Search Results (13)

In most mammals, a withdrawal of the pro-gestational hormone progesterone (P4) is necessary for labor onset. In murine cervix, P4 withdrawal is mediated by enzymes steroid 5-alpha-reductase type 1 (SRD5A1) and 20-alpha-hydroxysteroid-dehydrogenase (20α-HSD). Previously, we have shown that inflammatory stimuli induce 20α-HSD levels in uterine muscle (myometrium). Here, we hypothesized that (1) infectious inflammation alters the levels of both P4-metabolizing enzymes in mouse cervix, which consequently ceases P4-mediated inhibition of cervical remodeling, thereby inducing preterm labor (PTL); (2) a progestin, selective progesterone receptor modulator promegestone (aka R5020), non-metabolizable by 20α-HSD, can block lipopolysaccharide (LPS)-induced PTL in mice by maintaining P4 signaling and preventing cervical remodeling. Using RT-PCR and IHC/IF methods, we evaluated the effect of inflammation on the expression of both enzymes in mouse cervix and determined if R5020 can prevent cervical remodeling and PTL in mice. We found significant induction of SRD5A1 and 20α-HSD proteins (p < 0.01), as well as transcript levels of pro-inflammatory cytokines Il1b, Il6, chemokines Cxcl1, Ccl2, cervical ripening enzyme Has2, hyaluronic acid binding protein/HABP (p < 0.05), and a simultaneous decrease in major extracellular fibrillar proteins, collagen type 1 and type 3 (col1a1, col3a1), in mouse cervix during PTL. The prophylactic administration of R5020 in pregnant mice significantly inhibited cervical remodeling and prevented PTL irrespective of the route of LPS-induction, systemic or local. We concluded that R5020 is a promising novel drug application for preterm birth prevention. Full article

Prolactin (PRL) has recently been found to play a role in lipid metabolism in addition to its traditional roles in lactation and reproduction. However, the effects of PRL on lipid metabolism in liver and adipose tissues are unclear. Therefore, we aimed to study the role of PRL on lipid metabolism in goats. Twenty healthy eleven-month-old Yanshan cashmere goats with similar body weights (BWs) were selected and randomly divided into a control (CON) group and a bromocriptine (BCR, a PRL inhibitor, 0.06 mg/kg, BW) group. The experiment lasted for 30 days. Blood was collected on the day before BCR treatment (day 0) and on the 15th and 30th days after BCR treatment (days 15 and 30). On day 30 of treatment, all goats were slaughtered to collect their liver, subcutaneous adipose, and perirenal adipose tissues. A portion of all collected tissues was stored in 4% paraformaldehyde for histological observation, and another portion was immediately stored in liquid nitrogen for RNA extraction. The PRL inhibition had inconclusive effects found on BW and average daily feed intake (ADFI) in goats (p > 0.05). PRL inhibition decreased the hormone-sensitive lipase (HSL) levels on day 30 (p < 0.05), but the effects were inconclusive on days 0 and 15. PRL inhibition had inconclusive effects found on total cholesterol (TCH), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), and acetyl-CoA carboxylase (ACC) on days 0, 15, and 30 (p > 0.05). Furthermore, hematoxylin–eosin (HE) staining of the liver, subcutaneous adipose, and perirenal adipose sections showed that PRL inhibition had inconclusive effects on the pathological changes in their histomorphology (p > 0.05), but measuring adipocytes showed that the area of perirenal adipocytes decreased in the BCR group (p < 0.05). The qPCR results showed that PRL inhibition increased the expression of PRL, long-form PRL receptor (LPRLR), and short-form PRL receptor (SPRLR) genes, as well as the expression of genes related to lipid metabolism, including sterol regulatory element binding transcription factor 1 (SREBF1); sterol regulatory element binding transcription factor 2 (SREBF2); acetyl-CoA carboxylase alpha (ACACA); fatty acid synthase (FASN); 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR); 7-dehydrocholesterol reductase (DHCR7); peroxisome proliferator-activated receptor gamma (PPARG); and lipase E, hormone-sensitive type (LIPE) in the liver (p < 0.05). In the subcutaneous adipose tissue, PRL inhibition increased SPRLR gene expression (p < 0.05) and decreased the expression of genes related to lipid metabolism, including SREBF1, SREBF2, ACACA, PPARG, and LIPE (p < 0.05). In the perirenal adipose tissue, the inhibition of PRL decreased the expression of the PRL, SREBF2, and HMGCR genes (p < 0.05). In conclusion, the inhibition of PRL decreases the serum HSL levels in cashmere goats; the effects of PRL on lipid metabolism are different in different tissues; and PRL affects lipid metabolic activity by regulating different PRLRs in liver and subcutaneous adipose tissues, as well as by decreasing the expression of the PRL, SREBF2, and HMGCR genes in perirenal adipose tissue. Full article

