Serum albumin exposure enhances cell invasiveness and paclitaxel resistance in human neuroblastoma cells, with attenuation by valeriana-type iridoid glycosides.

Neuroblastoma, a prevalent extracranial solid tumor in children, arises from undifferentiated nerve cells. While tumor vasculature, often characterized by increased permeability, influences metastasis and recurrence, the direct impact of blood-borne molecules on tumor progression remains unclear. In the present study, we focused on the effect of exposure to albumin, one of the most abundant proteins in the serum, on human neuroblastoma cells. Albumin exposure elevated oxidative stress and led to mitochondria dysfunction via the activation of TGFß and PI3K pathways, accompanied by an increase in the metastatic and invasive properties of neuroblastoma cells. Proteins relevant to the induction of autophagy were upregulated in response to prolonged albumin exposure. Additionally, pre-exposure to albumin before treatment resulted in increased resistance to paclitaxel. Two valeriana-type iridoid glycosides, patrisophoroside and patrinalloside, recently isolated from Nardostachys jatamansi significantly mitigated the effect of albumin on oxidative stress, cell invasiveness, and chemoresistance. These findings illuminate the potential role of blood-borne molecules, such as albumin, in the progression and metastasis of neuroblastoma, as well as the possible therapeutic implications of valeriana-type iridoid glycosides in anti-cancer treatment.

Stability of valeriana-type iridoid glycosides from rhizomes of Nardostachys jatamansi and their protection against H2O2-induced oxidative stress in SH-SY5Y cells.

Nardostachys jatamansi is close to Valerian in consideration of their same psychoactive effects, such as sedation and neuroprotection. Valeriana-type iridoids are major active components of Valerian, but few valeriana-type iridoids have been isolated from N. jatamansi. Iridoid-targeting chemical investigation of the rhizomes of N. jatamansi resulted in the isolation of seven valeriana-type iridoid glycosides, four of which are previously undescribed. Their structures were determined through NMR spectroscopy, high-resolution mass spectrometry, and optical rotation experiments. In addition, the inaccurate configurations of patrinalloside and 6″-acetylpatrinalloside from previous reports were corrected. These compounds, unstable due to alcoholic solvents, were more stable in the mixtures than in purified forms, as monitored by the qNMR method, supporting the use of natural products as mixtures. Furthermore, the isolates, as well as crude and solvent partition extracts, were found to have a protective effect against hydrogen-peroxide-induced toxicity in human neuroblastoma cells, as confirmed by assays for cell viability and antioxidation. These findings suggest the potential therapeutic application of the valeriana-type iridoid glycosides isolated herein with improved biochemical stability.

Curcumin improves reversal learning in middle-aged rhesus monkeys.

Age-related impairments in cognitive function occur in multiple animal species including humans and nonhuman primates. Humans and rhesus monkeys exhibit a similar pattern of cognitive decline beginning in middle age, particularly within the domain of executive function. The prefrontal cortex is the brain region most closely associated with mediating executive function. Previous studies in rhesus monkeys have demonstrated that normal aging leads to an increase in myelin degradation in the prefrontal regions that correlates with cognitive decline. This myelin deterioration is thought to result, at least in part, from the age-related emergence of chronic low levels of inflammation. One therapeutic that may arrest the deleterious effects of neuroinflammation is curcumin (CUR), the primary component of the spice turmeric. CUR has been shown to be a potent anti-inflammatory and antioxidant and improves performance on tasks for working memory and motor function. In the present study, middle-aged monkeys (12-21 years old) were given daily dietary supplementation of 500 mg of curcumin or vehicle over a period of 3-4 years. Here, we present data from a series of both object and spatial reversal tasks. Compared to vehicle, the CUR group showed enhanced performance on object, but not spatial reversal learning. These findings suggest that curcumin may improve specific aspects of executive function. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Blood-brain barrier dysfunction as a potential therapeutic target for neurodegenerative disorders.

