RESUMO
Lactoferrin (Lf) is an iron-binding glycoprotein with potentially beneficial biological functions. However, the interaction between Lf and type 2 diabetes mellitus (T2DM) remains unclear. We hypothesized that Lf would improve hepatic insulin resistance and pancreatic dysfunction in diabetic mice. Male C57BL/6J mice were fed a high-fat diet for 15 weeks and injected with streptozotocin (STZ) for 5 consecutive days to establish a T2DM model. One week after STZ injection, mice with ≥11.1 mmol/L fasting blood glucose concentration were considered T2DM mice. These mice received 0.5% or 2% Lf solution for another 12 weeks. Biochemical parameters were measured, and histopathological examination of the pancreas and liver was performed. Hepatic protein expression related to the insulin signalling pathway was also assessed. Diabetic mice showed insulin resistance and abnormal glucolipid metabolism. Lf decreased serum concentrations of glycated serum protein, fasting insulin, cholesterol, and triglyceride and increased liver insulin sensitivity. Hematoxylin-eosin staining showed that Lf reversed the abnormal pancreatic islets of diabetic mice. Lf improved pancreatic dysfunction by reducing oxidative stress and inflammation responses. Furthermore, Lf upregulated the protein expression of insulin receptor, insulin receptor substrate-1, glucose transporter 4, phosphor phosphatidylinositol 3-kinase/phosphatidylinositol 3-kinase (PI3K), and phosphor protein kinase B/protein kinase B (AKT) in the liver. This study indicated that Lf supplementation improved hepatic insulin resistance and pancreatic dysfunction, possibly by regulating the PI3K/AKT signaling pathway in T2DM mice.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Insulina , Lactoferrina/efeitos adversos , Lactoferrina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estreptozocina/efeitos adversos , Estreptozocina/metabolismoRESUMO
BACKGROUND: Inflammation is the body's response to injury or infection and is important for healing and eliminating pathogens; however, prolonged inflammation is damaging and may lead to the development of chronic inflammatory disorders. Recently, there has been interest in exploiting antimicrobial peptides (AMPs) that exhibit immunoregulatory activities to treat inflammatory diseases. METHODS: In this study, we investigated the immunomodulatory effects of lactoferrin-derived lactoferricin AMPs from three different species (bovine, mouse, and human) with subtle differences in their amino acid sequences that alter their antimicrobial action; to our knowledge, no other studies have compared their immunomodulatory effects. Macrophages, key players in the induction and propagation of inflammation, were used to investigate the effects of species-specific lactoferricin peptides on inflammatory processes. RESULTS: Bovine lactoferricin was the only one of the three peptides studied that downregulated lipopolysaccharide (LPS)-induced pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6, in both human and mouse macrophages. Lactoferricin regulated inflammation through targeting LPS-activated nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Although the immunoregulatory role of lactoferricin during an inflammatory response in vivo is yet to be elucidated, further investigation with the use of animal models is warranted by the current findings. CONCLUSIONS: The ability of lactoferricin, especially that of bovine origin, to downregulate macrophage-mediated inflammatory responses suggests potential for the development of this peptide as a novel immunotherapeutic agent in the treatment of chronic inflammatory conditions.
Assuntos
Lactoferrina , Macrófagos , Animais , Bovinos , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Lactoferrina/efeitos adversos , Lactoferrina/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Peptídeos/farmacologiaRESUMO
Mucormycosis is a deadly infection which is caused by fungi of the order Mucorales including species belonging to the genus Rhizopus, Mucor, Mycocladus, Rhizomucor, Cunninghamella, and Apophysomyces. Despite antifungal therapy and surgical procedures, the mortality rate of this disease is about 90-100% which is exceptionally high. The hypersensitivity of patients with raised available serum iron indicates that the Mucorales are able to use host iron as a critical factor of virulence. This is because iron happens to be a crucial element playing its role in the growth of cells and development. In this review, we have described Lactoferrin (Lf) as a potential iron-chelator. Lf is a naturally occurring glycoprotein which is expressed in most of the biological fluids. Moreover, Lf possesses exclusive anti-inflammatory effects along with several anti-fungal effects that could prove to be helpful to the pathological physiology of inexorable mucormycosis cases. This literature summarises the biological insights into the Lf being considered as a potential fungistatic agent and an immune regulator. The review also proposes that unique potential of Lf as an iron-chelator can be exploited as the adjunct treatment for mucormycosis infection.
