Photobiomodulation Using a Low-Level Light-Emitting Diode Improves Cognitive Dysfunction in the 5XFAD Mouse Model of Alzheimer's Disease.

Photobiomodulation using low-level light-emitting diode can be rapidly applied in neurological and physiological disorders safely and noninvasively. Photobiomodulation is effective for chronic diseases because of fewer side effects than drugs. Here we investigated the effects of photobiomodulation using light-emitting diode on amyloid plaques, gliosis, and neuronal loss to prevent and/or recover cognitive impairment, and optimal timing of photobiomodulation initiation for recovering cognitive function in a mouse model of Alzheimer's disease. 5XFAD mice were used as an Alzheimer's disease model. Animals receiving photobiomodulation treatment were divided into two groups: an early group starting photobiomodulation at 2 months of age (5XFAD+Early), and a late group starting photobiomodulation at 6 months of age (5XFAD+Delay). Both groups received photobiomodulation 20 minutes per session three times per week for 14 weeks. The Morris water maze, passive avoidance, and elevated plus maze tests were performed at 10 months of age. Immunohistochemistry and Western blot were performed after behavioral evaluation. The results showed that photobiomodulation treatment at early stages reduced amyloid accumulation, neuronal loss, and microgliosis and alleviated the cognitive dysfunction in 5XFAD mice, possibly by increasing insulin degrading enzyme related to amyloid-beta degradation. Photobiomodulation may be an excellent candidate for advanced preclinical Alzheimer's disease research.

Isolinderalactone regulates the BCL-2/caspase-3/PARP pathway and suppresses tumor growth in a human glioblastoma multiforme xenograft mouse model.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor, which remains incurable. Plant extracts are a potential source of potent anticancer medicines. In this study, we investigated the effect of isolinderalactone from Lindera aggregata on tumor growth using U-87 human glioblastoma cells. Treatment with isolinderalactone inhibited cell viability and promoted apoptotic cell death. In addition, intraperitoneal injection of isolinderalactone significantly inhibited tumor growth in a human GBM xenograft mouse model. To identify the proteins involved in the induction of apoptosis in isolinderalactone-treated cells, we performed a human apoptosis proteome array analysis and western blotting. Isolinderalactone suppressed the expression of B-cell lymphoma 2 (BCL-2), as well as of survivin and X-linked inhibitor of apoptosis protein (XIAP), known as apoptosis inhibitors, and increased the level of cleaved caspase-3. In addition, isolinderalactone treatment increased cleaved poly(ADP-ribose) polymerase (PARP) and DNA damage. In xenograft tumor tissues, we observed high immunofluorescence of cleaved caspase-3 and TUNEL in isolinderalactone-treated group. Taken together, isolinderalactone enhances U-87 GBM cell apoptosis in vitro and in vivo and retards tumor growth, suggesting that isolinderalactone may be a potential candidate for anti-glioblastoma drug development.

Electroacupuncture preconditioning reduces ROS generation with NOX4 down-regulation and ameliorates blood-brain barrier disruption after ischemic stroke.

BACKGROUND: Electroacupuncture (EA) is a modern application based on combination of traditional manual acupuncture and electrotherapy that is frequently recommended as an adjuvant treatment for ischemic stroke. EA preconditioning can ameliorate blood-brain barrier (BBB) dysfunction and brain edema in ischemia-reperfusion injury; however, its mechanism remains unclear. This study investigated the preventive effects of EA preconditioning, particularly on BBB injury, followed by a transient middle cerebral artery occlusion (MCAO) model in mice. RESULTS: Mice were treated with EA (20 min) at Baihui (GV20) and Dazhui (GV14) acupoints once a day for 3 days before ischemic injury. Infarct volume, neurological deficits, oxidative stress, Evans blue leakage and brain edema were evaluated at 24 h after ischemia-reperfusion injury. EA preconditioning significantly decreased infarct volume and improved neurological function even after ischemic injury. In addition, both Evans blue leakage and water content were significantly reduced in EA preconditioned mice. Whereas the expression of tight junction proteins, ZO-1 and claudin-5, were remarkably increased by EA preconditioning. Mice with EA preconditioning showed the reduction of astrocytic aquaporin 4, which is involved in BBB permeabilization. In addition, we found that EA preconditioning decreased reactive oxygen species (ROS) in brain tissues after ischemic injury. The expression of NADPH oxidase 4 (NOX4), not NOX2, was significantly suppressed in EA preconditioned mice. CONCLUSIONS: These results suggest that EA preconditioning improve neural function after ischemic injury through diminishing BBB disruption and brain edema. And, the reduction of ROS generation and NOX4 expression by EA preconditioning might be involved in BBB recovery. Therefore, EA may serve as a potential preventive strategy for patients at high risk of ischemic stroke.

Pre-conditioning with transcranial low-level light therapy reduces neuroinflammation and protects blood-brain barrier after focal cerebral ischemia in mice.

