Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe/PS1dE9 mice.

Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). α/ß-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Aß) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Aß levels and neuroinflammation in the hippocampus of AD mice, and enhanced Aß phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.

Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis.

Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial activation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in microglia exposed to ischemia/reperfusion both in vivo and in vitro. In addition, adenovirus-associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase 2 (MDH2) and competitively inhibited the binding of MDH2 to the CXCL2 3' untranslated region (UTR), thus protecting against MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.

miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aß1-42-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.

LncRNA-1810034E14Rik reduces microglia activation in experimental ischemic stroke.

BACKGROUND: Activation of microglial cells plays an important role in neuroinflammation after ischemic stroke. Inhibiting the activation of microglial cells has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. METHODS: Oxygen-glucose deprivation in primary microglial cells and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as the in vitro and in vivo ischemic stroke models. Microarray analysis was performed to investigate the overall impact of long non-coding RNAs (lncRNAs) on the inflammation status of microglial cells. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers. ELISA was taken to measure the level of cytokines. Immunofluorescence was used to observe the activation of microglial cells. Western blotting was performed to test the p65 phosphorylation. RESULTS: In this study, we showed that LncRNA-1810034E14Rik was significantly decreased in LPS-treated or oxygen-glucose deprivation-induced microglial cells. Overexpression of 1810034E14Rik decreased the infarct volume and alleviated brain damage in MCAO mice. 1810034E14Rik overexpression reduced the expression of inflammatory cytokines not only in ischemic stroke mice but also in oxygen-glucose deprivation-induced microglial cells. Moreover, 1810034E14Rik overexpression could suppress the activation of microglial cells and inhibit the phosphorylation of p65. CONCLUSIONS: LncRNA-1810034E14Rik plays an anti-inflammatory role in ischemic stroke and regulates p65 phosphorylation, making it a potential target for stroke treatment.

Revealing a 5,000-y-old beer recipe in China.

The pottery vessels from the Mijiaya site reveal, to our knowledge, the first direct evidence of in situ beer making in China, based on the analyses of starch, phytolith, and chemical residues. Our data reveal a surprising beer recipe in which broomcorn millet (Panicum miliaceum), barley (Hordeum vulgare), Job's tears (Coix lacryma-jobi), and tubers were fermented together. The results indicate that people in China established advanced beer-brewing technology by using specialized tools and creating favorable fermentation conditions around 5,000 y ago. Our findings imply that early beer making may have motivated the initial translocation of barley from the Western Eurasia into the Central Plain of China before the crop became a part of agricultural subsistence in the region 3,000 y later.

Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein.

Spinocerebellar ataxia 3 (SCA3), which is a progressive neurodegenerative disease, is currently incurable. Emerging studies have reported that human umbilical cord mesenchymal stem cells (HUC-MSCs) transplantation could be a promising therapeutic strategy for cerebellar ataxias. However, few studies have evaluated the effects of HUC-MSCs on SCA3 transgenic mouse. Thus, we investigated the effects of HUC-MSCs on SCA3 mice and the underlying mechanisms in this study. SCA3 transgenic mice received systematic administration of 2 × 106 HUC-MSCs once per week for 12 continuous weeks. Motor coordination was measured blindly by open field tests and footprint tests. Immunohistochemistry and Nissl staining were applied to detect neuropathological alternations. Neurotrophic factors in the cerebellum were assessed by ELISA. We used western blotting to detect the alternations of heat shock protein 70 (HSP70), IGF-1, mutant ataxin-3, and apoptosis-associated proteins. Tunel staining was also used to detect apoptosis of affected cells. The distribution and differentiation of HUC-MSCs were determined by immunofluorescence. Our results exhibited that HUC-MSCs transplantation significantly alleviated motor impairments, corresponding to a reduction of cerebellar atrophy, preservation of neurons, decreased expression of mutant ataxin-3, and increased expression of HSP70. Implanted HUC-MSCs were mainly distributed in the cerebellum and pons with no obvious differentiation, and the expressions of IGF-1, VEGF, and NGF in the cerebellum were significantly elevated. Furthermore, with the use of HSP70 analogy quercetin injection, it demonstrated that HSP70 is involved in mutant ataxin-3 reduction. These results showed that HUC-MSCs implantation is a potential treatment for SCA3, likely through upregulating the IGF-1/HSP70 pathway and subsequently inhibiting mutant ataxin-3 toxicity.

Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing Aß deposition.

BACKGROUND: It is well known that Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-ß (Aß) deposition and synaptic dysfunction play important roles in the pathophysiology of Alzheimer's disease (AD). The Huatuo Zaizao pill (HT) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China, mainly for post-stroke rehabilitation and cognitive decline; however, the mechanism of cognitive function is not clear. In this study, we investigated the effect of HT on hippocampal synaptic function, Amyloid-ß (Aß) deposition in APP/PS1 AD transgenic mice. METHOD: Six-month-old APP/PS1 transgenic (Tg) mice were randomly divided into control, HT-treated, and memantine (MEM)-treated groups. Then, these groups were orally administered vehicle (for the control), HT (0.25 g/kg) and MEM (5 mg/kg) respectively for 4 weeks. The Morris water maze, Novel Object Recognition, and Open field tests were used to assess cognitive behavioral changes. We evaluated the effects of HT on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular tests. Synaptic morphology in the hippocampus was investigated by electron microscopy. Western blotting was used to assess synaptic-associated protein and Aß production and degrading levels. Immunofluorescence staining was used to determine the relative integrated density. RESULTS: HT can ameliorate hippocampus-dependent memory deficits and improve synaptic dysfunction by reversing LTP impairment in APP/PS1 transgenic mice. Moreover, HT reduces amyloid plaque deposition by regulating α-secretase and γ-secretase levels. CONCLUSION: HT can improve the learning and memory function of APP/PS1 transgenic mice by improving synaptic function and reducing amyloid plaque deposition.

Human albumin attenuates excessive innate immunity via inhibition of microglial Mincle/Syk signaling in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke. Microglial macrophage-inducible C-type lectin (Mincle) receptor launches microglial innate immunity after SAH, and thereby achieves a key step of early cerebral injury in SAH. We previously revealed albumin could improve long-term neurological outcomes after SAH. In this study, we examined the role of microglia-mediated innate immunity in the salutary effects of albumin. SAH was induced by endovascular perforation in rats. We found that albumin can significantly mitigate early neurovascular dysfunction of SAH rats. Albumin administration resulted in reduced Iba-1 and CD68 staining in cortex. Markers of microglia M1 polarization (iNOS, IL-1ß, CD16, and CD32) were remarkably suppressed. Neutrophil invasion was inhibited as chemokines (MCP-1, CINC-1, and CXCL-2) mRNA levels, myeloperoxidase (MPO) and intracellular adhesion molecule-1 (ICAM-1) expressions were decreased. Mechanistically, albumin bound with microglial Mincle receptor, and retarded Mincle/Syk/IL-1ß signaling in ipsilateral hemisphere subjected to SAH. In the cultured BV-2 microglial cells, we found Mincle and its ligand SAP130 mediate the cross-talk between neuronal necroptosis and microglial immunity response following SAH-related injury. Albumin could attenuate SAP130-induced Mincle upregulation and subsequent microglial inflammatory responses. The anti-inflammation effect of albumin was similar to the effect of genetic knockdown of Mincle. This effect may be attributed to a direct association between albumin and Mincle. The interaction also yielded a depression in the initiation of Mincle/Syk/IL-1ß pathway. In conclusion, our results indicate that albumin can ameliorate innate immune responses after SAH. This anti-inflammatory action may be through direct restraining microglial Mincle receptor.

