Gaining notoriety through translocation: a case of the apoptosis-inducing factor (AIF) in poly (ADP-ribose) polymerase (PARP)-1-dependent neuronal death

The enormous global burden of neurological and neurodegenerative diseases compels a frantic search for novel neurotherapeutics that will address the underlying pathologies, unlike most of the current pharmacological interventions that predominantly merely relieve symptoms of disease. A major challenge, however, is that the central nervous system (CNS), in contrast to most other well-studied systems, exhibits significant complexity that perhaps makes it one of the, if not the, least tractable to date, at least on the drug discovery landscape. Nevertheless, in the last few years, giant strides in CNS research have yielded significantly-improved understanding of the molecular underpinnings of the various pathological conditions of the brain, not least those associated with the death of neurones, including Parkinson\u2019s and Alzheimer\u2019s diseases. Accordingly, one pathway now known to be majorly involved in the induction of neuronal death is associated with the nuclear enzyme, poly (ADP-ribose) polymerase-1 (PARP-1), whose excessive activation generates a large amount of its polymer, poly (ADP-ribose) (PAR), which, in turn, causes an otherwise beneficial protein, normally resident in the mitochondria, the apoptosis-inducing factor (AIF), to exit its natural domain and enter the nucleus, where it causes large-scale DNA fragmentation and chromatin condensation, ultimately resulting in neuronal death. This review briefly explores the pathological cascade and suggests why targeting it in drug discovery - especially at the level of nuclear AIF translocation - is a rational and promising approach that may eventually deliver novel drugs for clinical use. In addition, the work illustrates how a clear knowledge of the spatio-temporal dynamics of molecular events is highly critical and, in fact, indispensable to a successful drug discovery and development campaign from the bench to the bedside, while at the same time highlighting the multi-disciplinary nature of the drug discovery enterprise

OLAX SUBSCORPIOIDEA OLIV. (OLACACEAE): AN ETHNOMEDICINAL AND PHARMACOLOGICAL REVIEW

Background Olax subscorpioidea Oliv. (Olacaceae) is a woody shrub that is widely distributed in Africa. It has trado-medicinal importance and is used in the treatment of asthma, cancer, convulsion, diabetes, intestinal worm infections, jaundice, mental illnesses, neurodegenerative disorders, sexually transmitted infections, swellings and rheumatism, and yellow fever. Aims To review available literature on the phytochemistry, ethnobotany, pharmacology and toxicity of Olax subscorpioidea Oliv. Methods Published findings were searched in online databases such as Web of Science, Scopus, Pubmed, Google Scholar and other relevant sources, and the data were sorted by relevance.  Combinations of keywords used in the search include Olax subscorpioidea, Olacaceae, Olax, Ewe Ifon, and African medicinal plants. Results The presence of alkaloids, anthraquinones, cardiac glycosides, flavonoids, phenolic compounds, proanthocyanidins, saponins, tannins and triterpenes has been reported from O. subscorpioidea. Cytotoxic santalbic acid was isolated from the methanol extract of the seed of this plant, while GC-MS and HPLC analyses of the n-butanol and n-hexane extracts of the leaf revealed the presence of caffeic acid, quercetin, morin, rutin, n-hexadecanoic acid (palmitic acid), 7,10,13-hexadecatrienoic acid and methyl ester, hentriacontane, 9,17-octadecadienal (Z)-, 9,12-octadecadienoic acid (Z,Z)-, squalene, nonacosane, octadecanoic acid. Bioactivity studies on this plant demonstrated its medicinal potential mainly as an analgesic, anthelmintic, anti-arthritic, antidepressant, antihyperglycaemic, anti-inflammatory, antioxidant, antimalarial and antimicrobial agent. Oral acute toxicity of the leaf extracts in rats appeared to be greater than 5,000 mg/kg body weight. Conclusion Published literature available to date on O. subscorpioidea provides some preliminary scientific basis for the ethnomedicinal uses of this plant. However, some ethnomedicinal uses have not been scientifically validated yet, and similarly, only a limited amount of information is available on properly isolated and identified phytochemicals from this plant that link to its bioactivitie

Synthesis, substitution kinetics, DNA/BSA binding and cytotoxicity of tridentate N^E^N (E = NH, O, S) pyrazolyl palladium(II) complexes

The pincer complexes, [Pd(L1)Cl]BF4 (PdL1), [Pd(L2)Cl]BF4 (PdL2), [Pd(L3)Cl]BF4 (PdL3), [Pd(L4)Cl]BF4 (PdL4) were prepared by reacting the corresponding ligands, 2,6-bis[(1H-pyrazol-1-yl)methyl]pyridine (L1), bis[2-(1H-pyrazol-1-yl)ethyl]amine (L2), bis[2-(1H-pyrazol-1-yl)ethyl]ether (L3), and bis[2-(1H-prazol-1-yl)ethyl]sulphide (L4) with [PdCl2(NCMe)]2 in the presence NaBF4. The solid‐state structures of complexes PdL1–PdL4 confirmed a tridentate coordination mode, with one chloro ligand completing the coordination sphere to afford square-planar complexes. Chemical behaviour of the complexes in solution confirms their stability in both aqueous and DMSO stock media. The electrochemical properties of the compounds showed irreversible two-electron reduction process. Kinetic reactivity of Pd complexes with the biological nucleophiles viz, thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5’-GMP) followed the order: PdL2  100 µM) when tested against the human cervical adenocarcinoma (HeLa) cell line and the transformed human lung fibroblast cell line (MRC-5 SV2)

