The effect of chlorophyllins on various odorants a measured by surface tension changes of liquids.
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Chemical Phenomena↗
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A note on the polarographic determination of ionic copper present in the commercially available copper chlorophyllins.
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Chlorophyll↗
A note on the determination of ionic copper present in commercially available copper chlorophyllins.
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Chlorophyll↗
Photosensitivity from chlorophyll-derived pigments.
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Animals↗
Photodestruction of human dental plaque bacteria: enhancement of the photodynamic effect by photomechanical waves in an oral biofilm model.
BACKGROUND AND OBJECTIVES: Periodontal disease results from the accumulation of subgingival bacterial biofilms on tooth surfaces. There is reduced susceptibility of these biofilms to antimicrobials for reasons that are not known. The goals of this study were to investigate the photodynamic effects of a conjugate between the photosensitizer (PS) chlorin(e6) (c(e6)) and a poly-L-lysine (pL) with five lysine residues on human dental plaque bacteria as well as on biofilms of the oral species Actinomyces naeslundii after their exposure to photomechanical waves (PW) generated by a laser in the presence of the conjugate. STUDY DESIGN/MATERIALS AND METHODS: Subgingival plaque samples from 12 patients with chronic destructive periodontitis were divided in 3 groups that were incubated for 5 minutes with 5 microM c(e6) equivalent from the pL-c(e6) conjugate in the presence of fresh medium (group I), PBS (group II), and 80% PBS/20% ethylenediaminetetra-acetic acid (EDTA) (group III) and were exposed to red light. Also, biofilms of A. naeslundii (formed on bovine enamel surfaces) were exposed to PW in the presence of 5 microM c(e6) equivalent from the pL-c(e6) conjugate and were then irradiated with red light. The penetration depth of the conjugate was measured by confocal scanning laser microscopy (CSLM). In both cases, after illumination serial dilutions were prepared and aliquots were spread over the surfaces of blood agar plates. Survival fractions were calculated by counting bacterial colonies. RESULTS: The PS/light combination achieved almost 90% killing of human dental plaque species. In biofilms of A. naeslundii, CSLM revealed that PW were sufficient to induce a 50% increase in the penetration depth of the pL-c(e6) conjugate into the biofilm. This enabled its destruction (99% killing) after photodynamic therapy (PDT). CONCLUSIONS: PW-assisted photodestruction of dental plaque may be a potentially powerful tool for treatment of chronic destructive periodontal disease.
Actinomyces↗
Antimicrobial photodynamic therapy combined with conventional endodontic treatment to eliminate root canal biofilm infection.
BACKGROUND AND OBJECTIVE: To compare the effectiveness of antimicrobial photodynamic therapy (PDT), standard endodontic treatment and the combined treatment to eliminate bacterial biofilms present in infected root canals. STUDY DESIGN/MATERIALS AND METHODS: Ten single-rooted freshly extracted human teeth were inoculated with stable bioluminescent Gram-negative bacteria, Proteus mirabilis and Pseudomonas aeruginosa to form 3-day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify bacterial burdens. PDT employed a conjugate between polyethylenimine and chlorin(e6) as the photosensitizer (PS) and 660-nm diode laser light delivered into the root canal via a 200-micro fiber, and this was compared and combined with standard endodontic treatment using mechanical debridement and antiseptic irrigation. RESULTS: Endodontic therapy alone reduced bacterial bioluminescence by 90% while PDT alone reduced bioluminescence by 95%. The combination reduced bioluminescence by >98%, and importantly the bacterial regrowth observed 24 hours after treatment was much less for the combination (P<0.0005) than for either single treatment. CONCLUSIONS: Bioluminescence imaging is an efficient way to monitor endodontic therapy. Antimicrobial PDT may have a role to play in optimized endodontic therapy.
Anti-Infective Agents↗
Inhibitory effect of chlorophyllin on the frequency of micronuclei induced by sodium nitrite in mice.
