ABSTRACT
Large animals could be important drivers of spatial nutrient subsidies when they ingest resources in some habitats and release them in others, even moving nutrients against elevational gradients. In high Andean deserts, vicuñas (Vicugna vicugna) move daily between nutrient-rich wet meadows, where there is abundant water and forage but high risk of predation by pumas (Puma concolor), and nutrient-poor open plains with lower risk of predation. In all habitats, vicuñas defecate and urinate in communal latrines. We investigated how these latrines impacted soil and plant nutrient concentrations across three habitats in the Andean ecosystem (meadows, plains, and canyons) and used stable isotope analysis to explore the source of fecal nutrients in latrines. Latrine soils had higher concentrations of nitrogen, carbon, and other nutrients than did nonlatrine soils across all habitats. These inputs corresponded with an increase in plant quality (lower C:N) at latrine sites in plains and canyons, but not in meadows. Stable isotope mixing models suggest that ~7% of nutrients in plains latrines originated from vegetation in meadows, which is disproportionately higher than the relative proportion of meadow habitat (2.6%) in the study area. In contrast, ~68% of nutrients in meadow latrines appear to originate from plains and canyon vegetation, though these habitats made up nearly 98% of the study area. Vicuña diel movements thus appear to concentrate nutrients in latrines within habitats and to drive cross-habitat nutrient subsidies, with disproportionate transport from low-lying, nutrient-rich meadows to more elevated, nutrient-poor plains. When these results are scaled up to the landscape scale, the amount of nitrogen and phosphorus subsidized in soil at plains latrines was of the same order of magnitude as estimates of annual atmospheric nitrogen and phosphorus deposition for this region (albeit far more localized and patchy). Thus, vicuña-mediated nutrient redistribution and deposition appears to be an important process impacting ecosystem functioning in arid Andean environments, on par with other major inputs of nutrients to the system.
Subject(s)
Camelids, New World , Animals , Ecosystem , Nitrogen , Nutrients , Phosphorus , Soil , IsotopesABSTRACT
Background: Bungarus multicinctus is one of the most dangerous venomous snakes prone to cardiopulmonary damage with extremely high mortality. In our previous work, we found that glutamine (Gln) and glutamine synthetase (GS) in pig serum were significantly reduced after Bungarus multicinctus bite. In the present study, to explore whether there is a link between the pathogenesis of cardiopulmonary injury and Gln metabolic changes induced by Bungarus multicinctus venom. We investigated the effect of Gln supplementation on the lung and heart function after snakebite. Methods: We supplemented different concentrations of Gln to mice that were envenomated by Bungarus multicinctus to observe the biological behavior, survival rate, hematological and pathological changes. Gln was supplemented immediately or one hour after the venom injection, and then changes in Gln metabolism were analyzed. Subsequently, to further explore the protective mechanism of glutamine on tissue damage, we measured the expression of heat-shock protein70 (HSP70), NF-κB P65, P53/PUMA by western blotting and real-time polymerase in the lung and heart. Results: Gln supplementation delayed the envenoming symptoms, reduced mortality, and alleviated the histopathological changes in the heart and lung of mice bitten by Bungarus multicinctus. Additionally, Gln increased the activity of glutamine synthetase (GS), glutamate dehydrogenase (GDH) and glutaminase (GLS) in serum. It also balanced the transporter SLC7A11 expression in heart and lung tissues. Bungarus multicinctus venom induced the NF-κB nuclear translocation in the lung, while the HO-1 expression was suppressed. At the same time, venom activated the P53/PUMA signaling pathway and the BAX expression in the heart. Gln treatment reversed the above phenomenon and increased HSP70 expression. Conclusion: Gln alleviated the glutamine metabolism disorder and cardiopulmonary damage caused by Bungarus multicinctus venom. It may protect lungs and heart against venom by promoting the expression of HSP70, inhibiting the activation of NF-κB and P53/PUMA, thereby delaying the process of snake venom and reducing mortality. The present results indicate that Gln could be a potential treatment for Bungarus multicinctus bite.
