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Special Issue "Anticancer Drugs".

The focus of this Special Issue of Pharmaceuticals is on the design, synthesis, and molecular mechanism of action of novel antitumor, drugs with a special emphasis on the relationship between the chemical structure and the biological activity of the molecules. This Special Issue also provides an understanding of the biologic and genotypic context in which targets are selected for oncology drug discovery, thus providing a rationalization for the biological activity of these drugs and guiding the design of more effective agents. In this Special Issue of Pharmaceuticals dedicated to anticancer dr

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… Molecular dynamics simulations are effectively used to demonstrate how the V366M mutation facilitates a mechanism for dual activities of human CYP17A1 requiring the conversion of pregnenolone to 17OH-pregnenolone, which re-enters the active site for conversion to dehydroepiandrosterone. …

[Congenital adrenal hyperplasia].

Congenital adrenal hyperplasia is generally considered to be a rare disease; however, the incidence of severe forms of CAH is probably great … yase deficiency is the second of two hypertensive forms of CAH. Deficient 17 alpha-hydroxylation of pregnenolone and progesterone result in decreased secretion of cortisol and sex steroids, but increased secretion of sodium-retaining corticoids (corticosterone and deoxycorticosterone). Females present with normal external genitalia but failure to develop secon …

Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency.

We performed molecular genetic analysis of 24 subjects from 19 families with 17-hydroxylase deficiency in Brazil. Of 7 novel CYP17 mutations, 2 (W406R and R362C) account for 50% and 32% of the mutant alleles, respectively. Both mutations were completely inactive when studied in COS-7 cells and yeast microsomes; however, phenotypic features varied among subjects. Some 46,XY individuals with these genotypes had ambiguous genitalia, and other subjects had normal blood pressure and/or serum potassium. We found mutations W406R and R362C principally in families with Spanish and Portuguese ancestry,

Roles of human CYP2A6 and 2B6 and rat CYP2C11 and 2B1 in the 10-hydroxylation of (-)-verbenone by liver microsomes.

(-)-Verbenone, a monoterpene bicyclic ketone, is a component of the essential oil from rosemary species such as Rosmarinus officinalis L., Verbena triphylla, and Eucalyptus globulus and is used for an herb tea, a spice, and a perfume. In this study, (-)-verbenone was found to be converted to 10-hydroxyverbenone by rat and human liver microsomal cytochrome p450 (p450) enzymes. The product formation was determined by high-performance liquid chromatography with UV detection at 251 nm. There was a good correlation between activities of coumarin 7-hydroxylation and (-)-verbenone 10-hydroxylation ca

Metabolism of tauromustine in liver and lung microsomes from various species.

1. The cytochrome P450 (CYP)-mediated metabolism of tauromustine has been evaluated in liver and lung microsomes from various species. Liver … ased 3-fold in liver microsomes from rat pretreated with phenobarbital, whereas treatment with cyanopregnenolone enhanced the denitrosation 11-fold, indicating the involvement of CYP3A. 4. Metabolism across a panel of 10 human liver microsomal samples demonstrated a correlation with testosterone 6beta-hydroxylation of demethylation (r2 = 0.86) and denitrosatio …

Keyword Index for Volume 108

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… population-based 1195 population-based data 691 population-based study 775 population studies 2455 positive predictive values 25 post-bereavement survey 1942 postoperative relapse 791 potential drug–drug interactions 1071 PP2A subunits 2590 predictive 1052, 1925 predictive biomarker 1238 pregnenolone …

Синергическое регенеративное, иммунодуляционное и антивоспалительное воздействие ваниллина и адипозы производных стволовых клеток в животной модели купризонного склероза.

ЦЕЛИ: Ваниллин как потенциальный терапевтический агент наряду с трансплантацией нейротрофических факторов, отделяющих клетки, считается перспективным средством лечения неврологических расстройств. В этом исследовании последствия ваниллина в сочетании с трансплантацией стволовых клеток, полученных человеком, были оценены с точки зрения дифференциации олигодендроцитов, повторного сглаживания и улучшения моторных функций. МАТЕРИАЛЫ И МЕТОДЫ: Женский C57BL/6 Мышей кормили кухонной зоной.400 мг/кг/сут.) 5 неделями, чтобы вызвать MS. Демилинированные мыши были разделены на группы MS, MS/vanillin, MS

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… demyelination in mouse brain is not due to depletion of copper ASN Neuro 2022 14 17590914221126367 36114624 10.1177/17590914221126367 PMC9483969 29 Ganji R Razavi S Ghasemi N Mardani M Improvement of remyelination in demyelinated corpus callosum using human adipose-derived stem cells (hADSCs) and pregnenolone …

Identification of a novel cuproptosis-related gene signature for multiple myeloma diagnosis.

