Department of Pharmacology and Toxicology
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Item Cellular and molecular mechanisms of cell damage and cell death in ischemia–reperfusion injury in organ transplantation(Molecular Biology Reports, 2024) Dugbartey, G.J.Ischemia–reperfusion injury (IRI) is a critical pathological condition in which cell death plays a major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs cellular metabo lism and decreases cellular bioenergetics through dysfunction of mitochondrial electron transport chain, causing a switch from cellular respiration to anaerobic metabolism, and subsequent cascades of events that lead to increased intracellular concentrations of Na+, H+ and Ca2+ and consequently cellular edema. Restoration of blood supply after ischemia provides oxygen to the ischemic tissue in excess of its requirement, resulting in over-production of reactive oxygen species (ROS), which overwhelms the cells’ antioxidant defence system, and thereby causing oxidative damage in addition to activating pro-infammatory pathways to cause cell death. Moderate ischemia and reperfusion may result in cell dysfunction, which may not lead to cell death due to activation of recovery systems to control ROS production and to ensure cell survival. However, prolonged and severe ischemia and reperfusion induce cell death by apoptosis, mitoptosis, necrosis, necroptosis, autophagy, mitophagy, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, pyroptosis, cuproptosis and parthanoptosis. This review discusses cellular and molecular mechanisms of these various forms of cell death in the context of organ transplantation, and their inhibition, which holds clinical promise in the quest to prevent IRI and improve allograft quality and function for a long-term success of organ transplantation.Item Redox System and Oxidative Stress-Targeted Therapeutic Approaches in Bladder Cancer(Antioxidants, 2024) Dugbartey, G.J.; Relouw, S.; McFarlane, L.; Sener, A.Bladder cancer (BCa) is the most common genitourinary malignancy, with a high global incidence and recurrence rate that is paired with an increasing caregiver burden and higher financial cost, in addition to increasing morbidity and mortality worldwide. Histologically, BCa is categorized into non-muscle invasive, muscle invasive, and metastatic BCa, on the basis of which the therapeutic strategy is determined. Despite all innovations and recent advances in BCa research, conventional therapies such as chemotherapy, immunotherapy, radiotherapy, and surgery fall short in the complete management of this important malignancy. Besides this worrying trend, the molecular basis of BCa development also remains poorly understood. Burgeoning evidence from experimental and clinical studies suggests that oxidative stress resulting from an imbalance between reactive oxygen species (ROS) generation and the body’s antioxidant production plays an integral role in BCa development and progression. Hence, ROS-induced oxidative stress-related pathways are currently under inves tigation as potential therapeutic targets of BCa. This review focuses on our current understanding regarding ROS-associated pathways in BCa pathogenesis and progression, as well as on antioxidants as potential adjuvants to conventional BCa therapyItem Evaluating the Effects of Kidney Preservation at 10 ◦C with Hemopure and Sodium Thiosulfate in a Rat Model of Syngeneic Orthotopic Kidney Transplantation(International Journal of Molecular Sciences, 2024) Taka, M.A.; Dugbartey, G.J.; Richard-Mohamed, M.; et al.Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 ◦C. However, SCS contributes to renal graft damage through ischemia–reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 ◦C. Therefore, this study aims to investigate whether SCS at 10 ◦C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia–reoxygenation for 24 h at 10 ◦C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 ◦C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 ◦C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 ◦C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications.Item An Acute And Sub-Acute Toxicological Assessment Of Reissantia Indica Plant Extract In Male Sprague-Dawley Rats: Hematological, Serum Biochemical And Histopathology(Scientific African, 2024) Amoateng, E.O.; Amoateng, P.; Ossei, P.P.S.; et al.The traditional use of medicinal plants in sub-Saharan health management lacks thorough toxicological evaluations, particularly concerning lethal dose levels. This study aims to assess the acute and sub-acute toxicity of Reissantia indica whole-plant extract (RIE) in male Sprague-Dawley rats, with a focal point on delineating its safety profile while exploring potential therapeutic applications. RIE, obtained through precise cold maceration in 70 % ethanol, underwent rigorous analysis. revealing diverse secondary metabolites, including alkaloids, flavonoids, terpenoids, and glycosides. Renowned for antioxidant, anti-inflammatory, and anticancer properties, these compounds enhance RIE’s pharmacological potential. In the acute toxicity study, RIE was orally administered at 500 and 5000 mg/kg. Sub-acute toxicity involved oral administration of the extract at various doses (5, 50 and 500 mg/kg) over 28 days, with comprehensive assessments, including hematological, biochemical, and histopathological evaluations. Results