ABSTRACT
B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic disorder characterized by the abnormal proliferation and accumulation of immature B-lymphoblasts arrested at various stages of differentiation. Despite advances in treatment, a significant percentage of pediatric patients with precursor B-ALL still relapse. Therefore, alternative therapies are needed to improve the cure rates for pediatric patients. TPEN (N, N, N', N'-tetrakis(2-pyridylmethyl)-ethylenediamine) is a pro-oxidant agent capable of selectively inducing apoptosis in leukemia cell lines. Consequently, it has been suggested that TPEN could be a potential agent for oxidative therapy. However, it is not yet known whether TPEN can selectively destroy leukemia cells in a more disease-like model, for example, the bloodstream and bone marrow (BM), ex vivo. This investigation is an extension of a previous study that dealt with the effect of TPEN on ex vivo isolated/purified refractory B-ALL cells. Here, we evaluated the effect of TPEN on whole BM from nonleukemic patients (control) or pediatric patients diagnosed with de novo B-ALL or refractory B-ALL cells by analyzing the hematopoietic cell lineage marker CD34/CD19. Although TPEN was innocuous to nonleukemic BM (n = 3), we found that TPEN significantly induced apoptosis in de novo (n = 5) and refractory B-ALL (n = 6) leukemic cell populations. Moreover, TPEN significantly increased the counts of cells positive for the oxidation of the stress sensor protein DJ-1, a sign of the formation of H2O2, and significantly increased the counts of cells positive for the pro-apoptotic proteins TP53, PUMA, and CASPASE-3 (CASP-3), indicative of apoptosis, in B-ALL cells. We demonstrate that TPEN selectively eliminates B-ALL cells (CD34 + /CD19 +) but no other cell populations in BM (CD34 + /CD19-; CD34-/CD19 + ; CD34-/CD19-) independent of age, diagnosis status (de novo or refractory), sex, karyotype, or immunophenotype. Understanding TPEN-induced cell death in leukemia cells provides insight into more effective therapeutic oxidation-inducing anticancer agents.
Subject(s)
Bone Marrow , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antigens, CD19/metabolism , Bone Marrow/metabolism , Child , Ethylenediamines , Humans , Hydrogen Peroxide/metabolism , Immunophenotyping , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapyABSTRACT
Annona cherimola is a tree belonging to the family Annonacea, whose fruit (cherimoya) is very desirable, but its seeds are considered waste. Present in these seeds are compounds that have been described as selective antiproliferative agents for cancer cells. The aim of this study was to evaluate the antiproliferative activity of ethanol macerate extract (EMCHS) obtained from A. cherimola seeds against the human stomach gastric adenocarcinoma (AGS) cell line and the normal human gastric epithelial cell line (GES-1). The EMCHS extract presented an IC50 of 80.43 µg/mL in AGS cells, and a selectivity index (SI) of 3.5-fold higher than that of cisplatin. In addition, the EMCHS extract showed apoptotic activity in AGS cells since 50 µg/mL. Overxpression of PUMA gene in both cells demonstrate that EMCHS activate the apoptotic route. Future studies should be carried out to elucidate anticancer activity of EMCHS in vivo. This work represents the first showing antiproliferative effects of crude extracts obtained from seeds of A. cherimola in AGS cells.
Subject(s)
Adenocarcinoma/drug therapy , Annona/chemistry , Apoptosis/drug effects , Plant Extracts/pharmacology , Seeds/chemistry , Stomach Neoplasms/drug therapy , Adenocarcinoma/pathology , Apoptosis Regulatory Proteins/genetics , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Epithelial Cells/drug effects , Ethanol , Gene Expression , Humans , Proto-Oncogene Proteins/genetics , Stomach/pathologyABSTRACT
Protopanaxadiol (PPD), a ginseng metabolite generated by the gut bacteria, was shown to induce colorectal cancer cell death and enhance the anticancer effect of chemotherapeutic agent 5-FU. However, the mechanism by which PPD promotes cancer cell death is not clear. In this manuscript, we showed that PPD activated p53 and endoplasmic reticulum (ER) stress and induced expression of BH3-only proteins Puma and Noxa to promote cell death. Induction of Puma by PPD was p53-dependent, whereas induction of Noxa was p53-independent. On the other hand, PPD also induced prosurvival mechanisms including autophagy and expression of Bcl2 family apoptosis regulator Mcl-1. Inhibition of autophagy or knockdown of Mcl-1 significantly enhanced PPD-induced cell death. Interestingly, PPD inhibited expression of genes involved in fatty acid and cholesterol biosynthesis and induced synergistic cancer cell death with fatty acid synthase inhibitor cerulenin. As PPD-induced ER stress was not significantly affected by inhibition of new protein synthesis, we suggest PPD may induce ER stress directly through causing lipid disequilibrium.
