Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kidney transplantation therapy can be divided into two periods: the induction periods during which immunosuppressants are aggressively administered, and the maintenance periods during which treatment is continued at a maintenance dosage. During the induction periods, which usually lasts for several months after surgery, the host defense mechanism in the patient is so profoundly impaired that major infections, including deep-seated mycosis, occur in most cases. The incidence of mycosis as a result of superinfection was quite high in the l960s and l970s, when steroids and antimetabolites were the mainstay immunosuppressants, and antibacterial agents were used without any specific purpose for fear of post-transplantation infections. The new calcineurin inhibitor ciclosporin was developed around 1980 and has since become the primary immunosuppressant used to prevent graft dysfunction after transplantation. As a result of its advent, use of steroids and antimetabolites has declined. Later studies have shown that ciclosporin selectively inhibits lymphocytes and provides more information on the pattern of bacterial infections after transplantation, making it possible to optimize the use of antibacterial agents. As a result, the incidence of bacterial infections and mycosis has dramatically declined. Candida and Aspergillus are most frequently detected in post-transplantation mycosis. But Cryptococcus is also occasionally seen. Antifungal agents such as flucytosine (5-FC) and ketoconazole are effective for deep-seated mycosis such as pulmonary infections which, occurring at a relatively early stage after transplantation, threaten a patients life. However, the coadministration of ketoconazole must be carefully done because it increases blood concentrations of calcineurin inhibitors such as ciclosporin and tacrolimus by inhibiting the production of cytochrome P-450. Amphotericin B, which is effective but is associated with nephrotoxicity, is usually used in a mouthwash or inhalation therapy. Dermatomycosis such as tinea versicolor due to fragility of the skin structure is not necessarily rare even in patients with a quasi-normal host defense mechanism and good renal function at a late stage in the maintenance phase. This paper outlines change in post-transplantation mycosis in recent years and presents some case reports.
 ...
PMID:[Mycosis in kidney transplant patients]. 1170 45

Protein serine/threonine phosphatase 2A (PP2A) is a critical regulator of numerous cellular signaling processes and a potential target for reactive electrophiles that dysregulate phosphorylation-dependent signal transduction cascades. The predominant cellular form of PP2A is a heterotrimeric holoenzyme consisting of a structural A, a variable B, and a catalytic C subunit. We studied the modification of two purified PP2A holoenzyme complexes (ABalpha(FLAG)C and ABdelta(FLAG)C) with two different thiol-reactive electrophiles, biotinyl-iodoacetamidyl-3,6-dioxaoctanediamine (PEO-IAB) and the biotinamido-4-[4'-(maleimidomethyl)cyclohexanecarboxamido]butane (BMCC). In vivo treatment of HEK 293 cells with these electrophiles resulted in alkylation of all three PP2A subunits. Electrophile treatment of the immunopurified FLAG-tagged holoenzymes produced a concentration-dependent adduction of PP2A subunits, as observed by Western blot analysis. Although both electrophiles labeled all three PP2A subunits, only BMCC inhibited the catalytic activity of both holoenzymes. Alkylation patterns in the A and B subunits were identical for the two electrophiles, but BMCC alkylated four Cys residues in the C subunit that were not labeled by PEO-IAB. Homology between the catalytic subunits of PP1 and PP2A enabled generation of a comparative model structure for the C subunit of PP2A. The model structure provided additional insight into contributions of specific BMCC-Cys adducts to PP2A enzyme inhibition. The results indicate that site selectivity of protein adduction should be a critical determinant of the ability of electrophiles to affect cellular signaling processes.
 ...
PMID:Inhibition of protein phosphatase 2A activity by selective electrophile alkylation damage. 1690 60

Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in patients who undergo haematopoietic stem cell transplantation (HSCT). History of IA before allogeneic HSCT is still challenging because of the high risk of recurrence after HSCT. Recent advances in early-stage diagnosis and new, more effective classes of antifungal agents have improved the management of IA in the HSCT recipients. We report two cases with acute myelogenous leukaemia after primary failure of induction chemotherapy with the patients developing pulmonary IA. They responded well to a combination of voriconazole (VCZ) and micafungin, resulting in a remarkable reduction of pulmonary IA lesions at short intervals. Thereafter, antifungal therapy was switched to liposomal amphotericin B (L-AmB), followed by conditioning regimen for allogeneic HSCT, because of the possibility of VCZ altering the metabolism of chemotherapeutic agents and calcineurin inhibitors. Successful engraftment was achieved without severe adverse side-effects or aggravation of IA after HSCT. Combining VCZ with micafungin followed by L-AmB throughout HSCT could be advantageous in stabilising IA in HSCT patients.
 ...
PMID:Successful allogeneic stem cell transplantation in two patients with acute myelogenous leukaemia and invasive aspergillosis by antifungal combination therapy. 2023 43