Search

Androgen production primarily occurs in Leydig cells located in the interstitial compartment of the testis. In aging males, testosterone is crucial for maintaining muscle mass and strength, bone density, sexual function, metabolic health, energy levels, cognitive function, as well as overall well-being. As men age, testosterone production by Leydig cells of the testes begins to decline at a rate of approximately 1% per year starting from their 30s. This review highlights recent findings concerning the use of natural polyphenolics compounds, such as flavonoids, resveratrol, and phenolic acids, to enhance testosterone production, thereby preventing age-related degenerative conditions associated with testosterone insufficiency. Interestingly, most of the natural polyphenolic antioxidants having beneficial effects on testosterone production tend to enhance the expression of the steroidogenic acute regulatory protein ( Star ) gene in Leydig cells. The STAR protein facilitates the entry of the steroid precursor cholesterol inside mitochondria, a rate-limiting step for androgen biosynthesis. Natural polyphenolic compounds can also improve the activities of steroidogenic enzymes, hypothalamus-pituitary gland axis signaling, and testosterone bioavailability. Thus, many polyphenolic compounds such as luteolin, quercetin, resveratrol, ferulic acid phenethyl ester or gigantol may be promising in delaying the initiation of late-onset hypogonadism accompanying aging in males.

The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure-activity study was carried out, which led to the discovery of several novel compounds (16a-c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5-, 12- and 15-LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA-approved 5-LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α-position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12- and 15-LO products. Compounds 16a, 17a far surpassed baicalein, a known 12-LO inhibitor, as inhibitors of 12-LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α-position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15-LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5-LO active site., (© 2024 Wiley Periodicals LLC.)

Although much less common than anthocyanins, 3-Deoxyanthocyanidins (3-DAs) and their glucosides can be found in cereals such as red sorghum. It is speculated that their bioavailability is higher than that of anthocyanins. Thus far, little is known regarding the therapeutic effects of 3-DAs and their O-β-D-glucosides on cancer, including prostate cancer. Thus, we evaluated their potential to decrease cell viability, to modulate the activity of transcription factors such as NFκB, CREB, and SOX, and to regulate the expression of the gene CDH1 , encoding E-Cadherin. We found that 4',7-dihydroxyflavylium chloride (P7) and the natural apigeninidin can reduce cell viability, whereas 4',7-dihydroxyflavylium chloride (P7) and 4'-hydroxy-7-O-β-D-glucopyranosyloxyflavylium chloride (P3) increase the activities of NFkB, CREB, and SOX transcription factors, leading to the upregulation of CDH1 promoter activity in PC-3 prostate cancer cells. Thus, these compounds may contribute to the inhibition of the epithelial-to-mesenchymal transition in cancer cells and prevent the metastatic activity of more aggressive forms of androgen-resistant prostate cancer.

Propolis was collected from honeybee hives in three geographically distinct Algerian climates and extracts were characterized for composition and bioactivity. Bees were identified as native subspecies using an in-silico DraI mtDNA COI-COII test. Over 20 compounds were identified in extracts by LC-MS. Extracts from the Medea region were more enriched in phenolic content (302±28 mg GAE/g of dry extract) than those from Annaba and Ghardaia regions. Annaba extracts had the highest flavonoid content (1870±385 mg QCE/g of dry extract). Medea extracts presented the highest free-radical scavenging activity (IC 50 =13.5 μg/mL) using the DPPH radical assay while Ghardaia extracts from the desert region were weak (IC 50 >100 μg/mL). Antioxidant activities measured using AAPH oxidation of linoleic acid were similar in all extracts with IC 50 values ranging from 2.9 to 4.9 μg/mL. All extracts were cytotoxic (MTT assay) and proapoptotic (Annexin-V) against human leukemia cell lines in the low μg/mL range, although the Annaba extract was less active against the Reh cell line. Extracts inhibited cellular 5-lipoxygenase product biosynthesis with IC 50 values ranging from 0.6 to 3.2 μg/mL. Overall, examined propolis extracts exhibited significant biological activity that warrant further characterization in cellular and in vivo models., (© 2024 The Authors. Chemistry & Biodiversity published by Wiley‐VHCA AG.)