Assuntos
Antifúngicos/uso terapêutico , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Lactoferrina/uso terapêutico , Mucorales/efeitos dos fármacos , Mucormicose/tratamento farmacológico , Animais , Antifúngicos/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Quelantes de Ferro/efeitos adversos , Lactoferrina/efeitos adversos , Mucorales/metabolismo , Mucorales/patogenicidade , Mucormicose/diagnóstico , Mucormicose/metabolismo , Mucormicose/microbiologia , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
INTRODUCTION: Necrotizing enterocolitis (NEC) is a devastating intestinal illness in premature infants characterized by severe intestinal inflammation. Despite medical interventions, NEC mortality remains alarmingly high, which necessitates improved therapies. Lactoferrin is among the most abundant proteins in human milk and has important immunomodulatory functions. While previous studies have indicated protective effects of lactoferrin against neonatal sepsis and NEC, the underlying mechanism remains unclear. We hypothesize that lactoferrin downregulates inflammation and upregulates proliferation in intestinal epithelium during NEC injury. MATERIALS AND METHODS: NEC was induced by hypoxia, gavage feeding of hyperosmolar formula and lipopolysaccharide between postnatal day P5 and P9 (n = 8). Breastfed mice were used as control (n = 7). Lactoferrin (0.3 g/kg/day) was administered once daily by gavage from P6 to P8 in both NEC (NEC + Lac; n = 9) and control mice (Cont + Lac; n = 5). Distal ileum was harvested on P9 and analyzed for disease severity, inflammation, and proliferation. Groups were compared using one-way ANOVA and t-test appropriately; p < 0.05 was considered significant. RESULTS: Compared to NEC group, lactoferrin-treated NEC mice had reduced disease severity, reduced inflammation markers IL-6 and TNF-α expression and increased intestinal stem cell marker Lgr5 + expression. Lactoferrin-treated NEC mice exhibited increased nuclear ß-catenin, indicating upregulated Wnt pathway, and increased Ki67 positivity, suggesting enhanced proliferation. Furthermore, lactoferrin administration to control mice did not affect intestinal inflammation as well as Lgr5 + stem cell expression and epithelial proliferation. This supports the safety of lactoferrin administration and indicates that the beneficial effects of lactoferrin are present when intestinal injury such as NEC is present. CONCLUSION: Lactoferrin administration reduces the intestinal injury in experimental NEC by downregulating inflammation and upregulating cell proliferation. This beneficial effect of lactoferrin in stimulating cell proliferation is mediated by the Wnt pathway. This experimental study provides insights on the mechanism of action of lactoferrin in NEC and the role of lactoferrin in enteral feeding.
