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Methods in Enzymology 2023In mammals there are two 3-oxo-4-ene steroid reductases that generate either A/B-trans or A/B cis-ring junctions in the steroid nucleus known as steroid 5α- and 5β-...
In mammals there are two 3-oxo-4-ene steroid reductases that generate either A/B-trans or A/B cis-ring junctions in the steroid nucleus known as steroid 5α- and 5β- reductases, respectively. There is only one steroid 5β- reductase in each species and these are members of the aldo-keto-reductase (AKR) protein superfamily. The corresponding human enzyme is AKR1D1, and it plays an essential role in bile-acid biosynthesis. Germline mutations in AKR1D1 give rise to bile-acid deficiency. Because of its central role in steroid metabolism and need for detailed structure-function studies there is a need to purify the enzyme to homogeneity and in high yield. We report the purification of milligram amounts of crystallographic quality homogeneous recombinant protein for structure-function studies and its characterization.
Topics: Animals; Humans; Oxidoreductases; Steroids; Bile Acids and Salts; Mammals
PubMed: 37802574
DOI: 10.1016/bs.mie.2023.04.012 -
The Tohoku Journal of Experimental... Aug 2011IgA nephropathy (IgAN) is the common cause of primary glomerulonephritis worldwide. The clinical course of IgAN is extremely variable and ranges from asymptomatic... (Review)
Review
IgA nephropathy (IgAN) is the common cause of primary glomerulonephritis worldwide. The clinical course of IgAN is extremely variable and ranges from asymptomatic microscopic hematuria to rapidly progressive renal failure. The pathogenetic mechanisms of IgAN are still unclear, but a hypothesis consisting of two pathways has been proposed. The first pathway is continuous antigenic stimulation of the innate immune system by the tonsillar mucosa via the mucosa-bone marrow axis. In the second pathway, the anomalous stimulated immune response in the bone marrow results in the production of aberrantly glycosylated IgA1 and its subsequent deposition within the mesangial area. Based on the hypothesis, tonsillectomy plus steroid pulse therapy were introduced. A recent meta-analysis showed that tonsillectomy with or without steroid pulse therapy resulted in clinical remission with favorable long-term efficacy in IgAN patients. Tonsillectomy plus steroid pulse therapy now seems to be an effective treatment for IgAN patients with hematuria and minimal proteinuria, and it is more effective in patients with less severe histological findings. The efficacy of the combination therapy depends on the duration of the IgAN. Randomized, controlled trials are needed to examine the efficacy of tonsillectomy plus steroid pulse therapy in different clinical stages of IgAN.
Topics: Clinical Trials as Topic; Combined Modality Therapy; Glomerular Mesangium; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Palatine Tonsil; Pulse Therapy, Drug; Steroids; Tonsillectomy; Treatment Outcome
PubMed: 21705849
DOI: 10.1620/tjem.224.243 -
Endocrine Reviews Oct 2015Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to... (Review)
Review
Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.
Topics: Animals; Biological Transport, Active; Humans; Molecular Targeted Therapy; Multienzyme Complexes; Mutation; Neoplasms; Steroids; Steryl-Sulfatase; Sulfate Adenylyltransferase; Sulfotransferases
PubMed: 26213785
DOI: 10.1210/er.2015-1036 -
F1000Research 2019Perinatal brain injury is a major cause of neurological disability in both premature and term infants. In this review, we summarize the evidence behind some established... (Review)
Review
Perinatal brain injury is a major cause of neurological disability in both premature and term infants. In this review, we summarize the evidence behind some established neuroprotective practices such as administration of antenatal steroids, intrapartum magnesium for preterm delivery, and therapeutic hypothermia. In addition, we examine emerging practices such as delayed cord clamping, postnatal magnesium administration, recombinant erythropoietin, and non-steroidal anti-inflammatory agents and finally inform the reader about novel interventions, some of which are currently in trials, such as xenon, melatonin, topiramate, allopurinol, creatine, and autologous cord cell therapy.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Brain Injuries; Erythropoietin; Female; Humans; Hypothermia, Induced; Infant, Newborn; Magnesium; Neuroprotection; Pregnancy; Randomized Controlled Trials as Topic; Steroids; Umbilical Cord
PubMed: 32047595
DOI: 10.12688/f1000research.20722.1 -
Indian Journal of Pharmacology 2020Although the use of steroids in the management of COVID-19 has been addressed by a few systematic review and meta-analysis, however, they also used data from "SARS-CoV"... (Meta-Analysis)
Meta-Analysis
PURPOSE
Although the use of steroids in the management of COVID-19 has been addressed by a few systematic review and meta-analysis, however, they also used data from "SARS-CoV" and "MERS-CoV." Again, most of these studies addressed only one severity category of patients or addressed only one efficacy endpoint (mortality). In this context, we conducted this meta-analysis to evaluate the efficacy and safety of steroid therapy among all severity categories of patients with COVID-19 (mild to moderate and severe to critical category) in terms of "mortality," "requirement of mechanical ventilation," "requirement of ICU" and clinical cure parameters.