Arctic char ( Salvelinus alpinus ) is facing the decline of its southernmost populations due to several factors including rising temperatures and eutrophication. These conditions are also conducive to episodes of cyclic hypoxia, another possible threat to this species. In fact, lack of oxygen and reoxygenation can both have serious consequences on fish as a result of altered ATP balance and an elevated risk of oxidative burst. Thus, fish must adjust their phenotype to survive and equilibrate their energetic budget. However, their energy allocation strategy could imply a reduction in growth which could be deleterious for their fitness. Although the impact of cyclic hypoxia is a major issue for ecosystems and fisheries worldwide, our knowledge on how salmonid deal with high oxygen fluctuations remains limited. Our objective was to characterize the effects of cyclic hypoxia on growth and metabolism in Arctic char. We monitored growth parameters (specific growth rate, condition factor), hepatosomatic and visceral indexes, relative heart mass and hematocrit of Arctic char exposed to 30 days of cyclic hypoxia. We also measured the hepatic protein synthesis rate, hepatic triglycerides as well as muscle glucose, glycogen and lactate and quantified hepatic metabolites during this treatment. The first days of cyclic hypoxia slightly reduce growth performance with a downward trend in specific growth rate in mass and condition factor variation compared to the control group. This acute exposure also induced a profound metabolome reorganization in the liver with an alteration of amino acid, carbohydrate and lipid metabolisms. However, fish rebalanced their metabolic activities and successfully maintained their growth and energetic reserves after 1 month of cyclic hypoxia. These results demonstrate the impressive ability of Arctic char to cope with its changing environment but also highlight a certain vulnerability of this species during the first days of a cyclic hypoxia event., Competing Interests: The authors declare no competing or financial interest., (© The Author(s) 2023. Published by Oxford University Press and the Society for Experimental Biology.)

The inflammatory response is an essential process for the host defence against pathogens. Lipid mediators are important in coordinating the pro-inflammatory and pro-resolution phases of the inflammatory process. However, unregulated production of these mediators has been associated with chronic inflammatory diseases such as arthritis, asthma, cardiovascular diseases, and several types of cancer. Therefore, it is not surprising that enzymes implicated in the production of these lipid mediators have been targeted for potential therapeutic approaches. Amongst these inflammatory molecules, the 12-hydroxyeicosatetraenoic acid (12(S)-HETE) is abundantly produced in several diseases and is primarily biosynthesized via the platelet's 12-lipoxygenase (12-LO) pathway. To this day, very few compounds selectively inhibit the 12-LO pathway, and most importantly, none are currently used in the clinical settings. In this study, we investigated a series of polyphenol analogues of natural polyphenols that inhibit the 12-LO pathway in human platelets without affecting other normal functions of the cell. Using an ex vivo approach, we found one compound that selectively inhibited the 12-LO pathway, with IC 50 values as low as 0.11 µM, with minimal inhibition of other lipoxygenase or cyclooxygenase pathways. More importantly, our data show that none of the compounds tested induced significant off-target effects on either the platelet's activation or its viability. In the continuous search for specific and better inhibitors targeting the regulation of inflammation, we characterized two novel inhibitors of the 12-LO pathway that could be promising for subsequent in vivo studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Data and interventions are lacking for family-centred perioperative care in adults. Perioperative information given to relatives by nurses or surgeons is associated with improved satisfaction and fewer symptoms of anxiety for relatives and the patient themselves. However, the frequency of the provision of information by anaesthesiologists to patients' relatives during surgery has never been reported., Methods: A cross-sectional survey was sent to French anaesthesiologists in October 2020 to inquire how often they provided information to patients' family members during surgery and what factors led to them providing information frequently (i.e. in more than half of cases)., Results: Among 607 anaesthesiologists, 53% (319/607) were male, with median age 47 (36-60) yr and nearly half (43%, 260/607) reported more than 20 years of clinical experience; most responders (96%, 580/607) mainly treated adults. Forty-nine (8%) anaesthesiologists declared that they frequently provide information to relatives during surgery. After multivariate analysis, age >50 yr, female gender, and paediatric practice were associated with providing information more frequently. Reasons for not providing information included a lack of time and dedicated space to talk to relatives. Urgent surgery or surgery lasting >2 h were identified as factors associated with provision of information to relatives., Conclusions: Giving information to relatives during surgery is not a common practice among anaesthesiologists. It depends on individual anaesthesiologists' personal characteristics and practice. Information during surgery could be provided systematically in situations identified as being the most important by anaesthesiologists in our survey. By creating new pathways of information, we could reduce stress and anxiety of patients and relatives., (© 2023 The Author(s).)

