Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

[Sulfur dioxide in the caudal ventrolateral medulla reduces blood pressure and heart rate in rats via the glutamate receptor and NOS/cGMP signal pathways].

This study was designed to investigate the cardiovascular effects of sulfur dioxide (SO2) in the caudal ventrolateral medulla (CVLM) of anesthetized rats and its mechanism. Different doses of SO2 (2, 20, 200 pmol) or artificial cerebrospinal fluid (aCSF) were injected into the CVLM unilaterally or bilaterally, and the effects of SO2 on blood pressure and heart rate of rats were observed. In order to explore the possible mechanisms of SO2 in the CVLM, different signal pathway blockers were injected into the CVLM before the treatment with SO2 (20 pmol). The results showed that unilateral or bilateral microinjection of SO2 reduced blood pressure and heart rate in a dose-dependent manner (P < 0.01). Moreover, compared with unilateral injection of SO2 (2 pmol), bilateral injection of 2 pmol SO2 produced a greater reduction in blood pressure. Local pre-injection of the glutamate receptor blocker kynurenic acid (Kyn, 5 nmol) or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 pmol) into the CVLM attenuated the inhibitory effects of SO2 on both blood pressure and heart rate. However, local pre-injection of nitric oxide synthase (NOS) inhibitor NG-Nitro-L-arginine methyl ester (L-NAME, 10 nmol) only attenuated the inhibitory effect of SO2 on heart rate but not blood pressure. In conclusion, SO2 in rat CVLM has cardiovascular inhibitory effects, and its mechanism is related to the glutamate receptor and NOS/cGMP signal pathways.

[Mitochondrial calcium uniporter knockdown in hippocampal neurons improved the learning and memory dysfunction of Alzheimer's disease mice].

Alzheimer's disease (AD) is a neurodegenerative disorder, which seriously affects health of the elderly, and is still irreversible up to now. Recent studies have indicated that mitochondrial dysfunction is a direct reason to promote the development of AD. Mitochondrial calcium uniporter (MCU), located in the inner membrane of mitochondria, is a key channel of mitochondrial Ca2+ uptake. Abnormal MCU expression results in imbalance of mitochondrial calcium homeostasis, ultimately leading to mitochondrial dysfunction. The purpose of this study was to determine the effects of MCU knockdown on AD hippocampal neurons and learning and memory function of AD model mice. Lentivirus and adeno-associated virus were used as vectors to transfect shRNA into hippocampal neurons (HT22 cells) and hippocampi of amyloid precursor protein (APP)/presenilin 1 (PS1)/tau AD transgenic mice, respectively, in order to interfere with MCU expression. The cellular activity of HT22 cells was detected by MTS method, and the changes of learning and memory dysfunction in APP/PS1/tau AD transgenic mice were tested by Y maze and Morris water maze. The results showed that MCU knockdown reversed the cellular activity of HT22 cells decreased by amyloid beta protein 1-42 (Aß1-42) or okadaic acid (OA). Knockdown of MCU in hippocampal neurons improved spontaneous alternation (spatial working memory), decreased escape latency, and increased time in target quadrant and number of platform crossing (spatial reference memory) of the APP/PS1/tau mice. This study suggests that MCU knockdown in hippocampal neurons has anti-AD effect, and it is expected to be a new strategy for prevention and treatment of AD.

A dual GLP-1 and Gcg receptor agonist rescues spatial memory and synaptic plasticity in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aß1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aß plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3ß levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aß and normalization of PI3K/AKT/GSK3ß cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.

A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-ß (Aß) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p-CREB, T286 p-CAMKII and S9 p-GSK3ß in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease.

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

Amyloid ß protein injection into medial septum impairs hippocampal long-term potentiation and cognitive behaviors in rats.

