Steroids最新文献

Background

Despite the potential of corticosteroids in treating community-acquired pneumonia (CAP), conflicting evidence exists regarding their effect on mortality. To address this gap and provide new insights, we conducted a pre-specified subgroup meta-analysis of corticosteroid use in CAP patients, focusing on the ICU versus non-ICU subsets.

Methods

We searched PubMed, Cochrane Central Register of Controlled Trials and SCOPUS from inception to May 2023 for randomized controlled trials (RCTs). The primary outcomes of interest were mortality, need for mechanical ventilation, need for ICU admission, and treatment failure. Secondary outcomes analysed were the need for hospital readmission, length of hospital stay, length of ICU stay, gastrointestinal (GI) bleeding, secondary infections, and hyperglycaemic events. The results were analysed through the random-effects model. A p-value < 0.05 was considered significant.

Results

Eighteen randomized controlled trials (n = 4472) analyzing patients with CAP were included. Our results suggest that corticosteroids significantly reduced the incidence of mortality (RR: 0.66; 95 % CI: 0.54, 0.81; P = <0.0001) and need for mechanical ventilation (RR: 0.57; 95 % CI: 0.44, 0.73; P = <0.00001). It was also observed that corticosteroids significantly decrease the lengths of ICU (MD: −1.67; 95 % CI: −2.97, −0.37; P = 0.01) and hospital stay (MD: −1.94; 95 % CI: −2.89, −0.98; P = 0.0001), while increasing the number of hyperglycemic events (RR: 1.68; 95 % CI: 1.32, 2.12; P = <0.0001) and hospital readmissions (RR: 1.19; 95 % CI: 1.04, 1.37; P = 0.01).

Conclusions

The results of this meta-analysis demonstrate that corticosteroids yield improved outcomes in CAP patients with regard to reduced mortality and the need for mechanical ventilation. It highlights the need for further large-scale RCTs with the proposed, specific stratifications.

This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1–5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21–25.

Inhibition assays against hCAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23, exhibited a K_i value of 88.1 nM for hCA VA, and a derivative of asiatic acid, compound 25, displayed an even lower K_i value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against hCA VA when compared to the benchmark compound acetazolamide (AAZ), which had a K_i value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse hCA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective hCA VA inhibitor prompts further exploration of its therapeutic applications.

Triple-negative breast cancer is a rare but highly heterogeneous breast cancer subtype with a limited choice of specific treatments. Chemotherapy remains the only efficient treatment, but its side effects and the development of resistance consolidate the urgent need to discover new targets. In TNBC, filamin A expression correlates to grade and TNM stage. Accordingly, this protein could constitute a new target for this BC subtype. Even if most of the data indicates its direct involvement in cancer progression, some contrasting results underline the need to deepen the studies. To elucidate a possible function of this protein as a TNBC marker, we summarized the main characteristic of filamin A and its involvement in physiological and pathological processes such as cancer. Lastly, we scrutinized its actions in triple-negative breast cancer and highlighted the need to increase the number of studies useful to better clarify the role of this versatile protein as a marker and target in TNBC, alone or in “collaboration” with other proteins with a relevant role in this BC subgroup.

Background

24-h urinary free cortisol (UFF) is recommended for screening of Cushing's syndrome (CS), a rare disease characterized by apparent cortisol and cortisone excess. We aimed to validate a simple LC-MS/MS method for accurate measurement of UFF and urinary free cortisone (UFE), establishment of reference ranges, and evaluation of performance for CS diagnosis.

Methods

Urine samples were processed using solid-phase extraction cartridges, followed by elution with methanol and acetonitrile. Analysis was performed via tandem mass spectrometry, utilizing multiple reaction monitoring and electrospray ionization source in positive ion mode.

Results

The assay displayed excellent linearity (r > 0.99) in the range of 0.05–100 ng/mL for cortisol and 0.25–500 ng/mL for cortisone, with lower limits of quantification (LLOQ) at 0.05 ng/mL for cortisol and 0.25 ng/mL for cortisone. The obtained results for intra-day and inter-day imprecision for both analytes were within the acceptable range of less than 10 %. The trueness values for both compounds were also within the acceptable limit of 15 %. No significant matrix effects or carry over observed in our method. The reference intervals of UFF, UFE and UFF:UFE ratio were 7.01–45.66 µg/24-h, 27.97–139.21 µg/24-h and 0.17–0.56, respectively. UFF > 56.75 µg/24-h showed 100 % specificity and 100 % sensitivity for CS diagnosis, which was superior to UFF:UFE ratio.

