Active Adaptive Strategies of Mallard Feet in Response to Changes in Wetness and Compactness of the Sand Terrain.

Mallards (Anas platyrhynchos) exhibit exceptional locomotive abilities in diverse terrains, such as beaches, swamps, and tidal flats. This capability is primarily attributed to their unique webbed toe structure and cooperative locomotion posture of their feet. Therefore, this study aims to further delve into the active adaptive strategies of mallard feet in response to diverse external environmental conditions. Six adult male mallards were selected for this research. Their locomotion on sandy surfaces with differing wetness levels and varying degrees of compaction were captured using a high-speed camera, and analysis of instantaneous and continuous changes in the primary joint angles of the mallards' feet, including the toe-webbed opening and closing angles, the tarsometatarsal-phalangeal joint (TMTPJ), and the intertarsal joint (ITJ). It was found that on loose sandy surfaces, increasing wetness expanded the ground contact area of the mallards' feet. This led to greater flexion at the TMTPJ joint during mid-stance, accompanied by decreased flexion of the ITJ during touch-down and mid-stance. Conversely, on compacted sand, increasing wetness resulted in a reduced foot effect area and lessened ITJ flexion at both touch-down and mid-stance. Furthermore, on looser sand, the ground contact area of the mallards' feet decreased, with an increase in ITJ buckling at touch-down. During the swing phase, sand wetness and compactness effected minimally on the feet of the mallards. On dry and loose sand ground, mallards will contract their second and fourth toes with webbing upon ground contact, covering and compacting the sand beneath while increasing ITJ flexion to mitigate sinking. This adaptation reduces the energy expended on sand and enhances body stability. In wet and compacted sand conditions, mallards expand their second and fourth toes upon ground contact and reduce ITJ flexion. Therefore, this coordinated foot and ITJ locomotion offers mallards a natural advantage when moving on various environmental media.

Tactile discrimination as a diagnostic indicator of cognitive decline in patients with mild cognitive impairment: A narrative review.

Background: Tactile discrimination, a cognitive task reliant on fingertip touch for stimulus discrimination, encompasses the somatosensory system and working memory, with its acuity diminishing with advancing age. Presently, the evaluation of cognitive capacity to differentiate between individuals with early Alzheimer's disease (AD) and typical older adults predominantly relies on visual or auditory tasks, yet the efficacy of discrimination remains constrained. Aims: To review the existing tactile cognitive tasks and explore the interaction between tactile perception and the pathological process of Alzheimer's disease. The tactile discrimination task may be used as a reference index of cognitive decline in patients with mild cognitive impairment and provide a new method for clinical evaluation. Methods: We searched four databases (Embase, PubMed, Web of Science and Google scholar). The reference coverage was from 1936 to 2023. The search terms included "Alzheimer disease" "mild cognitive impairment" "tactile" "tactile discrimination" "tactile test" and so on. Reviews and experimental reports in the field were examined and the effectiveness of different types of tactile tasks was compared. Main results: Individuals in the initial phases of Alzheimer's spectrum disease, specifically those in the stage of mild cognitive impairment (MCI), exhibit notable impairments in tasks involving tactile discrimination. These tasks possess certain merits, such as their quick and straightforward comparability, independence from educational background, and ability to circumvent the limitations associated with conventional cognitive assessment scales. Furthermore, tactile discrimination tasks offer enhanced accuracy compared to cognitive tasks that employ visual or auditory stimuli. Conclusions: Tactile discrimination has the potential to serve as an innovative reference indicator for the swift diagnosis of clinical MCI patients, thereby assisting in the screening process on a clinical scale.

Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

Aß-binding with alcohol dehydrogenase drives Alzheimer's disease pathogenesis: A review.