Assuntos
Proliferação de Células/efeitos dos fármacos , Enterocolite Necrosante/patologia , Células Epiteliais/fisiologia , Mucosa Intestinal/patologia , Lactoferrina/administração & dosagem , Regulação para Cima , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Progressão da Doença , Enterocolite Necrosante/fisiopatologia , Inflamação/fisiopatologia , Lactoferrina/efeitos adversos , Lactoferrina/fisiologia , Camundongos Endogâmicos C57BLRESUMO
Cancer patients receiving chemotherapy often experience taste and smell abnormalities (TSA). To date, the underlying molecular mechanisms of this frequent side-effect have not been determined and effective treatments are not available. This study assessed the feasibility of lactoferrin (LF) supplementation as a treatment for TSA and investigate the related mechanisms through salivary proteome analysis. Nineteen cancer patients with established TSA following chemotherapy administration were enrolled in this study. Cancer patients and additional 12 healthy subjects took LF supplements, 3 tablets per day (250 mg per tablet), for 30 days. Saliva was collected at three timepoints: baseline, 30-day LF supplementation, and 30-day post-LF supplementation. Patient's TSA level, salivary proteome, and salivary minerals at each LF treatment stage were analyzed. High TSA level was associated with high concentration of salivary Fe and loss of critical salivary immune proteins. LF supplementation significantly decreased the concentration of salivary Fe (P = 0.025), increased the abundance (P < 0.05) of salivary α-amylase and Zn-α-2-GP, and led to an overall increase of expression (≥2-fold changes) of immune proteins including immunoglobulin heavy chain, annexin A1, and proteinase inhibitor. Abundance of α-amylase and SPLUNC2 were further increased (P < 0.05) at 30-day post-LF supplementation in cancer patients. At the same time, total TSA score was significantly reduced (P < 0.001) in chemotherapy patients. This study demonstrated the feasibility of developing lactoferrin supplementation as a treatment to reduce TSA caused by chemotherapy and improve cancer patient's oral immunity.
Assuntos
Antineoplásicos/efeitos adversos , Suplementos Nutricionais , Lactoferrina/uso terapêutico , Transtornos do Olfato/terapia , Saliva/metabolismo , Proteínas e Peptídeos Salivares/metabolismo , Distúrbios do Paladar/terapia , Idoso , Antioxidantes/efeitos adversos , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Suplementos Nutricionais/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Cadeias Pesadas de Imunoglobulinas/metabolismo , Ferro/metabolismo , Lactoferrina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Minerais/metabolismo , Transtornos do Olfato/induzido quimicamente , Transtornos do Olfato/metabolismo , Transtornos do Olfato/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Proteômica/métodos , Saliva/enzimologia , Saliva/imunologia , Eliminação Salivar/efeitos dos fármacos , Autorrelato , Índice de Gravidade de Doença , Distúrbios do Paladar/induzido quimicamente , Distúrbios do Paladar/metabolismo , Distúrbios do Paladar/fisiopatologiaRESUMO
Shikonin (SHK) is a highly liposoluble naphthoquinone pigment has recently been investigated as a potential antiglioma agent. However, shikonin shows several limitations like poor aqueous solubility, short half-life and non-selective biodistribution. Herein, we have developed a nanoparticles (NPs) prepared from PEG-PLGA using an emulsion solvent evaporation method. Nanoparticle surfaces were modified by coating with lactoferrin (Lf) to improve the crossing of the blood brain barrier and targeting of glioma cells via receptor-mediated path-ways. X-ray powder diffraction and differential scanning calorimetry analysis revealed the amorphous nature of SHK encapsulated within the NPs. Moreover, the drug-loaded NPs exhibit narrow size distribution and high encapsulation efficiency. The in vitro release experiments of the NPs exhibited sustained release for more than 72h. When compared to free SHK and SHK/NPs, in vivo study demonstrated higher brain concentration of SHK, indicating a significant effect of Lf coated NPs on brain targeting. Accordingly, these findings provide evidence for the potential of Lf-modified NPs as a targeted delivery system for brain glioblastomas treatment.
