Learning-memory Ability Research Articles

Effect of electroacupuncture on proliferation and differentiation of endogenous neural stem cells and Jagged1/Notch1 pathway in hippocampus of APP/PS1 model mice

To investigate the effect of electroacupuncture(EA) stimulation on proliferation and diffe-rentiation of endogenous neural stem cells as well as Jagged1/Notch1 pathway in AD model mice, so as to explore its mechanism underlying amelioration of AD. A total of 40 6-week-old male APP/PS1 transgenic AD mice were randomly divided into EA group (n=20) and AD model group ( n=20), and other 20 normal C57BL/6J mice of the same age were used as the normal control group. The mice in the EA group received EA (10 Hz, 2 mA) at "Baihui"(GV20), "Fengfu"(GV16) and bilateral "Shenshu" (BL23) for 20 min, once daily, 6 days a week for 16 weeks. The mice's learning-memory ability was detected by Morris water maze tests. The Aβ senile plaques in the hippocampal CA1 region were detected by Congo red staining, the immunofluorescence double label of BrdU, neuronal nuclear antigen (NeuN) and astrocyte specific protein GFAP in dentate gyrus of hippocampus was performed for detecting the proliferation and differentiation of the endogenous neural stem cells. The expression levels of Nestin (neuron specific protein) and GFAP were detected by Western blot, and those of Jagged1 and Notch1 mRNAs and proteins in the hippocampus were detected by real-time fluorescence quantifative PCR and Western blot. Compared with the normal control group, the escape latencies at 2nd, 3rd and 4th day, and Aβ senile plaques were significantly increased (P<0.05, P<0.01), whereas the platform crossing times and time spent in the target quadrant, the expression levels of Jagged1 mRNA and Nestin protein were remarkably down-regulated (P<0.05) in the model group. Following EA intervention, the escape latencies at the 3rd and 4th day, Aβ senile plaques, immunofluorescence density of BrdU/GFAP, and GFAP protein expression were pronouncedly decreased (P<0.05, P<0.01), while the platform crossing times, platform quadrant residence time, immunofluorescence density of BrdU/NeuN, expression levels of Jagged1 and Notch1 mRNAs and proteins and Nestin protein evidently increased (P<0.05, P<0.01), suggesting an enhancement of proliferation and diffe-rentiation of endogenous neural stem cells into neurons and a suppression of the proliferation and differentiation towards astrocytes in the hippocampus. EA at GV20, GV16 and BL23 can improve the learning-memory ability, promote the proliferation and differentiation of endogenous neural stem cells towards neurons and inhibit the proliferation and differentiation of endogenous neural stem cells towards astrocytes in the hippocampus, which may be achieved by regulating Jagged1/Notch1 pathway.

The beneficial effect of 3,6'-Disinapoyl sucrose on the cognitive decline via CREB/BDNF signal pathway in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disorder with insidious onset and progressive development. There is an urgent need to find drugs that prevent, slow the progression of AD. We focus our attention on 3,6'-disinapoyl sucrose (DISS), an oligosaccharide with antidepressant and antioxidant activities. In this work, APP/PS1 transgenic mice were utilized to explore the neuroprotective impact of DISS to provide new applications for prevention and therapy of AD. To assess DISS's neuroprotective impact on learning and memory deficits in APP/PS1 transgenic mice using behavioral tests (Morris water maze, Novel object recognition test, and Passive avoidance test). Morphological alterations of hippocampus neurons were observed by Nissl staining and neuronal of apoptosis were assessed by TUNEL assay. By using ELISA, the expressions of inflammatory factors were evaluated, and Western blotting was used to measure the protein expressions of neuron-related regulators in the hippocampus. DISS significantly ameliorated the cognitive disorder in APP/PS1 transgenic mice, reduced apoptosis by decreasing the ratio of Bax/Bcl-2 in hippocampal neurons, and restored the abnormal secretion of inflammatory factors (IL-2, TNF-α, IL-1β, and IL-6). Moreover, the gavage of high-dose DISS can boost the expressions of CREB/BDNF. Overall, our results indicate that DISS improves cognitive function in APP/PS1 transgenic mice by inhibiting neural apoptosis and activating the CREB/BDNF signal pathway.

