Effects of copper nanoparticles on performance, muscle and bone characteristics and serum metabolites in broilers.

Three hundred and twenty day old Hubbard broilers were randomly allocated to four treatments (8 replicates, 10 birds/pen) and were raised under standard management conditions. Birds in the first group served as control and were fed a corn based diet, while birds in the remaining three groups i.e.; A, B and C were fed with a basal diet supplemented with copper nanoparticles (CuNP) at 5, 10 and 15 mg /kg of diet respectively for 35 days. Supplementation of CuNP linearly increased (P≤0.05) body weight (BW), average daily weight gain (ADWG) and feed intake (FI) in broilers. Uric acid, glucose levels in blood and feed conversion ratio (FCR) reduced linearly (P≤0.05) with CuNP supplementation in diet. Supplementation of CuNP in the diet also linearly increased (P≤0.05) tibia weight, length, diameter, weight/length index (W/L) and Tibiotarsal index (TT index). Inclusion of CuNP in broilers diet linearly increased the measured parameters of muscle i.e.; pH, fiber diameter, fiber cross-sectional area, fascicle diameter, fascicle cross-sectional area (P≤0.05). Concentration of copper, iron, calcium and phosphorous in blood also increased line-arly (P ≤ 0.05) with CuNP supplementation. Overall, CuNP positively affected the growth performance, histological characteristics of muscles, bone strength and serum metabolites in broilers.

Cytoprotective Antioxidant, Anti-Inflammatory, and Antifibrotic Impact of Celery Seed Oil and Manuka Honey Against Cyclophosphamide-Induced Cystitis in Rabbits.

Patients treated with cyclophosphamide (CP) usually suffer from severe hemorrhagic cystitis (HC). Our previous study exhibited that mesna + celery cotherapy partially ameliorated HC. Therefore, there is a substantial need to seek alternative regimens to get complete protection against CP-induced HC. The current study investigated the effects of mesna + celery seed oil (MCSO) or mesna + manuka honey (MMH) cotherapy against CP-induced HC in adult male rabbits. The forty rabbits were divided into four equal groups and treated for three weeks. The control group (G1) received distilled water and the second group (G2) received CP (50 mg/kg/week). The third group (G3) received CP + MCSO (CPMCSO regimen), and the fourth group (G4) received CP + MMH (CPMMH regimen). The urinary bladder (UB) specimens were processed to evaluate UB changes through histopathological, immunohistochemical, ultrastructural, and biochemical investigations. In G2, CP provoked HC features (urothelial necrosis, ulceration, and sloughing), UB fibrosis, and TNF-α immunoexpression. Besides, CP reduced the activity of antioxidant enzymes (GPx1, SOD3, and CAT) and elevated the serum levels of NF-κB, TNF-α, IL-1B, and IL-6 cytokines in G2 rabbits. In contrast, the CPMMH regimen caused significant increments of UB protection against HC in G4 rabbits compared to the partial protection by the CPMCSO regimen in G3. Therefore, our study indicated for the first time that the novel CPMMH regimen resulted in complete UB protection against CP-induced HC via combined antioxidant, anti-inflammatory, and antifibrotic properties.

Natural compounds as antiatherogenic agents.

Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.

Thyme oil alleviates Ova-induced bronchial asthma through modulating Th2 cytokines, IgE, TSLP and ROS.

