New Pimarane Diterpenoids Isolated from EtOAc-Extract of Apiospora arundinis Culture Medium Show Antibenign Prostatic Hyperplasia Potential.

Three new pimarane diterpenoids, libertellenones U-W (1-3), together with libertellenone C (4) and myrocin A (5) were isolated from an EtOAc-extract of Apiospora arundinis culture medium. The chemical structures of the new compounds were elucidated using MS, NMR, and CD spectroscopic data. Benign prostatic hyperplasia (BPH), the abnormal and pathological proliferation of epithelial and stromal cells in prostatic tissues, is a common disease in middle-aged and elderly men. In this study, the anti-BPH effects of myrocin A (5) were evaluated using BPH-1 and WPMY-1 cells. Treatment with myrocin A (5) exerted antiproliferative effects in BPH-1 and dihydrotestosterone (DHT)-stimulated WPMY-1 cells. In BPH, treatment with myrocin A (5) significantly suppressed the mRNA levels of androgen receptor (AR) and its downstream targets nuclear receptor coactivator 1 (NCOA1), proliferating cell nuclear antigen (PCNA) and kallikrein-related peptidase 3 (KLK3). Additionally, DHT-stimulated WPMY-1 cells demonstrated an upregulated mRNA levels of AR, NCOA1, PCNA, and KLK3. However, treatment with myrocin A (5) resulted in suppression of the mRNA levels. Moreover, myrocin A (5) docked computationally into the binding site of the androgen receptor (-5.5 kcal/mol).

Anti-Inflammatory Effect of Chestnut Honey and Cabbage Mixtures Alleviates Gastric Mucosal Damage.

Gastritis, one of the most common gastrointestinal disorders, damages the stomach lining as it causes a disproportion between the protective and ruinous factors of the gastric system. Cabbage (CB) is widely used to treat gastric lesions but requires the addition of natural sweeteners to counteract its distinct bitter taste. Therefore, this study sought to determine whether the combination of chestnut honey (CH)-which is known for its dark brown color and high kynurenic acid (KA) content-or KA-increased CH (KACH) with CB (CH + CB or KACH + CB) exerts synergistic effects for improving both taste and efficacy. Before confirming the gastroprotective effects in indomethacin (INDO)-induced rats, the anti-inflammatory activities of CH + CB and KACH + CB were assessed in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. As a result, treatment with either CH + CB or KACH + CB downregulated pro-inflammatory cytokine levels in LPS-stimulated RAW 264.7 macrophages by regulating the translocation of nuclear factor kappa B. Furthermore, both CH + CB and KACH + CB not only enhanced the levels of antioxidant enzymes but also triggered the activation of nuclear factor erythroid-related factor 2. Based on these effects, CH + CB or KACH + CB effectively protected the gastric mucosa in INDO-induced rats. Therefore, this study suggests that CH + CB and KACH + CB exert stronger gastroprotective effects when used together.

New fusidane-type nortriterpenoids from the Arctic marine-derived fungus Simplicillium lamellicola culture medium with their inhibitory effect on benign prostatic hyperplasia.

Three new fusidane-type nortriterpenoids, simplifusinolide A, 24-epi simplifusinolide A, and simplifusidic acid L (1-3), were isolated from the EtOAc extract of the Arctic marine-derived fungus Simplicillium lamellicola culture medium, together with fusidic acid (4) and 16-O-deacetylfusicid acid (5). The structures of the isolated compounds were elucidated by NMR and MS analyses. The absolute configurations of compounds 1-3 were established by the quantum mechanical calculations of electronic circular dichroism and gauge-including atomic orbital NMR chemical shifts, followed by DP4 + analysis. Benign prostatic hyperplasia (BPH) is a major urological disorder in men worldwide. The anti-BPH potentials of the isolated compounds were evaluated using BPH-1 and WPMY-1 cells. Treatment with simplifusidic acid L (3) and fusidic acid (4) significantly downregulated the mRNA levels of the androgen receptor (AR) and its downstream effectors, inhibiting the proliferation of BPH-1 cells. Specifically, treatment with 24-epi simplifusinolide A (2) significantly suppressed the cell proliferation of both BPH-1 and DHT-stimulated WPMY-1 cells by inhibiting AR signaling. These results suggest the potential of 24-epi simplifusinolide A (2), simplifusidic acid L (3) and fusidic acid (4) as alternative agents for BPH treatment by targeting AR signaling.