Electroacupuncture at "Baihui"（GV20） and "Yongquan"（KI1） improves learning-memory ability of APP/PS1 double transgenic mice by regulating endosomal-lysosomal system

To explore the mechanism of electroacupuncture（EA） in improving learning-memory ability in Alzheimer's disease （AD） mice from the perspective of endosomal-lysosomal system. Male APP/PS1 transgenic mice were randomly divided into model group and EA group （n=10 in each group） and 10 male C57BL/6 wild mice were taken as the normal group. EA （1 Hz/50 Hz, 1 mA） was applied at bilateral "Yongquan"（KI1） and acupuncture was applied at "Baihui" （GV20） for 15 min. The mice of the model and normal groups were subjected to restriction with the same method as those of the EA group for 15 min. The treatment was conducted once every other day for 6 weeks. The spatial learning-memory ability （shown by escape latency of place navigation test and the time of crossing the target platform and total swimming distance in the target quadrant in 1 min of spatial probe test ） was detected by Morris water maze test. The immunoactivity of senile plaques （SP） in the hippocampus tissue was detected by immunohistochemistry. The ultrastructural characters of hippocampal neurons were observed by transmission electron microscope, and the expression levels of Ras-related protein 5 （Rab5）, Ras-related protein 7 （Rab7） and cathepsin D （CTSD） in the hippocampus were detected by Western blot, separately. Compared with the normal group, the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD were significantly increased （P<0.05, P<0.01）, while the number of crossing the original platform and the total swimming distance in the platform quadrant were considerably reduced （P<0.05） in the model group. In contrast to the model group, the EA group had a marked decrease in the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD （P<0.05, P<0.01）, and a striking increase in the number of crossing the original platform and the swimming distance in the platform quadrant （P<0.05）. Results of transmission electron microscope showed an accumulation of endosome, lysosome, and endolysosomes in the hippocampal neurons in the model group, which was evidently milder in the EA group. EA of GV20 and KI1 can improve the learning-memory ability of AD mice, which may be related to its function in reducing hippocampal Aβ deposition and down-regulating endosomal-lysosomal system activity.

Electroacupuncture at "Baihui"（GV20） and "Yongquan"（KI1） improves learning-memory ability of APP/PS1 double transgenic mice by regulating endosomal-lysosomal system

To explore the mechanism of electroacupuncture（EA） in improving learning-memory ability in Alzheimer's disease （AD） mice from the perspective of endosomal-lysosomal system. Male APP/PS1 transgenic mice were randomly divided into model group and EA group （n=10 in each group） and 10 male C57BL/6 wild mice were taken as the normal group. EA （1 Hz/50 Hz, 1 mA） was applied at bilateral "Yongquan"（KI1） and acupuncture was applied at "Baihui" （GV20） for 15 min. The mice of the model and normal groups were subjected to restriction with the same method as those of the EA group for 15 min. The treatment was conducted once every other day for 6 weeks. The spatial learning-memory ability （shown by escape latency of place navigation test and the time of crossing the target platform and total swimming distance in the target quadrant in 1 min of spatial probe test ） was detected by Morris water maze test. The immunoactivity of senile plaques （SP） in the hippocampus tissue was detected by immunohistochemistry. The ultrastructural characters of hippocampal neurons were observed by transmission electron microscope, and the expression levels of Ras-related protein 5 （Rab5）, Ras-related protein 7 （Rab7） and cathepsin D （CTSD） in the hippocampus were detected by Western blot, separately. Compared with the normal group, the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD were significantly increased （P<0.05, P<0.01）, while the number of crossing the original platform and the total swimming distance in the platform quadrant were considerably reduced （P<0.05） in the model group. In contrast to the model group, the EA group had a marked decrease in the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD （P<0.05, P<0.01）, and a striking increase in the number of crossing the original platform and the swimming distance in the platform quadrant （P<0.05）. Results of transmission electron microscope showed an accumulation of endosome, lysosome, and endolysosomes in the hippocampal neurons in the model group, which was evidently milder in the EA group. EA of GV20 and KI1 can improve the learning-memory ability of AD mice, which may be related to its function in reducing hippocampal Aβ deposition and down-regulating endosomal-lysosomal system activity.