Bronchial asthma (BA) is a heterogeneous allergic respiratory disease with diverse inflammatory symptoms, pathology, and responses to treatment. Thyme is a natural product which is consisted of multiple phenolic compounds of therapeutic significance for treatment of cough and bronchitis. This study evaluated the efficacy of thyme oil against ovalbumin (OVA)-induced BA in an experimental rabbit model. Forty male rabbits were divided into four equal groups [control group (G1), OVA (G2), thyme oil (G3), and OVA plus thyme oil (G4)]. Animals were treated for 30 days, and clinical, histopathological (HP), histochemical (HC), immunohistochemical (IHC), morphometric, biochemical and flow cytometry methods were performed, followed by statistical analysis. All used methods revealed normal structure of the lung tissues in rabbits of G1 and G3. In contrast, the clinical examination of G2 rabbits revealed an obvious increase in the respiratory rate, sneezing and wheezing, whereas the HP, HC and IHC techniques exhibited substantial inflammatory changes in the peribronchio-vascular lung tissues with thinning, degeneration, apoptosis (using the TUNEL assay), necrosis, and shedding of the airway epithelium. Furthermore, the morphometric results confirmed significant increases in the numbers of inflammatory cells, goblet cells, eosinophils and apoptotic cells from (12, 0, 2, 2 cells) to (34,10, 16, 18 cells) respectively, as well as the area percentage of collagen fiber deposition and immunoexpression of eotaxin-1/10 high power fields. Additionally, the biochemical results revealed significant increases in the serum levels of TSLP, IL-4, IL-5, IL-9, IL-13, IgE and eotaxin-1 cytokines from (140, 40, 15, 38, 120, 100, 48) pg./ml to (360, 270, 130, 85, 365, 398, 110) pg./ml respectively, while analysis of ROS by flow cytometry revealed remarkable oxidative stress effects in G2 rabbits. On the other hand, treatment of rabbits with thyme oil in G4 substantially alleviated all OVA-induced alterations. Overall, our findings indicate for the first time that thyme oil can ameliorate OVA-induced BA via its immunomodulatory, anti-inflammatory, antiapoptotic, and antioxidant effects on the lung tissues of rabbits.

Therapeutic Potential of Polyphenols and their Nanoformulations in the Treatment of Colorectal Cancer.

BACKGROUND: Colorectal Cancer (CRC) ranks third among all cancer-related deaths around the globe. Chemotherapy may prolong the survival of CRC patients to some extent, but its clinical use is associated with grave side effects on overall health. Contrary to chemotherapy, the use of plant-derived therapeutic molecules offered advantages because of their reduced toxicity. Polyphenol is a group of phytochemicals that impart many therapeutic benefits in the treatment of diabetes, cardiovascular disease and cancer. Various signaling pathways, including Wnt/ß-catenin, MAPK/PI3K and TGF-ß/Smad, play very important roles in the development and progression of CRC. Polyphenols inhibit CRC progressions by modulating these signaling pathways e.g. curcumin and resveratrol impede cancer cell proliferation by inhibiting Wnt signaling. Because of their lower aqueous solubility, the therapeutic efficacy of polyphenols is not fully exploited. In order to increase their bioavailability and efficacy, the nanoformulations of polyphenols have been formulated and investigated against various CRC test models. The main objective of this review is to explore the potential roles of polyphenols and their nanoformulations in the treatment of colorectal cancer. METHODS: We used PubMed, Web of Science, ScienceDirect, Google Scholar and Scopus electronic databases by searching the keywords: nanoparticles, polyphenols, colorectal cancer, cell signaling pathways. Mostly, the articles were retrieved directly from the journals licensed to the library of Qassim University, Saudi Arabia. RESULTS: Literature analysis has shown that the polyphenols contain several important bioactive compounds, which showed potential effectiveness against CRC. Incorporating polyphenols into nanoparticles further enhanced their bioavailability and efficacy. The findings from various studies demonstrated that polyphenol-nanoformulations accelerated the apoptosis in CRC cells by upregulating the levels of caspases and Bax, whereas inhibiting the CRC cell proliferation by downregulating the expression of Bcl-2 and ERK1/2. CONCLUSION: This review provides a valuable resource on the important anti-CRC role of polyphenols and their nanoformulations. This review will expand our knowledge about the anti-CRC roles of polyphenols and their mechanisms of action through the multiple cell signaling pathways.

Tinospora cordifolia Aqueous Extract Alleviates Cyclophosphamide- Induced Immune Suppression, Toxicity and Systemic Candidiasis in Immunosuppressed Mice: In vivo Study in Comparison to Antifungal Drug Fluconazole.

