Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle.

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.

Prednisone and prednisolone effects on development, blood, biochemical and histopathological markers of Aquarana catesbeianus tadpoles.

Synthetic glucocorticoids are often found in surface waters and can cause harmful effects to aquatic organisms such as amphibians. In this work we evaluated the effects of the drugs prednisone (PD) and prednisolone (PL) on developmental, molecular, blood, biochemical and histological markers. Aquarana catesbeianus tadpoles were exposed for 16 days to environmentally relevant concentrations of 0, 0.1, 1 and 10 µg/L of both drugs. PD increased the transcript levels of the enzyme deiodinase III (Dio3), the hormones cortisol and T4 and delayed development. Changes in the thyroid gland occurred after tadpoles were exposed to both drugs, with a reduction in the diameter and number of follicles and an increase/or decrease in area. Also, both drugs caused a decrease in lymphocytes (L) and an increase in neutrophils (N), thrombocytes, the N:L ratio and lobed and notched erythrocytes. Increased activity of the enzymes superoxide dismutase, glutathione S-transferase and glucose 6-phosphate dehydrogenase was observed after exposure to PD. Furthermore, both drugs caused an increase in the activity of the enzymes catalase and glutathione peroxidase. However, only PD caused oxidative stress in exposed tadpoles, evidenced by increased levels of malondialdehyde and carbonyl proteins. Both drugs caused an increase in inflammatory infiltrates, blood cells and melanomacrophages in the liver. Our results indicate that PD was more toxic than PL, affecting development and causing oxidative stress.

Dose- and stage-dependent toxic effects of prenatal prednisone exposure on fetal articular cartilage development.

Prednisone is frequently used to treat rheumatoid diseases in pregnant women because of its high degree of safety. Whether prenatal prednisone exposure (PPE) negatively impacts fetal articular cartilage development is unclear. In this study, we simulated a clinical prednisone treatment regimen to examine the effects of different timings and doses of PPE on cartilage development in female and male fetal mice. Prednisone doses (0.25, 0.5, and 1 mg/kg/d) was administered to Kunming mice at different gestational stages (0-9 gestational days, GD0-9), mid-late gestation (GD10-18), or during the entire gestation (GD0-18) by oral gavage. The amount of matrix aggrecan (ACAN) and collagen type II a1(COL2a1), and expression of transforming growth factor ß1 (TGFß1) signaling pathway also demonstrated that the chondrocyte count and ACAN and COL2a1 expression reduced in fetal mice with early and mid-late PPE, with the reduction being more significant in the mice with early PPE than that in those with PPE at other stages. Prenatal exposure to different prednisone doses prevented the reduction of TGFß signaling pathway-related genes [TGFßR1, SMAD family member 3 (Smad3), SRY-box9 (SOX9)] as well as ACAN and COL2a1 mRNA expression levels in fetal mouse cartilage, with the most significant decrease after 1 mg/kg·d PPE. In conclusion, PPE can inhibit/restrain fetal cartilage development, with the greatest effect at higher clinical dose (1 mg/kg·d) and early stage of pregnancy (GD0-9), and the mechanism may be related to TGFß signaling pathway inhibition. The result of this study provide a theoretical and experimental foundation for the rational clinical use of prednisone.

Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men.

BACKGROUND: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. METHODS: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. FINDINGS: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40-266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94-277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69-4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52-3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. INTERPRETATION: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. FUNDING: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

Microbes, metabolites and muscle: Is the gut-muscle axis a plausible therapeutic target in Duchenne muscular dystrophy?