PURPOSE: Transcranial low-level light therapy (LLLT) has gained interest as a non-invasive, inexpensive and safe method of modulating neurological and psychological functions in recent years. This study was designed to examine the preventive effects of LLLT via visible light source against cerebral ischemia at the behavioral, structural and neurochemical levels. METHODS: The mice received LLLT twice a day for 2 days prior to photothrombotic cortical ischemia. RESULTS: LLLT significantly reduced infarct size and edema and improved neurological and motor function 24 h after ischemic injury. In addition, LLLT markedly inhibited Iba-1- and GFAP-positive cells, which was accompanied by a reduction in the expression of inflammatory mediators and inhibition of MAPK activation and NF-κB translocation in the ischemic cortex. Concomitantly, LLLT significantly attenuated leukocyte accumulation and infiltration into the infarct perifocal region. LLLT also prevented BBB disruption after ischemic events, as indicated by a reduction of Evans blue leakage and water content. These findings were corroborated by immunofluorescence staining of the tight junction-related proteins in the ischemic cortex in response to LLLT. CONCLUSIONS: Non-invasive intervention of LLLT in ischemic brain injury may provide a significant functional benefit with an underlying mechanism possibly being suppression of neuroinflammation and reduction of BBB disruption.

PMC-12, a Prescription of Traditional Korean Medicine, Improves Amyloid ß-Induced Cognitive Deficits through Modulation of Neuroinflammation.

PMC-12 is a prescription used in traditional Korean medicine that consists of a mixture of four herbal medicines, Polygonum multiflorum, Rehmannia glutinosa, Polygala tenuifolia, and Acorus gramineus, which have been reported to have various pharmacological effects on age-related neurological diseases. In the present study, we investigated whether PMC-12 improves cognitive deficits associated with decreased neuroinflammation in an amyloid-ß-(Aß-) induced mouse model and exerts the antineuroinflammatory effects in lipopolysaccharide-(LPS-) stimulated murine BV2 microglia. Intracerebroventricular injection of Aß 25-35 in mice resulted in impairment in learning and spatial memory, whereas this was reversed by oral administration of PMC-12 (100 and 500 mg/kg/day) in dose-dependent manners. Moreover, PMC-12 reduced the increase of Aß expression and activation of microglia and astrocytes in the Aß 25-35-injected brain. Furthermore, quantitative PCR data showed that inflammatory mediators were significantly decreased by administration of PMC-12 in Aß-injected brains. Consistent with the in vivo data, PMC-12 significantly reduced the inflammatory mediators in LPS-stimulated BV2 cells without cell toxicity. Moreover, PMC-12 exhibited anti-inflammatory properties via downregulation of ERK, JNK, and p38 MAPK pathways. These findings suggest that the protective effects of PMC-12 may be mediated by its antineuroinflammatory activities, resulting in the attenuation of memory impairment; accordingly, PMC-12 may be useful in the prevention and treatment of AD.

Longitudinal study on trace mineral compositions (selenium, zinc, copper, manganese) in Korean human preterm milk.

We measured selenium, zinc, copper and manganese concentrations in the human milk of Korean mothers who gave birth to preterm infants, and compared these measurements with the recommended daily intakes. The samples of human milk were collected postpartum at week-1, -2, -4, -6, -8, and -12, from 67 mothers who gave birth to preterm infants (< 34 weeks, or birth weight < 1.8 kg). All samples were analyzed using atomic absorption spectrophotometry. The concentrations of selenium were 11.8 ± 0.5, 11.4 ± 0.8, 12.7 ± 0.9, 11.4 ± 0.8, 10.8 ± 0.9, and 10.5 ± 1.3 µg/L, zinc were 7.8 ± 0.5, 9.1 ± 0.8, 7.2 ± 0.9, 8.0 ± 0.8, 7.4 ± 0.9, and 6.6 ± 1.2 mg/L, copper were 506 ± 23.6, 489 ± 29.4, 384 ± 33.6, 356 ± 32.9, 303 ± 35.0, and 301 ± 48.0 µg/L and manganese were 133 ± 4.0, 127 ± 6.0, 125 ± 6.0, 123 ± 6.0, 127 ± 6.0, and 108 ± 9.0 µg/L at week-1, -2, -4, -6, -8, and -12, respectively. The concentrations of selenium and zinc meet the daily requirements but that of copper is low and of manganese exceeds daily requirements recommended by the American Academy of Pediatrics, Committee on Nutrition.

Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats.

BACKGROUND: Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO), olive oil (OO), and beef tallow (BT) on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. METHODS: Male Sprague-Dawley rats were fed 15% (wt/wt) CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg), samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. RESULTS: Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. CONCLUSIONS: Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity.

Serial changes of fatty acids in preterm breast milk of Korean women.

Samples of breast milk were collected at postpartum weeks 1, 2, 4, 6, 8, and 12 from 104 Korean mothers who had delivered infants at less than 34 weeks or weighing less than 1.8 kg to investigate changes in fatty acid (FAs). Full-term breast milk (FBM) collected at the end of first week postpartum from 26 Korean women delivering healthy, term infants was used for comparison. Stability in relative FA composition was maintained during the first 3 months of lactation in preterm breast milk (PBM), and the relative composition of polyunsaturated FAs (PUFA), monounsaturated FAs, and saturated FAs remained constant in PBM. However, the ω6/ω3 ratio was significantly higher as lactation progressed owing to lower ω3 PUFA in PBM. The proportions of docosahexaenoic acid (DHA) and arachidonic acid (AA) in PBM gradually decreased over time, but the DHA/AA ratio was kept constant at 1.13, higher than that of Western countries. At the end of the first week, relative proportions of FAs were similar in PBM and FBM, but absolute concentrations of FA were higher in PBM.