Research Articles (Physiology)

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Years of running, chronic diseases, and allergies are associated with gradual onset Achilles tendon injuries in 61,252 running race entrants
(Wiley, 2024-11) Young, Jonah Dylan; Wood, Paola Silvia; Schwellnus, Martin Peter; Jordaan, Esme; Swanevelder, Sonja
BACKGROUND : Gradual-onset Achilles tendon injuries (GoATIs) in runners are common. Data show that chronic diseases are associated with GoATI. OBJECTIVE : To determine risk factors associated with a history of GoATIs among long-distance runners (21.1 and 56 km) entering a mass community-based running event. METHODS : Online pre-race medical screening questionnaire data from 76,654 consenting Two Ocean Marathon race entrants (71.8% entrants) were collected prospectively over 4 years (2012-2015); this cross-sectional study is a retrospective analysis of these data. A total of 617 entrants (0.8%) reported a GoATI in the last 12 months; 60,635 entrants reported no history of any running injury (controls). Categories of factors associated with GoATI were explored (univariate and multiple regression analyses): demographics (age group, sex, race, distance), training/racing history, and history of allergy, history of chronic disease, and Composite Chronic Disease Score. Prevalence and prevalence ratios (PRs; 95% CI) are reported. RESULTS : Factors associated with a higher prevalence of a history of GoATI (univariate analysis vs. controls) were older age (>31 years) (p < .001), male sex (PR = 1.76; p < .001), and longer race distance (56 km vs. 21.1 km) (PR = 2.06; p < .001). Independent factors associated with a history of GoATI (multiple regression) were increased years of recreational running (PR = 1.17 for every 5-year increase, p < .001), higher Composite Chronic Disease Score (PR = 2.07 for every 2-unit increase, p < .001), and allergy history (PR = 1.98 p < .001). CONCLUSION : Novel independent factors associated with a history of GoATI in distance runners were increased years of recreational running, chronic disease history, and allergy history. Runners at risk for GoATI could be targeted for injury prevention interventions. Future studies should focus on establishing a causal relationship.
Association between recorded physical activity and cancer progression or mortality in individuals diagnosed with cancer in South Africa
(BMJ Publishing, 2025-05) Mabena, Ntokozo; Rugbeer, Nivash; Lehmann, Sandra; Torres, Georgia; Patel, Deepak; Mabunda, Mosima; Greyling, Mike; Thornton, Jane S.; Choi, Yun-Hee; Stranges, Saverio; Patricios, Jon S.
OBJECTIVES : This study aimed to determine the association between progression and mortality in individuals with stage 1 cancer and their recorded physical activity before the diagnosis of the cancer. METHODS : We included 28 248 members with stage 1 cancers enrolled in an oncology programme in South Africa. Physical activity was recorded using fitness devices, logged gym sessions and participation in organised fitness events. Levels of physical activity over the 12 months before cancer diagnosis were categorised as no physical activity, low physical activity (an average of <60 min/week) and moderate to high physical activity (≥60 min/week). Measured outcomes were time to progression, time to death and all cause mortality. RESULTS : Physically active members showed lower rates of cancer progression and lower rates of death from all causes. The HR for progression to higher stages or death was 0.84 (95% CI 0.79 to 0.89), comparing low activity with no physical activity, and 0.73 (95% CI 0.70 to 0.77), comparing medium to high physical activity with no physical activity. The HR for all cause mortality was 0.67 (95% CI 0.61 to 0.74), comparing low physical activity with no activity, and 0.53 (95% CI 0.50 to 0.58), comparing medium to high physical activity with no physical activity. CONCUSIONS : Individuals engaging in any level of recorded physical activity showed a reduced risk of cancer progression or mortality than those not physically active. There was a further reduction among individuals with moderate to high levels of physical activity compared with those with lower levels.
