SUNScholar - Browsing by Author "Nell, Theo A."

Browsing by Author "Nell, Theo A."

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Chemoresistance : intricate interplay between breast tumor cells and adipocytes in the tumor microenvironment
(Frontiers Media, 2018-12-11) Mentoor, Ilze; Engelbrecht, Anna-Mart; Van Jaarsveld, Paul J.; Nell, Theo A.; Vella, Veronica
Excess adipose tissue is a hallmark of an overweight and/or obese state as well as a primary risk factor for breast cancer development and progression. In an overweight/obese state adipose tissue becomes dysfunctional due to rapid hypertrophy, hyperplasia, and immune cell infiltration which is associated with sustained low-grade inflammation originating from dysfunctional adipokine synthesis. Evidence also supports the role of excess adipose tissue (overweight/obesity) as a casual factor for the development of chemotherapeutic drug resistance. Obesity-mediated effects/modifications may contribute to chemotherapeutic drug resistance by altering drug pharmacokinetics, inducing chronic inflammation, as well as altering tumor-associated adipocyte adipokine secretion. Adipocytes in the breast tumor microenvironment enhance breast tumor cell survival and decrease the efficacy of chemotherapeutic agents, resulting in chemotherapeutic resistance. A well-know chemotherapeutic agent, doxorubicin, has shown to negatively impact adipose tissue homeostasis, affecting adipose tissue/adipocyte functionality and storage. Here, it is implied that doxorubicin disrupts adipose tissue homeostasis affecting the functionality of adipose tissue/adipocytes. Although evidence on the effects of doxorubicin on adipose tissue/adipocytes under obesogenic conditions are lacking, this narrative review explores the potential role of obesity in breast cancer progression and treatment resistance with inflammation as an underlying mechanism.
Decreased efficacy of doxorubicin corresponds with modifications in lipid metabolism markers and fatty acid profiles in breast tumors from obese vs. lean mice
(Frontiers Media, 2018-03-17) Mentoor, Ilze; Nell, Theo A.; Emjedi, Zaakiyah; Van Jaarsveld, Paul J.; De Jager, Louis; Engelbrecht, Anna-Mart; Sotgia, Federica
Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.
Distinct gender differences in anthropometric profiles of a peri-urban South African HIV population : a cross sectional study
(BioMed Central, 2015-02) Nell, Theo A.; Kruger, Maritza J.; Beukes, Dillan C.; Calitz, Esme; Essop, Rehana; Essop, M. Faadiel; Physiological Sciences
Background: Highly active antiretroviral therapy (HAART) has extended life expectancy and enhanced the well-being of HIV-positive individuals. Since there are concerns regarding HAART-mediated onset of cardio-metabolic diseases in the long-term, we evaluated the anthropometric profile of black HIV-infected individuals in a peri-urban setting (Western Cape, South Africa). Methods: A cross sectional study design was followed to describe the gender differences in different HAART treatment groups. HIV-positive patients (n = 44 males, n = 102 females; 20–40 years) were recruited for three groups: 1) control (HIV-positive, HAART-naïve), 2) HIV-positive (<3 years HAART), and 3) HIV-positive (>3 years HAART). Results: All participants underwent comprehensive anthropometric and bio-electrical impedance analyses. No significant differences were observed in the male treatment groups. HAART-naïve females are mostly overweight (73.90 ± 2.79). This is followed by a period of muscle wasting seen in the triceps skinfold (29.30 ± 2.19 vs 20.63 ± 1.83; p < 0.01), muscle mass (22.23 ± 0.46 vs 19.82 ± 0.54; p < 0.01), and fat free mass (49.40 ± 1.08 vs 44.16 ± 1.21; p < 0.01) upon HAART initiation (<3 years HAART). Thereafter all parameters measured had levels similar to that seen for the female HAART-naïve group. Females on <3 years HAART exhibited significantly decreased body cell mass (p < 0.01), protein mass (p < 0.01), muscle mass (p < 0.01), fat free mass (p < 0.01), and fat mass (p < 0.001) versus matched HAART-naïve controls. The W:H ratio for the female treatment groups placed the females overall at a higher risk for developing cardiovascular disease compared to the males. Conclusions: This study found striking gender-based anthropometric differences in black South African HIV-positive individuals on HAART. We also conclude from this observational study that no significant differences were found in the different male treatment groups. All female body composition parameters initially showed lower values (<3 years HAART). The female treatment group (>3 years HAART) displayed values similar to that seen in the HAART-naïve group. Higher W:H ratios in females receiving longer-term HAART potentially increases their risk for the future onset of cardio-metabolic complications.