Although Alzheimer's disease (AD) characterized with senile plaques and neurofibrillary tangles has been found for over 100 years, its molecular mechanisms are ambiguous. More worsely, the developed medicines targeting amyloid-beta (Aß) and/or tau hyperphosphorylation did not approach the clinical expectations in patients with moderate or severe AD until now. This review unveils the role of a vicious cycle between Aß-derived formaldehyde (FA) and FA-induced Aß aggregation in the onset course of AD. Document evidence has shown that Aß can bind with alcohol dehydrogenase (ADH) to form the complex of Aß/ADH (ABAD) and result in the generation of reactive oxygen species (ROS) and aldehydes including malondialdehyde, hydroxynonenal and FA; in turn, ROS-derived H2O2 and FA promotes Aß self-aggregation; subsequently, this vicious cycle accelerates neuron death and AD occurrence. Especially, FA can directly induce neuron death by stimulating ROS generation and tau hyper hyperphosphorylation, and impair memory by inhibiting NMDA-receptor. Recently, some new therapeutical methods including inhibition of ABAD activity by small molecules/synthetic polypeptides, degradation of FA by phototherapy or FA scavengers, have been developed and achieved positive effects in AD transgenic models. Thus, breaking the vicious loop may be promising interventions for halting AD progression.

Midbrain FA initiates neuroinflammation and depression onset in both acute and chronic LPS-induced depressive model mice.

Both exogenous gaseous and liquid forms of formaldehyde (FA) can induce depressive-like behaviors in both animals and humans. Stress and neuronal excitation can elicit brain FA generation. However, whether endogenous FA participates in depression occurrence remains largely unknown. In this study, we report that midbrain FA derived from lipopolysaccharide (LPS) is a direct trigger of depression. Using an acute depressive model in mice, we found that one-week intraperitoneal injection (i.p.) of LPS activated semicarbazide-sensitive amine oxidase (SSAO) leading to FA production from the midbrain vascular endothelium. In both in vitro and in vivo experiments, FA stimulated the production of cytokines such as IL-1ß, IL-6, and TNF-α. Strikingly, one-week microinfusion of FA as well as LPS into the midbrain dorsal raphe nucleus (DRN, a 5-HT-nergic nucleus) induced depressive-like behaviors and concurrent neuroinflammation. Conversely, NaHSO3 (a FA scavenger), improved depressive symptoms associated with a reduction in the levels of midbrain FA and cytokines. Moreover, the chronic depressive model of mice injected with four-week i.p. LPS exhibited a marked elevation in the levels of midbrain LPS accompanied by a substantial increase in the levels of FA and cytokines. Notably, four-week i.p. injection of FA as well as LPS elicited cytokine storm in the midbrain and disrupted the blood-brain barrier (BBB) by activating microglia and reducing the expression of claudin 5 (CLDN5, a protein with tight junctions in the BBB). However, the administration of 30 nm nano-packed coenzyme-Q10 (Q10, an endogenous FA scavenger), phototherapy (PT) utilizing 630-nm red light to degrade FA, and the combination of PT and Q10, reduced FA accumulation and neuroinflammation in the midbrain. Moreover, the combined therapy exhibited superior therapeutic efficacy in attenuating depressive symptoms compared to individual treatments. Thus, LPS-derived FA directly initiates depression onset, thereby suggesting that scavenging FA represents a promising strategy for depression treatment.

PEGylated-liposomal astaxanthin ameliorates Aß neurotoxicity and Alzheimer-related phenotypes by scavenging formaldehyde.

Alzheimer's disease (AD), which is a prevailing type of dementia, presents a significant global health concern. The current therapies do not meet clinical expectations. Amyloid-beta (Aß) has been found to induce endogenous formaldehyde (FA) accumulation by inactivating FA dehydrogenase (FDH); in turn, excessive FA triggers Aß aggregation that eventually leads to AD onset. Hence, scavenging FA by astaxanthin (ATX, a strong exogenous antioxidant) may be pursued as a promising disease-modifying approach. Here, we report that liposomal nanoparticles coupled with PEG (PEG-ATX@NPs) could enhance water-solubility of ATX and alleviate cognitive impairments by scavenging FA and reducing Aß deposition. To enable drug delivery to the brain, liposomes were used to encapsulate ATX and then coupled with PEG, which produced liposomal nanoparticles (PEGATX@NPs) with a diameter of <100 nm. The PEG-ATX@NPs reduced Aß neurotoxicity by both degrading FA and reducing FA-induced Aß assembly in vitro. Intraperitoneal administration of PEG-ATX@NPs in APPswe/PS1dE9 mice (APP/PS1, a familial model of AD), not only decreased the levels of brain FA and malondialdehyde (MDA, a typical product of oxidative stress), but also attenuated both intracellular Aß oligomerization and extracellular Aß-related senile plaque (SP) formation. These pathological changes were accompanied by rescued ability of spatial learning and memory. Collectively, PEG-ATX@NPs improved the water-solubility, bioavailability, and effectiveness of ATX. Thus, it has the potential to be developed as a safe and effective strategy for treating AD.

