35 research outputs found
Allergic diseases in the elderly
Demographic distribution of the population is progressively changing with the proportion of elderly persons increasing in most societies. This entails that there is a need to evaluate the impact of common diseases, such as asthma and other allergic conditions, in this age segment. Frailty, comorbidities and polymedication are some of the factors that condition management in geriatric patients. The objective of this review is to highlight the characteristics of allergic diseases in older age groups, from the influence of immunosenescence, to particular clinical implications and management issues, such as drug interactions or age-related side effects
Antimitotic drugs in the treatment of cancer
Cancer is a complex disease since it is adaptive
in such a way that it can promote proliferation and
invasion by means of an overactive cell cycle and in turn
cellular division which is targeted by antimitotic drugs
that are highly validated chemotherapy agents. However,
antimitotic drug cytotoxicity to non-tumorigenic cells and
multiple cancer resistance developed in response to drugs
such as taxanes and vinca alkaloids are obstacles faced in
both the clinical and basic research field to date. In this
review, the classes of antimitotic compounds, their mechanisms
of action and cancer cell resistance to chemotherapy
and other limitations of current antimitotic compounds are
highlighted, as well as the potential of novel 17-β estradiol
analogs as cancer treatment.Medical Research Council of South Africa, the Research Committee of the Faculty of Health Sciences of the University of Pretoria, the Cancer association of South Africa and the National Research Foundation.http://link.springer.com/journal/280hb201
The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance
INTRODUCTION
Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic.
RATIONALE
We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs).
RESULTS
Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants.
CONCLUSION
Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century
Autophagy induced by a sulphamoylated estrone analogue contributes to its cytotoxic effect on breast cancer cells
BACKGROUND : Autophagy can either be protective and confer survival to stressed cells, or it can contribute to cell
death. The antimitotic drug 2-ethyl-3-O-sulpamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol) is an in silico-designed
17-β-estradiol analogue that induces both autophagy and apoptosis in cancer cells. The aim of the study was to
determine the role of autophagy in ESE-15-ol-exposed human adenocarcinoma breast cancer cells; knowledge that
will contribute to future clinical applications of this novel antimitotic compound. By inhibiting autophagy and determining
the cytotoxic effects of ESE-15-ol-exposure, deductions could be made as to whether the process may confer
resistance to the drug, or alternatively, contribute to the cell death process.
METHODS AND RESULTS : Spectophometrical analysis via crystal violet staining was used to perform cytotoxicity studies.
Morphology studies were done using microscopic techniques namely polarization-optical transmitted light differential
interference light microscopy, fluorescent microscopy using monodansylcadaverine staining and transmission
electron microscopy. Flow cytometry was used to quantify the autophagy inhibition and assess cell viability. Results
obtained indicated that 3-methyladenine inhibited autophagy and increased cell survival in both MCF-7 and MDAMB-
231 cell lines.
CONCLUSION : This in vitro study inferred that autophagy inhibition with 3-methyladenine does not confer increased
effectiveness of ESE-15-ol in inducing cell death. Thus it may be concluded that the autophagic process induced by
ESE-15-ol exposure in MCF-7 and MDA-MB-231 cells plays a more significant role in cell death than conferring survival.Grants from the Medical Research Council of South Africa, the
Cancer Association of South Africa, National Research Foundation and the
Struwig-Germeshuysen Cancer Research Trust of South Africa.http://www.cancerci.comam2017Physiolog
In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells
BACKGROUND : Computer-based technology is becoming increasingly essential in biological research where drug
discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17β-estradiol
metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple
myeloma. Owing to 2ME2’s poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized
a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and
ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2
(1 μM), were assessed on morphology and apoptosis induction in cervical cancer cells.
RESULTS : Transmission electron microscopy, scanning electron microscopy and polarization-optical transmitted
light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including
apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed
apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted
in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more
pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8
activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating
the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower
pharmacological concentration (180 nM) compared to 2ME2 (1 μM physiological concentration).
CONCLUSION : Computer-based technology is essential in drug discovery and together with in vitro studies for the
evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and
time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro.
Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a
nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate
the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In
silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability
while preserving apoptotic activity in vitro.The Cancer Association of South
Africa, the Struwig Germeshuysen Trust, RESCOM (School of Medicine,
Research Committee of the Faculty of Health Sciences, University of Pretoria),
the National Research Foundation and the Medical Research Council of South
Africa.http://www.biolres.com/am2016Physiolog