Inhibitory effects of Centella asiatica (L.) Urban on enlarged prostate through androgen receptor and PI3K/Akt signaling pathways.

Centella asiatica (L.) Urban (C. asiatica) is a traditional herbal medicine that has been used for wound healing and anti-inflammation since ancient times. Various biological effects of C. asiatica ethanolic extract (CAE) were previously reported. However, in our previous study, C. asiatica aqueous extract (CAA) exhibited higher inhibitory activity on benign prostatic hyperplasia (BPH) than CAE. Therefore, the aim of this study was to investigate the effect of CAA on BPH, and elucidate the inhibitory mechanism through in vitro and in vivo experiments as well as metabolite analysis of CAA. A BPH rat model was induced by daily subcutaneous injection of testosterone propionate (TP, 3 mg kg-1) dissolved in corn oil for 4 weeks after castration. The experimental group, the CAA treatment group, was orally administered CAA (100 mg kg-1) for 4 weeks while inducing prostatic hyperplasia. Saw palmetto extract (Saw, 100 mg kg-1) and Finasteride (Fi, 1 mg kg-1) were used as positive controls and were administered orally for 4 weeks. CAA significantly inhibited androgen receptor signaling related factors overexpressed by dihydrotestosterone (DHT) treatment in prostate cell lines. Afterwards, the testosterone-induced BPH model was used to verify the alleviation efficacy of CAA in prostatic hyperplasia. Prostate size and the thickness of the prostate tissue epithelium were significantly decreased in the group treated with CAA compared to those in the BPH group. The results of protein expression in the prostate tissue confirmed that CAA inhibited androgen receptor signaling in BPH and decreased the expression of growth factors. Moreover, CAA suppressed the expression of the PI3K/Akt pathway and cell proliferation-related factors compared to the BPH group. Taken together, these results indicate that CAA improves the inhibitory efficacy of BPH by inhibiting the androgen receptor and PI3K/Akt pathways, suggesting that CAA may be a promising candidate for biopharmaceutical formulations of BPH.

AGL9: A Novel Hepatoprotective Peptide from the Larvae of Edible Insects Alleviates Obesity-Induced Hepatic Inflammation by Regulating AMPK/Nrf2 Signaling.

In this study, we investigated the anti-obesity properties of the novel peptide Ala-Gly-Leu-Gln-Phe-Pro-Val-Gly-Arg (AGL9), isolated from the enzymatic hydrolysate of Allomyrinadichotoma larvae. To investigate the preventive effects of AGL9 against hepatic steatosis and its possible mechanisms of action, we established an nonalcoholic fatty liver disease (NAFLD) model by feeding C57BL/6 mice a high-fat diet. NAFLD mice were administered 100 mg/kg AGL9 and 60 mg/kg orlistat via gavage (10 mL/kg) for 5 weeks, followed by the collection of blood and liver tissues. We found that AGL9 normalized the levels of serum alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, high-density lipoprotein, very low-density lipoprotein (LDL)/LDL, adiponectin, and leptin in these mice. Additionally, AGL9 activated the protein-level expression of 5' AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation and the transcript-level expression of sterol regulatory element-binding protein-1c, fatty acid synthase, superoxide dismutase, glutathione peroxidase, glucocorticoid receptor, nuclear respiratory factor 2, tumor necrosis factor-α, interleukin-1ß, interleukin-6, and monocyte chemoattractant protein-1 in hepatocytes. These results showed that AGL9 exhibited hepatoprotective effects by attenuating lipid deposition, oxidative stress, and inflammation via inhibition of AMPK/Nrf2 signaling, thereby reducing the production of hepatic proinflammatory mediators and indicating AGL9 as a potential therapeutic strategy for NAFLD.

Heat-Killed and Live Enterococcus faecalis Attenuates Enlarged Prostate in an Animal Model of Benign Prostatic Hyperplasia.

In the present study, we investigated the inhibitory effect of heat-killed Enterococcus faecalis (E. faecalis) and live E. faecalis on benign prostatic hyperplasia (BPH). The BPH rat model was established by administering male rats with testosterone propionate (TP, 5 mg/kg, in corn oil) via subcutaneous injections daily for four weeks after castration. The rats were divided into five groups: Con, corn oil-injected (s.c.) + DW administration; BPH, TP (5 mg/kg, s.c.) + DW administration; BPH+K_EF, TP (5 mg/kg, s.c.) + heat-killed E. faecalis (7.5 × 1012 CFU/g, 2.21 mg/kg) administration; BPH+L_EF, TP (5 mg/kg, s.c.) + live E. faecalis (1 × 1011 CFU/g, 166 mg/kg) administration; BPH+Fi, TP (5 mg/kg, s.c.) + finasteride (1 mg/kg) administration. In both of BPH+K_EF and BPH+L_EF groups, the prostate weight decreased and histological changes due to TP treatment recovered to the level of the Con group. Both of these groups also showed regulation of androgen-signaling factors, growth factors, and apoptosis-related factors in prostate tissue. E. faecalis exhibited an inhibitory effect on benign prostatic hyperplasia, and even heat-killed E. faecalis showed similar efficacy on the live cells in the BPH rat model. As the first investigation into the effect of heat-killed and live E. faecalis on BPH, our study suggests that heat-killed E. faecalis might be a food additive candidate for use in various foods, regardless of heat processing.

Exploring the Role of a Novel Peptide from Allomyrina dichotoma Larvae in Ameliorating Lipid Metabolism in Obesity.

The aim of this study was to identify an anti-obesity peptide from Allomyrina dichotoma and investigate the lipid metabolic mechanism. Enzymatically hydrolyzed A. dichotoma larvae were further separated using tangential flow filtration and consecutive chromatographic processes. Finally, an anti-obesity peptide that showed the highest inhibitory effect on lipid accumulation was obtained, and the sequence was Glu-Ile-Ala-Gln-Asp-Phe-Lys-Thr-Asp-Leu (EIA10). EIA10 decreased lipid aggregation in vitro and significantly reduced the accumulation of body weight gain, liver weight, and adipose tissue weight in high-fat-fed mice. Compared with the control group, the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL), insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in the high-fat diet (HFD) group increased significantly, and the content of high-density lipoprotein cholesterol (HDL) in the serum decreased significantly. On the contrary, the levels of TC, TG, and insulin in the EIA10 group decreased significantly, and the HDL content increased significantly compared with the HFD group. Additionally, EIA10 dramatically decreased mRNA and protein levels of transcription factors involved in lipid adipogenesis. Taken together, our results suggest that EIA10 could be a promising agent for the treatment and prevention of obesity.

Quantifying the efficiency of o-benzoquinones reaction with amino acids and related nucleophiles by cyclic voltammetry.

The reaction efficiency of o-benzoquinones with amines (L-lysine, Nα-acetyl-L-lysine, glycine, L-methionine and L-arginine), thiols (L-cysteine and Nα-acetyl-L-cysteine) and protein (bovine serum albumin) were determined at pH 5.0, 7.0 and 8.0 and scan rate of 10, 50 and 100 mV/s by cyclic voltammetry. Nucleophiles containing multiple nucleophilic groups and nucleophilic group possessing low pKa value would enhance the reactivity of nucleophiles towards o-benzoquinones. The reactivity of different o-benzoquinones with L-lysine/L-cysteine followed the order: protocatechuic acid quinone ≈ catechol quinone > 4-methylbenzoquinone ≈ caffeic acid quinone > rosmarinic acid quinone > chlorogenic acid quinone. The reactivity of quinones would be decreased by the steric hindrance of substituents on quinone ring, and it would also be weakened by enhancing electron cloud density of quinone ring. Adducts generated by the interaction of 4-methylbenzoquinone with amines and thiols were tentatively identified as amine-quinone adduct and thiol-phenol adduct respectively by UPLC-QTOF-MS/MS and cyclic voltammetry.

Inhibitory Effect of Centella asiatica Extract on DNCB-Induced Atopic Dermatitis in HaCaT Cells and BALB/c Mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused mainly by immune dysregulation. This study explored the anti-inflammatory and immunomodulatory effects of the Centella asiatica ethanol extract (CA) on an AD-like dermal disorder. Treatment with CA inhibited the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in a dose-dependent manner in inflammatory stimulated HaCaT cells by interferon-γ (IFN-γ) and TNF-α-triggered inflammation. Eight-week-old BALB/c mice treated with 2,4-dinitrochlorobenzene (DNCB) were used as a mouse model of AD. In AD induce model, we had two types treatment of CA; skin local administration (80 µg/cm2, AD+CA-80) and oral administration (200 mg/kg/d, AD+CA-200). Interestingly, the CA-treated groups exhibited considerably decreased mast cell infiltration in the ear tissue. In addition, the expression of IL-6 in mast cells, as well as the expression of various pathogenic cytokines, such as TNF-α, IL-4, IL-5, IL-6, IL-10, IL-17, iNOS, COX-2, and CXCL9, was reduced in both AD+CA-80 and AD+CA-200 groups. Collectively, our data demonstrate the pharmacological role and signaling mechanism of CA in the regulation of allergic inflammation of the skin, which supports our hypothesis that CA could potentially be developed as a therapeutic agent for AD.

Metabolomic Analysis of Morus Cultivar Root Extracts and Their Ameliorative Effect on Testosterone-Induced Prostate Enlargement in Sprague-Dawley Rats.

We investigated the metabolite changes of Morus roots (MRs) according to different cultivar families (Simheung, Daesim, Cheong-il, Sangchon, Daeseong, Suhong, Suwon, and Igsu) using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to understand the relationship between different cultivars and metabolite changes. Data were analyzed by partial least squares discriminant analysis (PLS-DA), and samples were successfully separated in PLS-DA scores. Eight metabolites in the electrospray ionization (ESI)-positive mode and 16 metabolites in the ESI-negative mode contributed to the separation in PLS-DA. Our data suggest that comparative analysis of MR metabolites according to different cultivars is useful to better understand the relationship between the different cultivars and metabolite changes. Furthermore, we analyzed the MRs for their ability to improve benign prostatic hyperplasia (BPH). LNCaP cells were used to evaluate the prostate-specific antigen (PSA) inhibitory activity of MRs, and, amongst them, the extract with the highest activity was selected. Igsu demonstrated the highest inhibition effect of prostate-specific antigen (PSA) expression among the MR cultivars. Igsu was also evaluated by administration in a testosterone-induced benign prostatic hyperplasia model in Sprague-Dawley rats. Igsu was shown to ameliorate BPH as evidenced by the prostate index, expression of androgen receptor (AR) signaling-related protein, growth factors, cell proliferation-related proteins, apoptosis-related proteins, mitogen-activated protein kinase (MAPK) signaling proteins, and histological analysis. Hence, this study strongly suggests that Igsu may have a beneficial effect of on BPH.

Effect of Paecilomyces tenuipes Extract on Testosterone-Induced Benign Prostatic Hyperplasia in Sprague-Dawley Rats.

: Benign prostatic hyperplasia (BPH) is one of the major public health concerns, which has a high prevalence rate and causes significant decline in men's quality of life. BPH is highly related to sexual hormone metabolism and aging. In particular, dihydrotestosterone (DHT), to which testosterone is modified by 5α-reductase (5AR), has a significant effect on BPH development. DHT binds to an androgen receptor (AR) and steroid receptor coactivator 1 (SRC-1); then, it induces the proliferation of a prostate cell and expression of prostate specific antigen (PSA). Paecilomyces tenuipes (P. tenuipes) is a mushroom that has been popularized by the artificial cultivation of fruiting bodies based on silkworms by researchers from the Republic of Korea. In a previous study, we identified the effect of PE on PSA mRNA expression in LNCaP cells. This suggests that PE may have an inhibitory effect on androgen signaling. Therefore, we confirmed the expression of androgen signaling-related factors, such as AR, SRC-1, and PSA in LNCaP. Furthermore, we confirmed the androgen signaling inhibitory effect of PE using the testosterone propionate (TP)-induced BPH rat model. A BPH rat model was established with a four-week treatment of daily subcutaneous injections of testosterone propionate (TP, 3 mg/kg) dissolved in corn oil after castration. The rats in the treatment group were orally gavaged P. tenuipes extract (PE), finasteride (Fi), or saw palmetto extract (Saw) with TP injection. DHT induced an increase in the expression levels of AR, SRC-1, and PSA proteins in LNCaP cells. On the contrary, the PE treatment reduced the expression levels. In vivo, the BPH group showed an increase in prostate size compared with the control group. The PE gavaged group showed a decrease in prostate size compared with the BPH group. In addition, the protein expressions of AR, 5AR2, and PSA were significantly lower in the PE gavaged group than BPH group in prostate tissue. These results suggest the beneficial effects of PE on BPH via the modulation of AR signaling pathway.

