The potency of PLGA-Encapsulated Epigallocatechin Gallate (EGCG) as adjuvant therapy for chronic kidney disease

Chronic kidney disease (CKD) prevalence keeps increasing worldwide and being particular concern due to its morbidity and mortality. However, current CKD therapy are known to be economically costly and not necessarily provide better outcomes. Epigallocatechin gallate (EGCG) is one of the substances that widely studied as perspective therapeutic agents of CKD due to its anti-inflammatory, antioxidant, and enhancing mitochondrial function ability. However, the use of EGCG is limited to low bioavailability and poor pharmacokinetic profile. Encapsulation of EGCG with PLGA is expected to increase the efficacy of EGCG especially for its use as the kidney protective agent and optimize therapy of CKD. Thus, this study aims to analyze the potency of PLGA-encapsulated EGCG as the adjuvant therapy for CKD. This study was a narrative review summarizes studies related to current adjuvant therapy of CKD. EGCG has beneficial effects in reducing pro-inflammatory cytokines among chronic kidney disease. EGCG also can increase scavenging of free radicals to decrease reactive oxygen species. EGCG is known to enhance mitochondrial function and increase mitochondrial protection to prevent apoptosis in various kidney diseases. Combination of PLGA encapsulation with EGCG has a beneficial effect in improving the delivery, bioavailability, stability, and the pharmacokinetic profile of EGCG. PLGA-encapsulated EGCG also provides a better therapeutic effect on preventing and decreasing progression of kidney damage. Finally, this study concluded that combination of PLGA-encapsulated EGCG has a potency as the adjuvant therapy of CKD.

Mitochondrial and redox modifications in early stages of Huntington disease

Defects in mitochondrial function and mitochondrial-related redox deregulation have been attributed to Huntington disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. Thus, in the present study, we analyzed changes in mitochondrial function and overreduced states associated with production of reactive oxygen species (ROS) at early stages and along disease progression in vivo in the brain by positron emission tomography (PET) and in skin fibroblasts of premanifest/early and manifest HD patients, and in YAC128 transgenic mouse brain (striatum and cortex) at early-symptomatic (3 month-old, mo) and symptomatic (6 to 12 mo) stages. In vivo human and mouse brain PET imaging was assessed using [64Cu]-ATSM; analysis of oxygen consumption rates was assessed by Seahorse analysis, hydrogen peroxide levels were determined using fluorescent probes and mitochondrial morphology by transmission electron microscopy in human skin fibroblasts and mouse striatal and cortical isolated mitochondria. Premanifest and prodromal HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number, concomitantly with enhanced basal and maximal respiration, proton (H+) leak and increased hydrogen peroxide levels, the later progressing to advanced HD stage, in human fibroblasts. Mitochondria from fibroblasts of premanifest HD carriers also showed reduced roundness, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. Pre/early-symptomatic YAC128 mouse striatal, but not cortical, isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production along with increased complex II and III activities, enhanced mitochondrial hydrogen peroxide and roundness, as revealed by brain ultrastructure analysis, further presenting defects in Ca2+ handling, supporting increased striatal susceptibility in the YAC128 mouse model. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter extending over late disease stages.

Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2

Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear. Herein, we investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks. We observed significant impairment in renal cortical mitochondrial function along with perturbed redox homeostasis, decreased kidney function and marked impairment in NRF2 signaling in aged Fischer 344 rats. Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, an NRF2 repressor. Sulforaphane treatment did not affect the renal NRF2 expression or activity and mitochondrial function in young rats. Taken together, our results provide novel insights into the protective role of the NRF2 pathway in kidneys during aging and highlight the therapeutic potential of sulforaphane in mitigating kidney dysfunction in elders.

Regulation of Mitochondrial Dynamics by Aerobic Exercise in Cardiovascular Diseases

Mitochondrial dynamics, including continuous biogenesis, fusion, fission, and autophagy, are crucial to maintain mitochondrial integrity, distribution, size, and function, and play an important role in cardiovascular homeostasis. Cardiovascular health improves with aerobic exercise, a well-recognized non-pharmaceutical intervention for both healthy and ill individuals that reduces overall cardiovascular disease (CVD) mortality. Increasing evidence shows that aerobic exercise can effectively regulate the coordinated circulation of mitochondrial dynamics, thus inhibiting CVD development. This review aims to illustrate the benefits of aerobic exercise in prevention and treatment of cardiovascular disease by modulating mitochondrial function.

Alterations in Energy Metabolism, Mitochondrial Function and Redox Homeostasis in GK Diabetic Rat Tissues Treated with Aspirin

Our recent studies have demonstrated that aspirin treatment prevents inflammatory and oxidative stress-induced alterations in mitochondrial function, improves glucose tolerance and pancreatic endocrine function and preserves tissue-specific glutathione (GSH)-dependent redox homeostasis in Goto-Kakizaki (GK) diabetic rats. In the current study, we have investigated the mechanism of action of aspirin in maintaining mitochondrial bioenergetics and redox metabolism in the liver and kidneys of GK rats. Aspirin reduced the production of reactive oxygen species (ROS) and oxidative stress-induced changes in GSH metabolism. Aspirin treatment also improved mitochondrial respiratory function and energy metabolism, in addition to regulating the expression of cell signaling proteins that were altered in diabetic animals. Ultrastructural electron microscopy studies revealed decreased accumulation of glycogen in the liver of aspirin-treated diabetic rats. Hypertrophic podocytes with irregular fusion of foot processes in the renal glomerulus and detached microvilli, condensed nuclei and degenerated mitochondria observed in the proximal convoluted tubules of GK rats were partially restored by aspirin. These results provide additional evidence to support our previous observation of moderation of diabetic complications by aspirin treatment in GK rats and may have implications for cautious use of aspirin in the therapeutic management of diabetes.

Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia–reperfusion acute kidney injury

Acute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI. The effects of female sex on long-term cardiac outcomes after AKI are unknown. Therefore, we examined the 1-year cardiorenal outcomes following a single episode of bilateral renal ischemia–reperfusion injury in female C57BL/6 mice using a model with similar severity of AKI and performed concomitantly to recently published male cohorts. To match the severity of AKI between male and female mice, females received 34 min of ischemia time compared to 25 min in males. Serial renal function, echocardiograms and blood pressure assessments were performed throughout the 1-year study. Renal histology, and cardiac and plasma metabolomics and mitochondrial function in the heart and kidney were evaluated at 1 year. Measured glomerular filtration rates (GFR) were similar between male and female mice throughout the 1-year study period. One year after AKI, female mice had preserved diastolic function, normal blood pressure, and preserved levels of cardiac ATP. Compared to males, females demonstrated pathway enrichment in arginine metabolism and amino acid related energy production in both the heart and plasma, and glutathione in the plasma. Cardiac mitochondrial respiration in Complex I of the electron transport chain demonstrated improved mitochondrial function in females compared to males, regardless of AKI or sham. This is the first study to examine the long-term cardiac effects of AKI on female mice and indicate that there are important sex-related cardiorenal differences. The role of female sex in cardiovascular outcomes after AKI merits further investigation.