Kidney transplant outcomes in minority populations: can we close the gap?

PURPOSE OF REVIEW: Health disparity in minority populations has been increasingly recognized over the last decade. The COVID-19 pandemic sheds a bright light on this very issue impressing upon the need for more research regarding healthcare in disparate populations. Although kidney transplantation remains the treatment of choice for end-stage renal disease management and longevity of life, access to transplantation remains a critical barrier in minority populations. The literature on disparity in access abounds but remains limited with regards to posttransplantation outcomes. The purpose of this review is to draw attention to existing research and literature in posttransplant outcomes and highlight the overall knowledge gap that persists in postkidney transplant care among disparate populations. RECENT FINDINGS: The current review focuses on important paradigm shifts in the determinants of outcomes in posttransplantation care in minority populations. It emphasizes a departure from immune mediated causes to more salient health inequities and socioeconomic factors contributing to patient and graft survival which require further investigation. SUMMARY: Despite increased awareness of health disparity in minority populations, outcomes data postkidney transplantation remains sparse. Critical to the future of kidney transplantation and improved healthcare coordination in minority populations will be a deeper understanding of contributing socio-economic variables in disparate outcomes.

Memory restorative ability of clioquinol in copper-cholesterol-induced experimental dementia in mice.

CONTEXT: Results from various studies indicate that the presence of certain heavy metals such as aluminum (Al), arsenic (As), copper (Cu), lead (Pb), and mercury (Hg) may enhance the aggregation of Aß and oxidative stress levels leading to neuronal toxicity and Alzheimer's disease (AD). Studies also reveal that anomalous brain copper-cholesterol (Cu-Ch) homeostasis may lead to memory deficits in Swiss albino mice. OBJECTIVE: The present study investigates the anti-amnesic potential of clioquinol (5-chloro-7-iodoquinolin-8-ol) in cognitive deficits associated with experimental dementia induced by Cu-Ch. MATERIALS AND METHODS: Administration of Cu-Ch {0.21 mg/kg, per os - 2% w/v, per os for 8 weeks} was used to induce dementia in Swiss albino mice. The Morris water maze (MWM) test was performed to assess the effect on learning and memory. A battery of biochemical estimations was performed following the MWM test such as brain-reduced glutathione (GSH), superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS), acetylcholinestrase (AChE) activity, and serum cholesterol levels. RESULTS: Administration of Cu-Ch produced a marked decline in MWM performance measured during the acquisition (78.9 ± 3.3) and retrieval trials (9.5 ± 2.4), reflecting impairment of learning and memory. Cu-Ch-treated mice also exhibited a marked accentuation of AChE activity (5.8 ± 0.55) and TBARS levels (9.74 ± 1.9) along with a decline in the GSH level (15.4 ± 3.3) and the SOD level (26 ± 2.5) when compared with the untreated control group. Administration of clioquinol significantly attenuated Cu-Ch-induced memory deficits and biochemical alterations. DISCUSSION AND CONCLUSION: The findings demonstrate memory restorative ability of clioquinol which may be attributed to its anti-cholinesterase, antioxidative, and cholesterol-lowering potential.

Liver X receptors: emerging therapeutic targets for Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder, typified by the pathological accumulation of ß-amyloid peptides (Aß) and neurofibrillary tangles within the brain, culminating to cognitive impairment. Epidemiological and biochemical data have suggested a link between cholesterol content, APP (amyloid precursor protein) processing, Aß, inflammation and AD. The intricacy of the disease presents considerable challenges for the development of newer therapeutic agents. Liver X receptors (LXRa and LXRß) are oxysterol activated nuclear receptors that play essential role in lipid and glucose homeostasis, steroidogenesis and inflammatory responses. LXR signalling impacts the development of AD pathology through multiple pathways. Reports indicate that genetic loss of either lxra or lxrß in APP/PS1 transgenic mice results in increased amyloid plaque load. Studies also suggest that ligand activation of LXRs in Tg2576 mice enhanced, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1, down regulated APP processing and Aß production with significant improvement in memory functions. LXR agonists have also depicted to inhibit neuroinflammation through modulation of microglial phagocytosis and by repressing the expression of cox2, mcp1 and iNos in glial cells. This review summarizes in brief the biology of LXRs, with an emphasis on their probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.

Bergenin ameliorates cognitive deficits and neuropathological alterations in sodium azide-induced experimental dementia.

