Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) globally, and novel treatments are urgently needed. Current therapeutic approaches for diabetic nephropathy (DN) are ...focussing on blood pressure control with inhibitors of the renin–angiotensin–aldosterone system, on glycaemic and lipid control, and life-style changes. In this review, we highlight new molecular insights aiding our understanding of the initiation and progression of DN, including glomerular insulin resistance, dysregulation of cellular substrate utilisation, podocyte–endothelial communication, and inhibition of tubular sodium coupled glucose reabsorption. We believe that these mechanisms offer new therapeutic targets that can be exploited to develop important renoprotective treatments for DN over the next decade.
The global burden of neurodegenerative disorders has increased substantially over the past 2 decades due to rising rates of population aging. Although neurodegenerative disorders differ in their ...clinical presentation, the underlying pathobiological processes are largely shared. Oxidative stress, among other mechanisms, is strongly implicated in neurodegenerative disorders and aging, and can potentially be targeted by antioxidative agents. Curcumin, a component of turmeric, is a compound that has received considerable attention for its therapeutic properties, and it is considered to be a powerful antioxidant. In this review, we analyzed the evidence for curcumin as an antioxidant in models of neurodegenerative disorders as well as oxido-nitrosative stress. A total of 1451 articles were found from 3 scientific literature databases (PubMed, Scopus, and Web of Science). After all exclusions, a final total of 64 articles were included in this review. The majority of the studies showed that curcumin, or derivatives thereof, were protective against oxidative and/or nitrosative stress in various cellular and animal models. Overall, curcumin protected against lipid and protein oxidation with a reduction in levels of malondialdehyde, and protein carbonyls, thiols and nitrotyrosines. Furthermore, it stimulated the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In conclusion, curcumin appears to be a promising compound for phytomedicine. However, due to some concerns about its efficacy, further targeted experiments are needed to identify its exact molecular targets and pathways responsible for its antioxidant effects.
•64 relevant articles were found in animal and cellular models of neurodegeneration, aging and oxido-nitrosative stress.•The majority of studies showed curcumin alleviated oxidative stress under a wide range of experimental conditions.•Curcumin inhibited lipid and protein oxidation by suppressing malondialdehyde and protein carbonyls.•Curcumin stimulated the activities of various antioxidant enzymes, including superoxide dismutase and catalase.
DNA damage, largely owing to oxidative stress, is a leading cause of defective sperm function. High levels of oxidative stress result in damage to sperm DNA, RNA transcripts, and telomeres and, ...therefore might provide a common underlying aetiology of male infertility and recurrent pregnancy loss, in addition to congenital malformations, complex neuropsychiatric disorders, and childhood cancers in children fathered by men with defective sperm cells. Spermatozoa are highly vulnerable to oxidative stress owing to limited levels of antioxidant defence and a single, limited DNA-damage detection and repair mechanism. Oxidative stress is predominantly caused by a host of lifestyle-related factors, the majority of which are modifiable. Antioxidant regimens and lifestyle modifications could both be plausible therapeutic approaches that enable the burden of oxidative-stress-induced male factor infertility to be overcome. Lifestyle interventions including yoga and meditation can substantially improve the integrity of sperm DNA by reducing levels of oxidative DNA damage, regulating oxidative stress and by increasing the expression of genes responsible for DNA repair, cell-cycle control and anti-inflammatory effects. Oxidative stress is caused by various modifiable factors, and the use of simple interventions can decrease levels of oxidative stress, and therefore reduce the incidence of both infertility and complex diseases in the resultant offspring.
Antibiotic resistance is a worldwide public health concern. Conjugative transfer between closely related strains or species of bacteria is an important method for the horizontal transfer of ...multidrug-resistance genes. The extent to which nanomaterials are able to cause an increase in antibiotic resistance by the regulation of the conjugative transfer of antibiotic-resistance genes in bacteria, especially across genera, is still unknown. Here we show that nanomaterials in water can significantly promote the horizontal conjugative transfer of multidrug-resistance genes mediated by the RP4, RK2, and pCF10 plasmids. Nanoalumina can promote the conjugative transfer of the RP4 plasmid from Escherichia coll to Salmonella spp. by up to 200-fold compared with untreated cells. We also explored the mechanisms behind this phenomenon and demonstrate that nanoalumina is able to induce oxidative stress, damage bacterial cell membranes, enhance the expression of mating pair formation genes and DNA transfer and replication genes, and depress the expression of global regulatory genes that regulate the conjugative transfer of RP4. These findings are important in assessing the risk of nanomaterials to the environment, particularly from water and wastewater treatment systems, and in the estimation of the effect of manufacture and use of nanomaterials on the environment.
