor ◽  
Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

scholarly journals Preclinical Evaluation of the HDAC Inhibitor Chidamide in Transformed Follicular Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Mengya Zhong ◽  
Jinshui Tan ◽  
Guangchao Pan ◽  
Yuelong Jiang ◽  
Hui Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Follicular Lymphoma ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Treatment Strategies ◽  
Annexin V ◽  
Gene Encoding ◽  
New Treatment ◽  
Transformed Follicular Lymphoma

The key factors leading to transformed follicular lymphoma (t-FL) include the aberrations of epigenetic modifiers as early and driving events, especially mutations in the gene encoding for histone acetyltransferase. Therefore, reversal of this phenomenon by histone deacetylase (HDAC) inhibitors is essential for the development of new treatment strategies in t-FL. Several t-FL cell lines were treated with various doses of chidamide and subjected to cell proliferation, apoptosis and cell cycle analyses with CCK-8 assay, Annexin V/PI assay and flow cytometry, respectively. Chidamide dose-dependently inhibited cell proliferation, caused G0/G1 cycle arrest and triggered apoptosis in t-FL cells. In addition, the effects of chidamide on tumor growth were evaluated in vivo in xenograft models. RNA-seq analysis revealed gene expression alterations involving the PI3K-AKT signaling pathway might account for the mechanism underlying the antitumor activity of chidamide as a single agent in t-FL. These findings provide a basis for further clinical exploration of chidamide as a promising treatment for FL.

scholarly journals Metabolic Modeling of Clostridium difficile Associated Dysbiosis of the Gut Microbiota

Processes ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
Author(s):  
Poonam Phalak ◽  
Michael Henson
Keyword(s):  
Clostridium Difficile ◽  
Treatment Strategies ◽  
E Coli ◽  
Biofilm Model ◽  
Commensal Species ◽  
Species Abundances ◽  
New Treatment ◽  
Biofilm Development

Recent in vitro experiments have demonstrated the ability of the pathogen Clostridium difficile and commensal gut bacteria to form biofilms on surfaces, and biofilm development in vivo is likely. Various studies have reported that 3%–15% of healthy adults are asymptomatically colonized with C. difficile, with commensal species providing resistance against C. difficile pathogenic colonization. C. difficile infection (CDI) is observed at a higher rate in immunocompromised patients previously treated with broad spectrum antibiotics that disrupt the commensal microbiota and reduce competition for available nutrients, resulting in imbalance among commensal species and dysbiosis conducive to C. difficile propagation. To investigate the metabolic interactions of C. difficile with commensal species from the three dominant phyla in the human gut, we developed a multispecies biofilm model by combining genome-scale metabolic reconstructions of C. difficile, Bacteroides thetaiotaomicron from the phylum Bacteroidetes, Faecalibacterium prausnitzii from the phylum Firmicutes, and Escherichia coli from the phylum Proteobacteria. The biofilm model was used to identify gut nutrient conditions that resulted in C. difficile-associated dysbiosis characterized by large increases in C. difficile and E. coli abundances and large decreases in F. prausnitzii abundance. We tuned the model to produce species abundances and short-chain fatty acid levels consistent with available data for healthy individuals. The model predicted that experimentally-observed host-microbiota perturbations resulting in decreased carbohydrate/increased amino acid levels and/or increased primary bile acid levels would induce large increases in C. difficile abundance and decreases in F. prausnitzii abundance. By adding the experimentally-observed perturbation of increased host nitrate secretion, the model also was able to predict increased E. coli abundance associated with C. difficile dysbiosis. In addition to rationalizing known connections between nutrient levels and disease progression, the model generated hypotheses for future testing and has the capability to support the development of new treatment strategies for C. difficile gut infections.

scholarly journals Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3784
Author(s):  
Anne M. Noonan ◽  
Amanda Cousins ◽  
David Anderson ◽  
Kristen P. Zeligs ◽  
Kristen Bunch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Single Agent ◽  
Recurrent Ovarian Cancer ◽  
Drug Combinations ◽  
Smac Mimetic ◽  
Synergistic Drug Combinations

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

scholarly journals Downregulation of METTL7B Inhibits Proliferation of Human Clear Cell Renal Cancer Cells In Vivo and In Vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Li ◽  
Shi Xu ◽  
Naixiong Peng ◽  
Zejian Zhang ◽  
Hua He ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Clear Cell ◽  
Tnm Classification ◽  
Treatment Strategies ◽  
Tumor Formation ◽  
Cell Renal Cell Carcinoma ◽  
Functional Studies ◽  
New Treatment

