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Annals of the Rheumatic Diseases Sep 2016Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.
OBJECTIVES
Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.
METHODS
3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone.
RESULTS
Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone.
CONCLUSIONS
Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.
Topics: Animals; Anterior Cruciate Ligament; Bone Remodeling; Bone Resorption; Bone and Bones; Cartilage, Articular; Disease Models, Animal; Disease Progression; Male; Mice; Mice, Inbred C57BL; Osteoarthritis; Osteoclasts; Piperidines; Quinazolinones; Random Allocation; Rats; Rats, Inbred Lew; Transforming Growth Factor beta
PubMed: 26470720
DOI: 10.1136/annrheumdis-2015-207923 -
International Journal of Nanomedicine 2021Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against...
BACKGROUND
Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects.
METHODS
HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs.
RESULTS
The optimized HTPMs had an HD of 17.8±0.5 nm and ZP of 14.40±0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility.
CONCLUSION
The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Compounding; Female; Humans; Membrane Potential, Mitochondrial; Mice, Inbred BALB C; Mice, Nude; Micelles; Paclitaxel; Piperidines; Polymers; Quinazolinones; Reactive Oxygen Species; Treatment Outcome; Triple Negative Breast Neoplasms; Vitamin E; Mice
PubMed: 33664573
DOI: 10.2147/IJN.S289096 -
Drug Discovery Today Sep 2022Halofuginone is a clinically active derivative of febrifugine that was first isolated from the Chinese herb Dichroa febrifuga. The beneficial biological effects of... (Review)
Review
Halofuginone is a clinically active derivative of febrifugine that was first isolated from the Chinese herb Dichroa febrifuga. The beneficial biological effects of halofuginone on various diseases including parasitic diseases, cancer, fibrosis, and autoimmune disorders have been investigated. Halofuginone has reduced toxic side effects when compared to febrifugine, an advantage that has led to the commercial availability of halofuginone-based antiparasitic drugs for animal use, and to human clinical trials for the treatment of tumors and fibrosis. This review summarizes advances in determining the mechanism of action of halofuginone, focusing on its antiparasitic role in malaria, cryptosporidiosis, coccidiosis, toxoplasmosis, and leishmaniasis. We discuss mechanistic insights into halofuginone's primary mode of action which involves inhibition of the prolyl-tRNA synthetase enzyme, which is crucial in protein synthesis. Halofuginone exemplifies the untapped wealth of plant-derived compounds in disease therapeutics.
Topics: Animals; Antiprotozoal Agents; Fibrosis; Humans; Malaria; Piperidines; Quinazolinones
PubMed: 35636724
DOI: 10.1016/j.drudis.2022.05.020 -
Nano-encapsulation of halofuginone hydrobromide enhances anticoccidial activity against in chickens.Biomaterials Science Feb 2023Coccidiosis is a worldwide epidemic intestinal disease with high incidence, which causes huge economic losses. Halofuginone hydrobromide (HF) is widely applied as an...
Coccidiosis is a worldwide epidemic intestinal disease with high incidence, which causes huge economic losses. Halofuginone hydrobromide (HF) is widely applied as an effective anticoccidial drug in the poultry industry. However, its therapeutic efficacy is severely restrained due to toxic effects, poor aqueous solubility and low permeability. Nanotechnology can improve the biological effect of drugs, and thus, reduce administered doses and toxic effects. The objective of this study was to investigate the therapeutic and preventive potential of novel HF-loaded D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) polymer micelles (HTPM) for preventing coccidiosis in chickens. The HTPM were approximately spherical with a hydrodynamic diameter of 12.65 ± 0.089 nm, a zeta potential of 8.03 ± 0.242 mV, a drug loading of 14.04 ± 0.12%, and an encapsulation efficiency of 71.1 ± 4.15%. HF was encapsulated in the polymer micelles through interactions with TPGS, as characterized by X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy. Cellular take up assays showed that TPGS polymer micelles could enhance drug internalization to alleviate intestinal apoptosis induced by coccidiosis and promote the necrosis of second-generation merozoites of . Notably, clinical trials proved that 1.5 mg L HTPM had a stronger anticoccidial effect on than that of 3 mg kg HF premix. Amplicon sequencing identified that HTPM could alleviate coccidiosis by restoring the structure of the gut microbiome. These findings indicated that the anticoccidial efficacy of HF was significantly enhanced after being encapsulated in polymer micelles, and further demonstrated the potential protective application of nano-encapsulating anticoccidial drugs as a promising approach to control coccidiosis in poultry. In summary, HTPM hold huge potential as an effective therapeutic agent for coccidiosis.
