Association between Serum GDF-15 and Cognitive Dysfunction in Hemodialysis Patients.

Cognitive dysfunction is more frequent in end-stage renal disease (ESRD) patients undergoing hemodialysis compared with the healthy population, emphasizing the need for early detection. Interest in serum markers that reflect cognitive function has recently increased. Elevated serum growth differentiation factor 15 (GDF-15) levels are known to be associated with an increased risk of decreased renal function and cognitive dysfunction. This study investigated the relationship between GDF-15 and cognitive dysfunction in hemodialysis patients using a retrospective analysis of 92 individuals aged ≥ 18 years. Cognitive function was assessed using the Korean version of the Mini-Mental Status Examination (K-MMSE), categorizing patients into normal (≥24 points) and cognitive dysfunction (<24 points). As a result, serum GDF-15 concentrations were at significantly higher levels in the cognitive dysfunction group (7500.42 pg/mL, p = 0.001). Logistic regression indicated an increased risk of K-MMSE scores < 24 points when serum GDF-15 exceeded 5408.33 pg/mL. After indoxyl sulfate exposure in HT22 cells, HT22 cells survival was decreased and GDF-15 expression in HT22 cells was increased. Similarly, exposure to indoxyl sulfate in mouse brain tissue resulted in an increased expression of GDF-15. This study highlights the potential of serum GDF-15 as a marker for cognitive dysfunction in hemodialysis patients, offering a valuable screening tool. Serum GDF-15 is related to cognitive dysfunction in hemodialysis patients and may be helpful in screening for cognitive dysfunction in hemodialysis patients.

Omega-3 Fatty Acids Attenuate Renal Fibrosis via AMPK-Mediated Autophagy Flux Activation.

The unilateral ureteral obstruction (UUO) injury model is well-known to mimic human chronic kidney disease, promoting the rapid onset and development of kidney injury. ω3-poly unsaturated fatty acids (PUFAs) have been observed to protect against tissue injury in many disease models. In this study, we assessed the efficacy of ω3-PUFAs in attenuating UUO injury and investigated their mechanism of action. The immortalized human proximal tubular cells human kidney-2 (HK2) were incubated for 72 h with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) in various concentrations, in the presence or absence of transforming growth factor (TGF)-ß. DHA/EPA reduced the epithelial-mesenchymal transition in the TGF-ß-treated HK2 cells by enhancing autophagy flux and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. C57BL/6 mice were divided into four groups and treated as follows: sham (no treatment, n = 5), sham + ω3-PUFAs (n = 5), UUO (n = 10), and UUO + ω3-PUFAs (n = 10). Their kidneys and blood were harvested on the seventh day following UUO injury. The kidneys of the ω3-PUFAs-treated UUO mice showed less oxidative stress, inflammation, and fibrosis compared to those of the untreated UUO mice. Greater autophagic flux, higher amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7, lower amounts of p62, and higher levels of cathepsin D and ATP6E were observed in the kidneys of the omega-3-treated UUO mice compared to those of the control UUO mice. In conclusion, ω3-PUFAs enhanced autophagic activation, leading to a renoprotective response against chronic kidney injury.

ω-3 Polyunsaturated Fatty Acids Improve the Blood-Brain-Barrier Integrity in Contrast-Induced Blood-Brain-Barrier Injury in Uremic Mice.

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood-brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia-reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.

Dual modulators of aggregation and dissociation of amyloid beta and tau: In vitro, in vivo, and in silico studies of Uncaria rhynchophylla and its bioactive components.