In this report the potency of chlorophyllin (CHL) was evaluated to prevent two types of damage produced by nitrite in mice: the increase of micronucleated polychromatic erythrocytes (MNPE) and the bone marrow toxicity, measured as the index of polychromatic erythrocytes/normochromatic erythrocytes (PE/NE). The study was done in eight groups of male mice. The first three groups were administered orally for 4 days with sodium nitrite (10, 15 and 20 mg/kg), the daily administration with nitrite was followed by an intraperitoneal administration of CHL (4 mg/kg), three more groups were administered with the same amounts of nitrite, a seventh group of mice was treated with distilled water while another was treated with CHL (4 mg/kg). Our study produced two main results: (a) no bone marrow injury was induced by any of the tested chemicals, as indicated with the PE/NE index, and (b) CHL protected (as high as 44%) the MNPE produced in nitrite treated mice.
Administration, Oral↗
Effects of chlorophyllin on mouse embryonic and fetal development in vivo.
Chlorophyllin (CHL) has proven that there is antimutagenic and anticarcinogenic activity in several organisms without causing lethal effects. However, there is no information about its effects when it is administered in gestation. In the present study, we assessed possible effects of CHL when it was administered to CD-1 mice on the 8th day of gestation using the same doses and administration route used in ours previous antimutagenic and antigenotoxic studies. Females were exposed to a single dose of CHL by i.p. injection (20, 40, 50, or 100mg/kg b.w.). On day 18 all dams were subjected to cesarean section and the fetuses were examined with common teratological methods. Results show that CHL-treatment induced total litter loss and is dose-dependent, probably due to either the interaction between CHL and some general control mechanisms of embryo development or by an impairment of maternal-fetal interactions. The analysis of uterine horns of the CHL-treated females with total litter loss revealed the presence of green rings in the uterus. Results show the inverse relationship between the number of live implants and the frequency of green rings, indicating implantation sites where embryo death and early resorptions occurred. Although CHL was given in a single dose on day 8 in this study, the results indicate that CHL is associated with significant embryo lethality.
Animals↗
Comparative antimutagenicity of chlorophyllin and five other agents against aflatoxin B1-induced reversion in Salmonella typhimurium strain TA98.
Chlorophyllin was studied for its antimutagenic activity against aflatoxin B1 in Salmonella typhimurium strain TA98 using the plate-incorporation test in the presence of S9 activation. Comparative antimutagenicity between chlorophyllin and certain commonly studied antimutagens (i.e., vitamins A, C, and E, retinoic acid, and beta-carotene) was also examined. A dose-related inhibition of aflatoxin B1 mutagenicity by chlorophyllin was observed, with the mutagenicity being abolished by 860 nmole chlorophyllin per plate. The inhibitory activity of chlorophyllin occurred only when cells were treated concurrently with chlorophyllin and aflatoxin B1. The antimutagenic potency of chlorophyllin was comparable to that of vitamin A and higher than that of retinoic acid and beta-carotene. Vitamins C and E had no effect on aflatoxin B1 mutagenicity under the conditions used. The results of toxicity tests and a reconstruction experiment showed that inhibition of the mutagenicity of aflatoxin B1 by chlorophyllin and the other active agents was due to antimutagenicity.
Aflatoxin B1↗
Antitransforming activity of chlorophyllin against selected carcinogens and complex mixtures.
Chlorophyllin, a derivative of chlorophyll, is known to be an antimutagenic agent. Studies were performed to determine whether chlorophyllin can also inhibit morphological transformation of BALB/3T3 cells induced by carcinogens and complex mixtures. Chlorophyllin was added to the cultures simultaneously with carcinogens or complex mixtures while the transformation assay was conducted. At concentrations that did not significantly affect cell growth, chlorophyllin was found to inhibit morphological transformation induced by N-methyl-N'-nitro-N-nitrosoguanidine, 3-methylcholanthrene, 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, aflatoxin B1, and extracts of coal dust, tobacco snuff, and chewing tobacco. In all cases, the mean number of transformed foci per flask treated with chlorophyllin was significantly lower than that of untreated cultures. The reduction in the number of transformed foci was dependent on the concentration of chlorophyllin tested. These results indicate that chlorophyllin is an antitransforming agent.
3T3 Cells↗
Active oxygen intermediates and chlorophyllin bleaching.
Bleaching of chlorophyllin, a water soluble copper containing porphyrin molecule, was investigated with regard to the potential role of active oxygen intermediate involvement. It was found that the bleaching was highly aerobic and also biphasic in nature. The aerobic photobleaching and the dark bleaching were effectively prevented by the addition of reductants such as ascorbate and cysteine. In addition, the reductant and peroxyl radical scavenger, Trolox, was highly effective in preventing bleaching. Catalase was moderately effective in preventing photobleaching whereas peroxidase and superoxide dismutase hastened the photobleaching process. It is concluded that the bleaching of chlorophyllin is a peroxidative process which does not involve singlet oxygen, superoxide, nor the .OH radical.