Topics: Animals; Eimeria tenella; Coccidiostats; Chickens; Micelles; Spectroscopy, Fourier Transform Infrared; Poultry Diseases; Coccidiosis; Polymers
PubMed: 36648120
DOI: 10.1039/d2bm01543a -
Molecules (Basel, Switzerland) Jan 2015Halofuginone is an analog of febrifugine-an alkaloid originally isolated from the plant Dichroa febrifuga. During recent years, halofuginone has attracted much attention... (Review)
Review
Halofuginone is an analog of febrifugine-an alkaloid originally isolated from the plant Dichroa febrifuga. During recent years, halofuginone has attracted much attention because of its wide range of beneficial biological activities, which encompass malaria, cancer, and fibrosis-related and autoimmune diseases. At present two modes of halofuginone actions have been described: (1) Inhibition of Smad3 phosphorylation downstream of the TGFβ signaling pathway results in inhibition of fibroblasts-to-myofibroblasts transition and fibrosis. (2) Inhibition of prolyl-tRNA synthetase (ProRS) activity in the blood stage of malaria and inhibition of Th17 cell differentiation thereby inhibiting inflammation and the autoimmune reaction by activation of the amino acid starvation and integrated stress responses. This review deals with the history and origin of this natural product, its synthesis, its known modes of action, and it's various biological activities in pre-clinical animal models and in humans.
Topics: Animals; Antimalarials; Antineoplastic Agents; Antiprotozoal Agents; Apoptosis; Clinical Trials as Topic; Humans; Piperidines; Quinazolinones
PubMed: 25569515
DOI: 10.3390/molecules20010573 -
Journal of Leukocyte Biology Dec 2017Fibrosis, which can be defined as an abnormal or excessive accumulation of extracellular matrix (ECM), particularly fibrillar collagens, is a key driver of progressive... (Review)
Review
Fibrosis, which can be defined as an abnormal or excessive accumulation of extracellular matrix (ECM), particularly fibrillar collagens, is a key driver of progressive organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), cirrhosis, nephropathy, and oral submucous fibrosis (OSF). It has been estimated to contribute to ∼45% of deaths in the developed world. Therefore, agents that target specific fibrotic pathways, with the consequence of slowing, arresting, or even reversing the progression of tissue fibrogenesis, are urgently needed. 7-Bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone (halofuginone), an analog of febrifugine, which specifically targets the pathogenesis of ECM proteins, inhibits tissue fibrosis and regeneration and even affects the development of tumors in various tissues. Four modes of actions of halofuginone against fibrosis have been presented: 1) Inhibition of mothers against decapentaplegic homolog 3 (Smad3) phosphorylation downstream of the TGF-β signaling pathway, 2) reduction of collagen amounts, 3) decreases in ECM protein, and 4) selective prevention of Th17 cell differentiation. In this review, we will mainly focus on the rationale for halofuginone against fibrosis.
Topics: Animals; Collagen; Extracellular Matrix Proteins; Fibrosis; Humans; Models, Biological; Piperidines; Quinazolinones; Th17 Cells
PubMed: 28986385
DOI: 10.1189/jlb.3RU0417-148RR -
EFSA Journal. European Food Safety... Nov 2020Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific...
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the coccidiostat STENOROL containing halofuginone hydrobromide (halofuginone HBr) as active substance. The FEEDAP Panel was not able to conclude on the safety of STENOROL for chickens and turkeys for fattening at the highest proposed use level. No incompatibilities or interactions with feedingstuffs, carriers, other approved additives or medicinal drugs are expected. Halofuginone HBr does not have antimicrobial activity at the highest dose proposed; it is not expected to exert adverse effects on chicken gut microbiota or select for resistance and cross-resistance with other antimicrobials. The Panel cannot conclude on the genotoxic potential of halofuginone HBr since an appropriate follow-up to exclude the mutagenic effect of the compound was not available. Therefore, the FEEDAP Panel cannot conclude on the safety of halofuginone HBr for the consumer. The additive is toxic by inhalation, dermal and ocular routes and is very irritant to both the eye and the skin. It is considered also a skin sensitiser. Inhalation exposure is considered a risk to persons handling the additive. Since the lack of genotoxic potential of halofuginone HBr has not been adequately demonstrated, it should be considered as an additional potential concern to users handling the additive. Due to limitations in some of the ecotoxicological studies, no conclusions can be drawn on the safety of the additive for the environment. The FEEDAP Panel is not in the position to conclude on the efficacy of STENOROL in chickens for fattening and in turkeys for fattening.
PubMed: 33209147
DOI: 10.2903/j.efsa.2020.6169 -
EFSA Journal. European Food Safety... Dec 2022Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety for the target species of the coccidiostat halofuginone...
Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety for the target species of the coccidiostat halofuginone hydrobromide from STENOROL® when used as a feed additive for chickens for fattening and turkeys. In its previous assessment, the FEEDAP Panel could not conclude on the safety of STENOROL® for the target species at the highest proposed use level of 3 mg halofuginone hydrobromide/kg complete feed. On the basis of the new data provided, the FEEDAP Panel updates its previous conclusions on the safety for the target species as follows: halofuginone hydrobromide from STENOROL® is safe for chickens for fattening and for turkeys up to a maximum of 12 weeks of age at the highest proposed concentration of 3 mg/kg complete feed. For chickens for fattening, a margin of safety of about 1.3 can be established while for turkeys for fattening a margin of safety cannot be established.
PubMed: 36545572
DOI: 10.2903/j.efsa.2022.7716 -
Circulation Research Aug 2020Increased protein synthesis of profibrotic genes is a common feature in cardiac fibrosis and heart failure. Despite this observation, critical factors and molecular...
RATIONALE
Increased protein synthesis of profibrotic genes is a common feature in cardiac fibrosis and heart failure. Despite this observation, critical factors and molecular mechanisms for translational control of profibrotic genes during cardiac fibrosis remain unclear.
OBJECTIVE
To investigate the role of a bifunctional ARS (aminoacyl-tRNA synthetase), EPRS (glutamyl-prolyl-tRNA synthetase) in translational control of cardiac fibrosis.
METHODS AND RESULTS
Results from reanalyses of multiple publicly available data sets of human and mouse heart failure, demonstrated that EPRS acted as an integrated node among the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at mRNA and protein levels (≈1.5-2.5-fold increase) in failing hearts compared with nonfailing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of globally () using CRISPR-Cas9 technology or in a Postn-Cre-dependent manner (; ) strongly reduces cardiac fibrosis (≈50% reduction) in isoproterenol-, transverse aortic constriction-, and myocardial infarction (MI)-induced heart failure mouse models. Inhibition of EPRS using a PRS (prolyl-tRNA synthetase)-specific inhibitor, halofuginone, significantly decreases translation efficiency (TE) of proline-rich collagens in cardiac fibroblasts as well as TGF-β (transforming growth factor-β)-activated myofibroblasts. Overexpression of EPRS increases collagen protein expression in primary cardiac fibroblasts under TGF-β stimulation. Using transcriptome-wide RNA-Seq and polysome profiling-Seq in halofuginone-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 (latent TGF-β-binding protein 2) and Sulf1 (sulfatase 1), which are translationally regulated by EPRS. SULF1 is highly enriched in human and mouse myofibroblasts. In the primary cardiac fibroblast culture system, siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition. Overexpression of SULF1 promotes TGF-β-induced myofibroblast activation and partially antagonizes anti-fibrotic effects of halofuginone treatment.
CONCLUSIONS
Our results indicate that EPRS preferentially controls translational activation of proline codon rich profibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling. Graphical Abstract: A graphical abstract is available for this article.
Topics: Amino Acyl-tRNA Synthetases; Animals; Case-Control Studies; Collagen; Disease Models, Animal; Enzyme Inhibitors; Female; Fibrosis; Heart Failure; Humans; Latent TGF-beta Binding Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Myofibroblasts; NIH 3T3 Cells; Proline-Rich Protein Domains; Protein Biosynthesis; Signal Transduction; Sulfotransferases
PubMed: 32611237
DOI: 10.1161/CIRCRESAHA.119.315999 -
Bioorganic & Medicinal Chemistry Apr 2014The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product febrifugine (also known as dichroine B) and its synthetic analogue, halofuginone,... (Review)
Review
The trans-2,3-disubstituted piperidine, quinazolinone-containing natural product febrifugine (also known as dichroine B) and its synthetic analogue, halofuginone, possess antimalarial activity. More recently studies have also shown that halofuginone acts as an agent capable of reducing fibrosis, an indication with clinical relevance for several disease states. This review summarizes historical isolation studies and the chemistry performed which culminated in the correct structural elucidation of naturally occurring febrifugine and its isomer isofebrifugine. It also includes the range of febrifugine analogues prepared for antimalarial evaluation, including halofuginone. Finally, a section detailing current opinion in the field of halofuginone's human biology is included.
Topics: Antimalarials; Humans; Molecular Structure; Parasitic Sensitivity Tests; Piperidines; Plasmodium; Quinazolines; Quinazolinones; Structure-Activity Relationship
PubMed: 24650700
DOI: 10.1016/j.bmc.2014.02.040