Panaxatriol saponins promotes angiogenesis and enhances cerebral perfusion after ischemic stroke in rats.

BACKGROUND: Panaxatriol saponins (PTS), an extract from the traditional Chinese herb Panax notoginseng, which has been used to treat ischemic stroke for many years in China. However, the mechanism underlying the effects of PTS remains unclear. This study aimed to determine whether PTS can protect against ischemic brain injury by promoting angiogenesis and to explore the possible mechanism by which it promotes angiogenesis. METHODS: Middle cerebral artery occlusion (MCAO) was induced in rats, and neurological deficit scores and brain infarct volumes were assessed. Micro-Positron emission tomography (PET) was adopted to assess cerebral perfusion, and real-time PCR and western blotting were used to evaluate vascular growth factor and Sonic hedgehog (Shh) pathway component levels. Immunofluorescence staining was used to determine capillary densities in ischemic penumbrae. RESULTS: We showed that PTS improved neurological function and reduced infarct volumes in MCAO rats. Micro-PET indicated that PTS can significantly increase 18F-fluorodeoxyglucose (18F-PDG) uptake by ischemic brain tissue and enhance cerebral perfusion after MCAO surgery. Moreover, PTS was able to increase capillary densities and enhance angiogenesis in ischemic boundary zones and up-regulate vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) expression by activating the Shh signaling pathway. CONCLUSION: These findings indicate that PTS exerts protective effects against cerebral ischemic injury by enhancing angiogenesis and improving microperfusion.

Opposite roles of bradykinin B1 and B2 receptors during cerebral ischaemia-reperfusion injury in experimental diabetic rats.

Bradykinin receptors play important roles in cerebral ischaemia-reperfusion (I/R) injury of non-diabetics. Their functions in diabetics, however, have not been studied. In this study, we hypothesized that bradykinin 1 receptor (B1R) and bradykinin 2 receptor (B2R) would be upregulated and participate in the regulation of diabetic ischaemic stroke. To investigate this, we first evaluated B1R and B2R expression at different time points after I/R in non-diabetic and diabetic rats (Sprague-Dawley) by using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence. Then, pharmacological inhibitors were separately administered via the tail vein to analyse their effects on cerebral ischaemia in diabetics. Both receptors were significantly upregulated after cerebral I/R in non-diabetic and diabetic rats. B1R expression in diabetic rats increased in a sharper manner than in non-diabetic rats, whereas B2R expression increased to the same level during the early stage of reperfusion but later became lower. Interestingly, the upregulated B1R was expressed in astrocytes, whereas B2R was mainly located in neurons in the ischaemic penumbra. Functional studies showed that inhibition of B1R significantly reduced infarct volume, neurological deficits, cell apoptosis, and neuron degeneration, probably by attenuating blood-brain barrier (BBB) disruption and post-ischaemic inflammation, at 24 h after reperfusion. In contrast, B2R antagonist had opposite effects, and exacerbated BBB penetrability and tissue inflammation. These findings suggest that B1R and B2R have detrimental and beneficial effects, respectively in diabetic cerebral ischaemia, which might open new avenues for the treatment of ischaemic stroke in diabetic patients through selective pharmacological blockade or activation.

TL-2 attenuates ß-amyloid induced neuronal apoptosis through the AKT/GSK-3ß/ß-catenin pathway.

ß-amyloid (Aß)-mediated neuronal apoptosis contributes to the progression of Alzheimer's disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether Dalesconol B (TL-2), a potent immunosuppressive agent with an unusual carbon skeleton, could inhibit Aß-induced apoptosis in vitro and in vivo and to explore the underlying mechanisms. Aß(1-42) was injected to bilateral hippocampus of mice to make the AD models in vivo. TL-2 was able to cross the blood-brain barrier and attenuate memory deficits in the AD mice. TL-2 also inhibited Aß(1-42)-induced neuronal apoptosis in vitro and in vivo. In addition, TL-2 could activate the AKT/GSK-3ß pathway, and inhibition of AKT and activation of GSK-3ß partially eliminated the neuroprotective effects of TL-2. Furthermore, TL-2 induced the nuclear translocation of ß-catenin and enhanced its transcriptional activity through the AKT/GSK-3ß pathway to promote neuronal survival. These results suggest that TL-2 might be a potential drug for AD treatment.

