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The bacterium Clostridium botulinum, well-known for producing botulinum neurotoxins, which cause the severe paralytic illness known as botulism, produces C2 toxin, a binary AB-toxin with ADP-ribosyltranferase activity. C2 toxin possesses two separate protein components, an enzymatically active A-component C2I and the binding and translocation B-component C2II. After proteolytic activation of C2II to C2IIa, the heptameric structure binds C2I and is taken up via receptor-mediated endocytosis into the target cells. Due to acidification of endosomes, the C2IIa/C2I complex undergoes conformational changes and consequently C2IIa forms a pore into the endosomal membrane and C2I can translocate into the cytoplasm, where it ADP-ribosylates G-actin, a key component of the cytoskeleton. This modification disrupts the actin cytoskeleton, resulting in the collapse of cytoskeleton and ultimately cell death. Here, we show that the serine-protease inhibitor α1-antitrypsin (α1AT) which we identified previously from a hemofiltrate library screen for PT from Bordetella pertussis is a multitoxin inhibitor. α1AT inhibits intoxication of cells with C2 toxin via inhibition of binding to cells and inhibition of enzyme activity of C2I. Moreover, diphtheria toxin and an anthrax fusion toxin are inhibited by α1AT. Since α1AT is commercially available as a drug for treatment of the α1AT deficiency, it could be repurposed for treatment of toxin-mediated diseases.
The bacterium Clostridium botulinum, well-known for producing botulinum neurotoxins, which cause the severe paralytic illness known as botulism, produces C2 toxin, a binary AB-toxin with ADP-ribosyltranferase activity. C2 toxin possesses two separate protein components, an enzymatically active A-component C2I and the binding and translocation B-component C2II. After proteolytic activation of C2II to C2IIa, the heptameric structure binds C2I and is taken up via receptor-mediated endocytosis into the target cells. Due to acidification of endosomes, the C2IIa/C2I complex undergoes conformational changes and consequently C2IIa forms a pore into the endosomal membrane and C2I can translocate into the cytoplasm, where it ADP-ribosylates G-actin, a key component of the cytoskeleton. This modification disrupts the actin cytoskeleton, resulting in the collapse of cytoskeleton and ultimately cell death. Here, we show that the serine-protease inhibitor α1-antitrypsin (α1AT) which we identified previously from a hemofiltrate library screen for PT from Bordetella pertussis is a multitoxin inhibitor. α1AT inhibits intoxication of cells with C2 toxin via inhibition of binding to cells and inhibition of enzyme activity of C2I. Moreover, diphtheria toxin and an anthrax fusion toxin are inhibited by α1AT. Since α1AT is commercially available as a drug for treatment of the α1AT deficiency, it could be repurposed for treatment of toxin-mediated diseases.
Background: The incidence of lung diseases is very high worldwide, especially in the case of lung cancer, pulmonary tuberculosis, and obstructive ventilatory dysfunctions. Alpha-1 antitrypsin (AAT) is synthesized mainly by hepatocytes, and one of its roles is to inhibit protease activity in the body's biological fluids following the phenomenon of programmed cell death, which is also called apoptosis. Acute lung diseases, but especially chronic ones, can cause, in addition to pulmonary and extrapulmonary manifestations, social and psychological impact, which is why a complex, interdisciplinary respiratory rehabilitation program is necessary. Objectives: Our study aimed to determine the correlation between alpha-1 antitrypsin values and lung diseases (pulmonary tuberculosis, lung cancer, asthma, and COPD) and to evaluate the influence of the individualized respiratory rehabilitation program in these diseases. Methods: We carried out a retrospective study between February 2022 and March 2023 in the Pneumology Department of the "Victor Babeș" Clinical Hospital of Infectious Diseases and Pneumoftiziology, Craiova. It included 189 patients diagnosed with pulmonary tuberculosis, lung cancer, or obstructive ventilatory dysfunctions (chronic obstructive pulmonary disease – COPD or asthma). Alpha-1 antitrypsin was collected from all patients. Respiratory rehabilitation was carried out both during hospitalization and in an out-patient setting for a maximum period of 6 months after discharge, with some patients even using telemedicine. Results: Increased values of alpha-1 antitrypsin were detected in advanced stages of the disease, and a clear improvement of clinical and functional parameters was observed after inclusion in the rehabilitation program. Conclusions: Detection of alpha-1 antitrypsin deficiency (AATD) is rare. The majority of patients diagnosed with lung cancer in advanced stages showed increased values of alpha-1 antitrypsin, AAT being able to be used as a follow-up marker in response to oncological treatment. Respiratory rehabilitation benefits in pulmonary tuberculosis, lung cancer, COPD, and asthma, regardless of the form of the disease. An interdisciplinary approach is necessary for the optimal treatment and control of lung diseases.
Background/Objectives: Breast cancer (BC) is a heterogeneous disease with multifactorial origins, including environmental, genetic, and immunological factors. Inflammatory cytokines, such as alpha 1 antitrypsin (α1-AT), are increased in BC and affect physiological and pathological conditions. This study aimed to evaluate the serum levels of α1-AT and perform a computational analysis of SERPINA1 in BC, as well as their association with molecular subtypes and clinical features. Methods: For the experimental analysis, we evaluated 255 women with BC and 53 healthy women (HW) in a cross-sectional study. Molecular subtypes were identified by immunohistochemistry and TNM was used for clinical staging. Soluble levels of α1-AT were quantified by ELISA. Computational analysis of SERPINA1 expression was performed using GEPIA and cBioPortal. Results: α1-AT was increased in BC women versus HW (75.8 ng/mL vs. 532.2 ng/mL). Luminal A had higher concentration (547.5 ng/mL) than Triple Negative (TN) (484.1 ng/mL), but the levels were not associated with clinical stage. The computational analysis showed that SERPINA1 is overexpressed in BC with differential expression among subtypes; its overexpression is associated with a better prognosis, longer disease-free survival, and overall survival. Conclusions: α1-AT levels are increased in women with BC women compared to HW. The Luminal A subtype shows higher soluble protein levels than the TN one. Furthermore, SERPINA1 mRNA overexpression in BC is linked to a protective effect.
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