Highlights ► The resistance of cancer cells to ROS might be due to a small population of CSCs. ► CSCs prevent ROS formation avoiding aerobic respiration and increasing glycolysis. ► Most radio- and ...chemotherapeutical treatments are based on ROS induction. ► ROS levels in a specific tumor would help define the best therapy for each patient.
Aging is characterized by a number of hallmarks including loss of mitochondrial homeostasis and decay in stress tolerance, among others. Unicellular eukaryotes have been widely used to study ...chronological aging. As a general trait, calorie restriction and activation of mitochondrial respiration has been proposed to contribute to an elongated lifespan. Most aging-related studies have been conducted with the Crabtree-positive yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and with deletion collections deriving from these conventional yeast models. We have performed an unbiased characterization of longevity using thirteen fungi species, including S. cerevisiae and S. pombe, covering a wide range of the Ascomycota clade. We have determined their mitochondrial activity by oxygen consumption, complex IV activity, and mitochondrial redox potential, and the results derived from these three methodologies are highly overlapping. We have phenotypically compared the lifespans of the thirteen species and their capacity to tolerate oxidative stress. Longevity and elevated tolerance to hydrogen peroxide are correlated in some but not all yeasts. Mitochondrial activity per se cannot anticipate the length of the lifespan. We have classified the strains in four groups, with members of group 1 (Kluyveromyces lactis, Saccharomyces bayanus and Lodderomyces elongisporus) displaying high mitochondrial activity, elevated resistance to oxidative stress, and elongated lifespan.
The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal ...cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.
Diabetic retinopathy remains the major cause of blindness among working age adults. Although a number of metabolic abnormalities have been associated with its development, due to complex nature of ...this multi-factorial disease, a link between any specific abnormality and diabetic retinopathy remains largely speculative. Diabetes increases oxidative stress in the retina and its capillary cells, and overwhelming evidence suggests a bidirectional relationship between oxidative stress and other major metabolic abnormalities implicated in the development of diabetic retinopathy. Due to increased production of cytosolic reactive oxygen species, mitochondrial membranes are damaged and their membrane potentials are impaired, and complex III of the electron transport system is compromised. Suboptimal enzymatic and nonenzymatic antioxidant defense system further aids in the accumulation of free radicals. As the duration of the disease progresses, mitochondrial DNA (mtDNA) is damaged and the DNA repair system is compromised, and due to impaired transcription of mtDNA-encoded proteins, the integrity of the electron transport system is encumbered. Due to decreased mtDNA biogenesis and impaired transcription, superoxide accumulation is further increased, and the vicious cycle of free radicals continues to self-propagate. Diabetic milieu also alters enzymes responsible for DNA and histone modifications, and various genes important for mitochondrial homeostasis, including mitochondrial biosynthesis, damage and antioxidant defense, undergo epigenetic modifications. Although antioxidant administration in animal models has yielded encouraging results in preventing diabetic retinopathy, controlled longitudinal human studies remain to be conducted. Furthermore, the role of epigenetic in mitochondrial homeostasis suggests that regulation of such modifications also has potential to inhibit/retard the development of diabetic retinopathy.
•Diabetes induces oxidative stress, and increased cytosolic reactive oxygen species damage retinal mitochondrial function and DNA.•Enzymes responsible for epigenetic modification are altered, and genes important in mitochondrial homeostasis are epigenetically modified.•The superoxide scavenging system and mtDNA-transcription are compromised, further fueling into the vicious cycle of free radicals.•Regulation of mitochondrial homeostasis has potential to offer therapeutic modalities for the treatment of diabetic retinopathy.
Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental ...trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.
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