OBJECTIVE: The present study was aimed to evaluate the effect of the aqueous extract of Tinospora cordifolia (AETC) against cyclophosphamide-induced immunosuppression and systemic Candida albicans infection in a murine model. METHODS: The protective effect of AETC against cyclophosphamide-induced leukopenia was evaluated by quantitative and qualitative analysis of the leukocytes. The immune-stimulating potential of AETC on macrophages was assessed by determining the levels of secreted cytokines. To determine the direct antifungal activity, AETC or fluconazole was administered to C. albicans infected mice. The efficacy of treatment was assessed by determining the survival rate, kidney fungal burden, the organ index and liver inflammation parameters. RESULTS: Cyclophosphamide administration resulted in substantial depletion of leukocytes, whereas AETC treatment induced the recovery of leukocytes in cyclophosphamide-injected mice. Moreover, AETC treatment of macrophages resulted in enhanced secretion of IFN-γ, TNF-α and IL-1ß. C. albicans infected mice treated with AETC at the doses of 50 and 100 mg/kg exhibited 40% and 60% survival rate, whereas the mice treated with fluconazole at a dose of 50 mg/kg showed 20% survival rate. Like survival data, the fungal load was found to be the lowest in the kidney tissues of mice treated with AETC at a dose of 100 mg/kg. Interestingly, mice infected with C. albicans demonstrated improvement in the organ indices and liver functioning after AETC treatment. CONCLUSION: These results suggest that AETC may potentially be used to rejuvenate the weakened immune system and eliminate systemic candidiasis in mice.

Thymoquinone Shows the Diverse Therapeutic Actions by Modulating Multiple Cell Signaling Pathways: Single Drug for Multiple Targets.

Thymoquinone (TQ), derived from the seeds of Nigella sativa, has lately been shown as a miracle drug because of its wide range of therapeutic effects against various diseases, including cancer, asthma, diabetes, colitis and infectious diseases. In the present review, we aimed to decipher the molecular mechanisms of therapeutic action of TQ by modulating the cell signaling pathways. Many in vivo and in vitro studies have demonstrated the therapeutic efficacy of TQ against a wide range of ailments. TQ possesses potent anti-inflammatory and immunomodulatory effects by specifically targeting the NF-kB, IL-1ß and TNF-α signaling pathways. The anticancer activity of TQ has been primarily shown by altering the expression of signal transducers and activator transcription (STAT3), PTEN and p53 genes. TQ alleviates the hyperglycemia-associated complications, the hepatic or renal ailments through its potent antioxidant and anti-inflammatory properties. Interestingly, the liposome- or nanoparticle-based TQ formulations have shown greater effectiveness against various diseases in animal models. Thus, the understanding of the molecular mechanisms of TQ action may lead to the development of its therapeutic formulations to cure a wide variety of diseases.

Role of Curcumin in Disease Prevention and Treatment.

Treatment based on traditional medicine is very popular in developing world due to inexpensive properties. Nowadays, several types of preparations based on medicinal plants at different dose have been extensively recognized in the diseases prevention and treatment. In this vista, latest findings support the effect of Curcuma longa and its chief constituents curcumin in a broad range of diseases cure via modulation of physiological and biochemical process. In addition, various studies based on animal mode and clinical trials showed that curcumin does not cause any adverse complications on liver and kidney function and it is safe at high dose. This review article aims at gathering information predominantly on pharmacological activities such as anti-diabetic, anti-microbial, hepato-protective activity, anti-inflammatory, and neurodegenerative diseases.

Immune-Stimulatory and Therapeutic Activity of Tinospora cordifolia: Double-Edged Sword against Salmonellosis.