The specific loss of cholinergic neurons and the progressive deficits of cognitive function are the most primary characteristics of Alzheimer's disease (AD). Although the neurotoxicity of amyloid ß protein (Aß) in AD has been investigated extensively, it is still unclear whether the Aß aggregated in the medial septum (MS), a major cholinergic nucleus projecting to the hippocampus, could affect hippocampal synaptic plasticity and further impair the memory behaviors. The present study investigated the effects of Aß injection into the MS on hippocampal long-term potentiation (LTP) and cognitive behaviors of rats by using Morris water maze (MWM), Y maze and in vivo hippocampal LTP recording. The effects of kainic acid (KA), an agent with specific neurotoxicity to GABAergic neurons, were also observed. The results showed that: (1) Intra-MS injection of Aß25-35, not KA, impaired spatial learning and memory of rats in classical and reversal MWM tests; (2) Both Aß25-35 and KA impaired novelty-seeking behavior of rats in Y maze; (3) Intra-MS injection of Aß25-35, not KA, suppressed in vivo hippocampal LTP in the CA1 region of rats; (4) Both Aß25-35 and KA did not affect the motor ability in behavioral tests and the hippocampal paired-pulse facilitation (PPF) in electrophysiological recording. These results indicate that intra-MS injection of Aß could impair spatial memory, cognitive flexibility and exploratory motivation, as well as hippocampal LTP in rats, suggesting that the cholinergic neurons in the MS and the septo-hippocampal projection could be important targets of neurotoxic Aß, and the specific damage of cholinergic neurons in the MS is likely responsible for the impairments of hippocampal synaptic plasticity and cognitive function in AD.

Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid ß protein in male rats.

Alzheimer's disease (AD) is an age-related mental disorder characterized by progressive loss of memory and multiple cognitive impairments. The overproduction and aggregation of Amyloid ß protein (Aß) in the brain, especially in the hippocampus, are closely involved in the memory loss in the patients with AD. Accumulating evidence indicates that the Aß-induced imbalance of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in the brain plays an important role in the AD pathogenesis and progression. The level of DHEA is elevated, while DHEAS is dramatically decreased in the AD brain. The present study tried to restore the balance between DHEA and DHEAS by using a non-steroidal sulfatase inhibitor DU-14, which increases endogenous DHEAS through preventing DHEAS converted back into DHEA. We found that: (1) DU-14 effectively attenuated the Aß1-42-induced cognitive deficits in spatial learning and memory of rats in Morris water maze test; (2) DU-14 prevented Aß1-42-induced decrease in the cholinergic theta rhythm of hippocampal local field potential (LFP) in the CA1 region; (3) DU-14 protected hippocampal synaptic plasticity against Aß1-42-induced suppression of long term potentiation (LTP). These results provide evidence for the neuroprotective action of DU-14 against neurotoxic Aß, suggesting that up-regulation of endogenous DHEAS by DU-14 could be beneficial to the alleviation of Aß-induced impairments in spatial memory and synaptic plasticity.

[Treatment of Mild-to-moderate Bronchial Asthma (Heat Wheezing Syndrome) Patients at Acute Onset with Western Medicine Combined Danlong Oral Liquid: a Multi-center, Randomized Double- blinded, Positive-controlled Clinical Trial].

OBJECTIVE: To observe the efficacy and safety of Danlong Oral Liquid (DOL) combined Western medicine (WM) in treating mild-to-moderate bronchial asthma patients (heat wheezing syndrome) at acute onset. METHODS: Totally 480 mild-to-moderate bronchial asthma patients (heat wheezing syndrome) at acute onset were randomly assigned to two groups in the ratio 3:1, the treatment group (360 cases) and the control group (120 cases). All patients received basic WM treatment. Patients in the treatment group took DOL, 10 mL each time, 3 times per day for 7 days in total, while those in the control group took Kechuanning Oral Liquid (KOL) , 10 mL each time, 3 times per day for 7 days in total. Efficacy for asthma symptoms, lung functions and scores of TCM syndrome and/or main symptoms were evaluated. RESULTS: The percentage of clinical control and significant effectiveness of asthma symptoms in the treatment group was significantly higher than that of the control group (77.36% vs 56.07%, P < 0.01). The percentage of clinical control and significant effectiveness of lung functions in the treatment group was significantly higher than that of the control group (74.28% vs 50.00%, P < 0.01). The anterior-posterior difference in scores of TCM syndrome was significantly superior in the treatment group than in the control group (-11.26 ± 4.70 vs -9.21 ± 5.09, P < 0.01). The anterior-posterior difference in scores of main symptoms was significantly better in the treatment group than in the control group (-6.58 ± 3.08 vs -5.16 ± 3.45, P < 0.01). The incidence of adverse reactions was significantly lower in the treatment group than in the control group [1.73% (6/346 cases) vs 10.17% (12/118 cases) , P < 0.05]. CONCLUSION: DOL combined WM was superior to KOL in treating mild-to-moderate bronchial asthma patients (heat wheezing syndrome) at acute onset.

Mitochondrial calcium uniporter knockdown in hippocampal neurons alleviates anxious and depressive behavior in the 3XTG Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca2+ (mCa2+) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa2+ uptake, induces the imbalance of mCa2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABAA receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Val8-GLP-1 remodels synaptic activity and intracellular calcium homeostasis impaired by amyloid ß peptide in rats.