Assuntos
Glioma/tratamento farmacológico , Lactoferrina/química , Nanopartículas/química , Naftoquinonas/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Lactoferrina/administração & dosagem , Lactoferrina/efeitos adversos , Nanopartículas/administração & dosagem , Nanopartículas/efeitos adversos , Naftoquinonas/administração & dosagem , Naftoquinonas/efeitos adversos , Naftoquinonas/uso terapêutico , Poliésteres/administração & dosagem , Poliésteres/efeitos adversos , Poliésteres/química , Poliésteres/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/química , Polietilenoglicóis/uso terapêutico , Ratos , Distribuição TecidualRESUMO
We report that a combination of anti-HIV-1 drug efavirenz (EFV), anti-microbial-spermicidal curcumin (Cur) and lactoferrin nanoparticles (ECNPs) act as MPT formulation. These nanoparticles are of well dispersed spherical shape with 40-70 nm size, with encapsulation efficiency of 63 ± 1.9% of Cur &61.5% ± 1.6 of EFV, significantly higher than that of single drug nanoparticles (Cur, 59 ± 1.34%; EFV: 58.4 ± 1.79). ECNPs were found to be sensitive at pH 5 and 6 and have not effected viability of vaginal micro-flora, Lactobacillus. Studies in rats showed that ECNPs delivers 88-124% more drugs in vaginal lavage as compared to its soluble form, either as single or combination of EFV and Cur. The ECNPs also shows 1.39-4.73 fold lower concentration of absorption in vaginal tissue and plasma compared to soluble EFV + Cur. Furthermore, ECNPs show significant reduction in inflammatory responses by 1.6-3.0 fold in terms of IL-6 and TNF-α in vaginal tissue and plasma compared to soluble EFV + Cur. ECNPs showed improved pharmacokinetics profiles in vaginal lavage with more than 50% of enhancement in AUC, AUMC, Cmax and t1/2 suggesting longer exposure of Cur and EFV in vaginal lavage compared to soluble EFV + Cur. Histopathological analysis of vaginal tissue shows remarkably lower toxicity of ECNPs compared to soluble EFV + Cur. In conclusion, ECNPs are significantly safe and exhibit higher bioavailability thus constitute an effective MPT against HIV.
Assuntos
Anti-Infecciosos/administração & dosagem , Benzoxazinas/administração & dosagem , Quimioprevenção/métodos , Curcumina/administração & dosagem , Lactoferrina/administração & dosagem , Nanopartículas/administração & dosagem , Profilaxia Pré-Exposição/métodos , Administração Intravaginal , Alcinos , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacocinética , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacocinética , Curcumina/efeitos adversos , Curcumina/farmacocinética , Ciclopropanos , Feminino , Lactobacillus/efeitos dos fármacos , Lactoferrina/efeitos adversos , Lactoferrina/farmacocinética , Viabilidade Microbiana/efeitos dos fármacos , Nanopartículas/efeitos adversos , Ratos , Vaginite/induzido quimicamente , Vaginite/patologiaRESUMO
Bovine lactoferrin (bLf) up-modulates intestinal IgA that is essential for homeostasis and which might confer protection to the distal small intestine that is vulnerable to inflammation. This study analyzed the effects of bLf administered orally on the IgA response at inductive (Peyer's patches) and effector (lamina propria) sites of the distal small intestine in mice. Groups of five healthy male BALB/c mice were orally treated with 5 mg of bLf for 7, 14, 21, or 28 days. Then, mice were killed and the distal small intestine was dissected. Intestinal fluid samples were analyzed to determine IgA and IgM levels by enzyme-immuno assay. Peyer's patches and lamina propria were analyzed for IgA(+) or IgM(+) plasma cells, B, CD4(+) T and CD8(+) T cells as well as CD4(+) T cells positive for either pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon-γ and interleukin (IL)-12] or for IgA-producing ILs (IL-4, -5, -10 and -6) by cytofluorometry. Antibodies, antibody-secreting cells, and B and T responses in both Peyer's patches and lamina propria were higher in bLf-treated than bLf-untreated mice. The generation of IL-10 and IL-6 CD4(+) T cells in Peyer's patches or TNF-α and IL-12 CD4(+) T cells in lamina propria showed similar response patterns. On days 14 and 28, cytokine/IL CD4(+) T cell responses were increased in Peyer's patches or decreased in lamina propria. The effect of bLf on the elicitation of IgA indicates a potential application of bLf as a nutraceutical to control inflammation in the distal small intestine.