Associating serum testosterone levels with African ancestral prostate cancer health disparities
(Nature Research, 2025-04) Lebelo, Maphuti Tebogo; Mmekwa, Naledi; Louw, Melanie; Jaratlerdsiri, Weerachai; Mutambirwa, Shingai B.A.; Loda, Massimo; Hayes, Vanessa M.; Bornman, Maria S. (Riana); riana.bornman@up.ac.za
Serum testosterone levels decrease in the aging male, while the risk for prostate cancer (PCa) increases concomitantly. Higher levels in younger men have been linked with racially driven PCa disparities, with African men disproportionately impacted. In turn, higher levels of serum lipids have been associated with aggressive disease, while racial disparity between serum testosterone, cholesterol and cancer mortality has been suggested. Having previously reported a 2.1-fold increased age-adjusted risk for aggressive PCa in Black South African over Black American men, we determined the serum testosterone and associated lipid levels in 250 Black South African men either with or without clinicopathologically diagnosed disease. Observing no associations with serum lipid levels, Black South Africans presented with testosterone levels between 1.24 (< 60 years) and 1.3-fold (≥ 60 years) greater than Black Americans. Notably, a rapid drop in total-, bioavailable- and free testosterone levels in men 65 years or older was significantly associated with PCa risk (P = 0.0057, 0.009 and 0.005, respectively), while irrespective of age, further associated with advanced disease (P = 0.004, 0.0012 and 0.0036, respectively). These preliminary data provide insights into the potential role of androgens in driving PCa health disparities, with important consequence for tailoring treatment for Black men.
Objective classification of countermovement jump force-time curve modality : within athlete-consistency and associations with jump performance
(Routledge, 2024) Bayne, Helen; Cockcroft, John; Robyn, Aneurin; Louw, Quinette; helen.bayne@up.ac.za
Force-time curves produced during a countermovement jump (CMJ) have traditionally been classified by visual observation as either unimodal (one concentric phase peak) or bimodal (two peaks). The association between CMJ modality and jump performance remains unclear and future studies may benefit from standardising and expanding modality classification. This study described a numerical method based on the timing and relative magnitude of concentric force-time curve prominences. Adult male elite rugby union players (n = 214) performed six CMJs on a force-instrumented treadmill and an algorithm using turning-point logic was applied to categorise jumps and define modality sub-groups. A sensitivity analysis demonstrated that the minimum prominence threshold (MPT) affected categorisation, as the proportion of bimodal jumps decreased with each 1% increase in MPT. Within-athlete consistency was also affected; between 43% and 63% of participants were consistently categorised as bimodal or unimodal depending on the selected MPT. Modified reactive strength index (RSImod), but not jump height or take-off momentum, was greater in unimodal jumps. Take-off momentum and RSImod were greater in subcategories where maximum force occurred early in the concentric phase. Future research should implement objective classification methods to enhance transparency and comparability and consider subcategories to investigate CMJ force production strategies.
Multi-target inhibitor CUDC-101 impairs DNA damage repair and enhances radiation response in triple-negative breast cell line
(MDPI, 2024-11-01) Seane, Elsie Neo; Nair, Shankari; Vandevoorde, Charlot; Bisio, Alessandra; Joubert, Anna Margaretha; annie.joubert@up.ac.za
BACKGROUND : Since the discovery that Histone deacetylase inhibitors (HDCAi) could enhance radiation response, a number of HDACi, mainly pan-HDAC inhibitors, have been studied either as monotherapy or in combination with X-ray irradiation or chemotherapeutic drugs in the management of breast cancer. However, studies on the combination of HDACi and proton radiation remain limited. CUDC-101 is a multitarget inhibitor of Histone deacetylases (HDACs), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2). In this paper, the effectiveness of CUDC-101 in enhancing radiation response to both proton and X-ray irradiation was studied. METHODS : MCF-7, MDA-MB-231, and MCF-10A cell lines were pre-treated with CUDC- 101 and exposed to 148 MeV protons, and X-rays were used as reference radiation. Colony survival, γ-H2AX foci, apoptosis, and cell cycle analysis assays were performed. RESULTS : γ-H2AX foci assays showed increased sensitivity to CUDC-101 in the MDA-MB-231 cell line compared to the MCF-7 cell line. In both cell lines, induction of apoptosis was enhanced in CUDC-101 pre-treated cells compared to radiation (protons or X-rays) alone. Increased apoptosis was also noted in CUDC-101 pre-treated cells in the MCF-10A cell line. Cell cycle analysis showed increased G2/M arrest by CUDC-101 mono-treatment as well as combination of CUDC-101 and X-ray irradiation in the MDA-MB-231 cell line. CONCLUSIONS : CUDC-101 effectively enhances response to both proton and X-ray irradiation, in the triple-negative MDA-MB-231 cell line. This enhancement was most notable when CUDC-101 was combined with proton irradiation. This study highlights that CUDC-101 holds potential in the management of triple-negative breast cancer as monotherapy or in combination with protons or X-ray irradiation.