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) in the elderly. Glucagon-like peptide-1 (GLP-1), a modulator in T2DM therapy, has been shown to have neuroprotective properties. However, the native GLP-1 can be rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV); the neuroprotective mechanism of GLP-1 in the central nervous system is still an open question, and whether GLP-1 can prevent amyloid ß (Aß)-induced synaptic dysfunction and calcium disorder is still unclear. The present study, by using patch clamp and calcium imaging techniques, investigated the effects of Val8-GLP-1(7-36), a GLP-1 analogue with profound resistance to DPP IV, on the excitatory and inhibitory synaptic transmission and intracellular calcium concentration ([Ca²âº](i) ) in the absence or presence of Aß1-40. The results showed that 1) Aß1-40 significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons of rat brain slices; 2) Val8-GLP-1(7-36) did not affect the activity of miniature postsynaptic currents but effectively protected against the Aß1-40-induced decrease in mEPSC and mIPSC frequency; 3) Aß1-40 significantly increased [Ca²âº](i) in primary neuronal cultures; and 4) Val8-GLP-1(7-36) alone did not change the intracellular calcium level but prevented Aß1-40-induced persistent elevation of [Ca²âº](i). These findings demonstrate for the first time that central application of Val8-GLP-1(7-36) could protect against Aß-induced synaptic dysfunction and intracellular calcium overloading, suggesting that the neuroprotection of GLP-1 may be involved in the remodeling of synaptic activity and intracellular calcium homeostasis in the brain.

Randomized and double-blind controlled clinical trial of extracorporeal cardiac shock wave therapy for coronary heart disease.

Our aim was to evaluate the safety and effectiveness of extracorporeal cardiac shock wave therapy (CSWT) for the patients with coronary heart disease (CHD) using a randomized, double-blind, controlled clinical trial design. Twenty-five patients with CHD were enrolled in this study. Fourteen of the patients were randomized into the CSWT group and 11 into the control group. We applied the CSWT procedure to each patient by using nine shock treatments during 3 months, but the shock wave (SW) energy was only applied to the patients in the CSWT group and not to the patients in the control group. Technetium-99m sestamibi myocardial perfusion, fluorine-18 fluorodeoxyglucose myocardial metabolism single-photon emission computed tomography (SPECT), and two-dimensional echocardiography were performed to identify segments of myocardial ischemia, myocardial viability, and ejection fraction before and after CSWT. We also followed the patients to evaluate adverse effects. After CSWT, the New York Heart Association class, the Canadian Cardiovascular Society angina scale, nitroglycerin dosage, myocardial perfusion and myocardial metabolic imaging scores of dual-isotope SPECT in the CSWT group were reduced significantly (P = 0.019, 0.027, 0.039, 0.000, 0.001, respectively), and the Seattle Angina Questionnaire scale, 6-min walking test, and left ventricular ejection fraction were increased significantly (P = 0.021, 0.024, 0.016, respectively) compared with those before the SW treatment. All of the parameters in the control group did not change significantly after the treatment (all P > 0.05). No serious adverse effects of CSWT were observed. Cardiac shock wave therapy is a safe and effective treatment for CHD patients.

Causal Association Between mTOR-Dependent Protein Levels and Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. OBJECTIVE: This study aims to investigate the causal effects of the mTOR signaling targets on AD. METHODS: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. RESULTS: The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). CONCLUSION: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.

Selective orexin 1 receptor antagonist SB-334867 aggravated cognitive dysfunction in 3xTg-AD mice.

Cognitive dysfunction is the main clinical manifestation of Alzheimer's disease (AD). Previous research found that elevated orexin level in the cerebrospinal fluid was closely related to the course of AD, and orexin-A treatment could increase amyloid ß protein (Aß) deposition and aggravate spatial memory impairment in APP/PS1 mice. Furthermore, recent research found that dual orexin receptor (OXR) antagonist might affect Aß level and cognitive dysfunction in AD, but the effects of OX1R or OX2R alone is unreported until now. Considering that OX1R is highly expressed in the hippocampus and plays important roles in learning and memory, the effects of OX1R in AD cognitive dysfunction and its possible mechanism should be investigated. In the present study, selective OX1R antagonist SB-334867 was used to block OX1R. Then, different behavioral tests were performed to observe the effects of OX1R blockade on cognitive function of 3xTg-AD mice exhibited both Aß and tau pathology, in vivo electrophysiological recording and western blot were used to investigate the potential mechanism. The results showed that chronic OX1R blockade aggravated the impairments of short-term working memory, long-term spatial memory and synaptic plasticity in 9-month-old female 3xTg-AD mice, increased levels of soluble Aß oligomers and p-tau, and decreased PSD-95 expression in the hippocampus of 3xTg-AD mice. These results indicate that the detrimental effects of SB-334867 on cognitive behaviors in 3xTg-AD mice are closely related to the decrease of PSD-95 and depression of in vivo long-term potentiation (LTP) caused by increased Aß oligomers and p-tau.

