Hepatic encephalopathy (HE) is a critical clinical complication. There is a consensus that ammonia plays a pivotal role in the pathogenesis of HE. Ammonia is a neurotoxin which induces a wide range ...of functional disturbances in the central nervous system (CNS). On the other hand, HE is associated with the increased free radical formation, tissue inflammation, disturbed neurotransmission, astrocytes swelling, brain edema, and brain herniation. In view of the severe CNS complications ensued HE, potential therapeutic points of intervention need to be vigorously investigated. A role for CNS mitochondrial damage and energy crisis has been considered in HE. It has been found that ammonia induces mitochondrial impairment as a result of a multifaceted interaction of different signaling molecules. Hence, ammonia-induced mitochondrial injury and compromised brain energy metabolism might play a vital role in the pathogenesis of ammonia neurotoxicity. This review focuses on the concept that mitochondrial dysfunction and cellular energy crisis indeed plays a critical role in the pathogenesis of hyperammonemia-induced brain injury. Further, it will highlight the potential therapeutic value of mitochondrial protecting agents and energy providers in the management of HE. The data collected in this review might provide clues to new therapeutic interventions aimed at minimizing HE-associated complications.
A schematic representation for the relationship between hyperammonemia, mitochondrial impairment, and brain energy crisis. Protecting brain mitochondria might serve as a viable therapeutic point of interference in the management of hepatic encephalopathy (HE). Ca2+: Calcium; Mn2+: Manganese; NH4+: ammonium ion. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The current study aimed to determine the effects of spirulina intake on cognitive function and metabolic status among patients with Alzheimer's disease (AD). This randomized, double‐blind, controlled ...clinical trial was done among 60 subjects with AD. Patients were randomly assigned to receive either 500 mg/day spirulina or a placebo (each n = 30) twice a day for 12 weeks. Mini‐mental state examination score (MMSE) was recorded in all patients before and after intervention. Blood samples were obtained at baseline and after 12 weeks’ intervention to determine metabolic markers. Compared with placebo, spirulina intake resulted in a significant improvement in MMSE score (spirulina group: +0.30 ± 0.99 vs. Placebo group: −0.38 ± 1.06, respectively, p = 0.01). In addition, spirulina intake decreased high‐sensitivity C‐reactive protein (hs‐CRP) (spirulina group: −0.17 ± 0.29 vs. Placebo group: +0.05 ± 0.27 mg/L, p = 0.006), fasting glucose (spirulina group: −4.56 ± 7.93 vs. Placebo group: +0.80 ± 2.95 mg/dL, p = 0.002), insulin (spirulina group: −0.37 ± 0.62 vs. Placebo group: +0.12 ± 0.40 μIU/mL, p = 0.001) and insulin resistance (spirulina group: −0.08 ± 0.13 vs. Placebo group: 0.03 ± 0.08, p = 0.001), and increased insulin sensitivity (spirulina group: +0.003 ± 0.005 vs. Placebo group: −0.001 ± 0.003, p = 0.003) compared with the placebo. Overall, our study showed that spirulina intake for 12 weeks in patients with AD improved cognitive function, glucose homeostasis parameters, and hs‐CRP levels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Diabetic retinopathy is one of the common and serious microvascular complications of diabetes mellitus, as hyperglycemia has metabolic effects on the retina. Hyperglycemia induces increased oxidative ...stress, which stimulates inflammation pathways and promotes vascular dysfunction of the retina that leads to increased capillary permeability and vascular leakage. One of the main factors involving diabetic retinopathy is the inflammation signaling pathways. In contemporary times, microRNAs (miRNAs) are identified as functional biomarkers for early detection and treatment of numerous diseases specifically diabetic retinopathy. MiRNAs can modulate gene expression through regulation of transcriptional and posttranscriptional of target genes. With that, miRNAs can regulate almost every cellular and developmental process, including the regulation of instinct immune responses and inflammation. The aim of this study is to investigate the role of miRNAs in inflammation pathways and the pathogenesis of diabetic retinopathy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this study we investigated the protective effects and possible mechanisms of pirfenidone (PF) in paraquat (PQ)-induced lung injury and fibrosis in mice. Lung injury was induced by injection of PQ ...(20 mg/kg). Thereafter, mice orally received water and PF (100 and 200 mg/kg) for four weeks. After 28 days, the inflammation and fibrosis were determined in the lungs by analysis of histopathology, bronchoalveolar lavage fluid (BALF) cell count, lung wet/dry weight ratio, hydroxyproline content, and oxidative stress biomarkers. Expression of several genes involved in fibrogenesis and modulation of reactive oxygen species (ROS) production, such as TGF-β1, α-SMA, collagen Iα and IV, NOX1, NOX4, iNOS, and GPX1 were determined using RT-qPCR. PF significantly decreased the lung fibrosis and edema, inflammatory cells infiltration, TGF-β1 concentration, and amount of hydroxyproline in the lung tissue. PF dose-dependently improved the expression level of the studied genes to the near normal. Decreasing of lung lipid peroxidation and catalase activity, and increasing of SOD activity in the treated mice were significant compared to the control group. Pirfenidone ameliorate paraquat induced lung injury and fibrosis partly through inhibition of inflammation and oxidative stress, and downregulation of genes encoding for profibrotic cytokines and enzymatic systems for ROS production.