Mechanisms of moxibustion preconditioning underlying improving learning-memory ability by regulating polarization of microglia via TLR4/NF-κB signaling pathway in AD rats

To observe the effect of moxibustion preconditioning on learning-memory ability, Toll like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signal pathway related proteins and microglia in rats with Alzheimer's disease (AD), so as to explore its possible mechanisms underlying improvement of AD. Male SD rats were randomly divided into normal, sham operation, AD model and pre-moxibustion groups, with 9 rats in each group. Moxibustion was applied to "Baihui"(GV20), "Shenshu"(BL23) and "Zusanli"(ST36) for 15 min, once daily, 6 days as a course of treatment for 3 courses. At the end of moxibustion, the AD model was established by injection of Aβ25-35 aggregation solution into the bilateral hippocampus. The sham operation group was only injected with the same amount of 0.9% Nacl solution. The spatial learning-memory ability of rats was detected by Morris water maze test, the ultrastructure of hippocampal neurons was observed by transmission electron microscope (TEM). The histopathological changes of hippocampus tissue were observed by HE staining, and the protein expression levels of TLR4 and NF-κB p65 in the hippocampus detected by Western blot, and the positive expressions of Iba-1, CD80 and CD206 in the hippocampal CA1 region were detected by immunofluorescence labeling. The contents of inflammatory factors IL-1β, TNF-α and IL-10 in the hippocampus were measured by ELISA. Compared with the sham operation group, the escape latency was significantly increased (P<0.01), and the number of platform quadrant crossing times was decreased (P<0.01) in the model group. In comparison with the model group, the increased escape latency and the decreased platform quadrant crossing times were reversed in the pre-moxibustion group (P<0.01). TEM and light microscope observation showed loose arrangement of cells, enlarged cell space, degeneration, swelling and deformation of hippocampal neurons, rupture of membranes of a large number of cells, reduction of mitochondria, dilation of endoplasmic reticulum, and matrix vacuoles, uneven distribution of organelles and cytoplasm, and being difficult in distinguishing the nuclear cytoplasm in the model group, which was relatively milder in the pre-moxibustion group. The expression levels of hippocampal NF-κB p65 and TLR4, the mean immunofluorescence density of Iba-1 and CD80, as well as the contents of IL-1β and TNF-α in hippocampal CA1 region were significantly increased in the model group than those in the sham operation group (P<0.01), and obviously decreased in the pre-moxibustion group than those in the model group (P<0.05, P<0.01). Whereas the expression of CD206 and the content of IL-10 were evidently decreased in the model group than those in the sham operation group (P<0.01), and strikingly increased in the pre-moxibustion group than those in the model group (P<0.01). No significant differences were found between the sham operation group and the normal group in all the indexes mention above (P>0.05). Pre-moxibustion at GV20, BL23 and ST36 can improve learning-memory ability in AD rats, which may be associated with its functions in promoting the polarization of microglia from M1 to M2 and reducing the neuroinflammatory response by way of TLR4/NF-κB signaling pathway.

"Huayu Tongluo" moxibustion improves learning-memory ability and promotes myelin regeneration by regulating Sonic Hedgehog signaling pathway in vascular dementia rats

To investigate the effect of "Huayu Tongluo" (resolving blood stagnation to dredge meridian-collaterals) moxibustion on remyelination and Sonic Hedgehog (Shh) signaling pathway in the corpus callosum of vascular dementia (VD) rats, so as to explore its mechanisms underlying improvement of VD. Male Wistar rats were randomized into sham-operation, model, medication and moxibustion groups, with 12 rats in each group.The VD model was established by bilateral common carotid artery occlusion. Moxibustion was applied to "Shenting"(GV24), "Baihui"(GV20) and "Dazhui"(GV14) for 20 min once a day, 7 d as a treatment course, for 3 courses, with one day's rest between every two courses. Rats of the medication group were treated by gavage of 10 mg/kg of chloromastine solution once a day, and the course of treatment was the same as that of the moxibustion group. The rat's learning-memory ability was assessed by Morris water maze test (escape latency). The neurological deficits were evaluated by using Longa's scale.The mRNA and protein expressions of Shh and Gli1 in the corpus callosum were measured by quantitative real-time fluorescence PCR and Western blot, separately. The ultrastructure of the myelin sheath and myelinated axons was observed under transmission electron microscopy (TCM). Compared with the sham-operation group, the neurologic score and escape latency were significantly increased and prolonged (P<0.01), and the mRNA and protein expression levels of Shh and Gli1 and the number of myelinated axons were obviously decreased in the model group (P<0.01). In comparison with the model group, the escape latency was apparently shortened (P<0.05), while the mRNA and protein expression levels of Shh and Gli1 as well as the number of myelinated axons were strikingly increased in both moxibustion and medication groups (P<0.01). Results of TCM showed that in the model group, the arrangement of myelin coil structures was sparse and fuzzy, and some structures were bulged and disbanded. The oligodendrocytes were irregular, and the number of myelin sheath was rare. These situations were relatively milder in both moxibustion and medication groups. "Huayu Tongluo" moxibustion can promote the differentiation and maturation of oligodendrocyte precursor cells after cerebral ischemia by regulating the expressions of Shh and Gli1 in Shh signaling pathway, thus promoting the regeneration of cerebral white matter myelin sheaths in VD rats, which may contribute to improving learning-memory ability.

Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer's disease via cGAS-STING

Alzheimer's disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear. In this study, we demonstrated that AD transgenic mice exhibited cognitive deficits accompanied by the elevated serum and brain inflammation. Treating with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) from the Chinese herb Polygonum multiflorum that has been well known for its unique anti-aging effect, learning-memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN-γ induced microglia activation showed that TSG reversed the polarization status of M1-type microglia to restore the quiescence, and cGAS-STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL-1β, IL-6, TNF-α, IFN-α and IFN-β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN-γ-stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS-STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS-STING inhibitors. Taken together, our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS-STING signaling pathway in AD.

Anti-fatigue effect of glycoprotein from hairtail (Trichiurus lepturus) by-products in a behavioral mouse model.

Hairtail (Trichiurus lepturus) is a kind of abundant marine fish, and its by-products contain rich protein resources, which can be better exploited and utilized in the food industry. In this study, the glycoprotein of hairtail by-products (GHB) was extracted using ultrasonic-assisted salt solution extraction with hairtail by-products as the raw material. The anti-fatigue effect of GHB was explored by mouse behavior experiments (shuttle box test, open field test and load swimming test). The results showed that the active escape times of the GHB group increased compared with the blank group in the shuttle box test, and the GHB group stayed in the central area for more time in the open field test. At the same time, the exhaustive swimming time of high-dose-group mice was 122.01% longer than that of the blank control group. GHB can improve the memory learning ability and activity of mice, and exert its anti-fatigue effect by eliminating excessive free radicals, slowing the metabolism of amino acids and proteins, and increasing glycogen reserves. This study provides a theoretical basis for the function mechanism of glycoprotein of hairtail by-products and the development of supplementary material in functional foods.

Empagliflozin improves kidney senescence induced by D-galactose by reducing sirt1-mediated oxidative stress.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received widespread attention because of their significant protective effects on the kidney. Previous studies have shown that Sirt1, as which is an antiaging protein, is closely related to the maintenance of redox homeostasis. The goal of this study was to determine whether empagliflozin could ameliorate D-galactose-induced renal senescence in mice, and examine the possible mechanisms of Sirt1.We constructed a rapid ageing model in mice by administering D-galactose. An ageing model was constructed by treating cells with high glucose. Treadmill and Y-maze tests were used to assess exercise tolerance and learning memory ability. Pathologically stained sections were used to assess kidney injury. Tissue and cell senescence were evaluated by senescence-associated β-galactosidase staining. The expression levels of P16, SOD1, SOD2 and Sirt1 were detected by immunoblotting.D-gal-treated mice exhibited significant age-related changes, as measured by behavioural tests and ageing marker protein levels. empagliflozin alleviated these ageing manifestations. In addition, Sirt1, SOD1 and SOD2 levels were downregulated in model mice and upregulated by empagliflozin treatment. Empagliflozin had similar protective effects at the cellular level, and these effects were reduced by the Sirt1 inhibitor.Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress.

Multi-omics analysis reveals BDE47 induces depression-like behaviors in mice by interfering with the 2-arachidonoyl glycerol-associated microbiota-gut-brain axis