Neuropsychiatric Behavioral Assessments in Mice After Acute and Long-Term Treatments of Low-Intensity Pulsed Ultrasound.

Introduction: To evaluate whether both acute and chronic low-intensity pulsed ultrasound (LIPUS) affect brain functions of healthy male and female mice. Methods: Ultrasound (frequency: 1.5 MHz; pulse: 1.0 kHz; spatial average temporal average (SATA) intensity: 25 mW/cm2; and pulse duty cycle: 20%) was applied at mouse head in acute test for 20 minutes, and in chronic experiment for consecutive 10 days, respectively. Behaviors were then evaluated. Results: Both acute and chronic LIPUS at 25 mW/cm2 exposure did not affect the abilities of movements, mating, social interaction, and anxiety-like behaviors in the male and female mice. However, physical restraint caused struggle-like behaviors and short-time memory deficits in chronic LIPUS groups in the male mice. Conclusion: LIPUS at 25 mW/cm2 itself does not affect brain functions, while physical restraint for LIPUS therapy elicits struggle-like behaviors in the male mice. An unbound helmet targeted with ultrasound intensity at 25-50 mW/cm2 is proposed for clinical brain disease therapy.

Phototherapy for age-related brain diseases: Challenges, successes and future.

Brain diseases present a significant obstacle to both global health and economic progress, owing to their elusive pathogenesis and the limited effectiveness of pharmaceutical interventions. Phototherapy has emerged as a promising non-invasive therapeutic modality for addressing age-related brain disorders, including stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), among others. This review examines the recent progressions in phototherapeutic interventions. Firstly, the article elucidates the various wavelengths of visible light that possess the capability to penetrate the skin and skull, as well as the pathways of light stimulation, encompassing the eyes, skin, veins, and skull. Secondly, it deliberates on the molecular mechanisms of visible light on photosensitive proteins, within the context of brain disorders and other molecular pathways of light modulation. Lastly, the practical application of phototherapy in diverse clinical neurological disorders is indicated. Additionally, this review presents novel approaches that combine phototherapy and pharmacological interventions. Moreover, it outlines the limitations of phototherapeutics and proposes innovative strategies to improve the treatment of cerebral disorders.

Valbenazine promotes body growth via growth hormone signaling during zebrafish embryonic development.

Vesicular monoamine transporter 2 (VMAT-2) functions by uptake of cytoplasmic monoamines into vesicles for storage. Valbenazine (VBZ) is a newly FDA-approved oral VMAT-2 inhibitor used for the treatment of movement disorders such as tardive dyskinesia (TD), and Tourette syndrome (TS). Clinical data shows that VBZ is a relatively safe drug with no cardiotoxicity or hepatotoxicity. However, the effect of VBZ on embryonic development remains unknown. Here, we use zebrafish larvae as an animal model to demonstrate that VBZ exposure causes premature hatching and increased body size and hyperactivity-like behaviors in zebrafish larvae. In addition, VBZ exposure leads to increased dopamine (DA) and Glutamate (Glu) levels. Moreover, an increase of growth hormone (gh) and enriched PI3K/AKT signaling were found in VBZ-exposed zebrafish larvae, which may explain their accelerated development. In summary, VBZ exposure may be developmentally toxic in zebrafish larvae.

Effects of the speed on the webbed foot kinematics of mallard (Anas platyrhynchos).

