The effects of androgens on metabolic functions in females

Prostate cancer has become a global health concern as it is one of the leading causes of mortality in males. With the emerging drug resistance to conventional therapies, it is imperative to unravel new molecular targets for disease prevention. Cytochrome P450 (P450s or CYPs) represents a unique class of mixed-function oxidases which catalyses a wide array of biosynthetic and metabolic functions including steroidogenesis and cholesterol metabolism. Several studies have reported the overexpression of the genes encoding CYPs in prostate cancer cells and how they can be used as molecular targets for drug discovery. But due to functional redundancy and overlapping expression of CYPs in several other metabolic pathways there are several impediments in the clinical efficacy of the novel drugs reported till now. Here we review the most crucial P450 enzymes which are involved in prostate cancer and how they can be used as molecular targets for drug discovery along with the clinical limitations of the currently existing CYP inhibitors.

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The relevance of adhesion G protein-coupled receptors in metabolic functions

Biological Chemistry ◽

10.1515/hsz-2021-0146 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Isabell Kaczmarek ◽

Tomáš Suchý ◽

Simone Prömel ◽

Torsten Schöneberg ◽

Ines Liebscher ◽

...

Keyword(s):

G Protein ◽

Drug Targets ◽

Metabolic Diseases ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Specific Expression ◽

Physiological Functions ◽

Metabolic Functions ◽

Central Nervous Systems ◽

G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

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Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽

10.3390/cancers13030396 ◽

2021 ◽

Vol 13 (3) ◽

pp. 396

Author(s):

Timon A. Bloedjes ◽

Guus de Wilde ◽

Jeroen E. J. Guikema

Keyword(s):

Multiple Myeloma ◽

Cell Metabolism ◽

Chromosomal Rearrangements ◽

Chromosomal Translocations ◽

Metabolic Effects ◽

Aberrant Expression ◽

Metabolic Functions ◽

Complex Chromosomal Rearrangements ◽

Cancer Cell Metabolism ◽

The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

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Cold-induction of afadin in brown fat supports its thermogenic capacity

Scientific Reports ◽

10.1038/s41598-021-89207-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Morten Lundh ◽

Ali Altıntaş ◽

Marco Tozzi ◽

Odile Fabre ◽

Tao Ma ◽

...

Keyword(s):

Cold Exposure ◽

Functional Enrichment ◽

Activation Process ◽

Target Tissue ◽

Cold Stimulation ◽

Brown Adipocytes ◽

Protein Levels ◽

Mrna Induction ◽

Metabolic Functions ◽

Brown Adipose

AbstractThe profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

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The change of gut microbiota in MDD patients under SSRIs treatment

Scientific Reports ◽

10.1038/s41598-021-94481-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yang Shen ◽

Xiao Yang ◽

Gaofei Li ◽

Jiayu Gao ◽

Ying Liang

Keyword(s):

Gut Microbiota ◽

Maximum Dose ◽

Antidepressant Treatment ◽

Intestinal Flora ◽

Alpha Diversity ◽

The Other ◽

Control Group ◽

Depressed Patients ◽

Metabolic Functions

AbstractThe alterations in the gut microbiota have been reported to be correlated with the development of depression. The purpose of this study was to investigate the changes of intestinal microbiota in depressed patients after antidepressant treatment. We recruited 30 MDD patients (MDD group) and 30 healthy controls (control group). The MDD group received individualized treatment with escitalopram at a maximum dose of 20 mg/day. After depressive symptoms improved to a HAMD scale score > 50%, a fecal sample was collected again and used as the follow-up group. The differences of gut microbiota between patients and controls, the characteristics of gut microbiota under treatment and the potential differences in metabolic functions were thus investigated. The Firmicutes/Bacteroidetes ratio was significantly different within three groups, and the ratio of follow-up group was significantly lower than those of the other two groups. Alpha diversity was significantly higher in MDD group than those of the other groups, and the alpha diversity was not significantly different between control and follow-up groups. The beta diversity of some patients resembled participants in the control group. The metabolic function of gut microbiota after treatment was still different from that of the control group. This study suggests that the intestinal flora of depressed patients has a tendency to return to normal under escitalopram treatment.

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Phylogenetic and metabolic diversity have contrasting effects on the ecological functioning of bacterial communities

FEMS Microbiology Ecology ◽

10.1093/femsec/fiab017 ◽

2021 ◽

Vol 97 (3) ◽

Author(s):

Constantinos Xenophontos ◽

Martin Taubert ◽

W Stanley Harpole ◽

Kirsten Küsel

Keyword(s):