NEW FINDINGS: What is the topic of this review? The contribution of gut microbial signalling to skeletal muscle maintenance and development and identification of potential therapeutic targets in progressive muscle degenerative diseases such as Duchenne muscular dystrophy. What advances does it highlight? Gut microbe-derived metabolites are multifaceted signalling molecules key to muscle function, modifying pathways contributing to skeletal muscle wasting, making them a plausible target for adjunctive therapy in muscular dystrophy. ABSTRACT: Skeletal muscle is the largest metabolic organ making up ∼50% of body mass. Because skeletal muscle has both metabolic and endocrine properties, it can manipulate the microbial populations within the gut. In return, microbes exert considerable influence on skeletal muscle via numerous signalling pathways. Gut bacteria produce metabolites (i.e., short chain fatty acids, secondary bile acids and neurotransmitter substrates) that act as fuel sources and modulators of inflammation, influencing host muscle development, growth and maintenance. The reciprocal interactions between microbes, metabolites and muscle establish a bidirectional gut-muscle axis. The muscular dystrophies constitute a broad range of disorders with varying disabilities. In the profoundly debilitating monogenic disorder Duchenne muscular dystrophy (DMD), skeletal muscle undergoes a reduction in muscle regenerative capacity leading to progressive muscle wasting, resulting in fibrotic remodelling and adipose infiltration. The loss of respiratory muscle in DMD culminates in respiratory insufficiency and eventually premature death. The pathways contributing to aberrant muscle remodelling are potentially modulated by gut microbial metabolites, thus making them plausible targets for pre- and probiotic supplementation. Prednisone, the gold standard therapy for DMD, drives gut dysbiosis, inducing a pro-inflammatory phenotype and leaky gut barrier contributing to several of the well-known side effects associated with chronic glucocorticoid treatment. Several studies have observed that gut microbial supplementation or transplantation exerts positive effects on muscle, including mitigating the side effects of prednisone. There is growing evidence in support of the potential for an adjunctive microbiota-directed regimen designed to optimise gut-muscle axis signalling, which could alleviate muscle wasting in DMD.

Toxic effect window of ovarian development in female offspring mice induced by prenatal prednisone exposure with different doses and time.

BACKGROUND: Prednisone is one of the most used synthetic glucocorticoids during pregnancy. Epidemiological investigations suggested that prenatal prednisone therapy could affect fetal development, but systematic studies on its effects on ovarian development and the "toxic effect window" remained scarce. METHODS: In this study, by simulating clinical application characteristics, Kunming mice were given prednisone by oral gavage with different doses (0.25 or 1.0 mg/kg·d) or at different time gestational days (GD) (GD0-9, GD10-18, or GD0-18). Blood and ovaries of fetal mice were collected on GD18, and the serum estradiol level and the related function indexes of ovarian granulosa cells and oocytes were detected. RESULTS: Compared with the control group, prenatal prednisone exposure (PPE) induced pathological injury and enhanced cell proliferation in fetal mice ovary. Furthermore, the expression of steroid synthesis functional genes in pre-granulosa cells, the oocyte function markers, and developmentally related genes was enhanced with different doses or at different time of PPE. The Hippo signaling was activated in the fetal ovary of PPE groups. The above changes were most significant in the low or high-dose and full-term PPE groups. CONCLUSION: PPE caused various cell developmental toxicity in the fetal ovary, especially in the low or high-dose, full-term exposure groups. The potential mechanism might be related to the activation of the Hippo signaling pathway.

Lupus Recipe inhibits cGVHD-induced lupus nephritis in mice and promote renal LC3-associated autophagy.

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). The chronic graft versus host disease (cGVHD) mouse model is a well-established model of SLE. LC3-associated autophagy plays a critical role in extracellular particle clearance, including pathogens and apoptotic cells. Lupus Recipe (LR) is a Chinese herbal compound that has been proven to be effective in treating SLE. In the study, we investigated the protective effects of LR or LR combined with prednisone on cGVHD mouse model and LC3-associated autophagy in the kidney. The mice were subjected to six groups. The LR treatment group received LR at the dosage of 1.15 and 2.3 g/kg/day, respectively. The corticosteroid treatment group received prednisone at a dosage of 5 mg/kg/day. The combination treatment group received LR at a dosage of 2.3 g/kg/day, and prednisone at 2.5 mg/kg/day. LR treatment reduced proteinuria and serum triglyceride levels, as well as spleen weight. LR also alleviated pathologic damage and immunoglobulin G deposition in the kidney. LR combined with a low dose of prednisone significantly improved kidney function and decreased serum triglyceride, total cholesterol, and spleen weight. In addition, combination treatment relieved kidney injury more effectively than LR alone. Western blot revealed that LR treatment or LR combined with prednisone increased the LC3-associated autophagy protein of Rubicon and Nox2, as well as LC3I levels in the kidney tissues. In conclusion, LR inhibited the manifestation of cGVHD-induced LN, which may attribute to the increased levels of LC3-associated autophagy.

Danshen injection induces autophagy in podocytes to alleviate nephrotic syndrome via the PI3K/AKT/mTOR pathway.