Enterprise stents for the treatment of symptomatic non-acute intracranial artery stenosis disease: safety and efficiency evaluation.

BACKGROUND: Enterprise stent was approved for the treatment of wide-necked intracranial aneurysms. However, it has been widely used in the endovascular treatment of intracranial artery stenosis, which is still controversial. The purpose of this study was to evaluate the safety and efficiency of the Enterprise stent in the endovascular treatment of intracranial artery stenosis disease. METHODS: We conducted a retrospective case series of 107 patients with intracranial artery stenosis who received Enterprise stent implantation at Nanjing Drum Tower Hospital from January 2020 to December 2022. The rates of recanalization, perioperative complications, in-stent restenosis at 3-12 months and stroke recurrence were assessed for endovascular treatment. RESULTS: A total of 107 individuals were included in this study, 88 were followed up, and 19 (17.8%) patients were lost to follow-up. The operation success rate was 100%, During the procedure,4（3.7%）patients had vasospasm, and 2(1.9%) patients showed symptomatic bleeding. The overall perioperative complication rate was 5.6%, including 2.8% distal artery embolism, 0.9% in-stent thrombosis, and 1.9% symptomatic bleeding. 88 (82.2%) patients were followed up from 3 to 12 months, of whom 12 (13.6%) had in-stent restenosis, 4 (4.7%) recurrent strokes and 2 died of pulmonary infection caused by COVID-19. Patients were divided into 3 groups according to the cerebral artery, including the middle cerebral artery group, internal carotid artery group, and vertebrobasilar artery group. CONCLUSIONS: In this study, the placement of the Enterprise stent in patients with symptomatic non-acute intracranial stenosis was successful. However, the occurrence of periprocedural and long-term complications after stenting remains of high concern.

Triaxial mechanical behaviours and life cycle assessment of sustainable multi-recycled aggregate concrete.

Multi-recycling of concrete waste presents a promising avenue for carbon-negative development and a circular economy. This study comprehensively assesses the triaxial mechanical performance and environmental impact of multi-recycled concrete (Multi-RAC) through three recycling cycles. The results reveal a triaxial failure mode similar to natural aggregate concrete (NAC). The peak stress and peak strain monotonically increase with confinement stress, showing a significant impact (enlarged by 171.4 % to 280.6 % and 397.4 % to 412.0 %, respectively) from 0 to 20 MPa. All P-values for recycling cycles and confining pressure are less than 0.05, with the confining pressure having a more significant effect. Three best-fit multivariate mixed models predict mechanical properties, and a modified elastoplastic model introduces the recycling cycles factor. Numerical simulations confirm the model's accuracy in predicting the triaxial mechanical properties of Multi-RAC. Comparative analysis reveals that the elastoplastic model-derived non-integral high order failure criterion outperforms the Willam-Warnke failure criterion and other conventional criteria. Regarding environmental impact, all indicators (GWP, POCP, AP, EP, and CED) decrease favourably with the increasing number of recycling cycles, with CED and EP playing the most significant roles. Compared to NAC, the five environmentally favorable indicators for RACIII decrease by 3.24 % to 50.6 %, respectively. These findings provide valuable insights for future research on developing eco-friendlier Multi-RAC for sustainable and green infrastructure.

Mapping the distribution of Nipah virus infections: a geospatial modelling analysis.

