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Future Therapy of Interstitial Lung Diseases
Published in Lourdes R. Laraya-Cuasay, Walter T. Hughes, Interstitial Lung Diseases in Children, 2019
It has long been established that lathyrogens such as ß-aminopropionitrile (BAPN) inhibit collagen formation. In experimental pulmonary fibrosis, BAPN has been shown to be effective in preventing collagen accumulation in silica,24 bleomycin,25,26 radiation,27 and cadmium chloride-induced fibrosis.28 There are many published reports on the toxic effects of BAPN on growing animals, a syndrome termed osteolathyrism, characterized by dislocations of joints, spinal deformities, and hind limb paralysis. It is less clear whether osteolathyrism develops in adult animals after a prolonged exposure; most reports suggest no effect or a milder disorder. The use and toxicity of BAPN has been evaluated in a few human trials of fibrosing diseases.13 Although some serious side effects such as rash, abnormal liver function tests, fever, and anemia were noted, the drug was well tolerated by most patients when given for a few weeks. Eight patients with severe ARDS and rapidly developing pulmonary fibrosis have been given BAPN intravenously for up to 2 weeks.13 The drug was well tolerated, but there was no obvious clinical benefit.
The Cardiovascular System
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Calvert Louden, David Brott, Chidozie J. Amuzie, Bindu Bennet, Ronnie Chamanza
Although drug-induced changes to the aorta are uncommon, aortic damage and aneurysm formation (with or without necrosis, and or/inflammation) has been reported with angiotensin II, catecholamines, allylamine and beta-aminopropionitrile (Daugherty et al. 2000; Haft 1974; Haft et al. 1972; Kumar et al. 1998; Lu et al. 2008). Aortic aneurysms are characterized by focal necrosis of medial aortic SMC, fragmentation and breaks of the elastic laminae and breakdown in the structural integrity of the aortic wall, resulting in “outpocketing” or nodular protrusions that can lead to rupturing into the thoracic or abdominal cavities. Chronic administration of high doses of adrenalin can produce aortic calcification, reactive inflammation, and saccular aortic dilatation (Haft et al. 1972). Vascular remodeling and alteration in expression of matrix metaloproteinases have been reported as a possible MOA for the development of aortic aneurysm (Nordon et al. 2009). In support of this hypothesis, inhibition of MMP2 and MMP 9 has been associated with aortic aneurysm formation. Aortic aneurysm caused by sweet pea (Lathyrus odoratous) ingestion is due to inhibition of lysyl oxidase by β-aminopropionitrile. Lysyl oxidase plays an important role in cross-linking of collagen and elastin in connective tissues and, therefore, is crucial to maintaining the structural integrity of elastic arteries such as the aorta (Boor et al. 1995).
Diseases Suspected to Be Connected with the Diet
Published in Stephen Seely, David L. J. Freed, Gerald A. Silverstone, Vicky Rippere, Diet-Related Diseases, 1985
Plants produce a whole arsenal of substances capable of interfering with the circulatory system. Haemagglutinins which can cause the clumping of blood corpuscles, are produced by literally hundreds of plants. Dicoumarol14 (or dicumerol, as spelt in American literature) is an antivitamin K present in sweet clover. It is an anticoagulant, capable of causing fatal haemorrhages in animals. (Warfarin, a synthetic chemical used as a rat poison and also as an anticoagulant in medicine, was developed on the model of dicoumarol.) Some fruits (pineapple, banana, avocado) contain serotonin, noradrenaline, dopamine, exactly the same substances, mentioned in the first chapter, which are produced by animals. These have a vasoconstrictor effect and tend to elevate the blood pressure. A substance called aminopropionitrile, present in chick peas and sweet peas, is responsible for the disease named lathyrism. This affects mainly the bones, but also the fibre structure of blood vessels, resulting in loss of elasticity, hence predisposing to rupture (aneurysms). Citral, an antivitamin A present in orange peel, has been observed to cause damage to the endothelium of blood vessels in animals. Gossypol, of male contraceptive fame, also has an effect on the heart, capable of causing death in animals by cardiac irregularity.
Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl4-induced liver fibrosis in rats
Published in Immunopharmacology and Immunotoxicology, 2019
Roohollah Mohseni, Zahra Arab Sadeghabadi, Mohammad Taghi Goodarzi, Jamshid Karimi
The regression of liver fibrosis has become one of the most important challenge facing scientists in recent years [5]. In terms of molecular aspect, lysyl oxidase (LOX) enzyme plays a critical role in the pathogenesis of liver fibrosis. High secretion and activity of LOX limit regression of liver fibrosis [6]. For this reason, downregulation and inhibition of the LOX enzyme can facilitate regression of liver fibrosis. For this reason, targeting the expression and function of LOX can be a new therapeutic approach for inhibiting hepatic fibrosis progression. Although, a recent study showed the selective inhibition of this enzyme by anti-LOX monoclonal antibody (simtuzumab) is not promising [7]. Also, it has been associated with the side effects including dyspnea, cough, and upper respiratory tract infection. On the other hand, the irreversible inhibition of LOX by beta-aminopropionitrile (BAPN) decreased the tissue stiffness by inhibiting collagen crosslinking in liver fibrosis but could not improve liver inflammation [6,7].
Crosslinking Enzyme Lysyl Oxidase Modulates Scleral Remodeling in Form-Deprivation Myopia
Published in Current Eye Research, 2018
Ying Yuan, Min Li, Qingzhong Chen, Rao Me, Yunjie Yu, Qing Gu, Guangsen Shi, Bilian Ke
β-Aminopropionitrile (BAPN) is an irreversible inhibitor of LOX that can bind covalently to the LOX active site and prevent newly synthesized collagen from assembling into the definitive crosslinked form. A previous study reported that inhibition of LOX activity by BAPN increased the progression of form-deprivation myopia (FDM).27 TGF-β is a multifunctional cytokine that is involved in diverse biological processes, including embryonic development, organogenesis, and stress responses.28 Dysfunctions of this cytokine can result in various diseases, including tissue fibrosis, cancer, and hereditary disorders.29,30 TGF-β has been shown to function as a direct inducer of LOX expression in both in vitro and in vivo studies.31 Our previous study revealed that TGF-β1-induced collagen expression in guinea pig scleral fibroblasts.32 However, whether BAPN or TGF-β1 regulated scleral LOX expression and was involved in scleral collagen remodeling are unknown.
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
There is no cure for HGPS. Nevertheless, since the discovery of the HGPS mutation in 2003 [1,2], multiple preclinical studies have continually yielded improvements in the understanding of progerin-dependent cellular and organismal alterations, paving the way for the development of new therapeutic approaches. Numerous drug-based strategies ameliorate progerin-induced alterations in cultured cells (reviewed in [4,5]), but only some have proved beneficial in HGPS mouse models with ubiquitous progerin expression. These include modulating inflammation by targeting NF-κB [6] and IL6 [7], decreasing progerin-lamin A/C interaction by JH4 and progerinin treatment [8,9], inducing progerin clearance by MG132 administration [10], and inhibiting N-acetyltransferase 10 (NAT10) using remodelin [11], although remodelin´s ability to specifically inhibit NAT10-catalyzed RNA acetylation has been recently questioned [12]. Additional molecules have been shown to reduce HGPS-associated cardiovascular alterations, such as tauroursodeoxycholic acid (an endoplasmic reticulum stress inhibitor) [13], β-aminopropionitrile (a lysyl oxidase inhibitor) [14], batimastat (a metalloprotease inhibitor) [15], and paclitaxel (a chemotherapeutic agent that stabilizes microtubules) [16]. Other therapeutic strategies shown to extend the lifespan and/or improve the progeroid phenotype of progerin-expressing mice include pyrophosphate treatment [17] and ATP-based therapy [18], dietary supplementation with sodium nitrite [19] and magnesium [20], dietary methionine restriction [21], and fecal microbiota transplantation from healthy animals [22]. Here, we discuss current and potential treatment options for HGPS based on drugs targeting progerin posttranslational modifications and genetic approaches to correct the HGPS-causing LMNA mutation and aberrant splicing.