BACKGROUND: Danshen injection (DSI) is an agent extracted from the Salvia miltiorrhiza Bunge, a natural drug commonly used to alleviate kidney diseases. However, the material basis and therapeutic effects of DSI on nephrotic syndrome (NS) remain unclear. PURPOSE: To investigate the material basis of DSI and the therapeutic effects and underlying mechanisms of NS. METHODS: NS models were established using adriamycin-induced BALB/c mice and lipopolysaccharide-induced mouse podocytes (MPC-5). Following DSI and prednisone administration, kidney coefficients, 24 h urine protein, blood urea nitrogen, and serum creatinine levels were tested. Histomorphology was observed by periodic acid-Schiff staining and hematoxylin and eosin staining of the kidney sections. The glomerular basement membrane and autophagosomes of the kidneys were observed using transmission electron microscopy. Nephrin and desmin levels in the glomeruli were tested using immunohistochemistry. The viability of MPC-5 cells was tested using cell counting kit-8 after chloroquine and rapamycin administration in combination with DSI. The in vivo and in vitro protein levels of phosphatidylinositol 3-kinase (PI3K), AKT, phosphorylated AKT (Ser473), mammalian target of rapamycin (mTOR), microtubule-associated protein light chain 3 (LC3), beclin1, cleaved caspase-3, and caspase-3 were detected using western blotting. RESULTS: Our results showed that DSI contained nine main components: caffeic acid, danshensu, lithospermic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, salvianolic acid C, salvianolic acid D, and 3, 4-Dihydroxybenzaldehyde. In in vivo studies, the NS mice showed renal function and pathological impairment. Podocytes were damaged, with decreased levels of autophagy and apoptosis, accompanied by inhibition of the PI3K/AKT/mTOR signaling. DSI administration resulted in improved renal function and pathology in NS mice, with the activation of autophagy and PI3K/AKT/mTOR signaling in the kidneys. Additionally, podocytes were less damaged and intracellular autophagosomes were markedly increased. In vitro studies have shown that DSI activated MPC-5 autophagy and reduced apoptosis via the PI3K/AKT/mTOR pathway. CONCLUSION: Collectively, this study demonstrated that DSI activated podocyte autophagy and reduced apoptosis via the PI3K/AKT/mTOR signaling, ultimately attenuating NS. Our study clarified the main components of DSI and elucidated its therapeutic effects and potential mechanisms for NS, providing new targets and agents for the clinical treatment of NS.

Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids.

OBJECTIVE: Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates heart metabolism through cardiomyocyte-autonomous mechanisms. While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism in normal and obese skeletal muscle. However, the effects of glucocorticoid intermittence on heart metabolism and heart failure remain unknown. Here we investigated the extent to which circadian time of dosing regulates the effects of the glucocorticoid prednisone in heart metabolism and function in conditions of single pulse or chronic intermittent dosing. METHODS AND RESULTS: In WT mice, we found that prednisone improved cardiac content of NAD+ and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The drug effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted glucocorticoid receptor (GR) ablation, and depended on an intact cardiomyocyte clock, as shown by inducible cardiomyocyte-restricted ablation of Brain and Muscle ARNT-like 1 (BMAL1). Conjugating time-of-dosing with chronic intermittence, we found that once-weekly prednisone improved metabolism and function in heart after myocardial injury dependent on circadian time of intake, i.e. with light-phase but not dark-phase dosing. CONCLUSIONS: Our study identifies cardiac-autonomous mechanisms through which circadian-specific intermittent dosing reconverts glucocorticoid drugs to metabolic boosters for the heart.

Chemotherapy for non-Hodgkin lymphoma in the hemodialysis patient: A comprehensive review.

Chemotherapy for non-Hodgkin lymphoma (NHL) in the hemodialysis (HD) patient is a challenging situation. Because many drugs are predominantly eliminated by the kidneys, chemotherapy in the HD patient requires special considerations concerning dose adjustments to avoid overdose and toxicities. Conversely, some drugs are removed by HD and may expose the patient to undertreatment, therefore the timing of drug administration in relation to HD sessions must be carefully planned. Also, the metabolites of some drugs show different toxicities and dialysability as compared with the parent drug, therefore this must also be catered for. However, the pharmacokinetics of many chemotherapeutics and their metabolites in HD patients are unknown, and the fact that NHL patients are often treated with distinct multiagent chemotherapy regimens makes the situation more complicated. In a realm where uncertainty prevails, case reports and case series reporting on actual treatment and outcomes are extremely valuable and can aid physicians in decision making from drug selection to dosing. We carried out an exhaustive review of the literature and adopted 48 manuscripts consisting of 66 HD patients undergoing 71 chemotherapy regimens for NHL, summarized the data, and provide recommendations concerning dose adjustments and timing of administration for individual chemotherapeutics where possible. The chemotherapy regimens studied in this review include, but are not limited to, rituximab, cyclophosphamide + vincristine + prednisolone (CVP) and cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP)-like regimens, chlorambucil, ibrutinib, bendamustine, methotrexate, platinum compounds, cytarabine, gemcitabine, etoposide, ifosfamide, melphalan, busulfan, fludarabine, mogamulizumab, brentuximab vedotin, and 90 Y-ibritumomab tiuxetan.

