scholarly journals The anthelmintic efficacy of plant-derived cysteine proteinases against the rodent gastrointestinal nematode, Heligmosomoides polygyrus, in vivo

Parasitology ◽  
2007 ◽  
Vol 134 (10) ◽  
pp. 1409-1419 ◽  
Author(s):  
G. STEPEK ◽  
A. E. LOWE ◽  
D. J. BUTTLE ◽  
I. R. DUCE ◽  
J. M. BEHNKE
Keyword(s):  
Cysteine Proteinase ◽  
Treatment Plant ◽  
Specific Inhibitor ◽  
Gastrointestinal Nematode ◽  
New Drugs ◽  
Intestinal Lumen ◽  
Cysteine Proteinases ◽  
Heligmosomoides Polygyrus

SUMMARYGastrointestinal (GI) nematodes are important disease-causing organisms, controlled primarily through treatment with synthetic drugs, but the efficacy of these drugs has declined due to widespread resistance, and hence new drugs, with different modes of action, are required. Some medicinal plants, used traditionally for the treatment of worm infections, contain cysteine proteinases known to damage worms irreversibly in vitro. Here we (i) confirm that papaya latex has marked efficacy in vivo against the rodent gastrointestinal nematode, Heligmosomoides polygyrus, (ii) demonstrate the dose-dependent nature of the activity (>90% reduction in egg output and 80% reduction in worm burden at the highest active enzyme concentration of 133 nmol), (iii) establish unequivocally that it is the cysteine proteinases that are the active principles in vivo (complete inhibition of enzyme activity when pre-incubated with the cysteine proteinase-specific inhibitor, E-64) and (iv) show that activity is confined to worms that are in the intestinal lumen. The mechanism of action was distinct from all current synthetic anthelmintics, and was the same as that in vitro, with the enzymes attacking and digesting the protective cuticle. Treatment had no detectable side-effects on immune cell numbers in the mucosa (there was no difference in the numbers of mast cells and goblet cells between the treated groups) and mucosal architecture (length of intestinal villi). Only the infected and untreated mice had much shorter villi than the other 3 groups, which was a consequence of infection and not treatment. Plant-derived cysteine proteinases are therefore prime candidates for development as novel drugs for the treatment of GI nematode infections.

scholarly journals Assessment of the anthelmintic effect of natural plant cysteine proteinases against the gastrointestinal nematode, Heligmosomoides polygyrus, in vitro

Parasitology ◽  
2004 ◽  
Vol 130 (2) ◽  
pp. 203-211 ◽  
Author(s):  
G. STEPEK ◽  
D. J. BUTTLE ◽  
I. R. DUCE ◽  
A. LOWE ◽  
J. M. BEHNKE
Keyword(s):  
Mechanism Of Action ◽  
Cysteine Proteinase ◽  
Gastrointestinal Nematode ◽  
Cysteine Proteinase Inhibitor ◽  
Cysteine Proteinases ◽  
Fruit Extract ◽  
Potent Effect ◽  
Kiwi Fruit ◽  
Heligmosomoides Polygyrus

We examined the mechanism of action and compared the anthelmintic efficacy of cysteine proteinases from papaya, pineapple, fig, kiwi fruit and Egyptian milkweed in vitro using the rodent gastrointestinal nematode Heligmosomoides polygyrus. Within a 2 h incubation period, all the cysteine proteinases, with the exception of the kiwi fruit extract, caused marked damage to the cuticle of H. polygyrus adult male and female worms, reflected in the loss of surface cuticular layers. Efficacy was comparable for both sexes of worms, was dependent on the presence of cysteine and was completely inhibited by the cysteine proteinase inhibitor, E-64. LD50 values indicated that the purified proteinases were more efficacious than the proteinases in the crude latex, with purified ficin, papain, chymopapain, Egyptian milkweed latex extract and pineapple fruit extract, containing fruit bromelain, having the most potent effect. The mechanism of action of these plant enzymes (i.e. an attack on the protective cuticle of the worm) suggests that resistance would be slow to develop in the field. The efficacy and mode of action make plant cysteine proteinases potential candidates for a novel class of anthelmintics urgently required for the treatment of humans and domestic livestock.

scholarly journals RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

2018 ◽  
Vol 47 (3) ◽  
pp. 1152-1166 ◽  
Author(s):  
Guang-Yang Yu ◽  
Xuan Wang ◽  
Su-Su Zheng ◽  
Xiao-Mei Gao ◽  
Qing-An Jia ◽  
...  
Keyword(s):  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Cell Apoptosis ◽  
Specific Inhibitor ◽  
New Drugs ◽  
Proteasome Subunit ◽  
Therapeutic Benefits ◽  
Pdx Models

