ABSTRACT
BACKGROUND: Hydatid disease is caused by the larval stages of the canine tapeworm Echinococcus granulosus. It is one of the most critical helminthic diseases, representing worldwide public health and socio-economic concern. AIM: This study aimed to investigate the expression of apoptosis and immune response within hepatic tissues of humans and sheep infected with the Hydatid cyst. METHODS: Paraffin-embedded tissue was prepared from each tissue sample and used for histopathological examination by Haematoxylin- Eosin. Also, toluidine blue staining was used for mast cell detection, while an immunohistochemical study was performed to assess CD3 T lymphocytes, CD4 helper T lymphocytes, CD8 cytotoxic T lymphocytes, CD20 memory B lymphocytes, CD68 macrophage, and caspase-3 antibodies. RESULTS: The histological examination revealed significant changes, including the infiltration of inflammatory cells, predominantly lymphocytes with scattered giant cells, necrotic hepatic tissue, and fibrosis. Toluidine blue stain revealed a higher number of mast cells (5 cells/field) in humans compared to sheep (3.6 cells/field). The immunohistochemical analysis confirmed that the CD3 were the most predominant inflammatory cell in the hepatic tissue of humans (intensive 70%), and sheep (moderate 38.47%). Caspase-3 was observed in all samples in different grades and mostly in human liver tissue. CONCLUSION: This data could aid in recognizing immunological markers for differentiating disease progression, as well as enhance the understanding of local immune responses to cystic Echinococcosis (CE). The findings could provide preliminary data for future studies on immune responses associated with Hydatid cysts.
Subject(s)
Echinococcosis, Hepatic , Sheep Diseases , Animals , Sheep/immunology , Echinococcosis, Hepatic/immunology , Echinococcosis, Hepatic/veterinary , Echinococcosis, Hepatic/parasitology , Sheep Diseases/immunology , Sheep Diseases/parasitology , Humans , Liver/parasitology , Liver/immunology , Liver/pathology , Male , Female , Echinococcosis/immunology , Echinococcosis/veterinary , Echinococcus granulosus/immunology , Apoptosis/immunology , Caspase 3/immunology , AdultABSTRACT
Background: Due to their simplicity, eco-friendliness, availability and non-toxicity, the greener fabrication of metal and metal oxide nanoparticles has been a highly attractive research area over the last decade. Aim: This study aimed to assess the antioxidant and antimicrobial activities of the green synthesized zinc oxide nanoparticles (ZnO-NPs) using an aqueous leaf extract of Ziziphus spina-christi. Method: The antioxidant property of ZnO-NPs was analyzed by the α, α-diphenyl-ß-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2). Additionally, the diffusion agar method assessed the antimicrobial activities against bacteria and fungi. Results: ZnO-NPs synthesized by Z. spina-christi had shown promising H2O2 and DPPH free radical scavenging actions compared to vitamin C. The ZnO-NPs exhibited significant antibacterial activity against the tested bacteria with various susceptibility as a concentration-dependent effect. The largest zone of inhibition for Staphylococcus aureus (S. aureus) was observed (36 ± 2 mm) compared to Escherichia coli (E. coli) (15 ± 2 mm) by the same concentration of ZnO-NPs. The ZnO-NPs showed remarkable antifungal activity against Aspergillus niger. Conclusion: It can be concluded that, ZnO-NP have been imposed as suitable antimicrobial agent being able to combat both S. aureus and E. coli in vitro.