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunomodulação , Inflamação/imunologia , Intestino Delgado/efeitos dos fármacos , Lactoferrina/administração & dosagem , Administração Oral , Animais , Bovinos , Citocinas/metabolismo , Suplementos Nutricionais , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina A/metabolismo , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Intestino Delgado/imunologia , Lactoferrina/efeitos adversos , Masculino , Camundongos Endogâmicos BALB CRESUMO
LfcinB9 is a peptide derived from lactoferricin B. In the present study, the effect and relative mechanism of LfcinB9 on human ovarian cancer cell line (SK-OV-3) in vitro and in vivo was investigated. The data obtained indicated that LfcinB9 exhibited low hemolysis activity and significantly inhibited the proliferation of SK-OV-3 cells in vitro. In addition, the apoptosis of SK-OV-3 cells was induced through up-regulating the production of reactive oxygen species and activating caspase-3, caspase-9 on both transcription and translation level. Finally, LfcinB9 significantly prevented the tumor growth in the SK-OV-3-bearing mice model. These results indicated that LfcinB9 could be a potential agent for the treatment of ovarian cancer.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Lactoferrina/farmacologia , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Ovário/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/efeitos adversos , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Biomarcadores/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Injeções Intralesionais , Lactoferrina/administração & dosagem , Lactoferrina/efeitos adversos , Lactoferrina/química , Lactoferrina/uso terapêutico , Camundongos Nus , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/uso terapêutico , Distribuição Aleatória , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
UNLABELLED: Objective Evaluate the safety and efficacy of bovine lactoferrin (bLf) versus the ferrous sulphate standard intervention in curing iron deficiency (ID) and ID anaemia (IDA) in pregnant women affected by hereditary thrombophilia (HT). Design Interventional study. Setting Secondary-level hospital for complicated pregnancies in Rome, Italy. Population 295 HT pregnant women (≥18 years) suffering from ID/IDA. Methods Women were enrolled in Arm A or B in accordance with their personal choice. In Arm A, 156 women received oral administration of 100 mg of bLf twice a day; in Arm B, 139 women received 520 mg of ferrous sulphate once a day. Therapies lasted until delivery. Main outcome measures Red blood cells, haemoglobin, total serum iron, serum ferritin (haematological parameters) were assayed before and every 30 days during therapy until delivery. Serum IL-6, key factor in inflammatory and iron homeostasis disorders, was detected at enrolment and after therapy at delivery. Possible maternal, foetal, and neonatal adverse effects were assessed. Results Haematological parameters were significantly higher in Arm A than in Arm B pregnant women (P ≤ 0.0001). Serum IL-6 significantly decreased in bLf-treated women and increased in ferrous sulphate-treated women. BLf did not exert any adverse effect. Adverse effects in 16.5 % of ferrous sulphate-treated women were recorded. Arm A women experienced no miscarriage compared to five miscarriages in Arm B women. Conclusions Differently from ferrous sulphate, bLf is safe and effective in curing ID/IDA associated with a consistent decrease of serum IL-6. The absence of miscarriage among bLf-treated women provided an unexpected benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01221844.