RESEARCH ACTIVITIES IN THE CENTRE FOR NATURAL PRODUCTS DISCOVERY IN 2023

In 2023, the Centre for Natural Products Discovery (CNPD) made significant strides in the scientific community through a series of impactful research initiatives. These efforts underscore our commitment to harnessing the world’s natural resources to advance health. The fertile research environment at the CNPD has given rise to various sections, each contributing innovative and practical applications. Our goal here is to provide a concise overview of our research activities for the year. While this summary is not exhaustive, it focuses on the work of our section leaders, which in turn encompasses the contributions of numerous other researchers both within and outside the CNPD

Cola rostrata K. Schum. constituents induce cytotoxicity through reactive oxygen species generation and mitochondrial membrane depolarisation

Aim: While the traditional use of Cola rostrata in treating illnesses and diseases has not been reported, the presence of cytotoxic principles has been reported in phylogenetically and biogeographically related species within the Cola genus. This study, therefore, evaluated the cytotoxic potential of extracts of the plant, and the associated cellular and molecular mechanisms. Methods: Activity-based fractionation of the extracts was carried out and cytotoxicity was assessed in the human cervical cancer cell line, HeLa, and the transformed human lung cell line, MRC5-SV2, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay complemented with brightfield imaging. The 2ʼ,7ʼ-dichlorofluorescein diacetate (DCFDA) assay was used to assess induction of cellular reactive oxygen species (ROS), while flow cytometry of 5,5ʼ,6,6ʼ-tetrachloro-1,1ʼ,3,3ʼ-tetraethyl-imidacarbocyanine iodide (JC-1)-stained cells assessed the loss of mitochondrial membrane potential (∆ΨM). Gas chromatography-mass spectrometry (GC-MS) analysis was carried out on an active fraction. Results: Extracts of the fruit epicarp and leaf were cytotoxic against the cell lines. Half-maximal inhibitory concentration (IC50) values for the 48 h cytotoxicity of the ethanol extract of the epicarp against HeLa and MRC5-SV2 cells were 48.0 μg/mL ± 12.1 μg/mL and 40.4 μg/mL ± 7.2 μg/mL, respectively, while fractions from second-level partitioning of the hexane fraction of the leaf extract elicited cytotoxicity with IC50 values ranging from 12.8 μg/mL ± 1.0 μg/mL to 39.6 μg/mL ± 7.2 μg/mL in both cell lines, following 48 h treatment. GC-MS revealed the presence of seventeen compounds in a hexane fraction of the leaf extract, including even- and odd-chain fatty acids, the most abundant of which were n-hexadecanoic acid, decanoic acid 10-(2-hexylcyclopropyl); and octadecanoic acid. The mechanisms of cytotoxicity of most active fractions involved generation of ROS and mitochondrial membrane depolarisation. Conclusions: The findings show that C. rostrata is rich in cytotoxic phytochemicals which could be isolated for developing new anti-cancer agents

West African medicinal plants and their constituent compounds as treatments for viral infections, including SARS-CoV-2/COVID-19

Objectives: The recent emergence of the COVID-19 pandemic (caused by SARS-CoV-2) and the experience of its unprecedented alarming toll on humanity have shone a fresh spotlight on the weakness of global preparedness for pandemics, significant health inequalities, and the fragility of healthcare systems in certain regions of the world. It is imperative to identify effective drug treatments for COVID-19. Therefore, the objective of this review is to present a unique and contextualised collection of antiviral natural plants or remedies from the West African sub-region as existing or potential treatments for viral infections, including COVID-19, with emphasis on their mechanisms of action. Evidence acquisition: Evidence was synthesised from the literature using appropriate keywords as search terms within scientific databases such as Scopus, PubMed, Web of Science and Google Scholar. Results: While some vaccines and small-molecule drugs are now available to combat COVID-19, access to these therapeutic entities in many countries is still quite limited. In addition, significant aspects of the symptomatology, pathophysiology and long-term prognosis of the infection yet remain unknown. The existing therapeutic armamentarium, therefore, requires significant expansion. There is evidence that natural products with antiviral effects have been used in successfully managing COVID-19 symptoms and could be developed as anti-COVID-19 agents which act through host- and virus-based molecular targets. Conclusion: Natural products could be successfully exploited for treating viral infections/diseases, including COVID-19. Strengthening natural products research capacity in developing countries is, therefore, a key strategy for reducing health inequalities, improving global health, and enhancing preparedness for future pandemics