Targeting benign prostate hyperplasia treatments: AR/TGF-ß/NOX4 inhibition by apocynin suppresses inflammation and proliferation.

INTRODUCTION: Apocynin (Apo), an NADPH oxidase (NOX) inhibitor, has been widely used to treat various inflammatory diseases. However, the therapeutic effects of Apo on benign prostatic hyperplasia (BPH), a multifactorial disease associated with chronic inflammation and hormone imbalance, remain unknown. OBJECTIVES: The link between androgen signaling, reactive oxygen species (ROS), and prostate cell proliferation may contribute to the pathogenesis of BPH; therefore, the aim of this study was to identify the specific signaling pathway involved and to demonstrate whether the anti-oxidant Apo plays a role in the prevention and treatment of BPH. METHODS: Ingenuity pathway analysis and si-RNA transfection were conducted to demonstrate the androgen receptor (AR) and NOX4 linkage in BPH. Pathological markers of BPH were measured by H&E staining, immunoblotting, ELISA, qRT-PCR, and immunofluorescence to examine the effect of Apo. Rats stimulated with testosterone and BPH-1 cells were used as BPH models. RESULTS: AR and NOX4 network-mediated oxidative stress was upregulated in the BPH model. Next, we examined the effects of Apo on oxidative stress and chronic prostatic inflammation in BPH mouse models. In a testosterone-induced BPH rat model, Apo alleviated pathological prostate enlargement and suppressed androgen/AR signaling. Apo suppressed the upregulation of proinflammatory markers and promoted the expression of anti-oxidant factors. Furthermore, Apo regulated the TGF-ß/Glut9/activin pathway and macrophage programming. In BPH-1 cells, Apo suppressed AR-mediated proliferation and upregulation of TGFB and NOX4 expression by alleviating oxidative stress. Apo activated anti-oxidant and anti-inflammatory systems and regulated macrophage polarization in BPH-1 cells. AR knockdown partially abolished the beneficial effects of Apo in prostate cells, indicating AR-dependent effects of Apo. CONCLUSION: In contrast with existing BPH therapies, Apo may provide a new application for prostatic disease treatment, especially for BPH, by targeting the AR/TGF-ß/NOX4 signaling pathway.

Effects of Magnoliae Flos on Atopic Dermatitis-Like Inflammation Evaluated via Extracellular Signal-regulated Kinase or Signal Transducers and Activators of Transcription 1/3 Signalling Pathways.

Atopic dermatitis is a chronic inflammatory skin  disease. Skin is the largest organ and plays a pivotal role in protecting the body. Not only does the skin act as a physical barrier against the external environment, but it also has its own immune system. Atopic dermatitis is caused by prolonged excessive inflammatory responses that worsen under imbalanced cutaneous immune system skin conditions. Although the prevalence and burden of atopic dermatitis is increasing, the standard therapeutic agents remain unclear due to  the complicated pathophysiology of the condition. The objective of this study is to examine the use of Magnoliae flos, the dried flower bud of Magnolia biondii or  related plants. The effects and underlying mechanism of  action of aqueous extract of the buds of Magnoliae flos (MF) were evaluated. Immortalized human keratinocytes (HaCaT) stimulated with tumour necrosis factor-α and interferon-γ mixture and NC/Nga mice stimulated with 2,4-dinitrochlorobenzene were used as atopic dermatitis models, in vitro and in vivo, respectively. The effects of MF were determined by measuring the suppression of pro-inflammatory signalling pathways, such as extracellular signal-regulated kinase or signal transducers and activators of transcription 1/3 and restoring skin barrier molecules. In conclusion, MF is a potential therapeutic alternative for the treatment of atopic dermatitis through repressing inflammatory pathways.