The present study was aimed at determining the activity of aqueous and methanolic extracts of Tinospora cordifolia (AETC and METC) against Salmonella typhimurium. In vitro anti-Salmonella activity of T. cordifolia was determined through the broth dilution and agar well diffusion assays. The immune-stimulating potential of AETC or METC was determined by measuring the cytokine levels in the culture supernatants of treated murine J774 macrophages. Antibacterial activity of AETC or METC was determined by treating S. typhimurium-infected macrophages and BALB/C mice. The toxicity of AETC or METC was determined by measuring the levels of liver inflammation markers aspartate transaminase (AST) and alanine transaminase (ALT) and antioxidant enzymes. Macrophages treated with AETC or METC secreted greater levels of IFN-γ, TNF-α, and IL-1ß. METC showed greater activity against S. typhimurium infection in macrophages and mice as well. Treatment with METC resulted in increased survival and reduced bacterial load in S. typhimurium-infected mice. Moreover, METC or AETC treatment reduced the liver inflammation and rescued the levels of antioxidant enzymes in S. typhimurium-infected mice. The results of the present study suggest that the use of T. cordifolia may act as a double-edged sword in combating salmonellosis.

Thymoquinone, an active constituent of Nigella sativa seeds, binds with bilirubin and protects mice from hyperbilirubinemia and cyclophosphamide-induced hepatotoxicity.

Some reports indicate that thymoquinone (TQ), the main constituent of Nigella sativa seeds, is hepatoprotective. The aim of this study was to determine whether TQ is able to bind directly to bilirubin, and whether TQ or liposomal formulation of TQ (Lip-TQ) can reduce cyclophosphamide (CYP)-induced liver toxicity, serum bilirubin level in mice. The binding of TQ with bilirubin was studied by UV-VIS, fluorescence and Near-UV CD spectroscopy. Inhibition of binding of bilirubin to erythrocytes by TQ was also examined. To increase the in vivo efficacy, Lip-TQ was prepared and used against CYP-induced toxicity. The protective role of TQ or Lip-TQ against CYP-induced toxicity was assessed by determining the liver function parameters, the levels of superoxide dismutase (SOD) and catalase (CAT), and histological studies. It was found that TQ binds to bilirubin and significantly inhibits the binding of bilirubin to erythrocytes. Lip-TQ (10 mg/kg) significantly reduced the levels of aspartate transaminase (AST) from 254 ± 48 to 66 ± 18 IU/L (P < 0.001), alanine transaminase (ALT) from 142 ± 28 to 47.8 ± 16 IU/L (P < 0.05) and serum bilirubin from 2.8 ± 0.50 to 1.24 ± 0.30 mg/dl (P < 0.05). Treatment with Lip-TQ reduced the CYP-induced inflammation and hemorrhage in liver tissues. Moreover, treatment with free or Lip-TQ protected the activity of SOD and CAT in CYP-injected mice. Therefore, TQ can reduce the level of bilirubin in systemic circulation in disease conditions that lead to hyperbilirubinemia and liver toxicity and hence may be used as a supplement in the treatment of liver ailments.

RETRACTED: Nicorandil vs nifedipine for the treatment of preterm labour: a randomized clinical trial.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The editors were alerted to the following concerning features of this trial: The submission date is impossible. Patients were recruited at 24 to 34 weeks (mean 31 w). 18% of participants delivered after 37 weeks. Average recruitment 26 per month. Recruitment ended September 2014 but the paper was received by journal on 23 October 2014. The second author, Sayyed T, is co-author of related retracted papers in BJOG. In view of these concerns we wrote to Dr Rezk who had no satisfactory explanation and declined to share the data. We have therefore decided to retract.

Implications of Green Tea and Its Constituents in the Prevention of Cancer via the Modulation of Cell Signalling Pathway.

Green tea is commonly used as a beverage worldwide, especially in China, Japan, Morocco, and Saudi Arabia. Green tea and its constituents have been considered very effective in the prevention and treatment of various diseases. It contains a variety of catechins, which show a pivotal role in the modulation of biological activities and also act as chemopreventive agents. Earlier studies have confirmed that green tea and its chief constituent epigallocatechin gallate (EGCG) have a potential role in the management of cancer through the modulation of cell signaling pathways. In this review, we focused on the beneficial effects of green tea and its constituents in the cancer prevention and treatment and its impact on modulation of molecular pathways.

Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways.

Cancer is the most dreadful disease worldwide in terms of morbidity and mortality. The exact cause of cancer development and progression is not fully known. But it is thought that cancer occurs due to the structural and functional changes in the genes. The current approach to cancer treatment based on allopathic is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a safe and effective mode of treatment is needed to control the cancer development and progression. Some medicinal plants provide a safe, effective and affordable remedy to control the progression of malignant cells. The importance of medicinal plants and their constituents has been documented in Ayurveda, Unani medicine, and various religious books. Curcumin, a vital constituent of the spice turmeric, is an alternative approach in the prevention of cancer. Earlier studies have shown the effect of curcumin as an antioxidant, antibacterial, antitumor and it also has a noteworthy role in the control of different diseases. In this review, we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer via the regulation of various cell signaling and genetic pathways.

Therapeutic Implications of Black Seed and Its Constituent Thymoquinone in the Prevention of Cancer through Inactivation and Activation of Molecular Pathways.

The cancer is probably the most dreaded disease in both men and women and also major health problem worldwide. Despite its high prevalence, the exact molecular mechanisms of the development and progression are not fully understood. The current chemotherapy/radiotherapy regime used to treat cancer shows adverse side effect and may alter gene functions. Natural products are generally safe, effective, and less expensive substitutes of anticancer chemotherapeutics. Based on previous studies of their potential therapeutic uses, Nigella sativa and its constituents may be proved as good therapeutic options in the prevention of cancer. Black seeds are used as staple food in the Middle Eastern Countries for thousands of years and also in the treatment of diseases. Earlier studies have shown that N. sativa and its constituent thymoquinone (TQ) have important roles in the prevention and treatment of cancer by modulating cell signaling pathways. In this review, we summarize the role of N. sativa and its constituents TQ in the prevention of cancer through the activation or inactivation of molecular cell signaling pathways.

Hookah smoking, nass chewing, and oesophageal squamous cell carcinoma in Kashmir, India.

BACKGROUND: Although cigarette smoking is an established risk factor for oesophageal squamous cell carcinoma (ESCC), there is little information about the association between other smoking and smokeless tobacco products, including hookah and nass, and ESCC risk. We conducted a case-control study in Kashmir Valley, India, where hookah smoking, nass chewing, and ESCC are common, to investigate the association of hookah smoking, nass use, and several other habits with ESCC. METHODS: We recruited 702 histologically confirmed ESCC cases and 1663 hospital-based controls, individually matched to the cases for age, sex, and district of residence from September 2008 to January 2012. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Ever-hookah smoking (OR=1.85; 95% CI, 1.41-2.44) and nass chewing (OR=2.88; 95% CI, 2.06-4.04) were associated with ESCC risk. These associations were consistent across different measures of use, including intensity, duration, and cumulative amount of use, and after excluding ever users of the other product and cigarette smokers. Our results also suggest an increased risk of ESCC associated with ever-gutka chewing and -bidi smoking. However, the latter associations were based on small number of participants. CONCLUSION: This study shows that hookah and nass use are associated with ESCC risk. As prevalence of hookah use seems to be increasing among young people worldwide, these results may have relevance not only for the regions in which hookah use has been a traditional habit, but also for other regions, including western countries.

Long dose exposure of hydrogen peroxide (H2O2) in albino rats and effect of Podophyllum hexandrum on oxidative stress.