Assuntos
Anemia Ferropriva/complicações , Anemia Ferropriva/tratamento farmacológico , Compostos Ferrosos/uso terapêutico , Deficiências de Ferro , Lactoferrina/uso terapêutico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Trombofilia/complicações , Trombofilia/tratamento farmacológico , Aborto Espontâneo/sangue , Aborto Espontâneo/prevenção & controle , Adolescente , Adulto , Anemia Ferropriva/sangue , Animais , Bovinos , Feminino , Compostos Ferrosos/efeitos adversos , Humanos , Recém-Nascido , Interleucina-6/sangue , Ferro/sangue , Lactoferrina/efeitos adversos , Gravidez , Complicações Hematológicas na Gravidez/sangue , Trombofilia/sangue , Adulto JovemRESUMO
Lactoferrin (LF) is a multifunctional immune protein found at high concentrations in human milk. Herein, the effect of dietary bovine LF (bLF) on mucosal and systemic immune development was investigated. Colostrum-deprived piglets were fed formula containing 130 [control (Ctrl)], 367 (LF1), or 1300 (LF3) mg of bLF/(kg body weight · d). To provide passive immunity, sow serum was provided orally during the first 36 h of life. Blood, spleen, mesenteric lymph node (MLN), and ascending colon (Asc) contents were collected on day 7 (n = 10-14/group) and day 14 (n = 10-12/group). Immune cell populations were quantified by flow cytometry and immunoglobulins (Igs) were measured by ELISA. Additionally, immune cells were isolated from spleen and MLNs (n = 7/group) on day 7 and stimulated ex vivo with phytohemagglutinin or lipopolysaccharide (LPS) ± LF for 72 h. Secreted cytokine concentrations were quantified by multiplex assay. Lymphocyte populations [cluster determinant (CD)4, CD8, and natural killer cells] developed normally and were unaffected by dietary bLF. LF3 piglets tended to have 1.4 to 2 times more serum IgG than Ctrl piglets (P = 0.07) or LF1 piglets (P = 0.03), but IgA in Asc contents was unaffected by bLF. Asc IgA was 4 times higher on day 14 than day 7. Spleen cells from LF3 piglets produced 2 times more interleukin (IL)-10 and tumor necrosis factor (TNF)-α ex vivo than those from Ctrl or LF1 piglets. MLN cells from LF1 and LF3 piglets produced 40% more IL-10 and tended to produce 40% more IL-6 (P = 0.05) than those from Ctrl piglets. However, ex vivo bLF did not affect the cytokine response of spleen or MLN cells to LPS. In summary, dietary bLF alters the capacity of MLN and spleen immune cells to respond to stimulation, supporting a role for LF in the initiation of protective immune responses in these immunologically challenged neonates.
Assuntos
Imunidade Inata , Imunidade nas Mucosas , Imunomodulação , Fórmulas Infantis , Lactoferrina/metabolismo , Leucócitos Mononucleares/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Animais Recém-Nascidos , Bovinos , Células Cultivadas , Colo Ascendente/citologia , Colo Ascendente/crescimento & desenvolvimento , Colo Ascendente/imunologia , Colo Ascendente/metabolismo , Citocinas/metabolismo , Feminino , Humanos , Imunoglobulinas/análise , Lactente , Lactoferrina/administração & dosagem , Lactoferrina/efeitos adversos , Lactoferrina/sangue , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Linfonodos/citologia , Linfonodos/crescimento & desenvolvimento , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Baço/citologia , Baço/crescimento & desenvolvimento , Baço/imunologia , Baço/metabolismo , Sus scrofa , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). RESULTS: Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835-1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms. CONCLUSIONS: There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Lactoferrina/administração & dosagem , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Lactoferrina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Placebos , Resultado do TratamentoRESUMO
BACKGROUND: Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials. METHODS: Ten patients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4+, CD8+, and regulatory T cells) and systemic cytokine levels were measured to assess immune response. RESULTS: Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with ≥9 weeks TTP had evidence of immunologic activity (three with increased NKC activity). CONCLUSIONS: The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistema Imunitário/efeitos dos fármacos , Lactoferrina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-6/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Lactoferrina/efeitos adversos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Projetos Piloto , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The anticancer activities of Lactoferrin (Lf) and Lf nanoliposomes in Caco-2 cells were observed in this study, and mitochondrial function (MTT assay), count kit-8(CCK-8), detection of intracellular reactive oxygen species (ROS) and apoptosis induction (AO/EB staining) assays were used to evaluate the anticancer activity. MTT results demonstrated that Lf nanoliposomes and Lf reduced the mitochondrial activity of cells in a manner of dose and time effect, and the viabilities of Caco-2 cell were significantly decreased in vitro following exposure to Lf nanoliposomes at the concentrations of 5 and 10 mg/mL. LDH leakage and ROS significantly increased in cells exposed to Lf nanoliposomes (≥5 mg/mL), while Lf induced ROS only at higher doses (10mg/mL). CCK-8 evaluation of cell proliferation and AO/EB double staining supported the anti-proliferative effects of Lf liposomes. Our findings demonstrated that the presence of Lf nanoliposome is more significant than Lf in inhibiting human tumor cells proliferation. Therefore, it can be concluded that Lf nanoliposomes are a potential therapeutic modality in the management of tumors.