Background/Aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. Methods: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. Results: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. Conclusions: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

scholarly journals Anthelmintic action of plant cysteine proteinases against the rodent stomach nematode,Protospirura muricola,in vitroandin vivo

Parasitology ◽  
2006 ◽  
Vol 134 (1) ◽  
pp. 103-112 ◽  
Author(s):  
G. STEPEK ◽  
A. E. LOWE ◽  
D. J. BUTTLE ◽  
I. R. DUCE ◽  
J. M. BEHNKE
Keyword(s):  
Detrimental Effect ◽  
Gastrointestinal Nematodes ◽  
Cysteine Proteinases ◽  
Trichuris Muris ◽  
Kiwi Fruit ◽  
Heligmosomoides Polygyrus ◽  
Anthelmintic Efficacy ◽  
Papaya Latex

Cysteine proteinases from the fruit and latex of plants, including papaya, pineapple and fig, were previously shown to have a rapid detrimental effect,in vitro, against the rodent gastrointestinal nematodes,Heligmosomoides polygyrus(which is found in the anterior small intestine) andTrichuris muris(which resides in the caecum). Proteinases in the crude latex of papaya also showed anthelmintic efficacy against both nematodesin vivo. In this paper, we describe thein vitroandin vivoeffects of these plant extracts against the rodent nematode,Protospirura muricola, which is found in the stomach. As in earlier work, all the plant cysteine proteinases examined, with the exception of actinidain from the juice of kiwi fruit, caused rapid loss of motility and digestion of the cuticle, leading to death of the nematodein vitro. In vivo, in contrast to the efficacy againstH. polygyrusandT. muris, papaya latex only showed efficacy againstP. muricolaadult female worms when the stomach acidity had been neutralized prior to administration of papaya latex. Therefore, collectively, our studies have demonstrated that, with the appropriate formulation, plant cysteine proteinases have efficacy against nematodes residing throughout the rodent gastrointestinal tract.

scholarly journals In vitro anthelmintic effects of cysteine proteinases from plants against intestinal helminths of rodents

2007 ◽  
Vol 81 (4) ◽  
pp. 353-360 ◽  
Author(s):  
Gillian Stepek ◽  
Ann E. Lowe ◽  
David J. Buttle ◽  
Ian R. Duce ◽  
Jerzy M. Behnke
Keyword(s):  
Rapid Development ◽  
Intestinal Helminths ◽  
Cysteine Proteinases ◽  
Trichuris Muris ◽  
Heligmosomoides Polygyrus ◽  
Development Of Resistance ◽  
Taxonomic Groups ◽  
Gi Helminths

AbstractInfections with gastrointestinal (GI) nematodes are amongst the most prevalent worldwide, especially in tropical climates. Control of these infections is primarily through treatment with anthelmintic drugs, but the rapid development of resistance to all the currently available classes of anthelmintic means that alternative treatments are urgently required. Cysteine proteinases from plants such as papaya, pineapple and fig are known to be substantially effective against three rodent GI nematodes, Heligmosomoides polygyrus, Trichuris muris and Protospirura muricola, both in vitro and in vivo. Here, based on in vitro motility assays and scanning electron microscopy, we extend these earlier reports, demonstrating the potency of this anthelmintic effect of plant cysteine proteinases against two GI helminths from different taxonomic groups – the canine hookworm, Ancylostoma ceylanicum, and the rodent cestode, Rodentolepis microstoma. In the case of hookworms, a mechanism of action targeting the surface layers of the cuticle indistinguishable from that reported earlier appears to be involved, and in the case of cestodes, the surface of the tegumental layers was also the principal location of damage. Hence, plant cysteine proteinases have a broad spectrum of activity against intestinal helminths (both nematodes and cestodes), a quality that reinforces their suitability for development as a much-needed novel treatment against GI helminths of humans and livestock.

scholarly journals Nematicidal effects of cysteine proteinases against sedentary plant parasitic nematodes

Parasitology ◽  
2007 ◽  
Vol 134 (12) ◽  
pp. 1831-1838 ◽  
Author(s):  
G. STEPEK ◽  
R. H. C. CURTIS ◽  
B. R. KERRY ◽  
P. R. SHEWRY ◽  
S. J. CLARK ◽  
...  
Keyword(s):  
Plant Extracts ◽  
Specific Inhibitor ◽  
Parasitic Nematodes ◽  
Cysteine Proteinases ◽  
Plant Parasitic Nematodes ◽  
Second Stage ◽  
Anthelmintic Efficacy ◽  
Plant Parasitic