Peptide based drug delivery systems to the brain

Abstract: With estimated worldwide cost over $1 trillion just for dementia, diseases of the central nervous system pose a major problem to health and healthcare systems, with significant socio-economic implications for sufferers and society at large. In the last two decades, numerous strategies and technologies have been developed and adapted to achieve drug penetration into the brain, evolving alongside our understanding of the physiological barriers between the brain and surrounding tissues. The blood brain barrier (BBB) has been known as the major barrier for drug delivery to the brain. Both invasive and minimally-invasive approaches have been investigated extensively, with the minimally-invasive approaches to drug delivery being more suitable. Peptide based brain targeting has been explored extensively in the last two decades. In this review paper, we focused on self-assembled peptides, shuttle peptides and nanoparticles drug delivery systems decorated/conjugated with peptides for brain penetration

(Pyrazolyl)pyridine ruthenium(III) complexes: Synthesis, kinetics of substitution reactions with thiourea and biological studies

Reactions of 2-bromo-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (L1), 2,6-di (1H-pyrazol-1-yl) pyridine (L2) and 2,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)pyridine (L3) with RuCl3·3H2O led to the formation of their respective metal complexes [RuCl3(L1)] (1), [RuCl3(L2)] (2) and [RuCl3(L3)] (3). Solid state structure of complex 3 established the formation of a six-coordinate mononuclear compound in which L3 is tridentately bound. The order of reactivity of the studied complexes with thiourea (TU) nucleophile is in the form 1?>?2?>?3, in line with density functional theory (DFT) studies. The complexes displayed minimal cytotoxic activity against the HeLa cell line, consistent with molecular docking experiments which showed weaker DNA binding affinities

Palladium(II) complexes of tridentate bis(benzazole) ligands: Structural, substitution kinetics, DNA interactions and cytotoxicity studies.

Reactions of 2,6-bis(benzimidazol-2-yl)pyridine (L1), 2,6-bis(benzoxazol-2-yl)pyridine (L2), and 2,6-bis(benzothiazol-2-yl)pyridine (L3) with [Pd(NCMe)2Cl2] in the presence of NaBF4 afforded the corresponding Pd(II) complexes, [Pd(L1)Cl]BF4, PdL1; [Pd(L2)Cl]BF4, PdL2; [Pd(L3)Cl]BF4, PdL3; respectively, while reaction of bis[(1H-benzimidazol-2-yl)methyl]amine (L4) with [Pd(NCMe)2Cl2] afforded complex [Pd(L4)Cl]Cl, PdL4. Characterisation of the complexes was accomplished using NMR, IR, MS, elemental analyses and single crystal X-ray crystallography. Ligand substitution kinetics of these complexes by biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5'-diphosphate disodium salt (5-GMP) were examined under pseudo-first order conditions. The reactivity of the complexes decreased in the order: PdL1 > PdL2 > PdL3 > PdL4, ascribed to electronic effects. Density functional theory (DFT) supported this trend. Studies of interaction of the Pd(II) complexes with calf thymus DNA (CT-DNA) revealed strong binding affinities via intercalative binding mode. Molecular docking studies established associative non-covalent interactions between the Pd complexes and DNA. The in vitro cytotoxic activities of PdL1-PdL4 were assessed in cancer cell lines HeLa and MRC5-SV2 and a normal cell line MRC-5, using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. PdL1 exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin's. Complex PdL1, unlike cisplatin, did not significantly induce caspase-dependent apoptosis

Development of Brain Targeting Peptide Based MMP-9 Inhibiting Nanoparticles for the Treatment of Brain Diseases with Elevated MMP-9 Activity.

Latent and active levels of cerebral matrix metalloproteinase 9 (MMP-9) are elevated in neurological diseases and brain injuries, contributing to neurological damage and poor clinical outcomes. This study aimed developing peptide-based nanoparticles with ability to cross the blood-brain-barrier (BBB) and inhibit MMP-9. Three amphiphilic peptides were synthesised containing brain-targeting ligands (HAIYPRH or CKAPETALC) conjugated with MMP-9 inhibiting peptide (CTTHWGFTLC) linked by glycine (spacer) at the N-terminus, and the peptide sequences were conjugated at the N- terminus to cholesterol. 19F NMR assay was developed to measure MMP-9 inhibition. Cell toxicity was evaluated by the LDH assay, and dialysis studies were conducted with/without fetal bovine serum. An in vitro model was employed to evaluate the ability of nanoparticles crossing the BBB. The amphiphilic peptide (Cholesterol-GGGCTTHWGFTLCHAIYPRH) formed nanoparticles (average size of 202.8 nm) with ability to cross the BBB model. MMP-9 inhibiting nanoparticles were non-toxic to cells, and reduced MMP-9 activity from kobs of 4.5 × 10-6s-1 to complete inhibition. Dialysis studies showed that nanoparticles did not disassemble by extreme dilution (40 folds), but gradually hydrolysed by serum enzymes. In conclusion, the MMP-9 inhibiting nanoparticles reduced the activity of MMP-9, with acceptable serum stability, minimal cell toxicity and ability to cross the in vitro BBB model