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Lactoferrina/farmacologia , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Estabilidade de Medicamentos , Estabilidade Enzimática , Humanos , Cinética , Lactoferrina/efeitos adversos , Lactoferrina/química , Lactoferrina/ultraestrutura , Peroxidação de Lipídeos/efeitos dos fármacos , Lipossomos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Nanosferas , Proteínas de Neoplasias/metabolismo , Tamanho da Partícula , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Receptores da Colecistocinina/metabolismoRESUMO
A hepatocellular carcinoma targeting lactoferrin (Lf) modified PEGylated liposome system was developed for improving drug efficacies to hepatic cancer cells. In this present work, PEGylated liposomes (PLS) were successfully prepared by the thin film hydration method combined with peglipid post insertion. Lf was covalently conjugated to the distal end of DSPE-PEG2000-COOH lipid by amide bound and loaded onto PEGylated liposomes surface as the targeting ligand. To confirm the targeting efficacies to hepatic cancer, coumarin-6 and DiR were encapsulated as fluorescent probes. The confocal microscopy and flow cytometry demonstrated that Lf conjugated PEGylated liposomes (Lf-PLS) were efficiently associated by HepG2 cells, while limited interaction was found for liposomes modified with a negative control protein. A similar pharmacokinetic behavior was observed in pharmacokinetics study of the liposomal formulations. Meanwhile, the in vivo imaging of liposomes in HepG2 tumor bearing mice indicated that Lf-PLS achieved more accumulation in tumor compared with PLS without Lf conjugated. The significant in vitro and in vivo results suggested that Lf-PLS might be a promising drug delivery system for hepatocellular carcinoma therapy with low toxicity.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Lactoferrina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Cumarínicos/administração & dosagem , Cumarínicos/química , Células Hep G2 , Humanos , Lactoferrina/efeitos adversos , Lactoferrina/química , Lactoferrina/farmacocinética , Lipossomos/administração & dosagem , Lipossomos/efeitos adversos , Lipossomos/química , Lipossomos/farmacocinética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Distribuição Aleatória , Tiazóis/administração & dosagem , Tiazóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. METHODS: Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. RESULTS: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29-47%; p = 0.05) and 15% (27-42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. CONCLUSION: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Lactoferrina/administração & dosagem , Lactoferrina/efeitos adversos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Prospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
IMPORTANCE OF THE FIELD: Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years. AREAS COVERED IN THIS REVIEW: Talactoferrin alpha is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue. WHAT THE READER WILL GAIN: Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alpha and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed. TAKE HOME MESSAGE: The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactoferrina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Medicina Baseada em Evidências , Humanos , Lactoferrina/efeitos adversos , Neoplasias Pulmonares/imunologia , Resultado do TratamentoRESUMO
PURPOSE: We evaluated safety and activity of talactoferrin, a novel immunomodulatory protein in a phase IB trial of patients with refractory solid tumors. METHODS: Thirty-six patients with metastatic cancer who had progressed on, or were ineligible for, standard chemotherapy received single-agent oral talactoferrin. Following dose-escalation, with no DLTs , patients were randomized to 4.5 or 9 g/day talactoferrin. RESULTS: Talactoferrin was well tolerated with apparent anti-cancer activity, particularly in NSCLC and RCC. One patient had a PR (RECIST) and 17 patients (47%) had stable disease (50% disease control rate). Median PFS in the twelve NSCLC and seven RCC patients was 4.2 and 7.3 months, respectively. There was no apparent difference in anti-tumor activity or adverse events between talactoferrin doses. CONCLUSIONS: Oral talactoferrin was well tolerated. Although evaluated in a small number of patients, talactoferrin appeared to have anti-cancer activity, particularly in NSCLC and RCC and should be evaluated further.