BackgroundMultiple myeloma (MM) ranks second among the most prevalent hematological malignancies. Recent studies have unearthed the promise of cuproptosis as a novel therapeutic intervention for cancer. However, no research has unveiled the particular roles of cuproptosis-related genes (CRGs) in the prediction of MM diagnosis.MethodsMicroarray data and clinical characteristics of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed gene analysis, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature e

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… Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci USA. 2011;108(25):10139‐10143. 10.1073/pnas.1019441108 38. Korotchkina LG, Patel MS. Mutagenesis studies of the phosphorylation sites of recombinant human pyruvate dehydrogenase. …

Silk-Ovarioids: establishment and characterization of a human ovarian primary cell 3D-model system.

STUDY QUESTION: What is the best protocol to establish a long-term stable three-dimensional (3D) model for human primary ovarian cells? SUM … , and by the detection of pro-angiogenic cytokines (e.g. IL-6, IL-8, and GM-CSF) and steroids (e.g. pregnenolone and epitestosterone) in the culture media. LARGE SCALE DATA: The RNA-sequencing count matrix is deposited in Gene Expression Omnibus with accession number GSE253571. Raw data are deposited in Swedish National Data Service with the DOI https://doi.o …

Baseline Functional Performance Predicts Better Long-Term Self-Reported Physical Function After Auto-HSCT.

Background/Objectives: Determination of baseline predictors of longer-term quality of life (QOL) after autologous hematopoietic stem cell transplantation (Auto-HSCT) may identify patients with the greatest supportive care needs. We hypothesized that baseline older age, weight loss, and worse functional performance would negatively predict QOL over two years post-HSCT. Methods: Physical function, body composition, and QOL were assessed before (PRE) and one month (1MO) after Auto-HSCT in U.S. Veterans (N = 23). QOL and survival were also assessed approximately every six months for two years afte

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… Plasma sex hormones including 17-hydroxypregnenolone (ng/mL), 17-hydroxyprogesterone (ng/mL), androstenedione (ng/mL), androsterone (ng/mL), dehydroepiandrosterone (DHEA; ng/mL), dihydrotestosterone (DHT; ng/mL), pregnenolone (ng/mL), progesterone (ng/mL), and total testosterone (ng/mL) were analyzed …

A Holistic Review of Oncological Drug Targets and Trajectories of Resistance in Cancer Therapy.

The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy. Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies. Human epidermal growth factor receptor, hormone receptors, and angiogenesis factors are among the established therapies in tumor reduction and managing side effects. Novel targeted therapies like KRAS G12C, Claudin-18 isoform 2 (CLDN18.2), Trophoblast cell-surface antigen 2 (TROP2), and epigenetic r

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… The activation of the steroidogenesis pathway leads to the conversion of cholesterol into pregnenolone, which further changes to 17α-Hydroxypregnenolone by 17α-hydroxylase activity performed by CYP17 (Cytochrome P450 17A1). … CYP17 enzyme adds a hydroxyl group (–OH) at the 17α position of pregnenolone and progesterone. The subsequent step incorporates the same enzyme for performing 17,20-lyase activity, releasing DHEA through the cleavage of the side chain located between carbons 17 and 20. …

Shilajit mitigates chemotherapeutic drug-induced testicular toxicity: Study on testicular germ cell dynamics, steroidogenesis modulation, and Nrf-2/Keap-1 signaling.

BACKGROUND: Medications, including chemotherapeutic drugs, contribute to male infertility as external factors by inducing oxidative stress in testicular cells. Shilajit is a naturally occurring bioactive antioxidant used in Ayurvedic medicine to treat a variety of ailments. OBJECTIVE: This study examines the potential of Shilajit to counteract the negative effects of the chemotherapeutic drug cyclophosphamide (CPA) on testicular germ cell dynamics. MATERIAL AND METHODS: Male Parkes mice received single intraperitoneal CPA injection (200 mg/kg BW) on day one, followed by daily supplementation

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… We found that Shilajit stimulates conversion of cholesterol to pregnanolone by stimulating the CYP11A1 enzyme and pregnenolone to testosterone by increasing the activity of Δ5 3β-HSD and 17β-HSD. …

Роль и диагностическая значимость Аполипопротеина D в отдельных нейродегенеративных расстройствах.

Всемирная организация здравоохранения в 2021 году назвала болезнь Альцгеймера и другие слабоумия седьмой по величине причиной смерти во всем мире. Нейродегенеративные расстройства являются прогрессивными, трудноразрешимыми и часто смертельными. Ранняя диагностика может дать пациентам возможность долго выжить с ослабленной симптоматологией из-за раннего вмешательства. Поэтому необходимы дальнейшие исследования по поиску неинвазивных биомаркеров нейродегенеративных заболеваний. Apopoprotein D (ApoD) — гликпротеин, содержащийся в липидном метаболизме, регулировании окислительного стресса и воспал

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… Biological Functions of Apolipoprotein D ApoD plays multiple roles in the body, as it can bind to various ligands, including progesterone, arachidonic acid (AA), retinoic acid, and pregnenolone [ 50 ]. …

Network Pharmacology Approaches Used to Identify Therapeutic Molecules for Chronic Venous Disease Based on Potential miRNA Biomarkers.