Domesticating cancer : an evolutionary strategy in the war on cancer
(Frontiers Media, 2017) Van Niekerk, Gustav; Nell, Theo A.; Engelbrecht, Anna-Mart
Since cancer shares the same molecular machinery as the host, most therapeutic interventions that aim to target cancer would inadvertently also adversely affect the host. In addition, cancer continuously evolves, streamlining its host-derived genome for a new single-celled existence. In particular, short-term clinical success observed with most antineoplastic therapies directly relate to the fact that cancer is constantly evolving. However, the clonal evolution of cancer occasionally also render cancer cells uniquely susceptible to therapeutic interventions, as is exemplified by the clinical relevance of synthetic lethality. Synthetic lethality describes a situation where the simultaneous loss of function in two genes results in lethality, but where a loss of function in either single gene is tolerated. This observation suggests that the evolution of cancer, usually seen as a major clinical challenge, may also afford a key opportunity in lowering on-target toxicities accosted with chemotherapy. As an example, by subjecting cancer to specific selection regimes, cancer can in effect be placed on evolutionary trajectories leading to the development of “targetable” phenotypes such as synthetic lethal interactions. However, such a selection regime would have to overcome a range of obstacles such as on-target toxicity and the selection of an evolvable trait. Since the majority of cancer evolution manifests as a loss of function, we suggest that the induction of auxotrophic phenotypes (i.e., where an organism lose the ability to synthesize specific organic compounds required for growth and thus become dependent on it from dietary sources) may represent an attractive therapeutic option. As an example, animals can obtain vitamin C either by de novo synthesis or from their diet. However, since the maintenance of synthetic pathways is costly, such pathways are often lost if no longer necessary, resulting in the organism being auxotrophic toward the dietary compound. Similarly, increasing the maintenance cost of a redundant pathway in cancer cells is likely to select for clones that have lost such a redundant pathway. Inhibition of a pathway, while supporting the activity of a compensating pathway, may thus induce auxotrophism in cancer cells but not in genomic stable host cells.
Inflammatory cytokines in type 2 diabetes mellitus as facilitators of hypercoagulation and abnormal clot formation
(BMC (part of Springer Nature), 2019-06-04) Randeria, Shehan N.; Thomson, Greig J. A.; Nell, Theo A.; Roberts, Timothy; Pretorius, Etheresia
Background: The global burden of type 2 diabetes mellitus (T2DM), together with the presence of cardiovascular risk in this population, is reaching pandemic levels. A prominent feature of T2DM is chronic and systemic inflammation, with the accompanying presence of circulating and dysregulated inflammatory biomarkers; which in turn is associated with abnormal clot formation. Methods: Here, we investigate the correlation between abnormal blood clotting, using thromboelastography (TEG), clot ultrastructure using scanning electron microscopy (SEM) and the presence of a dysregulated inflammatory cytokine profile, by examining various circulating biomarkers. Results: Our results show that many biomarkers, across TEG, cytokine and lipid groups, were greatly dysregulated in the T2DM sample. Furthermore, our T2DM sample’s coagulation profiles were significantly more hypercoagulable when compared to our heathy sample, and ultrastructural analysis confirmed a matted and denser clot structure in the T2DM sample. Conclusions: We suggest that dysregulated circulating molecules may in part be responsible for a hypercoagulable state and vascular dysfunction in the T2DM sample. We propose further that a personalized approach could be of great value when planning treatment and tracking the patient health status after embarking on a treatment regimes, and that looking to novel inflammatory and vascular biomarkers might be crucial.
Metabolic syndrome and body shape predict differences in health parameters in farm working women
(BioMed Central, 2018-04-04) Mentoor, Ilze; Kruger, Maritza; Nell, Theo A.