OBJECTIVES: The effect of Podophyllum hexandrum methanolic extract and alpha-tocopherol in reducing oxidative stress in male albino rats was evaluated. MATERIALS AND METHODS: Lipid peroxidation was monitored by measuring malondialdehyde (MDA) level in different tissues of rats. Activities of free radical scavenging enzymes (superoxide dismutase, glutathione peroxidase and catalase) were determined using H2O2 decomposition. RESULTS: Results showed that administration of H2O2 (0.1%) in drinking water of the rats, for 25 weeks, increased the malondialdehyde levels in liver, kidney and lung tissues of all the rats. However, rats receiving Podophyllum hexandrum extract and alpha-tocopherol had lower MDA levels in a dose dependent manner, which indicates decreased lipid peroxidation in these rats. Increase in the catalase activity appears to be a response to H2O2 accumulation. The decrease in the activity of catalase and increase in the activity of superoxide dismutase and glutathione peroxidase in different organs of the rats receiving Podophyllum hexandrum extract and alpha-tocopherol indicates the protective effect of the plant in combating oxidative stress undergone by the rats. OBJECTIVES: Rhizome of Podophyllum hexandrum have been ethnomedically claimed to possess a wide array of biological activities including anticancer activity. MATERIALS AND METHODS: To verify the folklore claim, this study was performed in a six Human carcinoma cell lines, Lung (A-549), Prostate (PC-3), Colon (Colo-25), Breast (MCF-7), Neuroblastoma (IMR-32) and CNS (SF-295) MCF-7 and MDA-MB-231. RESULTS: Methanol and 70% ethanolic extracts of the rhizome of Podophyllum hexandrum showed highest cytotoxic effect on MCF-7 (Breast) and Colo-25 (Colon) cell line, as determined with sulforhodamine-B (SRB) assay. CONCLUSIONS: These findings 1 - showed that Podophyllum hexandrum extract may ameliorate H2O2 induced oxidative stress by decreasing lipid peroxidation via alteration of the antioxidant defense system of the rats. 2 - these data also showed the anticancer activity of the plant extracts on different human cancer cell lines. However, further investigation is needed to assess the molecular mechanisms mediated anticancer activities of this plant.

Incidence and factors predicting the detection of prostate cancer after transurethral resection of the prostate for clinically benign disease.

INTRODUCTION: Transurethral resection of the prostate (TURP) is commonly performed as the surgical management of lower urinary tract symptoms due to clinically benign disease. However, prostate cancer is not uncommonly diagnosed after such a procedure. We, therefore, determined in a retrospective study the incidence and factors that might predict the detection of prostate cancer after TURP. PATIENTS AND METHODS: Between June 2005 and June 2007, a total of 476 men underwent TURP at our department. Of these, 411 men (86%) were thought to have benign disease and were included in the study. Univariate and multivariate logistic regression analyses using age, serum prostate-specific antigen (PSA), urinary retention status, prostate resection weight, FBC and U&E were performed to determine whether prostate cancer could be predicted. RESULTS: A total of 47 men (11.4%) were diagnosed with prostate cancer [24/47 with pT1a (51%) and 23/47 with pT1b (49%)]. Furthermore, the Gleason scores ranged from 5 to 9. Univariate logistic regression analyses revealed that only age (mean: 76 years, range: 54-90 vs. mean: 71 years, range: 49-91 for prostate cancer and non-cancer cases, respectively) and serum PSA (mean: 14.9 ng/ml, range: 0.4-78.0 vs. mean: 7.4 ng/ml, range: 0.2-90.0 for prostate cancer cases and non-cancer cases, respectively) were able to distinguish between cancer and non-cancer cases. In addition, using multivariate logistic regression, age and serum PSA were also the only variables that separated the two groups with a ROC-AUC of 70%. CONCLUSIONS: Our retrospective study has demonstrated that a substantial percentage of men are unexpectedly found to have prostate cancer after TURP. In addition, age and serum PSA were independent predictors of those who are likely to have prostate cancer.

Specific killing of multiple myeloma cells by (-)-epigallocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications.

Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea, is an antioxidant with chemopreventive and chemotherapeutic actions. Based on its ability to modulate growth factor-mediated cell proliferation, we evaluated its efficacy in multiple myeloma (MM). EGCG induced both dose- and time-dependent growth arrest and subsequent apoptotic cell death in MM cell lines including IL-6-dependent cells and primary patient cells, without significant effect on the growth of peripheral blood mononuclear cells (PBMCs) and normal fibroblasts. Treatment with EGCG also led to significant apoptosis in human myeloma cells grown as tumors in SCID mice. EGCG interacts with the 67-kDa laminin receptor 1 (LR1), which is significantly elevated in myeloma cell lines and patient samples relative to normal PBMCs. RNAi-mediated inhibition of LR1 resulted in abrogation of EGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCG activity in MM while sparing PBMCs. Evaluation of changes in gene expression profile indicates that EGCG treatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing the expression of death-associated protein kinase 2, the initiators and mediators of death receptor-dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positive regulators of apoptosis and NF-kappaB activation (CARD10, CARD14), and cyclin-dependent kinase inhibitors (p16 and p18). Expression of related genes at the protein level were also confirmed by Western blot analysis. These data demonstrate potent and specific antimyeloma activity of EGCG and provide the rationale for its clinical evaluation.

Immunomodulator tuftsin increases the susceptibility of Cryptococcus neoformans to liposomal amphotericin B in immunocompetent BALB/c mice.

The co-administration of immunomodulators and antibiotics has been proved very successful for treatment of opportunistic infectious diseases. In the present study, we evaluated the combination of liposomal amphotericin B (lip-Amp B) and immunomodulator tuftsin to cure Cryptococcus neoformans infection in BALB/c mice. Mice infected with C. neoformans were treated with Amp B deoxycholate and tuftsin free or tuftsin-loaded Amp B liposomes. The results of the present study demonstrated higher efficacy of tuftsin-loaded Amp B liposomes against experimental murine cryptococcosis, in terms of enhanced survival rate and reduced fungal burden in organs (lungs and brain) of the treated mice. Interestingly, pre-treatment of mice with liposomal tuftsin before challenging them with the C. neoformans infection resulted in 100% survival of the treated animals followed by treatment with lip-Amp B. Immunomodulator-based therapy seems likely to be more beneficial for treatment of fungal infectious diseases.

Incorporation of amphotericin B in tuftsin-bearing liposomes showed enhanced efficacy against systemic cryptococcosis in leucopenic mice.

OBJECTIVES: The role of the immunomodulator tuftsin in enhancing the antifungal activity of liposomal amphotericin B against Cryptococcus neoformans in leucopenic mice was assessed. METHODS: In the present study, we investigated the antifungal activity of amphotericin B liposomes with tuftsin grafted on the surface. Mice were treated with free amphotericin B as well as liposomal formulations after C. neoformans infection. For prophylactic studies, mice were pre-treated with liposomal tuftsin (50 microg/mL) for three consecutive days prior to C. neoformans infection (7 x 10(5) cfu/mouse). Chemotherapy, with tuftsin-free and tuftsin-bearing amphotericin B liposomes, was started 24 h post C. neoformans infection. The role of tuftsin in immunoaugmentative therapy was assessed by survival and cfu of treated mice. RESULTS: Amphotericin B entrapped in tuftsin-bearing liposomes showed increased anticryptococcal activity in the murine model. Moreover, tuftsin pre-treatment further augmented the antifungal activity of liposomal amphotericin B in leucopenic mice. Incorporation of tuftsin in liposomes resulted in increased anticryptococcal activity of liposomal amphotericin B compared with amphotericin B deoxycholate and conventional liposomal amphotericin B formulations. CONCLUSIONS: The enhanced anticryptococcal activity of amphotericin B in tuftsin-liposomes can be attributed to the immune-stimulating property of tuftsin. Tuftsin activates the key immune cells, due to the presence of its receptors on macrophages and neutrophils, for a better fight against pathogens. Simultaneous liposome-mediated delivery of amphotericin B to the site of infection kills the pathogens more effectively.