The blood-brain barrier (BBB) is composed of specific tight junction proteins and transporters expressed on the lining of endothelial cells of the vasculature in the brain. The structural and functional integrity of the BBB is one of the most critical factors for maintaining brain homeostasis and is mainly regulated by complex interactions between various cell types, such as endothelial cells, pericytes, and astrocytes, which are shaped by their differential responses to changes in microenvironments. Alterations in these cellular components have been implicated in neurodegenerative disorders. Although it has long been considered that BBB dysfunction is a mere ramification of pathological phenomena, emerging evidence supports its critical role in the pathogenesis of various disorders. In epilepsy, heightened BBB permeability has been found to be associated with increased occurrence of spontaneous seizures. Additionally, exaggerated inflammatory responses significantly correlate with increased BBB permeability during healthy aging. Furthermore, it has been previously reported that BBB disruption can be an early marker for predicting cognitive impairment in the progression of Alzheimer's disease. We herein review a potential role of the major cellular components of the BBB, with a focus on the contribution of BBB disruption, in neurodegenerative disease progression.

Aortic dissection and multimodality imaging.

Aortic dissection is a life-threatening emergency warranting expeditious diagnosis. Computed tomographic angiography (CTA) is the established gold standard test but is not always fool proof. We report the case of an 18-year-old male patient with traumatic type A aortic dissection which was not evident on the CTA, suggestive on the transthoracic echocardiogram (TTE) and eventually confirmed with a transesophageal echocardiogram (TEE). When the clinical suspicion for dissection is high and in the presence of complications of type A dissection, such as aortic regurgitation, it would be prudent to obtain further imaging with a TTE/TEE to rule in or rule out the diagnosis.

Gradual hypertension induction in middle-aged Cyp1a1-Ren2 transgenic rats produces significant impairments in spatial learning.

Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1-Ren2 xenobiotic-inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15-month-old transgenic rats were fed 0.15% indole-3-carbinol (I3C) chow to slowly induce renin-dependent hypertension over a 6-week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C-treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus-dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular-renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.

Oral curcumin supplementation improves fine motor function in the middle-aged rhesus monkey.

Aged individuals experience decreased fine motor function of the hand and digits, which could result, in part, from the chronic, systemic state of inflammation that occurs with aging. Recent research for treating age-related inflammation has focused on the effects of nutraceuticals that have anti-inflammatory properties. One particular dietary polyphenol, curcumin, the principal curcuminoid of the spice turmeric, has been shown to have significant anti-inflammatory effects and there is mounting evidence that curcumin may serve to reduce systemic inflammation. Therefore, it could be useful for alleviating age-related impairments in fine motor function. To test this hypothesis we assessed the efficacy of a dietary intervention with a commercially available optimized curcumin to ameliorate or delay the effects of aging on fine motor function of the hand of rhesus monkeys. We administered oral daily doses of curcumin or a control vehicle to 11 monkeys over a 14- to 18-month period in which they completed two rounds of fine motor function testing. The monkeys receiving curcumin were significantly faster at retrieving a food reward by round 2 of testing than monkeys receiving a control vehicle. Further, the monkeys receiving curcumin demonstrated a greater degree of improvement in performance on our fine motor task by round 2 of testing than monkeys receiving a control vehicle. These findings reveal that fine motor function of the hand and digits is improved in middle-aged monkeys receiving chronic daily administration of curcumin.

Cognitive impairment in heart failure: A protective role for angiotensin-(1-7).

Patients with congestive heart failure (CHF) have increased hospital readmission rates and mortality if they are concomitantly diagnosed with cognitive decline and memory loss. Accordingly, we developed a preclinical model of CHF-induced cognitive impairment with the goal of developing novel protective therapies against CHF related cognitive decline. CHF was induced by ligation of the left coronary artery to instigate a myocardial infarction (MI). By 4- and 8-weeks post-MI, CHF mice had approximately a 50% and 70% decline in ejection fraction as measured by echocardiography. At both 4- and 8-weeks post-MI, spatial memory performance in CHF mice as tested using the Morris water task was significantly impaired as compared with sham. In addition, CHF mice had significantly worse performance on object recognition when compared with shams as measured by discrimination ratios during the novel object recognition NOR task. At 8-weeks post-MI, a subgroup of CHF mice were given Angiotensin (Ang)-(1-7) (50mcg/kg/hr) subcutaneously for 4 weeks. Following 3 weeks treatment with systemic Ang-(1-7), the CHF mice NOR discrimination ratios were similar to shams and significantly better than the performance of CHF mice treated with saline. Ang-(1-7) also improved spatial memory in CHF mice as compared with shams. Ang-(1-7) had no effect on cardiac function. Inflammatory biomarker studies from plasma revealed a pattern of neuroprotection that may underlie the observed improvements in cognition. These results demonstrate a preclinical mouse model of CHF that exhibits both spatial memory and object recognition dysfunction. Furthermore, this CHF-induced cognitive impairment is attenuated by treatment with systemic Ang-(1-7). (PsycINFO Database Record