BACKGROUND: Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia. METHODS: In this geospatial modelling analysis, we developed an integrated database containing information on the distribution of Nipah virus infections in humans and animals from 1998 to 2021. We conducted phylodynamic analysis to examine the evolution and migration pathways of the virus and meta-analyses to estimate the adjusted case-fatality rate. We used two boosted regression tree models to identify the potential ecological drivers of Nipah virus occurrences in spillover events and endemic areas, and mapped potential risk areas for Nipah virus endemicity. FINDINGS: 749 people and eight bat species across nine countries were documented as being infected with Nipah virus. On the basis of 66 complete genomes of the virus, we identified two clades-the Bangladesh clade and the Malaysia clade-with the time of the most recent common ancestor estimated to be 1863. Adjusted case-fatality rates varied widely between countries and were higher for the Bangladesh clade than for the Malaysia clade. Multivariable meta-regression analysis revealed significant relationships between case-fatality rate estimates and viral clade (p=0·0021), source country (p=0·016), proportion of male patients (p=0·036), and travel time to health-care facilities (p=0·036). Temperature-related bioclimate variables and the probability of occurrence of Pteropus medius were important contributors to both the spillover and the endemic infection models. INTERPRETATION: The suitable niches for Nipah virus are more extensive than previously reported. Future surveillance efforts should focus on high-risk areas informed by updated projections. Specifically, intensifying zoonotic surveillance efforts, enhancing laboratory testing capacity, and implementing public health education in projected high-risk areas where no human cases have been reported to date will be crucial. Additionally, strengthening wildlife surveillance and investigating potential modes of transmission in regions with documented human cases is needed. FUNDING: The Key Research and Development Program of China.

A study on inhibition of the Aß1-42-induced inflammatory response by the Huatuo Zaizao pill through the NF-κB signaling pathway.

Introduction: The pathology of Alzheimer's disease (AD) includes ß-amyloid (Aß) (plaques) and neurofibrillary tangles (NFTs). This study aimed to explore the efficacy of Huatuo Zaizao pill (HTZP) in an AD mouse model induced by injecting Aß1-42, and the neuroprotective mechanism of HTZP in AD. Material and methods: C57BL/6 (B6) mice were randomly divided into 4 groups (n = 10, per group): control group, AD model group, and 2 different doses of HTZP treated groups. The Morris water maze test was carried out on AD mice to assess the learning ability after treatment with HTZP for 15 day. The levels of inflammatory factors and the nuclear factor-κB (NF-κB) pathway were examined by western blot and real-time polymerase chain reaction (PCR). The content of microglia was investigated by immunofluorescence. Results: This study revealed that a cognitive disorder could be mitigated when the AD mice were treated with HTZP, which might be associated with the decreased level of pro-inflammatory factors, and the inhibitory activities of microglia. Additionally, phosphorylation of IκB and NF-κB p65 could be reduced by prohibiting the neuroinflammation of NF-κB activation in the hippocampus of AD mice. Conclusions: These results showed that HTZP could mitigate a cognitive disorder, diminish the activation of microglia, and inhibit the content of inflammatory factors through the NF-κB pathway in Aß1-42-induced AD mice. HTZP may be an appropriate agent for AD treatment in the future.

Short-Term Exposure to Ambient Air Pollution and Influenza: A Multicity Study in China.