Chlorophyllides↗
Noninvasively induced degeneration of neocortical pyramidal neurons in vivo: selective targeting by laser activation of retrogradely transported photolytic chromophore.
Interactions among neuronal subpopulations determine brain development and function. The present study illustrates the ability to noninvasively and selectively lesion targeted subpopulations of neurons in a highly specific, temporally defined, and geographically localized manner. This method provides a fundamental advance toward rigorous investigation of the importance of identified neuronal subtypes. Projecting pyramidal neurons of rats and mice were targeted by retrograde transport of latex nanospheres from contralateral motor cortex containing a nontoxic chromophore (chlorin e6) that produces cytotoxic singlet oxygen during photoactivation by deeply penetrating 670-nm light. Geographically defined regions of cortex were exposed to laser illumination at 670 nm to activate singlet oxygen production by the intracellular chromophore, and animals were sacrificed from 4 h to 7 days following laser exposure. Brains were processed to display degenerating neurons using sensitive silver-staining procedures. Selective damage occurred to pyramidal neurons with known callosal projections, solely within layers II/III and V of the illuminated region. Such subpopulation specificity provides models for neural transplantation and analysis of anatomically distributed neuronal networks.
Animals↗
Apoptotic mechanisms in targeted neuronal cell death by chromophore-activated photolysis.
Apoptosis influences early development and later refinement in adult tissues. Experiments in which embryonic neurons or multipotent neural precursor cells are transplanted into regions of neuronal degeneration following targeted photolytic cell death show similar regulation of neuronal migration and differentiation. In those experiments, transplanted cells sought to restore normal cytoarchitecture by preferential migration into neuron deficient regions, assumption of pyramidal morphology, and early process elongation. Control transplants into intact and kainic acid lesioned cortex failed to elicit similar responses. We investigated the possibility that mechanisms of neuronal death common to apoptosis and targeted photolysis could explain the similar developmental influences. We assessed the pathways of cellular injury and eventual cell death in neuroblastoma and PC12 cell cultures labeled with nanospheres carrying the chromophore NH4-chlorin e6 and subjected to photoactivation (1) pharmacologically by scavengers of singlet oxygen and inhibitors of lysosomal proteases, (2) histologically by electron, fluorescence, and light microscopy, and (3) biochemically with binding of cellular DNA by propridium iodide, 3'-OH DNA end terminal labeling, and gel electrophoresis. We found that nanospheres were incorporated into lysosomes, and exposure to light energy led to singlet oxygen (1O2) production and cell death within both neuroblastoma and PC-12 cell lines. Scavengers of 1O2 prevented cell toxicity, while inactivation of lysosomal proteases reduced cell death. Morphologically, degenerating cells revealed release of proteases from lysosomes and disruption of cytoskeletal proteins. Apoptotic characteristics including early loss of cell adhesion, plasma membrane blebbing, and nuclear condensation and convolution were observed. Biochemically, DNA fragmentation was present in cells stained with propridium iodide and observed by 3'-OH end terminal labeling and gel electrophoresis. Thus, cells targeted by photolytically generated 1O2 undergo a form of cell autolysis whose final common pathway is apoptotic. The slow, nonnecrotic process of targeted neuronal cell death in vivo may activate many of the same physiological cues activated by programmed cell death during normal development and during organizational refinement in the adult vertebrate nervous system. This may potentially explain the migration and differentiation of neocortical neurons and neural precursors transplanted into these regions of neuronal degeneration.
Animals↗
Intraperitoneal photoimmunotherapy of ovarian carcinoma xenografts in nude mice using charged photoimmunoconjugates.