Subject(s)
Antioxidants , Metal Nanoparticles , Plant Extracts , Plant Leaves , Zinc Oxide , Ziziphus , Anti-Infective Agents , Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Anti-Bacterial Agents , Escherichia coli/drug effects , Hydrogen Peroxide , Green Chemistry TechnologyABSTRACT
BACKGROUND: As a consequence of their eco-friendliness, simplicity and non-toxicity, the fabrication of metal and metal oxide nanoparticles using greener chemistry has been a highly attractive research area over the last decade. AIM: In this study focused on the fabrication of silver-Zinc oxide nanocomposite (Ag-ZnO NCs) using Ruta chalepensis leaf extract and evaluating its potential biological activities, against Echinococcus granulosus in an in vitro and in vivo model using BALB/c mice. METHODS: In this study, the synthesis of Ag-ZnO NCs was accomplished using local R. chalepensis leaf extracts. The synthesized nanocomposites were identified using UV-Vis, SEM-EDX, XRD, and FTIR. For a short-term assessment of acute toxicity, BALB/c mice were given the prepared NCs orally. Dual sets of mice were also intraperitoneally injected with protoscoleces for secondary echinococcosis infection. Furthermore, a blood compatibility test was carried out on the nanocomposites. RESULTS: The synthesized Ag-ZnO NCs presented a surface plasmon peak at 329 and 422 nm. The XRD, SEM, and EDX confirmed the purity of the Ag-ZnO NCs. The FTIR spectra indicated the formation of Ag-ZnO NCs. Compared to the untreated infected mice, the treated-infected animals displayed an alteration in the appearance of the hepatic hydatid cysts from hyaline to whitish cloudy with a rough surface appearance. Lysis of RBCs at various doses of Ag-ZnONCs was significantly less than the positive contro,. CONCLUSION: These findings revealed that the Ag-ZnO NCs didn't cause any adverse symptoms and no mortality was observed in all administered groups of mice. The obtained outcomes confirmed that concentrations of up to 40 µg/mL of the bio-fabricated Ag-ZnONCs induced no notable harm to the red blood cells.
Subject(s)
Echinococcosis , Metal Nanoparticles , Nanocomposites , Ruta , Zinc Oxide , Animals , Mice , Zinc Oxide/pharmacology , Echinococcosis/drug therapy , Plant Extracts , Anti-Bacterial Agents/pharmacologyABSTRACT
The World Health Organization declared the novel coronavirus, named as SARS-CoV-2, as a global pandemic in early 2020 after the disease spread to more than 180 countries leading to tens of thousands of cases and many deaths within a couple of months. Consequently, this paper aims to summarize the evidence for the relationships between nutrition and the boosting of the immune system in the fight against the disease caused by SARS-CoV-2. This review, in particular, assesses the impact of vitamin and mineral supplements on the body's defence mechanisms against SARS-CoV-2. The results revealed that there is a strong relationship between the ingestion of biological ingredients like vitamins C-E, and minerals such as zinc, and a reduction in the effects of coronavirus infection. These can be received from either nutrition rich food sources or from vitamin supplements. Furthermore, these macromolecules might have roles to play in boosting the immune response, in the healing process and the recovery time. Hence, we recommend that eating healthy foods rich in vitamins C-E with zinc and flavonoids could boost the immune system and consequently protect the body from serious infections.