Background: Bergenin, 4-O-methyl gallic acid glucoside, is a bioactive compound found in the cortex of Mallotus japonicus (L.f.) Müll.Arg. along with many other natural resources including that from Bergenia species. The present study delineates the neuroprotective potential of bergenin through the modulation of PPAR-γ receptors. Method: Dementia was induced in the Wistar rats by intraperitoneal (i.p.) administration of sodium azide (12.5 mg/kg for the first 5 days followed by 10 mg/kg for the next 9 days). The rats were then exposed to the Morris water maze test to assess the effect on cognitive abilities followed by a series of biochemical and histopathological evaluations. Results: Sodium azide-treated rats exhibited a severe deterioration of memory as suggested by poor performance in the spatial learning task in addition to the enhancement of brain acetylcholinesterase potential, oxidative stress, inflammation, and amyloid-ß (Aß) accumulation. Administration of bergenin to sodium azide-treated rats significantly recovered cognition and related biochemical variations. Further, co-administration of Bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist with bergenin challenged its neuroprotective effects. Conclusions: The findings of our study exhibit that the cognitive restoration potential of bergenin may be attributed to its modulatory effects against cholinesterase, oxidative stress, and inflammatory markers, as well as its neuroprotective actions, thus aligning it as a possible therapy for Alzheimer's disease-related dementia. The study also fortifies the significance of PPAR-γ receptors in dementia.

Protective effects of caspase-9 and poly(ADP-ribose) polymerase inhibitors on ischemia-reperfusion-induced myocardial injury.

The present study was designed to investigate the cardio-protective effect of Ac-LEDH-cmk a selective caspase-9 inhibitor and 5-aminoisoquinolinone a selective Poly (ADP-ribose) polymerase inhibitor on ischemia and reperfusion induced apoptotic and necrotic cell death in rats. Isolated rat hearts were exposed to 30 minutes of global ischemia followed by 120 minutes of reperfusion using Langendorff's apparatus. Myocardial injury was assessed in the terms of infarct size, release of lactate dehydrogenase, creatine kinase enzymes and apoptotic index was assessed by DNA smearing on agarose gel electrophoresis. Pretreatments with specific inhibitor of caspase-9, Ac-LEHD-cmk (0.07 muM and 0.105 muM), and inhibitor of PARP, 5-aminoisoquinolinone (5 microM and 7.5 muM), significantly attenuated I/R induced increase in infarct size, release of lactate dehydrogenase and creatine kinase in the coronary effluent, and apoptotic index. Therefore, it may be concluded that inhibition of caspase-9 and PARP prevent ischemia and reperfusion-induced activation of apoptotic cascade and necrosis in rat myocardium.

Protective effect of a calcium channel blocker "diltiazem" on aluminum chloride-induced dementia in mice.

Many studies report that heavy metals such as aluminum are involved in amyloid beta aggregation and neurotoxicity. Further, high concentration of aluminum in the brain deregulates calcium signaling which contributes to synaptic dysfunction and halts neuronal communication which ultimately leads to the development of Alzheimer's disease. Recently, diltiazem, a calcium channel blocker clinically used in angina, is reported to decrease amyloid beta production by inhibiting calcium influx, decreasing inflammation and oxidative stress. However, the probable role of this drug in aluminum chloride (AlCl3)-induced experimental dementia is yet to be explored. Therefore, the present study is designed to investigate the effect of AlCl3-induced dementia in mice. Morris water maze test and elevated plus maze were utilized to evaluate learning and memory. Various biochemical estimations including brain acetylcholinesterase activity (AChE), brain total protein, thiobarbituric acid-reactive species (TBARS) level, reduced glutathione (GSH) level, nitrate/nitrite, and superoxide dismutase (SOD) were measured. AlCl3 significantly impaired learning and memory and increased brain AChE, brain total protein, TBARS, and nitrate/nitrite and decreased brain GSH or SOD. On the other hand, treatment with diltiazem significantly reversed AlCl3-induced behavioral and biochemical deficits. The present study indicates the beneficial role of diltiazem in AlCl3-induced dementia.

Retinoids as potential targets for Alzheimer's disease.

Vitamin A and its derivatives, the retinoids, modulate several physiological and pathological processes through their interactions with nuclear retinoid receptor proteins termed as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). An increasing body of evidence signifies the existence of retinoid signaling in diverse brain areas including cortex, amygdala, hypothalamus, hippocampus, and striatum suggesting its involvement in adult brain functions. Defective retinoid signaling has been evidenced in the pathology of Alzheimer's disease. Reports demonstrate that vitamin A deprived mice exhibit serious defects in spatial learning and memory signifying its importance in the maintenance of memory functions. Retinoid signaling impacts the development of AD pathology through multiple pathways. Ligand activation of RAR and RXR in APP/PS1 transgenic mice ameliorated the symptoms of AD and reduced amyloid accumulation and tau hyperphosphorylation. Retinoids also reduce the production of pro-inflammatory cytokines and chemokines by astrocytes and the microglia. Studies also suggest that neuronal cell lines treated with retinoid agonists exhibit an up-regulation in the expression and activity of choline acetyltransferase (ChAT). Reports depict that retinoic acid isomers enhance, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1 and abcg-1 proteins in astrocytes. Furthermore numerous studies also indicate antioxidant potential of retinoids. Through this review we concisely summarize the biology of retinoids, emphasizing on their probable neuroprotective mechanisms that will help to elucidate the pivotal role of these receptors in AD pathology.

