The Biological Implication of Semicarbazide-Sensitive Amine Oxidase (SSAO) Upregulation in Rat Systemic Inflammatory Response under Simulated Aerospace Environment.

The progress of space science and technology has ushered in a new era for humanity's exploration of outer space. Recent studies have indicated that the aerospace special environment including microgravity and space radiation poses a significant risk to the health of astronauts, which involves multiple pathophysiological effects on the human body as well on tissues and organs. It has been an important research topic to study the molecular mechanism of body damage and further explore countermeasures against the physiological and pathological changes caused by the space environment. In this study, we used the rat model to study the biological effects of the tissue damage and related molecular pathway under either simulated microgravity or heavy ion radiation or combined stimulation. Our study disclosed that ureaplasma-sensitive amino oxidase (SSAO) upregulation is closely related to the systematic inflammatory response (IL-6, TNF-α) in rats under a simulated aerospace environment. In particular, the space environment leads to significant changes in the level of inflammatory genes in heart tissues, thus altering the expression and activity of SSAO and causing inflammatory responses. The detailed molecular mechanisms have been further validated in the genetic engineering cell line model. Overall, this work clearly shows the biological implication of SSAO upregulation in microgravity and radiation-mediated inflammatory response, providing a scientific basis or potential target for further in-depth investigation of the pathological damage and protection strategy under a space environment.

Single-cell RNA-sequencing reveals the existence of naive and primed pluripotency in pre-implantation rhesus monkey embryos.

Naive pluripotency exists in epiblast cells of mouse pre-implantation embryos. However, whether the naive pluripotency is transient or nonexistent in primate embryos remains unclear. Using RNA-seq in single blastomeres from 16-cell embryos through to hatched blastocysts of rhesus monkey, we constructed the lineage segregation roadmap in which the specification of trophectoderm, epiblast, and primitive endoderm is initiated simultaneously at the early blastocyst stage. Importantly, we uncovered the existence of distinct pluripotent states in monkey pre-implantation embryos. At the early- and middle-blastocyst stages, the epiblast cells have the transcriptome features of naive pluripotency, whereas they display a continuum of primed pluripotency characteristics at the late and hatched blastocyst stages. Moreover, we identified potential regulators that might play roles in the transition from naive to primed pluripotency. Thus, our study suggests the transient existence of naive pluripotency in primates and proposes an ideal time window for derivation of primate embryonic stem cells with naive pluripotency.

DR5 related autophagy can promote apoptosis in gliomas after irradiation.

As a cancer treatment strategy, irradiation therapy is widely used that can cause DNA breakage and increase free radicals, which leads to different types of cell death. Among them, apoptosis and autophagy are the most important and the most studied cell death processes. Although the exploration of the relationship between apoptosis and autophagy has been a major area of focus, still the molecular mechanisms of autophagy on apoptosis remain unclear. Here, we have revealed that apoptosis was enhanced by the death receptor 5 (DR5) pathway, and the effect of autophagy on apoptosis was promoted by DR5 interacting with LC3B as well as Caspase8 in gliomas after irradiation. Interestingly, we observed that the addition of four different autophagy inducers, rapamycin (RAP), CCI779, ABT737 and temozolomide (TMZ), induced the differences of DR5 expression and cell apoptosis after irradiation. Unlike RAP and CCI779, ABT737 and TMZ were able to increase DR5 expression and further induce cell death. Therefore, we have concluded that DR5 plays a novel and indispensable role in promoting cell apoptosis under irradiation and suggest a potential therapeutic approach for glioblastoma treatment.

A Multifunctional Peptide-Conjugated AIEgen for Efficient and Sequential Targeted Gene Delivery into the Nucleus.

Gene therapy has immense potential as a therapeutic approach to serious diseases. However, efficient delivery and real-time tracking of gene therapeutic agents have not been solved well for successful gene-based therapeutics. Herein we present a versatile gene-delivery strategy for efficient and visualized delivery of therapeutic genes into the targeted nucleus. We developed an integrin-targeted, cell-permeable, and nucleocytoplasmic trafficking peptide-conjugated AIEgen named TD NCP for the efficient and sequential targeted delivery of an antisense single-stranded DNA oligonucleotide (ASO) and tracking of the delivery process into the nucleus. As compared with TD NCP/siRNA-NPs (siRNA functions mainly in the cytoplasm), TD NCP/ASO-NPs (ASO functions mainly in the nucleus) exhibited a better interference effect, which further indicates that TD NCP is a nucleus-targeting vector. Moreover, TD NCP/ASO-NPs showed a favorable tumor-suppressive effect in vivo.