Mechanistic sequence of histone deacetylase inhibitors and radiation treatment : an overview
(MDPI, 2024-05-08) Seane, Elsie Neo; Nair, Shankari; Vandevoorde, Charlot; Joubert, Anna Margaretha; annie.joubert@up.ac.za
Histone deacetylases inhibitors (HDACis) have shown promising therapeutic outcomes in haematological malignancies such as leukaemia, multiple myeloma, and lymphoma, with disappointing results in solid tumours when used as monotherapy. As a result, combination therapies either with radiation or other deoxyribonucleic acid (DNA) damaging agents have been suggested as ideal strategy to improve their efficacy in solid tumours. Numerous in vitro and in vivo studies have demonstrated that HDACis can sensitise malignant cells to both electromagnetic and particle types of radiation by inhibiting DNA damage repair. Although the radiosensitising ability of HDACis has been reported as early as the 1990s, the mechanisms of radiosensitisation are yet to be fully understood. This review brings forth the various protocols used to sequence the administration of radiation and HDACi treatments in the different studies. The possible contribution of these various protocols to the ambiguity that surrounds the mechanisms of radiosensitisation is also highlighted.
PhysioCAFUN : a competency-based curriculum development guideline to strengthen physiology education in Africa
(American Physiological Society, 2025-03) Alagbonsi, Abdullateef Isiaka; Essop, M. Faadiel; El-Wazir, Yasser; Nyakudya, Trevor Tapiwa; Fastone, Goma; Mojiminiyi, Frank; Saeed, Amal; Stienen, Ger J.M.; Balandya, Emmanuel; Raji, Yinusa; Bintou Sarr, Fatou; Samb, Abdoulaye; Ebrahim, Ashabilan; Pohl, Ulrich; Silverthorn, Dee U.
Physiology education in Africa faces challenges due to gaps in curricula across many of its universities, such as divergent content, a lack of standardized competencies, and suitable benchmarking. Here, we describe the development of the Physiology Curriculum for African Universities (PhysioCAFUN), a competency-based curriculum development guideline, as a first step to address such shortcomings. A committee of 15 physiologists from different African regions, Europe, and the United States was constituted to draft the PhysioCAFUN, which was introduced and revised during the joint East African Society of Physiological Sciences (EASPS) and African Association of Physiological Sciences (AAPS) conference held in Tanzania late 2023. The PhysioCAFUN consists of 23 modules. Modules 1–15 cover the organ systems, including principles and concepts of physiology, molecular biology, and cell physiology. Modules 16–23 contain optional content, including environmental physiology, pharmacology, and topics related to skill development. PhysioCAFUN serves as a freely available resource document for African stakeholders regarding the desired undergraduate physiology training and competencies. It will help universities in Africa, and elsewhere to draft a curriculum suitable for their local needs where there is a dearth of physiologists or to benchmark and revise their curricula where physiology programs are already in place. NEW & NOTEWORTHY : We described the development of Physiology Curriculum for African Universities (PhysioCAFUN), a competency-based curriculum development guideline to promote physiology education in Africa. This freely accessible resource document should help African universities where there is a dearth of physiologists and thus aid in drafting a curriculum suitable for their local needs. Likewise, it should assist universities globally where physiology programs are already in place to benchmark and/or revise their curriculum as may be needed.