A prominent characteristic of Alzheimer's disease (AD) is the deposition of both amyloid-ß (Aß) peptide and tau protein in the brain. Aß and tau not only induce toxicity through self-aggregation but also induce more potent toxicity through the synergistic action of Aß and tau. In particular, neurotoxic aggregates of Aß and tau directly affect several AD pathologies including neuroinflammation and cognitive decline. Therefore, there is increasing interest in strategies to modulate the aggregation and dissociation of Aß and tau for treatment of AD. Our recent study found that Uncaria rhynchophylla (UR) has a therapeutic effect on AD via the inhibition of Aß aggregation and attenuating Aß-mediated pathogenesis of AD. However, no studies have investigated whether UR has anti- and disaggregation effects on both Aß and tau. In this study, we showed the significant effects of UR on aggregation and dissociation of Aß42 and tau K18 using a thioflavin T (ThT) assay. In addition, histological study revealed an inhibitory effect of UR on the accumulation of Aß and tau and AD-related pathologies in 3xTg mice with both Aß and tau pathology. Furthermore, we found that rhynchophylline and corynoxeine, bioactive components of UR, could modulate the aggregation and dissociation of both Aß and tau using molecular docking simulation, isothermal titration calorimetry, and ThT assays. In conclusion, our results demonstrate that UR can inhibit the aggregation of Aß and tau and promote the degradation of their aggregates in AD.

Crude Saponin from Platycodon grandiflorum Attenuates Aß-Induced Neurotoxicity via Antioxidant, Anti-Inflammatory and Anti-Apoptotic Signaling Pathways.

Although Platycodon grandiflorum saponins exhibit many beneficial biological effects in various diseases and conditions, how they protect nerve cells against neurodegenerative diseases and Alzheimer's disease (AD) pathology is unknown. We investigated whether P. grandiflorum crude saponin (PGS) protects neurons from neurodegeneration caused by amyloid beta (Aß)-induced oxidative stress. Hippocampal neuron HT-22 cells were used in the in vitro experiment, and AD mice (5XFAD mice) were used as the in vivo model. Intracellular reactive oxygen species (ROS) was stained with DCF-DA and assessed using fluorescence microscopy. To elucidate the mechanism underlying neuroprotection, intracellular protein levels were assessed by western blotting. In 5XFAD mice, an animal model of AD, nerve damage recovery due to the induction of Aß toxicity was evaluated by histological analysis. PGS attenuates Aß-induced neurotoxicity by inhibiting Aß-induced reactive oxygen species (ROS) production and apoptosis in HT-22 cells. Furthermore, PGS upregulated Nrf2-mediated antioxidant signaling and downregulated NF-κB-mediated inflammatory signaling. Additionally, PGS inhibited apoptosis by regulating the expression of apoptosis-associated proteins. In addition, PGS ameliorated Aß-mediated pathologies, leading to AD-associated cognitive decline. Conclusions: Taken together, these findings suggest that PGS inhibits Aß accumulation in the subiculum and cerebral cortex and attenuates Aß toxicity-induced nerve damage in vitro and in vivo. Therefore, PGS is a resource for developing AD therapeutics.

Effect of cilostazol on arteriovenous fistula in hemodialysis patients / Efecto del cilostazol en una fístula arteriovenosa en pacientes en hemodiálisis

Background: The maturation and patency of permanent vascular access are critical in patients requiring hemodialysis. Although numerus trials have been attempted to achieve permanently patent vascular access, little have been noticeable. Cilostazol, a phosphodiesterase-3 inhibitor, has been shown to be effective in peripheral arterial disease including vascular injury-induced intimal hyperplasia. We therefore aimed to determine the effect of cilostazol on the patency and maturation of permanent vascular access. Methods: This single-center, retrospective study included 194 patients who underwent arteriovenous fistula surgery to compare vascular complications between the cilostazol (n=107) and control (n=87) groups. Results: The rate of vascular complications was lower in the cilostazol group than in the control group (36.4% vs. 51.7%; p=0.033), including maturation failure (2.8% vs. 11.5%; p=0.016). The rate of reoperation due to vascular injury after hemodialysis initiation following fistula maturation was also significantly lower in the cilostazol group than in the control group (7.5% vs. 28.7%; p<0.001). However, there were no significant differences in the requirement for percutaneous transluminal angioplasty (PTA), rate of PTA, and the interval from arteriovenous fistula surgery to PTA between the cilostazol and control groups. Conclusion: Cilostazol might be beneficial for the maturation of permanent vascular access in patients requiring hemodialysis. (AU)