In this study, the effect of the speed on the webbed foot locomotion of the mallard was analyzed based on a considerable number of reliable indoor test data. Four adult male mallards were selected for analysis, and the locomotion speed of the mallard was controlled using the treadmill at an accurate and adjustable speed. The locomotion pattern of the webbed foot of the mallard at different speeds was recorded using a high-speed camera. The changes in the position and conformation of the webbed foot during locomotion on a treadmill were tracked and analyzed using Simi-Motion kinematics software. The results indicated that the stride length of the mallard increased, and the stance phase duration was shortened with the increase of the speed, whereas the swing phase duration did not vary significantly. The duty factor decreased with the increase of the mallard speed but not drop below to 0.5, because the mallards flew with their wings, or moved backward relative to the treadmill with the further increase of the speed. Using the energy method to further distinguish gait, and through the percentage of congruity analysis, it was found that between 0.73 and 0.93 m/s, the gait experienced a transition from walking to grounded running, with no significant changes in spatiotemporal parameters. At speeds between 0.93 and 1.6 m/s, mallards adopt a grounded running gait. The instantaneous changes of the tarsometatarso-phalangeal joint (TMTPJ) angle and the intertarsal joint (ITJ) angle at touch-down, mid-stance and lift-off concomitant with the change of the speed were examined with the TMTPJ and ITJ angle as the research objects. Moreover, the continuous changes of the joint angles were examined in a complete stride cycle. The result indicated that the increase of the speed will also make the TMTPJ and ITJ angle change ahead of time in a stride cycle, proving the shortened stance phase duration. The ITJ angle changed much more than the TMTPJ. Thus, the above result reveals that the mallard primarily responds with the increase of the speed by adjusting the ITJ, instead of the TMTPJ. The vertical displacement of the toe joint points and the toe joint angle was studied (α joint angle is between the second toe and the third toe; ß joint angle is between the third toe and the fourth toe) with a complete stride cycle as the research object. The distal phalanxes of the second, third and fourth toes first contacted the ground, and the proximal phalanx touched the ground in turn during the early stance phase duration of the mallard, as indicated by the result of this study. However, the toes got off the ground in turn from the proximal phalanxes when the mallard foot got off the ground. With the decrease of the interphalangeal α and ß joint angles, the foot web tended to be close and rapidly recovered before the next touch-down. The above result reveals that the webbed foot of the mallard is a coupling system that plays a role in the adjustment of speed.

Tropospheric formaldehyde levels infer ambient formaldehyde-induced brain diseases and global burden in China, 2013-2019.

Although air pollutions cause human diseases, no epidemiological study has investigated the effect of exposure to air pollutants on brain diseases in the general population. Our objective was to examine the association between tropospheric airborne pollutants and human health risk and global burden, especially, attributable to indoor formaldehyde (FA) pollution in China. The data of tropospheric pollutants, such as: CO, NO, O3, PM2.5 or PM10, SO2, and FA in China, 2013-2019, which were derived from the database of satellite remote-sensing, were first calculated and then analyzed them according to satellite cloud pictures. The rate of prevalence, incidence, deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) of the Chinese population was obtained from the Global Burden of Diseases (GBD 2010). A linear regression analysis was used to evaluate the relationship between tropospheric FA concentrations and GBD indexes of human brain diseases, the numbers of fire plot, the average summer temperature, population density and car sales in China from 2013 to 2019. Our results showed that the levels of tropospheric FA could reflect the degree of indoor air FA pollution on a nationwide scale in China; in particular, only tropospheric FA exhibited a positive correlation with the rates of both prevalence and YLDs in brain diseases including: Alzheimer's disease (AD) and brain cancer, but not in Parkinson's disease and depression. In particular, the spatial-temporal changes in tropospheric FA levels were consistent with the geographical distribution of FA exposure-induced AD and brain cancer in both sex old adults with age (60-89). In addition, summer average temperature, car sales and population density were positively correlated with tropospheric FA levels in China, 2013-2019. Hence, mapping of tropospheric pollutants could be used for air quality monitoring and health risk assessment.

New Insights into Alzheimer's Disease: Novel Pathogenesis, Drug Target and Delivery.

Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid ß protein (Aß) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aß and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aß cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aß aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aß- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aß-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aß assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.

The expression of agmatinase manipulates the affective state of rats subjected to chronic restraint stress.

Agmatine is an endogenous polyamine produced from l-arginine and degraded by agmatinase (AGMAT). Studies in humans and animals have shown that agmatine has neuroprotective, anxiolytic, and antidepressant-like actions. However, little is known about the role of AGMAT in the action of agmatine or in the pathophysiology of psychiatric disorders. Therefore, this study aimed to investigate the role of AGMAT in the pathophysiology of MDD. In this study, we observed that AGMAT expression increased in the ventral hippocampus rather than in the medial prefrontal cortex in the chronic restraint stress (CRS) animal model of depression. Furthermore, we found that AGMAT overexpression in the ventral hippocampus elicited depressive- and anxiety-like behaviors, whereas knockdown of AGMAT exhibited antidepressant and anxiolytic effects in CRS animals. Field and whole-cell recordings of hippocampal CA1 revealed that AGMAT blockage increased Schaffer collateral-CA1 excitatory synaptic transmission, which was expressed both pre- and post-synaptically and was probably due to the inhibition of AGMAT-expressing local interneurons. Therefore, our results suggest that dysregulation of AGMAT is involved in the pathophysiology of depression and is a potential target for designing more effective antidepressants with fewer adverse effects to offer a better therapy for depression.