Clear cell renal cell carcinoma (ccRCC) is the most aggressive urologic tumor, and its incidence and diagonosis have been continuously increasing. Identifying novel molecular biomarker for inhibiting the progression of ccRCC will facilitate developing new treatment strategies. Although methyltransferase-like 7B (METTL7B) was identified as a Golgi-associated methyltransferase, the function and mechanism of METTL7B in ccRCC development and progression has not been explored. METTL7B expression were significantly upregulated in ccRCC tissues (n = 60), which significantly associated with TNM classification, tumor size, lymph node metastasis, and poor prognosis for ccRCC patients. Functional studies showed downregulation of METTL7B inhibited cell proliferation, migration in vitro, and xenograft tumor formation in vivo. In addition, METTL7B knockdown promoted cell cycle arrest at G0/G1phase and induced cellular apoptosis. Taken together, downregulation of METTL7B inhibits ccRCC cell proliferation and tumorigenesis in vivo and in vitro. These findings provide a rationale for using METTL7B as a potential therapeutic target in ccRCC patients.

scholarly journals MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Calvin VanOpstall ◽  
Srikanth Perike ◽  
Hannah Brechka ◽  
Marc Gillard ◽  
Sophia Lamperis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Treatment Strategies ◽  
Human Prostate ◽  
Protein Activity ◽  
Prostate Epithelial Cells ◽  
New Treatment ◽  
Hox Protein

The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.

scholarly journals Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
April C. Joice ◽  
Sihyung Yang ◽  
Abdelbasset A. Farahat ◽  
Heidi Meeds ◽  
Mei Feng ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Treatment Strategies ◽  
Parasite Burden ◽  
Pharmacokinetic Analysis ◽  
Content Type ◽  
New Treatment ◽  
Almost All

ABSTRACT Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular Leishmania donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

scholarly journals Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

2020 ◽  
Author(s):  
Shuai Ye ◽  
Dinara Sharipova ◽  
Marya Kozinova ◽  
Lilli Klug ◽  
Jimson D’Souza ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumor ◽  
Single Agent ◽  
Treatment Strategies ◽  
Clinical Problem ◽  
Stromal Tumor ◽  
Loss Of Function ◽  
Rtk Inhibitors

AbstractManagement of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA, and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical problem. Development of effective treatment strategies for refractory GIST subtypes requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype. Kinome profiling in combination with loss-of-function assays identified a significant role for the G2-M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

Repurposing auranofin as a Clostridioides difficile therapeutic

2019 ◽  
Author(s):  
Melanie L Hutton ◽  
Havva Pehlivanoglu ◽  
Callum J Vidor ◽  
Meagan L James ◽  
Melanie J Thomson ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Toxin Production ◽  
Spore Production ◽  
Clostridioides Difficile ◽  
New Treatment ◽  
Gut Damage

Abstract Background Clostridioides difficile (previously Clostridium difficile) is the leading cause of nosocomial, antibiotic-associated diarrhoea worldwide. Currently, the gold standard of treatment for C. difficile infection (CDI) is vancomycin or metronidazole, although these antibiotics also perturb the protective resident microbiota, often resulting in disease relapse. Thus, an urgent need remains for the development of new treatment strategies. Auranofin is an FDA-approved oral antirheumatic drug that was previously shown to inhibit C. difficile vegetative cell growth, toxin production and spore production in vitro. Objectives To determine the efficacy of auranofin as a CDI therapeutic by examining the effect of treatment on toxin and spore production in vitro and in vivo, and on disease outcomes in mice. Methods C. difficile cultures were treated with auranofin and examined for effects on sporulation and toxin production by sporulation assay and ELISA, respectively. Mice were pretreated with auranofin prior to infection with C. difficile and monitored for physiological conditions, survival and gut damage compared with control animals. Faeces from mice were analysed to determine whether auranofin reduces sporulation and toxin production in vivo. Results Auranofin significantly reduces sporulation and toxin production under in vitro conditions and in infected mice in vivo. Mice treated with auranofin lost less weight, displayed a significant increase in survival rates and had significantly less toxin-mediated damage in their colon and caecum compared with control mice. Conclusions Auranofin shows promise as a prospective therapeutic option for C. difficile infections.

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