Antecedentes: La maduración y la permeabilidad del acceso vascular permanente son fundamentales en los pacientes que requieren hemodiálisis. Aunque se han realizado numerosos ensayos para conseguir un acceso vascular permanentemente permeable, pocos han conseguido resultados destacables. El cilostazol, un inhibidor de la fosfodiesterasa 3, ha demostrado ser eficaz en la enfermedad arterial periférica, incluida la hiperplasia intimal inducida por lesiones vasculares. Por lo tanto, nuestro objetivo era determinar el efecto del cilostazol en la permeabilidad y la maduración del acceso vascular permanente. Métodos: Este estudio unicéntrico y retrospectivo incluyó 194 pacientes sometidos a una cirugía de fístula arteriovenosa para comparar las complicaciones vasculares entre los grupos de cilostazol (n=107) y de control (n=87). Resultados: La tasa de complicaciones vasculares fue menor en el grupo de cilostazol que en el grupo de control (36,4% frente a 51,7%; p=0,033), incluido el fracaso de la maduración (2,8% frente a 11,5%; p=0,016). La tasa de reintervención por lesión vascular tras el inicio de la hemodiálisis después de la maduración de la fístula también fue significativamente menor en el grupo de cilostazol que en el grupo de control (7,5% frente a 28,7%; p<0,001). Sin embargo, no hubo diferencias significativas en la necesidad de angioplastia transluminal percutánea (ATP), la tasa de ATP y el intervalo desde la cirugía de la fístula arteriovenosa hasta la ATP entre los grupos de cilostazol y de control. Conclusión: El cilostazol podría ser beneficioso para la maduración del acceso vascular permanente en pacientes que necesitan hemodiálisis. (AU)

Collecting Duct-Specific CR6-Interacting Factor-1-Deletion Aggravates Renal Inflammation and Fibrosis Induced by Unilateral Ureteral Obstruction.

Although inflammation and fibrosis, which are key mechanisms of chronic kidney disease, are associated with mitochondrial damage, little is known about the effects of mitochondrial damage on the collecting duct in renal inflammation and fibrosis. To generate collecting duct-specific mitochondrial injury mouse models, CR6-interacting factor-1 (CRIF1) flox/flox mice were bred with Hoxb7-Cre mice. We evaluated the phenotype of these mice. To evaluate the effects on unilateral ureteral obstruction (UUO)-induced renal injury, we divided the mice into the following four groups: a CRIF1flox/flox (wild-type (WT)) group, a CRIF1flox/flox-Hob7 Cre (CRIF1-KO) group, a WT-UUO group, and a CRIF1-KO UUO group. We evaluated the blood and urine chemistries, inflammatory and fibrosis markers, light microscopy, and electron microscopy of the kidneys. The inhibition of Crif1 mRNA in mIMCD cells reduced oxygen consumption and membrane potential. No significant differences in blood and urine chemistries were observed between WT and CRIF1-KO mice. In UUO mice, monocyte chemoattractant protein-1 and osteopontin expression, number of F4/80 positive cells, transforming growth factor-ß and α-smooth muscle actin staining, and Masson's trichrome staining were significantly higher in the kidneys of CRIF1-KO mice compared with the kidneys of WT mice. In sham mice, urinary 8-hydroxydeoxyguanosine (8-OHDG) was higher in CRIF1-KO mice than in WT mice. Moreover, CRIF1-KO sham mice had increased 8-OHDG-positive cell recruitment compared with WT-sham mice. CRIF1-KO-UUO kidneys had increased recruitment of 8-OHDG-positive cells compared with WT-UUO kidneys. In conclusion, collecting duct-specific mitochondrial injury increased oxidative stress. Oxidative stress associated with mitochondrial damage may aggravate UUO-induced renal injury.

Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.

Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.

Effect of cilostazol on arteriovenous fistula in hemodialysis patients.