Conclusions

We developed and validated a sensitive LC-MS/MS method to detect UFF and UFE. Our data indicate that UFF measured by the current LC-MS/MS assay exhibited high diagnostic performance for CS.

A series of 2E-furfurylidene-23-nor- and 24-nor-allobetulins has been synthesized by the Claisen-Schmidt condensation and conditions of their formation were studied in detail. It was found that among an expected 2E-furfurylidene-3-oxo-24-nor-allobetulin 4 two byproducts holding 3-oxo-4α-hydroxy- 5 and 3β,4α-dihydroxy- 6 substituents were formed, which could become the main products under the change of reaction time and amount of the base solution. Moreover, a conversion of individual 2E-furfurylidene-23-nor-3-oxo-4α-hydroxy- 5 into 2E-furfurylidene-23-nor-3β,4α-dihydroxy-derivative 6 under the treatment with the base solution was observed. An inversion of the configuration at C4 from 24-nor- to 23-nor-allobetulins for compounds 5 – 7 was proved by the NMR spectra. The probable explanation of compound 5 formation includes oxidation by atmospheric oxygen to 4-hydroperoxide, which was further transformed into 4-hydroxy-group. In the presence of the base the reduction C3(=O)-function of compound 5 occurs like Meerwein– Ponndorf–Verley reaction to give compound 6. As a result, a difference in the reactivity of native allobetulin scaffold and 24-nor-allobetulin in the Claisen-Schmidt condensation was observed and a first case of conversion 24-nor- to 23-nor-allobetulin derivatives was described.

Estrogens produced by the ovary play diverse roles in controlling physiological changes in the function of the female reproductive system. Although estradiol acts through classical nuclear receptors, its metabolites (EMs) act by alternative pathways. It has been postulated that EMs act through paracrine-autocrine pathways to regulate key processes involved in normal follicular growth, corpus luteum (CL) development, function, and regression. The present review describes recent advances in understanding the role of EMs in human ovarian physiology during the menstrual cycle, including their role in anovulatory disorders and their action in other target tissues.

Research published between 2001 and 2022 on the functionalization of remote positions of steroids, as well as the use of this technique in the generation of biologically active compounds has been reviewed. In the first section of the analysis established and novel methods for activation of sites deemed to be remote were reported. A series of manganese- (mainly), rhodium-, ruthenium- and osmium-centered porphyrins as catalysts in the presence of PIDA as oxidant have effected hydroxylation at C-1, -5, -6, -7, -11, -14, -15, -16, -17, -20, -24 and -25. Dioxiranes have been utilized in inserting hydroxyl groups at the 5, 12, 14, 15, 16, 17, 20, 24 and 25 positions (tertiary centers for the most part). Alcohols at C-12 and -16 were oxidized further to ketones. The Schönecker oxidation, discovered and developed during the period, has revolutionized the selective functionalization at C-12 of steroids possessing a 17-keto group. In the presence of iron-centered PDP- and MCP-based catalysts, hydrogen peroxide and acetic acid, substrates tended to be hydroxylated at C-6 and -12, with further oxidation to ketones often accompanying this reaction. The hypohalite reaction, utilizing the more modern Suarez conditions (irradiation in the presence of iodine and PIDA), was reported to facilitate the insertion of a hydroxyl moiety five atoms away from an existing alcohol oxygen. Steroidal-3β-diazoacetates tend to decompose on heating with di-rhodium-centered catalysts while activating carbons four or five atoms away. Chromium- and iron-based acetates were observed to functionalize C-5 and -25. Other reactions involving ring cleavage and halogenation, ketone irradiation and α-hydroxylation of ethers were also covered.

The syntheses of compounds with marked biological activity from readily available steroids is described in the second section of the study. Cyclopamine, cephalostatin-1, ritterazine B and three polyhydroxypregnanaes (pergularin, utendin and tomentogenin) were generated in sequences in which a key step required hydroxylation at C-12 using the Schönecker reaction. A crucial stage in the preparation of cortistatin A, the saundersioside core, eurysterol A, 5,6-dihydroglaucogenin C, as well as clinostatins A and B involved the functionalization of C-18 or -19 utilizing hypohalite chemistry. The synthetic route to xestobergsterol A, pavonin-4-aglycone and ouagabagenin included a transformation where ketone irradiation played a part in either producing a Δ¹⁴ or a C-19 activated steroid. The radical relay reaction, where a 17α-chloro-steroid was formed, was central in the generation of pythocholic acid. The lead tetraacetate reaction was pivotal in the functionalization of C-19 during the synthesis of cyclocitrinol.