Number of symptoms during the acute phase of SARS-CoV-2 infection in athletes is associated with multiorgan involvement : AWARE III
(Lippincott Williams and Wilkins, 2025) Snyders, Carolette; Dyer, Marlise; Jordaan, Esme; Scholtz, Leonie; Du Plessis, Andre; Mpe, Martin; Kaulback, Kelly; Schwellnus, Martin Peter; carolette.cloete@semli.co.za
OBJECTIVE : Acute respiratory infections (ARinf), including SARS-CoV-2 infection, can affect multiple organ systems that may influence return to sport (RTS) in athletes. Factors associated with multiorgan involvement in athletes with ARinf are lacking. The aim of this study was to explore whether factors such as demographics, sport participation, history of comorbidities/allergies, and number of acute symptoms are associated with multiorgan involvement in athletes with recent SARS-CoV-2 infection. DESIGN : Prospective cohort study with cross-sectional analysis. SETTING : Institutional clinical research facilities. PARTICIPANTS : Ninety-five athletes (18–60 years) underwent a comprehensive medical assessment 10 to 28 days after SARS-CoV-2 infection. INDEPENDANT FACTORS : Demographics, sport participation, history of comorbidities/allergies, and the number of acute symptoms (in 3 subgroups:1 = ≤5, 2 = 6-9, or 3 ≥ 10). MAIN OUTCOME MEASURES : Number of organs involved in athletes with recent SARS-CoV-2 infection. RESULTS : The number of organ systems involved was not associated with demographics (age, sex), sport participation (level and type), or history of comorbidities and allergies. However, the number of organ systems involved was significantly higher in athletes with 6 to 9 symptoms (subgroup 2) compared with those with ≤5 symptoms (subgroup 1) and this was more pronounced when comparing athletes with ≥10 symptoms (subgroup 3) with those with ≤5 symptoms (subgroup 1) (P < 0.0001). CONCLUSIONS : Total number of acute symptoms of SARS-CoV-2 infection is related to number of organ systems involved, which is a measure of disease severity, and could therefore influence RTS decision making. Future studies should explore whether this observation holds for athletes with ARinf caused by other pathogens.
COVID-19-induced diabetes mellitus : comprehensive cellular and molecular mechanistic insights
(MDPI, 2024-06) Nhau, Praise T.; Gamede, Mlindeli; Sibiya, Ntethelelo
Despite evidence demonstrating the risks of developing diabetes mellitus because of SARSCoV-2, there is, however, insufficient scientific data available to elucidate the relationship between diabetes mellitus and COVID-19. Research indicates that SARS-CoV-2 infection is associated with persistent damage to organ systems due to the systemic inflammatory response. Since COVID-19 is known to induce these conditions, further investigation is necessary to fully understand its longterm effects on human health. Consequently, it is essential to consider the effect of the COVID-19 pandemic when predicting the prevalence of diabetes mellitus in the future, especially since the incidence of diabetes mellitus was already on the rise before the pandemic. Additional research is required to fully comprehend the impact of SARS-CoV-2 infection on glucose tolerance and insulin sensitivity. Therefore, this article delves deeper into the current literature and links the perceived relationship between SARS-CoV-2 and diabetes. In addition, the article highlights the necessity for further research to fully grasp the mechanisms that SARS-CoV-2 utilises to induce new-onset diabetes. Where understanding and consensus are reached, therapeutic interventions to prevent the onset of diabetes could be proposed. Lastly, we propose advocating for the regular screening of diabetes and pre-diabetes, particularly for the high-risk population with a history of COVID-19 infection.
Evaluation of [68Ga]Ga-DOTA-AeK as a potential imaging tool for PET imaging of cell wall synthesis in bacterial infections
(MDPI, 2024-09) Koatale, Palesa Caroline; Welling, Mick M.; Mdanda, Sipho; Mdlophane, Amanda; Takyi-Williams, John; Durandt, Chrisna; Van den Bout, Iman; Cleeren, Frederik; Sathekge, Mike Machaba; Ebenhan, Thomas; thomas.ebenhan@up.ac.za
Please read abstract in article.
Identification of small-molecule antagonists targeting the growth hormone releasing hormone receptor (GHRHR)
(American Chemical Society, 2024-08-29) Matsoukas, Minos-Timotheos; Radomsky, Tarryn; Panagiotopoulos, Vasilis; Du Preez, Robin; Papadourakis, Michail; Tsianakas, Konstantinos; Millar, Robert P.; Anderson, Ross Calley; Spyroulias, Georgios A.; Newton, Claire L.