from the acute toxicity showed no mortality, suggesting a median lethal dose (LD50) exceeding 5000 mg/kg and indicating a substantial margin of safety. Sub-acute toxicity investigations spanning 28 days revealed no significant changes in body and organ weights, hematological and biochemical parameters, or histopathological signs compared to the control group. Histological examination of kidney, liver, heart, and lung sections from treated animals showed no signs of degeneration.Item Nitric oxide in kidney transplantation(Biomedicine & Pharmacotherapy, 2023) Dugbartey, G.J.Kidney transplantation is the treatment of choice for patients with kidney failure. Compared to dialysis therapy, it provides better quality of life and confers significant survival advantage at a relatively lower cost. However, the long-term success of this life-saving intervention is severely hampered by an inexorable clinical problem referred to as ischemia-reperfusion injury (IRI), and increases the incidence of post-transplant complications including loss of renal graft function and death of transplant recipients. Burgeoning evidence shows that nitric oxide (NO), a poisonous gas at high concentrations, and with a historic negative public image as an environ mental pollutant, has emerged as a potential candidate that holds clinical promise in mitigating IRI and pre venting acute and chronic graft rejection when it is added to kidney preservation solutions at low concentrations or when administered to the kidney donor prior to kidney procurement and to the recipient or to the reperfusion circuit at the start and during reperfusion after renal graft preservation. Interestingly, dysregulated or abnormal endogenous production and metabolism of NO is associated with IRI in kidney transplantation. From experi mental and clinical perspectives, this review presents endogenous enzymatic production of NO as well as its exogenous sources, and then discusses protective effects of constitutive nitric oxide synthase (NOS)-derived NO against IRI in kidney transplantation via several signaling pathways. The review also highlights a few isolated studies of renal graft protection by NO produced by inducible NOS.Item Therapeutic benefits of nitric oxide in lung transplantation(Biomedicine & Pharmacotherapy, 2023) Dugbartey, G.J.Lung transplantation is an evolutionary procedure from its experimental origin in the twentieth century and is now recognized as an established and routine life-saving intervention for a variety of end-stage pulmonary diseases refractory to medical management. Despite the success and continuous refinement in lung trans plantation techniques, the widespread application of this important life-saving intervention is severely hampered by poor allograft quality offered from donors-after-brain-death. This has necessitated the use of lung allografts from donors-after-cardiac-death (DCD) as an additional source to expand the pool of donor lungs. Remarkably, the lung exhibits unique properties that may make it ideally suitable for DCD lung transplantation. However, primary graft dysfunction (PGD), allograft rejection and other post-transplant complications arising from un avoidable ischemia-reperfusion injury (IRI) of transplanted lungs, increase morbidity and mortality of lung transplant recipients annually. In the light of this, nitric oxide (NO), a selective pulmonary vasodilator, has been identified as a suitable agent that attenuates lung IRI and prevents PGD when administered directly to lung donors prior to donor lung procurement, or to recipients during and after transplantation, or administered indirectly by supplementing lung preservation solutions. This review presents a historical account of clinical lung transplantation and discusses the lung as an ideal organ for DCD. Next, the author highlights IRI and its clinical effects in lung transplantation. Finally, the author discusses preservation solutions suitable for lung trans plantation, and the protective effects and mechanisms of NO in experimental and clinical lung transplantatItem Therapeutic benefits of nitric oxide in lung transplantation(Biomedicine & Pharmacotherapy, 2023) Dugbartey, G.J.Lung transplantation is an evolutionary procedure from its experimental origin in the twentieth century and is now recognized as an established and routine life-saving intervention for a variety of end-stage pulmonary diseases refractory to medical management. Despite the success and continuous refinement in lung transplantation techniques, the widespread application of this important life-saving intervention is severely hampered by poor allograft quality offered from donors-after-brain-death. This has necessitated the use of lung allografts from donors-after-cardiac-death (DCD) as an additional source to expand the pool of donor lungs. Remarkably, the lung exhibits unique properties that may make it ideally suitable for DCD lung transplantation. However, primary graft dysfunction (PGD), allograft rejection and other post-transplant complications arising from unavoidable ischemia-reperfusion injury (IRI) of transplanted lungs, increase morbidity and mortality of lung transplant recipients annually. In the light of this, nitric oxide (NO), a selective pulmonary vasodilator, has been identified as a suitable agent that attenuates lung IRI and prevents PGD when administered directly to lung