ABSTRACT
Cultured Myxococcota are predominantly aerobic soil inhabitants, characterized by their highly coordinated predation and cellular differentiation capacities. Little is currently known regarding yet-uncultured Myxococcota from anaerobic, nonsoil habitats. We analyzed genomes representing one novel order (o__JAFGXQ01) and one novel family (f__JAFGIB01) in the Myxococcota from an anoxic freshwater spring (Zodletone Spring) in Oklahoma, USA. Compared to their soil counterparts, anaerobic Myxococcota possess smaller genomes and a smaller number of genes encoding biosynthetic gene clusters (BGCs), peptidases, one- and two-component signal transduction systems, and transcriptional regulators. Detailed analysis of 13 distinct pathways/processes crucial to predation and cellular differentiation revealed severely curtailed machineries, with the notable absence of homologs for key transcription factors (e.g., FruA and MrpC), outer membrane exchange receptor (TraA), and the majority of sporulation-specific and A-motility-specific genes. Further, machine learning approaches based on a set of 634 genes informative of social lifestyle predicted a nonsocial behavior for Zodletone Myxococcota. Metabolically, Zodletone Myxococcota genomes lacked aerobic respiratory capacities but carried genes suggestive of fermentation, dissimilatory nitrite reduction, and dissimilatory sulfate-reduction (in f_JAFGIB01) for energy acquisition. We propose that predation and cellular differentiation represent a niche adaptation strategy that evolved circa 500 million years ago (Mya) in response to the rise of soil as a distinct habitat on Earth. IMPORTANCE The phylum Myxococcota is a phylogenetically coherent bacterial lineage that exhibits unique social traits. Cultured Myxococcota are predominantly aerobic soil-dwelling microorganisms that are capable of predation and fruiting body formation. However, multiple yet-uncultured lineages within the Myxococcota have been encountered in a wide range of nonsoil, predominantly anaerobic habitats, and the metabolic capabilities, physiological preferences, and capacity of social behavior of such lineages remain unclear. Here, we analyzed genomes recovered from a metagenomic analysis of an anoxic freshwater spring in Oklahoma, USA, that represent novel, yet-uncultured, orders and families in the Myxococcota. The genomes appear to lack the characteristic hallmarks for social behavior encountered in Myxococcota genomes and displayed a significantly smaller genome size and a smaller number of genes encoding biosynthetic gene clusters, peptidases, signal transduction systems, and transcriptional regulators. Such perceived lack of social capacity was confirmed through detailed comparative genomic analysis of 13 pathways associated with Myxococcota social behavior, as well as the implementation of machine learning approaches to predict social behavior based on genome composition. Metabolically, these novel Myxococcota are predicted to be strict anaerobes, utilizing fermentation, nitrate reduction, and dissimilarity sulfate reduction for energy acquisition. Our results highlight the broad patterns of metabolic diversity within the yet-uncultured Myxococcota and suggest that the evolution of predation and fruiting body formation in the Myxococcota has occurred in response to soil formation as a distinct habitat on Earth.
Subject(s)
Bacteria/cytology , Genome, Bacterial , Natural Springs/microbiology , Bacteria/genetics , Nitrites , Oklahoma , Peptide Hydrolases , Signal Transduction , Soil , Sulfates , Water MicrobiologyABSTRACT
The World Health Organization (WHO) declared COVID-19 (novel coronavirus) as a global pandemic in the middle of March 2020, after the disease spread to more than 150 countries and territories leading to tens of thousands of cases within a couple of months. To date, there are no effective pharmaceutical treatments available. As well as that, the novel vaccines have not yet been approved as establishing their efficacy will take time. This study aims to summarize the evidence regarding corticosteroids such as dexamethasone for the treatment of COVID-19. Electronic searches were conducted on 7 September 2020 on Google Scholar database, MEDLINE and PubMed. A further search was conducted on the World Health Organization's COVID-19 research article database. The findings of recent investigations that proved, both, the in vitro and in vivo activity of corticosteroids against COVID-19 and other coronavirus-related pneumonia were discussed. Low doses of corticosteroids (dexamethasone) could reduce the mortality in patients with severe COVID-19 disease; however, they had no effect on the mortality rate of those patients with a mild form of the condition. Moreover, the liberal use of corticosteroids was not advocated for, as high doses of the drug can cause more harm than good.
ABSTRACT
Necrotising enterocolitis (NEC) is a rare cause of the acute abdomen in adults and carries one of the highest mortality rates in gastroenterology. However, its rarity confines research to small case reports. Both its pathogenesis and aetiology remain enigmatic in adult patients, proving timely diagnosis and management a challenge. This paper reports on one case of NEC in an adult patient with underlying anorexia nervosa, following a seven-day period of starvation. She underwent emergency laparotomy for resection of necrotic bowel and subsequently made a good recovery. To date, there have only been eight reports linking NEC with anorexia nervosa. We review our patient in the context of plausible mechanisms hypothesised in these cases. Successful management depends on prompt diagnosis, resuscitation and surgical intervention.