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to i

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… . | 9 Progesterone | This hormone is an endogenous steroid derived from cholesterol via pregnenolone. …

Proteasome inhibition protects blood-brain barrier P-glycoprotein and lowers Aβ brain levels in an Alzheimer's disease model.

BackgroundLoss of P-glycoprotein (P-gp) at the blood-brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer's disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin-proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor

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… In this regard, we previously showed in transgenic human amyloid precursor protein (hAPP)-overexpressing mice that activating the pregnane X receptor with pregnenolone-16-carbonitrile induces P-gp protein expression and transport activity levels, which restores Aβ clearance and reduces brain Aβ levels …

Search for novel biomarkers of febrile neutropenia in hematological patients: an overview.

A single-center prospective study was conducted at a tertiary care hospital in Kuopio Finland over the past two decades, searching for novel biomarker candidates to predict complicated course of febrile neutropenia (FN) in hematological patients. In Dec 2006‒Dec 2015, 85 patients with acute myeloid leukemia and 179 autologous hematopoietic stem cell transplant recipients were included. More than 20 biomarkers were evaluated in subsequent patient cohorts and compared to C-reactive protein (CRP) and procalcitonin (PCT). The samples were taken on d0-d2 from the beginning of FN. Here, we provide a

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… Pregnenolone showed increased levels in patients with bacteremia [ 53 ]. Although currently based on only a few studies, non-targeted metabolomics may soon prove to be a useful adjunct in the evaluation of patients with FN. It may provide insights into the complex pathophysiology of FN and sepsis. …

The emerging role of osteoclasts in the treatment of bone metastases: rationale and recent clinical evidence.

The occurrence of bone metastasis is a grave medical concern that substantially impacts the quality of life in patients with cancer. The precise mechanisms underlying bone metastasis remain unclear despite extensive research efforts, and efficacious therapeutic interventions are currently lacking. The ability of osteoclasts to degrade the bone matrix makes them a crucial factor in the development of bone metastasis. Osteoclasts are implicated in several aspects of bone metastasis, encompassing the formation of premetastatic microenvironment, suppression of the immune system, and reactivation o

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… Researchers have recently found that malignant tumors expressing Cyp11a1 produce the steroid pregnenolone, which can promote the growth of bone metastases by enhancing osteoclastogenesis ( 161 ).However, researchers encounter various challenges in conducting preclinical and clinical investigations aimed …

Skeletal metastasis: treatments, mouse models, and the Wnt signaling.

Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process o

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… Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), which is re-sponsible for the conversion of progesterone and pregnenolone to testosterone precursors. This inhibition of alternate sources of testosterone results in an overall decrease in the amount of circulating testosterone. …

Calcium-Permeable Channels Cooperation for Rheumatoid Arthritis: Therapeutic Opportunities.

Rheumatoid arthritis is a common autoimmune disease that results from the deposition of antibodies-autoantigens in the joints, leading to long-lasting inflammation. The main features of RA include cartilage damage, synovial invasion and flare-ups of intra-articular inflammation, and these pathological processes significantly reduce patients' quality of life. To date, there is still no drug target that can act in rheumatoid arthritis. Therefore, the search for novel drug targets has become urgent. Due to their unique physicochemical properties, calcium ions play an important role in all cellula

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… TRPM3 channel stimulated by pregnenolone sulphate in synovial fibroblasts and negatively coupled to hyaluronan BMC Musculoskelet. Disord. 2010 11 111 10.1186/1471-2474-11-111 20525329 PMC2893450 79. Zhu S. Wang Y. Pan L. Yang S. Sun Y. Wang X. Hu F. …

Non-Exosomal and Exosomal Circulatory MicroRNAs: Which Are More Valid as Biomarkers?

MicroRNAs (miRNAs) are a group of small non-coding RNAs with approximately 19-25 nucleotides that are involved in regulating a range of developmental and physiological processes. Non-exosomal circulating and exosomal miRNAs have also been proposed to be useful in diagnostics as biomarkers for diseases and different types of cancer. In this review, the quantity of miRNAs and of reliable experimental data analyses of miRNAs that come from exosomal and non-exosomal sources are discussed from the perspective of their use as biomarkers for cancer and other diseases, including viral infections, nerv

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… Other than miRNAs, HDL is also reported to act as a carrier of fat-soluble vitamins [such as vitamin E ( Sattler et al., 1996 ) and vitamin D ( Vaisar et al., 2007 ; Alwaili et al., 2012 )], steroids (lipophilic thyroid hormone thyroxine [T4]; Benvenga et al., 1989 ), hormones (estrogen, pregnenolone …