Subject(s)
Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Lipid Metabolism/drug effects , Panax/metabolism , Sapogenins/pharmacology , Autophagy/drug effects , HCT116 Cells , Humans , Tumor Suppressor Protein p53/physiologyABSTRACT
Potentilla discolor has been used in traditional Chinese medicine for the treatment of hyperglycemia. However, the potential role of Potentilla discolor against cancer and its mode of action remain to be fully elucidated. The present study explored the apoptotic effect of methanol extract of Potentilla discolor (MEPD) in human mucoepidermoid carcinoma (MEC) cell lines of salivary glands. MEPD markedly suppressed the growth and induced apoptotic cell death in MC3 and YD15 cells. MEPD treatment significantly upregulated the expression of PUMA and reduced STAT3 phosphorylation. Overexpression of STAT3 partially recovered the growth of MEC cells inhibited by MEPD. In addition, dephosphorylation of STAT3 by cryptotanshinone (a potent STAT3 inhibitor) was sufficient to inhibit the growth of MEC cells and induce apoptosis via affecting PUMA protein. These results suggest that MEPD has a potential anticancer property via the STAT3/PUMA signaling axis in human MEC cells of salivary gland.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis Regulatory Proteins/metabolism , Apoptosis/drug effects , Carcinoma, Mucoepidermoid/metabolism , Plant Extracts/pharmacology , Potentilla/chemistry , Proto-Oncogene Proteins/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , HumansABSTRACT
Triple-negative breast cancer (TNBC; estrogen receptor-negative, progesterone receptor-negative and Her-2-negative) is often accompanied by a higher frequency of p53 gene mutations. Therefore, TNBC is challenging to treat due to a lack of biological targets and a poor sensitivity to conventional therapies. Curcumol is a monomer composition isolated from the ethanol extracts of Curcuma wenyujin, a Chinese medicinal herb traditionally used as a cancer remedy. Previous studies have revealed that curcumol is able to block proliferation in various human tumor cell lines. However, the underlying mechanisms have yet to be elucidated. The present study aimed to investigate the anticancer effects of curcumol in the human p53 mutant TNBC MDA-MB-231 cell line and its underlying mechanisms. Cell viability and growth were determined by MTT and a mice xenograft model assay, respectively. Cell cycle distribution was examined by flow cytometry. Apoptosis was evaluated by apoptotic morphology analysis with DAPI staining and flow cytometric analysis following Annexin V/propidium iodide staining. The protein expression in cells was evaluated by immunoblotting. Treatment of MDA-MB-231 cells with curcumol resulted in a significant inhibition of cell proliferation in vitro [half maximal inhibitory concentration (IC50)=240.7±85.0 µg/ml for 48 h and IC50=100.2±13.5 µg/ml for 72 h]. Curcumol treatment also resulted in the suppression of xenograft growth in vivo (100 or 200 µg/kg for 21 days), as well as G1 phase arrest and an apoptotic response, which were accompanied by the upregulation of p73 expression and the activation of the expression of p53 upregulated modulator of apoptosis (PUMA) and Bcl-2 antagonistic killer (Bak). No cleavage of poly (ADP-ribose) polymerase was detected. To the best of our knowledge, the present data demonstrate for the first time that curcumol inhibits the growth of MDA-MB-231 cells and triggers p53-independent apoptosis, which may be mediated by the p73-PUMA/Bak signaling pathway. Curcumol may, therefore, be a potential compound for use in the development of novel TNBC therapeutics.
ABSTRACT
Inadequate apoptosis contributes to synovial hyperplasia in rheumatoid arthritis (RA). Recent study shows that low expression of Puma might be partially responsible for the decreased apoptosis of fibroblast-like synoviocytes (FLS). Slug, a highly conserved zinc finger transcriptional repressor, is known to antagonize apoptosis of hematopoietic progenitor cells by repressing Puma transactivation. In this study, we examined the expression and function of Slug in RA FLS. Slug mRNA expression was measured in the synovial tissue (ST) and FLS obtained from RA and osteoarthritis patients. Slug and Puma mRNA expression in FLS by apoptotic stimuli were measured by real-time PCR analysis. FLS were transfected with control siRNA or Slug siRNA. Apoptosis was quantified by trypan blue exclusion, DNA fragmentation and caspase-3 assay. RA ST expressed higher level of Slug mRNA compared with osteoarthritis ST. Slug was significantly induced by hydrogen peroxide (H2O2) but not by exogenous p53 in RA FLS. Puma induction by H2O2 stimulation was significantly higher in Slug siRNA-transfected FLS compared with control siRNA-transfected FLS. After H2O2 stimulation, viable cell number was significantly lower in Slug siRNA-transfected FLS compared with control siRNA-transfected FLS. Apoptosis enhancing effect of Slug siRNA was further confirmed by ELISA that detects cytoplasmic histone-associated DNA fragments and caspase-3 assay. These data demonstrate that Slug is overexpressed in RA ST and that suppression of Slug gene facilitates apoptosis of FLS by increasing Puma transactivation. Slug may therefore represent a potential therapeutic target in RA.