SUMMARYCysteine proteinases from the fruit and latex of plants, such as papaya, pineapple and fig, have previously been shown to have substantial anthelmintic efficacy, in vitro and in vivo, against a range of animal parasitic nematodes. In this paper, we describe the in vitro effects of these plant extracts against 2 sedentary plant parasitic nematodes of the genera Meloidogyne and Globodera. All the plant extracts examined caused digestion of the cuticle and decreased the activity of the tested nematodes. The specific inhibitor of cysteine proteinases, E-64, blocked this activity completely, indicating that it was essentially mediated by cysteine proteinases. In vitro, plant cysteine proteinases are active against second-stage juveniles of M. incognita and M. javanica, and some cysteine proteinases also affect the second-stage juveniles of Globodera rostochiensis. It is not known yet whether these plant extracts will interfere with, or prevent invasion of, host plants.

scholarly journals Streptococcal cysteine proteinase releases kinins: a virulence mechanism.

1996 ◽  
Vol 184 (2) ◽  
pp. 665-673 ◽  
Author(s):  
H Herwald ◽  
M Collin ◽  
W Müller-Esterl ◽  
L Björck
Keyword(s):  
Ex Vivo ◽  
Direct Action ◽  
Cysteine Proteinase ◽  
Intraperitoneal Administration ◽  
Specific Inhibitor ◽  
Biologically Active ◽  
Bacterial Proteinase ◽  
Streptococcal Proteinase

Previous work has indicated a crucial role for the extracellular cysteine proteinase of Streptococcus pyogenes in the pathogenicity and virulence of this important human pathogen. Here we find that the purified streptococcal cysteine proteinase releases biologically active kinins from their purified precursor protein, H-kininogen, in vitro, and from kininogens present in the human plasma, ex vivo. Kinin liberation in the plasma is due to the direct action of the streptococcal proteinase on the kininogens, and does not involve the previous activation of plasma prekallikrein, the physiological plasma kininogenase. Judged from the amount of released plasma kinins the bacterial proteinase is highly efficient in its action. This is also the case in vivo. Injection of the purified cysteine proteinase into the peritoneal cavity of mice resulted in a progressive cleavage of plasma kininogens and the concomitant release of kinins over a period of 5 h. No kininogen degradation was seen in mice when the cysteine proteinase was inactivated by the specific inhibitor, Z-Leu-Val-Gly-CHN2, before administration. Intraperitoneal administration into mice of living S. pyogenes bacteria producing the cysteine proteinase induced a rapid breakdown of endogenous plasma kininogens and release of kinins. Kinins are hypotensive, they increase vascular permeability, contract smooth muscle, and induce fever and pain. The release of kinins by the cysteine proteinase of S. pyogenes could therefore represent an important and previously unknown virulence mechanism in S. pyogenes infections.

Cysteine proteinase activity is required for survival of the parasite in experimental acute amoebic liver abscesses in hamsters

Parasitology ◽  
2004 ◽  
Vol 129 (1) ◽  
pp. 19-25 ◽  
Author(s):  
A. OLIVOS-GARCÍA ◽  
E. TELLO ◽  
M. NEQUIZ-AVENDAÑO ◽  
A. GONZÁLEZ-CANTO ◽  
R. LÓPEZ-VANCELL ◽  
...  
Keyword(s):  
Mdck Cells ◽  
Cysteine Proteinase ◽  
Proteinase Activity ◽  
Target Cells ◽  
Cysteine Proteinases ◽  
Irreversible Inhibitor ◽  
Liver Abscesses ◽  
Cysteine Proteinase Activity

Axenic trophozoites ofEntamoeba histolyticastrain HM1-IMSS grownin vitroin the presence of E-64, a potent irreversible inhibitor of cysteine proteinases, preserved their viability, their rate of replication, their resistance to complement, their haemolytic capacity and their ability to destroy target cells, despite complete inhibition of total cysteine proteinase activity. On the other hand, their erythrophagocytic capacity and their ability to decrease TER of MDCK cells was partially decreased. The same trophozoites injected into the portal vein of hamsters receiving a maintaining dose of E-64 failed to cause tissue damage and were rapidly eliminated. Our results suggest that amoebic cysteine proteinase activity is not required for amoebic functions inin vitroconditions, but that it becomes necessary for survival of trophozoites inin vivoconditions, whatever other role (if any) it may play in the parasite's virulence.

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Reyaz Hassan Mir ◽  
Abdul Jalil Shah ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Potoo ◽  
Mohd. Akbar Dar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Protective Action ◽  
New Drugs ◽  
Huperzine A ◽  
Brain Disorder ◽  
Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

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