Auricular vagus nerve stimulation enhances central serotonergic function and inhibits diabetic neuropathy development in Zucker fatty rats.

Painful neuropathy is a frequent comorbidity in diabetes. Zucker diabetic fatty (fa/fa) rats develop type 2 diabetes spontaneously with aging and show nociceptive hypersensitivity at the age of 13 weeks. In preclinical and clinical studies, the treatment of diabetic neuropathy is challenging, but complementary medicine such as transcutaneous auricular vagus nerve stimulation (taVNS) appears beneficial to the relief of neuropathic pain. However, the mechanism behind the effectiveness of taVNS remains unclear. In this study, we show that daily 30-min taVNS (2/15 Hz, 2 mA) for consecutive 27 days effectively inhibited the development of nociceptive hypersensitivity in Zucker diabetic fatty rats as detected by thermal hyperalgesia and mechanical allodynia in hindpaw. We also demonstrated that this beneficial effect in nociceptive behavior is related to an elevated serotonin (5-HT) plasma concentration and an upregulated expression of 5-HT receptor type 1A (5-HT1AR) in hypothalamus. We conclude that daily 30-min taVNS sessions lessen diabetic neuropathy development by enhancing serotonergic function in genetically diabetes prone individuals. Perspective This article presents taVNS as a new approach to inhibit the development of diabetic neuropathy in genetically prone individuals. This approach could potentially help clinicians who seek to avoid the complication of neuropathic pain in diabetic patient or to relieve the pain if there was one.

An Intracellular H2 O2 -Responsive AIEgen for the Peroxidase-Mediated Selective Imaging and Inhibition of Inflammatory Cells.

Inflammatory cells have gained widespread attention because inflammatory diseases increase the risk for many types of cancer. Therefore, it is urgent and important to implement detection and treatment methods for inflammatory cells. Herein, we constructed a theranostic probe with aggregation-induced emission (AIE) characteristics, in which tetraphenylethene (TPE) was modified with two tyrosine (Tyr) moieties. Owing to the H2 O2 -dependent, enzyme-catalyzed dityrosine formation, Tyr-containing TPE (TT) molecules crosslink through dityrosine linkages to induce the formation of hydrophobic aggregates, activating the AIE process in inflammatory cells that contain H2 O2 and overexpress myeloperoxidase. The emission turn-on resulting from the crosslinking of TT molecules could be used to distinguish between inflammatory and normal cells. Moreover, the massive TT aggregates induced mitochondria damage and cell apoptosis. This study demonstrates that the H2 O2 -responsive peroxidase-activated AIEgen holds great promise for inflammatory-cell selective imaging and inhibition.

Inhibition of PTEN Attenuates Endoplasmic Reticulum Stress and Apoptosis via Activation of PI3K/AKT Pathway in Alzheimer's Disease.

Amyloid plaques and neurofibrillary tangles are pathologic hallmarks of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been implicated in the loss of neurons in AD. The phosphatase and tensin homolog deleted on chromosome ten (PTEN) plays an important role in regulating neuronal survival processes. However, the direct effects of the PTEN on ER stress and apoptosis in AD have not been elucidated. In this study, we demonstrate that the expression of PTEN and ER stress related proteins, GRP78 and CHOP, increased in APP/PS1 transgenic AD mice compared with WT mice. A PTEN inhibitor, dipotassium bisperoxo-(5-hydroxypyridine-2-carboxyl)-oxovanadate (bpv) could decrease apoptosis, induce AKT phosphorylation and inhibit the ER stress response proteins in hippocampus in APP/PS1 transgenic AD model mice. Furthermore, treatment with the specific PI3K inhibitor, LY294002, significantly blocked the anti-apoptotic effects of bpv in AD mice. The expression in GRP78, CHOP and apoptosis levels by bpv was reversed after PI3K inhibitor treatment. Taken together, our results indicate that the neuroprotective role of bpv involves the suppression of ER stress via the activation of the PI3K/AKT signalling pathways in APP/PS1 transgenic AD model mice.

Rapid detection of Clostridium difficile toxins and laboratory diagnosis of Clostridium difficile infections.