Background: High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD). Results: C57BL/6 mice (5–6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. Bacteroidetes, Firmicutes, and Proteobacteria were highly abundant in C-HFD group, while the Verrucomicrobia, Saccharibacteria (TM7), Actinobacteria, and Tenericutes were more abundant in F-HFD group. Other taxa in C-HFD group included the Bacteroides, Odoribacter, Sutterella, Firmicutes bacterium (AF12), Anaeroplasma, Roseburia, and Parabacteroides distasonis. An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (Acaca), Fatty acid synthase (Fasn), Stearoyl-CoA desaturase-1 (Scd1), Elongation of long-chain fatty acids family member 6 (Elovl6), Peroxisome proliferator-activated receptor-gamma (Pparg) and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (Hmgcr). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (CD36), Fatty acid binding protein-1 (Fabp1) and efflux (ATP-binding cassette G1 (Abcg1), Microsomal TG transfer protein (Mttp) in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (Tnfa), C-C motif chemokine ligand 2 (Ccl2), and Interleukin-12 (Il12), as well as a tendency for liver fibrosis. Conclusion: These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance. Full article

The porcine bulbourethral glands produce a gel-type secretion. Although the role of these contributions to reproductive success remains murky, the bulbourethral glands are major accessory sex glands in this species. Isometric growth in the early neonatal interval is followed by allometric growth in the late juvenile interval (6 to 11 weeks of age), while circulating endogenous steroids are low. The rate of allometric growth increases during the peripuberal interval (16 to 20 weeks of age) when systemic testosterone is relatively high. Gene expression for androgen receptor (AR) and for the steroid 5 alpha-reductase 2 (SRD5A2) enzyme that synthesizes the more potent androgen dihydrotestosterone from its precursor was evaluated by qPCR analyses of bulbourethral gland tissue. Tissues were collected from control boars (2 weeks to 40 weeks of age) and from littermates of these boars treated with letrozole to suppress endogenous estrogen synthesis. Gene expression for these two key proteins in androgen signaling was quite low during the initial allometric growth in the late juvenile and prepuberal intervals, suggesting that this initial growth was not primarily stimulated by androgens. These observations are consistent with a more direct estrogen-mediated inhibition of growth via GPER previously proposed, with the sensitivity extending into the late juvenile interval when estrogens as well as androgens are normally relatively low. Full article

Benign prostatic hyperplasia (BPH), characterized by the enlargement of the prostate gland and subsequent lower urinary tract symptoms, poses a significant health concern for aging men with increasing prevalence. Extensive efforts encompassing in vitro and in vivo models are underway to identify novel and effective agents for the management and treatment of BPH. Research endeavors are primarily channeled toward assessing the potential of compounds to inhibit cell proliferation, curb inflammation, and display anti-androgenic activity. Notably, through screening aimed at inhibiting 5-alpha reductase type 2 (5αR2) in human prostatic cells, two acyl compounds (1 and 2) were isolated from a bioactive fraction sourced from an association of marine sponges Poecillastra sp. and Jaspis sp. The complete structure of 1 was determined as (Z)-dec-3-enony (2S, 3S)-capreomycidine, ascertained by JBCA and ECD comparison. While the absolute configurations of 2 remained unassigned, it was identified as a linkage of a 2, 7S*-dihydoxy-9R*-methyloctadecanoyl group with the 2-amino position of a tramiprosate moiety referred to as homotaurine. Evaluation of both compounds encompassed the assessment of their inhibitory effects on key biomarkers (5αR2, AR, PSA, and PCNA) associated with BPH in testosterone propionate (TP)-activated LNCap and RWPE-1 cells. Full article