In Vivo Effects of Polymerized Anthocyanin from Grape Skin on Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a common chronic disease of the urinary system among elderly men. Especially, the metabolic imbalance of androgen in elderly men is one of the leading causes of BPH. Dihydrotestosterone (DHT) and converted testosterone by 5-α reductase type 2 (5AR2), binding with androgen receptor (AR), affect prostate proliferation and growth. In BPH, levels of androgen signaling-related protein expression are shown highly. Androgen signaling induces the overexpression of prostate-specific antigen (PSA) and cell proliferation factor such as proliferating cell nuclear antigen (PCNA) and cyclin D1. Grape skin anthocyanins are well known for their antioxidative, anti-cancer, anti-diabetes, anti-inflammatory, antimicrobial, and anti-aging activities. Polymerized anthocyanin (PA) downregulated the expression of androgen signaling-related proteins such as 5AR2, AR, and PSA in LNCaP cell lines. Furthermore, we investigated the effects on PA in testosterone propionate-induced BPH rat experiments. The oral administration of PA decreased the prostate weight in rats with TP-induced BPH. PA decreased the AR, 5AR2, SRC1, PSA, PCNA, and cyclin D1 expression in prostate tissues and the serum DHT levels, ameliorated the BPH-mediated increase of Bcl-2 expression, and increased the Bax expression. These results suggest that PA may be a potential natural therapeutic agent for BPH treatment.

Amphiphilic Triazine Polymer Derivatives as Antibacterial And Anti-atopic Agents in Mice Model.

Considering the emergence of bacterial resistance and low proteolytic stability of antimicrobial peptides (AMPs), herein we developed a series of ultra-short triazine based amphipathic polymers (TZP) that are connected with ethylene diamine linkers instead of protease sensitive amide bond. The most potent oligomers, TZP3 and TZP5 not only displayed potent antibacterial action on various drug-resistant pathogens but also exhibited a strong synergic antibacterial activity in combination with chloramphenicol against multidrug-resistant Pseudomonas aeruginosa (MDRPA). Since most of atopic dermatitis (AD) infections are caused by bacterial colonization, we evaluated the potency of TZP3 and TZP5 on AD in vitro and in vivo. In vitro AD analysis of these two polymers showed significant inhibition against the release of ß-hexosaminidase and tumor necrosis factor (TNF-α) from RBL-2H3 cells. In AD-like skin lesions in BALB/c mice model, these two polymers displayed significant potency in suppressing dermal and epidermal thickness, mast cell infiltration and pro-inflammatory cytokines expression. Moreover, these polymers exhibited remarkable efficacy over the allergies caused by the imbalance of Th1/Th2 by regulating total IgE and IgG2a. Finally, the impact of treatment effects of these polymers was examined through analyzing the weights and sizes of spleen and lymph node of AD-induced mice.

Sika deer (Cervus nippon) velvet antler extract attenuates prostate cancer in xenograft model.

The present study determines whether antler extract (AE) possesses inhibitory effects in a prostate cancer (PC) xenograft model and explores the underlying mechanism. After therapeutic intervention for two weeks, AE significantly inhibited prostate cancer xenograft tumor growth by 65.08%, and prostate-specific antigen (PSA) and serum dihydrotestosterone (DHT) levels. However, AE increased the serum testosterone level compared to the vehicle control group. Furthermore, our investigation of the inhibitory effects on angiogenesis and epithelial-to-mesenchymal transition (EMT)-related genes revealed that AE downregulated matrix metalloproteinase 2 (MMP)-2, (MMP)-9, vascular endothelial growth factor (VEGF), zinc finger protein (SNAIL1), twist-related protein 1 (TWIST1), and zinc-finger E-box-binding homeobox 1 (ZEB1) in vivo. In contrast, AE increased tissue inhibitor of MMP (TIMP)-1, (TIMP)-2, and E-cadherin. The results suggest that AE possesses potent anti-PC activity, and this is the first report on the anti-PC effect of AE in vivo.

Investigation of the Anti-Prostate Cancer Properties of Marine-Derived Compounds.

This review focuses on marine compounds with anti-prostate cancer properties. Marine species are unique and have great potential for the discovery of anticancer drugs. Marine sources are taxonomically diverse and include bacteria, cyanobacteria, fungi, algae, and mangroves. Marine-derived compounds, including nucleotides, amides, quinones, polyethers, and peptides are biologically active compounds isolated from marine organisms such as sponges, ascidians, gorgonians, soft corals, and bryozoans, including those mentioned above. Several compound classes such as macrolides and alkaloids include drugs with anti-cancer mechanisms, such as antioxidants, anti-angiogenics, antiproliferatives, and apoptosis-inducing drugs. Despite the diversity of marine species, most marine-derived bioactive compounds have not yet been evaluated. Our objective is to explore marine compounds to identify new treatment strategies for prostate cancer. This review discusses chemically and pharmacologically diverse marine natural compounds and their sources in the context of prostate cancer drug treatment.