A quantitative in vivo assay for craniofacial developmental toxicity of histone deacetylases

Background: Sulforaphane (SF, 1-isothiocyanato-4-(methyl-sulfinyl)-butane) is found in broccoli, cabbage and cauliflower. Methods: we performed a critical review on the antioxidative, chemopreventive and antitumor effects of SF from cruciferous vegetables against prostate cancers and molecular pathways. For a complete and reliable review, primary and secondary resources were used, including original and review articles, books and government documents published until March 2018. Articles that are in duplicity and disconnected are not considered for review. SF is derived from glucoraphanin (4-methyl-sulfinyl-butyl-glucosinate), being one of the most commonly found isothiocyanates in vegetables from Brassica spp., especially in broccoli samples. In vitro studies indicate that SF induces apoptosis in a dependent or non-dependent method of androgens by transcription of tumor suppressor genes, oxidation response and higher expression of phase II enzymes in prostate cancer cells. Sulforaphane also decreases transcription of the nuclear factor kB and antiapoptotic proteins, expression of cyclin D2 and survivin and DNA synthesis, increases Nrf2 gene activity, interferes with genome compacting by inhibition of histone deacetylases and disrupts Hsp90 complexes, which cause cell cycle arrest, mitosis interruption, activation of caspases and mitochondria depolarization. Conclusion: SF and cruciferous vegetables play antioxidative and chemopreventive role, delaying or blocking in vivo carcinogenesis, causing biochemical and epigenetic changes, preventing, delaying, or reversing preneoplastic or advanced prostate lesions, and frequently activating tumor cell death by intrinsic methods of apoptosis. These outcomes encourage the consumption of Brassica specimens, which could be easily achieved by the incorporation of food and vegetables rich in cruciferous isothiocyanates in the diet.

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Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

Current Cancer Drug Targets ◽

10.2174/1568009617666170623104030 ◽

2018 ◽

Vol 18 (4) ◽

pp. 365-371 ◽

Cited By ~ 2

Author(s):

Denis V. Mishchenko ◽

Margarita E. Neganova ◽

Elena N. Klimanova ◽

Tatyana E. Sashenkova ◽

Sergey G. Klochkov ◽

...

Keyword(s):

Lipid Peroxidation ◽

Acute Toxicity ◽

Histone Deacetylases ◽

Hydroxamic Acids ◽

Water Soluble ◽

Male Rat ◽

Hybrid Male ◽

Cyclic Hydroxamic Acids

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

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HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target

Cell Death and Disease ◽

10.1038/s41419-021-03417-0 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Chun Cheng ◽

Jun Yang ◽

Si-Wei Li ◽

Guofu Huang ◽

Chenxi Li ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Tumor Growth ◽

Therapeutic Target ◽

Histone Deacetylases ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

E Cadherin

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

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Gran1: A Granulysin-Derived Peptide with Potent Activity against Intracellular Mycobacterium tuberculosis

International Journal of Molecular Sciences ◽

10.3390/ijms22168392 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8392

Author(s):

Reiner Noschka ◽

Fanny Wondany ◽

Gönül Kizilsavas ◽

Tanja Weil ◽

Gilbert Weidinger ◽

...

Keyword(s):

Antimicrobial Activity ◽

Mycobacterium Tuberculosis ◽

Developmental Toxicity ◽

Super Resolution ◽

In Vivo Models ◽

Large Size ◽

Acid Fragment ◽

Powerful Approach ◽

Target Effects

Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 amino acid fragment within the putative cytolytic site of Granulysin (termed “Gran1”). We evaluated the antimicrobial activity of Gran1 against the major human pathogen Mycobacterium tuberculosis (Mtb) and a panel of clinically relevant non-tuberculous mycobacteria which are notoriously difficult to treat. Gran1 efficiently inhibited the mycobacterial proliferation in the low micro molar range. Super-resolution fluorescence microscopy and scanning electron microscopy indicated that Gran1 interacts with the surface of Mtb, causing lethal distortions of the cell wall. Importantly, Gran1 showed no off-target effects (cytokine release, chemotaxis, cell death) in primary human cells or zebrafish embryos (cytotoxicity, developmental toxicity, neurotoxicity, cardiotoxicity). Gran1 was selectively internalized by macrophages, the major host cell of Mtb, and restricted the proliferation of the pathogen. Our results demonstrate that the hypothesis-driven design of AMPs is a powerful approach for the identification of small bioactive compounds with specific antimicrobial activity. Gran1 is a promising component for the design of AMP-containing nanoparticles with selective activity and favorable pharmacokinetics to be pushed forward into experimental in vivo models of infectious diseases, most notably tuberculosis.