BACKGROUND: The maturation and patency of permanent vascular access are critical in patients requiring hemodialysis. Although numerus trials have been attempted to achieve permanently patent vascular access, little have been noticeable. Cilostazol, a phosphodiesterase-3 inhibitor, has been shown to be effective in peripheral arterial disease including vascular injury-induced intimal hyperplasia. We therefore aimed to determine the effect of cilostazol on the patency and maturation of permanent vascular access. METHODS: This single-center, retrospective study included 194 patients who underwent arteriovenous fistula surgery to compare vascular complications between the cilostazol (n=107) and control (n=87) groups. RESULTS: The rate of vascular complications was lower in the cilostazol group than in the control group (36.4% vs. 51.7%; p=0.033), including maturation failure (2.8% vs. 11.5%; p=0.016). The rate of reoperation due to vascular injury after hemodialysis initiation following fistula maturation was also significantly lower in the cilostazol group than in the control group (7.5% vs. 28.7%; p<0.001). However, there were no significant differences in the requirement for percutaneous transluminal angioplasty (PTA), rate of PTA, and the interval from arteriovenous fistula surgery to PTA between the cilostazol and control groups. CONCLUSION: Cilostazol might be beneficial for the maturation of permanent vascular access in patients requiring hemodialysis.

Platycodon grandiflorum Root Protects against Aß-Induced Cognitive Dysfunction and Pathology in Female Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by irreversible cognitive dysfunction. Amyloid beta (Aß) peptide is an important pathological factor that triggers the progression of AD through accumulation and aggregation, which leads to AD-related pathologies that consequently affect cognitive functions. Interestingly, several studies have reported that Platycodon grandiflorum root extract (PGE), besides exhibiting other bioactive effects, displays neuroprotective, anti-neuroinflammatory, and cognitive-enhancing effects. However, to date, it is not clear whether PGE can affect AD-related cognitive dysfunction and pathogenesis. Therefore, to investigate whether PGE influences cognitive impairment in an animal model of AD, we conducted a Y-maze test using a 5XFAD mouse model. Oral administration of PGE for 3 weeks at a daily dose of 100 mg/kg significantly ameliorated cognitive impairment in 5XFAD mice. Moreover, to elucidate the neurohistological mechanisms underlying the PGE-mediated alleviative effect on cognitive dysfunction, we performed histological analysis of hippocampal formation in these mice. Histopathological analysis showed that PGE significantly alleviated AD-related pathologies such as Aß accumulation, neurodegeneration, oxidative stress, and neuroinflammation. In addition, we observed a neuroprotective and antioxidant effect of PGE in mouse hippocampal neurons. Our findings suggest that administration of PGE might act as one of the therapeutic agents for AD by decreasing Aß related pathology and ameliorating Aß induced cognitive impairment.

Effect of cilostazol on arteriovenous fistula in hemodialysis patients.

BACKGROUND: The maturation and patency of permanent vascular access are critical in patients requiring hemodialysis. Although numerus trials have been attempted to achieve permanently patent vascular access, little have been noticeable. Cilostazol, a phosphodiesterase-3 inhibitor, has been shown to be effective in peripheral arterial disease including vascular injury-induced intimal hyperplasia. We therefore aimed to determine the effect of cilostazol on the patency and maturation of permanent vascular access. METHODS: This single-center, retrospective study included 194 patients who underwent arteriovenous fistula surgery to compare vascular complications between the cilostazol (n=107) and control (n=87) groups. RESULTS: The rate of vascular complications was lower in the cilostazol group than in the control group (36.4% vs. 51.7%; p=0.033), including maturation failure (2.8% vs. 11.5%; p=0.016). The rate of reoperation due to vascular injury after hemodialysis initiation following fistula maturation was also significantly lower in the cilostazol group than in the control group (7.5% vs. 28.7%; p<0.001). However, there were no significant differences in the requirement for percutaneous transluminal angioplasty (PTA), rate of PTA, and the interval from arteriovenous fistula surgery to PTA between the cilostazol and control groups. CONCLUSION: Cilostazol might be beneficial for the maturation of permanent vascular access in patients requiring hemodialysis.

Association of plasma level of growth differentiation factor-15 and clinical outcome after intraarterial thrombectomy.