During aging, the production of androgens by the testis Leydig cells gradually decreases. Phenolic compounds can improve testosterone biosynthesis and delay the onset of hypogonadal symptoms in males. In this study, sinapic acid phenethyl ester was evaluated for its ability to regulate gene expression and steroid production in Leydig cells. Specifically, the effects of this ester on the transcriptome of MA-10 Leydig cells were investigated by RNA-Seq. To better establish a structure-function relationship of the hydroxy-methoxyphenyl moiety of sinapic and phenethyl ester, its influences on gene expression were compared to those of its ferulic acid phenethyl ester analogue. According to the transcriptomic analysis, most genes encoding enzymes related to cholesterol biosynthesis are increased in response to sinapic acid phenethyl ester treatment of MA-10 Leydig cells. Interestingly, treatments with 10 μM of ferulic acid phenethyl ester increased cAMP-dependent Star promoter activation, gene expression and protein levels. In addition, treatments of MA-10 Leydig cells with 10 μM of sinapic or ferulic acid phenethyl ester resulted in increased progesterone production. Thus, our results indicate that sinapic and ferulic acid phenethyl esters can improve cholesterol and steroid biosynthesis in testicular Leydig cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

High-fat diets (HFDs) are often used to study metabolic disorders using different animal models. However, the underlying cellular mechanisms pertaining to the concurrent loss of metabolic homeostasis characteristics of these disorders are still unclear mainly because the effects of such diets are also dependent on the time frame of the experiments. Here, we used the fruit fly, Drosophila melanogaster, to investigate the metabolic dynamic effects following 0, 2, 4, 7 and 9 days of an exposure to a HFD (standard diet supplemented with 20% w/v coconut oil, rich in 12:0 and 14:0) by combining NMR metabolomics and GC-FID fatty acid profiling. Our results show that after 2 days, the ingested 12:0 and 14:0 fatty acids are used for both lipogenesis and fatty acid oxidation. After 4 days, metabolites from several different pathways are highly modulated in response to the HFD, and an accumulation of 12:0 is also observed, suggesting that the balance of lipid, amino acid and carbohydrate metabolism is profoundly perturbed at this specific time point. Following a longer exposure to the HFD (and notably after 9 days), an accumulation of many metabolites is observed indicating a clear dysfunction of the metabolic system. Overall, our study highlights the relevance of the Drosophila model to study metabolic disorders and the importance of the duration of the exposure to a HFD to study the dynamics of the fundamental mechanisms that control metabolism following exposure to dietary fats. This knowledge is crucial to understand the development and progression of metabolic diseases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Kidney cancer is one of the top ten cancer diagnosed worldwide and its incidence has increased the last 20 years. Clear Cell Renal Cell Carcinoma (ccRCC) are characterized by mutations that inactivate the von Hippel-Lindau (VHL) tumor suppressor gene and evidence indicated alterations in metabolic pathways, particularly in glutamine metabolism. We previously identified a small molecule, STF-62247, which target VHL-deficient renal tumors by affecting late-stages of autophagy and lysosomal signaling. In this study, we investigated ccRCC metabolism in VHL-deficient and proficient cells exposed to the small molecule. Metabolomics profiling using 1H NMR demonstrated that STF-62247 increases levels of glucose, pyruvate, glycerol 3-phosphate while glutamate, asparagine, and glutathione significantly decreased. Diminution of glutamate and glutamine was further investigated using mass spectrometry, western blot analyses, enzymatic activities, and viability assays. We found that expression of SLC1A5 increases in VHL-deficient cells treated with STF-62247, possibly to stimulate glutamine uptake intracellularly to counteract the diminution of this amino acid. However, exogenous addition of glutamine was not able to rescue cell viability induced by the small molecule. Instead, our results showed that VHL-deficient cells utilize glutamine to produce fatty acid in response to STF-62247. Surprisingly, this occurs through oxidative phosphorylation in STF-treated cells while control cells use reductive carboxylation to sustain lipogenesis. We also demonstrated that STF-62247 stimulated expression of stearoyl-CoA desaturase (SCD1) and peripilin2 (PLIN2) to generate accumulation of lipid droplets in VHL-deficient cells. Moreover, the carnitine palmitoyltransferase 1A (CPT1A), which control the entry of fatty acid into mitochondria for β-oxidation, also increased in response to STF-62247. CPT1A overexpression in ccRCC is known to limit tumor growth. Together, our results demonstrated that STF-62247 modulates cellular metabolism of glutamine, an amino acid involved in the autophagy-lysosome process, to support lipogenesis, which could be implicated in the signaling driving to cell death., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Johnson, Nowlan, Sahin, Barnett, Joy, Touaibia, Cuperlovic-Culf, Zofija Avizonis and Turcotte.)

