A novel prophylactic regimen is demanded for preventing bladder cancer recurrence, because of the high side-effect tolls of conventional adjuvant Bacillus Calmette-Guérin (BCG) immunotherapy, in addition to its o...A novel prophylactic regimen is demanded for preventing bladder cancer recurrence, because of the high side-effect tolls of conventional adjuvant Bacillus Calmette-Guérin (BCG) immunotherapy, in addition to its only moderate efficacy. In vitro and animal studies have demonstrated the anti-cancer properties of a medicinal mushroom called Ganoderma lucidum (GL). In this study, a pre-malignant human uroepithelial cells (HUC-PC) model was utilized to compare the effectiveness between ethanol extract of GL (GLe) and BCG on interleukin-6 (IL-6) secretion and lactate dehydrogenase (LDH) cytotoxicity. Additionally, parameters relevant to the BCG efficacy and safety, including free soluble fibronectin (FN) and cell-surface glycosaminoglycans (GAGs) levels were tested, following the exposure of GLe to the cells. GLe at 100 μg/ml and BCG at 4.8 × 107 CFU were shown to induce equivalent levels of IL-6, suggesting the potential synergism, while the tested concentrations of GLe were non-cytotoxic. During the initial four hours of GLe exposure, the free FN concentrations in harvested media were significantly reduced that might facilitate the binding of BCG for uroepithelial internalization to enhance BCG efficacy. Furthermore, the cell membrane-bound GAGs levels of HUC-PC cells were significant increased in response to GLe to suggest cellular protection from BCG infection. In summary, current findings suggest the potential additive synergism of GLe with the BCG efficacy, as well as its protective effects, and thus reducing the BCG toxicity.展开更多
Halobenzoquinones(HBQs),a class of water dis-infection byproducts(DBPs),have emerged as potential bladder carcinogens.However,evidence regarding the long-term health effects of HBQexposure and their potential to induc...Halobenzoquinones(HBQs),a class of water dis-infection byproducts(DBPs),have emerged as potential bladder carcinogens.However,evidence regarding the long-term health effects of HBQexposure and their potential to induce malignant trans-formation remains limited.Here,we examined the chronic effects of 2,6-dichlorobenzoquinone(2,6-DCBQ)exposure on human immor-talized uroepithelial cells(SV-HUC-1),with a focus on malignant transformation.Cells were continuously exposed to a noncytotoxic concentration of 2,6-DCBQfor over three months.The long-term transformed cells exhibited cellular and nuclear pleomorphism and anchorage-independent cell growth—a hallmark of cancer cell transformation.Proteomic analysis identified 60 differentially ex-pressed proteins(DEPs),20 of which are strongly associated with specific pathways of urinary bladder and urothelial cells.Enrichment analysis highlighted the actin cytoskeleton and extracellular matrix(ECM)-receptor interaction pathways.These molecular changes were supported by immunofluorescence assay,revealing filamentous actin disorganization and vinculin mislocalization in 2,6-DCBQ-treated cells.Together,these results suggest that cytoskeletal destabilization and adhesion collapse are key features associated with 2,6-DCBQ-induced malignant transformation,indicating that chronic exposure to low-level waterborne HBQs is associated with human bladder carcinogenesis.展开更多
The basic tissue engineering paradigm is tissue induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata.The insoluble signal ...The basic tissue engineering paradigm is tissue induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata.The insoluble signal acts as a three-dimensional scaffold for the initiation of de novo tissue induction and morphogenesis. The osteogenic soluble molecular signals of the transforming growth factor-β(TGF-β) supergene family,the bone morphogenetic/osteogenic proteins(BMPs/OPs) and,uniquely in the non-human primate Papio ursinus(P.ursinus),the three mammalian TGF-βisoforms induce bone formation as a recapitulation of embryonic development.In this paper,I discuss the pleiotropic activity of the BMPs/OPs in the non-human primate P. ursinus,the induction of bone by transitional uroepithelium,and the apparent redundancy of molecular signals initiating bone formation by induction including the three mammalian TGF-βisoforms.Amongst all mammals tested so far,the three mammalian TGF-βisoforms induce endochondral bone formation in the non-human primate P.ursinus only.Bone tissue engineering starts by erect-ing scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone.The molecular scaffolding lies at the hearth of all tissue engineering strategies including the induction of bone formation.The novel concept of tissue engineering is the generation of newly formed bone by the implantation of"smart"intelligent biomimetic matrices that per se initiate the ripple-like cascade of bone differentiation by induction without exogenously applied BMPs/OPs of the TGF-βsupergene family.A comprehensive digital iconographic material presents the modified tissue engineering paradigm whereby the induction of bone formation is initiated by intelligent smart biomimetic matrices that per se initiate the induction of bone formation without the exogenous application of the soluble osteogenic molecular signals. The driving force of the intrinsic induction of bone formation by bioactive biomimetic matrices is the shape of the implanted substratum.The language of shape is the language of geometry;the language of geometry is the language of a sequence of repetitive concavities,which biomimetizes the remodelling cycle of the primate osteonic bone.展开更多
文摘A novel prophylactic regimen is demanded for preventing bladder cancer recurrence, because of the high side-effect tolls of conventional adjuvant Bacillus Calmette-Guérin (BCG) immunotherapy, in addition to its only moderate efficacy. In vitro and animal studies have demonstrated the anti-cancer properties of a medicinal mushroom called Ganoderma lucidum (GL). In this study, a pre-malignant human uroepithelial cells (HUC-PC) model was utilized to compare the effectiveness between ethanol extract of GL (GLe) and BCG on interleukin-6 (IL-6) secretion and lactate dehydrogenase (LDH) cytotoxicity. Additionally, parameters relevant to the BCG efficacy and safety, including free soluble fibronectin (FN) and cell-surface glycosaminoglycans (GAGs) levels were tested, following the exposure of GLe to the cells. GLe at 100 μg/ml and BCG at 4.8 × 107 CFU were shown to induce equivalent levels of IL-6, suggesting the potential synergism, while the tested concentrations of GLe were non-cytotoxic. During the initial four hours of GLe exposure, the free FN concentrations in harvested media were significantly reduced that might facilitate the binding of BCG for uroepithelial internalization to enhance BCG efficacy. Furthermore, the cell membrane-bound GAGs levels of HUC-PC cells were significant increased in response to GLe to suggest cellular protection from BCG infection. In summary, current findings suggest the potential additive synergism of GLe with the BCG efficacy, as well as its protective effects, and thus reducing the BCG toxicity.