2,2′,4,4′-tetrabromodiphenyl ether (BDE47) is a foodborne environmental risk factor for depression, but the pathogenic mechanism has yet to be fully characterized. In this study, we clarified the effect of BDE47 on depression in mice. The abnormal regulation of the microbiome-gut-brain axis is evidenced closely associated with the development of depression. Using RNA sequencing, metabolomics, and 16s rDNA amplicon sequencing, the role of the microbiome-gut-brain axis in depression was also explored. The results showed that BDE47 exposure increased depression-like behaviors in mice but inhibited the learning memory ability of mice. The RNA sequencing analysis showed that BDE47 exposure disrupted dopamine transmission in the brain of mice. Meanwhile, BDE47 exposure reduced protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT), activated astrocytes and microglia cells, and increased protein levels of NLRP3, IL-6, IL-1β, and TNF-α in the brain of mice. The 16 s rDNA sequencing analysis showed that BDE47 exposure disrupted microbiota communities in the intestinal contents of mice, and faecalibaculum was the most increased genus. Moreover, BDE47 exposure increased the levels of IL-6, IL-1β, and TNF-α in the colon and serum of mice but decreased the levels of tight junction protein ZO-1 and Occludin in the colon and brain of mice. In addition, the metabolomic analysis revealed that BDE47 exposure induced metabolic disorders of arachidonic acid and neurotransmitter 2-Arachidonoyl glycerol (2-AG) was one of the most decreased metabolites. Correlation analysis further revealed gut microbial dysbiosis, particularly faecalibaculum, is associated with altered gut metabolites and serum cytokines in response to BDE47 exposure. Our results suggest that BDE47 might induce depression-like behavior in mice through gut microbial dysbiosis. The mechanism might be associated with the inhibited 2-AG signaling and increased inflammatory signaling in the gut-brain axis.

YQBS Improves Cognitive Dysfunction in Diabetic Rats: Possible Association with Tyrosine and Tryptophan Metabolism.

This study is aimed to determine the metabolomic effects of the hybrid medicine formula Yi-Qi-Bu-Shen (YQBS) on the neurotransmitter aspects of cognitive impairment in diabetic rats. In the current study, streptozotocin (STZ) was used to induce diabetic animal model in male Sprague Dawley (SD) rats. After successful establishment of diabetic SD rats' model, age-matched healthy SD rats and diabetic SD rats were treated with low and high doses of YQBS, and then tested for learning memory ability and analyzed for pathological changes. In addition, neurotransmitter metabolic changes in hippocampal subdivisions of rats from different treated groups were analyzed using liquid chromatography-mass spectrometry (LC-MS) technique. YQBS could significantly improve memory-cognitive impairment in diabetic rats as evidenced by the shortening of latency to target and the reduction of latency first entrance to target. Moreover, YQBS also improved the pathological alterations in the hippocampal region in the brains of diabetic rats. Metabolomic analysis showed that the expression of noradrenaline hydrochloride was down-regulated and the expressions of levodopa and 5-hydroxytryptophan were up-regulated in the hippocampal tissues of diabetic rats treated with YQBS. These findings demonstrate that YQBS has protective effects against diabetic cognitive dysfunction, which might act through alteration in tyrosine and tryptophan metabolism.

Moxibustion improves learning-memory ability by regulating apoptosis related proteins of hippocampus in diabetic rats with cognitive impairment

To investigate the effect of moxibustion on the proteins related with apoptosis and nuclear transcription factor kappa B (NF-κB) in hippocampus of diabetic rats with cognitive impairment (CI), so as to explore its mechanism underlying improvement of learning-memory ability. Thirty SD rats were randomly divided into normal, model and moxibustion groups (n=10 rats/group). The diabetic model was established by i.p. injection of streptozotocin solution (25 mg·kg-1·d-1), followed by high-fat diet raising for 4 weeks, and the CI model was confirmed by Morris water maze test. The rats in the moxibustion group were given moxibustion at "Shenting" (GV24), "Baihui" (GV20) and "Dazhui" (GV14) for 20 min each time, the treatment was conducted 6 times a week for 4 weeks. The learning-memory ability was detected by Morris water maze test, the random blood glucose of rats was measured by glucometer and test strips. The protein and mRNA expression levels of Bcl-2, Bax, Caspase-3 and NF-κB p65 in hippocampus were detected by Western blot and quantitative real-time PCR, separately. After modeling, the random blood glucose, escape latency, and the expression levels of Bax, Caspase-3 and NF-κB p65 proteins and mRNAs in the model group were significantly increased, while the expression levels of Bcl-2 protein and mRNA were decreased (P<0.001，P<0.01, P<0.05) in comparison with the normal group. Following the treatment, the modeling induced increase of blood glucose, escape latency, and the expression levels of Bax, Caspase-3 and NF-κB p65 proteins and mRNAs, as well as decrease of Bcl-2 protein and mRNA expression levels were reversed (P<0.05, P<0.01, P<0.001). Moxibustion can improve learning-memory ability in diabetic rats with cognitive impairment, which may be related to its function in regulating the expression levels of hippocampal Bcl-2, Bax, Caspase-3 and NF-κB.

Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats

Aims/introductionAs a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats.MethodBefore the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze.ResultsWe found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1β and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury.ConclusionsThe activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.

PENGUATAN PERUBAHAN PERILAKU DALAM PERCEPATAN PENURUNAN STUNTING

The implementation of community service carried out in Karawang Regency related to strengthening behavior change in accelerating stunting reduction is carried out with three activities, namely holding stunting prevention is important, stunting prevention socialization through bilingual pamphlets and outreach to pregnant women. The service implementation applies the community education method in the form of socialization. Community service is carried out within a month with locations in three hamlets, namely Kaliasin 2 Hamlet, Karang Mulya Hamlet and East Junta Hamlet. The results of the implementation of the service show that parents, especially mothers and prospective mothers, know and understand ways and steps to prevent and minimize stunting, increase community enthusiasm to maintain a healthy lifestyle as well as good parenting, increase awareness to participate in stunting programs and know how to prevent delays growth of toddlers, preventing children from being susceptible to infectious diseases, preventing poor performance in their learning focus and memory abilities.

Milk fat globule membrane concentrate as a nutritional supplement prevents age-related cognitive decline in old rats: A lipidomic study of synaptosomes

Aging is associated with a decline in cognitive abilities, mainly in memory and executive functioning. A similar but premature deterioration in cognitive capacities is the hallmark of mild cognitive impairment, Alzeimer’s disease and dementia. The biochemical mechanisms that cause these neurodegenerative disorders are poorly understood. However, some evidence suggests that insufficient dietary intakes of some phospholipids could impact on brain function and increase the risk of future cognitive impairment and dementia. We evaluated the cognitive and biochemical effects of supplementation with a milk fat globule membrane (MFGM) concentrate in aged rats.We observed that, compared to control animals, MFGM supplemented rats showed enhanced spatial working memory, but both groups exhibited similar reference spatial learning and emotional memory abilities. No significant differences between BDNF levels in the hippocampus and frontal cortex of treated rats as compared to controls were found. The nootropic effects observed were accompanied by significant changes in the lipid composition of synaptic membranes. MFGM supplementation increased the levels of EPA and DHA acids as well as the plasmalogens content in the synaptosomes isolated from the hippocampus (Synapt-HP) and the frontal cortex (Synapt-FC). In addition enhanced levels of phosphatidyl serine (PS), particularly PS(18:1/18:1), and phosphatidyl inositol (PI) molecular species were observed in Synapt-HP and Synapt-FC of treated animals.Lipidomic analysis also revealed greater concentration of phosphatidyl ethanolamine (PE) molecular species containing very long-chain fatty acids and PE plasmenyls in Synapt-HP as well as an increase of the SM content in Synapt-FC from the MFGM group. Although further studies are needed to confirm the underlying mechanism (individual or synergistic), these results suggest that MFGM supplementation could be employed as a dietary implement to restore the proper cerebral concentration of some bioactive lipids and prevent or slow the progression of age-related cognitive impairment.

Molar loss further exacerbates 2-VO-induced cognitive impairment associated with the activation of p38MAPK/NFκB pathway.

Vascular dementia is characterized by reduced cognitive function due to chronic cerebral hypoperfusion and has become a significant public health challenge as the global population ages. Recent studies suggested that molar loss, a common problem among the elderly, may trigger the development of cognitive decline. Our previous study found that the molar loss affected cognitive dysfunction, and the astrocytes in the hippocampus of chronic cerebral ischemia rats were affected, but the underlying mechanism is unclear. In this study, we established the animal model of molar loss with 2-VO rats and the Morris water maze was used to test the cognitive ability of rats in each group. The damage to neurons was observed via Nissl staining, and neuronal apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay in the hippocampus of the rats. Quantitative Real-Time PCR and immunohistochemistry and histology (IHC) were used to detect the expression of p38MAPK, NFκB, caspase 3, and iNOS in the hippocampus. The astrocytes were detected by IHC and Immunofluorescence analysis for GFAP. After 2-VO MO surgery, rats were administered DMSO or p38MAPK inhibitor (SB203580) by intrathecal injection. The Morris water maze test showed that the molar loss aggravated spatial memory learning ability with chronic cerebral ischemia decreased in the rats. The neuronal damage and more apoptotic cells were observed in the hippocampus of 2-VO rats. After the molar loss, the mRNA and protein expression of iNOS, p38MAPK, NFκB, and caspase 3 were further upregulated in 2-VO rats. Molar loss upregulated GFAP expression, and the p38MAPK-positive cells were labeled with the astrocyte marker GFAP. SB203580 reduced cognitive impairment and apoptosis of hippocampal neurons in 2-VO rats following the molar loss. Molar loss can aggravate cognitive impairment in 2-VO rats to a certain extent. The mechanism of molar loss exacerbating the cognitive decline in 2-VO rats may be associated with the activation of the p38MAPK-NFκB-caspase 3 signaling pathway, which induces neuronal apoptosis.