Anti-atopic dermatitis effect of fish collagen on house dust mite-induced mice and HaCaT keratinocytes.

Collagen, a major structural protein in mammalian tissues, is effective against skin wounds and osteoarthritis. Although bovine and porcine collagens have mainly been used, several potential risks of mammalian collagen have led to the use of fish collagen (FC) as an alternative. FC and its peptides are used as common cosmeceutical products because of their antihypertensive, anti-bacterial, and antioxidant activities. Despite the effects of FC on wrinkle reduction, UV-protection, and wound healing, the relationship between FC and atopic dermatitis (AD) has not yet been reported. Therefore, we investigated the anti-AD effects of FC against house dust mite (Dermatophagoides farinae, HDM)-induced AD in NC/Nga mice and TNF-α/IFN-γ-stimulated HaCaT keratinocytes. FC alleviated AD apparent symptoms, such as dermatitis score, transepidermal water loss, epidermal thickness, and mast cell infiltration upon declining pro-inflammatory cytokines and mediators, IL-6, IL-5, IL-13, TSLP, and TNF-α. The skin barrier protein, filaggrin, was also recovered by FC administration in vivo and in vitro. Immune response and skin barrier dysfunction are both mitigated by three routes of FC administration: oral, topical, and both routes via the regulation of IκB, MAPKs, and STATs pathways. In summary, FC could be a potential therapeutic agent for AD by regulating immune balance and skin barrier function.

Antioxidant mitoquinone suppresses benign prostatic hyperplasia by regulating the AR-NLRP3 pathway.

Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, has been used to treat several diseases. The present study aimed to investigate the therapeutic effects of MitoQ in benign prostatic hyperplasia (BPH) models and their underlying molecular mechanisms. In this study, we determined that MitoQ inhibited dihydrotestosterone (DHT)-induced cell proliferation and mitochondrial ROS by inhibiting androgen receptor (AR) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in prostate epithelial cells. Molecular modeling revealed that DHT may combine with AR and NLRP3, and that MitoQ inhibits both AR and NLRP3. AR and NLRP3 downregulation using siRNA showed the linkage among AR, NLRP3, and MitoQ. MitoQ administration alleviated pathological prostate enlargement and exerted anti-proliferative and antioxidant effects by suppressing the AR and NLRP3 signaling pathways in rats with BPH. Hence, our findings demonstrated that MitoQ is an inhibitor of NLPR3 and AR and a therapeutic agent for BPH treatment.

Apocynin alleviates weight gain and obesity-induced adipose tissue inflammation in high-fat diet-fed C57BL/6 mice.

Obesity involves chronic low-grade inflammation within adipose tissue. Apocynin (APO) is a therapeutic agent for the treatment of inflammatory diseases. Therefore, the present study aimed to investigate whether APO can reduce weight gain and obesity-induced adipose tissue inflammation. C57BL/6 mice were administered APO or orlistat (Orli) as a positive control with a high-fat diet (HFD) for 12 weeks. Lipopolysaccharide-stimulated 3T3-L1 adipocytes were used for the in vitro study. Our results showed a significantly lower white adipose tissue (WAT) mass index in 10 mg/kg APO-treated mice than in 20 mg/kg Orli-treated mice. Moreover, the protein expression of adipose triglyceride lipase, fatty acid synthase, sterol regulatory element-binding transcription factor 1, and peroxisome proliferator-activated receptor γ was reversed in the WAT of 10 mg/kg APO-treated mice. Furthermore, APO reduced the expression of the macrophage marker F4/80, decreased the mRNA levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, and increased the mRNA levels of interleukin-10 in WAT. APO decreased the phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p65 in vivo and in vitro. Notably, APO had a stronger effect on the amelioration of adipose tissue inflammation than Orli did. Our findings lay the foundation for research on the use of APO as an agent to ameliorate weight gain and obesity-induced inflammatory diseases.

Hesperidin ameliorates benign prostatic hyperplasia by attenuating cell proliferation, inflammatory response, and epithelial-mesenchymal transition via the TGF-ß1/Smad signaling pathway.