METHODS
11 databases were screened. Only randomized controlled trials (RCTs) or high quality (on the basis of risk of bias analysis) comparative-observational studies were included in the analysis. RevMan5.3 was used for the meta-analysis.
RESULTS
A total of 15 studies (3 RCT and 12 comparative-observational studies) were included. In the mechanically-ventilated COVID-19 population, treatment with dexamethasone showed significant protection against mortality (single study). Among severe and critically ill combined population, steroid administration was significantly associated with lowered mortality (risk ratio [RR] 0.83 [0.76-0.910]), lowered requirement of mechanical ventilation (RR 0.59 [0.51-0.69]), decreased requirement of intensive care unit (ICU) (RR 0.62 [0.45-0.86]), lowered length of ICU stay (single-study) and decreased duration of mechanical ventilation (two-studies). In mild to moderate population, steroid treatment was associated with a higher "duration of hospital stay," while no difference was seen in other domains. In patients at risk of progression to "acute respiratory distress syndrome," steroid administration was associated with "reduced requirement of mechanical ventilation" (single-study).
CONCLUSION
This study guides the use of steroid across patients with different severity categories of COVID-19. Among mechanically ventilated patients, steroid therapy may be beneficial in terms of reduced mortality. Among "severe and critical" patients; steroid therapy was associated with lowered mortality, decreased requirement of mechanical ventilation, and ICU. However, no benefit was observed in "mild to moderate" population. To conclude, among properly selected patient populations (based-upon clinical severity and biomarker status), steroid administration may prove beneficial in patients with COVID-19.
Topics: Dexamethasone; Humans; Steroids; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33666200
DOI: 10.4103/ijp.ijp_1146_20 -
The Journal of Steroid Biochemistry and... Jul 2015Many steroid hormones contain a Δ(4)-3-ketosteroid functionality that undergoes sequential reduction by 5α- or 5β- steroid reductases to produce 5α- or... (Review)
Review
Many steroid hormones contain a Δ(4)-3-ketosteroid functionality that undergoes sequential reduction by 5α- or 5β- steroid reductases to produce 5α- or 5β-dihydrosteroids; and a subsequent 3-keto-reduction to produce a series of isomeric tetrahydrosteroids. Apart from steroid 5α-reductase all the remaining enzymes involved in the two step reduction process in humans belong to the aldo-keto reductase (AKR) superfamily. The enzymes involved in 3-ketosteroid reduction are AKR1C1-AKR1C4. These enzymes are promiscuous and also catalyze 20-keto- and 17-keto-steroid reduction. Interest in these reactions exist since they regulate steroid hormone metabolism in the liver, and in steroid target tissues, they may regulate steroid hormone receptor occupancy. In addition many of the dihydrosteroids are not biologically inert. The same enzymes are also involved in the metabolism of synthetic steroids e.g., hormone replacement therapeutics, contraceptive agents and inhaled glucocorticoids, and may regulate drug efficacy at their cognate receptors. This article reviews these reactions and the structural basis for substrate diversity in AKR1C1-AKR1C4, ketosteroid reductases. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'.
Topics: 3-Hydroxysteroid Dehydrogenases; Animals; Humans; Protein Binding; Steroids; Substrate Specificity
PubMed: 25500069
DOI: 10.1016/j.jsbmb.2014.12.003 -
Leukemia May 2020Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and... (Review)
Review
Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and mortality. Systemic steroid therapy is the first-line treatment for aGVHD, although about half of patients will become refractory to treatment. As the number of patients undergoing alloHCT increases, developing safe and effective treatments for aGVHD will become increasingly important, especially for those whose disease becomes refractory to systemic steroid therapy. This paper reviews current treatment options for patients with steroid-refractory aGVHD and discusses data from recently published clinical studies to outline emerging therapeutic strategies.
Topics: Acute Disease; Drug Resistance; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mesenchymal Stem Cell Transplantation; Steroids
PubMed: 32242050
DOI: 10.1038/s41375-020-0804-2 -
The Journal of Investigative... Nov 2015Selection of a therapy for a patient with alopecia areata (AA) is frequently based on the age of the patient, disease extent, perhaps disease duration, patient... (Review)
Review
Selection of a therapy for a patient with alopecia areata (AA) is frequently based on the age of the patient, disease extent, perhaps disease duration, patient expectations, cost of therapy in terms of time commitment, and financial resources, as well as the results of screening laboratory studies that rule out the presence of other co-morbidities such as anemia, low iron stores, thyroid abnormalities, low vitamin D, or other autoimmune diseases. Although there is currently no cure for AA and no universally proven therapy that induces and sustains remission, many therapies are available which can be of benefit to both affected children and adults. Before selecting a treatment for patients with extensive long-standing AA, a scalp biopsy may provide useful information about the degree of inflammation and follicle differentiation. Recent clinical and translational research observations with the systemic Janus kinase (JAK) inhibitors and interleukin-2 (IL-2) have excited the clinical and AA patient communities and have led to clinical trials, as well as to the off-label use of these more expensive and targeted systemic therapies.
