Effect of lactoferrin protein on red blood cells and macrophages: mechanism of parasite-host interaction

BACKGROUND: Lactoferrin is a natural multifunctional protein known to have antitumor, antimicrobial, and anti-inflammatory activity. Apart from its antimicrobial effects, lactoferrin is known to boost the immune response by enhancing antioxidants. Lactoferrin exists in various forms depending on its iron saturation. The present study was done to observe the effect of lactoferrin, isolated from bovine and buffalo colostrum, on red blood cells (RBCs) and macrophages (human monocytic cell line-derived macrophages THP1 cells). METHODS: Lactoferrin obtained from both species and in different iron saturation forms were used in the present study, and treatment of host cells were given with different forms of lactoferrin at different concentrations. These treated host cells were used for various studies, including morphometric analysis, viability by MTT assay, survivin gene expression, production of reactive oxygen species, phagocytic properties, invasion assay, and Toll-like receptor-4, Toll-like receptor-9, and MDR1 expression, to investigate the interaction between lactoferrin and host cells and the possible mechanism of action with regard to parasitic infections. RESULTS: The mechanism of interaction between host cells and lactoferrin have shown various aspects of gene expression and cellular activity depending on the degree of iron saturation of lactoferrin. A significant increase (P<0.05) in production of reactive oxygen species, phagocytic activity, and Toll-like receptor expression was observed in host cells incubated with iron-saturated lactoferrin when compared with an untreated control group. However, there was no significant (P>0.05) change in percentage viability in the different groups of host cells treated, and no downregulation of survivin gene expression was found at 48 hours post-incubation. Upregulation of the Toll-like receptor and downregulation of the P-gp gene confirmed the immunomodulatory potential of lactoferrin protein. CONCLUSION: The present study details the interaction between lactoferrin and parasite host cells, ie, RBCs and macrophages, using various cellular processes and expression studies. The study reveals the possible mechanism of action against various intracellular pathogens such as Toxoplasma, Plasmodium, Leishmania, Trypanosoma, and Mycobacterium. The presence of iron in lactoferrin plays an important role in enhancing the various activities taking place inside these cells. This work provides a lot of information about targeting lactoferrin against many parasitic infections which can rule out the exact pathways for inhibition of diseases caused by intracellular microbes mainly targeting RBCs and macrophages for their survival. Therefore, this initial study can serve as a baseline for further evaluation of the mechanism of action of lactoferrin against parasitic diseases, which is not fully understood to date.

Screening of the 'pathogen box' identifies an approved pesticide with major anthelmintic activity against the barber's pole worm

There is a substantial need to develop new medicines against parasitic diseases via public-private partnerships. Based on high throughput phenotypic screens of largely protozoal pathogens and bacteria, the Medicines for Malaria Venture (MMV) has recently assembled an open-access 'Pathogen Box' containing 400 well-curated chemical compounds. In the present study, we tested these compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility, growth and development of H. contortus. We also studied the effect of the 'hit' compound on mitochondrial function by measuring oxygen consumption. Among the 400 Pathogen Box compounds, we identified one chemical, called tolfenpyrad (compound identification code: MMV688934) that reproducibly inhibits xL3 motility as well as L4 motility, growth and development, with IC50 values ranging between 0.02 and 3 μM. An assessment of mitochondrial function showed that xL3s treated with tolfenpyrad consumed significantly less oxygen than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Given that tolfenpyrad was developed as a pesticide and has already been tested for absorption, distribution, excretion, biotransformation, toxicity and metabolism, it shows considerable promise for hit-to-lead optimisation and/or repurposing for use against H. contortus and other parasitic nematodes. Future work should assess its activity against hookworms and other pathogens that cause neglected tropical diseases.

What do infectious diseases physicians do? a 2-week snapshot of inpatient consultative activities across Australia, New Zealand and Singapore

The practice of an infectious diseases (ID) physician is evolving. A contemporary understanding of the frequency and variety of patients and syndromes seen by ID services has implications for training, service development and setting research priorities. We performed a 2-week prospective survey of formal ID physician activities related to direct inpatient care, encompassing 53 hospitals throughout Australia, New Zealand and Singapore, and documented 1722 inpatient interactions. Infections involving the skin and soft tissue, respiratory tract and bone/joints together accounted for 49% of all consultations. Suspected/confirmed pathogens were primarily bacterial (60%), rather than viral (6%), fungal (4%), mycobacterial (2%) or parasitic (1%). Staphylococcus aureus was implicated in 409 (24%) episodes, approximately four times more frequently than the next most common pathogen. The frequency of healthcare-related infections (35%), immunosuppression (21%), diabetes mellitus (19%), prosthesis-related infections (13%), multiresistant pathogens (13%) and non-infectious diagnoses (9%) was high, although consultation characteristics varied between geographical settings and hospital types. Our study highlights the diversity of inpatient-related ID activities and should direct future teaching and research. ID physicians' ability to offer beneficial consultative advice requires broad understanding of, and ability to interact with, a wide range of referring specialities.

The molecular basis of copper-transport diseases

Copper (Cu) is a potentially toxic yet essential element. Menkes disease, a copper deficiency disorder, and Wilson disease, a copper toxicosis condition, are two human genetic disorders, caused by mutations of two closely related Cu-transporting ATPases. Both molecules efflux copper from cells. Quite diverse clinical phenotypes are produced by different mutations of these two Cu-transporting proteins. The understanding of copper homeostasis has become increasingly important in clinical medicine as the metal could be involved in the pathogenesis of some important neurological disorders such as Alzheimer's disease, motor neurone diseases and prion diseases.

