Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from Toxoplasma gondii in Asthma Therapeutic Vaccination Effectiveness

<b><i>Background:</i></b> We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. <b><i>Objectives:</i></b> In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. <b><i>Methods:</i></b> BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. <b><i>Results:</i></b> Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. <b><i>Conclusions:</i></b> Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.

Báo cáo ca bệnh nhi viêm tụy cấp tái diễn có đột biến gen spink1

Viêm tụy cấp tái diễn và viêm tụy mạn là vấn đề còn chưa được hiểu biết nhiều ở trẻ em. Yếu tố nguy cơ chính gây viêm tụy cấp tái diễn và viêm tụy mạn ở người lớn là rượu và thuốc lá trong khi ở trẻ em các đột biến di truyền và các bất thường về giải phẫu của các ống tụy đóng một vai trò quan trọng. Gen Serine Protease Inhibitor Kazal Type 1 (SPINK1) đã được biết là có liên quan chặt chẽ với viêm tụy mạn ở trẻ em. Khi gen này bị đột biến có thể làm giảm hoặc mất hoạt tính của chất ức chế serine protease Kazal typ 1, kích hoạt trypsinogen dẫn đến tự động tiêu hóa mô tụy dẫn đến viêm tụy. Một số đa hình di truyền của gen này biểu hiện nhiều đợt viêm tụy cấp tái diễn hoặc viêm tụy mạn. Chúng tôi trình bày một ca bệnh nhi 7 tuổi vào viện vì đau bụng, tiền sử có 9 đợt viêm tụy cấp từ năm 4 tuổi, được chẩn đoán viêm tụy cấp tái diễn lần 10. Giải trình tự gen phát hiện đột biến gen SPINK1, cho thấy vai trò của gen trong sinh bệnh học viêm tụy cấp tái diễn. Đây là hướng đi mới trong tiếp cận chẩn đoán các nguyên nhân viêm tụy ở trẻ em.

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

The most common hereditary disorder in adults, α1-antitrypsin deficiency (AATD), is characterized by reduced plasma levels or the abnormal functioning of α1-antitrypsin (AAT), a major human blood serine protease inhibitor, which is encoded by the SERine Protein INhibitor-A1 (SERPINA1) gene and produced in the liver. Recently, it has been hypothesized that the geographic differences in COVID-19 infection and fatality rates may be partially explained by ethnic differences in SERPINA1 allele frequencies. In our review, we examined epidemiological data on the correlation between the distribution of AATD, SARS-CoV-2 infection, and COVID-19 mortality rates. Moreover, we described shared pathogenetic pathways that may provide a theoretical basis for our epidemiological findings. We also considered the potential use of AAT augmentation therapy in patients with COVID-19.

Working from within: how secretory leukocyte protease inhibitor regulates the expression of pro-inflammatory genes

Secretory leukocyte protease inhibitor (SLPI) is a small but powerful member of the serine protease inhibitor family, which includes proteins such as elafin and alpha1 anti-trypsin. These proteins all have similar structure and antiprotease abilities, but SLPI has been found to have an additional role as an anti-inflammatory factor. It can inhibit the production of pro-inflammatory cytokines in cells stimulated with lipopolysaccharide, prevent neutrophil infiltration in murine models of lung and liver injury, and regulate the activity of the transcription factor NF-κB. In this review, we will revisit SLPI’s unique biochemistry, and then explore how its anti-inflammatory functions can be linked to more recent findings showing that SLPI can localize to the nuclei of cells, bind DNA, and act as a regulator of gene expression.

Crystal structure of nafamostat dimesylate

Nafamostat dimesylate {systematic name: [amino({6-[(4-{[amino(iminiumyl)methyl]amino}phenyl)carbonyloxy]naphthalen-2-yl})methylidene]azanium bis(methanesulfonate)}, C19H19N5O22 +·2CH3O3S−, is a broad-spectrum serine protease inhibitor and has been applied clinically as an anticoagulant agent during hemodialysis and for treatment of severe acute pancreatitis (SAP). Since nafamostat contains flexible moieties, it is necessary to determine the conformation to understand the structure–activity relationships. The divalent cation has a screw-like motif. The guanidinium group is approximately perpendicular to the naphthyl ring system, subtending a dihedral angle of 84.30 (14)°. In the crystal, the nafamostat molecules form columnar structures surrounded by a hydrophilic region.

Neuroserpin: structure, function, physiology and pathology

Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.