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•Lung injury and fibrosis are the main toxic effects of paraquat (PQ) poisoning.•Pirfenidone, the FDA-approved drug for IPF, reduces PQ-induced lung injury and fibrosis.•Pirfenidone reduces PQ-induced oxidative stress and inflammation in lungs.•Pirfenidone modulates the expression of genes involved in fibrosis and free radicals production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The aim of this review was to describe the preferred charged nano-particles (CNPs) for targeted delivery in tumor cells. Zeta Potential (ZP), which represents the surface charge of NPs was ...highlighted in cell entrance and interactions. In this regard, various types of endocytosis pathways which are involved in NPs' uptake were first introduced. Then, significance of positively charged NPs (PCNPs) in proton sponge effect corresponding to lysosomal escape was discussed. Cells prefer to endocyte the NPs with positive charge in passive targeting and gene delivery, while in active targeting; the charge of receptors' ligand binding site determines the NPs cellular uptake. Moreover, pH-sensitive NPs represent charge reversible behavior depending on pH changes which leads to longer blood circulation residence and higher uptake at acidic microenvironment of the cancer media. Role of the CNPs in overcoming multidrug resistance (MDR) and bypassing p-glycoprotein was further investigated.
A schematic representation of the effect of methotrexate-induced mitochondrial dysfunction and oxidative stress in the kidney and its relevance to renal injury and proximal tubular reabsorption ...defect.
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•Renal injury is a clinical complication associated with methotrexate (MTX) therapy.•MTX-induced renal injury is characterized as tissue damage and serum electrolytes imbalance.•There is no precise mechanism for MTX-induced renal injury.•Mitochondrial dysfunction, energy crisis, and oxidative stress seems to be fundamental mechanisms of MTX nephrotoxicity.
Methotrexate is a folate analog used against a wide range of diseases including malignancies and autoimmune disorders. On the other hand, clinical use of the MTX is associated with kidney injury and renal failure. There is no clear mechanism for MTX-induced renal injury. The current investigation was designed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of MTX-induced renal injury. Rats received MTX (a single dose of 20 or 30 mg/kg, i.p). Five days after MTX administration, serum biomarkers of kidney injury and tissue markers of oxidative stress were assessed. Moreover, kidney mitochondria were isolated, and several mitochondrial indices were determined. MTX-treated animals developed biochemical evidence of renal injury as judged by elevated serum blood urea nitrogen (BUN), creatinine (Cr) and along with hypokalemia, hypophosphatemia, hypocalcemia, and a decrease in serum glucose, and uric acid. Moreover, MTX caused an increase in kidney reactive oxygen species and lipid peroxidation. Renal glutathione reservoirs were also depleted, and tissue antioxidant capacity was decreased in MTX-treated animals. Kidney histopathological changes including interstitial inflammation, renal tubular degeneration, retraction glomeruli, and vascular congestion were also evident in MTX-treated rats. On the other hand, it was found that mitochondrial parameters including mitochondrial membrane potential, mitochondrial dehydrogenases activity, and mitochondrial glutathione and ATP content were decreased, while lipid peroxidation and mitochondrial permeabilization were increased with MTX treatment. These data suggest a role for mitochondrial dysfunction and oxidative stress in the mechanism of MTX nephrotoxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Taurine supplementation mitigates colistin-induced renal injury through antioxidative and mitochondria-dependent mechanisms.
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•Nephrotoxicity is a deleterious and dose-limiting side ...effect associated with colistin as an antibiotic.•The development of clinically applicable protective agents could enhance the efficacy of antibiotic drug therapy.•Taurine is the most abundant non-protein amino acid in the human body with several pharmacological actions.•The current study revealed a significant protective effect of taurine against colistin-induced renal injury.