The growth hormone-releasing hormone receptor (GHRHR) belongs to Class B1 of G protein-coupled receptors (GPCRs). Class B1 GPCR peptides such, as growth hormone-releasing hormone (GHRH), have been proposed to bind in a twostep model, where first the C-terminal region of the peptide interacts with the extracellular domain of the receptor and, subsequently, the N-terminus interacts with the seven transmembrane domain of the receptor, resulting in activation. The GHRHR has recently been highlighted as a promising drug target toward several types of cancer and has been shown to be overexpressed in prostate, breast, pancreatic, and ovarian cancer. Indeed, peptide GHRHR antagonists have displayed promising results in many cancer models. However, no nonpeptide GHRHR-targeting compounds have yet been identified. We have utilized several computational tools to target GHRHR and identify potential small-molecule compounds directed at this receptor. These compounds were validated in vitro using a cyclic adenosine monophosphate (cAMP) ELISA to measure activity at the GHRHR. In vitro results suggest that several of the novel small-molecule compounds could inhibit GHRH-induced cAMP accumulation. Preliminary analysis of the specificity/ selectivity of one of the most effective hit compounds indicated that the effect seen was via inhibition of the GHRHR. We therefore report the first nonpeptide antagonists of GHRHR and propose a structural basis for inhibition induced by the compounds, which may assist in the future design of lead GHRHR compounds for treating disorders attributed to dysregulated/aberrant GHRHR signaling.
Obstructive sleep apnea screening protocol and safety measures : advancing treatment quality and reducing medical emergency team activation in patients with atrial fibrillation, respiratory diseases, and frailty
(American Academy of Sleep Medicine, 2024-05) Otto, Monique
Despite ongoing research, the association of in-hospital medical emergency team activation (META) among patients with atrial fibrillation (AF) who are at risk for obstructive sleep apnea (OSA) is unclear. Using sleep questionnaires and other forms of screeners have become useful tools for such patients, but their sensitivity and specificity, application in various diseases and risk factors, and therefore, overall usefulness, require further study.1,2 For instance, a study by El-Sayed2 showed that the sensitivity of the Berlin, STOP (Snoring, Tiredness, Observed apnea, high blood Pressure), and STOP-BANG (Snoring, Tiredness, Observed apnea, high blood Pressure, BMI, Age, Neck circumference, Gender) questionnaires was high when screening for OSA; however, the low specificity of these questionnaires resulted in increased false positives and failure of exclusion of individuals at low risk.2 Undiagnosed and untreated OSA is associated with increased in-hospital morbidity and serves as a risk factor for cardiac complications, including hypertension, diabetes, and dyslipidemia, and diseases such as coronary artery disease and AF.1,3 In addition, pathophysiologic pathways related to OSA, such as alterations in intrathoracic pressure, intermittent hypoxemia, and autonomic nervous system fluctuations, may lead to atrial structural and electrical remodeling, resulting in predisposition to AF.4 Chen et al5 reported that the apnea-hypopnea and desaturation indices cannot fully represent the severity of OSA in patients with stroke. Instead, the mean desaturation value during nocturnal hypoxia must be used. Nocturnal hypoxia due to OSA was shown to be an independent predictor of AF in patients with subacute ischemic stroke, and it was concluded that the use of an overnight pulse oximeter to assess nocturnal hypoxia and to predict paroxysmal AF in patients with cryptogenic stroke requires further evaluation, illustrating the importance of reliable screening methods for OSA and its risk factors.1
The effects of exercise training as a treatment component of obstructive sleep apnea in diverse patient groups : current understanding and focus areas
(American Academy of Sleep Medicine, 2024-11) Otto, Monique
It has been established that exercise is an essential component of obstructive sleep apnea (OSA) treatment. However, despite ongoing research and important findings reported in the last decade,1–17 the effects of exercise on patients with OSA remain insufficiently understood. It is not fully clear whether certain subgroups would benefit more from exercise therapy than others, and whether certain types of exercise would be more beneficial than others.