BACKGROUND: Clostridium difficile is an anaerobic, spore-forming and Gram-positive bacillus. It is the major cause of antibiotic-associated diarrhea prevailing in hospital settings. The morbidity and mortality of C. difficile infection (CDI) has increased significantly due to the emergence of hypervirulent strains. Because of the poor clinical different between CDI and other causes of hospital-acquired diarrhea, laboratory test for C. difficile is an important intervention for diagnosis of CDI. OBJECTIVE: Laboratory tests for CDI can broadly detect either the organisms or its toxins. Currently, several laboratory tests are used for diagnosis of CDI, including toxigenic culture, glutamate dehydrogenase detection, nucleic acid amplification testing, cell cytotoxicity assay, and enzyme immunoassay towards toxin A and/or B. This review focuses on the rapid testing of C. difficile toxins and currently available methods for diagnosis of CDI, giving an overview of the role that the toxins rapid detecting plays in clinical diagnosis of CDI.

Salubrinal protects against Clostridium difficile toxin B-induced CT26 cell death.

Clostridium difficile (C. difficile) is considered to be the major cause of the antibiotic-associated diarrhea and pseudomembranous colitis in animals and humans. The prevalence of C. difficile infections (CDI) has been increasing since 2000. Two exotoxins of C. difficile, Toxin A (TcdA) and Toxin B (TcdB), are the main virulence factors of CDI, which can induce glucosylation of Rho GTPases in host cytosol, leading to cell morphological changes, cell apoptosis, and cell death. The mechanism of TcdB-induced cell death has been investigated for decades, but it is still not completely understood. It has been reported that TcdB induces endoplasmic reticulum stress via PERK-eIF2α signaling pathway in CT26 cell line (BALB/C mouse colon tumor cells). In this study, we found that salubrinal, a selective inhibitor of eIF2α dephosphorylation, efficiently protects CT26 cell line against TcdB-induced cell death and tried to explore the mechanism underlying in this protective effect. Our results demonstrated that salubrinal protects CT26 cells from TcdB-mediated cytotoxic and cytopathic effect, inhibits apoptosis and death of the toxin-exposed cells via caspase-9-dependent pathway, eIF2α signaling pathway, and autophagy. These findings will be helpful for the development of CDI therapies.

High mobility group box1 protein is involved in acute inflammation induced by Clostridium difficile toxin A.

High mobility group box1 (HMGB1), as a damage-associated inflammatory factor, contributes to the pathogenesis of numerous chronic inflammatory and autoimmune diseases. In this study, we explored the role of HMGB1 in CDI (Clostridium difficile infection) by in vivo and in vitro experiments. Our results showed that HMGB1 might play an important role in the acute inflammatory responses to C. difficile toxin A (TcdA), affect early inflammatory factors, and induce inflammation via the HMGB1-TLR4 pathway. Our study provides the essential information for better understanding the molecular mechanisms of CDI and the potential new therapeutic strategies for the treatment of this infection.

[Effects of Exogenous Nerve Growth Factor on Late Reperfusion after Myocardial Infarction].

This study demonstrates that nerve growth factor (NGF) plays a protective role in myocardial infarction and early reperfusion by reducing the myocardial cell apoptosis and by improving ventricular remodeling and seeks to assess the effects and mechanisms of NGF on late reperfusion after myocardial infarction. The models of late reperfusion were established by ligating the left main coronary artery and then cutting the suture 2 hours after coronary artery ligation. The rats in NGF treatment group were injected 10 µL Ad-NGF (by constructing the adenovirus vector Ad-NGF containing NGF gene) at four locations around infarction. The rats in adenoviral vector (Adv) group were injected 10 µL adenoviral cector as the NGF group. The late reperfusion group and the sham group were given normal saline as above, and the sham group underwent thracotomy without coronary ligation. On the 3rd, 7th, 14th and 28th day after operation, we investigated the role of NGF on late reperfusion by recording cardiac structure and function with echocardiography, by examining the expression of NGF and VIII factor with immunohistochemical method, and by evaluating the myocardial cell apoptosis with terminal dUTP nick end-labeling method (TUNEL). We found that the NGF group had higher expression of NGF protein (P < 0.01) and lower apoptosis index (AI) (P < 0.01 or P < 0.05) compared to the late reperfusion group and Adv group on all time points. The NGF group had remarkably higher level of neovascularization compared to the late reperfusion group on the 14th day (P < 0.01) and the 28th day (P < 0.05). The NGF group also had higher LVEF and FS levels compared to the late reperfusion group on the 14th day (P = 0.006, P = 0.006) and on the 28th day (P = 0.000, P = 0.000). Whereas the NGF group had lower LVEDD, LVESD (P = 0.038, P = 0.000) and lower LVEDV, LVESV (P = 0.001, P = 0.000) on the 28th day compared to late reperfusion group. In this experiment, the NGF gene carried by adenovirus vector had been transfected and obviously increased the expression of NGF protein in NGF group. NGF may help postpone the myocardial remodeling and improve the heart function by promoting the myocardial neovascularization and inhibiting myocardial apoptosis.