5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients.

BACKGROUND: Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response. METHODS: We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy. To investigate the correlation between 5hmC modifications and curative effectiveness, we separated patients into training (n = 56) and validation (n = 30) cohorts and developed a 5hmC-based logistic regression model from the training cohort to predict the treatment response in the validation cohort. RESULTS: In this study, we identified thirteen 5hmC markers associated with treatment response. The prediction performance of the logistic regression model, achieving 0.82 sensitivity and 0.75 specificity (AUC = 0.78), was superior to existing clinical indicators, such as LDH and stage. CONCLUSIONS: Our findings suggest that the 5hmC modifications in cfDNA at the time before R-CHOP treatment are associated with treatment response and that 5hmC-Seal may potentially serve as a clinical-applicable, minimally invasive approach to predict R-CHOP treatment response for DLBCL patients.

Elimination profiles of prednisone and prednisolone after different administration routes: Evaluation of the reporting level and washout periods to ensure safe therapeutic administrations.

Prednisolone (PRED) and prednisone (PSONE) are prohibited in sports competitions when administered by systemic routes, and they are allowed by other routes for therapeutic purposes. There is no restriction of use in out-of-competition periods. The present study aimed to evaluate the urinary excretion of PRED, PSONE, and their most important metabolites after systemic and nonsystemic treatments in order to verify the suitability of the current reporting level of 30 ng/ml used to distinguish allowed and prohibited administrations and to establish washout periods for oral treatments performed in out-of-competition periods. PRED was studied after dermatological administration (5 mg/day for 5 days, n = 6 males) and oral administration (5 mg, n = 6 males; 10 mg, n = 2 males). PSONE was studied after oral administration (10 mg, n = 2 males; 30 mg, n = 1 male and 1 female). Concentrations in urine were measured using an LC-MS/MS method. Concentrations after dermatological treatment were low for all metabolites. After oral administration, concentrations were very high during the first 24 h after administration ranging from 1.6 to 2261 ng/ml and from 4.6 to 908 ng/ml for PRED and PSONE, respectively. Concentrations of most of the metabolites measured were lower than 30 ng/ml from 24 h after all oral administrations. New reporting levels are proposed for PRED and PSONE considering data of our study and other information published after nonsystemic administrations of the compounds. Washout periods of at least 24 h are recommended to ensure no false positives when oral treatments need to be performed in out-of-competition periods.

Comparative efficacy of glucocorticoid receptor agonists on Th2 cell function and attenuation by progesterone.

BACKGROUND: Corticosteroids (CS)s suppress cytokine production and induce apoptosis of inflammatory cells. Prednisone and dexamethasone are oral CSs prescribed for treating asthma exacerbations. While prednisone is more commonly prescribed, dexamethasone is long acting and a more potent glucocorticoid receptor (GR) agonist. It can be administered as a one or two dose regime, unlike the five to seven days required for prednisone, a feature that increases compliance. We compared the relative ability of these two oral CSs to suppress type 2 inflammation. Since progesterone has affinity for the GR and women are more likely to relapse following an asthma exacerbation, we assessed its influence on CS action. RESULTS: Dexamethasone suppressed the level of IL-5 and IL-13 mRNA within Th2 cells with ~ 10-fold higher potency than prednisolone (the active form of prednisone). Dexamethasone induced a higher proportion of apoptotic and dying cells than prednisolone, at all concentrations examined. Addition of progesterone reduced the capacity of both CS to drive cell death, though dexamethasone maintained significantly more killing activity. Progesterone blunted dexamethasone-induction of FKBP5 mRNA, indicating that the mechanism of action was by interference of the CS:GR complex. CONCLUSIONS: Dexamethasone is both more potent and effective than prednisolone in suppressing type 2 cytokine levels and mediating apoptosis. Progesterone attenuated these anti-inflammatory effects, indicating its potential influence on CS responses in vivo. Collectively, our data suggest that when oral CS is required, dexamethasone may be better able to control type 2 inflammation, eliminate Th2 cells and ultimately lead to improved long-term outcomes. Further research in asthmatics is needed.