Excessively activated transforming growth factor-beta 1 (TGF-ß1) exacerbates benign prostatic hyperplasia (BPH) by triggering epithelial-mesenchymal transition (EMT) as well as epithelial and stromal cell differentiation. Hesperidin (HSP), a flavanone rich in citrus peels, exhibits a safe anti-cancer activity with few side effects. Although HSP reportedly inhibits cell growth in prostate cancer, studies on BPH have not yet been reported. Thus, this study aimed to figure out the therapeutic effect of HSP and its underlying mechanisms in BPH models in vivo and in vitro. To evaluate the anti-BPH effect of HSP in vivo, rats were injected with testosterone propionate (TP; 10 mg/kg, s.c.), finasteride (5 mg/kg, p.o.), and HSP (50 and 100 mg/kg, i.p.) for four weeks. The in vitro efficacy of HSP was evaluated using two prostate cell models, BPH-1 and dihydrotestosterone-stimulated WPMY-1 cells, for studying the interaction between epithelial and stromal cells. Both in vivo and in vitro, HSP inhibited prostate cell proliferation by suppressing the expression of androgen receptor-related markers. In addition, HSP reduced the expression levels of inflammatory and mesenchymal markers by blocking TGF-ß1 activation. Collectively, HSP alleviated BPH by attenuating prostate cell proliferation, the inflammatory response, and EMT by regulating the TGF-ß1/Smad signaling pathway. Thus, these results provide evidence for a new therapeutic approach against BPH.

Morus alba fruits attenuates atopic dermatitis symptoms and pathology in vivo and in vitro via the regulation of barrier function, immune response and pruritus.

BACKGROUND: Morus alba fruits (MAF) belong to the Moraceae family, which are known to be effective in treating diabetic, autoimmune, and hormonal diseases owing to its low toxicity. MAF, as excerpted from Donguibogam, a representative Korean medical encyclopedia protected by UNESCO, has been widely used to treat lumbago, arthritis, and diabetes. Based on these effects, MAF is investigated for unidentified effects of atopic dermatitis, characterized by complex etiology of skin barrier dysfunction, inflammation, and chronic pruritus. METHODS: The antioxidant, inflammatory, and immunomodulatory properties of MAF and its bioactive compounds have been widely reported. According to an examination of 1-chloro-2,4-dinitrobenzene-induced AD-like skin lesions in NC/Nga mice, AD symptoms, such as increased dermatitis score, scratching frequency, immunoglobulin E, trans-epidermal water loss, epidermal thickness, and infiltration of mast cells, were relieved by topical MAF administration. They effectively attenuated cytokines and chemokines, such as interleukin (IL)-4, IL-5, IL-6, IL-8, IL-13, IL-17A, IL-22, IL-1ß, tumor necrosis factor-α, thymic stromal lymphopoietin (TSLP), thymic- and activation-regulated chemokine, normal T cell expression, and macrophage-derived chemokine secretion at the mRNA level in TNF-α/IFN-γ induced HaCaT (human immortalized keratinocyte) cells. RESULTS: Both in vivo and in vitro models, MAF increased the expression of filaggrin, involucrin, and loricrin, as well as inhibited the activation of Janus kinase 2, signal transducer and activator of transcription proteins 1, and mitogen-activated protein kinase pathways, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38. Moreover, MAF reduced the expression of TSLP and periostin, which play important roles in skin pruritus as chronic pruritogenic factors. CONCLUSION: These data indicate that MAF could be used as a potential treatment for AD-like skin lesions by regulating the inflammatory response, improving physical skin barriers, and relieving symptomatic pruritus.

In vitro and in vivo Experimental Investigation of Anti-Inflammatory Effects of Peucedanum japonicum Aqueous Extract by Suppressing the LPS-Induced NF-[Formula: see text]B/MAPK JNK Pathways.