Recombinant Clostridium difficile toxin B induces endoplasmic reticulum stress in mouse colonal carcinoma cells.

Clostridium difficile is the main cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans and animals. Its pathogenicity is primarily linked to the secretion of two exotoxins (TcdA and TcdB). Although great progress in the toxic mechanism of TcdA and TcdB has been achieved, there are many conflicting reports about the apoptotic mechanism. More importantly, apoptotic endoplasmic reticulum (ER) stress has been reported in cells treated with Shiga toxins-another kind of cytotoxins that can cause diarrhea and colitis. Herein we checked whether TcdB can induce ER stress. The results showed that recombinant TcdB (rTcdB) activated molecular markers of unfolded protein response, suggesting that rTcdB induced ER stress in CT26 cells. However, rTcdB did not induce the up-regulation of C/EBP homologous protein (CHOP), a classic mediator of apoptotic ER stress, but it activated the precursor of cysteine aspartic acid-specific protease 12 (caspase-12), a controversial mediator of apoptotic ER stress. Besides, glucosyltransferase activity-deficient mutant recombinant TcdB induced ER stress, though it has no cytotoxic or cytopathic effect on CT26 cells. Altogether, these data demonstrated that ER stress induced by rTcdB is glucosyltransferase-independent, indicating that ER stress induced by rTcdB is non-apoptotic. This work also offers us a new insight into the molecular mechanism of CHOP protein expression regulation and the role of CHOP expression in ER stress.

A panel of genotypically and phenotypically diverse clinical Acinetobacter baumannii strains for novel antibiotic development.

Acinetobacter baumannii is one of the most important pathogens worldwide. The intrinsic and acquired resistance of A. baumannii, coupled with the slow pace of novel antimicrobial drug development, poses an unprecedented and enormous challenge to clinical anti-infective therapy of A. baumannii. Recent studies in the field of pathogenicity, antibiotic resistance, and biofilms of A. baumannii have focused on the model strains, including ATCC 17978, ATCC 19606, and AB5075. However, these model strains represent only a limited portion of the heterogeneity in A. baumannii. Furthermore, variants of these model strains have emerged that show significant diversity not only at the genotypic level but also reflected in differences at the phenotypic levels of capsule, virulence, pathogenicity, and antibiotic resistance. Research on A. baumannii, a key pathogen, would benefit from a standardized approach, which characterizes heterogeneous strains in order to facilitate rapid diagnosis, discovery of new therapeutic targets, and efficacy assessment. Our study provides and describes a standardized, genomically and phenotypically heterogeneous panel of 45 different A. baumannii strains for the research community. In addition, we performed comparative analyses of several phenotypes of this panel. We found that the sequence type 2 (ST2) group showed significantly higher rates of resistance, lower fitness cost for adaptation, and yet less biofilm formation. The Macrocolony type E (MTE, flat center and wavy edge phenotype reported in the literature) group showed a less clear correlation of resistance rates and growth rate, but was observed to produce more biofilms. Our study sheds light on the complex interplay of resistance fitness and biofilm formation within distinct strains, offering insights crucial for combating A. baumannii infection. IMPORTANCE: Acinetobacter baumannii is globally notorious, and in an effort to combat the spread of such pathogens, several emerging candidate therapies have already surfaced. However, the strains used to test these therapies vary across studies (the sources and numbers of test strains are varied and often very large, with little heterogeneity). The variation complicates the studies. Furthermore, the limited standardized resources of A. baumannii strains have greatly restricted the research on the physiology, pathogenicity, and antibiotic resistance. Therefore, it is crucial for the research community to acquire a standardized and heterogeneous panel of A. baumannii. Our study meticulously selected 45 diverse A. baumannii strains from a total of 2,197 clinical isolates collected from 64 different hospitals across 27 provinces in China, providing a scientific reference for the research community. This assistance will significantly facilitate scientific exchange in academic research.

Resistance mechanisms of tigecycline in Acinetobacter baumannii.