Δ1-Dehydrogenation and C20 Reduction of Cortisone and Hydrocortisone Catalyzed by Rhodococcus Strains.

Prednisone and prednisolone are steroids widely used as anti-inflammatory drugs. Development of the pharmaceutical industry is currently aimed at introducing biotechnological processes and replacing multiple-stage chemical syntheses. In this work we evaluated the ability of bacteria belonging to the Rhodococcus genus to biotransform substrates, such as cortisone and hydrocortisone, to obtain prednisone and prednisolone, respectively. These products are of great interest from a pharmaceutical point of view as they have higher anti-inflammatory activity than the starting substrates. After an initial lab-scale screening of 13 Rhodococcus strains, to select the highest producers of prednisone and prednisolone, we reported the 200 ml-batch scale-up to test the process efficiency and productivity of the most promising Rhodococcus strains. R. ruber, R. globerulus and R. coprophilus gave the Δ1-dehydrogenation products of cortisone and hydrocortisone (prednisone and prednisolone) in variable amounts. In these biotransformations, the formation of products with the reduced carbonyl group in position C20 of the lateral chain of the steroid nucleus was also observed (i.e., 20ß-hydroxy-prednisone and 20ß-hydroxy-prednisolone). The yields, the absence of collateral products, and in some cases the absence of starting products allow us to say that cortisone and hydrocortisone are partly degraded.

ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis.

Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.

Bacterial steroid-17,20-desmolase is a taxonomically rare enzymatic pathway that converts prednisone to 1,4-androstanediene-3,11,17-trione, a metabolite that causes proliferation of prostate cancer cells.

The adrenal gland has traditionally been viewed as a source of "weak androgens"; however, emerging evidence indicates 11-oxy-androgens of adrenal origin are metabolized in peripheral tissues to potent androgens. Also emerging is the role of gut bacteria in the conversion of C21 glucocorticoids to 11-oxygenated C19 androgens. Clostridium scindens ATCC 35,704 is a gut microbe capable of converting cortisol into 11-oxy-androgens by cleaving the side-chain. The desA and desB genes encode steroid-17,20-desmolase. Our prior study indicated that the urinary tract bacterium, Propionimicrobium lymphophilum ACS-093-V-SCH5 encodes desAB and converts cortisol to 11ß-hydroxyandrostenedione. We wanted to determine how widespread this function occurs in the human microbiome. Phylogenetic and sequence similarity network analyses indicated that the steroid-17,20-desmolase pathway is taxonomically rare and located in gut and urogenital microbiomes. Two microbes from each of these niches, C. scindens and Propionimicrobium lymphophilum, respectively, were screened for activity against endogenous (cortisol, cortisone, and allotetrahydrocortisol) and exogenous (prednisone, prednisolone, dexamethasone, and 9-fluorocortisol) glucocorticoids. LC/MS analysis showed that both microbes were able to side-chain cleave all glucocorticoids, forming 11-oxy-androgens. Pure recombinant DesAB from C. scindens showed the highest activity against prednisone, a commonly prescribed glucocorticoid. In addition, 0.1 nM 1,4-androstadiene-3,11,17-trione, bacterial side-chain cleavage product of prednisone, showed significant proliferation relative to vehicle in androgen-dependent growth LNCaP prostate cancer cells after 24 h (2.3 fold; P <  0.01) and 72 h (1.6 fold; P < 0.01). Taken together, DesAB-expressing microbes may be an overlooked source of androgens in the body, potentially contributing to various disease states, such as prostate cancer.

The first reported case of drug-induced hemolytic anemia caused by dimethyl fumarate in a patient with multiple sclerosis.