Photobiomodulation for Alzheimer's disease: photoelectric coupling effect on attenuating Aß neurotoxicity.

Alzheimer's disease (AD) and dementia are the most worrying health problems faced by people globally today. Although the pathological features of AD consisting of amyloid-beta (Aß) plaques in the extracellular space (ECS) and intracellular tau tangles are well established, the developed medicines targeting these two proteins have not obtained the expected clinical effects. Photobiomodulation (PBM) describes the therapeutic use of red light (RL) or near-infrared light (NIR) to serve as a noninvasive neuroprotective strategy for brain diseases. The present review discusses the mechanisms of the photoelectric coupling effect (light energy-induced special electronic transition-related alterations in protein structure) of PBM on reducing Aß toxicity. On the one hand, RL or NIR can directly disassemble Aß in vitro and in vivo. On the other hand, formaldehyde (FA)-inhibited catalase (CAT) and H2O2-inactived formaldehyde dehydrogenase (FDH) are formed a vicious circle in AD; however, light energy not only activates FDH to degrade excessive FA (which crosslinks Aß monomer to form Aß oligomers and senile plaques) but also sensitizes CAT to reduce hydrogen peroxide levels (H2O2, which can facilitate Aß aggregation and enhance FA generation). In addition, it also activates mitochondrial cytochrome-c to produce ATP in the neurons. Clinical trials of phototherapeutics or oral coenzyme Q10 have shown positive effects in AD patients. Hence, a promising strategy combined PBM with nanopacked Q10 has been proposed to apply for treating AD.

Opposite Roles of Co-enzyme Q10 and Formaldehyde in Neurodegenerative Diseases.

Most of neurodegenerative diseases (NDD) have no cure. The common etiology of neurodegenerations is unclear. Air pollutant-gaseous formaldehyde is notoriously known to induce demyelination and cognitive impairments. Unexpectedly, an amount of formaldehyde has been detected in the brains. Multiple factors can induce the generation and accumulation of endogenous formaldehyde. Excessive formaldehyde can induce oxidative stress to generate H2O2; in turn, H2O2 promote formaldehyde production. Clinical investigations have shown that an abnormal high level of formaldehyde but low level of coenzyme Q10 (coQ10) was observed in patients with NDD. Further studies have proven that excessive formaldehyde directly inactivates coQ10, reduces the ATP generation, enhances oxidative stress, initiates inflammation storm, induces demyelination; subsequently, it results in neurodegeneration. Although the low water solubility of coQ10 limits its clinical application, nanomicellar water-soluble coQ10 exhibits positive therapeutical effects. Hence, nanopackage of coQ10 may be a promising strategy for treating NDD.

New insight into brain disease therapy: nanomedicines-crossing blood-brain barrier and extracellular space for drug delivery.

INTRODUCTION: Brain diseases including brain tumor, Alzheimer's disease, Parkinson's disease, etc. are difficult to treat. The blood-brain barrier (BBB) is a major obstacle for drug delivery into the brain. Although nano-package and receptor-mediated delivery of nanomedicine markedly increases BBB penetration, it yet did not extensively improve clinical cure rate. Recently, brain extracellular space (ECS) and interstitial fluid (ISF) drainage in ECS have been found to determine whether a drug dissolved in ISF can reach its target cells. Notably, an increase in tortuosity of ECS associated with slower ISF drainage induced by the accumulated harmful substances, such as: amyloid-beta (Aß), α-synuclein, and metabolic wastes, causes drug delivery failure. AREAS COVERED: The methods of nano-package and receptor-mediated drug delivery and the penetration efficacy of nanomedicines across BBB and ECS are assessed. EXPERT OPINION: Invasive delivering drug via ECS and noninvasive near-infrared photo-sensitive nanomedicines may provide a promising benefit to patients with brain disease.