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An Interlaboratory Evaluation of Five Pairs of Teratogens and Non-teratogens in Post-implantation Rat Embryo Culture

Alternatives to Laboratory Animals ◽

10.1177/026119299602400211 ◽

1996 ◽

Vol 24 (2) ◽

pp. 201-209

Author(s):

Aldert H. Piersma ◽

Rudolf Bechter ◽

Nathalie Krafft ◽

Beat P. Schmid ◽

Jeanne Stadler ◽

...

Keyword(s):

Embryo Culture ◽

Developmental Toxicity ◽

Culture Method ◽

Rat Embryo ◽

Good Correspondence ◽

Substituted Pyridines ◽

Phthalic Ester ◽

Rat Embryo Culture ◽

Post Implantation

The usefulness of the post-implantation rat embryo culture method in screening xenobiotic compounds for developmental toxicity was validated in four laboratories with five pairs of compounds. This approach was chosen to provide information on the interlaboratory reproducibility of the results and to compare the effects of chemical analogues in embryo culture. By testing analogous compounds which are known to have different embryotoxic potencies in vivo, the discriminating power of the embryo culture method for the compound classes under study could be optimally assessed. The classes selected for testing were triazole antifungals, phthalic ester metabolites, substituted pyridines, sulphonamides and methylated xanthines. In summary, it was possible to distinguish between the compounds in three of the pairs, it was not possible to discriminate between the compounds of one pair, and it was possible to discriminate between the compounds of the other pair at two out of the four laboratories. The embryo culture results generally show a good correspondence with the embryotoxic properties of the compounds tested in vivo, although the embryo culture method appeared to be able to discriminate between only some of the pairs of chemical analogues. Some discrepancies may have arisen among the laboratories, because of methodological differences. These results suggest that the post-implantation rat embryo culture method may be a useful tool for screening xenobiotics within classes of compounds known to interfere with embryogenesis during the period of development represented in culture.

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Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

Archives of Toxicology ◽

10.1007/s00204-021-03128-7 ◽

2021 ◽

Author(s):

Danlei Wang ◽

Maartje H. Rietdijk ◽

Lenny Kamelia ◽

Peter J. Boogaard ◽

Ivonne M. C. M. Rietjens

Keyword(s):

Dose Response ◽

In Silico ◽

Response Curve ◽

Developmental Toxicity ◽

Toxicity Testing ◽

Maximal Effect ◽

Blood Concentrations ◽

Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

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Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives

Journal of Personalized Medicine ◽

10.3390/jpm11050336 ◽

2021 ◽

Vol 11 (5) ◽

pp. 336

Author(s):

Mohammed Ghiboub ◽

Ahmed M. I. Elfiky ◽

Menno P. J. de Winther ◽

Nicola R. Harker ◽

David F. Tough ◽

...

Keyword(s):

Histone Deacetylases ◽

Inflammatory Diseases ◽

Selective Inhibition ◽

In Vivo Studies ◽

Beneficial Effects ◽

Domain Specific ◽

Recent Advances ◽

Autoimmune And Inflammatory Diseases

Histone deacetylases (HDACs) and bromodomain-containing proteins (BCPs) play a key role in chromatin remodeling. Based on their ability to regulate inducible gene expression in the context of inflammation and cancer, HDACs and BCPs have been the focus of drug discovery efforts, and numerous small-molecule inhibitors have been developed. However, dose-limiting toxicities of the first generation of inhibitors, which typically target multiple HDACs or BCPs, have limited translation to the clinic. Over the last decade, an increasing effort has been dedicated to designing class-, isoform-, or domain-specific HDAC or BCP inhibitors, as well as developing strategies for cell-specific targeted drug delivery. Selective inhibition of the epigenetic modulators is helping to elucidate the functions of individual epigenetic proteins and has the potential to yield better and safer therapeutic strategies. In accordance with this idea, several in vitro and in vivo studies have reported the ability of more selective HDAC/BCP inhibitors to recapitulate the beneficial effects of pan-inhibitors with less unwanted adverse events. In this review, we summarize the most recent advances with these strategies, discussing advantages and limitations of these approaches as well as some therapeutic perspectives, focusing on autoimmune and inflammatory diseases.

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Novel 64Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases

ACS Medicinal Chemistry Letters ◽

10.1021/ml400191z ◽

2013 ◽

Vol 4 (9) ◽

pp. 858-862 ◽

Cited By ~ 11

Author(s):

Qingqing Meng ◽

Feng Li ◽

Sheng Jiang ◽

Zheng Li

Keyword(s):

Pet Imaging ◽

Histone Deacetylases

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