Integrated analysis of the lncRNA-associated ceRNA network in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that worsens with age. Long non-coding RNAs (lncRNAs) dysregulation and its associated competing endogenous RNA (ceRNA) network have a potential connection with the occurrence and development of AD. A total of 358 differentially expressed genes (DEGs) were screened via RNA sequencing, including 302 differentially expressed mRNAs (DEmRNAs) and 56 differential expressed lncRNAs (DElncRNAs). Anti-sense lncRNA is the main type of DElncRNA, which plays a major role in the cis and trans regulation. The constructed ceRNA network consisted of 4 lncRNAs (NEAT1, LINC00365, FBXL19-AS1, RAI1-AS1719) and 4 microRNAs (miRNAs) (HSA-Mir-27a-3p, HSA-Mir-20b-5p, HSA-Mir-17-5p, HSA-Mir-125b-5p), and 2 mRNAs (MKNK2, F3). Functional enrichment analysis revealed that DEmRNAs are involved in related biological functions of AD. The co-expressed DEmRNAs (DNAH11, HGFAC, TJP3, TAC1, SPTSSB, SOWAHB, RGS4, ADCYAP1) of humans and mice were screened and verified by real-time quantitative polymerase chain reaction (qRT-PCR). In this study, we analyzed the expression profile of human AD-related lncRNA genes, constructed a ceRNA network, and performed functional enrichment analysis of DEmRNAs between human and mice. The obtained gene regulatory networks and target genes can be used to further analyze AD-related pathological mechanisms to optimize AD diagnosis and treatment.

Orexin-A aggravates cognitive deficits in 3xTg-AD mice by exacerbating synaptic plasticity impairment and affecting amyloid ß metabolism.

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid ß (Aß) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aß levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aß and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aß production and decreasing Aß clearance through disruption of the circadian rhythm and sleep-wake cycle.

Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aß and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aß plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD.

A modified regimen of extracorporeal cardiac shock wave therapy for treatment of coronary artery disease.

BACKGROUND: Cardiac shock wave therapy (CSWT) improves cardiac function in patients with severe coronary artery disease (CAD). We aimed to evaluate the clinical outcomes of a new CSWT treatment regimen. METHODS: The 55 patients with severe CAD were randomly divided into 3 treatment groups. The control group (n = 14) received only medical therapy. In group A ( n = 20), CSWT was performed 3 times within 3 months. In group B ( n = 21), patients underwent 3 CSWT sessions/week, and 9 treatment sessions were completed within 1 month. Primary outcome measurement was 6-minute walk test (6MWT). Other measurements were also evaluated. RESULTS: The 6MWT, CCS grading of angina, dosage of nitroglycerin, NYHA classification, and SAQ scores were improved in group A and B compared to control group. CONCLUSIONS: A CSWT protocol with 1 month treatment duration showed similar therapeutic efficacy compared to a protocol of 3 months duration. CLINICAL TRIAL REGISTRY: We have registered on ClinicalTrials.gov, the protocol ID is CSWT IN CHINA.

Pathological Mechanism and Targeted Drugs of COPD.

Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis, emphysema, and small airway obstruction. Incompletely reversible airflow limitation, inflammation, excessive mucus secretion and bronchial mucosal epithelial lesions are the main pathological basis of the disease. The prevalence of COPD is increasingly worldwide, which has caused the burden on individuals and society. This paper summarizes the pathogenesis of COPD and clarifies the effect and mechanism of the latest targeted drugs for COPD. Besides, we focus on NOD-like receptor thermal protein domain associated protein 3 inflammasome (NLRP3 inflammasome). NLRP3 can promote production of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). NLRP3 is an important factor in the migratory aggregation of macrophages and neutrophils and the generation of oxidative stress. Inhibition of NLRP3 inflammasome indirectly blocks the inflammatory effects of IL-1ß and IL-18, which may be regarded as an ideal target for COPD treatment.