Effect of empagliflozin on cytoskeletal repair in the hippocampus of obese mice.

We aimed to investigate the effect of empagliflozin on hippocampal phosphorylated protein levels in obese mice. Sixteen obese mice successfully modeled on high-fat diet were randomly divided into high-fat feeding group (group H) and empagliflozin group (group H + empagliflozin, group E), eight mice in each group, and eight C57BL/6J male normal mice were selected as the control group (normal control, group C). Group E was treated with empagliflozin 10 mg/kg/d for 12 weeks, while mice in groups H and C were treated with equal amounts of saline. The spatial learning memory ability of the mice was determined by the Morris water maze experiment. Further, their body weights and serological indices were measured. Finally, total proteins were extracted from hippocampal tissues for functional analysis by the phosphorylated proteomics method. The results showed that escape latency was prolonged, retention time in the target quadrant was shortened, and the number of loop penetrations was reduced in the obese mice induced by a high-calorie diet compared with normal controls, whereas escape latency was shortened, retention time in the target quadrant was increased, and the number of loop penetrations was increased after empagliflozin treatment. Phosphoproteomics in the high-fat/control (H/C), empagliflozin/high-fat (E/H), and E/C groups showed 844, 1,552, and 1,512 differentially significant phosphorylation sites, respectively. The proteins corresponding to these differentially phosphorylated sites were mainly involved in neurodegenerative pathways and actin cytoskeleton regulation. Notably, myosin heavy chain 10 (MYH10), p21 protein-activated kinase 4 (PAK4), phosphatidylinositol 3 -phosphate 5-kinase (PIKfyve), and other differentially phosphorylated proteins were involved in actin cytoskeleton regulation. We concluded that empagliflozin protects cognitive functions by inducing serine phosphorylation in MYH10, PAK4, and PIKfyve in the hippocampal tissue of obese mice.

Ulinastatin affects focal cerebral ischemia-reperfusion injury via SOCS1-mediated JAK2/STAT3 signalling pathway.

Cerebral ischemia results in loss of cerebral blood flow, which contributes to neuronal damage, neurocognitive impairment, as well as learning and memory difficulties. Although reperfusion is necessary to restore the blood supply to the brain, it also leads to several detrimental effects on the brain. The purpose of this study was to assess the effects of ulinastatin (UTI) on preventing focal cerebral ischemia/reperfusion-induced injury (FCIRI). First, a rat model of FCIRI was established and treated with UTI. The effects of UTI on FCIRI in rats were evaluated using Morris water maze assay, triphenyl tetrazolium chloride staining, TUNEL, western blot assay, and enzyme-linked immunosorbent assay analysis. UTI was found to improve the learning memory ability, reduce infarction area, inhibit apoptosis and decrease inflammation in FCIRI rats. Messenger RNA microarray analysis of hippocampal tissues revealed that suppressor of cytokine signalling-1 (SOCS1) was the downstream target of UTI in FCIRI. SOCS1 depletion impaired the protective effect of UTI on FCIRI in rats. SOCS1 blocked the activation of the JAK2/STAT3 pathway. JAK2 inhibitor caused the JAK2/STAT3 pathway deficit, hence reversing the effect of sh-SOCS1 on FCIRI in rats. Taken together, our results demonstrate that UTI alleviated FCIRI in rats, which was, to some extent, related to SOCS1-mediated JAK2/STAT3 pathway.

Aerobic Exercise Regulates Apoptosis through the PI3K/Akt/GSK-3β Signaling Pathway to Improve Cognitive Impairment in Alzheimer's Disease Mice.