Peucedanum japonicum Thunberg has been used to treat cold, cough, and inflammatory diseases in Southern and Eastern Asia. The effects of P. japonicum root aqueous extract (PJ) on lipopolysaccharide (LPS)-induced inflammation were investigated in RAW264.7 macrophages and an animal model of septic shock. Lipopolysaccharides are endotoxins that trigger excessive inflammatory responses, similar to those elicited by gram-negative bacteria. Inflammation is characterized by a primary defense system against pathogens and the onset of sundry diseases or illnesses, and macrophages are important components of the phagocytic system during inflammatory processes. The present study evaluated the effects of PJ on the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and assessed the expression of enzymes that induce the production of pro-inflammatory mediators using western blotting. We also evaluated the production and mRNA expression of pro-inflammatory cytokines using enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Using western blotting, we determined whether nuclear factor-kappa B (NF-[Formula: see text]B) and c-Jun N-terminal kinase (JNK) are involved in the molecular mechanisms induced by PJ that suppressed LPS-induced inflammatory responses. We also found that PJ inhibited NF-[Formula: see text]B and JNK pathways in macrophages and reduced LPS-induced mortality in the mouse model of septic shock by inhibiting the activation of NF-[Formula: see text]B and JNK pathways that downregulated the expression of inflammatory mediators. These results indicated that PJ is an effective inflammatory suppressor.

Magnoliae flos Downregulated Lipopolysaccharide-Induced Inflammatory Responses via NF-κB/ERK-JNK MAPK/STAT3 Pathways.

Background: Magnoliae flos is the dried flower bud of Magnolia biondii and related plants. It has been used as a medicinal herb for the treatment of rhinitis, sinusitis, and sinus headaches. Nevertheless, the effects of Magnoliae flos in microbial infection or sepsis remain unclear. In this study, we investigated the anti-inflammatory effects of Magnoliae flos water extract (MF) in lipopolysaccharide- (LPS-) induced septic mice and LPS-stimulated RAW264.7 macrophages. Results: We found that MF reduced the mortality of LPS-challenged mice. Enzyme immunoassays and reverse transcription polymerase chain reaction analysis revealed that MF administration attenuated mRNA expression and protein production of proinflammatory mediators, including cyclooxygenase 2, inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-6. In parallel to these results in mice, pretreatment with MF suppressed the LPS-induced production of proinflammatory mediators in RAW264.7 macrophages. In addition, we found that MF exerted its suppressive effects by inhibiting the activation of the mitogen-activated protein kinase, nuclear factor-κB, and signal transducer and activator of transcription pathways at the protein level. Conclusion: MF could be a potential therapeutic agent for regulating excessive inflammatory responses in sepsis.

Purple Corn Extract Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis.

Purple corn (Zea mays L.), utilized as a natural pigment in food production and processing, has been used to treat obesity, cystitis, and urinary tract infections. However, no reports of its use for benign prostatic hyperplasia (BPH) exist. Purple corn extract (PCE) contains anthocyanins, particularly cyanidin-3-O-glucoside, which have various pharmacological characteristics. Therefore, this study sought to elucidate the ameliorative effect of PCE on BPH in dihydrotestosterone (DHT)-stimulated WPMY-1 cells and testosterone propionate (TP)-induced rats. Expression levels of the upregulated androgen receptor (AR) and its related genes in DHT-stimulated WPMY-1 cells were reduced by PCE, and proapoptotic gene expression increased by modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling cascade. PCE reduced the weight of the enlarged prostate by inhibiting the androgen/AR signaling-related markers. Histological variations in the prostate epithelium caused by TP injection were restored by PCE. Thus, PCE alleviates BPH by modulating prostate cell proliferation and apoptosis.

Euphorbia hirta Leaf Ethanol Extract Suppresses TNF-α/IFN-γ-Induced Inflammatory Response via Down-Regulating JNK or STAT1/3 Pathways in Human Keratinocytes.