BACKGROUND AND PURPOSE: As intraarterial thrombectomy (IAT) has been actively practiced, blood biomarkers that can predict outcomes after IAT have drawn attention. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine and the levels are increased during inflammation or other pathological conditions of various tissues, including the brain. However, GDF-15 levels have not been reported as a biomarker for IAT outcomes. This study was performed to evaluate whether GDF-15 was related to the extent of brain damage and whether it could predict patient prognosis after IAT. METHODS: Patients who showed large arterial occlusion and significant diffusion-perfusion mismatch on imaging underwent IAT. A total of 62 patients who underwent IAT and had blood samples for GDF-15 measurements were enrolled from July 2013 to May 2015. We assessed the infarct severity by consecutive changes on the National Institutes of Health Stroke Scale (NIHSS) during admission and the size of the infarction on brain imaging. Modified Rankin Scale scores (mRS) from 0 to 2 were considered good outcomes, representing functional independence at discharge and three months later. RESULTS: The levels of GDF-15 at the time of admission were significantly correlated with the NIHSS scored at 24 hours (r = 0.306, p = 0.016), three days after IAT (r = 0.261, p = 0.041), and at discharge (r = 0.266, p = 0.037), as well as the infarct size on diffusion-weighted image taken 24 h after IAT (r = 0.452, p = 0.001), but the levels were not correlated with the initial NIHSS or the infarct size before IAT. Multiple logistic regression showed that GDF-15 levels were an independent predictor of functional independence (mRS 0 - 2) at discharge (p = 0.028) and three months after IAT (p = 0.019). Other factors that could predict prognosis were good collateral status on the initial brain angiography and rapid recanalization within six hours from symptom onset. CONCLUSION: The GDF-15 level at the time of admission showed a significant positive correlation with the severity of cerebral damage and clinical outcome after IAT. This suggests that GDF-15 can provide useful prognostic information for patients who successfully underwent IAT in an emergency setting.

Omega-3 Fatty Acid-Type Docosahexaenoic Acid Protects against Aß-Mediated Mitochondrial Deficits and Pathomechanisms in Alzheimer's Disease-Related Animal Model.

It has been reported that damage to the mitochondria affects the progression of Alzheimer's disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aß) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aß in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aß-overexpressing model. We found that omega-3 PUFAs significantly improved Aß-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aß accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis.

Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia.

Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.

Author Correction: CD200R/Foxp3-mediated signalling regulates microglial activation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Red Ginseng Attenuates Aß-Induced Mitochondrial Dysfunction and Aß-mediated Pathology in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aß) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aß-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aß-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aß accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aß-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aß deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

Vitamin D-binding protein-loaded PLGA nanoparticles suppress Alzheimer's disease-related pathology in 5XFAD mice.

The aggregation and accumulation of amyloid beta (Aß) peptide is believed to be the primary cause of Alzheimer's disease (AD) pathogenesis. Vitamin D-binding protein (DBP) can attenuate Aß aggregation and accumulation. A biocompatible polymer poly (D,L-lactic acid-co-glycolic acid) (PLGA) can be loaded with therapeutic agents and control the rate of their release. In the present study, a PLGA-based drug delivery system was used to examine the therapeutic effects of DBP-PLGA nanoparticles in Aß-overexpressing (5XFAD) mice. DBP was loaded into PLGA nanoparticles and the characteristics of the DBP-PLGA nanoparticles were analyzed. Using a thioflavin-T assay, we observed that DBP-PLGA nanoparticles significantly inhibited Aß aggregation in vitro. In addition, we found that intravenous injection of DBP-PLGA nanoparticles significantly attenuated the Aß accumulation, neuroinflammation, neuronal loss and cognitive dysfunction in the 5XFAD mice. Collectively, our results suggest that DBP-PLGA nanoparticles could be a promising therapeutic candidate for the treatment of AD.

Synergistic anticancer effect of acteoside and temozolomide-based glioblastoma chemotherapy.