Sinapic acid is found in many edible plants and fruits, such as rapeseed, where it is the predominant phenolic compound. New sinapic acid phenethyl ester (SAPE) analogues were synthesized and screened as inhibitors of the biosynthesis of 5-lipoxygenase (5-LO) in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Inhibition of leukotriene biosynthesis catalyzed by 5-LO is a validated therapeutic strategy against certain inflammatory diseases and allergies. Unfortunately, the only inhibitor approved to date has limited clinical use because of its poor pharmacokinetic profile and liver toxicity. With the new analogues synthesized in this study, the role of the phenolic moiety, ester function, and bioisosterism was investigated. Several of the 34 compounds inhibited the biosynthesis of 5-LO products, and 20 compounds were 2-11 times more potent than zileuton in PMNL, which are important producers of 5-LO products. Compounds 5i (IC 50 : 0.20 μM), 5l (IC 50 : 0.20 μM), and 5o (IC 50 : 0.21 μM) bearing 4-trifluoromethyl, methyl, or methoxy substituent at meta -position of the phenethyl moiety were 1.5 and 11.5 times more potent than SAPE (IC 50 : 0.30 μM) and zileuton (IC 50 : 2.31 μM), respectively. Additionally, compound 9 (IC 50 : 0.27 μM), which was obtained after acetylation of the 4-hydroxyl of SAPE, was equivalent to SAPE and 8 times more active than zileuton. Furthermore, compound 20b (IC 50 : 0.27 μM) obtained after the bioisosteric replacement of the ester function of SAPE by the 1,2,4-oxadiazole heterocycle was equivalent to SAPE and 8 times more active than zileuton. Thus, this study provides a basis for the rational design of new molecules that could be developed further as anti 5-LO therapeutics.

The hydroxycinnamic acid scaffold is extremely versatile with various biological activities. This review will highlight the progress of the biological activities of hydroxycinnamic acids and their related synthetic analogs, including recently reported anti-cancer, anti-inflammatory, and antioxidant activities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In aging males, androgen production by testicular Leydig cells decreases at a rate of approximately 1% per year. Phenolic compounds may enhance testosterone biosynthesis and delay the onset of male hypogonadism. Gigantol is a bibenzyl compound isolated from several types of orchids of the genus Dendrobium. This compound has various biological activities, including antioxidant activity. However, its capacity to regulate gene expression and steroid production in testicular Leydig cells has never been evaluated. We investigated the effect of gigantol on MA-10 Leydig cells' gene expression using an RNA-Seq approach. To further investigate the structure-function relationship of the hydroxy-methoxyphenyl moiety of gigantol, experiments were also performed with ferulic acid and isoferulic acid. According to transcriptomic analysis, all genes coding for cholesterol biosynthesis-related enzymes are increased in response to gigantol treatment, resulting in increased lipid droplets accumulation. Moreover, treatments with 10 μM gigantol increased StAR protein levels and progesterone production from MA-10 Leydig cells. However, neither ferulic acid nor isoferulic acid influenced StAR protein synthesis and progesterone production in MA-10 Leydig cells. Thus, our findings indicate that gigantol improves cholesterol and steroid biosynthesis within testicular Leydig cells.

A series of thiazolidinediones (TZDs) were synthesized and screened for their effect on the mitochondrial respiration as well as on several mitochondrial respiratory system components of Drosophila melanogaster. Substituted and non-substituted 5-benzylidene and 5-benzylthiazolidine-2,4-diones were investigated. The effect of a substitution in position 3, at the nitrogen atom, of the thiozolidine heterocycle was also investigated. The designed TZDs were compared to UK5099, the most potent mitochondrial pyruvate carrier (MPC) inhibitor, in in vitro and in vivo tests. Compared to 5-benzylthiazolidine-2,4-diones 6-7 and 3-benzylthiazolidine-2,4-dione 8, 5-benzylidenethiazolidine-2,4-diones 2-5 showed more inhibitory capacity on mitochondrial respiration. 5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione (3) and 5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (5) were among the best compounds that compared well with UK5099. Additionally, TZDs 3 and 5, showed no effects on the non-coupled respiration and weak effects on pathways using substrates such as proline, succinate, and G3P. 5-Benzylidenethiazolidine-2,4-dione 3 showed a positive effect on survival and lifespan when added to Drosophila standard and high fat diet. Interestingly, analog 3 completely reversed the effects of high fat diet on Drosophila longevity and induced metabolic changes which suggests an in vivo inhibition of MPC at the mitochondrial level., (Copyright © 2021 Elsevier B.V. All rights reserved.)