Rating of perceived exertion associated with acute symptoms in athletes with recent SARS-CoV-2 infection : athletes with acute respiratory infection (AWARE) VI study
(National Athletic Trainers' Association, 2024-01) Kaulback, Kelly; Schwellnus, Martin Peter; Sewry, Nicola; Jordaan, Esme; Wood, Paola Silvia
CONTEXT : SARS-CoV-2 infection can affect the exercise response in athletes. Factors associated with the exercise response have not been reported. OBJECTIVE : To (1) describe heart rate (HR), systolic blood pressure (SBP), and rating of perceived exertion (RPE) responses to exercise in athletes with a recent SARS-CoV-2 infection and (2) identify factors affecting exercise Responses. DESIGN : Cross-sectional, experimental study. PATIENTS OR OTHER PARTCIPANTS : Male and female athletes (age ¼ 24.2 6 6.3 years) with a recent (,28 days) SARS-CoV-2 infection (n ¼ 72). SETTING : A COVID-19 Recovery Clinic for athletes. MAIN OUTCOME MEASURE(S) : Heart rate, SBP, and RPE were measured during submaximal exercise (modified Bruce protocol) at 10 to 28 days after SARS-CoV-2 symptom onset. Selected factors (demographics, sport, comorbidities, pre-infection training variables, and symptoms during the acute phase of the infection) affecting the exercise response were analyzed using random coefficient (linear mixed) models. RESULTS : Heart rate, SBP, and RPE increased progressively from rest to stage 5 of the exercise test (P ¼ .0001). At stage 5 (10.1 metabolic equivalents), a higher HR and a higher SBP during exercise were associated with younger age (P ¼ .0007) and increased body mass index (BMI; P ¼ .009), respectively. Higher RPE during exercise was significantly associated with a greater number of whole-body (P ¼ .006) and total number (P ¼ .004) of symptoms during the acute phase of infection. CONCLUSIONS : A greater number of symptoms during the acute infection was associated with a higher RPE during exercise in athletes at 10 to 28 days after SARS-CoV-2 infection. We recommend measuring RPE during the first exercise challenge after infection, as this may indicate disease severity and be valuable for tracking progress, recovery, and return to sport.
Exploring the in vitro effects of Zingerone on differentiation and signalling pathways in bone cell lines
(MDPI, 2024-12) De Vos, Brunhildé; Kasonga, Abe E.; Joubert, Anna Margaretha; Nyakudya, Trevor Tapiwa; trevor.nyakudya@up.ac.za
Objective: Ensuring adequate bone health is crucial for preventing conditions such as osteoporosis and fractures. Zingerone, a phytonutrient isolated from cooked ginger, has gained attention for its potential benefits in bone health. This study evaluated the osteoprotective potential of zingerone and its effects on differentiation and signalling pathways in vitro using SAOS-2 osteosarcoma and RAW264.7 macrophage cell lines, aiming to elucidate its mechanism of action in bone remodelling. Methods: SAOS-2 osteosarcoma and RAW264.7 macrophage cells were treated with zingerone at concentrations of 200 µM. Osteoblast differentiation was assessed by alkaline phosphatase (ALP) activity, bone mineralisation via Alizarin Red S stain, and gene expression markers (ALP, runt-related transcription factor 2 (Runx2), and osteocalcin) via quantitative polymerase chain reaction (q-PCR). Osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase (TRAP) staining, TRAP activity, and mitogen-activated protein kinase (MAPK) pathways. Results: Treatment with zingerone was non-toxic at 200 µM. Zingerone (200 µM) significantly stimulated the gene expression of ALP and Runx2 in SAOS-2 cells (p < 0.05) without statistically significantly enhancing SAOS-2 mineralisation via calcium deposits. Moreover, zingerone significantly inhibited osteoclast differentiation in RAW264.7 cells as evidenced by reduced TRAP staining and activity (p < 0.05). Conclusions: Zingerone shows promise in reducing osteoclast activity and supporting early osteoblast differentiation, suggesting its potential as a dietary supplement for bone health. Further in vivo and clinical studies are needed to confirm its role in managing osteoporosis.