OBJECTIVE: The objective of this study was to compare the efficacy of photoimmunoconjugates with cationic and anionic molecular charges on intraperitoneal photoimmunotherapy of ovarian cancer xenografts in nude mice. METHODS: The photosensitizer chlorin(e6) (c(e6)) was conjugated via a poly-l-lysine linker to the F(ab')(2) fragment of the murine anti-ovarian cancer monoclonal antibody OC125, resulting in a photoimmunoconjugate with a pronounced cationic charge. Alternatively, by succinylating the poly-l-lysine conjugate, a photoimmunoconjugate with a pronounced anionic charge was obtained. A murine model of ovarian cancer derived from intraperitoneal inoculation of NIH:OVCAR-5 cells was employed. The conjugate was injected intraperitoneally followed after 3 h by red light delivered through a fiber into the peritoneal cavity. These photoimmunotherapy treatments were repeated three times, and the results obtained with the anionic and cationic photoimmunoconjugates were compared with those obtained with free c(e6) and control. The extent of residual macroscopic disease and death from disease were the evaluable outcomes for tumoricidal and survival studies, respectively. RESULTS: In contrast to other intraperitoneal photosensitizers, mice showed no systemic toxicity or morbidity from the treatment. In this initial study the mean residual tumor weights in all treatment groups ranged from 33 to 73 mg, as compared with 330 mg in untreated controls (P < 0.0001), and the response to the cationic conjugate was significantly better than that to the anionic conjugate or free c(e6) (P < 0.005). The median survival for mice treated with cationic photoimmunoconjugate was 41 days, compared with 35 days in controls (P = 0.009). CONCLUSION: Photoimmunotherapy with a cationic photoimmunoconjugate produces results superior to those obtained with an anionic conjugate, and further optimization of the treatment regimen may lead to a potential treatment for advanced ovarian cancer.
Animals↗
Control of hypertrophic scar growth using antibody-targeted photolysis.
Hypertrophic scar is marked by excess collagen accumulation secondary to an increased vascularization response in the scar and an increase in fibroblast cell density. It is currently the most debilitating long-term complication of the surviving burn patient, and at present, there is no routinely effective form of therapy. In this study, we investigated the potential use of antibody-targeted photolysis (ATPL) in treating hypertrophic scars. An immunoconjugate consisting of a photosensitizer (Sn-chlorin e6) linked to a monoclonal antibody that binds to human myofibroblasts (PR2D3) was prepared, which in response to photoactivation produces singlet oxygen in close proximity to the target cell surface. The model used for these studies consisted of 1-mm 3 human hypertrophic scar tissue implants in athymic mice. These implants increase approximately 20-fold in volume over a period of 15 days. Four days after implantation immunoconjugate was injected directly into scar implants allowed to diffuse throughout for 24 hr before implants were illuminated with laser light at 630 nm (120 J/cm 2). ATPL treatment caused a significant reduction in total growth compared to the untreated controls (P < 0.05). No effect was observed when an irrelevant conjugate (anti-Pseudomonas aeruginosa) was used. Histological examination of the ATPL-treated implants 24 hr post-ATPL revealed the presence of a large number of lipid droplets indicative of massive cell damage and infiltration by mononuclear cells and neutrophils.
Animals↗
Mechanisms of chlorophyllin anticarcinogenesis: dose-responsive inhibition of aflatoxin uptake and biodistribution following oral co-administration in rainbow trout.
Chlorophyllin (CHL) is a potent blocking agent against aflatoxin B(1) DNA adduction and tumorigenesis in the trout model, but mechanisms responsible for this chemoprotection in vivo are not well established. This study employed aflatoxin B(2) (AFB(2)), a structural analogue of AFB(1) that cannot be metabolized directly to the 8,9-exo-epoxide electrophile, to investigate CHL effects on carcinogen uptake and distribution kinetics following oral exposure in trout. CHL was shown to form an AFB(2) complex in vitro with a dissociation constant (K(d) = 1.92 +/- 0.13 microM) comparable to that with AFB(1). Following gavage, [(3)H]AFB(2) equivalents distributed rapidly from the stomach to other organs including blood, liver, and eventually to bile as a major repository. Bile was found to contain almost entirely parent AFB(2) 1 h after gavage, with a single metabolite dominating 3-24 h and an additional metabolite prominent by 48 h after gavage. Addition of sufficient CHL (>/=13.9 mM) to assure >99% complexation of AFB(2) (0.906 microM) in the gavage mix resulted in 80-90% reduction in AFB(2) equivalents in liver and bile 3 h after gavage. In three separate kinetic studies of up to 120 h postgavage, addition of >/=13.9 mM CHL to the gavage mix reproducibly and markedly delayed the rate of AFB(2) loss from stomach, retarded its appearance in blood, liver, and bile, and reduced peak AFB(2) concentrations in those tissues by up to 60%. Introduction of a food bolus immediately after gavage prolonged AFB(2) residence in stomach and intestine but did not abrogate the inhibitory effects of CHL on AFB(2) uptake and distribution. These results demonstrate that oral co-treatment with CHL under conditions where complex formation is initially assured, substantially reduces AFB(2) systemic uptake and target organ bioavailability in the trout.