Subject(s)
Anorexia Nervosa/complications , Enterocolitis, Necrotizing , Abdomen/diagnostic imaging , Abdomen/surgery , Adolescent , Adult , Enterocolitis, Necrotizing/diagnosis , Enterocolitis, Necrotizing/etiology , Enterocolitis, Necrotizing/pathology , Enterocolitis, Necrotizing/surgery , Female , Humans , Young AdultABSTRACT
BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and aberrant keratinocyte differentiation. We have shown that treatment of reconstituted human skin with delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, increased the expression and processing of caspase-14, which is involved in cornification. Delphinidin also increases the expression of epidermal differentiation marker proteins. OBJECTIVES: To determine whether topical application of delphinidin can modulate pathological markers of psoriasiform lesions in flaky skin mice and if this is associated with increased epidermal differentiation and a reduction in proliferation and inflammation. METHODS: Five-week-old female homozygous flaky skin mice (fsn/fsn) were treated topically with delphinidin (0·5 mg cm(-2) and 1 mg cm(-2) skin areas, respectively), five times a week, up to 14 weeks of age. RESULTS: Treatment of flaky skin mice with delphinidin resulted in a reduction in (i) pathological markers of psoriasiform lesions; (ii) infiltration of inflammatory cells; and (iii) mRNA and protein expression of inflammatory cytokines. Delphinidin treatment also increased the expression and processing of caspase-14, and expression of filaggrin, loricrin, keratin-1 and keratin-10. Furthermore, there was a decrease in the expression of markers for cell proliferation (proliferating cell nuclear antigen and keratin-14) and modulation of tight junction proteins (occludin and claudin-1). In addition, delphinidin treatment increased the expression of activator protein-1 transcription factor proteins (JunB, JunD, Fra1 and Fra2). CONCLUSIONS: Delphinidin could be a promising agent for treatment of psoriasis and other hyperproliferative skin disorders.
Subject(s)
Anthocyanins/pharmacology , Dermatologic Agents/pharmacology , Psoriasis/prevention & control , Animals , Anthocyanins/administration & dosage , Caspase 14/metabolism , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Claudin-1/metabolism , Disease Models, Animal , Epidermis/drug effects , Female , Filaggrin Proteins , Intermediate Filament Proteins/metabolism , Leukocytes/drug effects , Membrane Proteins/metabolism , Mice, Transgenic , Occludin/metabolismABSTRACT
TiO2 thin films are of great interest as biocompatible coatings and also as photocatalytic self-cleaning and antimicrobial coatings. In this work we used ß-amyloid as a model for infectious protein to investigate the attachment and photocatalytic degradation. TiO2 films were prepared on stainless steel substrates using magnetron sputtering. The films were characterised before and after exposure to ß-amyloid (1-42), using XRD, Raman spectroscopy, XPS and AFM. The TiO2 film was mostly composed of the anatase phase with a relatively high surface roughness. The presence of Raman peaks at 1668cm(-1) and 1263cm(-1), with the XPS spectral feature for nitrogen at 400eV, confirmed the adsorption of amyloid on surface. Following exposure of the ß-amyloid contaminated TiO2 to UV-B irradiation a slight shift of amide modes was observed. Furthermore, the amide I spectra show an overall decrease in α-helix content with presence of a minor peak around 1591cm(-1), which is related to tryptophanyl and tyrosinyl radicals, which can lead to conformational change of ß-amyloid. The C1s band at 292.2eV suggests the formation of free carboxylic acid. The loss in the crucial structure of ß-amyloid leads to reduce the fibril formation, thought to be induced through a photocatalytic process.