Temozolomide (TMZ) is an alkylating agent commonly used as a first­line treatment for high­grade glioblastoma. However, TMZ has short half­life and frequently induces tumor resistance, which can limit its therapeutic efficiency. In the present study, it was hypothesized that combined treatment with TMZ and acteoside has synergistic effects in glioblastoma therapy. Using cell viability and wound­healing assays, it was determined that this treatment regimen reduced cell viability and migration to a greater extent than either TMZ or acteoside alone. Following previous reports that TMZ affected autophagy in glioma cells, the present study examined the effects of TMZ + acteoside combination treatment on apoptosis and autophagy. The TMZ + acteoside combination treatment increased the cleavage of caspase­3 and levels of B­cell lymphoma 2 (Bcl­2)­associated X protein and phosphorylated p53, and decreased the level of Bcl­2. The combination treatment increased microtubule­associated protein 1 light chain 3 and apoptosis­related gene expression. It was also determined that TMZ + acteoside induced apoptosis and autophagy through the mitogen­activated protein kinase signaling pathway. These findings suggest that acteoside has beneficial effects on TMZ­based glioblastoma therapy.

Uncoupled Endothelial Nitric Oxide Synthase Enhances p-Tau in Chronic Traumatic Encephalopathy Mouse Model.

AIMS: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease thought to be caused by repetitive traumatic brain injury (TBI) and subconcussive injuries. While hyperphosphorylation of tau (p-Tau), which is attributed to astrocytic tangles (ATs) and neurofibrillary tangles, is known to be involved in CTE, there are limited neuropathological or molecular data. By utilizing repetitive mild TBI (rmTBI) mouse models, our aim was to examine the pathological changes of CTE-associated structures, specifically the ATs. RESULTS: Our rmTBI mouse models showed symptoms of depressive behavior and memory deficit, alongside an increased p-Tau expression in their neurons and astrocytes in both the hippocampus and cortex. rmTBI induced oxidative stress in endothelial cells and nitric oxide (NO) generation in astrocytes, which were mediated by hypoxia and increased hypoxia-inducible factor 1-α (HIF1α). There was also correlated decreased regional cerebral tissue perfusion units, mild activation of astrocytes and NFκB phosphorylation, increased expression of inducible nitric oxide synthase (iNOS), increased endothelial nitric oxide synthase (eNOS) uncoupling with decreased tetrahydrobiopterin, and increased expression of nitrotyrosine, NADPH oxidase 2 (Nox2)/nuclear factor (erythroid-derived 2) factor 2 (Nrf2) signaling proteins. Combined, these effects induced peroxynitrite formation and hyperphosphorylation of tau in the hippocampus and cortex toward the formation of ATs. INNOVATION: Our model features molecular pathogenesis events of CTE with clinically relevant latency periods. In particular, this is the first demonstration of an increased astrocytic iNOS expression in an in vivo model. CONCLUSION: We propose a novel mechanism of uncoupled eNOS and NO contribution to Tau phosphorylation and AT formation in rmTBI brain, toward an increased molecular understanding of the pathophysiology of human CTE.

Jowiseungchungtang Inhibits Amyloid-ß Aggregation and Amyloid-ß-Mediated Pathology in 5XFAD Mice.

Alzheimer's disease (AD) is a neurodegenerative disease, which is accompanied by memory loss and cognitive dysfunction. Although a number of trials to treat AD are in progress, there are no drugs available that inhibit the progression of AD. As the aggregation of amyloid-ß (Aß) peptides in the brain is considered to be the major pathology of AD, inhibition of Aß aggregation could be an effective strategy for AD treatment. Jowiseungchungtang (JWS) is a traditional oriental herbal formulation that has been shown to improve cognitive function in patients or animal models with dementia. However, there are no reports examining the effects of JWS on Aß aggregation. Thus, we investigated whether JWS could protect against both Aß aggregates and Aß-mediated pathology such as neuroinflammation, neurodegeneration, and impaired adult neurogenesis in 5 five familial Alzheimer's disease mutations (5XFAD) mice, an animal model for AD. In an in vitro thioflavin T assay, JWS showed a remarkable anti-Aß aggregation effect. Histochemical analysis indicated that JWS had inhibitory effects on Aß aggregation, Aß-induced pathologies, and improved adult hippocampal neurogenesis in vivo. Taken together, these results suggest the therapeutic possibility of JWS for AD targeting Aß aggregation, Aß-mediated neurodegeneration, and impaired adult hippocampal neurogenesis.