Advanced age dissociates dual functions of the perirhinal cortex.

The perirhinal cortex (PRC) is proposed to both represent high-order sensory information and maintain those representations across delays. These cognitive processes are required for recognition memory, which declines during normal aging. Whether or not advanced age affects the ability of PRC principal cells to support these dual roles, however, is not known. The current experiment recorded PRC neurons as young and aged rats traversed a track. When objects were placed on the track, a subset of the neurons became active at discrete locations adjacent to objects. Importantly, the aged rats had a lower proportion of neurons that were activated by objects. Once PRC activity patterns in the presence of objects were established, however, both age groups maintained these representations across delays up to 2 h. These data support the hypothesis that age-associated deficits in stimulus recognition arise from impairments in high-order stimulus representation rather than difficulty in sustaining stable activity patterns over time.

The influence of objects on place field expression and size in distal hippocampal CA1.

The perirhinal and lateral entorhinal cortices send prominent projections to the portion of the hippocampal CA1 subfield closest to the subiculum, but relatively little is known regarding the contributions of these cortical areas to hippocampal activity patterns. The anatomical connections of the lateral entorhinal and perirhinal cortices, as well as lesion data, suggest that these brain regions may contribute to the perception of complex stimuli such as objects. The current experiments investigated the degree to which three-dimensional objects affect place field size and activity within the distal region (closest to the subiculum) of CA1. The activity of CA1 pyramidal cells was monitored as rats traversed a circular track that contained no objects in some conditions and three-dimensional objects in other conditions. In the area of CA1 that receives direct lateral entorhinal input, three factors differentiated the objects-on-track conditions from the no-object conditions: more pyramidal cells expressed place fields when objects were present, adding or removing objects from the environment led to partial remapping in CA1, and the size of place fields decreased when objects were present. In addition, a proportion of place fields remapped under conditions in which the object locations were shuffled, which suggests that at least some of the CA1 neurons' firing patterns were sensitive to a particular object in a particular location. Together, these data suggest that the activity characteristics of neurons in the areas of CA1 receiving direct input from the perirhinal and lateral entorhinal cortices are modulated by non-spatial sensory input such as three-dimensional objects. © 2011 Wiley-Liss, Inc.

Pattern separation deficits may contribute to age-associated recognition impairments.

Normal aging is associated with impairments in stimulus recognition. In the current investigation, object recognition was tested in adult and aged rats with the standard spontaneous object recognition (SOR) task or two variants of this task. On the standard SOR task, adult rats showed an exploratory preference for the novel object over delays up to 24 h, whereas the aged rats only showed significant novelty discrimination at the 2-min delay. This age difference appeared to be because of the old rats behaving as if the novel object was familiar. To test this hypothesis directly, rats participated in a variant of the SOR task that allowed the exploration times between the object familiarization and the test phases to be compared, and this experiment confirmed that aged rats falsely "recognize" the novel object. A final control examined whether or not aged rats exhibited reduced motivation to explore objects. In this experiment, when the environmental context changed between familiarization and test, young and old rats failed to show an exploratory preference because both age groups spent more time exploring the familiar object. Together these findings support the view that age-related impairments in object recognition arise from old animals behaving as if novel objects are familiar, which is reminiscent of behavioral impairments in young rats with perirhinal cortical lesions. The current experiments thus suggest that alterations in the perirhinal cortex may be responsible for reducing aged animals' ability to distinguish new stimuli from ones that have been encountered previously.