Liver X receptor agonist T0901317 reduces neuropathological changes and improves memory in mouse models of experimental dementia.

The present study has been undertaken to explore the potential of liver X receptor (LXR) modulator, T0901317, in dementia induced by streptozotocin (STZ) and cholesterol enriched diet. Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] and high fat diet (HFD, administered for 90 days) were used to induce dementia in separate groups of Swiss albino mice. The Morris water maze (MWM) test was used to evaluate the effect on cognitive functions. Brain homogenate was used to perform a series of biochemical studies such as, estimation of brain reduced glutathione (GSH), thiobarbituric acid reactive species (TBARS), acetylcholinestrase (AChE) activity and myeloperoxidase (MPO) levels. Serum cholesterol was also determined. STZ and HFD produced a significant decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a noticeable accentuation of AChE activity, TBARS and MPO levels along with reduction in GSH level. Further the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. T0901317 treatment significantly attenuated STZ and HFD-induced memory deficits, biochemical and histopathological alterations as well as HFD induced rise in cholesterol content. Hence the study indicates the potential role of liver X receptors in the pathophysiology of dementia. Therefore, the results demonstrate the defensive role of T0901317 in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative, anti-inflammatory and cholesterol lowering effects.

Animal models of dementia and cognitive dysfunction.

Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease and other cognitive deficits have pointed to novel strategies for drug development. Animal models have contributed noticeably to these advances and are an indispensible part in the evaluation of therapeutics. This review is an exhaustive study of animal models of dementia and cognitive dysfunction. A thorough and critical evaluation of current rodent models of dementia, and discussion about their role in drug discovery and development have been carried out. Since dementia has multiple pathophysiological mechanisms, we have tried to provide a detailed description of various types of animal models which would depict different pathophysiological stages and causes of dementia. This review aims to better understand the prognosis, biochemical, and behavioral alterations that occur during dementia and hence facilitate drug discovery and development.

Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia.

A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia.

All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of streptozotocin-induced dementia of Alzheimer's type.

Recent studies have revealed that aberrant vitamin A signaling may lead to memory deficits in rodents. Present study investigates the potential of all-trans-retinoic acid (ATRA) an agonist at retinoid acid family of receptors, in cognitive dysfunctions associated with experimental dementia. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v)] was administered on alternate days (day 1 and day 3) to induce dementia in Swiss albino mice. STZ mice were administered ATRA (10 mg/kg; 20 mg/kg, p.o.) for a total of 19 days following second i.c.v injection of STZ [day 4 to day 22]. Morris water maze (MWM) test was performed on days 19, 20, 21, 22 and 23 to assess learning and memory of the animals. Following MWM test, the animals were sacrificed for biochemical and histopathological studies. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice showed marked accentuation of AChE activity, TBARS and MPO levels along with fall in GSH level. Further the stained micrographs of STZ-treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. ATRA treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations. The findings demonstrate that the memory restorative ability of ATRA may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.

Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet.

The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.

Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer's disease.

Alzheimer's disease (AD) is the most common causes of dementia accounting for 50-60% of all cases. The pathological hallmarks of AD are the formation of extracellular plaques consisting of amyloid-ß protein, intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and presence of chronic neuroinflammation causing progressive decline in memory and cognitive functions. The current therapeutic strategies to improve memory deficits aim at preventing the formation and accumulation of amyloid-ß and tau phosphorylation. Beyond the plaque and tangle-related targets, other aspects of pathophysiology including molecular transport mechanism, oxidative damage, inflammation and glucose and lipid metabolism may also provide opportunities to slow down the progression of memory loss. A novel therapeutic approach to the treatment of AD is through the exploration of nuclear receptor agonists, peroxisome proliferator-activated receptors (PPARs), which have been clinically used as antidiabetic and dyslipidemic agents. The findings that PPAR agonists may possess antiamyloidogenic, anti-inflammatory, insulin-sensitizing, and cholesterol-lowering potential suggest that they could be interesting candidates for AD drugs. Through this review, we will discuss the probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.

Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications.

Poly(ADP-ribose) polymerases (PARPs) are a family of cell signaling enzymes present in eukaryotes, which are involved in the poly(ADP-ribosylation) of DNA binding proteins. While an 18 member superfamily of PARPs has been identified, however PARP-1 the most abundant isoform accounts for more than 90% of its functions. PARP-1 works as DNA damage nick sensor, which uses NAD(+) to form polymers of ADP-ribose (PAR) and nicotinamide. Three consequences of the activation of PARP-1 are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of proinflammatory genes. Consequently, pharmacological inhibition of PARP has the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). Through this article we have tried to develop a brief and simplified picture of the principal physiological and pathophysiological roles governed by PARP-1 and its therapeutic implications.