基金supported by grants from Alberta Innovates,the Canada Research Chairs(CRC)Program,and the Natural Sciences and Engineering Research Council of Canada(NSERC).Flow cytometry was performed at the University of Alberta’s Faculty of Medicine and Dentistry Flow Cytometry Facility,with additional support from the Faculty and the Canadian Foundation for Innovation(CFI).C.W.gratefully acknowledges financial support from the China Scholarship Council(CSC).
文摘Halobenzoquinones(HBQs),a class of water dis-infection byproducts(DBPs),have emerged as potential bladder carcinogens.However,evidence regarding the long-term health effects of HBQexposure and their potential to induce malignant trans-formation remains limited.Here,we examined the chronic effects of 2,6-dichlorobenzoquinone(2,6-DCBQ)exposure on human immor-talized uroepithelial cells(SV-HUC-1),with a focus on malignant transformation.Cells were continuously exposed to a noncytotoxic concentration of 2,6-DCBQfor over three months.The long-term transformed cells exhibited cellular and nuclear pleomorphism and anchorage-independent cell growth—a hallmark of cancer cell transformation.Proteomic analysis identified 60 differentially ex-pressed proteins(DEPs),20 of which are strongly associated with specific pathways of urinary bladder and urothelial cells.Enrichment analysis highlighted the actin cytoskeleton and extracellular matrix(ECM)-receptor interaction pathways.These molecular changes were supported by immunofluorescence assay,revealing filamentous actin disorganization and vinculin mislocalization in 2,6-DCBQ-treated cells.Together,these results suggest that cytoskeletal destabilization and adhesion collapse are key features associated with 2,6-DCBQ-induced malignant transformation,indicating that chronic exposure to low-level waterborne HBQs is associated with human bladder carcinogenesis.
基金Supported by South African Medical Research Council,University of the Witwatersrand,Johannesburg and the National Research Foundation of South Africa
文摘The basic tissue engineering paradigm is tissue induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata.The insoluble signal acts as a three-dimensional scaffold for the initiation of de novo tissue induction and morphogenesis. The osteogenic soluble molecular signals of the transforming growth factor-β(TGF-β) supergene family,the bone morphogenetic/osteogenic proteins(BMPs/OPs) and,uniquely in the non-human primate Papio ursinus(P.ursinus),the three mammalian TGF-βisoforms induce bone formation as a recapitulation of embryonic development.In this paper,I discuss the pleiotropic activity of the BMPs/OPs in the non-human primate P. ursinus,the induction of bone by transitional uroepithelium,and the apparent redundancy of molecular signals initiating bone formation by induction including the three mammalian TGF-βisoforms.Amongst all mammals tested so far,the three mammalian TGF-βisoforms induce endochondral bone formation in the non-human primate P.ursinus only.Bone tissue engineering starts by erect-ing scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone.The molecular scaffolding lies at the hearth of all tissue engineering strategies including the induction of bone formation.The novel concept of tissue engineering is the generation of newly formed bone by the implantation of"smart"intelligent biomimetic matrices that per se initiate the ripple-like cascade of bone differentiation by induction without exogenously applied BMPs/OPs of the TGF-βsupergene family.A comprehensive digital iconographic material presents the modified tissue engineering paradigm whereby the induction of bone formation is initiated by intelligent smart biomimetic matrices that per se initiate the induction of bone formation without the exogenous application of the soluble osteogenic molecular signals. The driving force of the intrinsic induction of bone formation by bioactive biomimetic matrices is the shape of the implanted substratum.The language of shape is the language of geometry;the language of geometry is the language of a sequence of repetitive concavities,which biomimetizes the remodelling cycle of the primate osteonic bone.