Acinetobacter baumannii is widely distributed in nature and in hospital settings and is a common pathogen causing various infectious diseases. Currently, the drug resistance rate of A. baumannii has been persistently high, showing a worryingly high resistance rate to various antibiotics commonly used in clinical practice, which greatly limits antibiotic treatment options. Tigecycline and polymyxins show rapid and effective bactericidal activity against CRAB, and they are both widely considered to be the last clinical line of defense against multidrug resistant A. baumannii. This review focuses with interest on the mechanisms of tigecycline resistance in A. baumannii. With the explosive increase in the incidence of tigecycline-resistant A. baumannii, controlling and treating such resistance events has been considered a global challenge. Accordingly, there is a need to systematically investigate the mechanisms of tigecycline resistance in A. baumannii. Currently, the resistance mechanism of A. baumannii to tigecycline is complex and not completely clear. This article reviews the proposed resistance mechanisms of A. baumannii to tigecycline, with a view to providing references for the rational clinical application of tigecycline and the development of new candidate antibiotics.

Coexistence of Multiple Functional Variants and Genes Underlies Genetic Risk Locus 11p11.2 of Alzheimer's Disease.

BACKGROUND: Genome-wide association studies have identified dozens of genetic risk loci for Alzheimer's disease (AD), yet the underlying causal variants and biological mechanisms remain elusive, especially for loci with complex linkage disequilibrium and regulation. METHODS: To fully untangle the causal signal at a single locus, we performed a functional genomic study of 11p11.2 (the CELF1/SPI1 locus). Genome-wide association study signals at 11p11.2 were integrated with datasets of histone modification, open chromatin, and transcription factor binding to distill potentially functional variants (fVars). Their allelic regulatory activities were confirmed by allele imbalance, reporter assays, and base editing. Expressional quantitative trait loci and chromatin interaction data were incorporated to assign target genes to fVars. The relevance of these genes to AD was assessed by convergent functional genomics using bulk brain and single-cell transcriptomic, epigenomic, and proteomic datasets of patients with AD and control individuals, followed by cellular assays. RESULTS: We found that 24 potential fVars, rather than a single variant, were responsible for the risk of 11p11.2. These fVars modulated transcription factor binding and regulated multiple genes by long-range chromatin interactions. Besides SPI1, convergent evidence indicated that 6 target genes (MTCH2, ACP2, NDUFS3, PSMC3, C1QTNF4, and MADD) of fVars were likely to be involved in AD development. Disruption of each gene led to cellular amyloid-ß and phosphorylated tau changes, supporting the existence of multiple likely causal genes at 11p11.2. CONCLUSIONS: Multiple variants and genes at 11p11.2 may contribute to AD risk. This finding provides new insights into the mechanistic and therapeutic challenges of AD.

[Relationship between depression and family function in old patients with coronary heart disease].

OBJECTIVE: To investigate the relationship between depression and family function in elderly patients with coronary heart disease. METHODS: 122 patients of 80 years old or above with coronary artery disease were invited to complete a questionnaire through face to face interview. The Hamilton Rating Scale for Depression (17th edition) was used to assess depression status and the APGDR Questionnaire was used to assess family functions. One-way analysis of variance and logistic regression analysis were performed to test the association of family functions with depression. RESULTS: 60.7% of the respondents had depression and 56.6% had severe abnormal family functions. The respondents with good family functions, moderate abnormal family functions and severe abnormal family functions had a depression score of 9.08, 20.72 and 26.88 respectively. The prevalence of depression in the patients with severe abnormal family functions was 3.274 times of that of those with good family functions. The prevalence of depression was also influenced by residency and care models. CONCLUSION: Depression is prevalent in elderly patients with coronary heart disease. It is associated with family functions.

Effects of ulinastatin, a urinary trypsin inhibitor, on synaptic plasticity and spatial memory in a rat model of cerebral ischemia/reperfusion injury.

Established therapies for cerebral ischemia-reperfusion injury are currently limited. The urinary trypsin inhibitor ulinastatin (UTI) is considered cytoprotective against ischemia-reperfusion injury in internal organs through its anti-inflammatory activity. We aimed to investigate the neuroprotective effects of UTI on learning and memory of rats after cerebral ischemia-reperfusion injury. Rats were treated with UTI at 10,000 U/kg body weight, then underwent ischemia and reperfusion by the middle cerebral arterial occlusion (MCAO) method. At various times after the onset of reperfusion, we evaluated neurologic impairment scores. Brain sections underwent immunohistochemical staining for synaptophysin and calcium-binding protein S100ß. Other rats underwent the Morris water maze test to determine the effects of UTI on learning and memory. Spatial reference learning and memory were improved with UTI treatment by down-regulating S100ß-positive cells and preventing the loss of neural cells. Thus, UTI has a neuroprotective role on synaptic plasticity and spatial memory with cerebral ischemia-reperfusion injury in rats.

miR-130-CYLD Axis Is Involved in the Necroptosis and Inflammation Induced by Selenium Deficiency in Pig Cerebellum.