BACKGROUND: Drug-induced hemolytic anemia is a rare and potentially fatal complication of drug treatment. Specific laboratory tests are crucial to confirm the diagnosis. CASE REPORT: A 38-year-old woman on treatment with dimethyl fumarate for multiple sclerosis presented with a 7-day history of weakness and fatigue. Laboratory tests revealed profound hemolytic anemia with hemoglobin levels of 4.7 g/dL (reference, 12.5-16.0), decreased haptoglobin, increased reticulocyte count, and increased indirect bilirubin. A first direct antiglobulin test was negative. The patient was started on prednisone 1 mg/kg/day, and dimethyl fumarate was withdrawn. A blood sample was drawn on Day 7 and sent to a reference laboratory. A direct antiglobulin test performed 7 days later was positive. Furthermore, an indirect antiglobulin test was positive only in the presence of the drug. RESULTS: The patient did not receive a blood transfusion, recovered clinically during the following days, and was discharged on Day 7. On Day 36, the patient's RBCs had normalized. She was changed to another disease-modifying treatment for her multiple sclerosis, and at 10-month follow-up she remained stable without any notable adverse effects. CONCLUSION: This case describes the first report of a dimethyl fumarate-induced hemolytic anemia. Laboratory results should always be interpreted within the clinical context. Specific laboratory expertise is often needed, given the complexity of the field.

Impact of prednisone in patients with repeated embryo implantation failures: Beneficial or deleterious?

INTRODUCTION: Corticotherapy is the leading medication worldwide for patients with history of repeated implantation failures (RIF) after IVF/ICSI. Nevertheless, we still do not know its local mechanism of action, hence its precise indication. Our objective is to document the impact of prednisone on the endometrial expression of immune biomarkers (CD56 cells count, IL-18/TWEAK, IL-15/Fn-14 mRNA ratio) at the time of uterine receptivity in a RIF population. MATERIALS AND METHOD: An endometrial biopsy was realized in the mid luteal phase for immune profiling: IL-15/Fn-14 and IL-18/TWEAK mRNA ratios were determined by quantitative RT-PCR and CD56 mobilization per IHC. Fifty-five patients with a RIF history were diagnosed to have local over-immune activation [high IL-18/TWEAK mRNA ratio, and/or high IL-15/Fn-14 mRNA ratio] likely to impair the implantation process. They underwent a second immune profiling with supplementation of prednisone. A paired comparison of the immune profile before and under prednisone was performed in the subset of patients subsequently pregnant under prednisone. FINDING: In 54.5% of the cases, both immune biomarkers were normalized and in 16.5%, only one was normalized under prednisone. In 29% we observed a paradoxical increase of both immune biomarkers. The IL-18/TWEAK mRNA ratio reflecting the Th-1/Th-2 local equilibrium was significantly reduced (0.29 versus 0.10, p = .004), through very significant increase of TWEAK expression, in patients who were subsequently pregnant under prednisone. CONCLUSION: Testing the response to prednisone in a RIF context may be very useful. Less than half of RIF patients with immune deregulation may be prednisone responders and would benefit from its administration.

Prednisone alleviates demyelination through regulation of the NLRP3 inflammasome in a C57BL/6 mouse model of cuprizone-induced demyelination.

Myelin abnormalities, oligodendrocyte damage, and concomitant glia activation are common in demyelinating diseases of the central nervous system (CNS). Increasing evidence has demonstrated that the inflammatory response triggers demyelination and gliosis in demyelinating disorders. Numerous clinical interventions, including those used to treat multiple sclerosis (MS), have confirmed prednisone (PDN) as a powerful anti-inflammatory drug that reduces the inflammatory response and promotes tissue repair in multiple inflammation sites. However, the underlying mechanism of PDN in ameliorating myelin damage is not well understood. In our study, a cuprizone (CPZ)-induced demyelinated mouse model was used to explore the mechanism of the protection provided by PDN. Open-field tests showed that CPZ-treated mice exhibited significantly increased anxiety and decreased exploration. However, PDN improved emotional behavior, as evidenced by an increase in the total distance traveled, and central distance traveled as well as the mean amount of time spent in the central area. CPZ-induced demyelination was observed to be alleviated in PDN-treated mice based on luxol fast blue (LFB) staining and myelin basic protein (MBP) expression analyses. In addition, PDN reduced astrocyte and microglia activation in the corpus callosum. Furthermore, we demonstrated that PDN inhibited the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathway and related inflammatory cytokines and chemokines, including TNF-α, CCL8, CXCL10 and CXCL16. PDN also reduced the serum corticosterone levels in the CPZ-treated mice. Taken together, these results suggest that inhibition of the NLRP3 signaling pathway may be a novel mechanism by which PDN exerts its protective actions in demyelinating diseases.