Oxidative stress is associated with insulin resistance and secretion, and antioxidant systems are essential for preventing and managing type 2 diabetes (T2DM). This study aimed to explore the polygenic variants linked to oxidative stress and the antioxidant system among those associated with T2DM and the interaction of their polygenic risk scores (PRSs) with lifestyle factors in a large hospital-based cohort (n = 58,701). Genotyping, anthropometric, biochemical, and dietary assessments were conducted for all participants with an average body mass index of 23.9 kg/m². Genetic variants associated with T2DM were searched through genome-wide association studies in participants with T2DM (n = 5383) and without T2DM (n = 53,318). The Gene Ontology database was searched for the antioxidant systems and oxidative stress-related genes among the genetic variants associated with T2DM risk, and the PRS was generated by summing the risk alleles of selected ones. Gene expression according to the genetic variant alleles was determined on the FUMA website. Food components with low binding energy to the GSTA5 protein generated from the wildtype and mutated GSTA5_rs7739421 (missense mutation) genes were selected using in silico analysis. Glutathione metabolism-related genes, including glutathione peroxidase (GPX)1 and GPX3, glutathione disulfide reductase (GSR), peroxiredoxin-6 (PRDX6), glutamate–cysteine ligase catalytic subunit (GCLC), glutathione S-transferase alpha-5 (GSTA5), and gamma-glutamyltransferase-1 (GGT1), were predominantly selected with a relevance score of >7. The PRS related to the antioxidant system was positively associated with T2DM (ORs = 1.423, 95% CI = 1.22–1.66). The active site of the GASTA proteins having valine or leucine at 55 due to the missense mutation (rs7739421) had a low binding energy (<−10 kcal/mol) similarly or differently to some flavonoids and anthocyanins. The PRS interacted with the intake of bioactive components (specifically dietary antioxidants, vitamin C, vitamin D, and coffee) and smoking status (p < 0.05). In conclusion, individuals with a higher PRS related to the antioxidant system may have an increased risk of T2DM, and there is a potential indication that exogenous antioxidant intake may alleviate this risk, providing insights for personalized strategies in T2DM prevention. Full article

In the last decade, cholesterol level has been implicated in several types of cancer, including breast cancer. In the current study, we aimed to investigate the condition of lipid depletion, hypocholesterolemia or hypercholesterolemia reproduced in vitro to analyze the response of different human breast cancer cells. Thus, MCF7 as the luminal A model, MB453 as the HER2 model and MB231 as the triple-negative model were used. No effect on cell growth and viability was detected in MB453 and MB231 cells. In MCF7 cells, hypocholesterolemia (1) reduced cell growth, and Ki67 expression; (2) increased ER/PgR expression; (3) stimulated the 3-Hydroxy-3-Methylglutaryl-CoA reductase and neutral sphingomyelinase and; (4) stimulated the expression of CDKN1A gene coding cyclin-dependent kinase inhibitor 1A protein, GADD45A coding growth arrest and DNA-damage-inducible alpha protein and, PTEN gene coding phosphatase and tensin homolog. All these effects were exacerbated by the lipid-depleted condition and reversed by the hypercholesterolemic condition. The relationship between cholesterol level and sphingomyelin metabolism was demonstrated. In summary, our data suggest that cholesterol levels should be controlled in luminal A breast cancer. Full article

The male reproductive system develops from a minimally functioning gonad and nonfunctioning accessory sex glands in the neonate; sex steroids, presumed to be primary influencers of these changes, have been characterized in multiple species. This study focused on the expression of the androgen receptor as the principal mediator of androgen-induced signaling; the 5α reductase enzyme that converts testosterone to the more active dihydrotestosterone; and colony stimulating factor 1, a mediator of macrophage influence on organ development in the pig. The time points chosen to evaluate normal developmental changes during the juvenile and prepubertal intervals included the inflection time points of 6.5 weeks of age at the nadir of circulating estradiol and testosterone concentrations in juveniles, and 11 weeks of age, when these concentrations begin to increase. The role of sex steroid signaling in the regulation of gene expression was evaluated by the blockade of androgen and estrogen receptors and reduction in endogenous estrogens. Expression of colony stimulating factor 1 in the testes gradually decreased during development; developmental profiles in the prostate and seminal vesicles were clearly different. Interference with sex steroid signaling had no effect on the expression of these three genes in testicular tissue and minimal and transient effects in prostate and seminal vesicles. Full article

Cannabidiol (CBD) is a plant-derived compound with antioxidant and anti-inflammatory properties. Pulmonary hypertension (PH) is still an incurable disease. CBD has been suggested to ameliorate monocrotaline (MCT)-induced PH, including reduction in right ventricular systolic pressure (RVSP), a vasorelaxant effect on pulmonary arteries and a decrease in the white blood cell count. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on the parameters of oxidative stress and inflammation in the lungs of rats with MCT-induced PH. In MCT-induced PH, we found a decrease in total antioxidant capacity (TAC) and glutathione level (GSH), an increase in inflammatory parameters, e.g., tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1), and cluster of differentiation 68 (CD68), and the overexpression of cannabinoid receptors type 1 and 2 (CB₁-Rs, CB₂-Rs). Administration of CBD increased TAC and GSH concentrations, glutathione reductase (GSR) activity, and decreased CB₁-Rs expression and levels of inflammatory mediators such as TNF-α, IL -1β, NF-κB, MCP-1 and CD68. In conclusion, CBD has antioxidant and anti-inflammatory effects in MCT-induced PH. CBD may act as an adjuvant therapy for PH, but further detailed preclinical and clinical studies are recommended to confirm our promising results. Full article

Benign prostatic hyperplasia (BPH) is the most common symptomatic abnormality of the human prostate characterized by uncontrolled proliferation of the prostate gland. In this study, we investigated the effect of bamboo, Phyllostachys pubescens, leaves extract (PPE) on human 5α-reductase type 2 (SRD5A2) gene promoter activity in human prostate cell lines and the protective effect of PPE on a testosterone-induced BPH rat model. PPE repressed human SRD5A2 promoter activity and its mRNA expression. The rats treated with PPE for 4 weeks showed a significantly attenuated prostate weight compared to vehicle control. PPE-treated rats also showed reduced serum dihydrotestosterone, testosterone, prostate-specific antigen, and SRD5A2 levels by testosterone injection. Quantitative real-time polymerase chain reaction showed that PPE treatment significantly decreased mRNA expression of SRD5A2, androgen receptor (AR), proliferating cell nuclear antigen (PCNA), and fibroblast growth factor 2 compared with the vehicle-treated, testosterone-injected rats in the prostate. Furthermore, PPE treatment showed reduced AR, PCNA, and tumor necrosis factor alpha expression in the prostate via immunohistofluorescence staining. In conclusion, oral administration of PPE prevented and inhibited the development and progression of enlarged prostate lesions in testosterone-induced animal models through various anti-proliferative and anti-inflammatory pharmacological effects and induced suppression of SRD5A2 gene expression. Full article

Chitooligosaccharides (COS) have a variety of biological activities due to their positively charged amino groups. Studies have shown that COS have antidiabetic effects, but their molecular mechanism has not been fully elucidated. The present study confirmed that COS can reduce hyperglycemia and hyperlipidemia, prevent obesity, and enhance histological changes in the livers of mice with type 2 diabetes mellitus (T2DM). Additionally, treatment with COS can modulate the composition of the gut microbiota in the colon by altering the abundance of Firmicutes, Bacteroidetes, and Proteobacteria. Furthermore, in T2DM mice, treatment with COS can upregulate the cholesterol-degrading enzymes cholesterol 7-alpha-hydroxylase (CYP7A1) and incretin glucagon-like peptide 1 (GLP-1) while specifically inhibiting the transcription and expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the key enzyme in cholesterol synthesis. Furthermore, using an oleic acid-induced hepatocyte steatosis model, we found that HMGCR can be directly transactivated by SET and MYND domain containing 3 (SMYD3), a transcriptional regulator, via 5′-CCCTCC-3′ element in the promoter. Overexpression of SMYD3 can suppress the inhibitory effect of COS on HMGCR, and COS might regulate HMGCR by inhibiting SMYD3, thereby exerting hypolipidemic functions. To the best of our knowledge, this study is the first to illustrate that COS mediate glucose and lipid metabolism disorders by regulating gut microbiota and SMYD3-mediated signaling pathways. Full article

Benign prostate hyperplasia (BPH) is one of the most common urological problems in mid-aged to elderly men. Risk factors of BPH include family history, obesity, type 2 diabetes, and high oxidative stress. The main medication classes for BPH management are alpha blockers and 5α-reductase inhibitors. However, these conventional medicines cause adverse effects. Lycogen™, extracted from Rhodobacter sphaeroides WL-APD911, is an anti-oxidant and anti-inflammatory compound. In this study, the effect of Lycogen™ was evaluated in rats with testosterone-induced benign prostate hyperplasia (BPH). Testosterone injections and Lycogen™ administration were carried out for 28 days, and body weights were recorded twice per week. The testosterone injection successfully induced a prostate enlargement. BPH-induced rats treated with different doses of Lycogen™ exhibited a significantly decreased prostate index (PI). Moreover, the Lycogen™ administration recovered the histological abnormalities observed in the prostate of BPH rats. In conclusion, these findings support a dose-dependent preventing effect of Lycogen™ on testosterone-induced BPH in rats and suggest that Lycogen™ may be favorable to the prevention and management of benign prostate hyperplasia. Full article

Type 2 diabetes is a major public health concern worldwide. Xylobiose (XB) consists of two molecules of d-xylose and is a major disaccharide in xylooligosaccharides that are used as prebiotics. We hypothesized that XB could regulate diabetes-related metabolic and genetic changes via microRNA expression in db/db mice. For six weeks, C57BL/KsJ-db/db mice received 5% XB as part of the total sucrose content of their diet. XB supplementation improved glucose tolerance with reduced levels of OGTT AUC, fasting blood glucose, HbA1c, insulin, and HOMA-IR. Furthermore, XB supplementation decreased the levels of total triglycerides, total cholesterol, and LDL-C. The expression levels of miR-122a and miR-33a were higher and lower in the XB group, respectively. In the liver, expressions of the lipogenic genes, including, fatty acid synthase (FAS), peroxisome proliferator activated receptor γ (PPARγ), sterol regulatory element-binding protein-1C (SREBP-1C), sterol regulatory element-binding protein-2 (SREBP-2), acetyl-CoA carboxylase (ACC), HMG-CoA reductase (HMGCR), ATP-binding cassette transporter G5/G8 (ABCG5/8), cholesterol 7 alpha-hydroxylase (CYP7A1), and sterol 12-alpha-hydroxylase (CYP8B1), as well as oxidative stress markers, including superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPX), and catalase, were also regulated by XB supplementation. XB supplementation inhibited the mRNA expressions levels of the pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1, as well as phosphorylation of c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK), p38 mitogen-activated protein kinases (MAPK), and extracellular signal-regulated kinases 1/2 (ERK1/2). These data demonstrate that XB exhibits anti-diabetic, hypolipogenic, and anti-inflammatory effects via regulation of the miR-122a/33a axis in db/db mice. Full article