Background: Sufficient evidence associate body shape to detrimental lifestyle diseases including the metabolic syndrome (MetS). The prevalence of the MetS, as well as effects of the MetS and body shape on body composition, insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP) and sex hormone parameters were investigated in a female farm worker population in the Western Cape. Methods: Women between the ages of 20–60 years were classified according to the International Diabetes Federation’s definition of the MetS. Assessments included body shape (android/gynoid), blood pressure, anthropometric, bioelectrical impedance analyses and blood analyses for fasting glucose and insulin, lipid profile, IGF-1, CRP, and sex hormone parameters. Results: The prevalence of the MetS was 52%, with abdominal obesity 68.8%, hypertension 66.4% and low high density lipoprotein-cholesterol (HDL-c) levels (64.1%) being the more prevalent MetS risk factors. The MetS, irrespective of body shape, was found to be associated with body mass index (p < 0.01), fat mass (%) (p < 0.01), waist circumference (p < 0.001), HDL-c (p < 0.001), systolic blood pressure (p < 0.05) and diastolic blood pressure (p < 0.01). No significant differences were observed for IGF-1, CRP and sex hormone parameters. Conclusion: The prevalence of the MetS and its individual risk factors were found to be significantly high in this female farm worker population. Additionally, the study showed that the MetS, body shape and/or both could predict differences in body composition, physiological and biochemical parameters in women.
Parkinson’s disease : a systemic inflammatory disease accompanied by bacterial inflammagens
(Frontiers Media, 2019-08-27) Adams, Buin; Nunes, J. Massimo; Page, Martin J.; Roberts, Timothy; Carr, Jonathan; Nell, Theo A.; Kell, Douglas B.; Pretorius, Etheresia
Parkinson’s disease (PD) is a well-known neurodegenerative disease with a strong association established with systemic inflammation. Recently, the role of the gingipain protease group from Porphyromonas gingivalis was implicated in Alzheimer’s disease and here we present evidence, using a fluorescent antibody to detect gingipain R1 (RgpA), of its presence in a PD population. To further elucidate the action of this gingipain, as well as the action of the lipopolysaccharide (LPS) from P. gingivalis, low concentrations of recombinant RgpA and LPS were added to purified fluorescent fibrinogen. We also substantiate previous findings regarding PD by emphasizing the presence of systemic inflammation via multiplex cytokine analysis, and demonstrate hypercoagulation using thromboelastography (TEG), confocal and electron microscopy. Biomarker analysis confirmed significantly increased levels of circulating proinflammatory cytokines. In our PD and control blood analysis, our results show increased hypercoagulation, the presence of amyloid formation in plasma, and profound ultrastructural changes to platelets. Our laboratory analysis of purified fibrinogen with added RgpA, and/or LPS, showed preliminary data with regards to the actions of the protease and the bacterial membrane inflammagen on plasma proteins, to better understand the nature of established PD.
Platelet activity and hypercoagulation in type 2 diabetes
(BMC (part of Springer Nature), 2018-11-02) Pretorius, Lesha; Thomson, Greig J. A.; Adams, Rozanne C. M.; Nell, Theo A.; Laubscher, Willem A.; Pretorius, Etheresia
Background: A strong correlation exists between type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), with CVD and the presence of atherosclerosis being the prevailing cause of morbidity and mortality in diabetic populations. T2DM is accompanied by various coagulopathies, including anomalous clot formation or amyloid fibrin(ogen), the presence of dysregulated inflammatory molecules. Platelets are intimately involved in thrombus formation and particularly vulnerable to inflammatory cytokines. Methods: The aim of this current study was therefore to assess whole blood (hyper)coagulability, platelet ultrastructure and receptor expression, as well as the levels of IL-1β, IL-6, IL-8 and sP-selectin in healthy and diabetic individuals. Platelet morphology was assessed through scanning electron microscopy (SEM), while assessment of GPIIb/IIIa receptor expression was performed with confocal microscopy and flow cytometry with the addition of FITC-PAC-1 and CD41-PE antibodies. IL-1β, IL-6 and IL-8 and sP-selectin levels were assessed using a multiplex assay. Results: In T2DM there is significant upregulation of circulating inflammatory markers, hypercoagulation and platelet activation, with increased GPIIb/IIIa receptor expression, as seen with flow cytometry and confocal microscopy. Analyses showed that these receptors were additionally shed onto microparticles, which was confirmed with SEM. Conclusions: Cumulatively, this provides mechanistic evidence that pathological states of platelets together with amyloid fibrin(ogen) in T2DM, might underpin an increased risk for cardiovascular events.
The prevalence of the metabolic syndrome in a farm worker community in the Boland district, South Africa
(BioMed Central, 2017) Kruger, Maritza J.; Nell, Theo A.
