1
Department of Biochemistry, Universidade Federal de São Paulo, Escola Paulista de Medicina, SP, Brazil
› InstitutsangabenGefördert durch:
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Finance Code 001
Gefördert durch:
Fundação de Amparo à Pesquisa do Estado de São Paulo
72017/06630-2017/07972-9
Gefördert durch:
Conselho Nacional de Desenvolvimento Científico e Tecnológico
401452/2016-6
Gefördert durch:
Conselho Nacional de Desenvolvimento Científico e Tecnológico
406542/2013-9
Proteases play a pivotal role in many signaling pathways; inhibitors of well-established proteases have shown a substantial therapeutic success. This study aimed to examine the in vivo effects of 3 protease inhibitors isolated from Bauhinia species: i) Bauhinia mollis elastase inhibitor, which blocks human neutrophil elastase (Kiapp 2.8 nM) and cathepsin G (Kiapp 1.0 nM) activities; ii) Bauhinia mollis trypsin inhibitor, a trypsin inhibitor (Kiapp 5.0 nM); and iii) Bauhinia bauhinioides cruzipain inhibitor, which inhibits elastase (Kiapp 2.6 nM), cathepsin G (Kiapp 160.0 nM), and the cysteine proteases cathepsin L (Kiapp 0.2 nM). Bauhinia bauhinioides cruzipain inhibitor, Bauhinia mollis elastase inhibitor, and Bauhinia mollis trypsin inhibitor were isolated using acetone and ammonium sulfate fractionations, DEAE-Sephadex, trypsin-Sepharose, and
Resource-Q chromatographies. Mice and rats were treated intraperitoneally with 1 dose of inhibitor; gastric mucosal lesions were induced by cold-restraint stress. Oral pretreatment of mice with Bauhinia mollis elastase inhibitor or Bauhinia mollis trypsin inhibitor (1 – 10 mg/kg) did not show anti-ulcer effect, while Bauhinia bauhinioides cruzipain inhibitor (0.1 – 1.0 mg/kg) produced a similar reduction of the index of mucosal damage at all effective doses (30 to 33% < control). In rats at doses lower than those used in mice, Bauhinia mollis elastase inhibitor and Bauhinia bauhinioides cruzipain inhibitor reduced the index of mucosal damage by 66% and 54% of controls, respectively. The results indicate a protective effect against gastric mucosal lesions associated with elastase inhibition but not inhibition of trypsin activities. Moreover, the lack of Bauhinia mollis elastase inhibitor efficacy observed in mice may possibly
be related to the reported structural differences of elastase in mice and rats.
3
Bhalke RD,
Giri MA,
Pal SC.
Antiulcer activity of methanol extract of leaves of Bauhinia racemosa Linn (Leguminaceae). Research J Pharm and Tech 2010; 4: 124-127
12
Kushimoto S,
Okajima K,
Okabe H,
Binder BR.
Role of granulocyte elastase in the formation of hemorrhagic shock-induced gastric mucosal lesions in the rat. Crit Care Med 1996; 24: 1041-1046
13
Liu W,
Okajima K,
Murakami K,
Harada N,
Isobe H,
Irie T.
Role of neutrophil elastase in stress-induced gastric mucosal injury in rats. J Lab Clin Med 1998; 132: 432-439
14
Murakami K,
Okajima K,
Uchiba M,
Harada N,
Liu W,
Okabe H,
Takatsuki K.
Role of granulocyte elastase in indomethacininduced gastric mucosal lesion formation in rats. J Lab Clin Med 1997; 130: 307-313
16
Okajima K,
Murakami K,
Liu W,
Uchiba M.
Inhibition of neutrophil activation by ranitidine contributes to prevent stress-induced gastric mucosal injury in rats. Crit Care Med 2000; 28: 2858-2865
18
Kessenbrock K,
Dau T,
Jenne DE.
Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response. J Mol Med 2011; 89: 23-28
19
Korkmaz B,
Horwitz MS,
Jenne DE,
Gauthier F.
Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 2010; 62: 726-759
24
Bonaventura A,
Liberale L,
Carbone F,
Vecchié A,
Diaz-Cañestro C,
Camici GG,
Montecucco F,
Dallegri F.
The pathophysiological role of neutrophil extracellular traps in inflammatory diseases. Thromb Haemost 2018; 118: 6-27
27
Sampieri CL,
de la Peña S,
Ochoa-Lara M,
Zenteno-Cuevas R,
León-Córdoba K.
Expression of matrix metalloproteinases 2 and 9 in human gastric cancer and superficial gastritis. World J Gastroenterol 2010; 16: 1500-1505
28
Bulgari M,
Sangiovanni E,
Colombo E,
Maschi O,
Caruso D,
Bosisio E,
DellʼAgli M.
Inhibition of neutrophil elastase and metalloprotease-9 of human adenocarcinoma gastric cells by chamomile (Matricaria recutita L.) infusion. Phytother Res 2012; 26: 1817-1822
30
Harada N,
Okajima K,
Liu W.
Rebamipide decreases the susceptibility of gastric mucosa to acid-induced injury in rats by inhibiting neutrophil activation. Dig Dis Sci 2005; 50: 56-62
32
Heinz A,
Jung MC,
Jahreis G,
Rusciani A,
Duca L,
Debelle L,
Weiss AS,
Neubert RHH,
Schmelzer CEH.
The action of neutrophil serine proteases on elastin and its precursor. Biochimie 2012; 94: 192-202
33
Johnson D,
Travis J.
The oxidative inactivation of human alpha-1-proteinase inhibitor. Further evidence for methionine at the reactive center. J Biol Chem 1979; 254: 4022-4026
34
Beatty K,
Bieth J,
Travis J.
Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem 1980; 255: 3931-3934
35
Taggart C,
Cervantes-Laurean D,
Kim G,
McElvaney NG,
Wehr N,
Moss J,
Levine RL.
Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity. J Biol Chem 2000; 275: 27258-27265
37
Oliva MLV,
Mendes CR,
Juliano MA,
Chagas JR,
Rosa JC,
Greene LJ,
Sampaio MU,
Sampaio CA.
Characterization of a tissue kallikrein inhibitor isolated from Bauhinia bauhinioides seeds: inhibition of the hydrolysis of kininogen related substrates. Immunopharmacology 1999; 45: 163-169
