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The current standard for the pharmacological management of lumbar disk herniation (LDH), involving non-steroidal anti-inflammatory drugs, muscle relaxants, and opioid analgesics, often carries a risk of adverse events. The search for alternative therapeutic options remains a vital objective, given the high prevalence of LDH and the critical impact on the quality of life. Shinbaro 2 is a clinically effective herbal acupuncture against inflammation and various musculoskeletal disorders. Therefore, we explored whether Shinbaro 2 exerts protective effects in an LDH rat model. The results showed that Shinbaro 2 suppressed pro-inflammatory cytokines, interleukin-1 beta, tumor necrosis factor-alpha, disk degeneration-related factors, matrix metalloproteinase-1,−3,−9, and ADAMTS-5 in LDH rats. Shinbaro 2 administration reinstated a behavioral activity to a normal level in the windmill test. The results indicated that Shinbaro 2 administration restored spinal cord morphology and functions in the LDH model. Therefore, Shinbaro 2 exerted a protective effect in LDH via actions on inflammatory responses and disk degeneration, indicating that future research is warranted to assess the action mechanisms further and validate its effects.

Colorectal cancer (CRC) is one of the most prevalent tumors with high metastatic potential; consequently, finding new drug candidates that suppress tumor metastasis is essential. Apoptolidin A is a macrocyclic lactone produced by Amycolatopsis sp. DW02G. It exhibits significant cytotoxicity against several cancer cell lines, but its effects on CRC cells remain unknown. Therefore, the present study investigated the antiproliferative and antimetastatic activities of apoptolidin A and its underlying molecular mechanisms in CRC cells. Apoptolidin A effectively inhibited CRC cell growth and colony formation. The induction of G0/G1 phase cell cycle arrest was associated with the downregulation of cyclin D1 and CDK4/6 expression. Long-term exposure to apoptolidin A also induced apoptosis as confirmed by the downregulation and upregulation of Bcl-2 and Bax expression, respectively. Moreover, apoptolidin A effectively upregulated the suppressed expression of N-Myc downstream-regulated gene 1 (NDRG1), a tumor suppressor gene, in a concentration-dependent manner in CRC cells. The antimetastatic potential of apoptolidin A was also correlated with the expression of epithelial–mesenchymal transition (EMT) biomarkers, including the upregulation of E-cadherin and downregulation of N-cadherin, vimentin, snail, and MMP9 in CRC cells. These findings suggest that apoptolidin A exerts antiproliferative and antimetastatic activities by regulating the NDRG1-activated EMT pathway in CRC cells.

The dried root of Angelica sinensis (A. sinensis) has been widely used in Chinese traditional medicine for various diseases such as inflammation, osteoarthritis, infections, mild anemia, fatigue, and high blood pressure. Searching for the secondary metabolites of A. sinensis has been mainly conducted. However, the bioactivity of coumarins in the plant remains unexplored. Therefore, this study was designed to evaluate the anti-inflammatory activity of glabralactone, a coumarin compound from A. sinensis, using in vitro and in vivo models, and to elucidate the underlying molecular mechanisms of action. Glabralactone effectively inhibited nitric oxide production in lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells. The downregulation of LPS-induced mRNA and protein expression of iNOS, TNF-α, IL-1β, and miR-155 was found by glabralactone. The activation of NF-κB and TRIF-dependent IRF-3 pathway was also effectively suppressed by glabralactone in LPS-stimulated macrophages. Glabralactone (5 and 10 mg/kg) exhibited an in vivo anti-inflammatory activity with the reduction of paw edema volume in carrageenan-induced rat model, and the expressions of iNOS and IL-1β proteins were suppressed by glabralactone in the paw soft tissues of the animal model. Taken together, glabralactone exhibited an anti-inflammatory activity in in vitro and in vivo models. These findings reveal that glabralactone might be one of the potential components for the anti-inflammatory activity of A. sinensis and may be prioritized in the development of a chemotherapeutic agent for the treatment of inflammatory diseases.