Background: In South Africa, not much is known about MetS in farm working communities. This study aimed to describe the prevalence of the MetS in a farm working population from the Boland winelands district of the Western Cape, South Africa. Methods A cross-sectional study was followed among farm workers (aged 20–60 years) from surrounding wine estates. The questionnaires used described socio-demographic status, ethnic background, alcohol consumption, smoking, exercise and daily medication. Anthropometric assessments were performed and blood pressure measurements taken prior to blood sampling for serum insulin, glucose and fasting lipogram profiles. Results The prevalence of the MetS was higher in women (46.3 vs 29.3%). Both men and women in the MetS group had a significantly higher waist circumferences (WC; p < 0.001 for both), whilst higher glucose levels were only significantly higher in the women (p < 0.001). Correlations showed significant differences between body mass index (BMI), WC and waist to hip ratio (W:H) and the different MetS risk factors. Conclusions The female population in this study showed higher prevalence rates for the individual risk factors and the MetS overall. There is an urgent need to develop culturally sensitive health promotion programs addressing risk factors for metabolic syndrome among farm workers.
Serum amyloid A binds to fibrin(ogen), promoting fibrin amyloid formation
(Nature Research (part of Springer Nature), 2019-02-28) Page, Martin J.; Thomson, Greig J. A.; Nunes, J. Massimo; Engelbrecht, Anna-Mart; Nell, Theo A.; De Villiers, Willem J. S.; De Beer, Maria C.; Engelbrecht, Lize; Kell, Douglas B.; Pretorius, Etheresia
Complex associations exist between inflammation and thrombosis, with the inflammatory state tending to promote coagulation. Fibrinogen, an acute phase protein, has been shown to interact with the amyloidogenic ß-amyloid protein of Alzheimer’s disease. However, little is known about the association between fibrinogen and serum amyloid A (SAA), a highly fibrillogenic protein that is one of the most dramatically changing acute phase reactants in the circulation. To study the role of SAA in coagulation and thrombosis, in vitro experiments were performed where purified human SAA, in concentrations resembling a modest acute phase response, was added to platelet-poor plasma (PPP) and whole blood (WB), as well as purified and fluorescently labelled fibrinogen. Results from thromboelastography (TEG) suggest that SAA causes atypical coagulation with a fibrin(ogen)-mediated increase in coagulation, but a decreased platelet/fibrin(ogen) interaction. In WB scanning electron microscopy analysis, SAA mediated red blood cell (RBC) agglutination, platelet activation and clumping, but not platelet spreading. Following clot formation in PPP, the presence of SAA increased amyloid formation of fibrin(ogen) as determined both with auto-fluorescence and with fluorogenic amyloid markers, under confocal microcopy. SAA also binds to fibrinogen, as determined with a fluorescent-labelled SAA antibody and correlative light electron microscopy (CLEM). The data presented here indicate that SAA can affect coagulation by inducing amyloid formation in fibrin(ogen), as well as by propelling platelets to a more prothrombotic state. The discovery of these multiple and complex effects of SAA on coagulation invite further mechanistic analyses.
Sickness-associated anorexia : mother nature’s idea of immunonutrition?
(Hindawi Publishing Corporation, 2016) Van Niekerk, Gustav; Isaacs, Ashwin W.; Nell, Theo A.; Engelbrecht, Anna-Mart
During an infection, expansion of immune cells, assembly of antibodies, and the induction of a febrile response collectively place continual metabolic strain on the host. These considerations also provide a rationale for nutritional support in critically ill patients. Yet, results from clinical and preclinical studies indicate that aggressive nutritional support does not always benefit patients and may occasionally be detrimental. Moreover, both vertebrates and invertebrates exhibit a decrease in appetite during an infection, indicating that such sickness-associated anorexia (SAA) is evolutionarily conserved. It also suggests that SAA performs a vital function during an infection. We review evidence signifying that SAA may present a mechanism by which autophagic flux is upregulated systemically. A decrease in serum amino acids during an infection promotes autophagy not only in immune cells, but also in nonimmune cells. Similarly, bile acids reabsorbed postprandially inhibit hepatic autophagy by binding to farnesoid X receptors, indicating that SAA may be an attempt to conserve autophagy. In addition, augmented autophagic responses may play a critical role in clearing pathogens (xenophagy), in the presentation of epitopes in nonprovisional antigen presenting cells and the removal of damaged proteins and organelles. Collectively, these observations suggest that some patients might benefit from permissive underfeeding.

Browsing by Author "Nell, Theo A."

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