Aflatoxins↗
Chlorophyllin chemoprevention in trout initiated by aflatoxin B(1) bath treatment: An evaluation of reduced bioavailability vs. target organ protective mechanisms.
Chlorophyllin (CHL) is known to inhibit DNA adduction and hepatocarcinogenesis in trout when administered at doses up to 4000 ppm in the diet with aflatoxin B(1) (AFB(1)). The principal protective mechanism is believed to involve CHL:AFB(1) complex formation, which may reduce systemic carcinogen absorption. However, mechanisms operative within the target organ in situ have not been ruled out. The present study used alternative CHL and AFB(1) exposures as well as hepatic metabolism studies to distinguish these mechanisms. Duplicate lots of 150 rainbow trout each were initiated by brief water bath exposure to 0.1 ppm AFB(1), with or without 500 ppm CHL in the water. The addition of 500 ppm CHL to the water bath, under conditions where AFB(1) is calculated to be >99% sequestered as the CHL:AFB(1) complex, reduced hepatic AFB(1)-DNA adduction by 95% and reduced hepatocarcinogenesis from 20.5% to 2%, compared with exposure to AFB(1) alone. Inclusion of 500 ppm CHL in the water bath also significantly reduced total body burden and hepatic levels of AFB(1) as well as AFB(2), a structural analogue of AFB(1) unable to directly form the 8,9-epoxide proximate electrophile but equally capable of complexing with CHL. By contrast, internal target organ CHL loading by pretreatment of trout with 4000 ppm dietary CHL for 7 days prior to (and 2 days following) AFB(1) waterbath exposure had no effect on AFB(1)-DNA adduction or tumorigenicity. Dietary CHL up to 8000 ppm had no effect on hepatic CYP2K1, CYP1A, glutathione transferase, UDP-glucuronosyl transferase, or, with one exception, the relative ratios among hepatic AFB(1) metabolites in vivo. These results support the hypothesis that CHL:AFB(1) complex formation and reduced systemic AFB(1) bioavailability is a principal mechanism for CHL chemoprevention in this model and that in situ target organ inhibitory mechanisms are relatively insignificant.
Aflatoxin B1↗
Chlorophyllin suppression of lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells.
Chlorophyllin (CHL), a water-soluble derivative of chlorophyll, functions as an anticarcinogen and antioxidant. In the present study, we investigated the effect of CHL on nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Treatment with CHL inhibited nitric oxide production in the LPS-stimulated RAW 264. 7 cells in a dose-related manner. Competitive RT-PCR analysis, using a DNA competitor as an internal standard, demonstrated that the treatment with 1, 10, and 50 microM CHL decreased LPS-induced iNOS mRNA expression in a concentration-dependent manner. Since the expression of the iNOS gene is mainly regulated by NF-kappaB, we then examined the effects of CHL on the NF-kappaB DNA binding activity, using an electrophoretic mobility shift assay. CHL down-regulated the NF-kappaB DNA binding on its cognate recognition site at the concentrations just noted. Employing a transfection and reporter gene expression system with p(NF-kappaB)(3)-chloramphenicol acetyl transferase (CAT), the treatment of CHL produced a dose-dependent inhibition of CAT activity in RAW 264.7 cells. Furthermore, CHL partially restored LPS-decreased IkappaBalpha, an inhibitory protein against NF-kappaB activation, in the cytosolic extract from the LPS-treated cells determined by immunoblot analysis. CHL also protected the hydroxyl radical-induced cytotoxicity in RAW 264.7 cells, indicating its antioxidant effect. These results suggest that CHL suppresses the nitric oxide production and iNOS mRNA expression mediated by the inhibition of NF-kappaB activation, and its action mechanism may be based on its antioxidant effect.
Animals↗