Lung cancer is the leading cause of cancer-associated deaths worldwide. In particular, non-small-cell lung cancer (NSCLC) cells harboring epidermal growth factor receptor (EGFR) mutations are associated with resistance development of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. Recent findings suggest that bone morphogenetic proteins (BMPs) and microRNAs (miRNAs) might act as oncogenes or tumor suppressors in the tumor microenvironment. In this study, for the first time, we identified the potential roles of BMPs and miRNAs involved in EGFR-TKI resistance by analyzing datasets from a pair of parental cells and NSCLC cells with acquired EGFR-TKI resistance. BMP4 was observed to be significantly overexpressed in the EGFR-TKI-resistant cells, and its mechanism of action was strongly associated with the induction of cancer cell energy metabolism through the modulation of Acyl-CoA synthetase long-chain family member 4. In addition, miR-139-5p was observed to be significantly downregulated in the resistant NSCLC cells. The combination of miR-139-5p and yuanhuadine, a naturally derived antitumor agent, synergistically suppressed BMP4 expression in the resistant cells. We further confirmed that LDN-193189, a small molecule BMP receptor 1 inhibitor, effectively inhibited tumor growth in a xenograft nude mouse model implanted with the EFGR-TKI-resistant cells. These findings suggest a novel role of BMP4-mediated tumorigenesis in the progression of acquired drug resistance in EGFR-mutant NSCLC cells. Keywords: bone morphogenetic protein 4, miR-139-5p, EGFR-TKI resistance, Acyl-CoA synthetase long-chain family member 4, energy metabolism, EGFR-mutant NSCLC cells, p53, fatty acid, yuanhuadine

Bone morphogenetic proteins (BMPs) are a diverse class of molecules with over 20 growth factor proteins that belong to the transforming growth factor-β (TGF-β) family and are highly associated with bone formation and disease development. Aberrant expression of various BMPs has been reported in several cancer tissues. Biological function studies have elicited the dual role of BMPs in both cancer development and suppression. Furthermore, a variety of BMP antagonists, ligands, and receptors have been shown to reduce or enhance tumorigenesis and metastasis. Knockout mouse models of BMP signaling components have also revealed that the suppression of BMP signaling impairs cancer metastasis. Herein, we highlight the basic clinical background and involvement of BMPs in modulating cancer progression and their dynamic interactions (e.g., with microRNAs) in the tumor microenvironment in addition to their mutations and roles in chemoprevention. We also suggest that BMPs should be considered a powerful putative therapeutic target in tumorigenesis and bone metastasis. Keywords: bone morphogenetic proteins, tumors, metastasis, miRNAs, drug treatment, biomarkers, mutations

Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the tumorigenesis and metastasis of numerous cancers, and STAT3 signaling is aberrantly activated in TNBC cells. In this study, a docetaxel-resistant TNBC cell line (MDA-MB-231-DTR) was established, and mechanisms for the antitumor activity of pulvomycin, a novel STAT3 inhibitor isolated from marine-derived actinomycete, were investigated. Levels of activated STAT3 (p-STAT3 (Y705)) increased in docetaxel-resistant cells, and knockdown of STAT3 recovered the sensitivity to docetaxel in MDA-MB-231-DTR cells. Pulvomycin effectively inhibited the proliferation of both cell lines. In addition, pulvomycin suppressed the activation of STAT3 and subsequently induced G0/G1 cell cycle arrest and apoptosis. Pulvomycin also significantly inhibited the invasion and migration of MDA-MB-231-DTR cells through the modulation of epithelial-mesenchymal transition markers. In an MDA-MB-231-DTR-bearing xenograft mouse model, the combination of pulvomycin and docetaxel effectively inhibited tumor growth through STAT3 regulation. Thus, our findings demonstrate that the combination of docetaxel and STAT3 inhibitors is an effective strategy for overcoming docetaxel resistance in TNBC.

Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.

Oxypeucedanin (OPD), a furocoumarin compound from Angelica dahurica (Umbelliferae), exhibits potential antiproliferative activities in human cancer cells. However, the underlying molecular mechanisms of OPD as an anticancer agent in human hepatocellular cancer cells have not been fully elucidated. Therefore, the present study investigated the antiproliferative effect of OPD in SK-Hep-1 human hepatoma cells. OPD effectively inhibited the growth of SK-Hep-1 cells. Flow cytometric analysis revealed that OPD was able to induce G2/M phase cell cycle arrest in cells. The G2/M phase cell cycle arrest by OPD was associated with the downregulation of the checkpoint proteins cyclin B1, cyclin E, cdc2, and cdc25c, and the up-regulation of p-chk1 (Ser345) expression. The growth-inhibitory activity of OPD against hepatoma cells was found to be p53-dependent. The p53-expressing cells (SK-Hep-1 and HepG2) were sensitive, but p53-null cells (Hep3B) were insensitive to the antiproliferative activity of OPD. OPD also activated the expression of p53, and thus leading to the induction of MDM2 and p21, which indicates that the antiproliferative activity of OPD is in part correlated with the modulation of p53 in cancer cells. In addition, the combination of OPD with gemcitabine showed synergistic growth-inhibitory activity in SK-Hep-1 cells. These findings suggest that the anti-proliferative activity of OPD may be highly associated with the induction of G2/M phase cell cycle arrest and upregulation of the p53/MDM2/p21 axis in SK-HEP-1 hepatoma cells.

Skin is an important barrier to protect the body from environmental stress. However, exposure to ultraviolet radiation (UV) and various environmental oxidative stresses can cause skin inflammation. Cyclooxygenase-2 (COX-2) is an inducible enzyme that mediates the formation of prostaglandin E2 (PGE2) against internal and external inflammatory stimulations. Therefore, the inhibition of COX-2 is an important approach to maintain skin health and prevent skin inflammation and carcinogenesis. Topsentin, a bis(indolyl)imidazole alkaloid isolated from the marine sponge Spongosorites genitrix, has been reported to exhibit anti-tumor and anti-microbial activities. However, the effect of topsentin on skin inflammation and its underlying molecular mechanism has not been elucidated. In the present study, we identified the photoprotective effects of topsentin on UVB irradiated human epidermal keratinocyte HaCaT cells. Topsentin suppresses COX-2 expression and its upstream signaling pathways, AP-1 and MAPK. Furthermore, topsentin inhibits miR-4485, a new biomarker selected from a microarray, and its target gene tumor necrosis factor alpha induced protein 2 (TNF-α IP2). The photoprotective effect of topsentin was also confirmed in a reconstructed human skin model. These findings suggest that topsentin may serve as a potential candidate for cosmetic formulations with skin inflammatory-mediated disorder.

Abstract.: NAD(P)H:quinone oxidoreductase 1 (NQO1), a phase II enzyme, plays an important role in the detoxification or chemoprotection of carcinogens, and induction of this enzyme is a target for the prevention of carcinogenesis. Natural stilbenoids have potential cancer chemopreventive activities, potentially through affecting NQO1 activity. Along this line, several stilbenoids were evaluated to procure more potent compounds for inducing NQO1 activity in cultured murine Hepa 1c1c7 cells. As a result, we found that 3,5-dimethoxy-trans-stilbene (DMS) possesses potent NQO1 induction activity through up-regulation of both protein and mRNA expression of NQO1 as determined by Western blot and reverse transcription–polymerase chain reaction analysis, respectively. DMS also increased protein expression of heme oxygenase-1 (HO-1), another phase II enzyme. This induction of NQO1 and HO-1 by DMS was closely related to the regulation of nuclear factor E2–related factor 2 (Nrf2). The translocation and activation of Nrf2 by DMS was also involved in the modulation of the upstream signal transduction molecule, protein kinase C δ. These findings suggest that DMS might have a cancer chemopreventive activity by inducing detoxifying enzymes such as NQO1 and HO-1. Keywords:: NAD(P)H:quinone oxidoreductase 1 (NQO1), nuclear factor E2–related factor 2 (Nrf2), 3,5-dimethoxy-trans-stilbene (DMS), heme oxygenase (HO-1), protein kinase C δ (PKCδ)

Yuanhuacine (YC), a daphnane diterpenoid from the flowers of Daphne genkwa, exhibited a potential growth inhibitory activity against human non-small cell lung cancer (NSCLC) cells. YC also suppressed the invasion and migration of lung cancer cells. However, the precise molecular mechanisms remain to be elucidated. In the present study, we report that YC significantly activated AMP-activated protein kinase (AMPK) signaling pathway and suppressed mTORC2-mediated downstream signaling pathway in H1993 human NSCLC cells. AMPK plays an important role in energy metabolism and cancer biology. Therefore, activators of AMPK signaling pathways can be applicable to the treatment of cancer. YC enhanced the expression of p-AMPKα. The co-treatment of YC and compound C (an AMPK inhibitor) or metformin (an AMPK activator) also confirmed that YC increases p-AMPKα. YC also suppressed the activation of the mammalian target of rapamycin (mTOR) expression, a downstream target of AMPK. Further study revealed that YC modulates mTORC2-associated downstream signaling pathways with a decreased expressions of p-Akt, p-protein kinase C alpha (PKCα), p-ras-related C3 botulinum toxin substrate 1 (Rac1) and filamentous actin (F-actin) that are known to activate cell growth and organize actin cytoskeleton. In addition, YC inhibited the tumor growth in H1993 cell-implanted xenograft nude mouse model. These data suggest the YC could be a potential candidate for cancer chemotherapeutic agents derived from natural products by regulating AMPK/mTORC2 signaling pathway and actin cytoskeleton organization.

Tyrosinase is the rate-limiting enzyme critical for melanin synthesis and controls pigmentation in the skin. The inhibition of tyrosinase is currently the most common approach for the development of skin-whitening cosmetics. Gagunin D (GD), a highly oxygenated diterpenoid isolated from the marine sponge Phorbas sp., has exhibited cytotoxicity toward human leukemia cells. However, the effect of GD on normal cells and the molecular mechanisms remain to be elucidated. In the present study, we identified for the first time the anti-melanogenic activity of GD and its precise underlying mechanisms in mouse melan-a cells. GD significantly inhibited melanin synthesis in the melan-a cells and a reconstructed human skin model. Further analysis revealed that GD suppressed the expression of tyrosinase and increased the rate of tyrosinase degradation. GD also inhibited tyrosinase enzymatic activity. In addition, GD effectively suppressed the expression of proteins associated with melanosome transfer. These findings suggest that GD is a potential candidate for cosmetic formulations due to its multi-functional properties.

Background: SHINBARO is a reined herbal formulation used to treat inflamed lesions and bone diseases. This study aimed to investigate the anti-osteoarthritic activities of intra-articular administration of SHINBARO and determine its underlying molecular mechanism in a monosodium iodoacetate (MIA)-induced osteoarthritis rat model. Methods: Male Sprague--Dawley rats received a single intra-articular injection of MIA into the infrapatellar ligament of the right knee. Subsequently, the rats were treated with normal saline, SHINBARO, and diclofenac once daily for 21 days. Rats treated with normal saline, but not MIA, comprised the control group. Histological changes in the femur of the MIA-induced osteoarthritis rat model were observed by micro-computed tomography scanning and staining with hematoxylin and eosin, and safranin-O fast green. Serum levels of PGE and anti-type II collagen antibodies in the 2 MIA-induced osteoarthritis rat model were measured using commercial kits. Protein levels of inflammatory enzymes (iNOS, COX-2), pro-inflammatory cytokines (TNF-α, IL-1β), and inflammatory mediators (NF-κB, IκB) in cartilaginous tissues were determined by western blot analysis. Results: Intra-articular administration of SHINBARO (IAS) at 20 mg/kg remarkably restrained the decrease in bone volume/total volume, being 28 % (P = 0.0001) higher than that in the vehicle-treated MIA group. IAS (2, 10, and 20 mg/kg) treatment significantly recovered the mean number of objects values with increased percentage changes of 13.5 % (P = 0.147), 27.5 % (P = 0.028), and 44.5 % (P = 0.031), respectively, compared with the vehicle-treated MIA group. The serum level of PGE2 in the IAS group at 20 mg/kg was markedly inhibited by 60.6 % (P = 0.0007) compared with the vehicle-treated MIA group, and the anti-collagen type II antibody level in the IAS group was reduced in a dose-dependent manner. IAS (20 mg/kg) effectively suppressed the induction of inflammation-mediated enzymes (iNOS and COX-2) and pro-inflammatory cytokines (TNF-α and IL-1β). IAS treatment also downregulated the NF-κB level and increased the IκB-a level in the MIA- induced osteoarthritis rat model. Conclusion: SHINBARO inhibited PGE2 and anti-type II collagen antibody production and modulated the balance of inflammatory enzymes, mediators, and cytokines in the MIA-induced osteoarthritis rat model. [ABSTRACT FROM AUTHOR]

Background JSOG-6 is used as a traditional medicine to relieve the symptoms associated with inflammation, rheumatism, and osteoporosis in Korea. In the present study, we investigated the effects of JSOG-6 on bone loss prevention both in in vitro and in vivo as well as its underlying mechanism of action. Methods Protection against bone loss was assessed in an ovariectomized (OVX) mouse model. Bone microarchitecture was measured using a micro-computed tomography to detect the parameters of three-dimensional structure of a trabecular bone. Serum biomarkers were also evaluated in an OVX-induced model. Osteoclasts derived from mouse bone marrow cells (BMCs) and osteoblastic MC3T3-E1 cells were also employed to investigate the mechanism of action. Results Oral administration of JSOG-6 significantly increased the bone mineral density (BMD) of the femur in OVX mice in vivo. Especially, the reduced Tb.No (trabecular bone number) in the OVX group was significantly recovered by JSOG-6 treatment. The serum levels of alkaline phosphatase (ALP), osteocalcin, C-terminal telopeptide, and tartrate-resistant acid phosphatase, biomarkers of bone resorption, were significantly elevated in OVX mice, but JSOG-6 effectively inhibited the increase in OVX mice. JSOG-6 was also found to enhance the osteoblastic differentiation and maturation with the increase of the density and ALP activity, a marker of osteoblastic differentiation, as well as calcium deposition, a marker of osteoblastic maturation in MC3T3-E1 cells. The effects of JSOG-6 on osteoblastic differentiation were also associated in part with the increase of ALP and OPN mRNA expressions and the decrease of RANKL mRNA expression in MC3T3-E1 cells. Conclusions The findings demonstrate that JSOG-6 induced protection against bone loss in OVX mice, and its anti-osteoporotic property might be, in part, a function of the stimulation of osteoblast differentiation and the inhibition of osteoclast formation. These findings suggest that JSOG-6 might be an applicable therapeutic traditional medicine for the regulation of the osteoporotic response. [ABSTRACT FROM AUTHOR]

Evaluates the cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs, based on the antitumor activity of 1,4,-naphthoquinone. Cytotoxic activity in human lung carcinoma, colon carcinoma and stomach carcinoma; Potent inhibitory activity; Selective inhibitory activity against topoisomerase I compared to topoisomerase II.