Subject(s)
Amyloid beta-Peptides/chemistry , Coated Materials, Biocompatible/chemistry , Titanium/chemistry , Adsorption , Catalysis , Microscopy, Atomic Force , Spectrum Analysis, Raman , Surface Properties , Ultraviolet Rays , X-Ray DiffractionSubject(s)
Colonic Polyps/diagnosis , Colonoscopy , Conscious Sedation , Deep Sedation , Female , Humans , MaleABSTRACT
INTRODUCTION: Gastrointestinal (GI) perforation is a common surgical presentation. In recent years, computed tomography (CT) has been shown to be accurate for predicting the site of GI perforation, and has become the investigation of choice. However the signs may be subtle or only indirectly related to the site or aetiology of perforation. SUBJECTS AND METHODS: A MEDLINE and PubMed search was performed for journals before June 2009 with MeSH major terms 'CT' and 'perforation'. Non-English speaking literature was excluded. RESULTS: Examples of GI perforation of various aetiologies are reviewed (inflammatory, neoplastic, traumatic and iatrogenic) high-lighting characteristic CT appearances as well as pitfalls in diagnosis. Features of perforation include the presence of free gas or fluid within the supra- and/or inframesocolic compartments, segmental bowel wall thickening, bowel wall discontinuity, stranding of the mesenteric fat and abscess formation. CONCLUSIONS: These differentiating features facilitate accurate multidisciplinary pre-operative evaluation, necessary to plan patient management and potential surgical approach.
Subject(s)
Intestinal Perforation/diagnostic imaging , Colonic Diseases/diagnostic imaging , Duodenal Diseases/diagnostic imaging , Esophagogastric Junction/diagnostic imaging , Humans , Intestine, Small/diagnostic imaging , Stomach Diseases/diagnostic imaging , Tomography, X-Ray Computed/methodsABSTRACT
BACKGROUND: Abdominal tuberculosis is a common complication of pulmonary tuberculosis. With the rising incidence of HIV, tuberculosis has become a major public health problem particularly in developing countries. METHODS: This is a retrospective study involving patients whose surgical specimens were processed at the central histopathology laboratory of the Ahmadu Bello University Teaching Hospital (ABUTH) Zaria--Nigeria, between January 1975 to December 2006. RESULTS: There were 68 males and 49 females, aged 12-70 years (mean 28.6 yrs 11 yrs). While paroxysmal dry cough was present in about 20 patients, abdominal pain and distension were very common. Concomitant pulmonary tuberculosis was confirmed in 15 patients (14%). The findings at Surgery in 66 patients are presented in fig. 2. Multiple deposits on the peritoneum and omentum were the commonest findings (48.7% and 26.2%) respectively CONCLUSION: Abdominal tuberculosis is not uncommon and there is need to establish an early less invasive diagnostic protocol.
Subject(s)
Abdominal Pain/etiology , Peritonitis, Tuberculous/complications , Tuberculosis, Gastrointestinal/complications , Abdomen , Abdominal Pain/surgery , Adolescent , Adult , Aged , Antitubercular Agents/therapeutic use , Biopsy , Child , Female , Hospitals, Teaching , Humans , Incidence , Incidental Findings , Laparotomy , Male , Middle Aged , Nigeria/epidemiology , Peritonitis, Tuberculous/drug therapy , Peritonitis, Tuberculous/epidemiology , Peritonitis, Tuberculous/surgery , Retrospective Studies , Tuberculosis, Gastrointestinal/drug therapy , Tuberculosis, Gastrointestinal/epidemiology , Tuberculosis, Gastrointestinal/surgery , Young AdultABSTRACT
Every year nearly 200,000 men in the United States are diagnosed with prostate cancer (PCa), and another 29,000 men succumb to the disease. Within certain regions of the world population based studies have identified a possible role for green tea in the prevention of certain cancers, especially PCa. One constituent in particular, epigallocatechin-3-gallate also known as EGCG has been shown in cell culture models to decrease cell viability and promote apoptosis in multiple cancer cell lines including PCa with no effect on non-cancerous cell lines. In addition, animal models have consistently shown that standardized green tea polyphenols when administered in drinking water delay the development and progression of PCa. Altogether, three clinical trials have been performed in PCa patients and suggest that green tea may have a distinct role as a chemopreventive agent. This review will present the available data for standardized green tea polyphenols in regard to PCa chemoprevention that will include epidemiological, mechanism based studies, safety, pharmacokinetics, and applicable clinical trials. The data that has been collected so far suggests that green tea may be a promising agent for PCa chemoprevention and further clinical trials of participants at risk of PCa or early stage PCa are warranted.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Camellia sinensis/chemistry , Catechin/analogs & derivatives , Flavonoids/therapeutic use , Phenols/therapeutic use , Phytotherapy , Plant Extracts/therapeutic use , Prostatic Neoplasms/prevention & control , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Catechin/pharmacology , Catechin/therapeutic use , Cell Survival/drug effects , Flavonoids/pharmacology , Humans , Male , Phenols/pharmacology , Plant Extracts/pharmacology , Polyphenols , TeaABSTRACT