Glioblastoma cells alter brain endothelial cell homeostasis and tight junction protein expression in vitro
(Springer, 2025-01) Mokoena, Xolisile; Mabeta, Peaceful Lucy; Cordier, Werner; Flepisi, Brian Thabile
BACKGROUND : Glioblastoma (GBM) is an aggressive therapy-resistant brain tumour that may impacts the integrity of the blood–brain barrier (BBB). The BBB is a protective barrier of the central nervous system formed mainly by endothelial cells. This study aimed to investigate the in vitro effect of GBM cells on the BBB. METHODS : Brain endothelial (bEnd.3) cells were used as a model of the BBB. Glioblastoma-conditioned media (CM) was extracted at the 48-h (h) time-point from the U87 GBM cells and diluted to 40% with fresh media. The effect of the U87-CM collected at 48 h on bEnd.3 cell growth was evaluated following 48 and 72 h of treatment using the xCELLigence system. Additionally, bEnd.3 cell growth was also investigated in a U87 and bEnd.3 co-culture model continuously for 48 h using the xCELLigence system. The migration of bEnd.3 cells was assessed following 48 and 72 h using the migration scratch assay. The barrier integrity was evaluated continuously for 1 h using the transwell permeability, and the tight junction (TJ) protein expression was evaluated using Western blot assay following 48 and 72 h. RESULTS : There was a significant decrease in bEnd.3 cell growth following 32 h (p < 0.05), 40 h (p < 0.01), and 48 h (p < 0.001) of treatment with U87-CM, while co-culturing of bEnd.3 and U87 cells increased cell growth following 16 h (p < 0.05), 24 h (p < 0.001), 32 h (p < 0.01), 40 h (p < 0.001), and 48 h (p < 0.001). The migration of bEnd.3 cells significantly increased following both 24 (p < 0.05) and 48 h (p < 0.01) of treatment with U87-CM. The permeability of bEnd.3 cells co-cultured with U87 for 48 h was significantly increased (p < 0.05) at the 15- and 30-min time points. Furthermore, the expression of ZO-1 and occludin was significantly increased (p < 0.05) in both bEnd.3 cells treated with U87-CM as well as bEnd.3 cells co-cultured with U87 cells. CONCLUSION : The current findings suggest that U87 cells alter the integrity of bEnd.3 cells possibly through the secretomes in the CM and through cell–cell interactions in co-culture models. This may assist in the understanding of the mechanisms by which GBM affects the BBB, which may aid in the management thereof.
Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma
(BioMed Central, 2024-12) Duraj, Tomás; Kalamian, Miriam; Zuccoli, Giulio; Maroon, Joseph C.; D’Agostino, Dominic P.; Scheck, Adrienne C.; Poff, Angela; Winter, Sebastian F.; Hu, Jethro; Klement, Rainer J.; Hickson, Alicia; Lee, Derek C.; Cooper, Isabella; Kofler, Barbara; Schwartz, Kenneth A.; Phillips, Matthew C.L.; Champ, Colin E.; Zupec-Kania, Beth; Tan-Shalaby, Jocelyn; Serfaty, Fabiano M.; Omene, Egiroh; Arismendi-Morillo, Gabriel; Kiebish, Michael; Cheng, Richard; El-Sakka, Ahmed M.; Pflueger, Axel; Mathews, Edward H. (Eddie); Worden, Donese; Shi, Hanping; Cincione, Raffaele I.; Spinosa, Jean P.; Slocum, Abdul K.; Iyikesici, Mehmet S.; Yanagisawa, Atsuo; Pilkington, Geoffrey J.; Chaffee, Anthony; Abdel-Hadi, Wafaa; Elsamman, Amr K.; Klein, Pavel; Hagihara, Keisuke; Clemens, Zsófia; Yu, George W.; Evangeliou, Athanasios E.; Nathan, Janak K.; Smith, Kris; Fortin, David; Dietrich, Jorg; Mukherjee, Purna; Seyfried, Thomas N.
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic fux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.