While the effects of progesterone on body weight and appetite in pre-menopausal conditions have been well elucidated, its effects in post-menopausal conditions have not been clarified. On the contrary, the effects of estrogen on body weight and appetite in post-menopausal conditions have been well established. In this study, the effects of progesterone treatment on body weight, appetite, and fat mass in ovariectomized rats were evaluated. In addition, the central and/or peripheral levels of oxytocin (OT), leptin, and their receptors, which are potent anorectic factors, were examined. Female rats were ovariectomized and divided into control, progesterone-treated, and estrogen-treated groups. Body weight, food intake, and subcutaneous fat mass were lower in both the progesterone and estrogen groups than in the control group. The estrogen group exhibited higher serum OT levels than the control group, whereas the OT levels of the progesterone and control groups did not differ. The serum leptin levels of both the progesterone and estrogen groups were lower than those of the control group. Gene expression analysis of OT, leptin, and their receptors in the hypothalamus and adipose tissue found few significant differences among the groups. Hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA levels involved in appetite regulation were slightly altered in the progesterone and estrogen groups. These findings suggest that progesterone treatment may have favorable effects on body weight, appetite, and fat mass regulation in post-menopausal conditions and that the mechanisms underlying these effects of progesterone differ from those underlying the effects of estrogen.

The adrenal gland produces steroid hormones that act in the homeostasis of organisms. During aging, alterations in the hormonal balance affect the adrenal glands, but these have not yet been fully described due to the lack of adequate animal models. The adrenal gland of the Mongolian gerbil has a morphology similar to the primate’s adrenal gland, which makes it a possible animal model for endocrine studies. Therefore, the current study aimed to study the morphophysiology of the adrenal gland under the effect of aging. For this purpose, males Meriones unguiculatus, aged three, six, nine, twelve, and fifteen months were used. Morphometric, immunohistochemical, and hormonal analyses were performed. It was observed that during aging the adrenal gland presents hypertrophy of the fasciculata and reticularis zones. Lipofuscin accumulation was observed during aging, in addition to changes in proliferation, cell death, and cell receptors. The analyses also showed that the gerbil presents steroidogenic enzymes and the production of steroid hormones, such as DHEA, like that found in humans. The data provide the first comprehensive assessment of the morphophysiology of the Mongolian gerbil adrenal cortex during aging, indicating that this species is a possible experimental model for studies of the adrenal gland and aging.

Decidualization, a crucial process for successful pregnancy establishment and maintenance, involves endometrial stromal cell differentiation. This process is orchestrated by estradiol (E2), progesterone, and other stimuli that increase intracellular cyclic adenosine monophosphate (cAMP) levels. The intracellular progesterone receptor (PR), encoded by the PGR gene, has a key role in decidualization.

This study aimed to understand the role of sex steroids and cAMP in regulating PGR expression during the in vitro decidualization of the human immortalized endometrial stromal cell line, T-HESC. We subjected the cells to individual and combined treatments of E2, medroxyprogesterone (MPA), and cAMP. Additionally, we treated cells with PR and estrogen receptor antagonists and a protein kinase A (PKA) inhibitor. We evaluated the expression of PGR isoforms and decidualization-associated genes by RT-qPCR.

Our findings revealed that cAMP induced PGR-B and PGR-AB expression by activating the PKA signaling pathway, while MPA downregulated their expression through the PR. Furthermore, downstream genes involved in decidualization, such as those coding for prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP1), and Dickkopf-1 (DKK1), exhibited positive regulation via the cAMP-PKA pathway. Remarkably, MPA-activated PR signaling induced the expression of IGFBP1 and DKK1 but inhibited that of PRL.

In conclusion, we have demonstrated that the PKA signaling pathway induces PGR gene expression during in vitro decidualization of the T-HESC human endometrial stromal cell line. This study has unraveled some of the intricate regulatory mechanisms governing PGR expression during this fundamental process for implantation and pregnancy maintenance.