AIM: An association between colonic carcinoma and Streptococcus bovis endocarditis/bacteraemia was first suggested in 1951. This knowledge has great clinical implications, yet we found scant awareness amongst general surgical trainees. The aim of this article was to review the evidence available in the literature and explore the pathophysiology behind this association. METHOD: The literature was reviewed, between 1950 and 2008, using Pubmed, Embase and Ovid database searches. We utilized different combinations of the keywords: Streptococcus bovis, endocarditis, septicaemia and colon cancer/carcinoma. Quality assessment was determined using the Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Studies were selected based on their relevance to the aims to be addressed. RESULTS: We included nine case reports and found 24 studies demonstrating an association between S. bovis bacteraemia/endocarditis and colon cancer; the reported incidence in studies was variable (6-67%). The majority of studies (20) were retrospective analysis of data; only four studies were prospective. A total of 12 of 24 studies also reported an association with extra-colonic malignancy (1-22%) and 12 with liver disease (3-57%). Eight studies relevant to the pathophysiology of this association were identified. CONCLUSION: Streptococcus bovis endocarditis and/or bacteraemia is an early clue to the likely presence of colorectal cancer. Whilst further studies are required to determine the precise pathophysiology, clinicians should be aware of this association. It is advisable to investigate rigorously for colon cancer in all patients presenting with S. bovis endocarditis/bacteraemia; such patients may also present with liver disease or, occasionally, extra-colonic malignancy.
Subject(s)
Bacteremia/complications , Colorectal Neoplasms/microbiology , Endocarditis/complications , Streptococcal Infections/complications , Streptococcus bovis , Bacteremia/microbiology , Endocarditis/microbiology , Humans , Liver Diseases/microbiology , Neoplasms/microbiology , Streptococcus bovis/isolation & purificationABSTRACT
Background: Abdominal tuberculosis is a common complication of pulmonary tuberculosis. With the rising incidence of HIV; tuberculosis has become a major public health problem particularly in developing countries. Methods: This is a retrospective study involving patients whose surgical specimens were processed at the central histopathology laboratory of the Ahmadu Bello University Teaching Hospital (ABUTH) Zaria - Nigeria; between January1975 to December 2006. Results: There were 68 males and 49 females; aged 12-70 years (mean 28.6yrs 11yrs). While paroxysmal dry cough was present in about 20 patients; abdominal pain and distension were very common. Concomitant pulmonary tuberculosis was confirmed in 15 patients (14). The findings at Surgery in 66 patients are presented in fig.2. Multiple deposits on the peritoneum and momentum were the commonest findings (48.7and 26.2) respectively. Conclusion: Abdominal tuberculosis is not uncommon and there is need to establish an early less invasive diagnostic protocol
Subject(s)
Hospitals , Incidence , Teaching , TuberculosisABSTRACT
Prostate cancer is one of the most prominent malignancies of elderly men in many Western countries including Europe and the United States with increasing trend worldwide. The growth of normal prostate as well as of prostate carcinoma cells depends on functional androgen receptor (AR) signaling. AR manifests the biological actions of androgens and its transcriptional activity is known to be influenced by signal transduction pathways. Here we show that Src, a nonreceptor tyrosine kinase, is overexpressed in androgen-independent prostate carcinoma C4-2 cells. Interestingly, the expression of Src was found to progressively increase (up to threefold) in transgenic adenocarcinoma of mouse prostate mice as a function of age and cancer progression. Blocking Src kinase function by a specific inhibitor, PP2, resulted in decreased AR transactivation function on two different reporters, mouse mammary tumor virus (MMTV) and prostate-specific antigen (PSA). Consistent with this, overexpression of a functional Src mutant also led to a dramatic decrease in AR transactivation potential in a hormone-dependent manner. Interference with Src function in C4-2 cells led to decreased recruitment of AR on the target gene PSA enhancer and also resulted in the abrogation of hormone-dependent PSA transcript induction. Src inhibition also led to a dramatic decrease in the cell invasion in addition to decreasing the cellular growth. We suggest that targeting Src kinase could be an effective strategy to inhibit prostate cancer growth and metastasis.