Topics: Adult; Alopecia Areata; Child; Dermatologic Agents; Holistic Health; Humans; Immunotherapy; Minoxidil; Phototherapy; Steroids
PubMed: 26551946
DOI: 10.1038/jidsymp.2015.41 -
Cardiovascular Therapeutics Oct 2016Direct mechanical compression of the frame struts on the adjacent bundle branch with local inflammatory reaction might cause conduction system disturbances and need for...
BACKGROUND
Direct mechanical compression of the frame struts on the adjacent bundle branch with local inflammatory reaction might cause conduction system disturbances and need for pacemaker implantation following transcatheter aortic valve implantation (TAVI). We assessed the impact of preprocedural anti-inflammatory steroid therapy on the occurrence of conduction disturbances following TAVI.
METHODS AND RESULTS
From a cohort of 324 patients who underwent transfemoral TAVI, 39 (12%) were pretreated with steroids because of iodine allergy (n=29) or active obstructive pulmonary disease (n=10). We compared the rate of occurrence of new conduction disturbances and pacemaker implantation between TAVI patients with (n=39) and without (n=285) steroid treatment, using Cox logistic regression estimates and proportional hazards models. The overall occurrence of new conduction defects and the need for new pacemaker implantation were similar among steroid and non-steroid-treated patients (38.4% vs 37.5% and 25.6% vs 25.3%, respectively). New conduction disturbances were more prevalent in patients treated with CoreValve prosthesis, low implantation, and smaller aortic annulus diameter (P<.001, P<.001, and P=.006, respectively). Thirty-day mortality and complication rates were similar between the groups.
CONCLUSION
Although safe, steroid treatment prior to TAVI failed to reduce the incidence of new conduction defects and the need for pacemaker implantation.
Topics: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; Arrhythmias, Cardiac; Cardiac Catheterization; Cardiac Pacing, Artificial; Chi-Square Distribution; Databases, Factual; Drug Administration Schedule; Drug Therapy, Combination; Female; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Hydrocortisone; Israel; Logistic Models; Male; Pacemaker, Artificial; Prednisone; Proportional Hazards Models; Prosthesis Design; Retrospective Studies; Risk Factors; Steroids; Time Factors; Treatment Outcome
PubMed: 27273567
DOI: 10.1111/1755-5922.12202 -
World Journal of Gastroenterology Mar 2021It is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain...
BACKGROUND
It is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain steroid-free remission. However, clinical studies focused on the achievement of steroid-free remission in refractory UC patients are insufficient. Cytapheresis (CAP) is a non-pharmacological extracorporeal therapy that is effective for active UC with fewer adverse effects. This study comprised UC patients treated with CAP and suggested the efficacy of CAP for refractory UC patients.
AIM
To clarify the efficacy of CAP in achieving steroid-free remission in refractory UC patients.
METHODS
We retrospectively reviewed the collected data from 55 patients with refractory UC treated with CAP. We analyzed the following points: (1) Efficacy of the first course of CAP; (2) Efficacy of the second, third, and fourth courses of CAP in patients who experienced relapses during the observation period; (3) Efficacy of CAP in colonic mucosa; and (4) Long-term efficacy of CAP. Clinical efficacy was evaluated using Lichtiger's clinical activity index or Sutherland index (disease activity index). Mucosal healing was evaluated using Mayo endoscopic subscore. The primary and secondary endpoints were the rate of achievement of steroid-free remission and the rate of sustained steroid-free remission, respectively. Statistical analysis was performed using the paired t-test and chi-squared test.
RESULTS
The rates of clinical remission, steroid-free remission, and poor effectiveness after CAP were 69.1%, 45.5%, and 30.9%, respectively. There were no significant differences in rate of steroid-free remission between patients with steroid-dependent and steroid-refractory UC. The mean disease activity index and Lichtiger's clinical activity index scores were significantly decreased after CAP ( < 0.0001). The rates of steroid-free remission after the second, third, and fourth courses of CAP in patients who achieved steroid-free remission after the first course of CAP were 83.3%, 83.3%, and 60%, respectively. Mucosal healing was observed in all patients who achieved steroid-free remission after the first course of CAP. The rates of sustained steroid-free remission were 68.0%, 60.0%, and 56.0% at 12, 24, and 36 mo after the CAP. Nine patients (36%) had maintained steroid-free remission throughout the observation period.
CONCLUSION
Our results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.
Topics: Colitis, Ulcerative; Cytapheresis; Humans; Remission Induction; Retrospective Studies; Steroids; Treatment Outcome
PubMed: 33828394
DOI: 10.3748/wjg.v27.i12.1194