Bacterial Communities ◽

Species Interactions ◽

Phylogenetic Diversity ◽

Molecular Mechanisms ◽

Linear Models ◽

Theory Development ◽

Metabolic Diversity ◽

Community Functioning ◽

Metabolic Functions ◽

Independent Effects

ABSTRACT Quantifying the relative contributions of microbial species to ecosystem functioning is challenging, because of the distinct mechanisms associated with microbial phylogenetic and metabolic diversity. We constructed bacterial communities with different diversity traits and employed exoenzyme activities (EEAs) and carbon acquisition potential (CAP) from substrates as proxies of bacterial functioning to test the independent effects of these two aspects of biodiversity. We expected that metabolic diversity, but not phylogenetic diversity would be associated with greater ecological function. Phylogenetically relatedness should intensify species interactions and coexistence, therefore amplifying the influence of metabolic diversity. We examined the effects of each diversity treatment using linear models, while controlling for the other, and found that phylogenetic diversity strongly influenced community functioning, positively and negatively. Metabolic diversity, however, exhibited negative or non-significant relationships with community functioning. When controlling for different substrates, EEAs increased along with phylogenetic diversity but decreased with metabolic diversity. The strength of diversity effects was related to substrate chemistry and the molecular mechanisms associated with each substrate's degradation. EEAs of phylogenetically similar groups were strongly affected by within-genus interactions. These results highlight the unique flexibility of microbial metabolic functions that must be considered in further ecological theory development.

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Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming

International Journal of Molecular Sciences ◽

10.3390/ijms22126292 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6292

Author(s):

Rubén Tovar ◽

Antonio Vargas ◽

Jesús Aranda ◽

Lourdes Sánchez-Salido ◽

Laura González-González ◽

...

Keyword(s):

Lipid Metabolism ◽

Caloric Restriction ◽

Energy Homeostasis ◽

Caloric Intake ◽

Endocannabinoid System ◽

Critical Periods ◽

Nutritional Programming ◽

Metabolic Functions ◽

Gene And Protein Expression ◽

Induced Changes

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.

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The Effect of Platelet-Rich Plasma on the Intra-Articular Microenvironment in Knee Osteoarthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22115492 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5492

Author(s):

Dawid Szwedowski ◽

Joanna Szczepanek ◽

Łukasz Paczesny ◽

Jan Zabrzyński ◽

Maciej Gagat ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Operative Treatment ◽

Animal Studies ◽

Platelet Rich Plasma ◽

Treatment Options ◽

Treatment Protocols ◽

Metabolic Functions ◽

Inflammatory Drugs ◽

Positive Effect

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.

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Metabolic Functions of Myo-inositol

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)76907-5 ◽

1960 ◽

Vol 235 (9) ◽

pp. 2522-2528

Author(s):

Amal Ghosh ◽

Frixos Charalampous ◽

Yolanda Sison ◽

Robert Borer

Keyword(s):

Metabolic Functions

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Specific microbiome profile in Takayasu’s arteritis and giant cell arteritis

Scientific Reports ◽

10.1038/s41598-021-84725-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anne Claire Desbois ◽

Dragos Ciocan ◽

David Saadoun ◽

Gabriel Perlemuter ◽

Patrice Cacoub

Keyword(s):

Giant Cell Arteritis ◽

Giant Cell ◽

Takayasu’S Arteritis ◽

Takayasu's Arteritis ◽

Close Link ◽

Linear Discriminant ◽

Metabolic Functions ◽

Microbiome Profile ◽

Healthy Donors ◽

Effect Size Measurement

AbstractRecent studies have provided evidence of a close link between specific microbiota and inflammatory disorders. While the vessel wall microbiota has been recently described in large vessel vasculitis (LVV) and controls, the blood microbiome in these diseases has not been previously reported (LVV). We aimed to analyse the blood microbiome profile of LVV patients (Takayasu’s arteritis [TAK], giant cell arteritis [GCA]) and healthy blood donors (HD). We studied the blood samples of 13 patients with TAK (20 samples), 9 patients with GCA (11 samples) and 15 HD patients. We assessed the blood microbiome profile by sequencing the 16S rDNA blood bacterial DNA. We used linear discriminant analysis (LDA) coupled with linear discriminant effect size measurement (LEfSe) to investigate the differences in the blood microbiome profile between TAK and GCA patients. An increase in the levels of Clostridia, Cytophagia and Deltaproteobacteria and a decrease in Bacilli at the class level were found in TAK patients compared with HD patients (LDA > 2, p < 0.05). Active TAK patients had significantly lower levels of Staphylococcus compared with inactive TAK patients. Samples of GCA patients had an increased abundance of Rhodococcus and an unidentified member of the Cytophagaceae family. Microbiota of TAK compared with GCA patients was found to show higher levels of Candidatus Aquiluna and Cloacibacterium (LDA > 2; p < 0.05). Differences highlighted in the blood microbiome were also associated with a shift of bacterial predicted metabolic functions in TAK in comparison with HD. Similar results were also found in patients with active versus inactive TAK. In conclusion, patients with TAK were found to present a specific blood microbiome profile in comparison with healthy donors and GCA subjects. Significant changes in the blood microbiome profiles of TAK patients were associated with specific metabolic functions.

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