Selenium (Se) is an essential trace element in creatures which deficiency can cause necroptosis and inflammation of multiple tissues. MicroRNAs (miRNAs) have been identified to participate multiple biological processes by regulating the expression of target genes. In the present study, the Se-deficient pig cerebellar model was established and conducted by light microscopy, qRT-PCR, and Western blot. Morphological observation exhibited necrosis-like lesions and inflammatory infiltration in the cerebellum of the Se-deficient group. Quantitative analysis result showed that Se deficiency significantly suppressed miR-130 expression, which in turn disinhibited the expression of CYLD. Meanwhile, in comparison to the control group, the expression levels of TNF-α pathway genes (TNF-α, TNFR1, and NF-κB p65) and necroptosis-related genes (RIPK1, RIPK3, and MLKL) in Se deficiency group were obviously increased (P < 0.05). Moreover, Se deficiency induced the occurrence of inflammation by upregulating the expression of inflammatory cytokines (IL-1ß, IL-2, IL-8, IL-18, IFN-γ, COX-2, PTGEs, and NLRP3). In conclusion, we proved Se deficiency could induce the deregulation of miR-130-CYLD axis to cause RIPK3-dependent necroptosis and inflammation in pig cerebellum.

Inhibition of TLR4 Induces M2 Microglial Polarization and Provides Neuroprotection via the NLRP3 Inflammasome in Alzheimer's Disease.

Accumulating evidence has indicated that activation of microglia and neuroinflammation reaction play a prominent role in Alzheimer's disease (AD). Inhibition of toll-like receptor 4 (TLR4) has been shown to be associated with immune responses and brain damage, but its effects on AD remain unclear. This study mainly aimed to investigate the protective effect of TAK-242 (TLR4-specific inhibitor) on microglial polarization and neuroprotection in an AD mouse model and the underlying mechanisms. We found that APP/PS1 transgenic AD mice exhibited a dramatic increase in TLR4 levels concomitant with a significantly higher expression of inflammatory microglia compared to C57BL/6 wild-type mice. Furthermore, inhibition of TLR4 by TAK-242 administration significantly improved neurological function, decreased the level of Bax, and caused a significant reduction in the levels of M1-markers (iNOS and TNFα), while the expressions of M2-phenotype markers (Trem-2 and Arg-1) were increased both in vivo and in vitro. Furthermore, TAK-242 treatment enhanced BV2 microglial phagocytosis. Moreover, Aß25 - 35 caused the upregulation of inflammatory cytokine production, MyD88, NF-kappaB-p65, and NLRP3, which could be ameliorated by NLRP3-siRNA or TAK-242. These findings indicated that TLR4 inhibition provided neuroprotection and promoted a microglial switch from the inflammatory M1 phenotype to the protective M2 phenotype in AD. The mechanism involved may be related to modulation of the MyD88/NF-kappaB/NLRP3 signaling pathway.

Neuroprotective effect of tormentic acid against memory impairment and neuro­inflammation in an Alzheimer's disease mouse model.

Cognitive impairment and neuro­inflammatory responses are the distinctive characteristics of Alzheimer's disease (AD). Tormentic acid (TA) is one of the major active components of Potentilla chinensis and has been demonstrated to have anti­inflammatory properties. However, the potential effects of TA on neuro­inflammatory responses and memory impairment in AD remain unknown. The present study investigated the therapeutic effect of TA on neuro­inflammation, as well as learning and memory impairment in AD mice. In addition, the effects of TA treatment were also examined in a co­culture system of microglia and primary neurons. Intraperitoneal administration of TA attenuated memory deficits in amyloid ß precursor protein/presenilin 1 transgenic mice, with a marked decrease in amyloid plaque deposition. TA also reduced microglial activation and decreased the secretion of pro­inflammatory factors in AD mice. Furthermore, pre­treatment with TA suppressed the production of pro­inflammatory markers, as well as the nuclear translocation of nuclear factor­κB (NF­κB) p65 induced by Aß exposure in BV2 cells. TA also reduced inhibited neurotoxicity and improved neuron survival in a neuron­microglia co­culture system. Taken together, these findings suggested that TA could attenuate neuro­inflammation and memory impairment, which may be closely associated with regulation of the NF­κB pathway.