Subject(s)
Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/pathology , Receptors, Androgen/metabolism , Androgens/metabolism , Animals , Cell Line, Tumor , Humans , Male , Mice , Mice, Transgenic , Models, Biological , Neoplasm Invasiveness , Prostatic Neoplasms/metabolism , Transcription, Genetic , TransgenesABSTRACT
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising candidate for cancer therapy, however, emergence of drug resistance limits its potential use. Here, we report for the first time that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, sensitizes TRAIL-resistant LNCaP cells to TRAIL-mediated apoptosis through modulation of intrinsic and extrinsic apoptotic pathways. When combined with EGCG, Apo2L/TRAIL exhibited enhanced apoptotic activity in LNCaP cells characterized by three major molecular events. First, apoptosis induction was accompanied by the upregulation of poly(ADP-ribose) polymerase cleavage and modulation of pro- and antiapoptotic Bcl2 family of proteins. A synergistic inhibition of inhibitors of apoptosis with concomitant increase in caspase cleavage was observed. Second, pretreatment of cells with EGCG resulted in modulation of death-inducing signaling cascade complex involving DR4/TRAIL R1, Fas-associated death domain and FLICE-inhibitory protein proteins. Last, we observed a synergistic inhibition in the invasion and migration of LNCaP cells. This effect was observed to be mediated through inhibition in the protein expression of vascular endothelial growth factor, uPA and angiopoietin 1 and 2. Further, the activity and protein expression of MMP-2, -3 and -9 and upregulation of TIMP1 in cells treated with a combination of EGCG and TRAIL was observed. These data might have implications for developing new strategies aimed at eliminating prostate cancer cells resistant to TRAIL.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Camellia sinensis/chemistry , Carcinoma/metabolism , Catechin/analogs & derivatives , Drug Resistance, Neoplasm/drug effects , Prostatic Neoplasms/metabolism , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/metabolism , Carcinoma/blood supply , Carcinoma/secondary , Catechin/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Synergism , Humans , Male , Neovascularization, Pathologic/metabolism , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/pathologySubject(s)
Foreign-Body Migration/etiology , Ileum , Surgical Sponges/adverse effects , Adult , Female , HumansABSTRACT
Cigarette smoke is a powerful inducer of inflammatory responses resulting in disruption of major cellular pathways with transcriptional and genomic alterations driving the cells towards carcinogenesis. Cell culture and animal model studies indicate that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol present in green tea, possesses potent anti-inflammatory and antiproliferative activity capable of selectively inhibiting cell growth and inducing apoptosis in cancer cells without adversely affecting normal cells. Here, we demonstrate that EGCG pretreatment (20-80 microM) of normal human bronchial epithelial cells (NHBE) resulted in significant inhibition of cigarette smoke condensate (CSC)-induced cell proliferation. Nuclear factor-kappaB (NF-kappaB) controls the transcription of genes involved in immune and inflammatory responses. In most cells, NF-kappaB prevents apoptosis by mediating cell survival signals. Pretreatment of NHBE cells with EGCG suppressed CSC-induced phosphorylation of IkappaBalpha, and activation and nuclear translocation of NF-kappaB/p65. NHBE cells transfected with a luciferase reporter plasmid containing an NF-kappaB-inducible promoter sequence showed an increased reporter activity after CSC exposure that was specifically