Skin inflammation may cause allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis. Euphorbia hirta (E. hirta) is a member of the Euphorbiaceae family and is well-known for its anti-asthma effects. E. hirta has traditionally been used to treat respiratory ailments, dysentery, jaundice, and digestive problems. However, its effects on skin inflammation remain unclear. Here, we determined the effects of 70% ethanol extract of E. hirta leaves (ELE) in vitro using human keratinocyte HaCaT cells, which constitute most epidermal skin cells. We determined the inhibitory effects of ELE on the inflammation caused by tumor necrosis factor (TNF)-α/interferon (IFN)-γ in keratinocytes using ELISA, immunoblotting, and qRT-PCR assay. ELE was found to reduce the production and mRNA expression of pro-inflammatory cytokines such as TNF-α or interleukin-6 and the expression of various proteins, including signal transducers, activators of transcription 1/3, and mitogen-activated protein kinase. Expression levels of these proteins were found to be upregulated in the TNF-α/IFN-γ-stimulated condition and downregulated by ELE treatment. These results indicate that ELE protects HaCaT cells against TNF-α/IFN-γ-induced skin inflammation.

Peucedanum japonicum Thunberg alleviates atopic dermatitis-like inflammation via STAT/MAPK signaling pathways in vivo and in vitro.

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disorder that exhibits clinical relapse. The disruption of the skin barrier increases the symptoms of AD, which is accompanied by a reduction in skin integrity. As an immune barrier, the skin plays a crucial role in regulating the inflammatory responses in AD. In this study, we used murine atopic dermatitis model using 2,4-dinitrochlorobenzen (DNCB), which is one of haptens to disrupt the skin barrier and generate the inflammation. As the small molecule, DNCB is easily penetrate the epidermis and binds to tissue proteins provoking immune responses. We evaluated the effects of an aqueous extract of Peucedanum japonicum Thunberg (PJT) in an experimental model of AD by measuring the mRNA and protein expression of cytokines and their related biomarkers. We examined the dorsal skin lesions, transepidermal water loss (TEWL), scratching behavior, expression of molecules related to skin barrier integrity, and histological changes in a murine model of DNCB- induced AD. We found out the down-regulatory effects of PJT on the AD-like symptoms or inflammatory dorsal lesions. For in vitro study, we used a mixture of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in human keratinocytes. The protein and mRNA expressions of skin barrier molecules and inflammatory markers were measured with western blotting and qRT-PCR assays, respectively. As a result, PJT alleviated the AD-like symptoms, and suppressed the inflammation caused by a TNF-α and IFN-γ in human keratinocytes. The regulatory effects of PJT appeared to be mediated via the mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription (STAT) signaling pathways both in vivo and in vitro. Altogether, the results indicated that PJT could serve as a promising therapeutic candidate for suppressing AD by inhibiting inflammation and improving the integrity of the skin barrier.

Reduction of tyrosine hydroxylase expression and increase of α-synuclein in the substantia nigra in a rat model of benign prostatic hyperplasia.

Parkinson's disease (PD) occurs when dopaminergic cells in the substantia nigra (SN) region are destroyed; however, the cause of the destruction of dopamine cells has not yet been determined. This study was performed to investigate whether changes in the hormones that cause benign prostatic hyperplasia (BPH) are related to pathological changes in PD. The pathological findings were examined by observing the lesion sites related to PD in a BPH rat model. BPH was induced in rats by subcutaneous injection of testosterone propionate for 4 weeks after castration. To investigate the changes in the SN regions, tyrosine hydroxylase (TH) and α-synuclein (α-syn) expression were analyzed by western blotting. TH expression, expressed in dopaminergic cells and used as a dopaminergic cell detection marker, decreased, whereas α-syn expression increased at the SN site. These results are quite similar to the pathological changes observed in patients with PD and Parkinsonism animal models. Our results showed an increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in the SN regions in the BPH group. Additionally, a decreased expression of B-cell lymphoma protein 2 and an increased expression of B-cell lymphoma protein 2-associated X, suggesting increased apoptosis, were observed in the BPH group. These results suggest that the pathological changes associated with PD may be caused by BPH or factors related to BPH. Thus, this study has presented a new avenue for an approach related to hormonal changes as a method to determine the cause of PD, for which the exact cause is not yet known.

Oral administration of berberine represses macrophage activation-associated benign prostatic hyperplasia: a pivotal involvement of the NF-κB.

Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in men over the age of 50. Clinical studies have suggested that chronic inflammation is associated with BPH pathoprogression. Berberine (BB) is a natural compound found in Berberis vulgaris, Coptis chinensis and Phellodendron amurense. Although several studies have documented that BB may be effective for inflammation, the effects of the oral administration of BB on BPH are not fully understood. The effects of BB on chronic prostatic inflammation were evaluated in a testosterone-induced BPH animal model. Orally administered BB alleviated the pathological alterations induced by BPH and significantly suppressed the expression of inflammatory markers while enhancing the expression of antioxidant factors. Furthermore, BB regulated the activation of macrophages via NF-κB signaling pathway inhibition in the BPH rat model. The effects and underlying signaling pathway of BB in RWPE-1 cells exposed to macrophage conditioned medium (CM) were also demonstrated in vitro. While CM stimulation induced prostatic cell proliferation and upregulated the expression of inflammatory factors, BB exerted anti-proliferation and anti-inflammatory effects in RWPE-1 cells. These findings propose that BB suppresses androgen-dependent BPH development by targeting NF-κB-mediated pro-inflammatory signaling.

Anti-Obesity Drug Orlistat Alleviates Western-Diet-Driven Colitis-Associated Colon Cancer via Inhibition of STAT3 and NF-κB-Mediated Signaling.

Many researchers have argued that Western diet (WD)-induced obesity accelerates inflammation and that inflammation is a link between obesity and colorectal cancer (CRC). This study investigated the effect of WDs on the development and progression of colitis-associated colon cancer (CAC) and the efficacy of the anti-obesity agent orlistat on WD-driven CAC in mice. The results revealed that the WD exacerbated CAC in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mice, which showed increased mortality, tumor formation, and aggravation of tumor progression. Furthermore, WD feeding also upregulated inflammation, hyperplasia, and tumorigenicity levels through the activation of STAT3 and NF-κB signaling in an AOM/DSS-induced mouse model. In contrast, treatment with orlistat increased the survival rate and alleviated the symptoms of CAC, including a recovery in colon length and tumor production decreases in WD-driven AOM/DSS-induced mice. Additionally, orlistat inhibited the extent of inflammation, hyperplasia, and tumor progression via the inhibition of STAT3 and NF-κB activation. Treatment with orlistat also suppressed the ß-catenin, slug, XIAP, Cdk4, cyclin D, and Bcl-2 protein levels in WD-driven AOM/DSS-induced mice. The results of this study indicate that orlistat alleviates colon cancer promotion in WD-driven CAC mice by suppressing inflammation, especially by inhibiting STAT3 and NF-κB activation.

Umbelliferone Ameliorates Benign Prostatic Hyperplasia by Inhibiting Cell Proliferation and G1/S Phase Cell Cycle Progression through Regulation of STAT3/E2F1 Axis.

Umbelliferone (UMB), also known as 7-hydroxycoumarin, is a derivative of coumarin, which is widely found in many plants such as carrots, coriander, and garden angelica. Although many studies have already revealed the various pharmacological properties of UMB, its effect on benign prostatic hyperplasia (BPH) remains unclear. Therefore, the present study aimed to elucidate the underlying mechanism of the anti-proliferative effect of UMB in a human benign prostatic hyperplasia cell line (BPH-1), as well as its ameliorative effect on BPH in testosterone propionate (TP)-induced rats. The results showed that UMB exerts an anti-proliferative effect in BPH-1 cells by modulating the signal transducer and activator of transcription 3 (STAT3)/E2F transcription factor 1 (E2F1) axis. UMB treatment not only inhibited androgen/androgen receptor (AR) signaling-related markers, but also downregulated the overexpression of G1/S phase cell cycle-related markers. In TP-induced rats, UMB administration demonstrated an anti-BPH effect by significantly reducing prostate size, weight, and epithelial thickness. In addition, UMB suppressed cell proliferation by reducing the expression of proliferating cell nuclear antigen (PCNA) and p-STAT3 (Tyr 705) in prostate tissue following TP injection. These findings suggest that UMB has pharmacological effects against BPH.

Rosmarinic acid represses colitis-associated colon cancer: A pivotal involvement of the TLR4-mediated NF-κB-STAT3 axis.

Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.