Assuntos
Antineoplásicos/uso terapêutico , Lactoferrina/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Demografia , Feminino , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Lactoferrina/administração & dosagem , Lactoferrina/efeitos adversos , Lactoferrina/farmacologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To compare the effects of bovine lactoferrin with ferrous sulfate on iron nutritional status and to evaluate their tolerability in 100 pregnant women with iron deficiency anemia. DESIGN: Prospective, randomized, controlled, double blind trial. SETTING: Obstetrics clinic of a University Department of Obstetrics and Gynecology. POPULATION: One-hundred pregnant, healthy women to be treated either with one capsule of 100 mg bovine lactoferrin twice a day (Group A; n=49) and 520 mg ferrous sulfate once a day (Group B; n=48). METHODS: After 30 days, we evaluated hemoglobin (Hb), serum ferritin, serum iron and total iron- binding capacity (TIBC) values. All women were asked to keep a diary of five potential gastrointestinal side effects (abdominal pain, nausea, vomiting, diarrhea and constipation). For each symptom, patients had to rate its severity according to a scale ranging from 0 (absent) to 3 (severe). MAIN OUTCOME MEASURES: Hb level before and after treatment. Secondary outcomes were serum ferritin, serum iron and TIBC levels and the difference in symptom scores between groups. RESULTS: In Groups A and B, Hb, serum ferritin and iron were significantly increased while TIBC was significantly reduced in comparison with basal values. No significant differences were observed between Groups A and B. The median scores of abdominal pain and constipation were significantly higher in patients treated with ferrous sulfate in comparison with those treated with bovine lactoferrin. CONCLUSIONS: The results show that bovine lactoferrin has the same efficacy as ferrous sulfate in restoring iron deposits with significantly fewer gastrointestinal side effects.
Assuntos
Anemia Ferropriva/tratamento farmacológico , Suplementos Nutricionais , Compostos Ferrosos/uso terapêutico , Hematínicos/uso terapêutico , Lactoferrina/uso terapêutico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Administração Oral , Adulto , Método Duplo-Cego , Feminino , Compostos Ferrosos/efeitos adversos , Hematínicos/efeitos adversos , Humanos , Lactoferrina/efeitos adversos , Gravidez , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Talactoferrin (TLF), a recombinant form of human lactoferrin (hLF), is an immunomodulatory iron-binding glycoprotein first identified in breast milk. Its immunomodulatory functions include activation of natural killer (NK) and lymphokine-activated killer cells and enhancement of polymorphonuclear cells and macrophage cytotoxicity. Studies in animal models have shown promising anticancer activity, and clinical antitumor activity has been observed in nonsmall cell lung cancer and other tumor types. The purpose of the current study was to evaluate the activity and safety of TLF in patients with refractory metastatic renal cell carcinoma (RCC). METHODS: Forty-four adult patients with progressive advanced or metastatic RCC who had failed prior systemic therapy received oral talactoferrin at a dose of 1.5 g twice daily on a 12-week-on 2-week-off schedule. Patients were evaluated for progression-free survival at 14 weeks, overall response rate, and progression-free and overall survival. RESULTS: TLF was well tolerated. No significant hematologic, hepatic, or renal toxicities were reported. The study met its predefined target with a 14-week progression-free survival rate of 59%. The response rate was 4.5%. The mMedian progression-free survival was 6.4 months and the median overall survival was 21.1 months. CONCLUSIONS: TLF is a well-tolerated new agent that has demonstrated preliminary signs of clinical activity. Given the lack of toxicity, the lack of rapid disease progression in this cohort, and the preclinical data on immune activation, a randomized study assessing its effects on disease progression in patients with metastatic RCC is rational.