Investigation of neopterin and neurophysiological measurements as biomarkers of anxiety and stress
(International Society for Neurofeedback & Research, 2024-03-29) Cronje, Rouxzan; Beukes, Johanni; Masenge, Andries; Du Toit, P.J.; Bipath, Priyesh; u17027617@tuks.co.za
The aim of this study was to investigate whether the inflammatory marker neopterin and certain neurophysiological measurements could be used as complementary markers for stress and anxiety symptoms as determined by the Depression, Anxiety, and Stress Scale (DASS-21) questionnaire. A cohort of 158 respondents completed the DASS-21 and biographical questionnaire which were used to stratify health sciences university students between Group A (n = 20), who had high levels of symptoms, and Group B (n = 20) who had normal levels of stress and anxiety. Neurophysiological measurements were taken from these participants, namely heart rate variability (HRV), blood pressure (BP), blood-volume pulse (BVP), electrodermal activity (EDA), and quantitative electroencephalography (qEEG). Each participant also donated a urine sample which was tested for neopterin concentration using an enzyme-linked immunosorbent assay (ELISA). Neopterin positively correlated with the stress and anxiety scores, while HRV and BVP were negatively correlated with these scores. In terms of qEEG, delta and hibeta wave activity increased in the left and frontal brain regions of participants with high mental health scores, whereas alpha wave activity decreased in these regions. High DASS scores were associated with elevated neopterin concentration and neurophysiological changes (brain waves, HRV, and BVP).
Unveiling the link : the potential roles of vitamin D in keloid pathophysiology
(Wiley, 2025-02) Kotze, Jaco; Nortje, Evangeline; Phulukdaree, Alisa; Fear, Mark William; Wood, Fiona; Bester, Janette; janette.bester@up.ac.za
Keloid disease, a fibroproliferative skin disorder, is characterised by scar tissue growth that extends beyond the original wound boundaries. Despite advancements, current treatments, particularly surgical excision, often result in high recurrence rates, ranging from 45% to 100%. Recent investigations into the role of vitamin D (vit D) in keloids present a promising avenue for novel therapeutic strategies. Studies have highlighted the multifaceted involvement of vit D, including its immunomodulatory effects and influence on key processes such as fibroblast activity, collagen production and extracellular matrix dynamics. Additionally, emerging research has explored the potential impact of vit D on epithelial-to-mesenchymal transition and endothelial dysfunction, both of which are implicated in keloid formation and progression. This review consolidates the current evidence linking vitamin D deficiency to keloid pathogenesis, shedding light on potential mechanisms and therapeutic targets. By elucidating the intricate interplay between vit D signalling and keloid development, this study paves the way for innovative treatment approaches that may enhance patient outcomes and mitigate the burden of this challenging dermatological condition.
Development of water-soluble nanoformulations of novel pyrazolone derivatives and the evaluation of their antibacterial and antioxidant activities
(Springer, 2025-02) Igbokwe, Nkeiruka N.; Ismail, Eman A.; Obakachi, Vincent A.; Ntsethe, Aviwe; Gamede, Mlindeli; Karpoormath, Rajshekhar; Faya, Mbuso A.
Poor aqueous solubility and stability hinder the clinical translation of pyrazolone-based derivatives despite their various biological activities. This study aimed to address these issues by developing water-soluble nanoformulations of two specific pyrazolone derivatives, Compounds I and II, selected based on their promising structural features and previous biological activity data. PLGA/poloxamer-based nanoformulations were prepared and optimized for size, PDI, zeta potential (ZP), and entrapment efficiency (EE). The optimized formulations demonstrated sizes of 166.6 ± 7.12 nm and 192.5 ± 1.08 nm, PDI of 0.129 ± 0.042 and 0.132 ± 0.025, ZP of − 14.14 ± 2.90 mV and − 10.77 ± 1.515 mV, and %EE of 84.20 ± 0.930 and 81.5 ± 2.051, respectively. A sustained drug release was observed over 48 h, with cumulative releases of approximately 37% and 53%, for both formulations, and characterized by a complex drug release behavior. The formulations exhibited significant antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus (SA), with greater than 90% cell death for SA and greater than 80% for MRSA, observed using the flow cytometer. Also, enhanced antioxidant activity was observed using DPPH, FRAP, and NO methods, showing better radical scavenging than standard gallic acid and bare compounds. The hemolysis assay confirmed the biocompatibility of the developed formulation, with a hemolysis percentage of less than 5%. This study highlights the successful development of water-soluble nanoformulations with significant antibacterial and antioxidant activities, emphasizing the impact of solubility enhancement on biological efficacy and suggesting potential pharmaceutical applications for these agents.

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