donors prior to donor lung procurement, or to recipients during and after transplantation, or administered indirectly by supplementing lung preservation solutions. This review presents a historical account of clinical lung transplantation and discusses the lung as an ideal organ for DCD. Next, the author highlights IRI and its clinical effects in lung transplantation. Finally, the author discusses preservation solutions suitable for lung transplantation, and the protective effects and mechanisms of NO in experimental and clinical lung transplantation.Item Nitric oxide in kidney transplantation(Biomedicine & Pharmacotherapy, 2023) Dugbartey, G.J.Kidney transplantation is the treatment of choice for patients with kidney failure. Compared to dialysis therapy, it provides better quality of life and confers significant survival advantage at a relatively lower cost. However, the long-term success of this life-saving intervention is severely hampered by an inexorable clinical problem referred to as ischemia-reperfusion injury (IRI), and increases the incidence of post-transplant complications including loss of renal graft function and death of transplant recipients. Burgeoning evidence shows that nitric oxide (NO), a poisonous gas at high concentrations, and with a historic negative public image as an environ mental pollutant, has emerged as a potential candidate that holds clinical promise in mitigating IRI and pre venting acute and chronic graft rejection when it is added to kidney preservation solutions at low concentrations or when administered to the kidney donor prior to kidney procurement and to the recipient or to the reperfusion circuit at the start and during reperfusion after renal graft preservation. Interestingly, dysregulated or abnormal endogenous production and metabolism of NO is associated with IRI in kidney transplantation. From experi mental and clinical perspectives, this review presents endogenous enzymatic production of NO as well as its exogenous sources, and then discusses protective effects of constitutive nitric oxide synthase (NOS)-derived NO against IRI in kidney transplantation via several signaling pathways. The review also highlights a few isolated studies of renal graft protection by NO produced by inducible NOS.Item From nature's bounty to drug discovery: Leveraging phytochemicals and molecular approaches to combat multi-drug-resistant (MDR) tuberculosis(Indian Journal of Tuberculosis, 2023) Nalam, S.M.; Chintamaneni, P.K.; Amoateng, P.; et al.A large number of people annually lose their lives to tuberculosis (TB), which is an age-old disease caused by the Mycobacterium tuberculosis. The global spread of TB is a concern for all regions. The south-east Asian region recorded 46% of all new TB cases in 2021, followed by the African and western Pacific regions with 23% and 18%, respectively. Researchers are always searching at natural substances for potential alternative therapeutics to tackle the worrisome growth in multi-drug-resistant (MDR) tuberculosis due to the high costs associated with developing new treatments and unfavourable side effects of currently used synthetic pharmaceuticals. Phytochemicals show promising results as a future health aid due to their multi-targeting ability on pathogen cells. In the search for new drug leads, the Ayurvedic and Siddha medical systems have made an extensive use of ethnomedicinal tools, including the use of plants like Amalaki (Emblica officinalis Gaertn.), Guduchi (Tinospora cordifolia willd.), Sariva (Hemidesmus indicus R.Br.), Kustha (Saussurea lappa Falc.), turmeric (Curcuma longa Mal.) and Green tea (Camellia sinensis Linn.). These sources are high in flavonoids, polyphenols, tannins and catechins, has been shown to reduce the risk of TB. In this overview, we look at how natural sources like plants, algae and mushrooms have helped researchers to find new drug leads, and how to back these natural sources through mapping the molecular approaches and other approaches has helped them to defeat MDR.Item Physiological role of hydrogen sulfide in the kidney and its therapeutic implications for kidney diseases(Biomedicine & Pharmacotherapy, 2023) Dugbartey, G.J.For over three centuries, hydrogen sulfide (H2S) has been known as a toxic and deadly gas at high concentrations, with a distinctive smell of rotten eggs. However, studies over the past two decades have shown that H2S has risen above its historically notorious label and has now received significant scientific attention as an endogenously produced gaseous signaling molecule that participates in cellular homeostasis and influences a myriad of physiological and pathological processes at low concentrations. Its endogenous production is enzymatically regulated, and when dysregulated, contributes to pathogenesis of renal diseases. In addition, exogenous H2S administration has been reported to exhibit important therapeutic characteristics that target multiple molecular pathways in common renal pathologies in which reduced levels of renal and plasma H2S were observed. This review highlights functional anatomy of the kidney and renal production of H2S. The review also discusses current understanding of H2S in renal physiology and seeks to lay the foundation as a new targeted therapeutic agent for renal pathologies such as hypertensive nephropathy, diabetic kidney disease and water balance disorders.