inhibited by EGCG pretreatment. Immunoblot analysis showed that pretreatment of NHBE cells with EGCG resulted in a significant downregulation of NF-kappaB-regulated proteins cyclin D1, MMP-9, IL-8 and iNOS. EGCG pretreatment further inhibited CSC-induced phosphorylation of ERK1/2, JNK and p38 MAPKs and resulted in a decreased expression of PI3K, AKT and mTOR signaling molecules. Taken together, our data indicate that EGCG can suppress NF-kappaB activation as well as other pro-survival pathways such as PI3K/AKT/mTOR and MAPKs in NHBE cells, which may contribute to its ability to suppress inflammation, proliferation and angiogenesis induced by cigarette smoke.
Subject(s)
Anticarcinogenic Agents/pharmacology , Bronchi/drug effects , Catechin/analogs & derivatives , NF-kappa B/metabolism , Smoke , Tea , Antioxidants , Apoptosis/drug effects , Bronchi/cytology , Bronchi/metabolism , Catechin/pharmacology , Cyclin D1/metabolism , Cyclooxygenase 2/metabolism , DNA/genetics , DNA/metabolism , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Matrix Metalloproteinase 9/metabolism , Membrane Proteins/metabolism , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/genetics , Phosphorylation/drug effects , Signal Transduction , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVE: The majority of young adults referred with rectal bleeding to a colorectal specialist clinic have a very low risk of serious disease such as cancer, and a high chance of gaining symptom relief by simple dietary changes. To determine whether young low-risk patients with rectal bleeding can be managed with a structured telephonic interview and dietary advice, rather than an outpatient visit. METHOD: A single-blinded, prospective, randomized controlled trial was performed in two stages. Patients under 40 years with rectal bleeding only were offered inclusion. Part-I trial: Patients were interviewed on telephone by the colorectal nurse specialist (CNS) and randomized to receive dietary advice (Advice Group) or not (Control Group). All patients were seen in clinic 6 weeks later by a doctor 'blinded' to their trial status. Part-II trial: Patients were interviewed on telephone by the CNS and again randomized to an Advice Group or a Control Group. The Control Group were seen in clinic 6 weeks later. The Advice Group were telephoned again 6 weeks later, and if their bleeding had stopped, were not brought to clinic. All patients were tracked for a year after the study to ensure no adverse diagnoses came to light. RESULTS: Part-I trial: 63 of 89 eligible patients were contactable and none refused the study. Seventy per cent of the Advice Group compared with 33% (P = 0.001) of the Control Group had symptomatic improvement when seen in clinic. Approximately 30% of each group required further treatment. Part-II trial: 54 of 94 eligible patients were contactable. However a further nine declined to enter the trial; 90% of patients in the Advice Group had improved at 6 weeks as judged by telephone interview compared with 56% of patients in the Control Group (P = 0.024) who were seen in clinic. The 90% of patients who improved in the Advice Group did not need to come to clinic to be seen. In both parts of the trial, the CNS identified a small number of patients with urgent symptoms at interview and brought them to clinic. The majority had anal fissures or haemorrhoids although in Part-II, one patient had ulcerative colitis and one had colorectal cancer. CONCLUSION: Telephonic consultation is an effective way of identifying those patients with urgent symptoms among a cohort of young adults referred to the hospital with rectal bleeding. Telephonic dietary advice leads to resolution of rectal bleeding in the majority of patients without urgent symptoms.