Formic acid induces hypertension-related hemorrhage in hSSAOTG in mice and human.

Hypertension is a confirmed risk factor for cerebral hemorrhage in humans. Which endogenous factor directly induces hypertension-related hemorrhage is unclear. In this study, 42 hemorrhagic patients with hypertension and hyperlipidemia and 42 age-matched healthy controls were enrolled. The contents of serum semicarbazide-sensitive amine oxidase (SSAO) and formic acid (FC, FC is a final product of SSAO through the oxidation of endogenous formaldehyde, which results from the enzymatic oxidative deamination of the SSAO substrate, methylamine) were examined in the patients after stroke. Hemorrhagic areas were quantified by computer tomography. In the animal study, hemorrhagic degree was assessed by hemotoxylin & eosin or tissue hemoglobin kits. The relationship between FC and blood pressure/hemorrhagic degree was examined in wild-type mice and hSSAOTG mice fed with high-fat diets or high-fat and -salt diets. The results showed that the levels of serum FC were positively correlated with blood pressure and hemorrhagic areas in hemorrhagic patients. Transfection of microRNA-134 could enhance SSAO expression in human vascular smooth muscle cells. Consistently, after treatment with high-fat and -salt diets, hSSAOTG mice exhibited higher levels of miR134 and FC, higher blood pressure, and more severe hemorrhage than wild-type mice. Interestingly, folic acid reduced hypertension and hemorrhage in hSSAOTG mice fed with high-fat diets. These findings suggest that FC is a crucial endogenous factor for hypertension and hemorrhage.

Acute high-altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation.

INTRODUCTION: Acute high-altitude hypoxia exposure causes multiple adverse neurological consequences. However, the exact mechanisms are still unclear, and there is no targeted treatment with few side effects. Excessive cerebral formaldehyde (FA) impairs numerous functions, and can be eliminated by nano-packed coenzyme Q10 (CoQ10). AIMS: In this study, we aimed to investigate whether cerebral FA was accumulated after hypobaric hypoxia exposure, and further explored the preventative effect of CoQ10 through FA elimination. RESULTS: Accumulated cerebral FA was found in C57BL/6 mice after acute high-altitude hypoxia exposure, which resulted in FA metabolic disturbance with the elevation of semicarbazide-sensitive amine oxidase, and declination of aldehyde dehydrogenase-2. Excessive FA was also found to induce neuronal ferroptosis in vivo. Excitingly, administration with CoQ10 for 3 days before acute hypobaric hypoxia reduced cerebral FA accumulation, alleviated subsequent neuronal ferroptosis, and preserved neurological functions. CONCLUSION: Cerebral FA accumulation mediates neurological deficits under acute hypobaric hypoxia, and CoQ10 supplementation may be a promising preventative strategy for visitors and sojourners at plateau.

Formaldehyde toxicity in age-related neurological dementia.

The primordial small gaseous molecules, such as: NO, CO, H2S and formaldehyde (FA) are present in the brains. Whether FA as well as the other molecules participates in brain functions is unclear. Recently, its pathophysiological functions have been investigated. Notably, under physiological conditions, learning activity induces a transient generation of hippocampal FA, which promotes memory formation by enhancing N-methyl-D-aspartate (NMDA)-currents. However, ageing leads to FA accumulation in brain for the dysregulation of FA metabolism; and excessive FA directly impairs memory by inhibiting NMDA-receptor. Especially, in Alzheimer's disease (AD), amyloid-beta (Aß) accelerates FA accumulation by inactivating alcohol dehydrogenase-5; in turn, FA promotes Aß oligomerization, fibrillation and tau hyperphosphorylation. Hence, there is a vicious circle encompassing Aß assembly and FA generation. Even worse, FA induces Aß deposition in the extracellular space (ECS), which blocks the medicines (dissolved in the interstitial fluid) flowing into the damaged neurons in the deep cortex. However, phototherapy destroys Aß deposits in the ECS and restores ISF flow. Coenzyme Q10, which scavenges FA, was shown to ameliorate Aß-induced AD pathological phenotypes, thus suggesting a causative relation between FA toxicity and AD. These findings suggest that the combination of these two methods is a promising strategy for treating AD.