BACKGROUND: Air pollution is a major risk factor for planetary health and has long been suspected of predisposing humans to respiratory diseases induced by pathogens like influenza viruses. However, epidemiological evidence remains elusive due to lack of longitudinal data from large cohorts. OBJECTIVE: Our aim is to quantify the short-term association of influenza incidence with exposure to ambient air pollutants in Chinese cities. METHODS: Based on air pollutant data and influenza surveillance data from 82 cities in China over a period of 5 years, we applied a two-stage time series analysis to assess the association of daily incidence of reported influenza cases with six common air pollutants [particulate matter with aerodynamic diameter ≤2.5µm (PM2.5), particulate matter with aerodynamic diameter ≤10µm (PM10), NO2, SO2, CO, and O3], while adjusting for potential confounders including temperature, relative humidity, seasonality, and holiday effects. We built a distributed lag Poisson model for one or multiple pollutants in each individual city in the first stage and conducted a meta-analysis to pool city-specific estimates in the second stage. RESULTS: A total of 3,735,934 influenza cases were reported in 82 cities from 2015 to 2019, accounting for 72.71% of the overall case number reported in the mainland of China. The time series models for each pollutant alone showed that the daily incidence of reported influenza cases was positively associated with almost all air pollutants except for ozone. The most prominent short-term associations were found for SO2 and NO2 with cumulative risk ratios of 1.094 [95% confidence interval (CI): 1.054, 1.136] and 1.093 (95% CI: 1.067, 1.119), respectively, for each 10 µg/m3 increase in the concentration at each of the lags of 1-7 d. Only NO2 showed a significant association with the daily incidence of influenza cases in the multipollutant model that adjusts all six air pollutants together. The impact of air pollutants on influenza was generally found to be greater in children, in subtropical cities, and during cold months. DISCUSSION: Increased exposure to ambient air pollutants, particularly NO2, is associated with a higher risk of influenza-associated illness. Policies on reducing air pollution levels may help alleviate the disease burden due to influenza infection. https://doi.org/10.1289/EHP12146.

MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.

Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer's disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-ß levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.

Comparative study on epidemiological and etiological characteristics of patients with acute diarrhea with febrile or non-febrile symptoms in China.

BACKGROUND: Acute diarrhea with fever can potentially represent a more severe form of the disease compared to non-febrile diarrhea. This study was to investigate the epidemiological characteristics and enteric pathogen composition of febrile-diarrheal patients, and to explore factors including pathogens associated with fever by age group. METHODS: A nationwide surveillance study of acute diarrheal patients of all ages was conducted in 217 sentinel hospitals from 31 provinces (autonomous regions or municipalities) in China between 2011 and 2020. Seventeen diarrhea-related pathogens, including seven viruses and ten bacteria, were investigated and their association with occurrence of fever symptoms was assessed using multivariate logistic analysis. RESULTS: A total of 146,296 patients with acute diarrhea (18.6% with fever) were tested. Th diarrheal children below 5 years had the highest frequency of fever (24.2%), and related to significantly higher prevalence of viral enteropathogens (40.2%) as compared with other age groups (P < 0.001). Within each age group, the febrile-diarrheal patients were associated with a significantly higher prevalence of bacterial pathogens than afebrile-diarrheal patients (all P < 0.01). There was discrepancy when each pathogen was compared, i.e., nontyphoidal Salmonella (NTS) was overrepresented in febrile vs non-febrile patients of all age groups, while the febrile vs non-febrile difference for diarrheagenic Escherichia coli (DEC) was only significant for adult groups. The multivariate analysis revealed significant association between fever and infection with rotavirus A among children [odds ratio (OR) = 1.60], for DEC in adult groups (OR = 1.64), for NTS in both children (OR = 2.95) and adults (OR = 3.59). CONCLUSIONS: There are significant discrepancy of the infected enteric pathogens in patients with acute diarrhea with fever between age groups, and it is valuable for priority detection of NTS and rotavirus A in patients with children < 5 years old and NTS and DEC in adult patients. The results may be useful in identifying dominant pathogen candidates for the application of diagnostic assays and prevention control.

Aberrant Energy Metabolism in Alzheimer's Disease.

To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer's disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

Imperatorin inhibits mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and alleviates neuroinflammation in ischemic stroke.

AIMS: Microglia-mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post-stroke neuroinflammation is not fully understood. METHODS: Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT-PCR, ELISA, and Western blot. The activation of MAPK and NF-κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume. RESULTS: Imperatorin suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF-κB pathways might contribute to the protective effects of imperatorin. CONCLUSIONS: Imperatorin downregulated MAPK and NF-κB signaling pathways and exerted anti-inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke.