Complementary and Alternative Medicinein the US

Junxuan Lu 한의병리학회 2005 대한동의병리학회 학술대회논문집 Vol.2005 No.8

Direct and Intervertebral DiscMediated Sensitization of Dorsal Root Ganglion Neurons by Hypoxia and Low pH

Junxuan Ma,Despina Stefanoska,Sibylle Grad,Mauro Alini,Marianna Peroglio 대한척추신경외과학회 2020 Neurospine Vol.17 No.1

Objective: Ischemia-related risk factors are consistently correlated with discogenic pain, but it remains unclear how the ischemia-associated hypoxia and acidosis influence the peripheral sensory nervous system, namely the dorsal root ganglion (DRG), either directly or indirectly via intervertebral disc (IVD) mediation. Methods: Bovine tail IVD organ cultures were preconditioned in different hypoxic and/or acidic conditions for 3 days to collect the conditioned medium (CM). The DRG-derived ND7/23 cells were either treated by the IVD CM or directly stimulated by hypoxic and/or acidic conditions. Neuronal sensitization was evaluated using calcium imaging (Fluo-4) after 3 days. Results: We found that direct exposure of DRG cell line to hypoxia and acidosis increased both spontaneous and bradykinin-stimulated calcium response compared to normoxia-neutral pH cultures. Hypoxia and low pH in combination showed stronger effect than either parameter on its own. Indirect exposure of DRG to hypoxia-acidosis-stressed IVD CM also increased spontaneous and bradykinin-stimulated response, but to a lower extent than direct exposure. The impact of direct hypoxia and acidosis on DRG was validated in a primary sheep DRG cell culture, showing the same trend. Conclusion: Our data suggest that targeting hypoxia and acidosis stresses both in IVD and DRG could be a relevant objective in discogenic pain treatment.

Oriental herbs as a source of novel anti-androgen and prostate cancer chemopreventive agents

LÜ,, Junxuan,KIM, Sung- Hoon,JIANG, Cheng,LEE, HyoJeong,GUO, Junming Nature Publishing Group 2007 Acta Pharmacologica Sinica Vol.28 No.9

<P>Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to the patients. Recent studies show that even these hormone-refractory PCa require ligand-independent AR signaling for survival. As current chemotherapy is largely ineffective for PCa and has serious toxic sideeffects, we have initiated a collaborative effort to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. We highlight our discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent. We have identified the following mechanisms to account for the specific anti-AR actions: rapid block of AR nuclear translocation, inhibition of binding of 5alpha-dihydrotestesterone to AR and increased proteasomal degradation of AR protein. Furthermore, decursin lacks the agonist activity of the 'pure' anti-androgen bicalutamide and is more potent than bicalutamide in inducing PCa apoptosis. Structure-activity analyses reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell cycle arrest and proapoptotic activities. This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/ AR agents from complex herbal mixtures.</P>

Anti-angiogenic and anti-tumor activities of Kamikaekyuk-tang

Eun-Ok Lee,Hyo Jeong Lee,Junxuan Lu,Sung Hoon Kim 한의병리학회 2005 대한동의병리학회 학술대회논문집 Vol.2005 No.8

Anti-Cancer, Anti-Diabetic and Other Pharmacologic and Biological Activities of Penta-Galloyl-Glucose

Zhang, Jinhui,Li,Kim, Sung-Hoon,Hagerman, Ann E.,Lü,, Junxuan Springer-Verlag 2009 Pharmaceutical research Vol.26 No.9

Ka-mi-kae-kyuk-tang oriental herbal cocktail attenuates cyclophosphamide-induced leukopenia side effects in mouse

Seo, Inweon,Kim, Seung-Hyung,Lee, Jeong-Eun,Jeong, Soo-Jin,Kim, Young Chul,Ahn, Kyoo Seok,Lu, Junxuan,Kim, Sung-Hoon Informa Healthcare 2011 Immunopharmacology and immunotoxicology Vol.33 No.4

<P>Ka-mi-kae-kyuk-tang (KMKKT) is an Oriental herbal medicinal cocktail and has been shown to have potent antiangiogenic, anticancer, and antimetastatic activities in preclinical animal models without observable side effects. We previously found that in prostate cancer xenograft experiments, treating tumor-bearing mice with KMKKT alleviated the body weight loss toward the end of the study, suggesting a general health-promoting activity. We investigated whether KMKKT alleviated cancer chemotherapy drug-induced leukopenia and other hematotoxicity <I>in vivo</I> using a mouse model. KMKKT was given once daily orally for 10 days to the mice before they were given cyclophosphamide (CPA) daily injection for 4 days. KMKKT blunted CPA-induced decrease in red blood cells, hemoglobin content, and the total white blood cell/leukocyte counts. Examination of the multiple organ sites involved in hematopoiesis, and lymphocyte differentiation and maturation showed the attenuated changes induced by CPA in each and every type of cells examined. Particularly, some of the cell types are fully restored in the bone marrow and even overstimulated in the Sca-1<SUP>++</SUP>, CD117<SUP>++</SUP>, or Sca1<SUP>++</SUP>/CD117<SUP>++</SUP> and CD34<SUP>++</SUP>/CD117<SUP>++</SUP> stem cells, supporting a role of KMKKT to stimulate hematopoietic stem cell (HSC) signaling to compensate for CPA-induced destruction of leukocytes and other cell types. Taken together, KMKKT might be a safe and effective herbal complementary and alternative medicine (CAM) modality to alleviate cancer drug-induced hematological side effects in addition to its anticancer activities. Preclinical investigations with other chemo- and radiation modalities are warranted to support planning translation consideration for human patients.</P>

Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells.

Hu, Hongbo,Chai, Yubo,Wang, Lei,Zhang, Jinhui,Lee, Hyo Jeong,Kim, Sung-Hoon,Lü,, Junxuan American Association for Cancer Research, Inc 2009 Molecular Cancer Therapeutics Vol.8 No.10

<P>Penta-1,2,3,4,6-O-galloyl-beta-d-glucose (PGG) suppresses the in vivo growth of human DU145 and PC-3 prostate cancer xenografts in nude mice, suggesting potential utility as a prostate cancer chemotherapeutic or chemopreventive agent. Our earlier work implicates caspase-mediated apoptosis in DU145 and LNCaP prostate cancer cells as one mechanism for the anticancer activity. We show here that, in the more aggressive PC-3 prostate cancer cell line, PGG induced programmed cell deaths lacking the typical caspase-mediated apoptotic morphology and biochemical changes. In contrast, PGG induced patent features of autophagy, including formation of autophagosomes and lipid modification of light chain 3 after 48 hours of PGG exposure. The 'autophagic' responses were also observed in the murine TRAMP-C2 cells. Caspase inhibition exacerbated PGG-induced overall death. As for molecular changes, we observed a rapid inhibition of the phosphorylation of mammalian target of rapamycin-downstream targets S6K and 4EBP1 by PGG in PC-3 and TRAMP-C2 cells but not that of mammalian target of rapamycin itself, along with increased AKT phosphorylation. Whereas the inhibition of phosphatidylinositol 3-kinase increased PGG-induced apoptosis and autophagy, experiments with pharmacologic inducer or inhibitor of autophagy or by knocking down autophagy mediator Beclin-1 showed that autophagy provided survival signaling that suppressed caspase-mediated apoptosis. Knocking down of death receptor-interacting protein 1 kinase increased overall death without changing light chain 3-II or caspase activation, thus not supporting death receptor-interacting protein 1-necroptosis for PGG-induction of autophagy or other programmed cell death. Furthermore, PGG-treated PC-3 cells lost clonogenic ability. The induction by PGG of caspase-independent programmed cell death in aggressive prostate cancer cell lines supports testing its merit as a potential drug candidate for therapy of caspase-resistant recurrent prostate cancer.</P>

A synthetic decursin analog with increased in vivo stability suppresses androgen receptor signaling in vitro and in vivo.

Zhang, Yong,Shaik, Ahmad Ali,Xing, Chengguo,Chai, Yubo,Li, Li,Zhang, Jinhui,Zhang, Wei,Kim, Sung-Hoon,L?, Junxuan,Jiang, Cheng M. Nijhoff ; Kluwer Academic Publishers 2012 Investigational new drugs Vol.30 No.5

<P>Targeting androgen receptor (AR) signaling with agents distinct from current antagonist drugs remains a rational approach to the prevention and treatment of prostate cancer (PCa). Our previous studies have shown that decursin and isomer decursinol angelate (DA), isolated from the Korean medicinal herb Angelica gigas Nakai, interrupt AR signaling and possess anti-PCa activities in vitro. In the LNCaP PCa cell model, these pyranoccoumarin compounds exhibit properties distinct from currently used antagonists (e.g., Casodex). However, both are rapidly de-esterified to decursinol, a partial AR agonist. We report here that a synthetic decursin analog, decursinol phenylthiocarbamate (DPTC), has greater in vivo stability than the parent compounds. DPTC-decursinol conversion was undetectable in mice. Furthermore, in LNCaP cells, DPTC decreased prostate specific antigen (PSA) expression, down-regulated AR abundance and mRNA and inhibited AR nuclear translocation. The effect of DPTC on AR and PSA mRNA and protein abundance was also observed in VCaP cells expressing wild type AR. DPTC inhibited growth of both PCa cell lines through G(1) cell cycle arrest and apoptosis, as did decursin and DA. Furthermore, i.p. administration of DPTC for 3 weeks suppressed the expression of AR target genes probasin and Nkx3.1 in mouse prostate glands. Overall, our data suggest that DPTC represents a prototype lead compound for development of in vivo stable and active novel decursin analogs for the prevention or therapy of PCa.</P>

Galbanic acid decreases androgen receptor abundance and signaling and induces G₁ arrest in prostate cancer cells

Zhang, Yong,Kim, Kwan‐,Hyun,Zhang, Wei,Guo, Yinglu,Kim, Sung‐,Hoon,Lü,, Junxuan Wiley Subscription Services, Inc., A Wiley Company 2012 International journal of cancer: Journal internati Vol.130 No.1

<P><B>Abstract</B></P><P>Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4‐2 <I>vs</I>. AR(−) DU145 and PC‐3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb <I>Ferula assafoetida</I> and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(−) PCa cells. GBA induced a caspase‐mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR‐dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G<SUB>1</SUB> arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D<SUB>1</SUB> without the causal involvement of cyclin‐dependent kinase (CDK) inhibitory proteins P21<SUP>Cip1</SUP> and P27<SUP>Kip1</SUP>. In summary, the novelty of GBA as an anti‐AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti‐AR and cell cycle arrest actions plus the anti‐angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.</P>

Anti-androgen receptor signaling and prostate cancer inhibitory effects of sucrose- and benzophenone-compounds.

Wang, Zhe,Lee, Hyo-Jeong,Wang, Lei,Jiang, Cheng,Baek, Nam-In,Kim, Sung-Hoon,L?, Junxuan Kluwer Academic/Plenum Publishers 2009 Pharmaceutical research Vol.26 No.5

<P>Novel agents that target multiple aspects of androgen receptor (AR) signaling are desirable for chemoprevention and treatment of prostate cancer (PCa). We aimed to identify compounds isolated from medicinal herbs as such drug candidates.</P>