Copper in disorders with neurological symptoms: Alzheimer`s, Menkes, and Wilson Diseases

Copper is an essential element for the activity of a number of physiologically important enzymes. Enzyme-related malfunctions may contribute to severe neurological symptoms and neurological diseases: copper is a component of cytochrome c oxidase, which catalyzes the reduction of oxygen to water, the essential step in cellular respiration. Copper is a cofactor of Cu/Zn-superoxide-dismutase which plays a key role in the cellular response to oxidative stress by scavenging reactive oxygen species. Furthermore, copper is a constituent of dopamine-β-hydroxylase, a critical enzyme in the catecholamine biosynthetic pathway. A detailed exploration of the biological importance and functional properties of proteins associated with neurological symptoms will have an important impact on understanding disease mechanisms and may accelerate development and testing of new therapeutic approaches. Copper binding proteins play important roles in the establishment and maintenance of metal-ion homeostasis, in deficiency disorders with neurological symptoms (Menkes disease, Wilson disease) and in neurodegenerative diseases (Alzheimer’s disease). The Menkes and Wilson proteins have been characterized as copper transporters and the amyloid precursor protein (APP) of Alzheimer’s disease has been proposed to work as a Cu(II) and/or Zn(II) transporter. Experimental, clinical and epidemiological observations in neurodegenerative disorders like Alzheimer’s disease and in the genetically inherited copper-dependent disorders Menkes and Wilson disease are summarized. This could provide a rationale for a link between severely dysregulated metal-ion homeostasis and the selective neuronal pathology.

Diet, nutrition and the prevention of chronic diseases : report of a Joint WHO/FAO Expert Consultation

This report examines the science base of the relationship between diet and physical activity patterns and the major nutrition-related chronic diseases. Recommendations are made to help prevent death and disability from major nutrition-related chronic diseases.

Purchase commitments : Big business bias or solution to the 'neglected diseases' dilemma?

Miniscule research resources are allocated to researching the diseases of developing countries such as malaria, tuberculosis (TB), dengue fever, river blindness, Chagas disease and leishmaniasis, and the strains of HIV prevalent in Africa. Plainly, the patent system and the commercial model of drug research fail to respond to the needs of the poor for the simple reason that the poor exercise little purchasing power. But pressures are mounting on governments and corporations to tackle the ‘neglected diseases’ calamity. An important argument in an intense global debate is that corporations would respond to the needs of developing countries if the diseases of the poor could be made profitable. This is the idea developed by Kremer and Glennerster in a crisply written book, Strong Medicine: Creating Incentives for Pharmaceutical Research on Neglected Diseases.

A critical look at the role of self-management for people with arthritis and other chronic diseases

Most patients with chronic conditions, such as osteoarthritis, only have contact with healthcare professionals for a few hours over the course of a year. Good self-management programs are, therefore, critical for patients to cope with their conditions on a daily basis. Drs Osborne, Jordan and Rogers discuss the importance of engaging patients, clinicians and policymakers in the development and implementation of self-management programs.

Effectiveness of prevention programmes for obesity and chronic diseases amongst immigrants to developed countries - a systematic review

Objective: To determine whether interventions tailored specifically to  particular immigrant groups from developing to developed countries  decrease the risk of obesity and obesity-related diseases.

Design: Databases searched were MEDLINE (1966–September 2008), CINAHL (1982–September 2008) and PsychINFO (1960–September 2008), as well as Sociological Abstracts, PsychARTICLES, Science Direct, Web of Knowledge and Google Scholar. Studies were included if they were randomised control trials, ‘quasi-randomised’ trials or controlled before-and-after studies. Due to the heterogeneity of study characteristics only a narrative synthesis was undertaken, describing the target population, type and reported impact of the intervention and the effect size.

Results: Thirteen studies met the inclusion criteria. Ten out of thirteen (77 %) studies focused on diabetes, seven (70 %) of which showed significant improvement in addressing diabetes-related behaviours and glycaemic control. The effect on diabetes was greater in culturally tailored and facilitated interventions that encompassed multiple strategies. Six out of the thirteen studies (46 %) incorporated anthropometric data, physical activity and healthy eating as ways to minimise weight gain and diabetes-related outcomes. Of the six interventions that included anthropometric data, only two (33 %) reported improvement in BMI Z-scores, total skinfold thickness or proportion of body fat. Only one in three (33 %) of the studies that included cardiovascular risk factors reported improvement in diastolic blood pressure after adjusting for baseline characteristics. All studies, except four, were of poor quality (small sample size, poor internal consistency of scale, not controlling for baseline characteristics).

Conclusions: Due to the small number of studies included in the present review, the findings that culturally tailored and facilitated interventions produce better outcomes than generalised interventions, and that intervention content is more important than the duration or venue, require further investigation.

Quantification of urbanization in relation to chronic diseases in developing countries : a systematic review

During and beyond the twentieth century, urbanization has represented a major demographic shift particularly in the developed world. The rapid urbanization experienced in the developing world brings increased mortality from lifestyle diseases such as cancer and cardiovascular disease. We set out to understand how urbanization has been measured in studies which examined chronic disease as an outcome. Following a pilot search of PUBMED, a full search strategy was developed to identify papers reporting the effect of urbanization in relation to chronic disease in the developing world. Full searches were conducted in MEDLINE, EMBASE, CINAHL, and GLOBAL HEALTH. Of the 868 titles identified in the initial search, nine studies met the final inclusion criteria. Five of these studies used demographic measures (such as population density) at an area level to measure urbanization. Four studies used more complicated summary measures of individual and area level data (such as distance from a city, occupation, home and land ownership) to define urbanization. The papers reviewed were limited by using simple area level summary measures (e.g., urban rural dichotomy) or having to rely on preexisting data at the individual level. Further work is needed to develop a measure of urbanization that treats urbanization as a process and which is sensitive enough to track changes in “urbanicity” and subsequent emergence of chronic disease risk factors and mortality.