Neuronal apoptosis is an important factor in the etiology of Alzheimer's disease (AD). Aerobic exercise (AE) enhances learning and memory, improves cognitive impairment, increases telomere binding protein expression, and decreases apoptosis regulators, but it remains unclear whether it can improve cognitive impairment caused by neuronal apoptosis in AD. Therefore, this study investigated whether an 8-week running table exercise intervention could reduce apoptosis and improve cognitive function in the hippocampal neurons of AD model mice. After the exercise intervention, we evaluated the learning memory ability (positioning, navigation, and spatial search) of mice using a Morris water labyrinth, Nissl staining, immunohistochemistry, and protein application to detect hippocampal PI3K/Akt/GSK-3β signaling pathway protein and hippocampal neuronal cell apoptosis protein B cell lymphoma 2 (Bcl-2) and apoptosis-promoting protein bcl-2-related X (Bax) protein expression. The results showed that aerobic exercise improved the location and spatial exploration ability of mice, increased the number of PI3K- and p-Akt-positive cells, increased the expression of PI3K, p-Akt, and bcl-2 proteins, decreased the expression of GSK-3β and Bax proteins, and increased the bcl-2/Bax ratio of mice. The results suggest that aerobic exercise can reduce apoptosis and improve cognitive function in AD mice. The molecular mechanism may involve activation of the PI3K/Akt/GSK-3β signaling pathway.

Effect of moxibustion on autophagy lysosome function mediated by mTOR/TFEB pathway and lncRNA H19 expression in APP/PS1 double transgenic mice

To observe the effect of moxibustion (Moxi) at acupoints of Governor Vessel on autophagy lysosomal function and lncRNA H19 in amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic Alzheimer's disease (AD) mice, so as to explore its underlying mechanisms in relieving AD. Fifty two male APP/PS1 double transgenic AD mice were randomly divided into model, Moxi, Moxi+inhibitor and medication (rapamycin) groups, with 13 mice in each group. Other 13 male C57BL/6J mice of the same age were selected as the control group. The mice of the Moxi group received aconite cake-separated Moxi stimulation at "Baihui" (GV20), "Dazhui"(GV14) and "Fengfu" (GV16), for 15 min, those of the Moxi+inhibitor group received intraperitoneal injection of 3-methyladenine (an inhibitor of PI3K for suppressing autophagy) 1.5 mg· kg-1 · d-1 on the basis of Moxi, and those of the medication group received intraperitoneal injection of rapamycin 2 mg· kg-1 · d-1. The treatment was conducted once daily for 2 weeks. The mouse's learning-memory ability was detected by Morris water maze tests. The hippocampus tissue was sampled for observing the formation of autophagy by using transmission electron microscope, detecting the expression of Aβ_(1-42) protein with immunohistochemical staining, and for detecting the expression levels of long noncoding RNA H19 (lncRNA H19), mammalian target of rapamycin kinase (mTOR), nuclear transcription factor EB (TFEB), Cathepsin D and lysosome associated membrane protein-1 (LAMP1) genes and proteins as well as microtubule associated protein 1 light chain 3B (LC3B)-Ⅱ/LC3B-Ⅰand autophagy protein p62 protein by quantitative real-time PCR and Western blot, respectively. In contrast to the control group, the model group had an evident increase in the escape latency of Morris water maze test, and in the expression levels of Aβ_(1-42) protein, lncRNA H19 mRNA, mTOR mRNA and protein, and p62 protein (P<0.05), and a significant decrease in the expression levels of TFEB, Cathepsin D, LAMP1 mRNAs and proteins and LC3B-Ⅱ/LC3B-Ⅰ (P<0.05). After the treatment and relevant to the model and Moxi+inhibitor groups, both the Moxi and medication groups had an obvious down-regulation in the levels of latency of Morris water maze, expression levels of Aβ_(1-42) protein, lncRNA H19 mRNA, mTOR mRNA and protein, and p62 protein (P<0.05), and a significant up-regulation in the levels of TFEB, Cathepsin D, LAMP1 mRNAs and proteins and LC3B-Ⅱ/LC3B-Ⅰ (P<0.05). Moxi at acupoints of Governor Vessel can improve cognitive function of AD mice, which may be associated with its functions in inhibiting mTOR/TFEB pathway by down-regulating the expression of lncRNA H19, improving autophagy lysosomal function, promoting autophagy and clearing away Aβ1-42 in the hippocampus.