Colistin (COL) belongs to the polymixin class of antibiotics used as the last line antibiotic against drug-resistant infections. However, nephrotoxicity is the major deleterious and dose-limiting side effect associated with COL therapy. Oxidative stress and mitochondrial impairment are suspected mechanisms involved in COL-induced nephrotoxicity. Taurine is one of the most abundant amino acids in the human body with antioxidant and mitochondria protecting properties. The current study was designed to evaluate the potential nephroprotective properties of taurine against COL-associated nephrotoxicity. Mice were treated with COL (15 mg/kg/day, i.v, for 7 consecutive days) alone or in combination with taurine (500 and 1000 mg/kg, i.p). Plasma biomarkers of nephrotoxicity in addition of kidney tissue markers of oxidative stress were evaluated. Additionally, kidney mitochondria were isolated, and several mitochondrial indices were assessed. The COL-associated renal injury was evident by a significant increase in plasma markers of renal injury including creatinine (Cr), and blood urine nitrogen (BUN). COL treatment also caused a significant increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH reservoirs and antioxidant capacity were also decreased in COL-treated animals. Mitochondrial parameters including mitochondrial dehydrogenase activity, membrane potential, GSH, and ATP were significantly decreased while mitochondrial LPO, permeabilization, and GSSG content were increased in the kidney of COL-treated mice. It was found that taurine (500 and 1000 mg/kg, i.p) treatment alleviated COL-induced oxidative stress and mitochondrial dysfunction in the kidney tissue. The data obtained from the current study suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by COL. On the other hand, taurine supplementation protected kidney through decreasing oxidative stress and regulating mitochondrial function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•In hydraulic fracturing tests, on average, the breakdown pressure values of cyclic injection are reduced by 30% compared to monotonic injection. Therefore, the effect of the hydraulic fatigue ...phenomenon is clearly visible.•The fracture geometry in the samples subjected to cyclic injection is in the form of a network of multiple and intersecting fractures, while that subjected to monotonic injection is in the form of a single flat surface.•In the samples with horizontal stress difference, the sample fracturing is not affected by sample anisotropy in a way that the single fracture surface with relative curvature grows in the direction of the maximum stress.•In the cyclic injection using the damaged-controlled method (cycle duration: 16 s), the Energy caused by the injection has been concentrated around the borehole, and as a result, a complex fracture network with short crack lengths has been created; meanwhile, the cyclic injection using the ramp signals method (cycle duration: 8 s) tends to form simple cracks with higher expansion and penetration.
Hydraulic fracturing is commonly used to enhance the hydraulic conductivity of geothermal, oil, and gas reservoirs, particularly those situated in enclosed and unconventional formations. Shale oil and gas reservoirs exhibit distinct characteristics in rock mechanics parameters, morphology, natural fracture geometry, and geological features. Structural anisotropy in materials generally arises from changes in grain type and size, weak layering, and variations in layering angles. This study aims to investigate the impact of two key factors, namely cyclic injection and structural anisotropy, on the hydraulic fracturing process. To achieve this goal, the phenomenon of hydraulic fatigue in rock was examined through various cyclic injection methods, and true-triaxial hydraulic fracturing tests were conducted on cubic samples composed of different materials and layers. To evaluate and analyze the fracture morphology of these samples, CT scan X-ray imaging technology was employed. The results revealed that samples subjected to cyclic injection exhibited an average breakdown pressure approximately 30% lower than those subjected to monotonic injection. Fracture geometry in the cyclic injection samples displayed a network pattern with multiple crack branches, while monotonic injection primarily resulted in a single-surface pattern. In samples with differences in horizontal stress, the anisotropy of the sample did not affect the fracture, and the single fracture surface extended in the direction of maximum stress. The energy generated by cyclic injection using the damage-controlled method (cycle duration: 16 s) was concentrated around the borehole, creating a complex fracture network with shorter crack lengths. Conversely, cyclic injection using the ramp signals method (cycle duration: eight seconds) produced more straightforward cracks with greater expansion and penetration. Examination of CT scan images of the fractured samples revealed average tortuosity and fracture volume fraction parameters of 1.117 and 0.027 for cyclic injection, respectively, in contrast to 1.026 and 0.008 for monotonic injection. Furthermore, the S-N damage model based on the results of true-triaxial hydraulic fracturing was introduced to describe rock damage behavior and the concept of fatigue under cyclic loads.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in ...cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues’ AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease.
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Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other ...hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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